Drug-Induced

Diseases
Prellelliion, Delectioll,
alld Manllgemel1l
TisdaleFM_i-xxii 1/27/10 9:46 PM Page i

Prevention, Detection,
and Management
Second Edition

James E. Tisdale, PharmD

Professor
School of Pharmacy & Pharmaceutical Sciences
Purdue University
Adjunct Professor
School of Medicine
Indiana University
Indianapolis, Indiana

Douglas A. Miller, PharmD

Professor
Department of Pharmacy Practice
College of Pharmacy and Health Sciences
Wayne State University
Detroit, Michigan

American Society of Health-System Pharmacists®

TisdaleFM_i-xxii 1/27/10 9:46 PM Page ii

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Because of ongoing research and improvements in technology, the information and

its applications contained in this text are constantly evolving and are subject to the
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ISBN 978-1-58528-205-0
TisdaleFM_i-xxii 1/27/10 9:46 PM Page iii

“The mediocre teacher tells. The good teacher explains.

The superior teacher demonstrates. The great teacher inspires.”
—WILLIAM WARD

This book is dedicated to the great teachers who inspire us.

TisdaleFM_i-xxii 1/27/10 9:46 PM Page iv
TisdaleFM_i-xxii 1/27/10 9:46 PM Page v

CO N T E N T S

Dedication iii CHAPTER 5

Foreword ix Evaluating Patients for Drug-Induced Diseases 40
Preface xi Douglas A. Miller and James E. Tisdale
Levels of Evidence xii
Contributors xiii SECTION II
Reviewers xix Drug-Induced Dermatologic Diseases
SECTION I CHAPTER 6
Magnitude/Significance of Drug Allergy, Pseudoallergy, and
Drug-Induced Diseases: Impact Cutaneous Diseases 51
on the Health Care System Lynne M. Sylvia

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

CHAPTER 4 SECTION III

Postmarketing Surveillance for Drug-Induced Drug-Induced Neurological Diseases
Diseases 31 CHAPTER 10
Hugh H. Tilson Seizures 179
Timothy E. Welty

v
TisdaleFM_i-xxii 1/27/10 9:46 PM Page vi

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
TisdaleFM_i-xxii 1/27/10 9:46 PM Page vii

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

SECTION VIII SECTION X

Drug-Induced Gastrointestinal Diseases Drug-Induced Hematological Diseases
C H A P T E R 37 C H A P T E R 47
Upper Gastrointestinal Ulceration 729 Thrombocytopenia 929
Dianne B. Williams and J. Russell May Kellie L. Jones and Patrick J. Kiel

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
TisdaleFM_i-xxii 1/27/10 9:46 PM Page viii

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

SECTION XII Index 1065

Miscellaneous Drug-Induced Diseases
TisdaleFM_i-xxii 1/27/10 9:46 PM Page ix
F O R E WO R D
S ocietal expectations regarding medication
safety have changed dramatically over the
years. When I began my career in pharmacy, drug-
induced diseases were rarely the subject of public
concern. Patients typically had no knowledge of
the potential dangers of their drug therapy, and
health care practitioners did little to educate their
patients regarding possible adverse effects and
drug-induced diseases. Today, however, patients
expect to be fully informed about the risks of pre-
scribed drugs. They expect that regulatory agen-
cies, pharmaceutical manufacturers, and their
health care providers will protect them from
drug-induced diseases. The standard of care for
ensuring medication safety has clearly changed.
And, importantly, change will continue. In the
years ahead, society will insist on even better pro-
tection and at some point in the future it seems
likely that we will look back to our practice today
and ask why we accepted such low standards for
drug safety.
But who will lead the next wave of progress in
preventing drug-induced diseases? Will improve-
ment be driven by health care professionals and
scientists, using the best models of practice and
science available? Or will it be necessary for socie-
ty to use its political and economic power to
achieve continuing improvement? The interest in
the first edition of Drug-Induced Diseases:
Prevention, Detection and Management (DID-1), pub-
lished in 2005, suggests that the health profes-
sions are ready to lead. And the information
included in this second edition (DID-2), when
applied properly, will help health practitioners in
their quest to continuously improve the standard
of care as it relates to safe and effective medication
use. This text will be useful to current practition-
ers and students alike.
Helping health care students develop the
knowledge and skills needed to properly address
drug-induced diseases will be critical to the mis-
sion of improving drug safety, and DID-2 provides
much of the foundation for this instruction.
Prevention, detection, and management of drug-
induced diseases challenges the full scope of
knowledge and skills for pharmacists, physicians,
nurses, and other health care providers. It
requires extensive knowledge of physiology,
chemistry, genomics, and other biomedical sci-
ences, as well as human behavior. To be most
effective, health care practitioners must not only
understand complex biomedical science but also
must be skillful in patient consultation and edu-
cation. Effectiveness in these roles requires life-
long learning to keep pace with rapidly changing
information about drugs and their effects. In fact,
the issue of drug safety in general is an excellent
focus for interprofessional education in health
care.
DID-2 will also serve as an essential resource
for current health care practitioners. Prevention,
detection, and management of drug-induced dis-
eases requires a low-tech, personal approach in
addition to the latest in biomedical science find-
ings from patient consultation and education to
pharmacogenomic assessment. It requires a care-
ful, individualized approach to each patient, con-
sidering their overall health status, age, literacy,
as well as population investigative tools of epi-
demiology. DID-2 helps organize this information
in an easily retrievable format. The disease-orient-
ed approach is useful and logical. The text pro-
ix
TisdaleFM_i-xxii 1/27/10 9:46 PM Page x
x Foreword
vides needed structure to the identification and
categorization of drug-induced diseases and it
describes well the interactions of the many com-
ponents of the health care system that influence
drug-induced diseases. Tisdale and Miller, along
with their many contributors, are to be com-
mended for producing an extraordinary work that
is the standard for understanding drug-induced
diseases and the broader topic of drug safety.
Joseph T. DiPiro, PharmD, FCCP
Dean
South Carolina College of Pharmacy
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.)
A dvances in pharmacotherapy have resulted in
substantial improvement in patients’ out-
comes and well-being. Specific examples can be
found in virtually all therapeutic areas:
angiotensin-converting enzyme inhibitors, adren-
ergic b-receptor blocking agents, aspirin, lipid-low-
ering and antihypertensive drug therapies, among
others, for cardiovascular disease; antimicrobial
agents for a variety of infectious diseases, including
antiretroviral agents for management of acquired
immunodeficiency syndrome; improved drug ther-
apy for mental illness, cancer, neurologic disorders,
diabetes, and many other diseases. These advances
have prolonged and improved the quality of life
for millions.
The effects of drugs, however, are not always
entirely beneficial. Although they may cure or pos-
itively affect disease, drugs are also capable of caus-
ing new diseases or exacerbating those that already
exist. Since the first edition of this book was pub-
lished in 2005, numerous drugs have been with-
drawn from the market in the United States as a
result of morbidity or mortality associated with
drug-induced diseases. Examples include pemoline
(hepatotoxicity), pergolide (heart valve damage),
tegasarod (stroke and myocardial infarction), apro-
tinin (increased risk of death, likely due to kidney
and cardiovascular toxicity), and efalizumab (pro-
gressive focal leukoencephalopathy). Despite best
efforts to ensure that all drugs are safe and effec-
tive, drug-induced diseases develop in millions of
patients each year.
Pharmacists, physicians, nurses, and other
health care professionals are on the front lines of
patient care and pharmacotherapy and must be
knowledgeable about the risk of drug-induced dis-
eases and methods of detection, prevention, and
management. Students in the health professions
must learn that pharmacotherapy has both bene-
fits and risks. And both practitioners and students
must appreciate that simply knowing that a given
drug can cause a particular disease may not be
enough because, as Heraclitus suggested, unless
one expects that a relatively unlikely event will
occur, its occurrence may be overlooked. Every
time a patient presents with a new disease or an
exacerbation of an existing condition, someone
needs to ask, “Could this be drug-induced?”
The purpose of this book is to provide a com-
prehensive source of information regarding the
detection, prevention, and management of drug-
induced diseases for current and future health care
practitioners. Our hope is that it will also encour-
age practitioners to expect the unexpected.
As in the first edition of Drug-Induced Diseases:
Prevention, Detection and Management (DID-1), we
consider drug-induced diseases to be a specific sub-
set of adverse effects caused by drugs a subset char-
acterized by the severity of symptoms and
outcomes. For the purposes of this book, we have
defined a drug-induced disease as an unintended
effect of a drug that results in mortality or morbid-
ity with symptoms sufficient to prompt a patient
to seek medical attention, require hospitalization,
or both.
As with DID-1, DID-2 has been structured to
facilitate readers’ ability to find specific informa-
tion related to drug-induced diseases. The first sec-
tion describes the changing regulatory, legal, and
practice landscapes as they relate to drug-induced
diseases, provides a general overview of the epi-
demiology and public health impact of these con-
ditions, discusses factors that may contribute to
the development of drug-induced diseases and
xi
TisdaleFM_i-xxii 1/27/10 9:46 PM Page xii

xii Preface

describes the structure and strategy of postmarket-
ing surveillance for their detection and characteri-
zation, and provides a general approach to patient
evaluation. The remainder is organized around spe-
cific diseases for which drugs have been implicated
as causative agents or, in some cases, the organ sys-
tem that is involved. Disease-related chapters fol-
low a consistent structure: causative agents,
epidemiology, mechanisms, clinical presentation
and differential diagnosis, risk factors, morbidity
and mortality, methods of prevention, manage-
ment, and information for patients. Each chapter
underwent blinded external review by one or more
content experts.
Numerous changes and, we believe, significant
improvements have been incorporated into DID-2.
Two chapters have been added: “Drug Safety and
Drug-Induced Disease: The Regulatory, Legal, and
Practice Environments” and “Evaluating Patients
for Drug-Induced Diseases.” Chapters from DID-1
have been expanded and, as would be expected,
information throughout has been carefully updat-
ed by the contributors. “Diarrhea and
Constipation” was a single chapter in DID-1, but
has now been divided into two chapters. Similarly,
the information regarding drug-induced arrhyth-
mias now comprises two chapters: “Supraventric-
ular Arrhythmias” and “Ventricular Arrhythmias.”
Each chapter includes a series of standard
tables that are in a consistent format throughout.
New drugs implicated as the cause of specific dis-
ease(s) have been added, as well as new informa-
tion regarding epidemiology, mechanisms, risk
factors, prevention, and management. DID-2 is
more exhaustively referenced than DID-1 and the
index has been expanded and improved.
Each of the “agents implicated” tables in DID-
2 includes an indication of the strength of the evi-
dence that links a listed drug to the specific
drug-induced disease (thanks to Dr. Ross Tsuyuki
for this suggestion). A “Level of Evidence” designa-
tion of “A” has been assigned when there is evi-
dence of causality from one or more randomized,
controlled clinical trials. A designation of “B” indi-
cates that there is evidence of causality from non-
randomized clinical trials, prospective
observational studies, cohort studies, retrospective
studies, case-control studies, meta-analyses, and/or
postmarketing surveillance studies. A designation
of “C” has been assigned when evidence of causal-
ity is from one or more published case reports or
case series.
Undertaking a book such as this is not an easy
task, and we gratefully acknowledge the work of
the chapter authors and expert external content
reviewers. Without their significant contributions,
this book could not have been completed. We also
gratefully acknowledge the support, guidance, and
assistance of the staff at the American Society of
Health-System Pharmacists. We sincerely hope that
this work assists practitioners in their efforts to
continually improve patient outcomes related to
drug therapy.
JAMES E. TISDALE
DOUGLAS A. MILLER
September 2009

Definitions of the “Level of Evidence” Designations Used Throughout This Text

Level of Evidence Designation Description
A There is evidence of causality from one or more randomized, controlled
clinical trials.
B There is evidence of causality from nonrandomized clinical trials, prospec-
tive observational studies, cohort studies, retrospective studies, case-con-
trol studies, meta-analyses, and/or postmarketing surveillance studies.
C There is evidence of causality from one or more published case reports or
case series.
TisdaleFM_i-xxii 1/27/10 9:46 PM Page xiii
CO N T R I B U TO R S
Steven R. Abel, BS, PharmD
Assistant Dean for Clinical Programs
Bucke Professor and Head, Department of
Pharmacy Practice
School of Pharmacy & Pharmaceutical Sciences
Purdue University
Indianapolis, Indiana
Shawn D. Anderson, PharmD
Clinical Pharmacy Specialist-Cardiology
Section
Department of Veterans Affairs
Clinical Assistant Professor
Department of Pharmacotherapy and
Translational Research
University of Florida
Gainesville, Florida
Crystal S. Blankenship, PharmD
National Clinical Therapy Specialist
Hemophilia Health Services
Accredo Health Group, Inc.
Nashville, Tennessee
Laura M. Borgelt, PharmD, FCCP, BCPS
Associate Professor
Departments of Clinical Pharmacy and Family
Medicine
University of Colorado Denver
Aurora, Colorado
Mary C. Borovicka, PharmD, BCPS, BCPP
Associate Professor of Pharmacy Practice
University of Toledo College of Pharmacy
Psychiatric Pharmacy Specialist
Louis Stokes VA Medical Center
Brecksville, Ohio
Sheila Botts, PharmD, BCPP, FCCP
Assistant Professor
Pharmacy Practice and Science
College of Pharmacy
University of Kentucky
Lexington, Kentucky
Erika N. Brown, BS, MS, PharmD
Clinical Pharmacy Specialist
University of Texas M.D. Anderson Cancer Center
Houston, Texas
Karim Anton Calis, PharmD, MPH, FASHP, FCCP
Senior Clinical Investigator
Eunice Kennedy Shriver National Institute of
Child Health and Human Development and
National Institute of Diabetes and Digestive
and Kidney Diseases
National Institutes of Health
Bethesda, Maryland
Clinical Professor, University of Maryland School
of Pharmacy
Baltimore, Maryland
Professor, Virginia Commonwealth University
School of Pharmacy
Richmond, Virginia
Jessica Campaign, PharmD
Assistant Professor of Pharmacy
College of Pharmacy
University of New Mexico
Albuquerque, New Mexico
Estela Ceja, PharmD
Clinical Pharmacy Specialist-Pediatrics
University of Texas
M.D. Anderson Cancer Center
Houston, Texas
xiii
TisdaleFM_i-xxii 1/27/10 9:46 PM Page xiv
xiv Contributors
Jack J. Chen, PharmD, FCCP, BCPS, CGP
Associate Professor, Neurology
Movement Disorders Clinic
Loma Linda University
Schools of Medicine and Pharmacy
Loma Linda, California
Judy T. Chen, PharmD, BCPS, CDE
Clinical Assistant Professor
School of Pharmacy & Pharmaceutical Sciences
Purdue University and Wishard Health Services
Indianapolis, Indiana
Devra K. Dang, PharmD, BCPS, CDE
Associate Clinical Professor
University of Connecticut School of Pharmacy
Assistant Clinical Professor
University of Connecticut School of Medicine
Storrs, Connecticut
Christine J. Davis, BSc (Gen), BScPharm, ACPR,
PharmD
Assistant Professor
Faculty of Pharmacy, University of Manitoba
Winnipeg, Manitoba
Canada
Betty J. Dong, PharmD, FASHP, FCCP
Professor of Clinical Pharmacy and Family and
Community Medicine
Departments of Clinical Pharmacy and Medicine
Clinical Pharmacist Specialist, Thyroid Clinic
University of California San Francisco
San Francisco, California
Julie A. Dopheide, PharmD, BCPP
Associate Professor,
Clinical Pharmacy, Psychiatry, and the Behavioral
Sciences
University of Southern California
Schools of Pharmacy and Medicine
Los Angeles, California
Christopher A. Fausel, PharmD, BCPS, BCOP
Clinical Director, Oncology Pharmacy Services
Indiana University Simon Cancer Center
Indiana University School of Medicine
Indianapolis, Indiana
Edward F. Foote, PharmD, BCPS, FCCP
Professor and Chair of Pharmacy Practice
Nesbitt College of Pharmacy and Nursing
Wilkes University
Wilkes-Barre, Pennsylvania
Lisa L. Forsyth, PharmD
Clinical Specialist, Surgical Critical Care
Beaumont Hospital
Royal Oak, Michigan
Matthew A. Fuller, PharmD, BCPS, BCPP, FASHP
Clinical Pharmacy Specialist, Psychiatry
Louis Stokes Cleveland Department of Veterans
Affairs Medical Center
Clinical Associate Professor of Psychiatry
Case Western Reserve University
Adjunct Associate Professor of Clinical Pharmacy
University of Toledo
Toledo, Ohio
Candice L. Garwood, PharmD, BCPS
Assistant Professor
Department of Pharmacy Practice
College of Pharmacy and Health Sciences
Wayne State University
Clinical Specialist—Ambulatory Care
Harper University Hospital
Detroit, Michigan
Jane M. Gervasio, PharmD, BCNSP, FCCP
Associate Professor and Vice Chair of Pharmacy
Practice
Butler University College of Pharmacy and Health
Science
Nutrition Support Pharmacist, Clarian Health
Partners
Indianapolis, Indiana
Jasmine D. Gonzalvo, PharmD
Clinical Assistant Professor
School of Pharmacy & Pharmaceutical Sciences
Purdue University
Indianapolis, Indiana
Jessica L. Gören, PharmD, BCPP
Associate Professor
University of Rhode Island
Kingston, Rhode Island
John G. Gums, PharmD, FCCP
Professor of Pharmacy and Medicine
Associate Chair, Department of Pharmacotherapy
and Translational Research
Director of Clinical Research in Family Medicine
Departments of Pharmacotherapy and
Translational Research and Community Health
and Family Medicine
University of Florida
Gainesville, Florida
TisdaleFM_i-xxii 1/27/10 9:46 PM Page xv
Jon D. Herrington, PharmD, BCPS, BCOP
Hematology/Oncology Clinical Specialist
Scott & White Memorial Hospital
Associate Professor
Department of Medicine
Texas A&M Health Science Center
Adjunct Associate Professor
University of Texas College of Pharmacy
Austin, Texas
James M. Hoffman, PharmD, MS, BCPS
Medication Outcomes & Safety Officer
Pharmaceutical Department
St. Jude Children’s Research Hospital
Assistant Professor of Clinical Pharmacy
University of Tennessee Health Science Center
Memphis, Tennessee
Mark T. Holdsworth, PharmD, BCOP
Associate Professor of Pharmacy and Pediatrics
College of Pharmacy
University of New Mexico
Albuquerque, New Mexico
Kellie L. Jones, PharmD, BCOP
Clinical Associate Professor
School of Pharmacy & Pharmaceutical Sciences
Purdue University
Indianapolis, Indiana
Yaman Kaakeh, PharmD, BCPS
Clinical Assistant Professor
School of Pharmacy & Pharmaceutical Sciences
Purdue University
Pramodini B. Kale-Pradhan, PharmD
Associate Professor
Department of Pharmacy Practice
College of Pharmacy and Health Sciences
Wayne State University and St. John Hospital and
Medical Center
Detroit, Michigan
Kristine E. Keplar, PharmD
Clinical Pharmacist
St Anthony’s Memorial Hospital
Effingham, Illinois
Adjunct Associate Professor of Pharmacy Practice
Butler University College of Pharmacy and Health
Sciences
Indianapolis, Indiana
Patrick J. Kiel, PharmD, BCPS
Clinical Pharmacy Specialist, Hematology/Stem
Cell Transplant
Indiana University Simon Cancer Center-Clarian
Health
Indianapolis, Indiana
Contributors xv
Julie M. Koehler, PharmD
Associate Professor and Chair
Department of Pharmacy Practice
Butler University College of Pharmacy and Health
Sciences
Family Medicine Clinical Pharmacist
Departments of Pharmacy and Family Medicine
Methodist Hospital of Clarian Health
Indianapolis, Indiana
W. Greg Leader, PharmD
Interim Dean
Professor, Clinical Pharmacy Practice
University of Louisiana Monroe
College of Pharmacy
Monroe, Louisiana
Karen W. Lee, PharmD, BCPS
Associate Director for Professional Development
University of Massachusetts Medical School
Clinical Pharmacy Services-Commonwealth
Medicine
Shrewsbury, Massachusetts
Mary Lee, PharmD, BCPS, FCCP
Vice President and Chief Academic Officer
Pharmacy and Health Science Education
Midwestern University
Professor of Pharmacy Practice
Chicago College of Pharmacy
Downers Grove, Illinois
Edward Li, PharmD, BCOP
Oncology Scientist, Drugs & Biologics Program
National Comprehensive Cancer Network (NCCN)
Adjunct Assistant Professor
Wilkes University Nesbitt School of Pharmacy
Wilkes-Barre, Pennsylvania
John R. Litaker, MSc, MMedSc, PhD
Managing Director
The Litaker Group, LLC
Austin, Texas
Janis J. MacKichan, PharmD, FAPhA
Professor and Vice Chair
Department of Pharmacy Practice
Northeastern Ohio Universities Colleges of
Medicine and Pharmacy
Rootstown, Ohio
Robert MacLaren, BSc, PharmD, FCCM, FCCP
Associate Professor
University of Colorado Denver
Aurora, Colorado
TisdaleFM_i-xxii 1/27/10 9:46 PM Page xvi

xvi Contributors

Mark J. Makowsky, BSP, PharmD
Assistant Professor
Faculty of Pharmacy and Pharmaceutical Sciences
University of Alberta
Edmonton, Alberta
Canada
Henri R. Manasse, Jr., PhD, ScD, FFIP
Executive Vice President and Chief Executive
Officer
American Society of Health-System Pharmacists
Bethesda, Maryland
Darius L. Mason, PharmD, BCPS
Assistant Professor
ANephRx (Albany Nephrology Pharmacy Group)
Department of Pharmacy Practice
Albany College of Pharmacy and Health Sciences
Albany, New York
J. Russell May, PharmD, FASHP
Clinical Professor
Department of Clinical and Administrative
Pharmacy
University of Georgia College of Pharmacy
Augusta, Georgia
Douglas A. Miller, PharmD
Professor
Department of Pharmacy Practice
College of Pharmacy and Health Sciences
Wayne State University
Detroit, Michigan
Monica L. Miller, PharmD, MSc
Clinical Assistant Professor
School of Pharmacy & Pharmaceutical Sciences
Purdue University
Indianapolis, Indiana
Brice Labruzzo Mohundro, PharmD
Assistant Professor
University of Louisiana at Monroe College of
Pharmacy
Baton Rouge, Louisiana
Jean M. Nappi, PharmD, FCCP, BCPS
Professor of Clinical Pharmacy & Outcome
Sciences
South Carolina College of Pharmacy-MUSC
Campus
Professor of Medicine
Medical University of South Carolina
Charleston, South Carolina
Robert Lee Page II, PharmD, MSPH, FAHA, FCCP,
FASHP, FASCP, BCPS, CGP
Associate Professor of Clinical Pharmacy and
Physical Medicine
Clinical Specialist, Division of Cardiology
University of Colorado Denver, Schools of
Pharmacy and Medicine
Aurora, Colorado
Amy Barton Pai, PharmD, BCPS, FASN
Associate Professor
Albany College of Pharmacy and Health Sciences
Albany, New York
Dennis Parker Jr., PharmD
Assistant Professor
Department of Pharmacy Practice
College of Pharmacy and Health Sciences
Wayne State University
Clinical Specialist - Neuroscience
Detroit Receiving Hospital
Detroit, Michigan
Charles D. Ponte, PharmD, BC-ADM, BCPS, CDE,
CPE, FAPhA, FASHP, FCCP
Professor of Clinical Pharmacy and Family
Medicine
West Virginia University
Robert C. Byrd Health Sciences Center
Schools of Pharmacy and Medicine
Morgantown, West Virginia
Frank Pucino, Jr., PharmD, BCPS, FASHP, FDPGEC
Senior Clinical Investigator
National Institute of Arthritis and Musculoskeletal
and Skin Diseases
National Institutes of Health
Bethesda, Maryland
Colette B. Raymond, PharmD, MSc, ACPR
Staff Development/Practice Evaluation Pharmacist
Winnipeg Regional Health Authority Pharmacy
Program
Winnipeg, Manitoba, Canada
Cynthia Reilly, BSPharm
Director, Practice Development Division
American Society of Health-System Pharmacists
Bethesda, Maryland
Denise H. Rhoney, PharmD, FCCP, FCCM
Associate Professor
Department of Pharmacy Practice
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

Roohollah Sharifi, MD, FACS Mary K. Stamatakis, BS Pharmacy, PharmD

Professor of Urology and Surgery Associate Dean for Academic Affairs and
College of Medicine Educational Innovation
University of Illinois at Chicago Associate Professor
Section Chief of Urology West Virginia University School of Pharmacy
Jesse Brown Veterans Administration Hospital Morgantown, West Virginia
Chicago, Illinois
David M. Swope MD
Amy Heck Sheehan, PharmD Associate Professor of Neurology
Associate Professor Loma Linda University
School of Pharmacy & Pharmaceutical Sciences Loma Linda, California
Purdue University
Indianapolis, Indiana Lynne M. Sylvia, PharmD
Clinical Pharmacy Specialist
Frank E. Silvestry, MD Tufts Medical Center
Associate Professor of Medicine Adjunct Clinical Professor
Cardiovascular Division Northeastern University School of Pharmacy
University of Pennsylvania School of Medicine Boston Massachusetts
Director, Penn Cardiac Care at Radnor
Radnor Pennsylvania Hugh H. Tilson, MD, DrPH
Adjunct Professor, Public Health Leadership
Judith A. Smith, PharmD, BCOP, FCCP, FISOPP University of North Carolina School of Public
Associate Professor & Director Pharmacology Health
Research Chapel Hill, North Carolina
Department of Gynecology Oncology, Division of
Surgery James E. Tisdale, PharmD
University of Texas M.D. Anderson Cancer Center Professor
Houston, Texas School of Pharmacy & Pharmaceutical Sciences
Purdue University
Kevin M. Sowinski, PharmD, FCCP Adjunct Professor
Professor School of Medicine
School of Pharmacy & Pharmaceutical Sciences Indiana University
Purdue University Indianapolis, Indiana
Adjunct Professor
School of Medicine CoraLynn B. Trewet, MS, PharmD, BCPS
Indiana University Assistant Clinical Professor
Indianapolis, Indiana University of Iowa
Broadlawns Family Health Center
Des Moines, Iowa
TisdaleFM_i-xxii 1/27/10 9:46 PM Page xviii

xviii Contributors

Ross T. Tsuyuki, BSc (Pharm), PharmD, MSc
(Clin Epi), FCSHP, FACC
Professor of Medicine (Cardiology)
Director, EPICORE Centrre/COMPRIS
Faculty of Medicine and Dentistry
University of Alberta
Edmonton, Alberta, Canada
Craig Williams, PharmD, FNLA
Clinical Associate Professor of Pharmacy
OHSU College of Pharmacy
Clinical Associate Professor of Medicine
Oregon Health and Science University School of
Medicine
Portland, Oregon

Sheryl F. Vondracek, PharmD, FCCP Dianne B. Williams, PharmD, BCPS

Associate Professor
University of Colorado Denver
Department of Clinical Pharmacy
Aurora, Colorado
Lori D. Wazny, BSc (Pharm), PharmD
Pharmaceutical Care Coordinator-Manitoba Renal
Program
Winnipeg, Manitoba, Canada
Timothy E. Welty, MA PharmD, FCCP, BCPS
Professor and Chair
Department of Pharmacy Practice
University of Kansas
Lawrence, Kansas
Marie M. Wenzel, PharmD, BCPS
Associate Director of Clinical Services
University of Massachusetts Medical School
Clinical Pharmacy Services-Commonwealth
Medicine
Shrewsbury, Massachusetts
Clinical Associate Professor
Campus Director for Pharmacy Practice
Experiences
University of Georgia College of Pharmacy
Augusta, Georgia
James P. Wilson, PharmD, PhD, FASHP
Center for Pharmacoeconomic Studies
College of Pharmacy
University of Texas
Austin, Texas
Susan M. Wilson, PharmD, BCPS
Clinical Pharmacy Manager
Crittenton Hospital Medical Center
Pharmacy Systems, Inc.
Rochester, Michigan

Sheila M. Wilhelm, PharmD, BCPS

Assistant Professor
Department of Pharmacy Practice
College of Pharmacy and Health Sciences
Wayne State University
Clinical Specialist—Internal Medicine
Harper University Hospital
Detroit, Michigan
TisdaleFM_i-xxii 1/27/10 9:46 PM Page xix
REVIEWERS
Jennifer M. Anthone, PharmD
Creighton University Medical Center
Omaha, Nebraska
Jacquelyn L. Bainbridge, PharmD, FCCP
Professor, Department of Clinical Pharmacy and
Department of Neurology
University of Colorado Denver
Aurora, Colorado
Gretchen M. Brophy, PharmD, BCPS, FCCP,
FCCM
Professor of Pharmacy and Neurosurgery
Virginia Commonwealth University
Medical College of Virginia
Richmond, Virginia
Susan P. Bruce, PharmD, BCPS
Associate Professor & Chair, Pharmacy Practice
Northeastern Ohio Universities
Colleges of Medicine & Pharmacy
Rootstown, Ohio
Charles F. Caley, PharmD, BCPP
Associate Clinical Professor
University of Connecticut School of Pharmacy
Storrs, Connecticut
Kimberly A. Cappuzzo, PharmD, MS, CGP
Senior Regional Medical Liaison
Metabolic Bone Team
Amgen Scientific Affairs
Richmond, Virginia
Sheryl L. Chow, BS. Pharm, PharmD, BCPS (AQ
Cardiology)
Assistant Professor
Department of Pharmacy Practice and
Administration
Western University of Health Sciences
Pomona, California
Catherine Christen, PharmD
Clinical Pharmacist
University of Michigan Health System and
College of Pharmacy
Clinical Assistant Professor
University of Michigan College of Pharmacy
Ann Arbor, Michigan
Susan E. Conway, PharmD
Associate Professor
University of Oklahoma College of Pharmacy
Oklahoma City, Oklahoma
Tanna Cooper, PharmD, BCPS
Clinical Pharmacy Specialist, Digestive Diseases
Intensive Care Unit
Medical University of South Carolina
Charleston, South Carolina
xix
TisdaleFM_i-xxii 1/27/10 9:46 PM Page xx
xx Reviewers
William E. Dager PharmD, BCPS, FCSHP, FCCP,
FCCM
Pharmacist Specialist, UC Davis Medical Center
Sacramento, California
Clinical Professor of Pharmacy, UC San Francisco
San Francisco, California
Clinical Professor of Medicine, UC Davis School
of Medicine
Sacramento, California
Clinical Professor of Pharmacy, Touro School of
Pharmacy
Vallejo, California
John W. Devlin, PharmD, BCPS, FCCM, FCCP
Associate Professor
Northeastern University School of Pharmacy
Adjunct Associate Professor
Tufts University School of Medicine
Boston, Massachusetts
Sarah E. Donegan, PharmD, BCOP
Senior Drug Information Analyst, Oncology
Specialist
American Society Health-System Pharmacists
Bethesda, Maryland
Thomas C. Dowling, PharmD, PhD, FCP
Associate Professor and Vice Chair
University of Maryland Baltimore School of
Pharmacy
Baltimore, Maryland
Kaelen C. Dunican, BSPharm, PharmD
Assistant Professor of Pharmacy Practice
Massachusetts College of Pharmacy and Health
Sciences
School of Pharmacy- Worcester/Manchester
Worcester, Massachusetts
Krystal L Edwards, PharmD, BCPS
Associate Professor of Pharmacy Practice
Texas Tech University Health Sciences Center -
School of Pharmacy
Dallas, Texas
Jennifer D. Faulkner, PharmD, BCPP
Director of Education, Pharmacy Service
Central Texas Veterans Health Care System
Temple, Texas
Marcus Ferrone, PharmD, BCNSP
Director, Drug Product Services Laboratory
Associate Professor of Clinical Pharmacy
University of California, San Francisco
San Fransisco, California
Richard G. Fiscella, PharmD, MPH
Clinical Professor
Department of Pharmacy Practice
Adjunct Assistant Professor
Department of Ophthalmology
Chicago, Illinois
Dustin D. French, PhD
Research Scientist
VA Center of Excellence on Implementing
Evidence Based Practice
Regenstrief Institute Inc
Indiana University School of Medicine
Indianapolis, Indiana
Jeffrey A. Johnson, BSP, PhD
Canada Research Chair in Diabetes Health
Outcomes
Professor, School of Public Health
University of Alberta
Edmonton, Alberta
Canada
Melissa C. Jones, PharmD, BCPS
Assistant Dean for Admissions
Associate Professor of Pharmacy Practice
South University School of Pharmacy
Savannah, Georgia
Melanie S. Joy, PharmD, FCCP
Associate Professor
UNC Schools of Medicine and Pharmacy
Division of Nephrology and Hypertension
UNC Kidney Center
Chapel Hill, North Carolina
Michael P. Kane, PharmD, FCCP, BCPS
Professor, Department of Pharmacy Practice
Albany College of Pharmacy and Health Sciences
Clinical Pharmacy Specialist
The Endocrine Group, LLP
Albany, New York
Joseph Kishel, PharmD, BCPS, AQ-ID
Clinical Scientific Director
Cubist Pharmaceuticals
Palmyra, Pennsylvania
Michael Kotlyar, PharmD
Associate Professor
University of Minnesota
Department of Experimental and Clinical
Pharmacology
College of Pharmacy
Minneapolis, Minnesota
TisdaleFM_i-xxii 1/27/10 9:46 PM Page xxi

Reviewers xxi

Robert J. Kuhn, PharmD Lynette Moser, PharmD

Professor of Pharmacy Practice and Science
University of Kentucky College of Pharmacy
Lexington, Kentucky
Gary M. Levin, PharmD, BCPP, FCCP
Dean & Professor
LECOM School of Pharmacy - Bradenton
Bradenton, Florida
Mark A. Malesker, PharmD, FCCP, BCPS
Professor of Pharmacy Practice and Medicine
Creighton University
Omaha, Nebraska
Assistant Professor
Department of Pharmacy Practice
College of Pharmacy and Health Sciences
Wayne State University
Clinical Specialist - Cardiology
Harper University Hospital
Detroit, Michigan
Mark A. Munger, PharmD, FCCP
Professor, Department of Pharmacotherapy
Associate Dean for Academic Affairs
University of Utah College of Pharmacy
Salt Lake City, Utah

J. Russell May, PharmD, FASHP Keith M. Olsen, PharmD, FCCP, FCCM

Clinical Professor Professor and Chair, Department of Pharmacy
Department of Clinical and Administrative Pharmacy Practice
University of Georgia College of Pharmacy University of Nebraska Medical Center College of
Augusta, Georgia Pharmacy
Omaha, Nebraska
Joseph E. Mazur, PharmD, BCPS, BCNSP
Clinical Pharmacy Manager, Medical University of Kari L. Olson, BSc(Pharm), PharmD, BCPS
South Carolina Clinical Pharmacy Specialist
Critical Care Clinical Specialist, Medical Intensive Kaiser Permanente Colorado
Care Unit Aurora, Colorado
Clinical Associate Professor, South Carolina
College of Pharmacy Carol A. Ott, PharmD, BCPP
Charleston, South Carolina Clinical Assistant Professor
School of Pharmacy & Pharmaceutical Sciences
Patrick L. McKercher, RPh, PhD Purdue University
Kalamazoo, Michigan Indianapolis, Indiana

Douglas A. Miller, PharmD Brian R. Overholser, PharmD

Professor Assistant Professor
Department of Pharmacy Practice School of Pharmacy & Pharmaceutical Sciences
College of Pharmacy and Health Sciences Purdue University
Wayne State University Adjunct Assistant Professor
Detroit, Michigan School of Medicine
Indiana University
Candis M. Morello, PharmD, CDE, FCSHP Indianapolis, Indiana
Associate Professor of Clinical Pharmacy
University of California, San Diego Robert B. Parker, PharmD, FCCP
La Jolla, California Professor
Skaggs School of Pharmacy and Pharmaceutical Department of Clinical Pharmacy
Sciences University of Tennessee
Ambulatory Care Pharmacist Specialist Memphis, Tennessee
Veteran’s Affairs San Diego Healthcare System
San Diego, California Mary H. Parker, PharmD, BCPS (AQ Cardiology),
CPP
Anna K. Morin, PharmD, RPh Director, Cardiovascular Risk Reduction Clinics
Associate Professor Clinical Pharmacist Practitioner
Department of Pharmacy Practice LeBauer HeartCare
Massachusetts College of Pharmacy and Health Greensboro, North Carolina
Sciences
Worcester, Massachusetts
TisdaleFM_i-xxii 1/27/10 9:46 PM Page xxii

xxii Reviewers

Nicole R. Pinelli, PharmD, MS James E. Tisdale, PharmD

Assistant Professor Professor
Department of Pharmacy Practice School of Pharmacy & Pharmaceutical Sciences
College of Pharmacy and Health Sciences Purdue University
Wayne State Univeristy and Henry Ford Hospital Adjunct Professor
Detroit, Michigan Indiana University
School of Medicine
Theresa R. Prosser, PharmD, AE-C, BCPS, FCCP Indianapolis, Indiana
Professor of Pharmacy Practice
St. Louis College of Pharmacy Toby C. Trujillo, PharmD, BCPS (AQ Cardiology)
St. Louis, Missouri Associate Professor
University of Colorado Denver
Cynthia A. Sanoski, B.S., PharmD, FCCP, BCPS School of Pharmacy - Department of Clinical
Chair, Department of Pharmacy Practice Pharmacy
Associate Professor Aurora, Colorado
Jefferson School of Pharmacy
Thomas Jefferson University Sony Tuteja, PharmD, BCPS
Philadelphia, Pennsylvania Associate
University of Iowa College of Pharmacy
Terry L. Schwinghammer, PharmD, FCCP, FASHP, Department of Pharmaceutics and Experimental
BCPS Therapeutics
Professor and Chair, Department of Clinical Iowa City, Iowa
Pharmacy
West Virginia University School of Pharmacy Mary L. Wagner, PharmD, M.S.
Morgantown, West Virginia Associate Professor
Ernest Mario School of Pharmacy
Stacy S. Shord, PharmD, BCOP Rutgers, The State University of New Jersey
U.S. Food and Drug Administration Piscataway, New Jersey
Center for Drug Evaluation and Research
Office of Clinical Pharmacology Barbara S. Wiggins, PharmD, BCPS (AQ
Division of Clinical Pharmacology 5 Cardiology), CLS, FAHA,FNLA, FCCP
Silver Spring, Maryland Diplomate, Accreditation Council for Clinical
Lipidology
Glen L. Stimmel, PharmD, BCPP Pharmacy Clinical Specialist-Cardiology
Professor of Clinical Pharmacy and Psychiatry University of Virginia Health System
University of Southern California Clinical Assistant Professor in Internal Medicine
Schools of Pharmacy and Medicine University of Virginia School of Medicine
Los Angeles, California Charlottesville, Virginia

Jeffrey S. Stroup, PharmD, BCPS Sheila M. Wilhelm, PharmD, BCPS

Associate Professor of Medicine Assistant Professor
Oklahoma State University Center for Health Department of Pharmacy Practice
Sciences College of Pharmacy and Health Sciences
Tulsa, Oklahoma Wayne State University
Clinical Specialist - Internal Medicine
Robert L. Talbert, PharmD, FCCP, BCPS, FAHA Harper University Hospital
Professor Detroit, Michigan
College of Pharmacy, The University of Texas at
Austin Gary C. Yee, PharmD, FCCP, BCOP
Austin, Texas Professor and Associate Dean
Professor of Medicine, School of Medicine College of Pharmacy
University of Texas Health Science Center at San University of Nebraska Medical Center
Antonio Omaha, Nebraska
San Antonio, Texas
TisdaleColorInsert 1/15/10 9:47 AM Page 1

FIGURE 8–3 Drug-Induced Phototoxicity and Photoallergy317

The photo on the left depicts a case of drug-induced phototoxicity secondary to demethylchlortetracy-
cline use for treatment of acne. The woman was wearing a hat that protected her face and neck from
sunlight exposure, but her hands were exposed to sunlight while holding a railing at a sporting event.
The photo on the right depicts a case of drug-induced photoallergy secondary to trimethoprim–sul-
famethoxazole use for Pneumocystis jiroveci pneumonia prophylaxis. Eczema and hyperpigmentation of
the sun-exposed areas are noted. (Photos reprinted with permission from Wolff K, Johnson RA,
Suurmond D. Fitzpatrick’s Color Atlas and Synopsis of Clinical Dermatology: Common and Serious
Diseases. 5th ed. New York, NY: McGraw-Hill; 2005:226-269.)

FIGURE 29–2 Transthoracic echocardiogram with

color Doppler map from the parasternal window in
the long axis of the same patient as in Figure 29–1,
demonstrating a jet of moderate mitral regurgitation
(arrow) directed slightly posteriorly, due to mild
restriction of the posterior leaflet, as is characteris-
tic of anorexiant-induced valvulopathy. LV = left
ventricle; RV = right ventricle.

FIGURE 29–3 Apical 4-chamber view from a

transthoracic echocardiogram from the same patient
as in Figures 29-1 and 29-2, demonstrating a jet of mod-
erate mitral regurgitation (arrow) directed slightly pos-
teriorly and laterally, due to mild restriction of the
posterior leaflet, characteristic of anorexiant induced
valvulopathy. LA = Left atrium; LV = Left ventricle; RA =
Right atrium; RV = Right ventricle.
TisdaleColorInsert 1/15/10 9:47 AM Page 2
TisdaleC01_1-13 1/20/10 10:48 PM Page 1

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 2 Epidemiology and Public Health Impact of Drug-Induced Diseases

CHAPTER 3 Factors Contributing to Drug-Induced Diseases

CHAPTER 4 Postmarketing Surveillance for Drug-Induced Diseases

CHAPTER 5 Evaluating Patients for Drug-Induced Diseases

TisdaleC01_1-13 1/20/10 10:48 PM Page 2
TisdaleC01_1-13 1/20/10 10:48 PM Page 3
CHAPTER 1
Drug Safety and Drug-Induced
Diseases: The Regulatory, Legal,
and Practice Environments
T he regulatory, legal, and practice environments
in health care surrounding drug safety have
been the subject of much scrutiny in recent years.
The highly publicized market withdrawal of almost
a dozen widely used drug products for safety rea-
sons between 2000 and 2006 has served as a focal
point of concerns about the safety of the United
States (U.S.) drug-approval and safety surveillance
systems.1 Since 1969, 75 drugs and combination
drug products have been removed from the U.S.
market for safety reasons. This represents less than
1% of all marketed drugs.2 Other safety-related reg-
ulatory actions (e.g., labeling changes, such as the
addition of precautions, contraindications, or
black box warnings) are far more common and,
although less publicized, have the potential for sig-
nificant impact on patient safety if these therapies
are not properly managed. Other adverse events of
medication therapy, such as medication errors,
have also heightened public awareness and con-
cern about all aspects of drug safety. As medication
experts, pharmacists play a critical role in ensuring
drug safety through their activities in selecting and
monitoring drug therapy, communicating risk ver-
sus benefit to patients to allow for informed deci-
sion making, and reporting suspected adverse drug
events and drug-induced diseases.
The extent of adverse drug events, which
includes but is not limited to drug-induced dis-
eases, is staggering. Since its inception in 1969
through 2002, the Adverse Event Reporting System
(AERS) of the Food and Drug Administration (FDA)
received approximately 2.3 million reports of
adverse events on more than 6,000 drug products.2
In 2006, the FDA Center for Drug Evaluation and
Research recorded 471,000 safety reports via AERS
Henri R. Manasse, Jr. and Cynthia Reilly
and issued 16 public health advisories (i.e., descrip-
tions of safety concern with recommended
actions).3 The Center for Biologics Evaluation and
Research received more than 19,000 reports via the
Vaccine Adverse Event Reporting System as well as
approximately 4,000 AERS reports. Meanwhile, it is
commonly held that most adverse events are not
reported to spontaneous reporting systems in the
United States.
Drug-induced disease can result from unantici-
pated or anticipated drug effects. Disease also can
occur from product impurities, as was the case with
deaths attributed to the use of contaminated
heparin in 2008.4 Vigilance on the part of regulato-
ry authorities, drug manufacturers, clinicians, and
patients is necessary to minimize the potential for
harm that is inherent in drug use.
DRUG SAFETY: THE REGULATORY
ENVIRONMENT
The FDA and Regulatory Efforts
to Ensure Drug Safety
Until recently, FDA efforts to provide drug safety
had largely focused on premarket strategies.
However, as the history of the agency demonstrates
(Figure 1–1), much of the FDA’s regulatory authority
was created in response to harm, or concern for
harm, associated with drugs already on the market.5
The origins of the FDA can be traced back to the late
1860s, when its predecessor, the Bureau of
Chemistry, was established as part of the
Department of Agriculture. Over the years, there
were repeated attempts to introduce legislation to
3
TisdaleC01_1-13 1/20/10 10:48 PM Page 4

4 SECTION I • Magnitude/Significance of Drug-Induced Diseases: Impact on the Health Care System

FDA Transferred to the Department of Health, Education

and Welfare (Predecessor to Department of Health and
Name Changed to Food and Drug Administration (FDA)
FDA Predecessor, the Bureau of Chemistry, Established

Kefauver–Harris Amendments Enacted

Food, Drug, and Cosmetic Act Enacted

FDA Amendments Act (FDAA) Enacted

Federal Food and Drug Act Enacted
in the Department of Agriculture

Sentinel Initiative Launched

FDAA Reauthorized

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
of possible harm to patients, and the potential
for its occurrence.
Regulatory options following drug approval
include clinician and patient warnings, labeling
changes, and product withdrawals. To increase
transparency as well as consumer and clinician
awareness, the Prescription Drug User Fee Act (a
component of FDAA 2007 that authorizes the FDA
to use fees collected from pharmaceutical manufac-
turers to conduct safety activities) requires the FDA
to generate quarterly reports that include informa-
tion on recently identified, potentially serious risks
and new safety information generated from the
AERS database.8,9 Introduction of this program and
enhanced reporting via the MedWatch program
generate extensive amounts of safety information.
While this is beneficial, it has also generated con-
cern among clinicians because the most appropri-
ate course of action when a safety concern arises is
frequently unclear. Safety information is and
always will be an evolving area, but the FDA and
professional associations such as the American
Society of Health-System Pharmacists are collabo-
rating to determine how this information can be
made available in ways that are most useful to cli-
nicians and their patients.
Restricted drug distribution systems (RDDS)
have been used to provide continued availability of
drugs that are associated with significant safety
concerns but provide a health benefit if used
appropriately in specific patient populations.
RDDS can include clinician or facility registration,
patient registries that are used to track and evalu-
ate response to therapies, and performance-linked
access systems. The FDA can request that these pro-
grams be established for drugs that are already
approved or as a condition for approval. For exam-
ple, in 1999, the drug thalidomide, which had pre-
viously been removed from world markets, was
approved in the U.S. for the treatment of lesions
caused by Hansen’s disease, or leprosy.10 However,
to prevent or reduce the risk of significant drug-
induced disease, thalidomide is available only
through physicians and pharmacists registered in
the System for Thalidomide Education and
Prescribing Safety (STEPS) program. The drug can-
not be prescribed for women of childbearing age,
unless the patient meets certain criteria (e.g., abili-
ty to comprehend and follow pregnancy precau-
tions). The physician must also document proof of
a negative pregnancy test 24 hours prior to initia-
tion of therapy and on an ongoing basis while the
drug is used. Oral and printed patient education
materials are also a significant component of the
STEPS program.
Thalidomide is 1 of almost two dozen drugs
marketed in the U.S. that have an RDDS (Table
5
TABLE 1–1 FDA-Approved Drugs with RDDS11
Drugs
• Clofaziminea
• Gefitinib
• Dofetilide
• Bosentan
• Iloprost
• Ambrisentan
• Encainidea
• Clozapine
• Sodium oxybate
• Buprenorphine tablets
• ␣1-Proteinase inhibitor (Human)
• Alosetron
• Cisapridea
• Mifepristone
• Isotretinoin
• Alendronate (40 mg tablet only)
• Natalizumab
• Lenalidomide
• Thalidomide
FDA = Food and Drug Administration; RDDS = Restricted Drug
Distribution Systems.
a
Drug available only through FDA-established compassionate-
use programs.
1–1).11 This list is expected to grow based on the
FDA’s increased authority to require these pro-
grams under the Prescription Drug User Fee Act IV
(PDUFA IV). In March 2009, the FDA initiated
plans to introduce the first class-wide REMS for
opioids by holding a series of stakeholder meetings
to discuss options to ensure that the benefits of
these drugs continue to outweigh the risks associ-
ated with their use. At publication, the proposed
REMS, including whether it would include the
more restrictive elements of RDDS, was not avail-
able.12 While these programs provide for ongoing
availability of drug therapies, they also present
challenges to clinicians and patients.13 RDDS are
not currently standardized, and each drug manu-
facturer may establish its own management
processes, including clinician registration require-
ments. The variability and complexity of these
processes have the potential to delay or limit
patient access to therapies, especially as patients
move between health care settings. At the urging of
professional organizations and others, the FDA is
evaluating strategies to minimize unintended con-
TisdaleC01_1-13 1/20/10 10:48 PM Page 6
6 SECTION I • Magnitude/Significance of Drug-Induced Diseases: Impact on the Health Care System
sequences that these programs may have on the
continuity of care and patient access to these high-
risk drugs.
A recent trend toward shortened time frames
for drug approval has been criticized as a signifi-
cant contributor to drug safety problems, but this
perception is misleading because it implies a direct
cause-and-effect relationship between shortened
average time to drug approval and drug with-
drawals or other safety issues. Safety concerns can
arise throughout a product’s life cycle.14 An exam-
ple is aprotinin, an antithrombolytic agent that
was used in cardiac surgery for 14 years before
accumulating reports of increased morbidity and
mortality led to its voluntary withdrawal from the
U.S. market in late 2007.15
An FDA assessment of the timing of safety-
related actions for 444 new molecular entities
(NMEs) approved between 1991 and 2006 demon-
strated that regulatory actions occur throughout a
product’s life cycle.16 Among drugs approved by
the FDA during that time frame, 78% had a least
one safety-related action and 3% were withdrawn
from U.S. market. A subanalysis of drugs approved
from 1991 through 1995 (i.e., representing drugs
that were marketed for a minimum of 13 years)
found that 27% of NMEs underwent changes or
additions to boxed warnings, warnings, or precau-
tions sections of the FDA-approved labeling. No
drugs in this subgroup were removed from the
market. For drugs marketed less than 5 years (i.e.,
those approved from 2003 through 2006), 44%
underwent safety-related labeling changes, and
there were no market withdrawals. These data
demonstrate that safety actions occur on an ongo-
ing basis and that newer drugs are not necessarily
more prone to safety issues. Rather, it is likely that
new safety signals will be generated throughout
the life cycle of a drug.
DRUG SAFETY IN THE
LEGAL ENVIRONMENT
Drug safety has been the subject of countless court
rulings, with most cases focusing on who is respon-
sible for ensuring the safe use of drug products—
pharmaceutical manufacturers, prescribers, other
health care professionals, or a combination of
these entities.
Pharmaceutical Manufacturers
State and federal courts have commonly found
pharmaceutical manufacturers to be the primary
entity responsible for drug safety. Historically,
there has been significant litigation against
pharmaceutical manufacturers alleging that they
hid, misrepresented, or otherwise failed to meet
the obligation to inform clinicians and patients
about known or suspected risks associated with a
drug’s use. In Feldman v. Lederle Laboratories
(1984), one of the more unusual cases, the New
Jersey Supreme Court ruled in favor of plaintiff
Feldman, who claimed that the drug manufac-
turer had failed to provide sufficient informa-
tion and warnings to physicians about the
potential for tooth discoloration from its tetra-
cycline product, demeclocycline.17 Ms. Feldman
was prescribed and dispensed samples of the
drug by her father, a physician and pharmacist,
several times when she was an infant and tod-
dler. The company claimed that at the time Ms.
Feldman received demeclocycline, information
about this side effect was not fully known, and
therefore not included in the labeling and pre-
scribing information approved by the FDA.
However, abnormalities in tooth development
and discoloration associated with tetracycline
products were reported in published studies of
laboratory animals and children with cystic
fibrosis who received high doses. A lower court
had found the manufacturer not liable because
the company had asked the FDA for guidance on
whether to include a warning in the labeling of
all of its tetracycline products, but the agency
advised against including this information in
demeclocycline labeling based on a lack of suffi-
cient evidence. However, the state supreme court
disagreed with the lower court’s decision, noting
that the FDA’s response did not prevent the
manufacturer from providing this information
or relieve the company of its responsibility to do
so.
There are several unusual circumstances in this
case, including uncertainty as to whether Ms.
Feldman received demeclocycline or another tetra-
cycline. Because samples were used, no prescrip-
tion or dispensing records were available to
confirm the plaintiff’s assertion. In addition, most
product-liability cases include the manufacturer
and prescriber as litigants, but in this instance,
legal action was directed only toward the drug
manufacturer, not the prescriber (the patient’s
father).
In Brown v. American Home Products Corporation
Diet Drugs, the federal courts approved a negotiat-
ed settlement in the class-action product-liability
case of fenfluramine–phentermine (“fen-phen”) or
dexfenfluramine with phenteramine.18 The class-
action lawsuit found that product manufacturers
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CHAPTER 1 • Drug Safety and Drug-Induced Diseases: The Regulatory, Legal, and Practice Environments
for fenfluramine (marketed as Pondomin by
American Home Products, Inc.) and dexfenflu-
ramine (marketed as Redux by Wyeth) possessed
extensive information, including published case
reports, animal studies, case reports in patients tak-
ing drugs with similar effects on serotonin, and
unpublished studies conducted by the manufactur-
er, showing that the drugs could cause damage to
heart valves and lead to valvular regurgitation. The
court found that despite having this information,
the manufacturer continued to market the drug
combination until the drugs were withdrawn from
the market in 1997, without further investigating
these reports or warning prescribers or patients
through labeling or other mechanisms. The settle-
ment created a $2.5 billion fund to compensate
patients for harm and cover current and future
associated health care costs based on factors such
as length of therapy and extent of harm.
A 2001 U.S. Supreme Court case ruled that
patients cannot sue pharmaceutical companies for
withholding information during the drug-
approval process in instances in which the FDA
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
court decision allowing an exemption in Michigan
law that permitted patients who had received
troglitazone to sue the product manufacturers for
punitive damages by alleging fraud, even in
instances when the FDA did not allege or find evi-
dence of fraud.19 Similar exemptions exist in seven
other states.
A decision in March 2009 by the U.S. Supreme
Court may have a pronounced effect on the man-
ner in which pharmaceutical manufacturers view
and operationalize their duty to warn of significant
adverse drug events in product labeling. In Wyeth v.
Levine, the court upheld a state trial and supreme
court decision that awarded damages to a Vermont
woman whose arm was amputated because of gan-
grene that developed following administration of
promethazine by intravenous (IV) push.20 The
product’s FDA-approved labeling included informa-
tion on the preferred route of administration (deep
intramuscular injection), warnings about the
potential for gangrene (especially with intraarterial
or subcutaneous administration), and a preference
for IV infusion administration when the drug is
administered intravenously. However, the trial
court found that the patient’s injuries would not
have occurred if the product’s labeling included
adequate warning, including specific information
about the danger of IV push administration. The
Supreme Court agreed with the trial court and dis-
agreed with the pharmaceutical manufacturer’s
7
argument that it was protected from state-law
claims because of federal labeling requirements and
the FDA’s approval of the existing product’s label.
In general, those requirements allow a manufactur-
er to change labeling only following FDA approval
of the proposed change. However, the court noted
that the manufacturer could have strengthened the
safety warning through the “Changes Being
Affected” regulation, which allows labeling changes
that improve safety while the manufacturer is in
the process of seeking the FDA’s official approval of
that change. In issuing its decision, the court
emphasized that the pharmaceutical manufacturer,
not the FDA, is ultimately responsible for the accu-
racy and completeness of the product labeling and
that the FDA’s regulatory authority is intended to
be complementary to, not preemptive of, a state’s
role in drug safety. This decision may have far-
reaching impact on other ongoing product-liability
cases, including those asserting harm from altered
glucose metabolism and diabetes from olanzapine
use and drug-induced hepatitis associated with
troglitazone use. 19,21
Pharmacists’ and Other
Clinicians’ Duty to Warn
According to the National Association of Chain
Drug Stores, as of October 2008 there were approx-
imately 50 state and federal lawsuits involving the
pharmacist’s duty to warn.22 The majority of these
cases have found that pharmacists are not liable for
patient harm resulting from adverse drug events or
drug-induced disease. These decisions are generally
based on the learned intermediary doctrine, which
assigns responsibility for drug selection to the pre-
scriber based on his or her knowledge of the drug
and the individual patient. Pharmacists have gen-
erally been considered “sellers” of the drug product
or service, and the courts have considered dispens-
ing to be an extension of the physicians’ order.
Several decisions have noted that if pharmacists’
liability was permitted, it could undermine the
physician–patient relationship by calling pre-
scribers’ authority into question.23 Based on exist-
ing case law, it is unclear how the learned
intermediary doctrine would be applied to phar-
macists who select drug therapy under collabora-
tive practice agreements or with the significant
expansion of information that would be available
to pharmacists from proposed national or univer-
sal electronic health records. In Jones v. Irvin and K-
Mart, the plaintiff appellate argued that the
practice of pharmacy had changed dramatically,
that the pharmacist had greater knowledge of the
dangers associated with drugs than physicians, and
TisdaleC01_1-13 1/20/10 10:48 PM Page 8
8 SECTION I • Magnitude/Significance of Drug-Induced Diseases: Impact on the Health Care System
therefore the pharmacists’ duty to warn warranted
new consideration. The court found that while this
advanced knowledge may be true, the physician’s
role as learned intermediary is predominant.24
However, future courts may take a more expansive
view of the pharmacist’s role.
While the learned intermediary principle has
frequently shielded pharmacists and their employ-
ers from liability, it negatively affects efforts to
establish pharmacists as medication experts and
independent practitioners. Most importantly,
pharmacists have a professional obligation to
ensure safe care, regardless of legal liability. Patient
education, including risk communication, is a sig-
nificant component of the commitment that all
pharmacists make through their education, licen-
sure, and subsequent practice.
THE DRUG-APPROVAL PROCESS
AND OTHER FACTORS THAT
AFFECT DRUG-INDUCED DISEASE
The drug-approval process is expected to assess the
efficacy and, to a certain extent, the safety of new
drug products, but it should be noted that several
characteristics of that process and the subsequent
environment of drug use contribute to drug-
induced disease. Patient populations in preap-
proval clinical trials are, by necessity, narrowly
structured and defined. Strict inclusion and exclu-
sion criteria often exclude patients with multiple
diseases and advanced disease and patients of a cer-
tain sex, age, or race. Even the largest clinical trial
conducted across multiple study sites evaluates a
drug’s use in a number of patients that is small in
comparison with the broader use of the drug
postapproval—use that includes individuals with
characteristics not studied during the approval
process.
Drug-induced disease can also be attributed to
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
but with variations in dose or route of administra-
tion. Subtle changes in manufacturing processes
can also contribute to drug-induced diseases. For
example, between 1998 and 2001, there was a dra-
matic increase in the number of pure red-cell apla-
sia (PRCA) cases in patients with chronic kidney
disease.25,26 PRCA is a known, but very rare, side
effect that can occur when anti-erythropoietin
antibodies form in response to erythropoietin
treatment. Most events occurred in patients treated
with an erythropoietin product supplied by one
manufacturer, but cases also occurred in patients
treated with a similar product. On further analyses,
the dramatic increase in adverse events was attrib-
uted to a change in the stabilizers in one manufac-
turer’s product and subsequent storage, handling,
and subcutaneous administration of that product.
Education regarding proper use of the various for-
mulations resulted in a significant decrease in the
number of PRCA cases.
Product contamination has also resulted in sig-
nificant morbidity and mortality, most recently in
the case of serious adverse events associated with
heparin that occurred from November 2007
through February 2008.4,27 Patient events included
62 deaths, with other reports of patients experienc-
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-
ence of oversulfated chondroitin sulfate in the
active pharmaceutical ingredient from an overseas
plant that processes heparin from pig intestines.
The contaminant was not detected in random sam-
pling of manufacturing plants, in part because it
mimics heparin in commonly used tests. Follow-up
tests conducted by the FDA found that the contam-
inant accounted for 5% to 20% of the total mass of
each sample tested. It was alleged that the contam-
ination with chondroitin was a purposeful act.28
Plans to increase overseas inspections and to mod-
ify current standards for assessing the purity of
heparin were also announced. This incident illus-
trated the importance of oversight and inspection
of the complete product-development process,
including assessment of the raw materials. It also
noted that even in a more robust system of inspec-
tions, purposeful adulteration may occur at any-
time by unscrupulous suppliers of raw materials
and manufacturers, as well as criminal acts by pri-
vate citizens, as occurred with acetaminophen
adulteration in the early 1980s.
RECOMMENDATIONS TO
IMPROVE DRUG SAFETY
During the past decade a number of public and pri-
vate entities have assessed drug safety efforts in the
U.S. and made recommendations to improve that
process. Many of these recommendations, such as
development of a national database for enhanced
collection and assessment of adverse drug events
and drug-induced diseases, were included in
PDUFA IV, and their implementation is underway.
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CHAPTER 1 • Drug Safety and Drug-Induced Diseases: The Regulatory, Legal, and Practice Environments
The following describes major reports and the cur-
rent status of their recommendations.
Institute of Medicine (IOM)
In its landmark 2006 report, The Future of Drug
Safety: Promoting and Protecting the Health of the
Public, the IOM issued more than two dozen rec-
ommendations to improve drug safety.29 The
report, which focused on postmarketing safety,
identified structural and procedural barriers at the
FDA that hampered efforts to enhance drug safety.
The report stated that preapproval data are inher-
ently limited in their ability to identify infrequent
adverse events and that existing approaches for
data collection following drug approval are not
adequate to address this shortcoming. The report’s
authors called for increased, proactive postmarket-
ing surveillance by the FDA, as well as additional
authority for the FDA to control manufacturers’
postapproval marketing activities. Many of the
IOM’s recommendations, including strengthened
authority to require REMS, were included in
PDUFA IV. Strategies to better inform the public,
such as establishment of an advisory committee to
address communication of risks, have also been
implemented. However, the IOM’s recommenda-
tion to prevent potential harm by restricting
direct-to-consumer advertising for a period of 2
years following drug approval, and require that
labeling and marketing materials for these prod-
ucts contain a symbol to designate the recent
approval status, were controversial and not
addressed in the reauthorization of the legislation.
Other IOM reports, including Preventing
Medication Errors (2006) and Knowing What Works
in Health Care: A Roadmap for the Nation (2008)
have also addressed drug safety.30,31 While these
reports focus on the broader context of avoidable
harm from drug therapies and comparative effec-
tiveness, respectively, they include components on
drug-induced disease and postmarketing safety sur-
veillance.
Government Accountability Office (GAO)
In 2006, the GAO issued the report, Drug Safety:
Improvement Needed in FDA’s Postmarket Decision-
Making and Oversight Process, which evaluated drug
safety processes based on an assessment of regula-
tory actions for four drugs: leflunomide (Avara),
cerivastatin (Baycol), valdecoxib (Bextra), and cis-
apride (Propulsid).1 Leflunomide remains available,
but the other drugs were voluntarily withdrawn
from the U.S. market following several safety
assessments by FDA staff and subsequent regulato-
9
ry actions. A major finding in the GAO report was
instances in which conflicting recommendations
were made by divisions within FDA’s Center for
Drug Evaluation and Research. As a result, deci-
sions were either not made or were made counter
to the recommendations of another FDA group
without a clear process for resolving the disparate
views.
The GAO identified a lack of collaboration and
communication between the two predominant
offices involved in drug safety—the Office of New
Drugs (OND), which is responsible for drug
approval and for initiating regulatory actions, and
the Office of Drug Safety (ODS), which predomi-
nantly focuses on postmarketing safety. The GAO
described the ODS as serving in an advisory capac-
ity to the OND, based on its finding that the ODS
had no authority to initiate a regulatory action.
The report identified a lack of documented process-
es for decision making, including an absence of cri-
teria to determine the appropriate regulatory
action when a safety concern is identified.
Significant progress has been made to address
shortcomings identified in the GAO report, such as
better coordination and more frequent meetings
with the ODS risk-management advisory commit-
tee and the OND’s disease-specific advisory com-
mittees. Other recommendations, including the
establishment of clearly defined processes to
resolve conflicts of opinion between the offices,
remain unresolved. The report describes a draft
policy entitled “Process for Decision-making
Regarding Major Postmarketing Safety-related
Actions” that remains unavailable to the public at
the time of this writing. While the GAO report
focuses on the lack of criteria and processes, it
should be noted that risk assessment and decisions
about drug safety are not an exact science. It
requires careful balancing of the pros and cons of
providing continued availability of a drug, and is
based on evidence that, by nature, is constantly
evolving.
FDA
The FDA has also assessed existing processes and
taken numerous steps to enhance drug safety. In late
2007, the FDA’s Science Board Subcommittee on
Science and Technology published, FDA Science and
Mission at Risk: Report of the Subcommittee on Science
and Technology.3 The report was requested by then
Commissioner Andrew von Eschenbach to review
the adequacy of the agency’s science and technolo-
gy resources to meet current and future challenges.
The report concluded that the agency’s resources
had decreased, despite an increase in responsibilities
TisdaleC01_1-13 1/20/10 10:48 PM Page 10
10 SECTION I • Magnitude/Significance of Drug-Induced Diseases: Impact on the Health Care System
that resulted from the speed of scientific discoveries,
increased and more complex products, and the
increasingly global nature of the drug industry. The
subcommittee recommended that the existing
deficits in resources in scientific research programs;
recruitment, development and retention of expert
staff; and information technology must be corrected
in order to meet these challenges.
Among the report’s specific recommendations
was the need to strengthen and coordinate the sci-
ence program across the FDA’s centers. The need
for collaboration with external scientific and
research programs, including the Agency for
Healthcare Research and Quality’s Centers for
Education and Research on Therapeutics, the
Centers for Disease Control and Prevention, the
National Institutes of Health, and others when the
expertise is not available at the FDA was identified.
It is anticipated that the Reagan–Udall Foundation,
an independent organization mandated by PDUFA
IV, will assist in the development of these and
other public–private partnerships as part of its
charge to assist the FDA in modernizing its activi-
ties to address the rapid pace of change in the sci-
entific and regulatory environments.
Other recommendations in the report include
broadening staff with the statistical and epidemio-
logic expertise needed to analyze collected data as
well staff with expertise in risk assessment and its
quantitative measurement. A major focus of the
report was the need to establish information stan-
dards that permit sharing and aggregation of
information from public and private postmarket-
ing safety surveillance databases. The report noted
that these standards were critical, especially with
the establishment of new sciences, including phar-
macogenetics, nanotechnology, and cell-based
products, for which collection of the extent and
types of data will not be supported by current sys-
tems.
In terms of funding these improvements, the
report stated that appropriation provided by
PDUFA IV provided only a small portion of that
which is needed. The Science Board called for a
2009 budget to address the identified shortcom-
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,
and consumer sectors through entities such as the
Alliance for a Stronger FDA.32 The Alliance, whose
members include former Secretaries of the
Department of Health and Human Services and
Commissioners of the FDA, aims to build aware-
ness about current deficits in funding and advocate
for increased federal appropriations in order to
decrease the FDA’s reliance on user fees paid by
drug manufacturers.
Other FDA efforts to enhance drug safety have
included improved guidance to industry on pre-
marketing risk assessment, development and use of
risk-minimization action plans, and pharmacovigi-
lance and pharmacoepidemiologic assessment.33-35
Consumer awareness and education has also been a
major focus, including new regulations that require
inclusion of MedWatch reporting information on
drug packaging and patient information leaflets for
prescription and nonprescription drugs and in
direct-to-consumer television advertising.36-38
Improving Data Collection and Use
At the core of efforts to improve drug safety, there
is reliance on the extent and quality of informa-
tion used to inform these decisions. Safety infor-
mation gained from premarketing as well as
postmarketing studies is often described as data
that are unreported, underreported, and unpub-
lished. The International Committee of Medical
Journal Editors Uniform Requirements for
Manuscripts Submitted to Biomedical Journals
requirement that researchers register human sub-
jects research via www.clincialtrials.gov as a condi-
tion of publication and the editor’s obligation to
publish negative studies represent the combined
efforts of regulatory and private entities to address
these shortcomings.39 Other efforts have focused
on developing standards for reporting drug-
induced diseases and other adverse drug events.
The Consolidated Standards of Reporting Trials
[CONSORT], in “Better Reporting of Harms in
Randomized Trials: An Extension of the CONSORT
Statement,” recommends the use of standardized
terminology and inclusion of harms information
in the publication abstract as mechanisms to assist
clinicians, researchers, and patients in the critical
appraisal of clinical trial results.40
Public and private collaborations to improve
active surveillance, including data mining in large
population-based databases, are described in
Chapter 4.
DRUG SAFETY CHALLENGES
AND OPPORTUNITIES
As noted in the FDA Science Board report, the rapid
rate of new-drug development, the evolving role of
evidence-based medicine, and advancing science
and technology will offer ongoing and new chal-
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

first-in-class drugs, nanotechnology, cell-based disposition, including absorption, distribution,

therapies, large-molecule biologics, and follow-on
biologics will be among many challenges in assess-
ing and ensuring postmarketing drug safety.
Pharmacogenomics and personalized drug thera-
py have the potential to improve the prediction and
prevention of drug-induced disease from the per-
spective of both individual patients and entire popu-
lations. One of the earliest known genetic variations
to result in drug-induced disease is glucose-6-phos-
phate dehydrogenase deficiency, which results in the
breakdown of red blood cells when a person is
exposed to certain drugs (e.g., antimalarial drugs,
aspirin, nonsteroidal antiinflammatory drugs, quini-
dine, quinine, and sulfonamide antibiotics). More
recent discoveries include variations in the organic
anion transporter SLCO1B1 that are associated with
an increased risk of statin-related myopathy.41
Many factors contribute to genetic variation in
response to drug therapy. Polymorphisms, which
can be affected by the interplay of more than one
genetic variation, may lead to differences in drug
and excretion.42 These differences can lead to
decreased or increased pharmacologic effect, with
the latter more frequently resulting in toxicity or
undesired drug effects. Genetic differences in drug
transporters also play a role in response to drug
therapies. Examples of drugs, genetic variables, and
the proposed associated adverse drug event are
described in Table 1–2.42,43
Some genetic polymorphisms are more com-
mon in certain racial groups; therefore, ethnicity
has been used to predict drug response in the
absence of more specific genetic information for an
individual patient.44 For example, the relative risk
of angioedema or cough associated with the use of
angiotensin-converting–enzyme (ACE) inhibitors
has been projected as 3.0 and 2.7 for blacks and
East Asians, respectively, as compared with whites.
Other studies, including the Gruppo Italiano per lo
Studio della Sopravvivenza nell’Infarto Miocardico
(GUSTO)-1 trial found that intracranial hemor-
rhage or moderate to severe bleeding following

TABLE 1–2 Examples of Drug-Induced Diseases Associated with Genetic Variation42,43

Drug Genetic Variation Adverse Drug Event
or Drug-Induced Disease
Abacavir HLA Hypersensitivity reaction
ACE inhibitors Bradykinin B2 receptor ACE-induced cough and
angioedema
Carbamazepine HLA-B*1502 allele Stevens–Johnson syndrome,
toxic epidermal necrolysis
Cisplatin, carboplatin, and oxaliplatin Changes in gene expression Peripheral neurotoxicity
in the dorsal-root ganglia
resulting in apoptosis
(Cdkn1a, Ckap2, Bid3, S100a8,
S100a9), inflammation
(S100a8, S100a9, Cd163,
Mmp9), and nerve growth
and regeneration (Mmp9,
Gfap, Fabp7)
Digoxin P glycoprotein 3435TT Increased drug accumulation
genotype and potential for digoxin
toxicity
Mercaptopurine Thiopurine methyltransferase Hematopoietic toxicity
polymorphism
Oral contraceptives Variation in prothrombin Increased risk of DVT or
and factor V cerebral vascular thrombosis
Trimethoprim–sulfamethoxazole, KCNE2 variants in potassium Increased QT interval
clarithromycin, quinidine channels prolongation, morbidity,
and mortality
ACE = angiotensin-converting enzyme; DVT = deep-vein thrombosis; HLA = human leukocyte antigen.
TisdaleC01_1-13 1/20/10 10:48 PM Page 12
12 SECTION I • Magnitude/Significance of Drug-Induced Diseases: Impact on the Health Care System
thrombolytic therapy was more in common in
black patients.44,45 While these and other studies
give credence to ethnicity as a determinant of
adverse events, shortcomings in the data, includ-
ing inconsistent definitions and reporting of eth-
nicity and adverse events, limit its application to
clinical practice. Most drug-induced diseases,
including ACE-inhibitor–induced cough, have
been theorized as a complex interaction of ethnic
and other factors such as age, sex, and comorbid
disease.46 When considered in total, these predic-
tive factors can be used to improve drug safety by
guiding drug selection and monitoring.
The inclusion of genetic biomarker informa-
tion, and its clinical application, in FDA-approved
drug labeling is becoming more common.
However, currently there is no requirement that
pharmaceutical manufacturers complete genetic
studies. Whether these studies are voluntary or
required, more research (including practical clini-
cal trials) and better systems for collecting and ana-
lyzing these data are needed. Even with improved
data, uncertainties will remain about the extent to
which genetics affects drug response and the inter-
play of genetics with other variables, including
concomitant therapies, diet, and other patient
variables. At present, the clinical significance of
genetic variation and genetic testing in drug safety
and effectiveness are much debated.
As the regulatory and legal environments
evolve, clinicians will continue to play a central
role in improving drug safety and preventing drug-
induced disease. The identification and manage-
ment of adverse effects, participation in
spontaneous reporting efforts, and provision of
patient education that addresses both the risk and
benefit of therapies are critical and core clinician-
responsibilities. As illustrated by the example of
thalidomide, drugs with significant safety concerns
can provide great health benefits when properly
managed. Medication-therapy management and
other care provided by pharmacists are essential
components of the drug-safety system.
References
1. General Accounting Office. Drug safety: improvement
needed in FDA’s postmarket decision-making and oversight
process. GAO-06-402. Available at:
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2. Wysowski DK, Swartz L. Adverse drug event surveillance
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FDA%20Report%20on%20Science%20and%20Technolog
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System (AERS). Available at
http://www.fda.gov/cder/aers/potential_signals/default.ht
m. Accessed November 20, 2008.
10. Thalidomide prescribing information. Summit, NJ:
Celgene Corporation, 2007.
11. McEvoy GK, ed. AHFS drug information 2008. Bethesda,
MD: American Society of Health-System Pharmacists;
2008.
12. FDA. Opioid Drugs and Risk Evaluation and Mitigation
Strategies (REMS): FDA to Meet with Drug Companies
about REMS for Certain Opioid Drugs. Available at
http://www.fda.gov/Drugs/DrugSafety/InformationbyDru
gClass/ucm163647.htm. Accessed June 22, 2009.
13. American Society of Health-System Pharmacists (ASHP).
PDUFA reauthorization: opportunity to improve
continuity of care for patients treated with high risk
drugs. Available at:
http://www.ashp.org/s_ashp/docs/files/GAD_ASHP_RDDS
_IssueSumm0307.pdf. Accessed March 8, 2009.
14. Lasser KE, Allen PD, Woolhandler SJ, et al. Timing of
new black box warnings and withdrawals for prescription
medications. JAMA. 2002;287:2215-2220.
15. FDA News. FDA requests marketing suspension of
Trasylol. Available at:
http://www.fda.gov/bbs/topics/NEWS/2007/NEW01738.h
tml. Accessed January 28, 2009.
16. FDA. Maximizing the public health benefit of adverse
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:
http://biotech.law.lsu.edu/cases/drugs/Feldman_v_Lederle
.htm. Accessed March 8, 2009.
18. MPHLS, Louisiana State University. Brown v American
Home Products Corporation Diet Drugs, No. 99-20593
(E.D.Pa. 08/28/2000). Available at:
http://biotech.law.lsu.edu/cases/Drugs/brown_v_AHPC_b
rief.htm. Accessed Xxxxx XX, 20XX.
19. Warner-Lambert Co. v. Kent . No 06-1498, 552 U.S., 2008
WL 552875 (2008)
20. Wyeth v. Levine 555 U.S. 06-1249 (2009).
21. Alaska vs. Eli Lilly. 3AN-06-5630C1 (2008).
TisdaleC01_1-13 1/20/10 10:48 PM Page 13
CHAPTER 1 • Drug Safety and Drug-Induced Diseases: The Regulatory, Legal, and Practice Environments
22. National Association of Chain Drug Stores. Pharmacists’
duty to warn: lawsuits claiming that pharmacies must
warn consumers about dangers associated with
prescription drugs, revised 10/21/08. Available at
http://www.nacds.org/user-
assets/pdfs/gov_affairs/dutytowarn.pdf. Accessed April
14, 2009.
23. Beck J, Vale A. Drug and medical device product liability
deskbook (Litigation Series). New York, NY: Law Journal
Press; 2004.
24. Jones v. Irvin and K-Mart. 602 F.Supp. 399. (S.D. Ill. 1986)
25. Bennett CL, Luminari S, Nissenson AR, et al. Pure red-cell
aplasia and epoetin therapy. N Engl J Med.
2004;351:1403-1408.
26. Cournoyer D, Toffelmire EB, Wells GA, et al. Anti-
erythropoietin antibody-mediated pure red cell aplasia
after treatment with recombinant erythropoietin
products: recommendations for minimization of risk. J
Am Soc Nephrol. 2004;15:2728-2734.
27. FDA. Information on adverse event reports and heparin.
Available at:
http://www.fda.gov/cder/drug/infopage/heparin/adverse_
events.htm. Accessed April 27, 2008.
28. United States House of Representatives Subcommittee on
Oversight and Investigations, Committee on Energy and
Commerce. Transcript of testimony of Janet Woodcock,
Director, Center for Drug Evaluation and Research.
Available at: http://energycommerce.house. Accessed
April 27, 2009.
29. Institute of Medicine (IOM). The future of drug safety:
promoting and protecting the health of the public.
Washington, DC: National Academies Press; 2007.
30. IOM. Preventing medication errors. Washington, DC:
National Academies Press; 2006.
31. IOM. Knowing what works in health care: a roadmap for the
nation. Washington, DC: National Academies Press; 2008.
32. Alliance for a Stronger FDA. Alliance for a Stronger FDA
fact sheet. Available at http://www.strengthenfda.org.
Accessed January 28, 2009.
33. FDA. Guidance for industry: development and use of risk
minimization action plans. Available at:
http://www.fda.gov/cder/guidance/6358fnl.pdf. Accessed
March 8, 2009.
34. FDA. Guidance for industry: premarket risk assessment.
http://www.fda.gov/CDER/guidance/6357fnl.pdf.
Accessed March 8, 2009.
35. FDA. Guidance for industry: good pharmacovigilance
and pharmacoepidemiologic assessment.
13
http://www.fda.gov/Cder/Guidance/6359OCC.pdf.
Accessed March 8, 2009.
36. Final rule. Toll-free number for reporting adverse events
on labeling for human drug products. Fed Regist.
2008;73:63886-63897.
37. Notice: risk communication committee; notice of
meeting. Fed Regist. 2008;73:22959-22960.
38. Notice: agency information collection activities;
proposed collection; comment requested; experimental
study: Toll-free number for consumer reporting of drug
product side effects in direct-to-consumer television
advertisements for prescription drugs. Fed Regist.
2008;73:72058-62.
39. International Committee of Medical Journal Editors.
Uniform Requirements for Manuscripts Submitted to
Biomedical Journals. Available at: http://www.icmje.org.
Accessed January 28, 2009.
40. Ioannidis JP, Evans SJ, Gøtzsche PC, et al. Better
reporting of harms in randomized trials: an extension of
the CONSORT statement. Ann Intern Med. 2004;141:781-
788.
41. SEARCH Collaborative Group, Link E, Parish S, Armitage
J, et al. SLCO1B1 variants and statin-induced
myopathy—a genomewide study. N Engl J Med.
2008;359:789-799.
42. Evans WE, McLeod HL. Pharmacogenomics—drug
disposition, drug targets, and side effects. N Engl J Med.
2003;348:538-549.
43. Alaedini A, Xiang Z, Kim H, et al. Up-regulation of
apoptosis and regeneration genes in the dorsal root
ganglia during cisplatin treatment. Exp Neurol.
2008;210:368-374.
44. McDowell SE, Coleman JJ, Ferner RE. Systematic review
and meta-analysis of ethnic differences in risks of adverse
reactions to drugs used in cardiovascular medicine. BMJ.
2006;332:1177–1181.
45. Bjornsson TD, Wagner JA, Donahue SR, et al. A review
and assessment of potential sources of ethnic differences
in drug responsiveness. J Clin Pharmacol. 2003;43:943-
967.
46. Morimoto T, Gandhi TK, Fiskio JM, et al. Development
and validation of a clinical prediction rule for
angiotensin-converting enzyme inhibitor-induced cough.
J Gen Intern Med. 2004;19:684-691.
TisdaleC02_14-22 1/12/10 1:53 PM Page 14
CHAPTER 2
Epidemiology and Public Health
Impact of Drug-Induced Diseases
M edications are an essential component of
modern health care. Individuals take medica-
tions to help them feel better, overcome particular
illnesses, treat infections, and improve quality of
life. Currently, there are 4,750 drugs available on
the United States (U.S.) market, in a total of 17,992
drug products.1 Therapeutic benefits associated
with both prescription and nonprescription med-
ications often imply safety and calculated risks to
the general public. However, despite the healing
benefits of medications, risks remain that can lead
to adverse events and drug-induced diseases.
Public assumptions of drug safety may partial-
ly be attributable to the approval and regulatory
process of the Food and Drug Administration
(FDA). Drugs approved by the FDA undergo a rigor-
ous testing and clinical trial process before
approval to ensure their safety and efficacy. Yet,
some people, including health care practitioners,
may assume that FDA approval implies absolute
safety, despite the fact that there are risks associat-
ed with using any medication. Even the FDA recog-
nizes that every approved drug carries some risk
and that “for every drug [the] FDA approves, the
benefits are balanced against [these] risks.”2 These
risks may be mild or severe depending on the par-
ticular product, expected dose, or patient popula-
tion, and may subsequently manifest as a
drug-induced disease.
Medication errors are one cause of drug-
induced diseases. In 2000, the Institute of
Medicine reported the extent and impact of errors
in health care in its publication To Err Is Human.3
This report noted that medication errors were “one
of the most common types of error” and that sub-
stantial numbers of people were affected.3 Other
sources of drug-induced disease are related to the
14
John R. Litaker and James P. Wilson
pharmacologic characteristics of the product itself
and do not necessarily involve dispensing or dose
errors. Pharmacists and physicians should be keen-
ly aware of the known potential adverse events
associated with each drug, because these events are
detailed in the product’s safety insert. Even well-
known products such as aspirin are associated with
serious adverse events. Indeed, speculation
abounds that aspirin would not meet today’s FDA
risk–benefit balance because of serious adverse
events such as gastrointestinal bleeding.4
This chapter focuses on the epidemiology of
drug-induced diseases and the impact on both the
public’s health and the health care system. The
cost of drug-induced diseases to the health care sys-
tem is also discussed.
OVERVIEW OF EPIDEMIOLOGY
Epidemiology has its historical roots dating back to
the philosopher Hippocrates, who, as early as the
4th century B.C., recognized the relationship
between disease and environmental, temporal, and
geographical factors.5,6 In more recent times, epi-
demiology gained considerable attention when
John Snow, a physician and epidemiologist, used
epidemiologic techniques to identify the source of
cholera epidemics in London in the mid-1850s. He
mapped the location of each cholera case and
noted an association between its geographic loca-
tion and the company that supplied water to that
location. Morbidity and mortality were highest
among people who received water from the
Southward Company. Further research determined
that cholera was spread by contaminated water
from this company.
TisdaleC02_14-22 1/12/10 1:53 PM Page 15
CHAPTER 2 • Epidemiology and Public Health Impact of Drug-Induced Diseases
John Last, in A Dictionary of Epidemiology,
defines epidemiology as the “study of the occur-
rence of disease or other health-related characteris-
tics in human populations,”7 whereas Jekel et al.8
define it as “the study of factors that determine the
occurrence and distribution of disease in a popula-
tion.” More specific to drug-induced diseases is the
term “pharmacoepidemiology,” which is defined
as “the study of the distribution and determinants
of drug-related events in populations and the
application of this study to efficacious drug treat-
ment.”9 Common to all three definitions is the
idea of disease distribution, or diffusion, and dis-
ease determinants, or causal factors. Indeed, deter-
mining why and how diseases spread from place to
place is the essence of epidemiology.
Determining the epidemiology of drug-
induced diseases and their impact on the public’s
health requires a sound, methodologic system to
establish: (1) the frequency of drug-induced dis-
eases; (2) nonmedical factors contributing to drug-
induced diseases; (3) particular medications, doses,
and routes of administration associated with drug-
induced diseases; (4) the temporal and geographic
distribution of drug-induced diseases; and (5) spe-
cific patient characteristics associated with drug-
induced diseases. Epidemiology and its specific
tools are extremely useful and important in under-
standing drug-induced diseases. Epidemiology pro-
vides a scientific and rigorous approach toward
answering specific questions and can be used to
identify associations, provide strength of evidence,
and establish causality. A variety of epidemiologic
techniques and research methods are available,
including ecologic studies, cohort studies, cross-
sectional, case–control studies, and randomized,
controlled trials. The reader is advised to consult
an epidemiologic textbook for more detailed expla-
nations of these and other study methods.
LEVELS OF EVIDENCE
Levels of evidence are used to stratify epidemiolog-
ic tools according to the strength of influence that
these studies may contribute to the decision-mak-
ing process. The basis for this strength of influence
is the study design itself. For example, an experi-
mental-design study will naturally have more
influence than a nonexperimental-design study.
Table 2–1 identifies the three levels of evidence,
with the associated study type, that are used
throughout this book.
However, the reader is cautioned not to rely on
the randomized clinical trial as the sole factor in
15
TABLE 2–1 Levels of Evidence for Drug-Induced
Diseases Used in this Book
Level of Evidence Source of Evidence
A One or more randomized,
controlled clinical trial
B Nonrandomized clinical trials,
prospective observational stud-
ies, cohort studies, retrospective
studies, case–control studies,
meta-analyses, and/or postmar-
keting surveillance studies
C Evidence from one or more pub-
lished case reports or case series
the decision-making process. Each study type has a
specific role to play in the decision-making
process, but this role is limited to the type of evi-
dence that the study can provide. In addition,
emerging outcomes (whether it is a disease or an
adverse drug event) may not readily appear as a
problem in its early stages. In such instances, case
reports may be the only source of evidence that
such a problem is occurring. A prime example of
this is a retrospective review of case reports from
the mid-1950s of individuals in Africa, North
America, Western Europe and the Middle East
reportedly dying of a wasting disease.10 At the time
that the case reports were compiled, blood samples
were taken from the dying individuals and stored.
Three decades later, researchers tested these blood
samples and found that these individuals were
infected with the human immunodeficiency virus.
OVERVIEW OF PUBLIC HEALTH
Public health is concerned with the programs, serv-
ices, and institutions involved with preventing dis-
ease, meeting the health needs of the population,
and emphasizing the proper distribution, alloca-
tion, and access to health services for all citizens. In
England, public health has been defined as “the sci-
ence and art of preventing disease, prolonging life,
and promoting health through organized efforts of
society.”11 Public health officials use epidemiology
as a tool to help with risk-factor analysis, evidence-
based policy-setting, and decision analysis.
In addition to epidemiology, biostatistical
analyses are used to help public health officials
determine the probability and causal relations
between drug use and an adverse event. Indeed,
biostatistics can help determine at the most basic
TisdaleC02_14-22 1/12/10 1:53 PM Page 16
16 SECTION I • Magnitude/Significance of Drug-Induced Diseases: Impact on the Health Care System
level whether an occurrence is due to chance
alone or to an association with a drug. For exam-
ple, during the past 5 years there has been sub-
stantial controversy regarding the administration
of the measles, mump, and rubella (MMR) vaccine
in the United Kingdom and the possible link of
the vaccination to autism. Biostatistics and epi-
demiology have been used to determine whether
autism is more or less likely to occur in vaccinat-
ed children as compared with the general popula-
tion. The basic premise is that if autism is more
likely to develop in vaccinated children (as deter-
mined statistically) than in children in the gener-
al population, then the association should be
further explored to determine whether causality
exists. That is, does the vaccine cause autism? Or
is there some unaccounted factor that also occurs,
but is unrecognized, that causes autism in vacci-
nated children? Epidemiologic investigations sug-
gest that there is no evidence linking MMR
vaccination to autism, thus highlighting the
importance of epidemiology.12
EPIDEMIOLOGY OF
DRUG-INDUCED DISEASES
Epidemiology is important in the study of drug-
induced diseases. Among other things, epidemiol-
ogy as applied to pharmaceuticals can be used to
investigate the therapeutic effects, risks, and use of
drugs in society. Epidemiology is often used to help
explain morbidity and mortality questions associ-
ated with particular medications. In August 2003,
epidemiologists from the U.S. Department of
Defense were asked to determine whether there
was a causal relationship between the antimalarial
drug mefloquine and unexplained domestic
killings among recently returned soldiers from
Afghanistan.13 No causal link between mefloquine
and the violence was established.
A key obstacle in identifying the cause of drug-
induced diseases is recognizing the reaction as a
drug-induced disease and being able to distinguish
it from spontaneous (i.e., occurring without taking
the drug), yet similar, clinical manifestations that
are not drug-related.14 Another obstacle is deter-
mining the numerator (i.e., number of patients
with a drug-induced disease) and denominator
(i.e., population who took the drug) necessary to
calculate the morbidity or mortality rate associated
with a particular drug.
In trying to determine causality of a potential
drug-induced disease by a particular drug, it is
important to remember that association does not
imply causation. Simply put, this means that while
a reaction may appear to occur in tandem with a
particular drug, it does not necessarily imply that
the drug caused the reaction. Indeed, the impor-
tance of determining causality was outlined by
Professor Sir Austin Bradford Hill, from the London
School of Hygiene and Tropical Medicine, in 1965.
In particular, Hill stated: “Our observations reveal
an association between two variables, perfectly
clear-cut and beyond what we would care to attrib-
ute to the play of chance. What aspects of that
association should we especially consider before
deciding that the most likely interpretation of it is
causation?”15 Hill suggested that the following
aspects should be considered before causality can
occur, and these are presented with a specific
emphasis on drug-induced diseases:
• Strength of association: Is there a strong asso-
ciation between a suspected drug-induced
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
effect exists. An example is the strength of
association between pregnant women tak-
ing thalidomide and giving birth to a dis-
figured child. Indeed, this association was
so strong that thalidomide was withdrawn
from the German market in November
1961 and was not commercially available
again until the U.S., in July 1998, intro-
duced it to treat erythema nodosum lepro-
sum, but with specific safeguards to prevent
it from being used by pregnant women.16
• Consistency: Does the suspected drug-
induced disease occur repeatedly in differ-
ent persons, at different times, and in
different places? Indeed, consistency is a
hallmark feature that must occur before
causality can even be suggested.
• Specificity: Is the suspected drug-induced
disease specific to that drug? For example,
individuals who take excessive doses of
digitalis for heart failure often see “halos.”
When they stop taking the drug and the
plasma digitalis concentrations decrease,
the halo effect disappears. Could there be
other causes for these patients seeing halos
or is it likely only due to digitalis over-
dose?
• Temporality: Does the suspected drug-
induced disease manifest before or after
drug exposure? To even consider causality,
TisdaleC02_14-22 1/12/10 1:53 PM Page 17
CHAPTER 2 • Epidemiology and Public Health Impact of Drug-Induced Diseases
the person must be exposed to the drug
before the occurrence of the adverse out-
come. If the person is not exposed to the
drug before the drug-induced disease
occurs, then causality cannot be consid-
ered.
• Biologic gradient: Does the incidence of the
suspected drug-induced disease increase
when higher doses of the drug are taken?
For example, can we detect increased toxici-
ty with increased doses of a particular drug
(e.g., acetaminophen and liver toxicity)?
• Plausibility: Is the suspected causation plau-
sible? That is, if a particular adverse event
occurs after administration of a particular
drug, is it biologically (pharmacologically
and physiologically) plausible that the drug
caused the event or was it merely coinci-
dental?
• Coherence: Does the suspected causation
conflict or support that which is generally
known about the disease and its progressive
pathology?
• Experiment: Is it possible to manipulate the
degree of exposure to prevent or enhance
the outcome? For example, if a particular
drug is suspected of causing a rash in a
patient, does the rash disappear after dis-
continuing the medication, and does subse-
quent rechallenge cause the rash to
reappear? (Note that rechallenge is rarely
desirable or ethically appropriate in a clini-
cal setting.)
• Analogy: Can the previous experience with
a particular drug causing a particular drug-
induced disease be used to enhance our
ability to detect or accept a similar outcome
with a different drug under similar circum-
stances? For example, because of the
thalidomide debacle of the 1960s, we now
know that it is within the realm of possibil-
ity that a drug taken during pregnancy can
cause birth defects.
In addition to the Hill criteria, Naranjo et al.17 pro-
posed a method for estimating the probability of
adverse reactions. This method uses a probability
scale to determine “causality of [adverse drug reac-
tions] in a variety of clinical situations.” 17 While
the term causality should be replaced with correla-
tion, the proposed method is shown to have high
between-rater and within-rater reliability on both
initial testing and retesting. Clinicians may wish to
use this scale as a tool to assess correlation between
a medication and an adverse drug event.
17
CATEGORIZATION OF DRUG-
INDUCED ADVERSE EVENTS
Once association between a drug and an adverse
event is determined, it is useful to classify the
adverse event. Four categories have been suggested
to aid in the proper management of any iatrogenic
illness:14
1. Conscious risk
2. Unexpected complications
3. Inept care
4. Overzealous care
Conscious risk and unexpected complications
represent adverse events due to “balanced,
informed consideration of benefits and risks.”15 In
essence, these two types of drug-induced adverse
events are part of the normal risk–benefit consider-
ation inherent when prescribing any drug for any
condition to any person. That is, there is always
the potential for unintended or unpredictable drug
effects on the body. However, both conscious risk
and unexpected complications can be mitigated by
knowing the risk factors associated with the drug-
induced disease, assessing patients for these risk
factors, providing optimal doses, and identifying
other therapeutic interventions.15 The latter two
categories represent “errors of omission” and
“errors of commission,” respectively,15 and repre-
sent inappropriate medication use due to a lack of
understanding or education about the drug and its
impact in the patient for whom it is prescribed.
QUANTIFYING THE IMPACT OF
DRUG-INDUCED EVENTS
Determining the quantitative impact of a drug-
induced disease to society requires the use of a rig-
orous and fact-based epidemiologic approach.
Several methods for quantifying the impact have
been developed, with the simplest being the attrib-
utable risk percent measure reported by Cole and
MacMahon in 1971.18 This simple approach relies
on the odds ratio and is expressed as:
P = (OR – 1)/OR,
where P is the probability that the symptom is the
result of taking the drug, and OR is the ratio of the
odds of exposure among the cases to the odds of
exposure among the controls, and is usually
accompanied by 95% confidence intervals to aid in
the interpretation of statistical significance.
TisdaleC02_14-22 1/12/10 1:53 PM Page 18
18 SECTION I • Magnitude/Significance of Drug-Induced Diseases: Impact on the Health Care System
An example is to determine the quantitative
impact of a drug-induced disease of two alternative
therapies for the same condition. In 2004, the safe-
ty and tolerability of two aerosolized antifungal
prophylaxis medications in lung transplant recipi-
ents were assessed. Subjects receiving amphotericin
B deoxycholate were more likely to have experi-
enced an adverse event than subjects receiving
amphotericin B lipid complex (OR, 2.16; 95% con-
fidence interval, 1.10–4.24; P = 0.02).19 Using the
equation above, the quantitative impact of adverse
events due to amphotericin B deoxycholate is:
P = (2.16 – 1)/2.16 = 53.7%.
However, additional criteria (e.g., Hill’s causali-
ty criteria) must also be considered before making
a definitive judgment on causality.
PUBLIC HEALTH IMPACT OF
DRUG-INDUCED DISEASES
Drug-induced diseases exert a considerable impact
on society. They are costly, result in considerable
morbidity, and may result in death. Some adverse
drug effects are not clinically significant, yet “most
[would] agree that any condition that results in
hospitalization is significant.”20 In this book, a
drug-induced disease is defined as an unintended
effect of a drug that may result in mortality or mor-
bidity, with symptoms sufficient to prompt a
patient to seek medical attention and/or require
hospitalization. Costs associated with drug-
induced diseases have considerable implications
for public health policy and planning. For exam-
ple, costs associated with drug-induced diseases
not only divert health care resources, but also have
measurable (e.g., hospitalization) and societal (e.g.,
lost time from work) costs. From a clinical stand-
point, prevention of drug-induced diseases is
preferable to treatment after the fact. Fortunately,
many drug-induced diseases are preventable. This
section explores issues related to the public health
implication of drug-induced diseases.
Determining the Incidence of
Drug-Induced Disease
Determining the incidence of drug-induced dis-
eases can be a daunting task, chiefly because it is
difficult to determine the associated numerator
and denominator. The numerator is defined as the
number of new drug-induced disease events occur-
ring during a defined period, while the denomina-
tor is defined as the population at risk for the
drug-induced disease during the same period. In
the general population, the denominator is the
number of people exposed to a particular medica-
tion and could be identified by using computerized
prescription data or medical records. In reality,
however, numerous obstacles exist in determining
the denominator, because it is difficult to identify
the population of interest and to determine how
many people in this population were exposed to
the drug. Determining the numerator is also diffi-
cult, because there is no systematic method of
assessing the occurrence of drug-induced diseases
in individuals, unless the occurrence is serious
enough to warrant further medical attention.20
Data from hospital admission studies can be
used as an appropriate measure of drug-induced
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
hospitalization are deemed serious enough to be
clinically significant and thus would seem to repre-
sent a higher burden to society. Indeed, Nelson and
Talbert note that “the rate of drug-related admis-
sions is a measure of a subset of the clinically sig-
nificant related morbidity. Determining this rate
could identify some of the cases of drug-related
morbidity.”20
Another obstacle in determining the incidence
of drug-induced diseases is that, in many cases,
medications are not recognized as the cause of the
symptom or disease. Therefore, a particular med-
ication may not be recorded or reported as a poten-
tial cause. Clinicians may be slow in recognizing a
drug-induced disease because not all adverse events
are reported in the literature or necessarily known
to the FDA at the time of approval. For rare events
(e.g., a drug-induced disease occurring in 1 of every
10,000 people), the likelihood of detection before
approval and widespread use is low, because the
clinical trial process, although rigorous, is not
designed to identify all drug-related adverse events.
It is often only after a drug reaches the market, and
hence a much larger patient population, that rare
events are identified. Therefore, the importance of
postmarketing surveillance activities and signal-
detection activities cannot be overstated.
Drug-Related Hospital Admissions
As noted earlier, drug-induced hospital admissions
are a sign of serious clinical events. Sometimes
these admissions are avoidable and other times
they are not. For example, a patient with a known
allergy to penicillin who is subsequently prescribed
this drug and has anaphylactic shock is a case of an
TisdaleC02_14-22 1/12/10 1:53 PM Page 19
CHAPTER 2 • Epidemiology and Public Health Impact of Drug-Induced Diseases
avoidable hospital admission. On the other hand,
a patient may receive a medication that causes a
drug–drug, drug–food, or drug–laboratory interac-
tion with subsequent hospitalization that is
unavoidable, because these interactions were previ-
ously undescribed, were previously unknown, or
were idiosyncratic in nature.
In a 1993 review, the incidence of drug-related
hospital admissions was reported to range from
0.2% to 21.7%, with the median rate of drug-relat-
ed hospitalizations of 4.9%.21 The author defined
drug-related hospitalizations as adverse events that
could cause a side effect, excessive effect, idiosyn-
cratic effect, or hypersensitivity. All of the reviewed
studies were conducted in large hospitals, with
most located in urban areas. Sample sizes (or total
admission numbers) ranged from 41 to 11,891,
with a total patient population size of 69,187. Only
nine of these studies reported incidence rates
above 7.0%, representing just 6.3% of the patient
population assessed (4,420/69,187). The highest
reported incident rate of 21.7% occurred in a
teaching hospital with oncology patients as the
predominant patient population. The major impli-
cated medications for drug-related admissions in
this group were theophylline, chemotherapy
agents, and trimethoprim–sulfamethoxazole. In
another review, covering the period from 1959
through 1992, the rate of drug-related hospital
admissions ranged from 0.3% to 16.8% of all hos-
pital admissions, with a median value of 5.6%.14
Determining the rate of drug-induced hospital
admissions is dependent on the study population,
the ability to extract sufficient medical informa-
tion, and the study method. Most studies of drug-
related admissions rely on a medical record review
by a clinical pharmacist. Such a review typically
defines a drug-induced admission and establishes
criteria for objectively determining whether an
admission meets that definition. The definition of
drug-related admission can include an adverse drug
reaction, dose-related therapeutic failures, improp-
erly treated conditions, and drug interactions.
Among studies assessing drug-related admissions,
wide ranging results are possible due to variation in
prescribing patterns, differences in patient popula-
tions, and differences in defining drug-induced ill-
ness.
The true extent of drug-related hospital admis-
sions remains a mystery, because it is not possible
to make a collective determination of the overall
prevalence based on a collection of disparate stud-
ies. As Manasse pointed out, although published
reports provided useful information about drug
misadventuring, these reports were extremely lim-
ited “in establishing a national mortality, morbidi-
19
ty, or incidence rate.”22 However, there is some
information that these studies can provide about
drug-related hospital admissions. For example,
reports can inform us about the types of drugs and
drug classes frequently implicated in drug-related
hospital admissions and about potential causes of
drug-related problems (e.g., drug–drug interaction,
noncompliance, etc).
Many studies have identified drug types and
drug classes frequently implicated in causing drug-
induced hospital admissions. Although the results
of these studies vary in terms of drug classes impli-
cated and the number of adverse events associated
with each drug class, some general trends are
noted. For example, cardiovascular drugs are often
implicated in drug-induced hospital admissions.
Chiefly, among this group are digitalis, diuretics,
and angiotensin-converting enzyme inhibitors. See
Table 2–2 for a list of drug classes commonly asso-
ciated with drug-induced hospital admissions.
COSTS
Costs associated with drug-induced diseases can be
quite substantial. Unfortunately, because of
methodologic problems in determining causality
and because of the numerator/denominator prob-
lem, only a few attempts have been made to assess
direct costs associated with drug-induced diseases.
An attempt was made to estimate monetary costs
associated with hospitalization due to drug-
induced diseases in Australia.23 However, this study
simply calculated a mean average cost based on
average length of stay and average daily cost of
hospital care. The report did not include costs of
outpatient visits, return visits to a physician’s
TABLE 2–2 Drug Classes Commonly Associated
with Drug-Related Hospital Admissions
• Antidiabetics/hypoglycemics
• Cardiovascular agents (e.g., ACEa inhibitors,
diuretics, digoxin)
• Psychotropics
• Gastrointestinal drugs
• NSAIDsb
• Anticonvulsants
• Antineoplastics
• Corticosteroids
• Antibiotics
a
NSAIDs, non-steroidal anti-inflammatory drugs.
b ACE, Angiotensin-converting enzyme
TisdaleC02_14-22 1/12/10 1:53 PM Page 20
20 SECTION I • Magnitude/Significance of Drug-Induced Diseases: Impact on the Health Care System
office, pharmacy costs, or additional treatment
costs. Table 2–3 describes items that should be
included in a comprehensive health economic
assessment.
A more comprehensive cost-of-illness
approach associated with drug-related morbidity
and mortality was conceived by researchers at the
Center for Pharmaceutical Economics at the
University of Arizona based on a probability path-
way model.24 In this model, costs were determined
based on specific outcomes associated with treat-
ment. When a patient receives drug therapy, four
possible outcomes are possible: (1) optimal thera-
peutic outcome, in which the patient recovers
from the illness; (2) treatment failure; (3) a new
medical problem; and (4) a combination of treat-
ment failure and a new medical problem.
Therefore, this model went beyond addressing
drug-induced diseases, and included drug-related
events including treatment failures. It stands to
reason that attaining an optimal therapeutic out-
come is the desired end result. For patients who do
not reach this outcome, additional scenarios are
possible: no further treatment, an additional
physician visit, additional treatment, an emer-
gency department visit, hospitalization, long-term
care admission, or death.
Based on this cost-of-illness model, total esti-
mated morbidity and mortality costs for drug-relat-
TABLE 2–3 Costs to Consider When Conducting
a Health Economic Evaluation
Direct medical costs
• Hospitalization
• Outpatient service (including ancillary services)
• Pharmacy costs
• Diagnostic procedures and tests (e.g., laboratory
tests, electrocardiography, and chest radiography)
• Surgery
• Extended nursing or home health costs
Direct nonmedical costs
• Transportation to and from the medical provider
• Services (e.g., meals on wheels and social
assistance)
• Adopting devices and instruments
Indirect costs
• Sick leave
• Reduced productivity
• Early retirement
• Premature death
ed diseases were $76.6 billion in 1995.24 A follow-
up study in 2001, using the same cost-of-illness
model, reported annual drug-related morbidity
and mortality costs (in 2000 dollars) of $177.4 bil-
lion.25 By comparison, the cost of cardiovascular
diseases and stroke were estimated to be $393.5 bil-
lion in 2005, and the 2004 cost for all cancers was
$190 billion.26
When these figures are broken down by cost
center, hospitalization was the single highest cost
driver for drug-related morbidity and mortality,
with 1995 expenditures of $47.4 billion and 2000
expenditures of $121.5 billion (Figure 2–1). In
1995, for example, 62% of the total cost was repre-
sented by hospital admissions. In the 2001 study,
hospital admissions accounted for 69% of the total
costs. This increase is most likely due to higher
costs associated with hospitalizations rather than
an increased incidence of drug-related diseases.
Costs associated with new medical problems due to
a previously prescribed pharmacologic treatment
are also expensive. Johnson and Bootman24 esti-
mated that hospitalization costs associated with a
new medical problem were $5,504 in 1995, as com-
pared with $12,797 in 2000.25
However, it should be noted that the expendi-
tures presented in this model are estimates. Indeed,
hospitalization expenses from the 1995 study
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,
Einarson21 reported an overall incidence of drug-
related hospital admissions ranging from 0.2% to
21.7%, with a median value of 4.9%. Hallis14
reported an incidence of drug-related hospital
admissions ranging from 0.3% to 16.8%, with a
median value of 5.8%. Johnson and Bootman24
acknowledge this discrepancy by noting that esti-
mates (such as by Einarson21) focused on hospital
admissions due to noncompliance or adverse drug
reactions. Johnson and Bootman24 further note
that estimates in their model included “negative
therapeutic outcomes owing to all types of drug-
related problems” and, as such, the estimated num-
bers of hospital admissions “would be expected to
be greater.” Despite this explanation, these num-
bers appear to be high as compared with empirical
evidence and should be judged cautiously in this
light. From a clinical perspective, the rate of drug-
related hospitalizations may be more appropriately
in line with the median estimates of 4.9% and
5.6% reported by Einarson21 and Hallis,14 respec-
tively, because their studies represent wide reviews
of the published literature on the subject.
TisdaleC02_14-22 1/12/10 1:53 PM Page 21

CHAPTER 2 • Epidemiology and Public Health Impact of Drug-Induced Diseases 21

Estimated Health Care Utilization Costs Associated with

Drug-Related Morbidity and Mortalitya
Billions

$120 ⫹156.1%

$100

$80

$60

⫹127.7%
$40

⫹85.3%
$20
⫹8.3%
⫹81.9%

Physician visits Additional ED visits Hospital LTC

prescriptions admissions admissions
Expenditure Typeb
1995 2000

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
also a major concern for pharmacists, physi-
cians, and other health care providers. Mortality
associated with drug-induced diseases presents
an emotional and economic burden to society,
especially in cases for which the cause is pre-
ventable. The mean death rate due to adverse
drug reactions was reported to be 5% of all hos-
pitalized patients admitted for a drug-related
problem.22 This is over 16 times higher than the
mortality rate of 0.3% for all other hospital
admissions.22 In addition, the cost of hospital-
ization with resultant mortality is one of the
most expensive costliest single pathways identi-
fied by Johnson and Bootman as a treatment
outcome.24 In 1995, for example, drug-related
mortality due to a new medical problem had a
total pathway cost of $5,504.24 In 2001, drug-
related mortality due to a new medical problem
that resulted in death had a total pathway cost
of $12 797.25
Finally, it should be noted that although there
are morbidity, mortality, and economic costs asso-
ciated with adverse drug reactions, there are also
significant opportunity costs to public health
when medications known to be safe and effective
are not used. For example, childhood vaccination
rates have declined in some cities throughout the
U.S. because of fears of autism. As such, there has
been an increase in the incidence of mumps and
measles in some communities. This increase in pre-
ventable illnesses not only impacts the individual,
but also exerts a concomitant effect on the com-
munity population, as herd immunity is reduced
and individuals not previously susceptible to the
illness may become susceptible.
TisdaleC02_14-22 1/12/10 1:53 PM Page 22
22 SECTION I • Magnitude/Significance of Drug-Induced Diseases: Impact on the Health Care System
CONCLUSION
Drug-induced diseases are a continuing concern for
patients and health care practitioners alike. All
drugs have the potential to precipitate an adverse
event, which, in its most serious form, can lead to
a drug-induced disease. Clinical trials and regulato-
ry approval processes are often very good at identi-
fying the most common types of adverse events
and the patients in whom they are likely to occur.
However, not all drug-induced diseases can be
identified a priori, no matter how carefully medica-
tions are prescribed or regulated. The interplay of
drugs with complex physiologic factors makes
drug-induced diseases something that must be con-
sidered as part of the risk–benefit profile associated
with the administration of any medication.
Epidemiology, however, is useful in assisting cli-
nicians in identifying potential associative or causal
influences on diseases induced by a specific drug. At
the population level, the examples outlined in this
chapter demonstrate the potential for epidemiology
to not only identify causal inferences (e.g., thalido-
mide and birth defects), but to also rule out inap-
propriate causal inferences (e.g., MMR and autism).
At the patient level, causal inferences may be due to
the complexity of the patient’s condition, physio-
logic responses, and the specific pharmacodynamic
interplay associated with a specific medication. The
ability to use tools related to association and causa-
tion as described by Hill15 and Naranjo et al.17 can
be useful in identifying potential causal interac-
tions at the patient level.
References
1. FDA Adverse Event Report System [database online].
Available at: http://www.fda.gov/cder/aers/default.htm
2. FDA Website. Frequently asked questions: Once the FDA
approves a drug, does this mean that the product is
perfectly safe? Available at:
http://www.fda.gov/cder/about/faq/default.htm#6.
Accessed June 28, 2009.
3. Kohn LT, Corrigan JM, Donaldson MS. To Err Is Human:
Building a Safer Health System. Washington, DC: National
Academies Press; 2000.
4. Lowe D. Aspirin: not approvable. Medical Progress Today.
2005. Available at:
http://www.medicalprogresstoday.com/spotlight/spotligh
t_indarchive.php?id=1039. Accessed May 10, 2009.
5. Beaglehole R, Bonita R, Kjellström T. Basic Epidemiology.
Geneva: World Health Organization; 1993.
6. Litaker JR, Chou JY, Novak S, et al. Implications of SARS:
medical geography and surveillance in disease detection.
Ann Pharmacother. 2003;37:1841-1849.
7. Last JM. A Dictionary of Epidemiology. 3rd ed. New York,
NY: Oxford University Press; 1995.
8. Jekel JF, Elmore JG, Katz DL. Epidemiology, Biostatistics,
and Preventive Medicine. Philadelphia, PA: W. B. Saunders
Company; 1996.
9. Begaud B. Dictionary of Pharmacoepidemiology. Chichester,
England: John Wiley & Sons; 2001.
10. Huminer D, Rosenfield JB, Pitlik SD. AIDS in the pre-
AIDS era. Rev Infect Dis. 1987;9:1102-1108.
11. Public Health in England. The Report of the Committee of
Inquiry into the Future Development of the Public Health
Function. Cmnd 289. London, England: HMSO; 1988.
12. DeStefano F, Bhasin TK, Thompson WW, et al. Age at
first measles-mumps-rubella vaccination in children with
autism and school-matched control subjects: a
population-based study in metropolitan Atlanta.
Pediatrics. 2004;113:259-266.
13. News Round-up. US army to investigate side effects of
mefloquine. BMJ. 2004;328:660.
14. Hallis J. Drug related hospital admissions in
subspecialties of internal medicine. Dan Med Bull.
1996;43:141-155.
15. Hill AB. The environment and disease: association or
causation? President’s address. Proc R Soc Med.
1965;58:295-300.
16. FDA Approves Thalidomide for Hansen’s Disease Side Effect,
Imposes Unprecedented Restrictions on Distribution.
Available at:
http://www.fda.gov/bbs/topics/answers/ans00887.html.
Accessed May 10, 2009.
17. 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.
18. Cole P, MacMahon B. Attributable risk percent in case
control. Br J Prev Soc Med. 1971;25:242-244.
19. Drew RH, Dodds AE, Benjamin DK Jr, et al. Comparative
safety of amphotericin B limpid complex and
amphotericin B deoxycholate as aerosolized antifungal
prophylaxis in lung-transplant recipients.
Transplantation. 2004;77:232–237.
20. Nelson KM, Talbert RL. Drug-related hospital admissions.
Pharmacotherapy. 1996;16:701-707.
21. Einarson TR. Drug-related hospital admissions. Ann
Pharmacother. 1993;27:832-840.
22. Manasse HR Jr. Medication use in an imperfect world:
drug misadventuring as an issue of public policy, part 1.
Am J Hosp Pharm. 1989;46:929-944.
23. Roughead EE, Gilbert AL, Primrose JG, et al. Drug-related
hospital admissions: a review of Australian studies
published 1988–1986. Med J Aust. 1998;168:405-408.
24. Johnson JA, Bootman JL. Drug-related morbidity and
mortality. Arch Intern Med. 1995;155:1949-1956.
25. Ernst FR, Grizzle AJ. Drug-related morbidity and
mortality: updating the cost-of-illness model. J Am Pharm
Assoc. 2001;41:192-199.
26. American Heart Association. Heart Disease and Stroke
Statistics—2005 Update. Dallas, TX: American Heart
Association; 2005.
TisdaleC03_23-30 1/12/10 2:26 PM Page 23
CHAPTER 3
Factors Contributing to
Drug-Induced Diseases
M any factors can predispose patients to drug-
induced diseases. Some drug-induced diseases
are associated with specific patient and/or drug-
related factors or idiosyncrasies. Others may result
from actions on the part of the prescriber who
decides on the need for a given drug in a particular
patient, the pharmacist who dispenses a drug to
the patient, the nurse who administers a drug to
the patient, or the patient who takes the drug. This
chapter describes factors that commonly con-
tribute to the development of drug-induced dis-
eases. The major categories of factors are those
associated with pharmacokinetics and pharmaco-
dynamics, adherence to therapy, and medication
errors.
PHARMACOKINETIC AND
PHARMACODYNAMIC FACTORS
Toxic or exaggerated responses to normal drug
doses can lead to drug-induced diseases and other
adverse events for two reasons. First, excessively
high concentrations of unbound drug or metabo-
lite at the site of action may occur as a result of
unusual pharmacokinetics (absorption, distribu-
tion, metabolism, excretion) of the drug or
metabolites. Second, response to a given concen-
tration of unbound drug or metabolite at the site of
action (pharmacodynamics) may be exaggerated or
unusual because of many factors, including
changes in the number and/or binding affinity of
target receptors as well as alterations in signal-
transduction pathways. The pharmacokinetic and
pharmacodynamic behaviors of drugs may be
Janis J. MacKichan and Mary W. L. Lee
influenced by factors related to disease, physiolog-
ic status, concomitantly administered drugs or
food, and lifestyle. Pharmacokinetics and pharma-
codynamics also are highly influenced by
interindividual differences in genes that code for
drug-metabolizing enzymes, drug transporters, tar-
get receptors, and ion channels.1 Specific factors
influencing pharmacokinetics and pharmacody-
namics that may contribute to the development of
drug-induced diseases are discussed in the follow-
ing sections.
Concurrent Diseases
The effects of disease on pharmacokinetics have
been extensively reviewed2 and examples are
shown in Table 3–1.3-7 For drugs or drug metabo-
lites that are highly dependent on the kidney or
liver for elimination, usual doses produce higher-
than-normal serum drug concentrations in
patients with kidney or liver disease respectively.
This results in an exaggerated response, particular-
ly for drugs with narrow therapeutic index.
Cardiovascular diseases, such as acute myocardial
infarction or heart failure, may reduce hepatic
blood flow and decrease the elimination of drugs
that are normally highly extracted by the liver.
Serum concentrations and response are increased if
such drugs are administered intravenously.
Hypothyroidism may be associated with a decrease
in both hepatic and renal drug clearances.
Many diseases can also decrease the serum pro-
tein binding of drugs. For example, kidney and
liver diseases have been associated with decreased
albumin binding of some drugs. These changes
23
TisdaleC03_23-30 1/12/10 2:26 PM Page 24

24 SECTION I • Magnitude/Significance of Drug-Induced Diseases: Impact on the Health Care System

TABLE 3–1 Examples of Disease Effects on Drug Pharmacokinetics and Pharmacodynamics3-7

Disease Drug Mechanism
Kidney Cefepime This antibiotic has a wide therapeutic index, but its high depend-
ence on the kidney for elimination makes dose reductions critical
in patients with severe kidney disease. There have been numerous
reports of life-threatening cefepime-induced neurotoxicity in
patients with acute kidney failure.
Morphine Morphine does not substantially depend on the kidney for elimina-
tion. However, one of its active metabolites, morphine-6-
glucuronide, is highly dependent on renal elimination. A prolonged
duration of sedation and respiratory depression has been
reported when usual doses of morphine are administered to
patients with kidney disease.
Liver Midazolam The clearance of midazolam, which is metabolized by phase I
oxidative metabolism, is decreased in patients with moderately
severe cirrhosis, while the clearance of oxazepam (metabolized by
phase II conjugation) is not. It is proposed that phase I oxidation
reactions are more sensitive to impaired hepatic oxygenation as
compared with conjugation reactions.
Opioids Patients with liver disease have an unusual sensitivity to opioids
and sedatives, such that small doses can precipitate encephalopa-
thy. Increased density and affinity of opiate receptors in the brain
is proposed as the explanation.
Cardiovascular/ pulmonary Lidocaine Lidocaine is highly extracted by the liver; therefore, its hepatic
clearance is sensitive to the reduction in cardiac output in patients
with heart failure. Patients with heart failure who receive normal
infusion rates of lidocaine often develop excessively high unbound
lidocaine concentrations and possible toxicity.
Digoxin Enhanced toxicity of digoxin is observed in patients with cor pul-
monale or ischemic heart disease. Factors contributing to the
toxicity include hypoxia and higher concentrations of endogenous
and exogenous catecholamines.
Hypothyroidism Digoxin Decreased renal excretion of digoxin and increased receptor sensi-
tivity are believed to explain the exaggerated response to digoxin
in patients with hypothyroidism when usual doses are adminis-
tered.
Electrolyte imbalance Digoxin Potassium and magnesium both compete with digoxin for myocar-
dial receptors. Thus, hypokalemia and hypomagnesemia are associ-
ated with increased myocardial uptake of digoxin and toxicity
when usual doses are administered.

generally do not result in an altered clinical
response, however, because the concentration of
unbound drug is unaffected. Nevertheless, misin-
terpretation of total serum drug concentrations of
highly protein-bound drugs that are routinely
monitored may lead a clinician to inappropriately
increase the dose, thus resulting in toxicity.8
Concurrent diseases may also be associated
with enhanced pharmacodynamic responses to
drugs for a variety of reasons, as shown by the
examples in Table 3–1. For instance, the incidence
of skin rashes and serious dermatologic adverse
effects such as Stevens–Johnson syndrome is
increased in patients with human immunodefi-
ciency virus (HIV) infection who are taking
trimethoprim–sulfamethoxazole. Patients with
cytomegalovirus infection who are taking ampi-
cillin are also at increased risk for skin rashes.
Although the precise mechanisms are unknown,
desensitization procedures generally reduce the
TisdaleC03_23-30 1/12/10 2:26 PM Page 25
CHAPTER 3 • Factors Contributing to Drug-Induced Diseases
severity of the adverse effect if rechallenge with the
drug is necessary.9
Physiologic Conditions
The pharmacokinetics of a drug may be affected by
age, pregnancy, and sex.10 In general, the rate of
elimination of a drug is impaired in premature
newborns, increases in early childhood to more
efficient rates than those in adults, and then pro-
gressively declines with advancing age. In addi-
tion, elderly patients may also suffer from
decreased mental status or diminished physical
function. When these physiologic conditions are
compounded by decreased elimination of some
drugs (e.g., benzodiazepines), the patient is more
susceptible to drug-induced falls or physical
injury.11 A variety of physiologic changes during
pregnancy may affect the pharmacokinetics of
drugs, but no consistent patterns have been identi-
fied. The higher serum concentrations of digoxin
reported in pregnant patients may be caused by
increased bioavailability resulting from decreased
gastric emptying time. Women have a higher risk
of drug-induced adverse events as compared with
men, which has been attributed to the fact that
they take more drugs than men, have lower activi-
ty of drug-metabolizing enzymes, and have estro-
gen-related effects on drug receptors, as in the case
of drug-induced torsades de pointes.12,13
Drug–Drug Interactions
Drug–drug interactions may cause altered pharma-
cokinetics (bioavailability, distribution, clearance)
or altered pharmacodynamics by additive or antag-
onistic effects. Such interactions have been exten-
sively reviewed and are often a predictable and
preventable cause of morbidity and mortality.14-17
By far the most frequent contributing factors to
drug-induced disease resulting from drug interac-
tions are those that affect bioavailability and drug
elimination. A large number of important interac-
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
inhibitors of these systems.14-16 Most drug–drug
interactions involving metabolism are attributable
to enzymes in the cytochrome P-450 family which
may be inhibited by other drugs. Tables listing the
most common isozymes, their known substrates,
and their inhibitors and inducers are designed to
help clinicians avoid or minimize serious conse-
quences of particular drug combinations.14,18
P-glycoprotein, a transporter protein expressed
on the luminal surfaces of intestinal epithelial
25
cells, biliary hepatocytes, and renal tubular cells,
transports drug from within the cell to the intes-
tine, bile, or urine, respectively. Inhibition of P-gly-
coprotein can therefore increase the bioavailability
and decrease renal and biliary excretion of affected
drugs, thus increasing their serum concentrations.
Other interaction mechanisms that may result in
reduced renal excretion include reduction of the
glomerular filtration rate and increased reabsorp-
tion of drug into blood from the renal tubule.
Examples of drug-drug interactions involving
increased bioavailability, decreased metabolism,
and/or decreased biliary and renal excretion are
shown in Table 3–2.14,19-26
Drugs that displace other drugs from serum
protein-binding sites without affecting their
metabolism cause only transient increases in
unbound drug concentration, and hence do not
generally result in adverse effects. Displacement of
drugs such as warfarin (long half-life, small volume
of distribution, and narrow therapeutic range) can
be clinically important, however, and necessitate a
temporary reduction in the dose of the affected
drug.8
Serious drug–drug interactions may also occur
when drugs produce additive effects through dif-
ferent mechanisms. Examples include: (1) the com-
bined blood-pressure–lowering effects of calcium
channel-blockers and ␤-blockers; (2) the increased
risk of gastrointestinal bleeding resulting from
nonsteroidal antiinflammatory drug (NSAID)–
induced gastric erosion in patients taking warfarin;
and (3) exaggerated cyclic guanine monophos-
phate (cGMP)–mediated smooth-muscle relaxation
caused by the combination of sildenafil (which
inhibits cGMP degradation) and nitrates (which
increase GMP production), leading to potentially
serious hypotension.27 An example of a drug–drug
interaction involving active or toxic metabolites is
the potentiation of acetaminophen hepatotoxicity
in patients receiving enzyme inducers such as
rifampin, presumably by increasing the formation
of toxic acetaminophen metabolites.28
Drug–Food Interactions
Drug–food interactions have been extensively
reviewed.15,29,30 One of the most serious drug–food
interactions occurs with first generation nonselec-
tive monoamine oxidase inhibitors and tyramine,
an amino acid found in aged or fermented foods
and beverages. The suppressed metabolism of large
amounts of tyramine may result in hypertensive-
crisis, the so-called cheese reaction.31 Components
of grapefruit juice are known to suppress the
presystemic elimination of certain drugs that are
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26 SECTION I • Magnitude/Significance of Drug-Induced Diseases: Impact on the Health Care System

TABLE 3–2 Examples of Pharmacokinetic Drug–Drug Interactions That Can Result in Toxicity14,19-26
Mechanism
Bacterial inactivation of gut flora
Inhibition of drug-metabolizing
enzymes
Inhibition of drug transport
Decreased organ blood flow
Increased renal reabsorption
NSAID = nonsteroidal antiinflammatory drug.
Example
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.
The atypical antipsychotic clozapine is a substrate for CYP1A2, while fluvoxe-
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.
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.
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.
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.

either metabolized in the intestinal wall by the
cytochrome P-450 isozyme CYP3A4, are substrates
for P-glycoprotein, or both, resulting in increased
bioavailability. Drugs for which bioavailability
increases dramatically when taken with grapefruit
juice include lovastatin, simvastatin, buspirone,
and amiodarone.14,29 If alternative, noninteracting
drugs are not available, patients may need to avoid
drinking grapefruit juice.
In general, an increase in drug bioavailability
caused by food intake is not a problem if doses
throughout the course of treatment are taken con-
sistently at a fixed time relative to a meal.
However, a clinically important drug–food interac-
tion was reported for a particular once-daily theo-
phylline product, which has since been
reformulated. When taken with high-fat meals, a
sudden, rapid release of a large amount of theo-
TisdaleC03_23-30 1/12/10 2:26 PM Page 27
CHAPTER 3 • Factors Contributing to Drug-Induced Diseases
phylline occurred, leading to excessively high
serum theophylline concentrations.29
The salt, protein, or vitamin content of the diet
also may affect the renal excretion of drugs. For
example, a patient taking lithium who initiates a
low-salt diet for treatment of hypertension or heart
failure excretes less lithium, resulting in higher
serum lithium concentrations and potential toxic-
ity, given this drug’s narrow therapeutic range.32 A
low-protein diet is associated with decreased renal
clearance of oxypurinol, apparently through
enhanced reabsorption efficiency by the uric acid
transporter system.29
Lifestyle Factors
Alcohol and caffeine consumption can affect both
the pharmacokinetics and the pharmacodynamics
of other drugs, leading to serious drug-induced dis-
eases.15 There are many examples of alcohol exag-
gerating the central nervous system depressant
effects of drugs, including benzodiazepines, phe-
nothiazines, tricyclic antidepressants, opiates, and
antihistamines. Caffeine has an additive and
potentially dangerous stimulant effect when taken
with ephedrine in herbal weight-loss and athletic
performance–enhancing supplements.33
Genetic Variability
As a result of the rapidly evolving field of pharma-
cogenomics, interindividual differences in drug-
related toxicity and therapeutic response are not
always considered to be “idiosyncratic” respons-
es.34 Rather, it is widely recognized that genetic
makeup is responsible for a significant portion of
drug-induced diseases. Many genes that encode
metabolic enzymes or drug transporters are poly-
morphic, meaning that some groups of patients
with certain gene variants have relatively inactive
enzymes or transporters, while others have unusu-
ally active forms. In addition, the proportion of
patients with active or inactive forms may differ
among racial groups.
Polymorphisms in metabolizing enzymes have
been extensively reviewed.1,35-38 Patients with low
N-acetyltransferase activities, known as “slow acety-
lators,” are more likely to suffer from peripheral
nerve damage when administered standard isoni-
azid doses as compared with fast acetylators.
Likewise, slow acetylators of hydralazine are more
likely to suffer from hydralazine-induced lupus ery-
thematosus. At least four of the major cytochrome
P-450 isozymes (CYP2A6, CYP2C9, CYP2C19,
CYP2D6) responsible for oxidative drug metabolism
are polymorphic in nature. Patients with gene vari-
27
ants that produce low-activity enzymes for the
metabolism of warfarin experience a higher risk of
serious bleeding events.39 Severe and potentially
fatal hematologic toxicity occurs in the small per-
centage of patients receiving azathioprine or mer-
captopurine who have a genetic deficiency in the
thiopurine methyltransferase enzyme.35
Polymorphisms in receptors, ion channels, or
other proteins involved in drug response also
occur. These result in widely variable pharmacody-
namic responses among patients despite similar
concentrations of the drug at the site of action.
Examples include the polymorphisms in: (1)
dopamine receptors, which affect the risk of drug-
induced tardive dyskinesia; (2) skeletal-muscle
ryanodine receptors, which affect the risk of anes-
thesia-induced malignant hyperthermia; (3) potas-
sium or sodium channels, which affect the risk of
potentially fatal torsades de pointes when certain
antiarrhythmic drugs are administered;34 (4) glu-
cose-6-phosphate dehydrogenase, which if defi-
cient, leads to red-cell hemolysis in patients who
take drugs with a high redox potential, such as
aspirin, nitrofurantoin, sulfonamides, and quini-
dine; and (5) the major histocompatibility com-
plex, which mediates hypersensitivity reactions to
drugs such as abacavir and nevirapine.40
The future holds promise that drug-induced
adverse effects may be avoided by genetic screen-
ing of patients prior to initiation of drug therapy. It
is becoming the standard of care to test patients for
the lack of thiopurine methyltransferase prior to
initiating azathioprine therapy to reduce the risk of
severe and sometimes fatal toxicity, or the lack of
glucose-6-phosphate dehydrogenase prior to dap-
sone therapy to avoid dapsone-induced hemolytic
anemia.41 In some cases, combinations of gene
variants have been better predictors of drug effects
than single gene variants. The presence of a combi-
nation of three gene variants in one Australian
population accurately predicted serious hypersen-
sitivity to abacavir, a drug used to treat patients
with HIV. Genotyping for this combination is now
routinely used in that population prior to initiat-
ing therapy.38 The use of pharmacogenetic diag-
nostic tests is slowly gaining acceptance by
clinicians and will undoubtedly become increas-
ingly important for the safe use of a growing num-
ber of drugs.42,43
ADHERENCE TO
PRESCRIBED THERAPY
The terms adherence and compliance are often used
interchangeably. However, noncompliance implies
TisdaleC03_23-30 1/12/10 2:26 PM Page 28
28 SECTION I • Magnitude/Significance of Drug-Induced Diseases: Impact on the Health Care System
that the patient is intentionally or willfully not fol-
lowing directions for medication use, which may
or may not be the case. For this reason, some pre-
fer the term nonadherence, because it places no
blame on either the patient or the health care pro-
fessional. Common causes of nonadherence are
listed in Table 3–3. Regardless of the cause, nonad-
herence can lead to drug-induced disease. Patients
may take more or less drug than prescribed or rec-
ommended, modify medications in an inappropri-
ate fashion (e.g., crush a sustained-release tablet),
or continue to take a prescribed drug even though
the underlying medical condition for which the
drug was originally prescribed has resolved. Any of
these actions can put patients at increased risk for
drug-induced disease.
It is estimated that the prevalence of medica-
tion nonadherence is 40% to 70%.44-46 McDonnell
and Jacobs analyzed the cause for hospital admis-
sions from preventable adverse drug reactions.47 Of
158 drug-related hospital admissions over an 11-
month period, patient nonadherence with a pre-
TABLE 3–3 Common Causes of Medication
Nonadherence
Cultural beliefs of the patient
Mistrust of health professional: patient does not agree
with health care management
Patient wants to speed up response to treatment and
takes more drug than is recommended
Patient is unable to read written materials provided by
health care professional and is afraid to take
medication.
A long time passes between follow-up visits with
health professional; patient begins to feel that treat-
ment is not important.
Patient forgets to take medication during the day
Patient has difficulty opening bottles that contain
medications
Patient has physical limitations and cannot administer
medication as prescribed (e.g., patient has severe
arthritis and cannot administer insulin injection)
Patient cannot afford medication
Patient has psychological disorder and fails to compre-
hend need to take medication.
Health care professional fails to educate patient about
proper medication use, dose, and administration tech-
niques.
Patient fails to understand proper prescribing direc-
tions because of language barrier
scribed medication regimen was the identified
cause of 33% of these admissions. Unfortunately,
health care providers typically are unable to identi-
fy patients at risk for nonadherence. Patient age,
sex, race, intelligence, and educational background
have not been shown to be predictive of adherence
or nonadherence to a prescribed drug regimen.48
Many strategies have been used to improve
adherence to medication regimens, including ver-
bal instruction, supplementary written instruction
sheets or videotaped instructions, phone call
reminders, supplementary educational programs
for the patient and family caregivers, self-monitor-
ing flow sheets, switching from multiple daily dos-
ing of a medication to once-daily dosing, changing
the time of day that a medication is administered,
special reminder packaging, and others. Until the
most effective strategy or strategies to improve
adherence can be identified, it is recommended
that health care professionals keep drug regimens
simple, provide clear and complete instructions,
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
every opportunity.46
MEDICATION ERRORS
Medication errors contribute significantly to the
problem of drug-induced disease. These errors can
include a variety of problems involving any step in
the drug-use process.49 One study of hospitalized
patients reported that 49%, 26%, 14%, and 11% of
errors occur in the prescribing, administering, dis-
pensing, and transcribing stages, respectively, of
the drug-use process.50 In another study, 67% of
hospital admissions caused by adverse drug reac-
tions were attributed to inadequate patient moni-
toring (e.g., failure to order appropriate laboratory
tests to monitor drug response or failure to respond
appropriately to abnormal laboratory-test results)
and 51% were caused by inappropriate drug
doses.47 In one study of more than 2,000 elderly
patients, it was estimated that 63% of elderly out-
patients are receiving one or more medications
that are not necessary.51 This overuse can signifi-
cantly increase the risk of drug-induced disease in
a very vulnerable population.
Fortunately, not all medication errors result in
clinically significant problems. In one study of hos-
pitalized patients, only 7 of 100 medication errors
were thought to be serious enough to cause
harm.52 However, in view of the overall frequency
of medication errors that occur each year, a 7%
TisdaleC03_23-30 1/12/10 2:26 PM Page 29
CHAPTER 3 • Factors Contributing to Drug-Induced Diseases
proportion of serious medication errors may result
in many affected lives.
Medication errors and drug-induced diseases
may result from the limitations of an individual
practitioner, from problems latent in the system or
setting in which the practitioner operates, or from
a combination of the above. In most cases, medica-
tion errors are caused by system-related problems
including the absence of redundancies and system
defenses needed to detect and counter an error in
an individual’s judgment before the medication
reaches the patient.53-55
Reduction of medication errors has been a
focus of two recent Institute of Medicine reports,
To Err Is Human: Building a Safer Health System,56
and Crossing the Quality Chasm: A New Health
System for the 21st Century. 57 These reports suggest
a number of strategies that may be used in health
care settings to help reduce the incidence of med-
ication errors and their resultant drug-induced dis-
eases.
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oxidase A and B that do not cause significant tyramine
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37. Humma LM, Terra SG. Pharmacogenetics and
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45. Weintraub M. Compliance in the elderly. Clin Geriatr
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47. McDonnell PJ, Jacobs MR. Hospital admissions resulting
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48. McDonald HP, Garge AX, Haynes RB. Interventions to
enhance patient adherence to medication prescriptions.
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49. Krahenbuhl-Melcher A, Schlienger R, Lampert M, et al.
Drug-related problems in hospitals: a review of the recent
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50. Bates DW, Cullen DJ, Laird N, et al. Incidence of adverse
drug events and potential adverse drug events:
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51. Larouche ML, Charmes JP, Nouaille Y, et al. Is
inappropriate medication use a major cause of adverse
drug reactions in the elderly? Br J Clin Pharmacol.
2007;63:177-186.
52. Bates DW, Boyle DL, Vander Vliet MB, et al. Relationship
between medication errors and adverse drug events. J
Gen Intern Med. 1995;10:199-205.
53. Vincent C. Understanding and responding to adverse
events. N Engl J Med. 2003;348:1051-1056.
54. Grissinger MC, Globus NJ, Fricker MP. The role of
managed care pharmacy in reducing medication errors. J
Manag Care Pharm. 2003;9:62-65.
55. Leape LL, Bates DW, Cullen DJ, et al. Systems analysis of
adverse drug events. JAMA. 1995;274:35-43.
56. Kohn LT, Corrigan JM, Donaldson MS, eds. To Err is
Human: Building a Safer Health System. Washington, DC:
National Academies Press; 2000.
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2001.
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CHAPTER 4
Postmarketing Surveillance
for Drug-Induced Diseases
E nsuring safe therapeutics is a responsibility of
the public health care system that is shared by
the full spectrum of the health care enterprise—
from the patient and the individual prescriber to
the manufacturer and regulatory agencies.
Postmarketing attention to drug-induced diseases
encountered in day-to-day practice is the responsi-
bility of every health care practitioner and his or
her patients. At the same time, programs of post-
marketing surveillance for drug-induced diseases
are essential components of our nation’s broader
public health organizations. Postmarketing moni-
toring activities are critically important because
premarketing investigation alone cannot define
completely the safety profile of a drug. Systematic,
population-level surveillance is crucial because
independent clinical observation and incremental
learning by practitioners alone can never provide
an adequate understanding of the majority of safe-
ty issues that manifest after marketing. And yet,
paradoxically, these independent clinical observa-
tions are at the heart of population-level surveil-
lance. Systematic study approaches beyond
individual case reports are needed to complement
spontaneous reporting, and the promise of larger
and more accessible population-based data for this
purpose requires concerted efforts to ensure accept-
able population-level protections.
RECOGNIZING THE LIMITS
OF PREMARKETING DATA
When a drug is approved for marketing under the
provisions of the Food, Drug and Cosmetic Act, or
under similar laws around the world, the product is
deemed to meet several official requirements,
Hugh H. Tilson
which often are stated in shorthand as “safe and
effective.” But the meaning of that phrase is wide-
ly misinterpreted. There is not a broad understand-
ing among the medical community of the burden
of proof required to obtain the Food and Drug
Administration’s (FDA’s) approval to market a drug.
The sponsor of a New Drug Application must
have demonstrated that the product is efficacious,
usually through well-controlled studies. While
some flexibility is afforded for agents addressing
urgent needs and grave conditions, the approval
process typically requires completion of two well-
controlled, blinded, randomized clinical trials,
with clear separation of efficacy end points against
placebo when possible, or against a rigorous,
appropriate standard intervention that is already
approved. Far less clear are the preapproval stan-
dards for proof of a new drug’s safety, as distinct
from its efficacy. In general, the profile of adverse
effects associated with the agent, both self-limiting
side effects and serious unexpected and untoward
effects induced by the drug, must be such that the
threat of these adverse effects is not proven to out-
weigh the drug’s likely benefit. Practicality and
necessity often temper the stringency of this
requirement in a number of ways. These limita-
tions could be expressed as the “rule of too”: too
small, too brief, too healthy, and too homoge-
neous.
In practice, the number of patients required to
satisfactorily demonstrate efficacy in a clinical trial
becomes, by default, the number required to
demonstrate the absence of major toxicity. In gener-
al, the number of persons exposed to a new drug
before approval for marketing is granted may be as
few as 2000 to 3000. Under these circumstances, the
apparent absence of unacceptably frequent or intol-
31
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32 SECTION I • Magnitude/Significance of Drug-Induced Diseases: Impact on the Health Care System
erably severe adverse outcomes of treatment can
provide only statistical assurance that the likelihood
of such drug-induced illnesses, if they exist, is less
than 1 in 1,000. Moreover, the duration of such
preapproval studies is generally only as long as is
needed to comply with FDA requirements. Thus, the
occurrence of an excess of heart attacks following 18
months of therapy would be missed even in a rela-
tively large preapproval database of shorter studies.
The hothouse environment of the well-con-
trolled, blinded, and randomized study further
limits what we can know about the new drug’s per-
formance in wider clinical use following its
approval. Naturally, preapproval studies are gener-
ally conducted under tightly controlled circum-
stances, with carefully designed protocols that
exclude patients who appear to present the threat
of confusing results. These can include patients
affected by concurrent illnesses, taking concomi-
tant medications, and with specific risk factors or
patients belonging to potentially risky population
strata, such as the poor, ethnic minorities, chil-
dren, pregnant women, and the elderly.
In summary, our understanding of the proba-
bility (risk) of incurring a drug-induced disease
from a newly approved drug is limited by the
nature of the system for premarketing study and
the approval process.
THE NEED FOR POPULATION-
BASED SURVEILLANCE
FOLLOWING MARKETING
Systematic approaches to detection, quantifica-
tion, and education concerning drug-induced dis-
ease following marketing have emerged only
relatively recently, with the advent of clinical trials
approximately 50 years ago. Then, as now, the
medical community educated itself largely by
means of the published word, via clinical and sci-
entific journals. Before randomized, controlled
clinical trials were introduced, this “education by
publication” typically took the form of anecdotal
case histories, describing incidents of illness fol-
lowing drug therapy, in which the drug was
blamed for the undesired outcome. As part of the
reform of the Food, Drug and Cosmetic Act, volun-
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 only way to know of potential drug-induced
problems that are unlikely to be detected in the
preapproval drug development process is to moni-
tor real-world experience after introduction of
those products into the marketplace.
The cornerstone of population-based surveil-
lance for medication-induced illness, as with pub-
lic health monitoring of many emerging problems,
is the technique of encouraging all practitioners to
participate in a system of spontaneous voluntary
reporting. Here, the logic is to invite a heightened
awareness, particularly regarding new drugs, that
adverse outcomes following therapy—particularly
those that are otherwise unexpected—may be
attributable to the therapy. Therefore, if there is
any index of suspicion, any member of the treating
team, as well as the patient or his or her family is
encouraged to report, albeit on a voluntary basis.
Clinical detection of any single drug-induced
disease or injury in a single patient is extremely dif-
ficult. In professional training we are taught to
“expect the unexpected.” In most cases, drug-
induced illness does not manifest itself in dramati-
cally different ways from any illness that may be
treated in a physician’s office or pharmacist’s prac-
tice. Sudden death, liver or kidney failure,
encephalopathy, heart attack, and other events may
occur for no particular reason. Even Stevens–
Johnson syndrome, often thought of as a classic
drug-induced disease, has as its two most frequent
causes “cause not apparent” and viral infection,
with drug-induced listed third.1 Thus, the experi-
ences of the individual clinician, however impor-
tant in guiding continuing decision-making in
much of medicine, are inadequate for informing us
about drug-induced disease. On one hand, a clini-
cian witnessing one or two dramatic adverse events
following the use of a specific drug may consider
that drug a “bad actor,” when the events may have
been a rare coincidence or perhaps not drug-related
at all. On the other hand, having never had a prob-
lem with the drug may simply be a function of the
rarity of the drug-induced illness, the luck of the
draw, or failure to link, for example, the kidney fail-
ure in one or two patients with the drug or drugs
they were taking. There is, in short, no substitute for
population-level surveillance to determine the pres-
ence or absence of relatively rare problems or an
increase in the incidence of otherwise not-so-rare
adverse events over baseline. Thus, as in other pub-
lic health enterprises, the aggregate experience in a
population serves as the most effective sentinel or
signaling tool for possible problems.
THE SPONTANEOUS REPORTING
SYSTEM IN AMERICA
In this book, we differentiate between adverse drug
reactions (ADRs), also referred to as adverse effects or
side effects, and drug-induced disease. However, in
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CHAPTER 4 • Postmarketing Surveillance for Drug-Induced Diseases
every sense, the latter are a subset of the former.
Thus, our primary system for detecting and tracking
drug-induced diseases at the national level is the
spontaneous adverse reactions reporting system
(SRS), which is the nation’s system for tracking all
ADRs. Many have criticized the system as being a
“nonsystem,” comprising a loosely administered
chain of events in which those in positions to detect
ADRs—the patients and the clinicians who work
with them—are encouraged, voluntarily and without
incentive, to call such incident to the attention of
those who are in a better position to assemble, ana-
lyze, and act upon the ADRs. Indeed, the activities
constituting the SRS are not systematic and are not
integrated into the rest of the nation’s systems of
public health and safety surveillance. As a result, the
protections that this component of the nation’s sur-
veillance systems could provide are not guaranteed.
For the system to effectively capture and apply
data concerning ADRs, a certain chain of events
must transpire. Someone must detect that an
adverse event has happened and must suspect that
the adverse event might be associated with a drug
exposure. This detection and interpretation must
then be translated into action—the act of reporting
the event, usually to an unseen, remote recipient.
This event must be communicated to someone in
the system who will decide to incorporate it with
information from other major sources—in the
United States (U.S.), typically either a government
agency such as the FDA’s MedWatch system or the
Vaccine Adverse Event Reporting System or one or
more intermediaries. The primary such intermedi-
ary in the U.S. is the research-based, brand-name
pharmaceutical company. Pharmaceutical manu-
facturers receive, process, manage, analyze, and
report well over 80% of all ADRs that eventually
come to the attention of the FDA.2 For manufactur-
ers, further reporting of ADRs, reported sponta-
neously and voluntarily from the field, is
mandatory.
THE ACTORS AND THEIR ROLES
It is worthwhile to examine the roles of each of the
personal “actors” and the processes involved in
postmarketing surveillance, and explore some of
the challenges involved in linking them into an
effective system.
The Clinician
The point of departure for surveillance in the SRS is
the reporter—the person, usually a clinician, who
recognizes that something untoward, unexpected,
33
and generally unwanted has occurred and suspects
that the event is associated with a drug. (In princi-
ple, the SRS also could recognize unintended but
positive effects such as the unexpected hair growth
observed with minoxidil, which led to the develop-
ment of Rogaine and the sustained penile erection
observed as an unexpected side effect of an antihy-
pertensive drug that eventually became Viagra). A
patient can introduce this information into the SRS
either by reporting it directly to the manufacturer
or a regulatory agency via a consumer report or by
seeking medical care and calling it to the attention
of the provider who then reports it to one of these
agencies. Most providers—physicians, nurses, den-
tists, and pharmacists—claim that they have not
been trained sufficiently in the detection, manage-
ment, and reporting of ADRs to function effective-
ly as reporters in this system. Indeed, most indicate
that they have not reported a single ADR in the
past year, nor would they know how to report one
had they wished to do so.2 Moreover, most
providers suggest that they see very few ADRs in
their practice, even though, given the nature and
frequency of drug-associated adverse events, we
know that they occur during the routine practice
of all health care providers. Many health profes-
sion educators attribute the lack of awareness of
ADR prevalence on the failure of health curricula
to educate emerging clinicians on the critical bal-
ance between a systems-thinking sensibility and
the traditional art and science approach. The
Association of American Medical Colleges has
acknowledged the lack of broad consensus around
the competencies required to be taught in profes-
sional education for effective participation in the
nation’s drug safety system. The result has been a
far-reaching comprehensive inventory of such
competencies to be incorporated in all training
programs.3
It also must be noted that very few drug-induced
diseases are unique clinical entities. Rather, drugs are
partially or broadly responsible for causing or aggra-
vating many common clinical conditions.
Identifying drugs as a potential cause requires com-
plex clinical analysis. Furthermore, the drug may
have been obtained through another prescriber, self-
prescribed from the home medicine cabinet, or
combined with an alternative or complementary
medicine (prescribed or otherwise) or an unusual or
unexpected dietary pattern. The patient may not
have adhered to the recommended regimen, result-
ing in overdosing, underdosing, or (most common-
ly) episodic dosing, the latter two resulting in the
adverse outcome of unexpected or periodic treat-
ment failure. The patient may not recall fully or
accurately which medications he or she has taken,
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34 SECTION I • Magnitude/Significance of Drug-Induced Diseases: Impact on the Health Care System
or in what quantity, or in the case of illicit-drug use,
may not wish to disclose this information. And, of
course, the patient is generally taking medications
to treat an underlying or intercurrent illness, the
progression of which may be confused with the
drug-attributable illness. Clearly, identifying (or, ide-
ally, preventing) drug-induced disease requires a
partnership between patient, physician, and phar-
macist based on full disclosure, open discussions,
and awareness of potential risk factors.
The clinician must not merely recognize the ill-
ness, but also must endure the complexities of clin-
ical attribution in differential diagnoses. This is no
easy task, particularly given that the complexities
of clinical pharmacology are themselves rapidly
evolving. Having made a provisional association
between drug and disease, the first concern of the
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
patient visit, without the burdensome administra-
tive tasks of reporting to an invisible and remote
third party. No economic incentive exists to do so
either, as voluntary reporting is expected to be per-
formed pro bono. Indeed, ADR reporting likely will
generate subsequent questions and requests for
more data from the agent receiving the report, cre-
ating a potentially significant inconvenience,
which could discourage reporting. And, although
in the wake of the Institute of Medicine’s (IOM) To
Err Is Human report,4 we are admonished not to
“name, blame, or shame” those who report and
attempt to repair errors (in this case, in prescribing,
warning, or monitoring), there nevertheless may
be fear that admitting to a decision that caused an
adverse outcome could result in a lawsuit or other
censure. Current tort law does little to allay this
anxiety. The extent to which these barriers con-
tribute to underreporting is not known. Based on
populations prospectively and objectively moni-
tored, the underreporting ratio, even for severe or
serious ADRs (actual illnesses induced by medica-
tions) is estimated to be 10-fold or worse.5
The Patient
The patient is the point of departure for the post-
marketing surveillance system. Preventing drug-
induced disease in the individual patient through
awareness of the likely consequences of specific cir-
cumstances, such as risk factors and drug interac-
tions, requires a partnership between the
physician, pharmacist, and patient and must
include full disclosure, open discussion, and aware-
ness of potential risks. In addition, the patient may
be a direct reporter of potential drug-induced dis-
ease. The SRS receives reports from patients or their
advocates every day; up to 20% of reports are from
patients/consumers.6 While good surveillance
practice recommends that patients be referred to a
primary caregiver when making a report directly,
the Council for International Organizations of
Medical Sciences (CIOMS) working group conclud-
ed that it is the quality of the report and not the
nature of the reporter that is essential.7 Thus, while
in Europe consumer reports are generally not
included in the SRS, in the U.S. and Canada they
are. Thus, patient education regarding potential
drug-induced illness and heightened awareness of
reporting avenues and action all result in a
stronger likelihood that the SRS will learn about
important drug-induced diseases directly from the
patient.
The Manufacturer
A key factor in the SRS in the U.S., much misunder-
stood and generally underestimated, is the role of
the entity marketing the drug (particularly in the
early stages of marketing), the research-based phar-
maceutical company. As an innovator, operating
under an Investigational New Drug Application,
these companies also are referred to in the regula-
tory context as sponsors, since they sponsor New
Drug Applications. The sponsor is responsible,
under federal law, for compliance with all applica-
ble federal regulations relating to the safety, effica-
cy, and purity of its products, including the
conduct of regular ongoing product surveillance.8
Under these provisions, the sponsor is expected to
maintain vigilance over the safety of its products,
including receipt, management, and further
reporting of all ADRs from any source, including
the published literature, ongoing clinical trials,
and, primarily, the reporters who use, manage, and
prescribe their products, as described above. Under
the applicable regulations, sponsors are expected
to maintain a program that provides an immediate
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-
national consensus reports by CIOMS and interna-
tional management agreements under the
International Conferences on Harmonization)
from the nonserious.
Any report meeting the criteria for serious or
potentially serious effects must be transmitted to
FDA within 15 days of its initial receipt. This
requirement is not limited to the U.S., as the regu-
lations speak specifically to products sold any-
where in the world. Thus, any report documenting
an event that is serious and outside the product
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CHAPTER 4 • Postmarketing Surveillance for Drug-Induced Diseases
label (unexpected, unlabeled, or unlisted) that is
received by the company, its affiliate, or its agent
anywhere the drug is marketed requires immediate
transmittal to the FDA. Furthermore, such cases
also require sponsors to analyze the completeness
of the description carefully and to follow up
regarding incomplete data and/or information
needed to ascertain both severity and outcome
associated with serious drug-related illness. Enough
information is needed to help with both causality
assessments for the individual case and risk-factor
assessment for evolving case series. This latter
requirement results in the reporting practitioner
being pursued for more and better information.
The CIOMS Working Group has outlined best prac-
tices for pharmacovigilance to provide guidance
for sponsors in their vital roles in this public health
paradigm.7 These best practices include regular,
scheduled, comprehensive reviews of each of their
products. For every drug under their responsibility,
the sponsor prepares a summary report, currently
known as a “Periodic Safety Update Report,” which
describes the overall experience over a particular
period of time and in the population under surveil-
lance.
The modern scientific research-based pharma-
ceutical company provides a broad spectrum of
services to the treating community, including drug
information services that constitute a primary
interface between the company and health care
practitioners. A physician, nurse, dentist, or phar-
macist may contact the company for information
regarding its products and accumulated reported
clinical experiences or new information regarding
their use. Typically, the purpose of the call is not
really to report anything, but to learn more about
the drug product in question and its use. It is a
requirement that the contact be viewed as sponta-
neous and that it be considered as a reportable pos-
sible ADR. Thus, the better the drug information
system, the more calls it receives, and the more
reports of potential ADRs are generated. This
process can create a significant artifact in the
numerator as attempts are made to evaluate the rel-
ative incidence of ADRs associated with a particu-
lar drug.
The Regulatory Authority
Ultimately, all ADR reports arrive at the responsible
regulatory authority office, either by direct submis-
sion (though this is growing less common) or
through the responsible intermediary, the sponsor
company. In the U.S. model of public health, the
role of the government is to ensure conditions in
which people can be healthy, a role that requires
35
healthy and active partnerships between govern-
ment and the private sector, which in this case is
the regulated pharmaceutical industry.9 However,
the FDA is the ultimate arbiter of a company’s ade-
quacy concerning compliance activities, both on a
report-by-report level and overall as a partner in
public health protection. Each report receives
triage in the agency. Serious reports, such as those
describing reactions most likely to result in drug-
induced disease or injury, receive priority atten-
tion, particularly those that also qualify as
unexpected. Each sponsor also receives compliance
oversight from the agency, including a program of
FDA site visits and compliance audits to ensure an
intact reporting system with full transparent dis-
closure from sponsor to agency.
Attribution of a problem being considered for
an ADR report requires the clinician to consider
the possibility of a causal relationship between an
event and a drug, in the context of multiple other
possible causal explanations for the same event.
Rarely is such a causal relationship unambiguous.
Rather, the clinician must apply complex logic,
including consideration of the timing of the event,
the presence of other possibly causal exposures, the
natural history of the underlying disease, and so
forth. The SRS operates on the fundamental
assumption that a report would not be submitted
unless a reporter had some concern or suspicion
about a possible causal relationship to the drug.
Thus, all SRS reports are considered possibly attrib-
utable. The evolution of the system, however,
brings this assumption into question. For example,
more and more information comes to the atten-
tion of the system because of proactive study or
detailed information-seeking in association with
an individual report. This challenges scientists and
practitioners involved in the science of surveil-
lance to differentiate between truly spontaneous
and possibly attributable reports and the reports
that are elicited.
The pivotal role of the FDA in this public
health system has made it particularly vulnerable
to public criticism. Concerns about unexpected
serious drug-induced diseases being undetected for
too long (e.g., cardiac events associated with rofe-
coxib or celecoxib, suicides associated with selec-
tive serotonin receptor inhibitors) resulted in the
FDA Commissioner’s request to the IOM to con-
duct a thorough study of the system and the role
and contributions of the FDA. In a landmark
report, the IOM calls for sweeping reforms in the
manner in which the FDA approaches its roles, and
specifically defines the critical changes necessary
to entail the creation of a new “culture of drug
safety.”10 In this new culture, the public health
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36 SECTION I • Magnitude/Significance of Drug-Induced Diseases: Impact on the Health Care System
efforts at detection of and protection against drug-
induced diseases must assume a position equal in
importance to those of the review and approval of
new drugs.
THE SCIENCE OF SURVEILLANCE
Spontaneous Reporting
Surveillance is one of the tools of epidemiology,
the fundamental science of public health, and the
core tool for public health assurances in the phar-
maceutical sector. Paradoxically, the surveillance
activities in this sector are separated from those at
work in the rest of the public health landscape.
Most public health surveillance activities in the
U.S. are a function of state and local public health
agencies. Surveillance information about acute dis-
eases of epidemic potential is consolidated and
managed by each of the 50 states and forwarded to
the Centers for Disease Control and Prevention
(CDC) for aggregation and national reporting
through such vehicles as the Morbidity and
Mortality Weekly Report and, more recently, the
Health Alert Network.
By accident of historical evolution, surveillance
for drug safety, and more recently for medication
errors, has been handled in the parallel universe of
pharmaceutical manufacturers and the FDA. The
tools and their applications, however, are remark-
ably similar to those used in the rest of public
health. Each system designates events of interest. In
the case of the CDC, these are reportable suspected
cases of infection of epidemic potential, or more
recently, conditions of potential for chronic disease
epidemics. For the FDA, they are suspected cases of
drug-induced disease that could signal potential
problems for others taking the drug. Each surveil-
lance system: (1) attempts to learn as much about
each case as is feasible within the constraints of vol-
untary reporting; (2) seeks to discern aspects of the
case that might provide an indication of unusual or
unique circumstances (risk factors) to aid in under-
standing the extent of risk to others; and (3)
attempts to develop some estimate of the frequen-
cy and evolution of the cases to define the gravity
of a public health threat. Thus, a central require-
ment of both surveillance systems is the participa-
tion of well-trained, vigilant public health
professionals. These professionals ensure that case
reports are examined and analyzed, singly and in
aggregate, by the trained eyes of those who under-
stand the subtleties of epidemiologic signaling sys-
tems and can detect patterns and parallels from a
patchwork of data, gathered from disparate sources.
Individual Case and
Population-Based Analysis
The report rate is a key subtlety of the system. Rate
calculations require both a numerator (the report-
ed cases) and a denominator (the exposed popula-
tion). Calculating these elements within a
voluntary reporting framework is an intrinsically
uncertain process. Whenever surveillance data are
accumulated under such voluntary circumstances,
inevitably many variations exist in what is report-
ed. When, by whom, to whom, and how reports
are submitted become critical elements in surveil-
lance analysis. Put another way, the surveillance
numerator, based on voluntary reports, captures a
sub-subset of all such events—those that the physi-
cian or pharmacist is willing to take the time and
trouble to report from among the larger number of
events that come to the attention of a patient or
practitioner. Various environmental factors influ-
ence reporting and, consequently, may periodical-
ly and temporarily change the signaling capacities
of the system. A recent journal or newspaper report
can cause a cascade of interest and reports from the
field, and the passage of time is a well-known
cofactor of declining interest in reporting. The
emergence of drug information services within
industry compounds the challenge and impacts
the numerator as described above. Calculating the
denominator—the population exposed to a drug—
also is a challenge. Many drugs are “sold” from
company to distributor, but remain somewhere in
the supply pipeline not yet available to patients.
Much is prescribed but never dispensed; much is
dispensed but never taken. Therefore, efforts to
estimate the population exposed requires sophisti-
cation, and estimates must be used carefully and
with many caveats. Thus, the surveillance practi-
tioner must be trained carefully to understand and
recognize these factors when attempting to gener-
alize from individual reports to a concern about an
increased incidence of such reports over a popula-
tion-expected baseline. Consequently, the trained
professional in the drug-induced disease world
refers to “report rates,” and not “incidence” when
discussing these reports and their trends.
Proactive/Sentinel Surveillance
Because of the weaknesses in the existing SRS,
many have suggested a more aggressive effort at
monitoring populations using methods beyond
voluntary reporting; once again, turning to the
time-honored methods of public health epidemiol-
ogy. The field that specializes in epidemiologic
population-based research methods, coupled with
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CHAPTER 4 • Postmarketing Surveillance for Drug-Induced Diseases
public health approaches to spontaneous reports,
has been designated “Pharmacoepidemiology.”11,12
Intensive inpatient monitoring, the first such
scheme, was very productive in detecting increases
in the frequencies of otherwise expected diseases in
association with drug use, permitting statistical
associations to generate signals.13 However, such
systems have proven expensive and limited with
respect to the numbers of individuals exposed, par-
ticularly with new drugs, and have fallen into dis-
use, except as ad hoc studies focused on specific
new drugs, with an intense effort to discover the
number of exposures nationwide.
The Large Automated Multipurpose
Population-Based Systems
Contemporary health care operates within a con-
tinuing revolution in medical informatics, fueled
by the advent of large automated databases that
support computerized medical records and pre-
scribing, and wireless hand-held devices in ambu-
latory medical practice. As a result, many large
components of the health care delivery system
have available to them automated data describing
every drug prescribed, every subsequent major
diagnosis associated with a hospitalization (admis-
sion and discharge), and of course, longer-term
monitoring for late or latent outcomes. These data
sets have been called “large automated multipur-
pose population-based systems” (LAMPS). They
clearly light the path to drug-use monitoring at the
population level when examining increases in the
frequencies of major illnesses, which might, in
turn, signal possible drug-induced disease.
Certainly, the LAMPS already have amply demon-
strated their value as tools for use by the pharma-
coepidemiologist when conducting formal
observational studies to test signals from other sys-
tems, such as the SRS.
The LAMPS, however, have several critical limi-
tations as surveillance tools. The power of a signal
generator is tied directly to the size of the exposed
population. Thus, a database owned by a health
maintenance organization (HMO), even one reflect-
ing the medical transactions of millions of enrolled
individuals, may not encompass enough exposure
to any single drug, particularly a new drug in the
early phases of marketing, to detect any but the
most commonly associated drug-induced diseases.
This is true particularly in key population sub-
groups in which a possible increased risk of medica-
tion-induced illness may occur. Understanding the
potential of LAMPS to contribute to our under-
standing of drug-induced disease is important, as is
recognizing their limitations.
37
Society has the responsibility to monitor for
those drug-induced diseases that are sufficiently
severe to create an unacceptable burden on indi-
viduals, as well as those that are serious and fre-
quent enough to create a public health burden. For
the former, a system to detect the very rare but
unacceptably severe reaction is needed. For this,
the SRS, with all of its faults, is the only existing
tool that can be considered sufficient. But for the
latter, monitoring and quantitating both the
occurrence of excess medical adversity risk and
documenting excess morbidity, mortality, and cost
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-
sive development of programs of automated
population based “active surveillance.”10 In
response, Congress, in the Food and Drug
Administration Authorization Act (FDAAA) of
2007, has mandated the FDA to develop a sentinel
surveillance system based on such automated pop-
ulation-based data systems with the objective of
being able to monitor, prospectively, a population
of 25 million by 2010 and 100 million by 2012.
This mandate has, in turn, spawned major activity
across the breadth of the public health system,
with emerging LAMPs now recognized and har-
nessed for drug safety surveillance as well as
research. Major health plans, including United
Health Care, WellPoint (formerly Blue Cross/Blue
Shield), Aetna, and the collaborative HMO
Research Network, among others, have made the
data available to leading researchers for such explo-
rations. Academia, in its critical role in the public
health system, has organized centers of excellence,
notable among these under the Centers for
Education and Research on Therapeutics program,
to assist the FDA in this endeavor. Industry, as a
key partner in the system, has organized and fund-
ed (through the National Institutes of Health
Foundation) an independent effort at testing new
methods for cross-system data summary and analy-
sis for prospective (sentinel) development of sig-
nals of potential drug-induced diseases (the
Pharmaceutical Manufacturers’ Association
Observational Medical Outcomes Program). In
addition, the FDA has organized and initiated a
vigorous process for exploring the path to respond-
ing to the FDAAA mandate for sentinel surveil-
lance
The special situation of medication errors
demands a third monitoring method. But what
system exists to monitor, compile, analyze, and
develop proper interventions regarding these
errors? Part of the nation’s response has been
developing institution-based reporting and contin-
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38 SECTION I • Magnitude/Significance of Drug-Induced Diseases: Impact on the Health Care System
uous improvement systems. These are vital because
root causes can be locally identified and remedied
in institutional systems and practices. They are
inadequate, however, in detecting flaws in product
presentation or design, name confusion, look-alike
packaging, or confusing product information. For
these, integration into a more comprehensive
national detection system is also required.
Therefore, several key leadership organizations
have taken decisive action, notably the MEDMARX
system of the U.S. Pharmacopeia, which is a
national database for medication errors.
THE WAY FORWARD:
CAN YOU IMAGINE?
Protecting society against preventable drug-induced
diseases and device-associated injury, through early
detection of possible problems emerging from ther-
apies, is the primary objective of a public
health–oriented drug safety surveillance system.
Such protections require, at the population level, an
affordable, effective system of monitoring for seri-
ous adverse events that occur in the population in
excess of that which is expected in association with
disease and natural causes alone. To achieve this
objective, we must make progress on three fronts.
First, the reporter must be more attuned both to
monitoring for possible drug-induced illness and to
reporting it effectively. Second, the system must be
more efficient in retrieving and managing the
resulting data and more effective in harnessing data
to existing systems of surveillance. Third, new tech-
nologies, made available through the rapid dissem-
ination of automation into medical practice, must
be harnessed to the task effectively.
These goals, in turn, will require three ambitious
sets of activity. First, medical, pharmacy, and other
health professionals must do a better job of reaching
the practitioner with salient messages about drug-
induced diseases and with convincing efforts to har-
ness the time and energy of the busy practitioner.
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
the SRS has been suggested as a promising device.
But an even more promising strategy is to make the
act of reporting one that reaps rewards in terms of
useful information that makes a direct contribution
to patient care. Can you imagine a truly easy, user-
friendly, and useful system populated by truly pub-
lic health–oriented satisfied reporters?
Secondly, public health agencies, notably the
CDC and the FDA, working with state and local
public health–surveillance professionals, should
undertake a thorough and systematic examination
of existing methods of population-based surveil-
lance to better align systems and the incentives to
strengthen them. While the SRS may be the most
powerful generator of warnings of rare but unac-
ceptable toxicities, better-integrated and better-
aligned signal generators are needed for
drug-induced diseases that, while possibly less
severe, are occurring with greater frequency in the
population at large. Certainly these include pre-
ventable errors in the use of medications and their
avoidable consequences. Can you imagine a truly
seamless and integrated system of surveillance for
all problems of public health importance?
Finally, those working in the field of informa-
tion technology to support medical practice, par-
ticularly (but not limited to) those involved in
developing and promulgating the automated
medical record, personal digital assistant, and
other hand-held technologies, must work togeth-
er to build data systems that are compatible with
efficient and accurate conduct of the medical pur-
poses for which they are intended. Equally critical
is the development of data standards and refine-
ments needed to provide the public health sur-
veillance system (and, of course, the research
enterprise) with the data required to perform
these vital functions in a timely, effective, and
affordable way. Can you imagine a national sur-
veillance system that does not require any busy
therapy team members, including the patient, to
remember to report information and to recall
where to submit it, because the automated system
that supports their transactions can do this for
them? Can you imagine a system that minimizes
the administrative tasks and maximizes patient
well-being, perhaps even one which is capable of
“finding” problems before they become clinically
apparent and enabling us to prevent them from
becoming major public health problems? The
protection of the public health requires us to
imagine these things.
References
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8. Food and Drug Administration. Post marketing reporting
of adverse drug experience. Available from:
www.fda.gov/cder. Accessed March 3, 2009.
9. The Institute of Medicine. The Future of the Public’s Health
in the 21st Century. Washington, DC: The National
Academies Press; 2002.
10. The Institute of Medicine. The Future of Drug Safety:
Promoting and Protecting the Health of the Public.
Washington, DC: The National Academies Press; 2006.
11. Hartzman AG, Tilson HH, Chan KA, eds.
Pharmacoepidemiology and Therapeutic Risk Management.
Cincinnati, OH: Harvey Whitney Books; 2008.
12. Strom BS, Kimmel SE, eds. Textbook of
Pharmacoepidemiology. 4th ed. Hoboken, NJ: Wiley; 2007.
13. Boston Collaborative Drug Surveillance Program.
Available at: www.bu.edu/bcdsp. Accessed March 3, 2009.
TisdaleC05_40-48 1/12/10 2:28 PM Page 40
CHAPTER 5
Evaluating Patients for
Drug-Induced Diseases
A s discussed in Chapter 2, there are nearly 5000
unique drug entities available for human use
in the United States. A survey of an ambulatory
population revealed that 50% of adults regularly
used at least one prescription drug and 7% regular-
ly used five or more. Herbal products and other
natural supplements were taken by 14% of the
population, and 16% of regular prescription-drug
users also took an herbal product or natural supple-
ment.1 Since almost every drug a patient takes has
the potential to cause an adverse effect and an
associated drug-induced disease, the likelihood
that a health care practitioner will encounter
patients with one of these drug-related problems is
quite high.
Unfortunately, clinicians are often slow to
recognize adverse drug reactions and their associ-
ated drug-induced diseases. Sometimes they are
not recognized at all. Patients’ symptoms can eas-
ily be confused with those of commonly encoun-
tered and naturally occurring disease states.
Sometimes an adverse drug effect may be mistak-
en for an exacerbation of a patient’s preexisting
condition. Not all adverse drug effects or associat-
ed drug-induced diseases are well documented in
the literature or even known to the Food and
Drug Administration (FDA) at the time of
approval. Rare events may be identified only long
after a drug reaches the market and following its
use in thousands of patients. Despite these diffi-
culties, early detection and correction of drug
reactions and drug-induced diseases can help
reduce morbidity and mortality and is therefore
critically important.
Drug reactions can be divided into four gener-
al classes.2 Type A reactions are predictable, com-
40
Douglas A. Miller and James E. Tisdale
mon, and related to the pharmacologic action of
the drug. These may include reactions associated
with drug toxicity or overdose (e.g., acetamino-
phen-induced hepatic failure), side effects (e.g.,
sedation due to antihistamines), secondary effects
(e.g., diarrhea caused by oral antibiotics), or drug
interactions.
Type B reactions are unpredictable, uncom-
mon, and usually not related to the pharmacolog-
ic actions of the drug. These include allergic or
pseudoallergic reactions as well as reactions gener-
ally described as “idiosyncratic” (e.g., primaquine-
induced hemolytic anemia in a glucose-
6-phosphate dehydrogenase–deficient patient). An
idiosyncratic reaction is defined as an uncharacter-
istic, nonimmunologic response to a drug that is
not related to its pharmacologic actions.
Type C reactions are associated with long-term
drug therapy (e.g., analgesic nephropathy), and
Type D reactions are carcinogenic and teratogenic
effects. About 80% of adverse drug reactions are
classified as Type A.3 Type C and D reactions are
delayed in onset and are rare compared to Type A
and B reactions.
To help ensure that a drug-induced disease is
not overlooked in a patient or inappropriately
attributed to another cause, clinicians must have a
high “index of suspicion”—a notion, feeling, or
hunch that something might be the case—where
drug therapy is concerned. Whenever a patient
presents with a new symptom or a symptom that
has intensified or changed over time, the clinician
must at least entertain the notion that the occur-
rence might be drug-related. Every drug that a
patient is taking or has recently taken should be
considered and ruled out as a possible cause. This
TisdaleC05_40-48 1/12/10 2:28 PM Page 41
CHAPTER 5 • Evaluating Patients for Drug-Induced Diseases
is easier in some situations and with some drugs
and reaction types than others.
PATIENT EVALUATION
Perhaps the most important tool for evaluating a
possible drug-induced disease is the medication
history. Taking a careful history can yield many
clues that will help the clinician rule in or rule
out a drug-induced disease. Information that
should be collected as part of the medication his-
tory is listed in Table 5–1. Information may be
gathered from many sources, including the
patient, medication containers, a spouse or care-
giver, the patient’s medical records, or another
health care provider, such as the patient’s primary
care physician or pharmacist. The accuracy of the
medication history depends not only on the accu-
racy of the source data but also on the skill and
knowledge of the health care provider who col-
lects the information and puts it all together.
Asking the right questions in the right way can
elicit information regarding a patient’s medica-
tion use that otherwise might be overlooked.
Table 5–2 lists suggestions for obtaining an accu-
rate medication history. Information available to
a physician at the time of admission may be inac-
curate and could result in an incomplete or inac-
curate medication history.4,5 Because of more
extensive knowledge of various drugs and drug
products, greater focus on medication therapy
issues and access to more information sources,
pharmacists often are able to perform more com-
plete medication histories.6,7
Information regarding prescription drugs
(including any sample medications, inhalers,
creams, ointments, patches, medications adminis-
tered in a doctor’s office or clinic), over-the-count-
er (OTC; nonprescription) drugs, vitamins, herbals
(nutraceuticals, health supplements), and illicit
drugs should be collected. Smoking history and
alcohol use should also be documented. The name
of each medication, its strength, formulation
(tablet, capsule, liquid, extended-release), dose,
route, and frequency should be recorded. The
objective is to determine how a medication has
actually been used rather than how it was pre-
scribed. A precise history of when therapy with the
medication was started and stopped and when the
last dose was taken is critical to the investigation of
a possible drug-induced disease. In some cases, it is
important to know not only about current medica-
tions but also about medications that were taken in
the past and recently discontinued. Although some
patients are very good historians, it is not always
41
possible to rely solely on information the patient
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-
ful information.
It is also important to collect a careful history
of the suspected adverse drug event. What did the
patient notice, and when did it start? How did the
problem progress? Was there a temporal relation-
ship between the onset of symptoms and the
addition or discontinuation of any medications
and, if so, was the timing of the event similar to
that reported previously for a specific drug or
drugs for that disease? Has the patient experi-
enced similar reactions in the past? Can the
patient provide any insight into what he or she
suspects may be causing the problem? Did the
patient attempt to self-medicate to treat the prob-
lem? If so, what treatment was tried, and was it
effective? Do any treatments or activities seem to
make the problem better? Does anything seem to
make it worse?
A careful physical exam focusing on the organ
system(s) involved and the collection of laborato-
ry data can provide objective information that is
helpful in determining whether or not a drug-
induced disease is present. Depending on the reac-
tion type and organ system(s) involved,
evaluation of renal function (blood urea nitrogen,
serum creatinine, and estimated creatinine clear-
ance), hepatic function (alanine aminotransferase,
aspartate aminotransferase, alkaline phosphatase,
total and direct bilirubin, total protein, albumin,
international normalized ratio), blood counts,
and/or urinalysis may be helpful and necessary.
Special laboratory tests (e.g., antinuclear antibod-
ies, histamine metabolites, complement concen-
tration, patch tests) are available and helpful in
some situations. Noninvasive procedures (e.g.,
electrocardiography, computed tomography) and
even invasive procedures (e.g., kidney or lung
biopsy) may be required for some patients.
Specific elements of the physical exam and labora-
tory evaluation important in the differential diag-
nosis of drug-induced diseases are discussed in
Chapters 6 to 55.
The patient’s history and physical exam should
be carefully reviewed for the presence of risk fac-
tors known to be associated with the drug-induced
disease suspected. Race, sex, age, genetic and envi-
ronmental factors, concomitant drug therapy,
comorbidities, immune status, alcohol and tobacco
use, and a host of other factors may impact
patients’ relative risk for a drug-induced disease.
Specific risk factors for the various drug-induced
diseases are included in Chapters 6 to 55.
TisdaleC05_40-48 1/12/10 2:28 PM Page 42

42 SECTION I • Magnitude/Significance of Drug-Induced Diseases: Impact on the Health Care System

TABLE 5–1 Information That Should Be Included in the Medication History

• Patient information
• Age (date of birth)
• Sex
• Height
• Weight
• Race
• Prescription medications currently being taken or used by the patient
• Name of the medication
• Strength
• Formulation (tablet, capsule, extended-release, etc.)
• Dose
• Route
• Frequency
• Reason started
• When started
• Date and time of last dose
• Prescription medications taken or used in the past 6 months
• Name of the medication
• Strength
• Formulation (tablet, capsule, extended-release, etc.)
• Dose
• Route
• Frequency
• When started and stopped
• Reason discontinued
• Nonprescription (over-the-counter [OTC]) medications currently being taken or used by the patient (including
vitamins, herbal products, health supplements, energy enhancers or “nutraceuticals”)
• Name of the product
• Strength
• Formulation
• Dose
• Route
• Frequency
• Reason started
• When started
• Date and time of last dose
• Nonprescription (OTC) medications (including vitamins, herbal products, health supplements, energy enhancers
or “nutraceuticals”) taken or used in the past 6 months
• Name of the product
• Strength
• Formulation
• Dose
• Route
• Frequency
• When started and stopped
• Reason for discontinuing use
• Current and/or past use of tobacco
• Type (cigarettes, pipe, cigar, smokeless tobacco)
• Frequency (e.g., number of packs per day)
• Date started
• Last use
(Continued)
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CHAPTER 5 • Evaluating Patients for Drug-Induced Diseases 43

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

cohort studies, retrospective studies, case–control

DIFFERENTIAL DIAGNOSIS
Once subjective and objective information
regarding a suspected drug-induced disease has
been collected, the known adverse effect profile of
each drug to which the patient has been exposed
should be evaluated to determine whether there is
a likely culprit. Evidence of the ability to cause
drug-induced diseases is better for some drugs
than others, and, even when evidence is totally
lacking, it must be remembered that there was a
first report for every adverse drug effect recog-
nized today.
Authors of chapters in this text have catego-
rized the strength of evidence that a given drug
causes a specific drug-induced disease as Level A,
B or C. Level A indicates that there is evidence of
causation from one or more randomized, con-
trolled clinical trials. Level B indicates evidence
of causation derived from nonrandomized clini-
cal trials, prospective observational studies,
studies, meta-analyses, and/or postmarketing sur-
veillance studies. When there have been one or
more published case reports or case series impli-
cating a given drug as the causative agent of a
specific drug-induced disease, the evidence is cat-
egorized as Level C. Although they may not pro-
vide proof of causation, case reports are by far the
most common evidence available for most drug-
induced diseases and are very important to our
understanding of these adverse drug events.
Additional B-level evidence should become avail-
able as more structured approaches to postmar-
keting surveillance are implemented (see
Chapters 1 and 4).
Perhaps the most challenging aspect of evalu-
ating a particular patient with a suspected drug-
induced disease is assessing causation for the
observed signs or symptoms. In 1981, Naranjo et
al. described a method that could be used to esti-
mate the probability that a given event was drug-
induced.8 Although a number of other methods
TisdaleC05_40-48 1/12/10 2:28 PM Page 44
44 SECTION I • Magnitude/Significance of Drug-Induced Diseases: Impact on the Health Care System
TABLE 5–2 Suggestions for Improving the
Accuracy of the Medication History
• Carefully review the patient’s medical chart and/or
other available records before starting the interview
in order to be efficient when questioning and gather-
ing information.
• When possible, set up a special time to do the inter-
view in a private area. The interviewer should not
appear rushed and should maintain eye contact and
be polite, friendly, and nonjudgmental.
• Use primarily open-ended questions (e.g., “What do
you take for back pain?”) rather than closed-ended
questions (e.g., “Do you take anything for your back
pain?”) during the interview.
• Be nonjudgmental and make sure to not lead the
patient into saying what he/she thinks the interviewer
wants to hear. The objective is to find out how med-
ications are actually being used and not how the
patient was told to use them.
• Remember to ask patients about medications other
than those they take orally (e.g., “Do you use eye-
drops”). Patients often forget to mention creams,
ointments, patches, eye or ear drops, and inhalers.
• To help stimulate a patient’s memory, ask about medica-
tions they take for medical conditions they are known
to have (e.g., “What do you take for your glaucoma?”).
• Ask patients about medications prescribed by special-
ists they may see (e.g., “Do you see an allergist? What
medications does he/she prescribe for you?”).
• Ask patients whether his or her physician recently
started, stopped, or made any changes to the
medications that he or she is taking.
• Call the patient’s community pharmacist to deter-
mine an exact medication, dosage strength, direc-
tions for use, and adherence (refill history).
• For inquiring about nonprescription medications, addi-
tional prompts may include, “What do you take for ...”
• Headache
• Cold/flu
• Allergies
• Sinus
• Cough
• Sleeplessness
• Drowsiness
• Weight loss /gain
• Heartburn
• Stomach upset
• Gas
• Constipation
• Diarrhea
• Muscle or joint pain
• Skin problems
have been described since, the “Naranjo Scale”
(Table 5–3) has proved useful for assessing causa-
tion of adverse drug events and continues to be
used today for that purpose.9-13
There are obvious limitations to the use of the
scale. In order to accumulate points for each ques-
tion, the dose of the suspected drug would have to
be increased or decreased to see whether the reac-
tion worsened or improved, the drug would have
to be discontinued to see whether the reaction sub-
sided and then readministered to see whether the
reaction reappeared, and the patient would have to
receive a placebo to see whether it precipitated a
similar reaction. These maneuvers are not always
practical or possible in clinical practice, and clini-
cians are therefore often left with a Naranjo Scale
probability rating that is less than definitive.
Nevertheless, the widespread use of the Naranjo
Scale, particularly by journals assessing case reports
submitted for publication, suggests that it provides
a structured basis for assessment in a standardized
and relatively reproducible format.
When it is possible, probable, or highly proba-
ble that a medication is causing a disease, the cli-
nician must decide whether to continue therapy
with that medication or modify the patient’s ther-
apeutic regimen. As with all decisions regarding
drug therapy, the relative risks and benefits of
each course of action must be carefully consid-
ered. The substitution of an agent less likely to
cause the disease may be an option in some cases.
When an adverse drug event is known to be relat-
ed to dose or serum concentration, reducing the
dose of the offending agent or changing the fre-
quency of administration or dosing schedule may
be viable options. Although it is generally not a
good idea to treat an adverse effect of one drug
with a second drug, there are times when this
approach is acceptable (e.g., chemotherapy-
induced nausea and vomiting). Desensitization is
sometimes an option for patients with drug-
induced diseases that are immunologically medi-
ated.
Situations in which there is more than one pos-
sible culprit drug can create an even greater chal-
lenge for clinicians. In some cases it may be
necessary to discontinue all of the possible offend-
ing agents and then reinitiate therapy with one
drug at a time following resolution of the drug-
induced disease. In other cases, the Naranjo Scale
probability rating for each of the possible culprits
or the associated level of evidence (e.g., 2 case
reports vs. 20 case reports vs. evidence of causation
from one or more randomized, controlled clinical
trials) might provide useful clues as to which agent
is the most likely offender.
TisdaleC05_40-48 1/12/10 2:28 PM Page 45

CHAPTER 5 • Evaluating Patients for Drug-Induced Diseases 45

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.

used only with caution. When patients are warned

DOCUMENTING AND REPORTING
DRUG-INDUCED DISEASES
Patient Education
Patient education and good documentation are
critical to the prevention of a recurrent adverse
drug event or drug-induced disease in a given
patient. The patient needs to know the nature of
the reaction that occurred, the generic name and
trade names of the causative agent, the generic
name and trade names of other medications that
might be expected to cause similar reactions, and
whether these agents must be avoided entirely or
about potential adverse effects of an entire class of
drugs (e.g., angiotensin-converting–enzyme
inhibitors, sulfa-containing compounds, benzodi-
azepines), they should be given the generic name
and trade names of drugs included in that class. All
of this information should be put in writing, and
the patient should receive a copy to keep with
important medical records at home as well as
copies to give to each of their other health care
providers (e.g., physicians, dentists, nurse clini-
cians, pharmacists). A description of the adverse
event should be included in the patient’s medical
record and, when hospitalization has occurred, in
the discharge summary and in any follow-up corre-
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46 SECTION I • Magnitude/Significance of Drug-Induced Diseases: Impact on the Health Care System
spondence with admitting or referring physicians.
Depending on the severity and acuity of the reac-
tion, patients should be advised to obtain and wear
a medical alert bracelet.
Reporting Drug-Induced Diseases
Proper reporting can also be important in efforts to
help prevent drug-induced diseases in others who
will be exposed to the drug in the future. Some
adverse drug effects and their associated drug-
induced diseases have been well documented and
are well known to health care providers. Because
they are well known, these adverse events can
sometimes be prevented with careful drug use
and/or patient monitoring. Unfortunately, some
adverse drug effects and drug-induced diseases
have not yet been recognized or characterized.
These are unexpected and therefore not yet pre-
ventable. Identifying and characterizing these
events, and therefore increasing the likelihood that
they can be prevented in the future, is the focus of
the voluntary “MedWatch” program operated by
the FDA.14
MedWatch was established by the FDA in 1993
as a method to stimulate voluntary reporting of
serious adverse events by health care professionals
and patients. The system collects spontaneous
reports of adverse events involving drugs (prescrip-
tion and OTC), biologics, devices, and special
nutritional products, including dietary supple-
ments, medical foods, and infant formulas.
Adverse reactions associated with vaccines are
reported to FDA through the Vaccine Adverse
Event Reporting System (VAERS), rather than
through MedWatch. A spontaneous report is an
observation of an adverse event that is made dur-
ing direct patient care and subsequently reported
either directly to the FDA or indirectly to the FDA
through the drug’s manufacturer. Observations
made during clinical trials are not included as part
of this spontaneous reporting system. The
MedWatch system is also used to collect informa-
tion regarding product quality problems, reports of
suspected counterfeit products, and reports of
medication- and device-use errors that may have
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-
ous adverse events. For the purpose of this report-
ing system, an “adverse event” is defined as any
unfavorable and unintended sign, symptom, or
disease temporally associated with the use of a
medicinal product, whether or not it is considered
to be related to the product. The FDA defines “seri-
ous adverse events” as those that are fatal, life-
threatening, permanently or significantly dis-
abling, require or prolong hospitalization, cause a
congenital anomaly, or require intervention to pre-
vent permanent impairment or damage.
Notwithstanding these definitions, the FDA
encourages health professionals to report any
adverse event judged to be clinically significant.
The adverse event does not have to be previously
unreported or uncommon. Suspicion that a med-
ical product may be related to a serious event is suf-
ficient reason to submit a report, and proof of
causality is not necessary.
Reports can be filed online (www.fda.gov/med-
watch), via a toll-free phone line (1-800-FDA-
1088), by fax (1-800-FDA-0178), or by prepaid
mail. The core elements of the report include the
reporter’s name, the suspect drug or device, a nar-
rative report of the adverse event or problem, and
patient information (identifier, sex, age, weight).
The FDA holds patient identity information in
strict confidence. Reporting does not violate provi-
sions of the Health Insurance Portability and
Accountability Act (HIPAA), which specifically per-
mits covered entities (such as pharmacists, physi-
cians, or hospitals) to report adverse events and
other information related to the quality, effective-
ness, and safety of FDA-regulated products both to
the manufacturers and directly to the FDA.
Once received by the FDA, reports of adverse
events are entered into a postmarketing surveillance
database that can be examined for similar reports
and used to develop case series. When a report or a
series of reports define a previously unrecognized
safety issue, the FDA can order a formal epidemio-
logic evaluation, require labeling changes (including
boxed warnings), place restrictions on prescribing or
dispensing of the drug, or if necessary, order that the
product be withdrawn from the market.
Heath care providers can obtain information
generated through the FDA MedWatch program by
accessing their Web site at www.fda.gov/med-
watch. Information is also disseminated via e-mail
to those who subscribe online and through a large
number of professional organizations that partner
with FDA for that purpose.
CONCLUSION
Morbidity and mortality associated with drug-
induced diseases continue to be a major concern for
all health care practitioners and add significantly to
health care costs. Although some drug-induced dis-
eases are identified during clinical trials and the
TisdaleC05_40-48 1/12/10 2:28 PM Page 47
CHAPTER 5 • Evaluating Patients for Drug-Induced Diseases
drug-approval process, others are not recognized
until long after the drug is marketed and available
for routine use. Although all drugs have the poten-
tial to cause drug-induced diseases, it is easy to over-
look a drug as a possible cause of a patient’s illness.
All health care providers would be well advised
to always ask themselves, “Could this be drug-relat-
ed?” whenever confronted with a patient experi-
encing new or worsening symptoms.
References
1. Kaufman DW, Kelly JP, Rosenberg L, et al. Recent
patterns of medication use in the ambulatory adult
population of the United States: the Slone Survey. JAMA.
2002;287:337-344.
2. Rawlins M, Thompson W. Mechanisms of adverse drug
reactions. In: Davies D, ed. Textbook of Adverse Drug
Reactions. New York: Oxford University Press; 1991:18-45.
3. deShazo R, Kemp S. Allergic reactions to drugs and
biologic agents. JAMA. 1997;278:1895-1906.
4. Gonski PN, Stahters GM, Freiman JS, et al. A critical review
of admission and discharge medications in an elderly
Australian population. Drugs Aging. 1993;3:358-362.
5. Tam VC, Knowles SR, Cornish PL, et al. Frequency, type
and clinical importance of medication history errors at
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admission to hospital: a systematic review. CMAJ.
2005;173:510-515.
6. Walchle RD, McKercher PL, Cooper JW. Physician-,
nurse-, and pharmacist-conducted patient drug histories.
Contemp Pharm Pract. 1980;3:75-78.
7. Reeder TA, Mutnick A. Pharmacist- versus physician-
obtained medication histories. Am J Health-Syst Pharm.
2008;65:857-860.
8. 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.
9. Kramer MS, Leventhal JM, Hutchinson TA, et al. An
algorithm for the operational assessment of adverse drug
reactions. I. Background, description, and instructions
for use. JAMA. 1979;242:623-632.
10. Karch FE, Lasagna L. Toward the operational
identification of adverse drug reactions. Clin Pharmacol
Ther. 1977;21:247-254.
11. Koh Y, Li SC. A new algorithm to identify the causality
of adverse drug reactions. Drug Saf. 2005;28:1159-1161.
12. Berry LL, Segal R, Sherrin TP, et al. Sensitivity and
specificity of three methods of detecting adverse drug
reactions. Am J Hosp Pharm. 1988;45:1534-1539.
13. Michel DJ, Knodel LC. Comparison of three algorithms
used to evaluate adverse drug reactions. Am J Hosp
Pharm. 1986;43:1709-1714.
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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 6 Allergy, Pseudoallergy and Cutaneous Diseases

CHAPTER 7 Systemic Lupus Erythematosis-like Syndrome

CHAPTER 8 Photosensitivity

CHAPTER 9 Alopecia, Hirsutism and Hypertrichosis

TisdaleC06_49-97 1/20/10 10:54 PM Page 50
TisdaleC06_49-97 1/20/10 10:54 PM Page 51
CHAPTER 6
Drug Allergy, Pseudoallergy,
and Cutaneous Diseases
T he terms drug allergy and drug hypersensitivity are
often used synonymously to describe adverse
drug reactions mediated by the immune system.
Drug hypersensitivity is more descriptive because
this adverse drug reaction results from an overre-
sponse or “hyperresponse” of the immune system,
leading to host tissue damage. During a hypersen-
sitivity reaction, the drug or its reactive metabolite
serves as the antigen, which is subsequently
recognized and processed by the immune system,
culminating in the production of drug-specific
antibodies or sensitized T lymphocytes. The anti-
gen–antibody reaction can target a variety of cells
and body tissues, leading to organ-specific or more
generalized systemic adverse events. The hallmark
characteristics of a drug hypersensitivity reaction
are1-3: (1) an onset usually ranging from 5 to 21
days after initial exposure to the drug (indicative of
a sensitization period), (2) an association with the
usual or standard dose of a drug, (3) the presence of
histamine-related or other immune-mediated signs
and symptoms, often including eosinophilia, (4)
reversibility of symptoms after discontinuation of
the causative drug, and (5) a faster appearance of
the reaction (within hours to days) after reintro-
duction of the implicated drug.
The term drug pseudoallergy describes allergic-
like reactions. These events are not associated with
the production of antibodies or sensitized T lym-
phocytes but are otherwise clinically indistinguish-
able from hypersensitivity reactions.4,5 During a
pseudoallergic reaction, the drug does not serve as
an antigen; rather, the drug has the ability via its
chemistry or pharmacology to directly stimulate
the release or activation of inflammatory media-
tors from mast cells, basophils, or other body tis-
sues. Pseudoallergic reactions vary in presentation
Lynne M. Sylvia
from localized skin rashes and skin flushing to
more severe events, including bronchospasm,
angioedema, and hypotension.4 Synonyms include
drug intolerance and anaphylactoid reaction.4,5 The
latter term refers only to pseudoallergic reactions
that mimic anaphylaxis (e.g., bronchospasm,
angioedema, urticaria, hypotension) but which are
non-IgE-mediated. A comparison of the features of
hypersensitivity and pseudoallergic reactions is
provided in Table 6–1.
Cutaneous eruptions, the most common man-
ifestation of drug-induced disease, can result from
both immune- and non-immune-mediated mecha-
nisms (e.g., pharmacologic effects, idiosyncrasy).
Therefore, drug-induced skin eruptions and sys-
temic skin diseases are discussed in a separate sec-
tion of this chapter. Allergic-mediated urticaria,
angioedema, and the immune complex diseases
associated with dermatologic manifestations
(serum sickness–like syndrome, vasculitis) will be
discussed in this section.
DRUG ALLERGY AND
PSEUDOALLERGY
CAUSATIVE AGENTS
A list of the drugs most frequently implicated in
causing hypersensitivity reactions is provided in
Table 6–2.1,3,6-123 If a particular drug of concern is
not included in this table, it should not be assumed
that the drug is incapable of eliciting an immune
response. Many drugs are not identified as anti-
genic until well after approval and use in an
extended patient population. To determine a drug’s
potential to serve as an antigen, three drug-related
51
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52 SECTION II • Drug-Induced Dermatologic Diseases
TABLE 6–1 Differentiating Features of Hypersensitivity versus Pseudoallergic Reactions1-5
Characteristic Hypersensitivity
Clinical presentation Highly variable; ranging from a localized
erythematous rash to life-threatening
reactions including anaphylaxis, Stevens–
Johnson syndrome and toxic epidermal
necrolysis
Sensitization period Required; usually ranging from 5 to 21
days after drug initiation
Antibody involvement Yes; IgE, IgG, IgM or sensitized T lymphocytes
Mechanism Drug can serve as a complete antigen or
drug or its reactive metabolite can
serve as a hapten
Risk factors Highly variable; dependent on drug
or patient (host)
Pretreatment Not routinely recommended; yield of
antibody produced by any given antigenic
drug too unpredictable to fully
antagonize via pretreatment
Treatment Dependent on signs and symptoms
of reaction; includes antihistamines,
epinephrine, and corticosteroids
properties should be considered. First, the molecu-
lar weight of a drug can influence its antigenicity.
Drugs of molecular weight >4,000 Da such as
erythropoietin, insulin, or other polypeptide
hormones, are more capable of serving as com-
plete antigens than are low-molecular-
weight drugs (<1,000 Da).124 Biologic agents (e.g.,
antisera, antithymocyte globulin, intravenous
immunoglobulin) also fit in this category of large
polypeptides. Second, drugs containing foreign
proteins or large polypeptides of nonhuman origin
(e.g., streptokinase, beef or pork insulin,
chimeric/murine-derived monoclonal antibodies,
L-asparaginase) have the ability to serve as com-
plete antigens.2,124 The most common antigenic
drugs (e.g., penicillins, sulfonamides) are of low
molecular weight (<1,000 Da) and do not contain
a foreign protein. These agents possess a third
drug-related property related to conferring anti-
genic potential, which is the ability of the parent
drug or its reactive metabolite to bind covalently to
a carrier protein in vivo, thereby forming a com-
plete antigen. The term hapten is used to describe a
drug (or a metabolite) that must bind to a tissue or
cell protein in order to serve as a complete anti-
Pseudoallergy
Highly variable; ranging from infusion-
related reactions such as skin flushing to
severe reactions mimicking anaphylaxis
(i.e., anaphylactoid reactions)
Not required; reaction can occur within seconds
to minutes after administration of first dose
No
Based on its chemical or pharmacologic
properties, drug stimulates release of
or activates inflammatory mediators
Highly variable; dependent on drug
or patient (host)
Pretreatment regimens have been well-
studied and recommended for some
drugs; may be recommended to block
pharmacologic effects of drug on
effector pathways
Dependent on signs and symptoms
of reaction; may include dose
reduction, alteration in rate of
infusion, or treatment with antihistamines,
epinephrine, or corticosteroids
gen.125 Identifying a drug’s reactive metabolites
and the potential of these metabolites to bind to
carrier proteins is not readily achieved in premar-
keting studies126; thus, the allergic potential of
many low-molecular-weight drugs is not deter-
mined until the postmarketing phase of study.
Drugs that are commonly associated with
pseudoallergic reactions are listed in Table 6–3.127-
146
A drug’s ability to cause a pseudoallergic reac-
tion can often be determined by a review of the
drug’s chemical and/or pharmacologic properties.
Classic examples of pseudoallergy are anaphylac-
toid reactions to radiocontrast media, opiate-
induced urticaria or generalized pruritus, and
“red–man” syndrome with vancomycin.4,5
When reviewing Tables 6–2 and 6–3, it should
be noted that some drugs are listed as causing both
hypersensitivity and pseudoallergic reactions. For
example, vancomycin-induced red man syndrome
is thought to be due to a pseudoallergic reaction,
whereas vancomycin-associated blood dyscrasias
and anaphylaxis are attributed to more rare hyper-
sensitivity reactions.53,110,111 Captopril,127,147
30,133-135
ciprofloxacin, and protamine2,3 have also
been reported to cause both true hypersensitivity
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CHAPTER 6 • Drug Allergy, Pseudoallergy, and Cutaneous Diseases 53

TABLE 6–2 Agents Implicated in Drug-Induced Hypersensitivity Reactions

Drug Incidence Level of Evidence
(see page xii for explanation)

ANAPHYLAXIS, URTICARIA, ANGIOEDEMA, AND BRONCHOSPASM

Amphotericin B6,7 NK C
Aprotinin8 NK C
L-Asparaginase9 NK C
Aspartame10,11 NK C
Aspirin3,12 NK C
Atracurium13-15 NK C
Azathioprine16,17 NK C
Basiliximab18 NK C
Carboplatin9 NK C
Carboxymethylcellulose19 NK C
Ceftriaxone20 NK C
Cephalosporins22,23 0.001–0.1% C
Cetirizine21 NK C
24
Cetuximab NK C
Chymopapain25 NK C
Cisplatin9 NK C
Clavulanic acid 26 NK C
Deferoxamine27 NK C
Etoposide9 NK C
Excipients10,11,19,28,29 NK C
Fluoroquinolones30 NK C
Gentamicin31 NK C
Ibuprofen12 NK C
Insulin3 NK C
Iron dextran32 NK C
Isoniazid33,34 NK C
Lepirudin35 NK C
Leuprorelin36 NK C
Mivacurium15 NK C
Omalizumab37 0.2%a C
Paclitaxel38 NK C
Pantoprazole39 NK C
Penicillins3,40,41 0.01–0.05% B
Phytonadione42 NK C
Polysorbate 8029 NK C
Povidone–iodine43,44 NK C
Risperidone45 NK C
Rocuronium46 NK C
Sodium benzoate47 NK C
(Continued)
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54 SECTION II • Drug-Induced Dermatologic Diseases

TABLE 6–2 Agents Implicated in Drug-Induced Hypersensitivity Reactions (Continued)

Drug Incidence Level of Evidence

ANAPHYLAXIS, URTICARIA, ANGIOEDEMA, AND BRONCHOSPASM (Continued)
Streptokinase48 NK C
Sumatriptan49 NK C
50
Suxamethonium NK C
9
Teniposide NK C
13
Thiopental NK C
Tobramycin51 NK C
52
Triamcinolone NK C
53
Vancomycin NK C
54
Zidovudine NK C
SERUM SICKNESS–LIKE REACTION
Bupropion55-58 NK C
Cefaclor59-61 NK B
Ciprofloxacin62 NK C
63
Fluoxetine NK C
Itraconazole64 NK C
Meropenem65 NK C
Minocycline66-68 NK C
Penicillins37,38 NK C
Protamine1,3 NK C
Rituximab69 NK C
Streptokinase3,70,71 NK C
Sulfites11 NK C
Sulfonamides55 NK C
Vaccines3 NK C
VASCULITIS
Allopurinol72-74 NK C
Beta-lactam antibiotics72-74 NK C
Celecoxib75 NK C
Cephalosporins72-74 NK C
Colony-stimulating factors73 NK C
Docetaxel76 NK C
Etanercept73 NK C
Fluticasone77 NK C
Fluoroquinolones73 NK C
Hydralazine73 NK C
Infliximab78 NK C
Interferon-2b79 NK C
Isotretinoin73 NK C
Leukotriene antagonists80 NK C
(Continued)
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CHAPTER 6 • Drug Allergy, Pseudoallergy, and Cutaneous Diseases 55

TABLE 6–2 Agents Implicated in Drug-Induced Hypersensitivity Reactions (Continued)

Drug Incidence Level of Evidence

VASCULITIS (Continued)
Methimazole73 NK C
Methotrexate73 NK C
Minocycline73 NK C
Nonsteroidal antiinflammatory drugs73 NK C
Penicillamine73 NK C
Phenytoin73 NK C
Propylthiouracil81,82 NK C
Rofecoxib83 NK C
Vancomycin73 NK C
HYPERSENSITIVITY SYNDROMES
Abacavir84,85 NK B
Allopurinol86-88 NK C
Carbamazepine89,90 NK B
Dapsone NK C
Lamotrigine91 NK C
Levofloxacin NK C
Minocycline NK C
Nevirapine92 NK C
Oxcarbazepine NK C
Paclitaxel9 NK C
Phenytoin89,90 NK C
Phenobarbital89,90 NK C
Trimethoprim–sulfamethoxazole NK C
Terbinafine NK C
Valproic acid93 NK C
ALLERGIC-MEDIATED BLOOD DISORDERS
Cephalosporins94-96 NK C
Heparin97,98 1–5% B
Histamine H2-receptor blockers99-102 NK C
Methimazole103,104 NK B
Methyldopa95 NK C
Penicillins95,96 NK C
Piperacillin105,106 NK B
Procainamide99 NK C
Propylthiouracil98,99 NK B
Quinidine95,96 NK C
Quinine95,96,107 NK C
Trimethoprim–sulfamethoxazole108 NK C
(Continued)
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56 SECTION II • Drug-Induced Dermatologic Diseases
TABLE 6–2 Agents Implicated in Drug-Induced Hypersensitivity Reactions
Drug
ALLERGIC-MEDIATED BLOOD DISORDERS (Continued)
Valproic acid109
Vancomycin110,111
OTHER
Cimetidine112
Clindamycin113
Corticosteroids114,115
Diazepam116
Hetastarch117
Insulin118,119
Lidocaine120
Progesterone121
Psyllium122
Vaccines3,123
NK=Not known
and anaphylactoid reactions. Intravenous adminis-
tration of immunoglobulin G (IVIG) is most com-
monly associated with infusion-related reactions
such as fever and arthralgias. However, IVIG can
also cause an IgE-mediated reaction in patients
with selective IgA deficiency.2 In situations in
which a drug can cause both types of reactions, it
is often difficult to distinguish between true hyper-
sensitivity and the more predictable pseudoallergic
response. The features listed in Table 6–1 can be
helpful in differentiating these events. Most impor-
tantly, the signs, symptoms, and severity of the
reaction, rather than its mechanism, should drive
clinicians’ decision making.
EPIDEMIOLOGY
The combination of drug hypersensitivity, intoler-
ance, and pseudoallergic reactions has been esti-
mated to comprise 25% of all adverse drug events.1
Hypersensitivity reactions are considered to be
rare, representing 6% to 10% of all adverse drug
reactions.1,126,148 In 2002, Hunziker et al.149 provid-
ed an analysis of 12,785 adverse drug reactions of
probable or definite association occurring in inpa-
tients between 1974 and 1993. Drug allergy or
pseudoallergy accounted for 13% of the adverse
drug reactions. Differentiation between allergy and
pseu- doallergy as the cause of the adverse event
could not be achieved because of the lack of valid
(Continued)
Incidence Level of Evidence
NK C
NK C
NK C
NK C
NK C
NK C
NK C
NK C
NK C
NK C
NK C
NK C
skin testing or other in vitro testing methods to
determine the presence of drug-specific antibod-
ies.149
The epidemiology of anaphylaxis, including
drug-induced anaphylaxis, has been reevaluated by
a working group composed of experts in allergy
and immunology.150 The expert panel estimated
the frequency of anaphylaxis at 50 to 2,000
episodes per 100,000 persons, or a lifetime preva-
lence of 0.05% to 2%.150 Neugut et al.151 reported
that the most serious cases of drug-induced ana-
phylaxis have been associated with the use of peni-
cillin and radiocontrast media. Penicillin is
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.)
annually.1 Nonfatal anaphylaxis attributed to peni-
cillin has been reported in 0.7% to 10% of the gen-
eral population, whereas fatal cases have occurred
in 0.002% of the general population.151 Non-IgE-
mediated anaphylaxis (i.e., anaphylactoid reac-
tions) associated with radiocontrast media have
occurred in 0.22% to 1% of patients, particularly in
those receiving an agent with high osmolarity.151
Angioedema is estimated to occur in only 0.1%
to 1.2% of patients treated with angiotensin-con-
verting–enzyme (ACE) inhibitors. However, 25% to
38% of cases of angioedema seen in the emergency
department (ED) have been attributed to ACE
inhibitor therapy.152,153 In an 8-year retrospective
study, 12 of 49 patients (24.5%) presenting to the
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CHAPTER 6 • Drug Allergy, Pseudoallergy, and Cutaneous Diseases 57

TABLE 6–3 Agents Implicated in Pseudoallergic Reactions

Drug Incidence Level of Evidence
(see page xii for explanation)

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-
py with an ACE inhibitor.152 A second retrospective
case–control study revealed an association between
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-
ma were 5 times more likely to be taking an ACE
inhibitor (odds ratio [OR], 5.1; 95% confidence
interval [CI], 2.03–12.89).153
The incidences of hypersensitivity and
pseudoallergic reactions associated with the
majority of implicated drugs are unknown. The
estimated incidences of hypersensitivity and
pseudoallergic reactions associated with some
implicated drugs are presented in Tables 6–2 and
6–3.
MECHANISMS
Hypersensitivity Reactions
The exact mechanisms by which drugs serve as
allergens and elicit immune responses are not
completely understood. Gaps in our understand-
ing of these mechanisms can be attributed, in part,
to the lack of a validated animal model of drug
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58 SECTION II • Drug-Induced Dermatologic Diseases
hypersensitivity.126,154 Another influencing factor
is the difficulty in identifying and isolating the
antigenic components and metabolites of poten-
tial drug allergens. Although much is unknown
about the mechanisms by which drugs cause
hypersensitivity reactions, it is known that a sin-
gle drug, such as penicillin, can cause a variety of
hypersensitivity reactions via different mecha-
nisms.154 On the basis of current evidence and
existing models of hapten-mediated allergy, a
number of complex stages appear to be involved
in the generation of an immune response to a
drug. These stages are:
1. Formation of a complete antigen;
2. Processing of the complete antigen by
antigen-presenting cells;
3. Recognition of the antigenic determinant
by the T lymphocytes;
4. Generation of a drug-specific antibody or
sensitized T cells;
5. Elicitation of a clinical immune response.
Stage 1: Formation of a Complete Antigen
Most drugs that serve as allergens are low-molecu-
lar-weight compounds (<1,000 Da) and are too
small to initiate an immune response alone. To be
recognized by the immune system, these drugs
must bind, usually covalently, to a high-molecular-
weight carrier protein, thereby forming a complete
antigen. The extent to which a drug binds to plas-
ma proteins is not relevant in this situation; the
reversible binding between a drug and albumin
does not result in a bond strong enough to allow
for the formation of a complete antigen.125 The
hapten hypothesis, first described in 1966, offers
an understanding of this stage of immune process-
ing.125 The parent drug rarely has the ability to
bind to tissue or cellular proteins and serve as a
hapten. For most low-molecular-weight drug aller-
gens, the hapten is a reactive metabolite of the par-
ent drug, formed via metabolism in the liver, skin
keratinocytes, or white cells.154-156 As an example,
sulfamethoxazole is well recognized as a highly
allergenic compound, but a reactive metabolite,
the nitroso-sulfamethoxazole derivative, not the
parent compound, serves as the primary hap-
ten.157,158
Stage 2: Processing of the Complete Antigen by
Antigen-Presenting Cells
Once a hapten–protein conjugate has been formed,
it must undergo antigen processing. This crucial
stage involves recognition of the complete antigen
by antigen-presenting cells (APCs). A number of
cells serve as APCs, including macrophages, den-
dritic cells, cutaneous Langerhans’ cells, and B lym-
phocytes.154,155 With many drug allergens, the
complete antigen is believed to diffuse across the
cell membrane of the APC and be internalized into
the lysosomes of the APC.155 Metabolism by prote-
olytic enzymes in the lysosomes allows for break-
down of the complete antigen to a smaller,
hapten–peptide fragment.126 The last step in this
stage of processing is the binding of the
hapten–peptide fragment with major histocompat-
ibility complex (MHC) class I or II molecules that
have been synthesized by the APC.126,154-156
Expression of the hapten–MHC complex on the
surface of the APC allows recognition by T lym-
phocytes and further progression of the immune-
mediated reaction.
Stage 3: Recognition of the Antigenic
Determinant by the T Lymphocytes
A number of theories exist describing the manner
in which T-helper cells recognize the hapten–MHC
complex. In particular, it is theorized that three
signals must occur in order for T-helper cells to
become activated.154,156,159,160 The first signal is
completed by the interaction of the hapten–MHC
complex with an antigen receptor on the surface
of the T-helper cell. The second signal is believed
to involve an interaction between specific recep-
tors on the APC and the T-helper cell, resulting in
the release of cytokines (cell messengers), such as
interleukin (IL)-1 or IL-6. If this second signal does
not occur, it is believed that the T-helper cells lose
their responsiveness to the antigen and the
immune reaction ceases to progress.154,155,160 Thus,
some patients may process a drug allergen but the
immune reaction may be blunted at this stage or
at other stages in the process. The third signal
involves activation of the CD4+ T lymphocytes
with the release of specific cytokines from these
activated T lymphocytes. Depending on the
cytokines released, the T lymphocytes differenti-
ate into either T-helper type 1 (Th1) or T-helper
type 2 (Th2) cells.155,159 Differentiation of the T-
helper lymphocyte is an important step in the
determination of the type of immune reaction to
a specific drug allergen. Genetic factors are
believed to influence T-helper–cell phenotyping in
addition to influencing the type of cytokines
released from activated T-helper cells. Dominance
of cytokines IL-4 and IL-13 lead to the production
of Th2 cells, whereas secretion of IL-2 and interfer-
on-␤ favors the production of Th1 cells.155,161
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CHAPTER 6 • Drug Allergy, Pseudoallergy, and Cutaneous Diseases
Stage 4: Generation of a Drug-Specific
Antibody or Sensitized T Cells
Immune responses to a drug can lead to the gener-
ation of an antibody (humoral immune response)
or sensitized T cells (cellular or delayed immune
response). If a patient’s response to an allergen is
mediated by Th2 cells, a humoral response will
occur with IgE, IgG, or IgM as the responding anti-
body. Th2 cells have the ability to secrete a number
of cytokines, primarily IL-4 and IL-13, which stim-
ulate the production of IgE from plasma cells. Th2
cells also secrete IL-5, which activates eosinophils,
and IL-3 and IL-10, which are involved in mast-cell
differentiation.155,161 Patients who have a Th1-
dominant response to a drug are more likely to
generate a cellular immune response with the pro-
duction of drug-specific sensitized T lymphocytes
(CD4+, CD8+, or both).1 At this stage of the
immune process, memory cells (either T or B lym-
phocytes) are also produced to retain memory for
the drug allergen. Memory cells allow for the faster
onset of an immune reaction upon reexposure to
the antigen.
Stage 5: Elicitation of a
Clinical Immune Response
Completion of stages 1 through 4 may not occur
until days 5 to 21 of continued drug therapy. This
period of sensitization explains the latency in the
clinical presentation of the immune reaction. It is
also important to consider that some patients
may generate an antibody response to a drug
allergen, but the event will not progress to the
elicitation of a clinical reaction. For example,
approximately 40% of patients treated with peni-
cillin for at least 10 days will produce drug-specif-
ic IgG without manifesting a hypersensitivity
response.3
If a clinical immune response occurs, its pres-
entation will differ depending on the responding
antibody. Since 1968, the Gell and Coombs162
classification has been used to differentiate drug
hypersensitivity reactions based on their mecha-
nism and clinical presentation. On the basis of
this classification system, hypersensitivity reac-
tions are described as types 1 through 4. It is
important to consider that not all drug hypersen-
sitivity reactions can be described using this clas-
sification method.158 For example, some drug
hypersensitivity reactions exhibit features of
more than one type (e.g., drug rash with
eosinophilia and systemic symptoms [DRESS]). In
addition, some allergic reactions are mediated by
antibodies not included in the classification (e.g.,
59
autoantibodies associated with procainamide-
induced syndrome resembling systemic lupus ery-
thematosus). Allergic syndromes not addressed by
this classification include lupus-like reactions,
granulomatous vasculitis, Churg–Strauss syn-
drome, some mucocutaneous diseases, and
DRESS. Although limited in its application, the
Gell and Coombs classification is useful in com-
paring and contrasting the mechanisms, timing,
and the targeted cells of destruction of at least
65% of drug hypersensitivity reactions. A descrip-
tion of the Gell and Coombs classification is pro-
vided in Table 6–4.
If a patient generates IgE as the responding
antibody to a drug allergen, the event is classified
by Gell and Coombs as a type I, or immediate
hypersensitivity, reaction. IgE is commonly
referred to as a homocytotropic antibody because
of its strong affinity for the Fc receptors on mast
cells and basophils.124 IgE avidly binds to
basophils in the blood and mast cells located in
the skin and respiratory and gastrointestinal tracts
and the connective tissue surrounding the blood
vessels.163 When a patient is reexposed to the aller-
genic drug, cross-linking occurs between the hap-
ten–protein complex and IgE bound to the surface
of mast cells, basophils, or both. Cross-linking
between the drug and two molecules of IgE causes
an influx of calcium ions that triggers degranula-
tion of the mast cells and basophils.163 The end
result is the extracellular release of a number of
preformed inflammatory mediators such as hista-
mine, heparin, and proteases. Influx of calcium
also activates phospholipase A2 and stimulates the
release of arachidonic acids, which can be bio-
transformed into a number of secondary media-
tors, including leukotrienes, prostaglandins, and
platelet-activating factor.164 The cytokine known
as tumor necrosis factor ␤ has also been implicat-
ed as a mediator. Collectively, these mediators of
anaphylaxis can cause increased vascular perme-
ability, a wheal-and-flare reaction, smooth-muscle
contraction resulting in bronchospasm, nausea,
vomiting, recruitment of inflammatory cells, acti-
vation of vagal pathways, decreased coronary
blood flow, and delayed atrioventricular conduc-
tion.164,165
Type II, or cytotoxic, reactions are usually
mediated by IgG or IgM. During these reactions,
the drug hapten typically binds to a cell-surface
protein in the membrane of a blood cell (e.g., red
cell, platelet, neutrophil).94,95 A complexation reac-
tion between the responding antibody (IgG or
IgM) and the drug hapten bound to the surface
protein leads to destruction of the affected cells
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60 SECTION II • Drug-Induced Dermatologic Diseases

TABLE 6–4 Gell and Coombs Classification of Drug Hypersensitivity Reactions1,155,162

Classification Timing Antibody Targeted Cells Clinical Presentation
Type 1 Minutes to 2 hr; IgE Mast cells Anaphylaxis, isolated urticaria,
usually occurs after Basophils angioedema, bronchospasm,
the second exposure to abdominal cramping,
the drug; may be respiratory arrest,
delayed for up to 48 hr cardiovascular collapse,
after exposure arrhythmias, eosinophilia
Type II 7–21 days after IgG or IgM Blood cells (red Cytopenias (hemolytic anemia,
initiation of the drug cells, platelets, mature thrombocytopenia, some
neutrophils) neutropenias)
Vasculitides (some)
Type III 5–21 days after IgG or IgM Skin, joint tissue, Serum sickness–like illness
initiation of the drug kidney, liver Vasculitides (some)
Morbilliform or maculopapular
rash
Urticaria (late onset)
Glomerulonephritis
Interstitial nephritis
Erythema multiforme
Stevens–Johnson syndrome
Type IV Variable; usually within Sensitized T Skin, liver, kidney, lungs Contact dermatitis
24–48 hr after drug lymphocyte Exanthematous reactions
exposure including maculopapular rash
Bullous or pustular eruptions
Stevens–Johnson syndrome
Toxic epidermal necrolysis
Interstitial pneumonitis
Granulomatous hepatitis

(i.e., hemolysis, thrombocytopenia, neutropenia).
Cell-bound antibody can also activate comple-
ment, a series of 25 plasma proteins that, when
activated, assist in cell lysis.94,95,161 Activated com-
plement proteins possess a variety of properties,
including the ability to degranulate mast cells
(C3a, C5a), the ability to form a membrane attack
complex (C5a and C9a), and the ability to stimu-
late opsonization to amplify the immune
response.161
Type III reactions, commonly referred to as
immune complex reactions, are usually mediated
by IgG. During these events, the drug hapten typi-
cally forms a complete antigen by binding cova-
lently with an amino acid component (such as the
lysine or cysteine residues) of a plasma protein.
The hapten–protein complex then stimulates the
production of IgG. Binding between IgG and the
circulating complete antigen results in the forma-
tion of immune complexes, which often circulate
throughout the bloodstream and activate the com-
plement cascade before depositing on targeted cells
or tissues.163 Complement-mediated migration of
phagocytes and the release of pyrogens manifests
as a fluid phase or serum sickness–like reaction
consisting of fever, malaise, and lymphadenopa-
thy.166
Activation of complement proteins C3a and
C5a can also result in degranulation of mast cells
with the release of histamine. Eventually, the
immune complex may deposit in a variety of tis-
sues, including the walls of blood vessels, glomeru-
lar cells, joint tissue, alveoli, and cells in the skin.
After deposition on the targeted tissue, the
immune complex can mediate cell destruction
with the assistance of complement.166
Type IV reactions, commonly referred to as
delayed or cellular immune responses, are mediat-
ed by sensitized CD4 and CD8 T lymphocytes.
Upon activation, T lymphocytes secrete cytokines
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CHAPTER 6 • Drug Allergy, Pseudoallergy, and Cutaneous Diseases
(e.g., IL-5, IL-8) that recruit monocytes, neu-
trophils, and eosinophils to mediate the hypersen-
sitivity reaction.167 Type IV reactions involve a
wide range of clinical events including contact der-
matitis from a topically applied medication and
more systemic conditions involving lymphoid
organs. The presence of lymphocytic infiltrates
often suggests a type IV hypersensitivity reaction.
A complete review of the mechanisms by which
drugs cause type IV reactions has been pub-
lished.167
Pseudoallergic Reactions
Drugs cause pseudoallergic reactions by a number
of mechanisms, including: (1) direct stimulation
of mast cells resulting in the release of histamine
(e.g., opiates, polymyxin, protamine, diamines
such as pentamidine, polyethoxylated castor oil),
(2) nonimmunologic activation of the comple-
ment cascade (e.g., radiocontrast media, prota-
mine), and (3) alteration of the metabolism or
production of inflammatory mediators (e.g., ACE
inhibitors, aspirin, and nonsteroidal antiinflam-
matory drugs [NSAIDs]).3-5 The direct stimulatory
effects of drugs on mast cells appear to be dose-
related and tend to predominate on mast cells in
the skin. Ciprofloxacin, vancomycin, and muscle
relaxants such as succinylcholine and opiates (e.g.,
codeine, morphine) have been shown to elicit
urticarial reactions in normal skin at concentra-
tions of ≥100 ␮g/mL.3 The mechanism by which
the ACE inhibitors cause angioedema is not com-
pletely understood; however, inhibition of the
breakdown of bradykinin and substance P may
partially explain this adverse event. Angiotensin-
converting enzyme, a nonspecific dipeptidase
enzyme, not only converts angiotensin I to
angiotensin II but is also involved in the inactiva-
tion of bradykinin, substance P, and neurokinin
A.168 Elevations in the concentrations of
bradykinin and substance P can lead to inflamma-
tion, increased vascular permeability, and vasodi-
lation. Aspirin-induced asthma, also known as
aspirin-exacerbated respiratory disease (AERD), is
believed to result from an imbalance between the
production of prostaglandins and leukotrienes
from arachidonic acids.169 Inhibition of cyclooxy-
genase-1 (COX-1) leads to decreased production of
prostaglandin E2, a modulating prostaglandin in
bronchial tissue, and an increased propensity for
arachidonic acids to be synthesized via the lipoxy-
genase pathway. Increased production of
leukotrienes C4, D4, and E4 is associated with
smooth-muscle contraction manifesting as bron-
61
chospasm, inflammation, and increased mucus
production.169
CLINICAL PRESENTATION AND
DIFFERENTIAL DIAGNOSIS
The signs and symptoms of a number of specific
allergic syndromes are provided in Table 6–5. The
clinical presentation of drug hypersensitivity is
highly variable and dependent on the responding
antibody and the targeted tissues. Hypersensitivity
syndromes may include anaphylaxis; angioedema;
urticaria; immune complex diseases manifesting as
a serum sickness–like illness, lupus-like reaction,
hypersensitivity vasculitis, or DRESS; and mucocu-
taneous syndromes such as Stevens–Johnson syn-
drome (SJS) and toxic epidermal necrolysis (TEN).
In addition, allergic drug reactions may be the
cause of disorders of the blood, kidney, liver, and
pulmonary system. Conditions to consider in the
differential diagnoses of these syndromes are listed
in Table 6–6. The mucocutaneous syndromes and
DRESS are discussed in the section on “Cutaneous
Diseases.”
Anaphylaxis, the most severe form of a type I,
or IgE-mediated, reaction, constitutes a medical
emergency. The onset of anaphylaxis is usually
within minutes to 2 hours after exposure to the
causative drug.170 In rare cases, the onset can be
delayed for up to 48 hours after exposure. No
standardized definition of anaphylaxis
exists.151,164,170 Using some definitions, involve-
ment of a shock organ, either the lungs or heart,
is a requirement for a diagnosis of anaphylaxis.164
Most recently, anaphylaxis has been described as
a life-threatening reaction that results from the
sudden systemic release of mast cell and basophil
mediators.170 In the majority of patients, the ini-
tial sign of anaphylaxis is generalized urticaria
with or without angioedema; however, in some
patients, urticaria may be delayed or absent.164,170
On the basis of a review of two retrospective series
of a total of 835 patients with anaphylaxis, respi-
ratory symptoms are the second most commonly
occurring manifestations of anaphylaxis, fol-
lowed by dizziness, unconsciousness, and gas-
trointestinal symptoms.164 An elevated serum
tryptase concentration is indicative of the release
of stored mediators from mast cells.
Concentrations of tryptase, an enzyme that is
stored in the secretory granules of the mast cell,
become elevated in the serum within 1 to 2 hours
after the onset of anaphylaxis and persist for as
long as 6 hours after the event.164,170 ␤-Tryptase is
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62 SECTION II • Drug-Induced Dermatologic Diseases

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
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CHAPTER 6 • Drug Allergy, Pseudoallergy, and Cutaneous Diseases 63

TABLE 6–6 Conditions to Consider in the Differential Diagnosis of Drug Hypersensitivity

Anaphylaxis164,165,170
• Asthma
• Carcinoid syndrome
• Cardiogenic shock
• Croup
• Exercise-induced anaphylaxis
• Idiopathic anaphylaxis
• Insect stings or bites
• Latex allergy
• Panic attack
• Septic shock
• Systemic mastocytosis
• Systemic capillary leak syndrome
• Scombroid fish poisoning
• Vasodepressor (vasovagal neurocardiogenic) syncope
• Vocal-cord dysfunction syndrome
Angioedema248
• Insect stings or bites
• Food allergy
• Idiopathic or hereditary angioedema
• Hereditary or acquired C1 esterase inhibitor deficiency
• Systemic capillary leak syndrome
• Latex allergy
• Systemic mastocytosis
Urticaria248
• Cutaneous mastocytosis
• Mastocytosis in association with hematologic disorders (e.g., leukemia)
• Cholinergic urticaria
• e-induced urticaria
• Infection (Epstein–Barr virus; hepatitis A, B, and C; gastrointestinal parasites)
• Foods (peanuts, nuts, fish, shellfish, wheat, eggs, milk, soybeans, fruits)
• Food additives (benzoates, sulfites, monosodium glutamate, FD&C [Food, Drug, and Cosmetic] dyes)
• Scombroid fish poisoning
• Occupational exposures (latex, chromates in cement industry, cosmetics, plants)
• Serum sickness
Serum sickness–like reaction55,175
• Autoimmune disease (rheumatoid arthritis, lupus erythematosus)
• Hepatitis A, B, C
• Hypersensitivity vasculitis
• Infection (aspergillosis, histoplasmosis, coccidioidomycosis, blastomycosis, Epstein–Barr virus, cytomegalovirus)
Hypersensitivity vasculitis72-74
• Infection (bacterial endocarditis, hepatitis B or C, occult abscess)
• Rheumatic diseases
• Malignancy (lymphoma, Hodgkin’s disease, metastatic carcinoma, multiple myeloma)
• Autoimmune disease (rheumatoid arthritis, systemic lupus erythematosus, Wegener’s granulomatosis)
Hypersensitivity syndrome175
• Cutaneous lymphoma
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64 SECTION II • Drug-Induced Dermatologic Diseases
released only during episodes of mast-cell degran-
ulation, whereas concentrations of ␣-tryptase are
elevated in patients with a large mast-cell burden
(e.g., mastocytosis).170 Anaphylaxis is most sug-
gestive when the ratio of total (␣ + ␤) tryptase to
␤-tryptase is 10 or less.170 Serum platelet-activat-
ing factor may also be a biomarker of anaphylax-
is.171 A late phase of anaphylaxis, characterized by
erythema, edema, and excess mucus production
with mucus plug formation, occurs 8 to 12 hours
after the initial attack and can last for up to 32
hours.170 The late-phase reaction is attributed to
the effects of leukotrienes, such as leukotriene B4,
which stimulate the migration of macrophages to
the sites of tissue damage.164,165
Urticaria with pruritis, a common manifesta-
tion of anaphylaxis, can also occur as a sole mani-
festation of a type I reaction. On subsequent
exposure to the causative agent, urticaria may
progress to include an anaphylactic presentation.
Drug-induced angioedema can also occur as a sole
manifestation of allergy, or it can occur with
urticaria or as part of an anaphylactic event.172
Angioedema, also known as giant urticaria, or
angioneurotic edema, presents as nonpitting
edema that extends beyond the epidermis to
involve the deep dermis, mucous membranes, and
subcutaneous tissues.172 Angioedema secondary to
ACE inhibitors is typically confined to the head
and neck, presenting as localized swelling of the
face (tongue, lips, and eyelids) with edema of the
mucous membranes of the mouth, throat, and
nose.127,173,174 Rarely, the edematous reaction can
extend to the gastrointestinal tract, hands, feet,
and genitalia.
The presentation of drug-induced allergic
blood disorders is included in Table 6–5.
Depending on the causative drug, the patient may
present with hemolytic anemia, thrombocytope-
nia, or granulocytopenia.94,95 These peripherally-
mediated blood disorders typically occur within 5
to 21 days after drug initiation.94,95 The affected
blood-cell counts decline rapidly as compared with
the relatively slow decline in the counts observed
with bone-marrow mediated blood disorders. In
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
group of conditions including serum sickness–like
disease (SSLD), hypersensitivity vasculitis, and
lupus-like reaction.166 SSLD is a mild and tran-
sient form of the serum sickness that originally
occurred with the administration of horse serum
in the form of diphtheria antitoxin. The predom-
inant feature of an SSLD is a cutaneous eruption
that manifests within 5 to 21 days after drug ini-
tiation.166 Approximately 90% of patients have
either an urticarial reaction due to complement-
mediated activation of the mast cells (one third of
patients) or a maculopapular rash on the
abdomen and extremities with possible extension
to the palms and soles (two thirds of
patients).55,166,175 The rash is usually preceded by a
prodromal phase consisting of fever and malaise,
arthralgias, and lymphadenopathy. In rare
instances, the reaction can extend to involve the
kidney (i.e., glomerulonephritis). SSLD has been
reported in association with a number of drugs,
including ␤-lactam antibiotics,55 bupropion,56-58
cefaclor,59-61 ciprofloxacin,62 minocycline,66-68 and
sulfonamides. 55 Drug-induced SSLD is often
described as a mild condition that is self-limiting
after discontinuation of the causative agent.
However, in some cases, it progresses to a more
serious vasculitis. Any evidence of mucous mem-
brane involvement (i.e., mucocutaneous lesions
of the mouth, genitalia, naries) may suggest the
development of a more progressive condition,
such as SJS.
Drug-induced vasculitides are associated with
acute inflammatory and necrotic lesions of the
arteries, arterioles, venules, and capillaries.
Consistent with other immune complex diseases,
an initial prodromal period is noted within 1 to 3
weeks after drug initiation and usually consists of
fever, arthralgias, and sore throat.72,175 Cutaneous
vasculitis, described as either a purpuric or macu-
lopapular rash of the lower extremities, is the most
common presenting manifestation.73 The purpuric
lesions can progress to necrotic ulcerations, and
the vasculitic process can extend to include the
kidneys, lungs, nasal mucosa, and ears. A number
of drugs, such as propylthiouracil, hydralazine,
minocycline, phenytoin, and allopurinol, can
induce vasculitis through the production of anti-
neutrophil cytoplasmic autoantibodies.72 Other
terms used to describe this condition include
leukocytoclastic vasculitis, polyarteritis nodosa,
and Churg–Strauss syndrome.
RISK FACTORS
The rarity of drug hypersensitivity reactions sug-
gests a reliance on contributory or predisposing
factors. Risk factors for drug hypersensitivity reac-
tions have been categorized as either drug-related
or patient (host)-related. Many extensive reviews
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CHAPTER 6 • Drug Allergy, Pseudoallergy, and Cutaneous Diseases
have been published describing predisposing fac-
tors for both the induction of an immune response
to a drug and the elicitation of an allergic drug
reaction2,3,176-178; however, debate continues as to
the influence of these factors on the risk of reactiv-
ity. Most risk factors have been identified through
small-scale studies and indirect clinical observa-
tions. In addition, the majority of the risk assess-
ments have been determined from the study of
penicillin.176 At present, it is not known whether
risk factors associated with the penicillins can be
extrapolated with confidence to other antigenic
drugs. Proposed risk factors for drug allergy are list-
ed in Table 6–7. In addition, risk factors associated
with specific drugs (e.g., the penicillins, sulfon-
amides, radiocontrast media) are identified.
The three most commonly described drug-
related risk factors for a hypersensitivity reaction
are increased molecular size (molecular weight
≥4,000 Da), chemical composition consisting of
proteins or polypeptides, and the ability of the
drug or its reactive metabolite to bind covalently to
a carrier protein.176,177 The presence of proteins of
nonhuman origin (e.g., chimeric monoclonal anti-
bodies containing murine-based components, pork
insulin, streptokinase) or the inclusion of antigenic
excipients (e.g., FD&C [Food, Drug, and Cosmetic]
dyes, peanut oil, soybean emulsion, sulfites) also
increase the risk of drug reactivity. Other proposed
drug-related factors include route of drug adminis-
tration, dose, and frequency of administration.
Sensitization to a drug can occur via any route of
administration, and allergic reactions have been
reported in association with all routes of drug
administration.3,124 However, once a patient has
been sensitized to a drug, subsequent administra-
tion of that drug by the parenteral route has been
associated with increased severity of an allergic
drug reaction.178 This observation is largely
explained by the higher rate of drug delivery with
the parenteral route versus other routes of admin-
istration, particularly the oral route.178 Allergic
reactions can occur with any dose of a drug, but
sensitization is more likely to be achieved with
continuous drug dosing rather than single-dose
therapy.3 Rarely, an allergic reaction may be dose-
dependent, as with penicillin-associated hemolytic
anemia, which is observed only with continuous
intravenous dosing of ≥20 million units daily.125
More commonly, once a patient has been sensi-
tized to a drug, the severity of the reaction is usu-
ally proportional to the dose administered. The
frequency of exposure to a given allergic com-
pound has consistently been shown to increase the
risk of an immune response, particularly involving
65
TABLE 6–7 Risk Factors for Drug Hypersensitivity
and Pseudoallergic Reactions
Hypersensitivity Reactions
Drug-related factors1-3,176-178
• Chemical properties (molecular weight, polypeptide
composition, foreign protein)
• Dose and duration of therapy
• Frequency of treatment courses
Coexisting conditions
• Active infection with Epstein–Barr virus (aminopeni-
cillins)189
• Active infection with human immunodeficiency virus
(sulfonamides, dapsone, penicillins, ciprofloxacin,
phenytoin)190
• Cystic fibrosis (␤-lactams)193
• HHV-6 (DRESS)191,192
Genetic factors
• HLA B*5701 (abacavir)183
Patient history
• History of a previous reaction to the specific agent
Pseudoallergic reactions
Drug-related factors1-5
• Dose (vancomycin, opiates)
• Infusion rate (vancomycin, paclitaxel)
Patient factors1-5
• Female sex (radiocontrast media)197
• Atopy (radiocontrast media, aspirin)198,202
• Asthma (radiocontrast media, aspirin)198,202
• Race (angiotensin-converting–enzyme inhibitors)200,201
Concomitant drug therapy
• ␤-Blockers (radiocontrast media)198,199
DRESS = drug rash with eosinophilia and systemic symptoms;
HHV-6 = human herpesvirus 6; HLA = human leukocytic antigen.
IgE. Humoral drug sensitivity is finite and there is
a large degree of interpatient variation in the dura-
tion of sensitivity. As such, the shorter the interval
between treatment regimens with a sensitizing
drug, the more likely the patient will have retained
sensitivity and be able to mount an allergic reac-
tion.1,3,124,177
Proposed patient-specific risk factors include
age, sex, genetic predisposition, and concomitant
conditions. Allergic reactions to some drugs have
been reported more commonly among patients in
specific age groups; however, age has not been con-
sistently identified as a risk factor.2,179 For example,
anaphylaxis associated with penicillin has been
reported more commonly in patients between the
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66 SECTION II • Drug-Induced Dermatologic Diseases
ages of 20 and 49 years than in children.180 This
finding relates less to the specific age of the patient
than to the number of potential exposures to the
specific allergenic drug. Within the age of 20 to 49
years, a greater likelihood exists that a patient has
been previously exposed and possibly sensitized to
a penicillin, thereby increasing the risk of reactivi-
ty on subsequent exposure. Allergic drug reactions
do occur in children, particularly in those who
receive frequent courses of antibiotics for chronic
otitis media, chronic bouts of bronchitis, or infec-
tions associated with cystic fibrosis. Therefore, the
frequency and number of exposures, rather than
age, are more likely to increase risk. For unknown
reasons, drug allergy occurs more frequently in
female than male patients. Bigby et al.179 reported
a 35% higher incidence of drug-induced allergic
cutaneous reactions in women than in men. More
recently, in a study of penicillin allergy, Macy et
al.181 also found that women were at higher risk.
Genetic factors may influence a patient’s risk of
drug allergy. In order for T-helper cells to recognize
a drug as an antigen, the drug hapten–protein
complex must be co-presented with MHC class
molecules on the surface of antigen-presenting
cells.155,156,159 In this regard, patients with certain
MHC characteristics (or human leukocyte antigens
[HLA]) may be at higher risk of reacting to a given
antigenic compound as compared with patients
without the specific MHC molecules. For example,
in patients infected with human immunodeficien-
cy virus (HIV), susceptibility to abacavir-induced
hypersensitivity has been found to be associated
with the presence of HLA-B*5701, HLA DR7, and
HLA-DQ3.182,183 HLA-DR4 was present in 19 of 26
patients (73%) with hydralazine-associated lupus,
as compared with 4 of 16 hydralazine-treated
patients without lupus (25%).184 With further
research in pharmacogenomics, the risk of reacting
to additional antigenic compounds may be found
to be associated with certain histocompatibility
types.
In addition to encoding for histocompatibility
phenotypes, genetic factors can influence the
metabolic deactivation of drugs via phase 1 or
phase 2 metabolism. For example, severe reactions
to sulfamethoxazole have been noted in patients
with hereditary deficiency in N-acetyltransferase
(slow acetylators).185 Rieder et al.186 reported that
19 of 21 (90%) patients with sulfonamide hyper-
sensitivity were slow acetylators, as compared with
a 55% frequency of slow acetylators in a race-
matched control group (P<0.008). It has also been
suggested that patients with a hereditary deficien-
cy in epoxide hydrolase are at higher risk of anti-
convulsant hypersensitivity syndrome because of a
lesser ability to detoxify the arene oxide metabolite
of the aromatic anticonvulsants.187,188 In addition
to encoding for drug metabolic activity, genes also
encode for the type of T cell receptor and costimu-
latory molecules/cytokines involved in the signal-
ing of allergic reactions.
Although often implicated as a predisposing
factor, atopy has not been found to increase the
risk of drug allergy.176,178 Patients who are atopic
have high IgE responsiveness to environmental
allergens, manifesting as allergic rhinitis, allergic
asthma, and atopic dermatitis. Originally, it was
theorized that the high IgE responsiveness report-
ed in atopic patients could increase the risk of IgE
sensitization to drugs. Studies have shown that a
history of atopy does not influence the likelihood
of a patient being sensitized to a drug. However, if
an atopic patient becomes sensitized to a drug, evi-
dence suggests that the reaction will be more
severe than that observed in nonatopic
patients.1,177
Concomitant viral infections may also predis-
pose a patient to an allergic drug reaction. Pullen et
al.189 reported ampicillin-associated morbilliform
rash in 18 of 19 (95%) patients with acute
Epstein–Barr virus (EBV) infection. In comparison,
a morbilliform skin rash develops in approximate-
ly 5% to 10% of the general population exposed to
an aminopenicillin (e.g., ampicillin, amoxicillin).41
Patients infected with other viral pathogens, such
as human herpes-virus 6 (HHV-6) and HIV, have
also exhibited an increased risk of drug allergy. In
HIV-infected patients, 29% to 65% of those treated
with sulfamethoxazole exhibited an allergic or
allergic-like reaction and the risk of reactivity to a
number of other drugs (e.g., ciprofloxacin, dap-
sone, foscarnet, penicillins, phenytoin, rifampin)
has also been shown to be increased.190 Most
recently, HHV-6 has been linked to an increased
risk of DRESS.191,192 The mechanism by which viral
infections increase the risk of drug reactivity is not
completely understood. Proposed mechanisms
include virally mediated alterations in drug metab-
olism, upregulation of MHC class II molecules on
APCs, and the increased release of cytokines such
as interferon-␤, which amplify the immune
response.154,159,160
Cystic fibrosis is a risk factor for allergic reac-
tions to ␤-lactam antibiotics. At least 20% of
patients with cystic fibrosis have an allergic reac-
tion during an antibiotic treatment course, and the
risk increases with the number of treatment cours-
es.193 The most commonly reported allergenic ␤-
lactam antibiotic in these patients is piperacillin194;
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CHAPTER 6 • Drug Allergy, Pseudoallergy, and Cutaneous Diseases
however, increased rates of reactivity have also
been demonstrated with other antipseudomonal
penicillins and cephalosporins.195,196 Current evi-
dence suggests that these reactions are not typical-
ly mediated by the ␤-lactam ring, but are more
likely to be reactions to the side chains of the
agents.
Risk factors for pseudoallergy are highly
dependent on the specific causative drug. For exam-
ple, the risk of an anaphylactoid reaction to a radio-
contrast agent is higher in women,197 patients with
atopy or asthma,198 and patients receiving ␤-adren-
ergic blocker therapy with either a nonselective or
selective agent.198,199 Patients at increased risk of
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
longer acting agents (i.e., enalapril, lisinopril).200
Aspirin intolerance manifesting as aspirin-induced
asthma is more commonly observed in patients
with history of asthma with or without allergic
rhinitis or nasal polys.202 Aspirin- or NSAID-
induced exacerbations of urticaria or angioedema
are more common in atopic patients with history of
idiopathic urticaria or angioedema.203
The most reliable risk factor for hypersensitivi-
ty and most pseudoallergic reactions is history of a
prior reaction to the drug. For example, a patient
with a history of an anaphylactoid reaction to a
radiocontrast agent has a 16% to 44% risk of hav-
ing a reaction on reexposure, particularly to a high-
osmolarity agent.204 For the penicillins, a reliable
skin testing method with a high negative predic-
tive value has allowed for more accurate determi-
nations of the risk of reactivity on reexposure. In a
patient with a positive history of an IgE-mediated
reaction to a penicillin, a positive skin-prick test
reveals a 50% to 70% risk of an IgE-mediated reac-
tion on reexposure.1,205 In contrast, a negative skin
test indicates only a 2% to 3% risk of an IgE-medi-
ated reaction on reexposure.205 Unfortunately, reli-
able skin-test reagents for other highly allergenic
drugs have not been produced, thereby limiting
the ability to accurately assess the risk of reactivity
to other allergenic drugs.
MORBIDITY AND MORTALITY
In 2002, a task force assembled by the
Immunotoxicology Technical Committee, part of
the nonprofit Health and Environmental Sciences
Institute, provided an estimate of the impact of
drug hypersensitivity reactions on the health care
67
system.126 On the basis of the assumption that 6%
to 10% of adverse drug reactions are related to
hypersensitivity, it was estimated that 137,000 to
230,000 hospital admissions in 1998 in the U.S.
were attributed to drug hypersensitivity reactions.
Using cost estimates determined in 1997 for the
treatment of adverse drug reactions in hospitalized
patients, the task force estimated that the annual
cost of hospital-based management of drug hyper-
sensitivity reactions is $275 million to $600 mil-
lion.126 It was further hypothesized that the total
annual cost for management of both inpatient-
and outpatient-related drug hypersensitivity reac-
tions could approach $1 billion.
PREVENTION
Hypersensitivity Reactions
Drug hypersensitivity reactions have consistently
been considered to be unpredictable in nature and
largely unpreventable. However, continuing
advances in pharmacogenomic research may alter
the level of preventability of these events.
Prospective screening for the presence of the HLA-
B*5701 allele has been shown to lower the risk of
hypersensitivity to abacavir.183 In a double-blind,
controlled study, 1,956 HIV-infected patients were
randomly assigned to receive either prospective
screening for HLA-B*5701 prior to the initiation of
abacavir or a standard-of-care approach to aba-
cavir therapy.183 Prospective screening for HLA-
B*5701 with subsequent avoidance of abacavir in
identified carriers prevented the occurrence of
immunologically confirmed hypersensitivity reac-
tions. All patients in whom an immunologically
confirmed hypersensitivity reaction to abacavir
developed during the 6-week study were in the
control group and were later determined to be car-
riers of HLA-B*5701.183 Screening was associated
with a negative predictive value of 100% and a
positive predictive value of 47.9% in this primari-
ly white population.183 The investigators calculat-
ed that only 14 patients would have to be screened
to prevent one case of abacavir hypersensitivity.
Screening for the HLA-B*5701 allele is currently
available.
Once a patient has had an allergic reaction to a
drug, a number of measures can be taken to pre-
vent a subsequent reaction. The most important
preventive measure is patient education. In partic-
ular, patients should be educated regarding avoid-
ance of the causative drug and any cross-reactive
drugs in the future. Guidelines for the avoidance of
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68 SECTION II • Drug-Induced Dermatologic Diseases
hypersensitivity reactions to common drug aller-
gens are provided below.
␤-Lactam Antibiotics
Whenever possible, a non–␤-lactam antibiotic
should be used in patients with a history of peni-
cillin allergy. If a ␤-lactam antibiotic is medically
necessary (i.e., treatment of syphilis in a pregnant
woman, patient with cystic fibrosis and pneumo-
nia) in a patient with history of IgE-mediated aller-
gy, epicutaneous (prick, scratch) skin testing is the
preferred technique for assessing the likelihood of
a reaction on reexposure. The skin-testing proce-
dure is described in Figure 6–1. Penicillin is rapidly
hydrolyzed to a number of reactive metabolites or
antigenic determinants. Ninety-five percent of the
penicillin molecules that covalently bind to pro-
teins are in the form of benzyl penicilloyl, com-
monly known as the major determinant of
penicillin.158 Reactive metabolites found in lesser
quantities, such as penilloate and penicilloate, are
referred to as minor determinants. Both the major
and minor determinants can elicit an IgE-mediated
response; thus, both are recommended to be used
when skin testing for IgE responsiveness.
Commercially available benzylpenicilloyl-polyly-
sine (Pre-Pen), the major determinant bound to
protein, was removed from the U.S. market in
2004, and the minor determinants are also not
commercially available. Dilute concentrations of
penicillin G have been used with some success to
generate the minor determinants.205 When used
together for skin testing (i.e., Pre-Pen and diluted
penicillin G), 97% of patients with a negative skin
test have been able to tolerate a penicillin subse-
quently.1,205 Patients with a positive skin test to
either determinant, and a positive allergy history,
have been shown to have a 50% to 70% risk of
reacting with an IgE-mediated response to peni-
cillin on reexposure.1,205 This risk of reactivity can
also be applied to semisynthetic penicillins,
cephalosporins, and carbapenems.206-209 Little to
no risk of a cross reaction exists between penicillin
and aztreonam, a monobactam.210 Until Pre-Pen is
made available commercially, there is no reliable
means by which to test for IgE-mediated penicillin
allergy. The radioallergosorbent test is considered
unreliable as a measure of IgE reactivity to peni-
cillin, and the negative predictive value of testing
solely with the minor determinants is not
known.211 Obtaining a thorough allergy history is
currently the primary means by which to identify
patients at risk for severe reactions to penicillin.
When there is high suspicion of IgE-mediated
hypersensitivity and treatment with a ␤-lactam
FIGURE 6–1 Skin Testing for IgE Responsiveness to ␤-
Lactam Antibiotics
Step 1. Epicutaneous (scratch, prick) test with ben-
zylpenicilloyl-polylysine (Pre-Pen) and the minor deter-
minants. Make a nonbleeding scratch of the skin with a
lancet. Administer the dose of the reagents (below):
• Pre-Pen(r), full strength dilution; one drop
• Penicillin G, 10,000 U/mL; 1 drop
Step 2. Evaluate the scratch sites within 10–15 minutes.
A positive test result is the presence of itching or an
erythematous or wheal reaction at either site of the
scratch tests. If the reaction is positive, do not proceed
with further testing.
Step 3. If the scratch test is negative, proceed with
intradermal testing.
• Pre-Pen, full strength; 0.02 mL intradermally
• Penicillin G, 10,000 U/mL; 0.02mL intradermally
• Administer a positive control (histamine) and a
negative control (saline)
Step 4. Evaluate the sites of intradermal injections
within 15–20 minutes. A positive reaction is the pres-
ence of itching, erythema or wheal >4 mm, or a wheal
reaction >50% the size of the original size of the bleb
from the injection of either Pre-Pen or the minor deter-
minants (penicillin G). Assess the site of histamine and
saline control. If the histamine control site is not posi-
tive, consider interference by antihistaminergic agents.
antibiotic is required, desensitization to a specific
␤-lactam may be achieved using a number of differ-
ent desensitization protocols.212-214
It is important to keep in mind that skin test-
ing only indicates the potential for an IgE-mediat-
ed reaction to penicillin. Skin testing does not
reveal the risk of having an IgG-, an IgM- or a cell-
mediated reaction. Patients with a history of SJS,
exfoliative dermatitis, or TEN associated with a
penicillin should not undergo skin testing.
In addition to ␤-lactam–mediated allergic reac-
tions, side chain-specific reactions have been
described with a number of penicillins, particular-
ly the aminopenicillins and piperacillin.215-217 As
such, a patient with an allergy to one of these peni-
cillins may not react to other penicillins. The struc-
tural similarities and differences between the
penicillins are depicted in Figure 6–2. In a patient
with history of an urticarial or other IgE-mediated
reaction to an aminopenicillin or piperacillin, skin
testing with Pre-Pen and the minor determinants is
the preferred method to rule out ␤-lactam–mediat-
ed allergy. If the skin test result is negative, the
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CHAPTER 6 • Drug Allergy, Pseudoallergy, and Cutaneous Diseases 69

H H
S
R-CONH CH3

N CH3
O
H COOH

R⫺ R⫺

Benzylpenicillin CH2 CH2

(Penicillin G) Ampicillin
NH2

Phenoxymethylpenicillin OCH2 Amoxicillin HO CH

(Penicillin V)
NH2

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

FIGURE 6–2 Similarities and Differences in the Structures of Various Penicillins

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.

patient may be challenged with a penicillin with a
structurally different side chain. In the absence of
Pre-Pen, assessing the risk of a ␤-lactam–mediated
allergy versus a side-chain–mediated reaction is
highly dependent on the accuracy and complete-
ness of the patient’s allergy history. In addition to
causing side-chain–mediated allergic reactions,
some penicillins have been associated with the
development of nonimmunologically mediated
drug eruptions. Maculopapular rash with an
TisdaleC06_49-97 1/20/10 10:54 PM Page 70
70 SECTION II • Drug-Induced Dermatologic Diseases
aminopenicillin (i.e., amoxicillin, ampicillin) may
be an idiosyncratic reaction, particularly in a
patient with acute EBV infection.189,215
The risk of cross reactivity between penicillins
and cephalosporins is low, particularly between
penicillin and the second- and third-generation
agents. On the basis of laboratory studies, the risk
of cross reactivity between penicillins and the first-
generation cephalosporins is less than 10%, and
the risk of a cross reaction between the penicillins
and the third-generation cephalosporins is as low
as 1%.1,40,207 One meta-analysis included nine stud-
ies in which the risk of cephalosporin allergy was
compared in penicillin-allergic and non–penicillin-
allergic patients. Compared to nonallergic patients,
the risk of cross reactivity in penicillin-allergic
patients was highest in association with the first-
generation cephalosporins (OR, 4.79; 95%
CI, 3.71–6.17).218 The first generation agents
included in the analysis (i.e cephalothin,
cephaloridine, cephalexin) had R1 substitutions
similar to that of penicillin. The odds ratios for risk
of cross-reactivity to the second- and third-genera-
tion cephalosporins were 1.13 (95% CI, 0.61–2.12)
and 0.45 (95% CI, 0.18–1.13), respectively.218 The
lower risk of cross reactivity between these agents
and penicillin may be attributed to structural dif-
ferences in the R1 substitution on the ␤-lactam
ring. In patients with a history of maculopapular
rash associated with a penicillin, the benefits of the
use of a second- or third-generation cephalosporin
may substantially outweigh the potential risk of a
cross reaction. In patients with a history of an IgE-
mediated reaction, cephalosporins should be
avoided. If deemed medically necessary, a
cephalosporin can be administered via a graded
challenge, or attempts can be made to desensitize
the patient to the cephalosporin.23
Carbapenems
Carbapenem drugs include doripenem, ertapenem,
imipenem, and meropenem. These agents contain
a ␤-lactam ring attached to a modified thiazolidine
ring with two side chains. The risk of a cross reac-
tion between a penicillin and a carbapenem is
unclear. In three retrospectively designed studies of
patients with a history of penicillin allergy, the
rates of cross reactions to a carbapenem (e.g.,
imipenem, meropenem) were 9.2%,219 9.5%,220 and
11%.221 Each study was limited by its retrospective
design, heavy reliance on self-reported penicillin
allergy histories, and the lack of skin testing to
confirm IgE reactivity. In two prospectively
designed studies, skin testing was used to measure
reactivity to imipenem in patients with document-
ed, skin-test-confirmed penicillin allergy.222,223 In
one of these studies, patients with negative results
on skin testing for imipenem underwent graded
challenge dosing of imipenem to a total dose of
500 mg.223 None of the 110 patients reacted to
imipenem on a graded challenge. Although the
results of this study are encouraging, a limitation
was the inclusion of patients who were allergic to
aminopenicillins. Forty-six percent of the patients
with penicillin allergy reported that the allergy was
due to amoxicillin, and 17.5% were allergic to
amoxicillin. An additional 12% were allergic to
piperacillin. Considering the high likelihood of
side-chain-specific reactions to these agents, exclu-
sion of these patients from the study sample would
have been optimal. In a patient with confirmed
IgE-mediated allergy to penicillin, therapy with a
carbapenem should be avoided. If deemed medical-
ly necessary, the carbapenem can be administered
as a graded challenge or desensitization may be
performed.214 The risk of cross reactivity between
the carbapenems is also unknown. Imipenem-sen-
sitive patients tolerating meropenem following
graded challenge224 and meropenem desensitiza-
tion214 have been reported.
Cephalosporins
A patient with a cephalosporin allergy should be
interviewed in depth to obtain information on all
antibiotics that have evoked allergic reactions and
those that have been administered without adverse
incident. Patients with a history of reactivity to
one cephalosporin may or may not exhibit reactiv-
ity to other cephalosporins or penicillins.23
Although cephalosporins share the antigenic ␤-lac-
tam ring of the penicillins, they are more likely to
cause allergic reactions mediated by side chains at
either the R1 or R2 positions. Structural similarities
and differences in the cephalosporins based on R1
and R2 substitutions are depicted in Figure 6–3.
In a patient with a history of an urticarial or
other IgE-mediated reaction to a cephalosporin,
either the antigenic ␤-lactam ring or an antigenic
side chain of the cephalosporin may serve as the
antigenic determinant. Skin testing with Pre-Pen
and the minor determinant mixture of penicillin
was routinely advised to identify the likelihood of
a ␤-lactam allergy. With the current lack of avail-
ability of Pre-Pen, determination of ␤-lactam aller-
gy is highly dependent on taking an allergy
history. If a patient with history of suspected
cephalosporin allergy reveals upon interview that
he or she has tolerated penicillins and other ␤-lac-
tam antibiotics in the past, there is a greater likeli-
hood that the patient has reacted to a side chain of
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CHAPTER 6 • Drug Allergy, Pseudoallergy, and Cutaneous Diseases 71

H H
S
R1-CONH

N
O R2
COOH

R1⫺ ⫺R2 R1⫺ ⫺R2

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
of the cephalosporin’s side chains may aid in the
determination of potential cross-reactive agents.
For example, cefaclor and cephalexin have identi-
cal side chains at the R1 position and cephalothin
and cefotaxime have similar side chains at the R2
position.22 Ceftazidime shares a common side
chain with aztreonam.22,23 Overall, the risk of cross
reactivity between cephalosporin antibiotics is
believed to be greater than the risk of cross reactiv-
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72 SECTION II • Drug-Induced Dermatologic Diseases

ity between the cephalosporins and the penicillins.
In patients with selective allergy to a cephalo-
sporin, decisions regarding the use of alternative
cephalosporins should be based on the severity of
the allergic reaction, the availability of equally
effective non–␤-lactam antibiotics, and the struc-
ture-specific feature (i.e., R1 and R2 substitutions)
of the cephalosporin.
Sulfa Drugs
In a patient with a documented or reported sulfa
allergy, the first step to prevention of a subsequent
reaction is accurate and complete history taking.
Clarification is needed as to the specific sulfa drug
to which the patient reacted in the past, and
whether he or she has taken other sulfa drugs with-
out incident. Sulfa drugs, by definition, possess a
sulfamoyl (SO2NH2) moiety. Sulfate salts (e.g., mor-
phine sulfate, atropine sulfate), sulfites, and sul-
fides are not members of the “sulfa” drug class.
Sulfa drugs include sulfonamide antibiotics, thi-
azide diuretics, loop diuretics (e.g., bumetanide,
furosemide, torsemide), oral sulfonylurea hypo-
glycemic agents, carbonic anhydrase inhibitors
(e.g., acetazolamide, dorzolamide), celecoxib,
metolazone, sumatriptan, and zonisamide. Sulfa
drugs can be further categorized based on the pres-
ence or absence of an aromatic amine group in the
N4 position. Sulfonamide antibiotics (e.g., sulfadi-
azine, sulfamethoxazole, sulfapyridine) have an
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
influence the type of reactivity to a sulfa drug and
the potential for the sulfa drug to be reactive.157,225
Compared with nonantibiotic sulfonamides, the
sulfonamide antibiotics are associated with a high-
er frequency of severe allergic reactions such as SJS.
Sulfonamide antibiotics also have an N1 sub-
stituent consisting of a 5- to 6-member hetero-
cyclic ring containing ≥1 nitrogen, which has been
linked to the development of IgE-mediated reac-
tions.157 The structural differences between the sul-
fonamide antibiotics and the nonantibiotic
sulfonamides are illustrated in Figure 6–4.
Although sulfa drugs are well recognized as
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

‘SAM’ prototype Sulfanilamide

R⫽H
3 2 O Sulfamethoxazole
N4 site where reactive
4 CH3
metabolites responsible H2N S NH R
for reactions are formed 1
O
5 6 R⫽ O
N

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
CHAPTER 6 • Drug Allergy, Pseudoallergy, and Cutaneous Diseases
drug and the risk of cross reactivity to other sulfa
drugs are not completely known. The lack of a
commercially available, reliable reagent for skin
testing limits the value of such testing for deter-
mination of sulfa allergy. Arndt and Jick,226 as part
of the Boston Collaborative Drug Surveillance
program, compared the frequency with which dif-
ferent sulfa drugs caused allergic reactions in a
cohort of prospectively monitored inpatients. The
risk of reactivity to sulfamethoxazole was the
highest at 6% (10 of 169), followed by sulfisoxa-
zole (1.7%, or 8 of 462), chlorothiazide (0.28%, or
2 of 707), hydrochlorothiazide (0%, or 0 of
1,263), and tolbutamide (0%, or 0 of 702).226 On
the basis of this study, sulfamethoxazole is fre-
quently cited as the most reactive of the sulfa
class. Strom et al.227 studied the risk of cross reac-
tivity between a sulfonamide antibiotic (e.g., sul-
famethoxazole) and nonantibiotic sulfonamides
(e.g., acetazolamide, loop diuretic, sulfonylurea,
thiazide) in a retrospective cohort. Study patients
received a nonantibiotic sulfonamide at least 60
days after having experienced an allergic reaction
to a sulfonamide antibiotic. The risk of an allergic
reaction in these patients within 30 days of
receipt of the nonantibiotic sulfonamide was
compared with that of a control group of patients
without history of sulfa allergy. Of the 969
patients with history of sulfa allergy, 96 (9.9%)
had a reaction to the nonantibiotic sulfonamide
as compared with 315 (1.6%) of the 19,257
patients without a history of sulfa allergy.227
Based on the results of this study, the risk of a
cross reaction between the sulfa subclasses is con-
sidered low. In fact, patients in this study with a
history of sulfonamide antibiotic allergy exhibit-
ed a higher risk of subsequent reactivity to a peni-
cillin (14%) than to a nonantibiotic sulfonamide
(9.9%). When interpreting the findings of this
study, consideration should be given to study
design (i.e., retrospective cohort), and the broad
definition for drug allergy that included eczema-
tous reactions.
In a patient who is allergic to a specific sulfa
drug (e.g., sulfamethoxazole) and requires treat-
ment with another sulfa agent (e.g., a loop diuret-
ic), consideration should be given to the severity
of the patient’s previous allergic reaction. Sulfas
can cause serious mucocutaneous events such as
SJS and TEN, and they can also cause relatively
mild maculopapular rash or other isolated skin
rash. The severity of the reaction should largely
influence the decision as to whether the causative
sulfa drug or other sulfa drugs should be adminis-
tered in the future. Although the structures of the
sulfa agents may influence reactivity, cases of sus-
73
pected cross reactions between sulfonamide
antibiotics and nonantibiotics have been report-
ed.228,229 If therapy with a sulfa drug is deemed
necessary in a patient with history of sulfa allergy,
consideration may also be given to the administra-
tion of graded challenge doses. At least two cases
have been published describing the successful
administration of graded challenge doses of loop
diuretics in patients with a history of sulfa aller-
gy.230,231
Tetracyclines
The risk of cross reactivity between the tetracyclines
is unknown. Serum sickness–like reactions have
been reported in association with tetracycline,
doxycycline, and minocycline.232 Minocycline is
considered to be the most antigenic agent in the
tetracycline class, based on the number and severi-
ty of the reported cases (i.e., lupus-like, serum
sickness-like reaction).68 The antigenicity of
minocycline has been attributed to its unique
amino acid side chain.232 Until more is known
about the antigenic properties of this drug class, it
may be best to avoid the use of all tetracyclines in
patients with a history of a severe reaction to any
specific tetracycline.
Aromatic Anticonvulsants
A high degree of cross reactivity exists between
the aromatic anticonvulsants (e.g., carba-
mazepine, phenobarbital, phenytoin). In vitro
lymphocyte testing has revealed cross reactivity
between all three of these anticonvulsants in 40
of 50 patients (80%) with anticonvulsant hyper-
sensitivity syndrome (AHS).187 Thus, patients with
AHS associated with one aromatic anticonvulsant
should be advised to avoid the others. Moreover,
the family members of patients with AHS may be
at increased risk of AHS.233 In patients in whom
AHS develops, underlying seizure disorders can be
safely treated with benzodiazepines, gabapentin,
or valproic acid. Oxcarbazepine, the 10-keto
derivative of carbamazepine, has exhibited both
in vitro and in vivo cross reactivity with carba-
mazepine. Some patients with AHS induced by
carbamazepine have been subsequently treated
with oxcarbazepine without incident,234 while
others have had severe cross reactions. 235
Lamotrigine, a structurally dissimilar anticonvul-
sant, has also been reported to cause an anticon-
vulsant hypersensitivity syndrome due to an
unknown mechanism.91 For information on pre-
vention of DRESS and SJS due to anticonvulsants,
see the section on “Cutaneous Diseases” in this
chapter.
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74 SECTION II • Drug-Induced Dermatologic Diseases

Pseudoallergic Reactions inhibitor.237 Although ARBs have no direct effects

Unlike hypersensitivity reactions, many pseudoal-
lergic reactions can be prevented by the adminis-
tration of pretreatment regimens. Recommended
pretreatment regimens for selected agents are pro-
vided in Table 6–8. In addition, some pseudoaller-
gic reactions are best prevented by avoidance of
the causative agent and other pharmacologically
similar drugs in the future.
ACE Inhibitors
Patients with ACE-inhibitor–induced angioedema
should be educated to avoid all ACE inhibitors in
the future. Reexposure to the causative agent or to
another ACE inhibitor may result in more severe
reactions.236 In addition, at least 20 cases of
angioedema associated with the use of an
angiotensin-receptor blocker (ARB) have been pub-
lished.126-129,237 A review of 19 cases of ARB-induced
angioedema revealed that 6 of the 19 patients
(32%) had a history of angioedema to an ACE
on the catabolism of bradykinin or substance P, it
is postulated that they may cause vasodilation and
increased vascular permeability through indirect
effects on bradykinin or histamine.168,238 ARBs are
not contraindicated in patients with a history of
ACE-inhibitor–induced angioedema, but they
should be used with caution after careful weighing
of the perceived benefits and risks of therapy.
Gavras and Gavras238 described 10 patients with a
history of ACE-inhibitor–induced angioedema who
were subsequently treated with an ARB without
incident.
Salicylates
A patient with a history of an allergic or allergic-
like reaction to a salicylate presents a clinical chal-
lenge to the caregiver. Aspirin and NSAIDs can
cause both true hypersensitivity reactions (e.g.,
ibuprofen-induced anaphylaxis)239 and pseudoal-
lergic reactions (e.g., exacerbations of asthma,

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.
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CHAPTER 6 • Drug Allergy, Pseudoallergy, and Cutaneous Diseases
urticaria, angioedema). In this setting, it is crucial
to obtain an accurate allergy history. If a patient’s
history suggests reactivity to a specific NSAID and
lack of reactivity to NSAIDs of other chemically
dissimilar classes, a true hypersensitivity reaction
should be suspected.12 Such patients should be
advised to avoid the specific NSAID and any struc-
turally similar agent (e.g., all propionic acid deriv-
atives) because of the risk of cross reactivity. In
patients with asthma who describe an exacerbation
after the administration of aspirin or another COX-
1 inhibitor, a pseudoallergic reaction should be sus-
pected.12 These patients are at risk of severe asthma
exacerbations resulting from the pharmacologic
effects of aspirin and other potent COX-1
inhibitors on prostaglandin and leukotriene syn-
thesis.169 Patients with aspirin- or NSAID-induced
asthma should be advised to avoid all COX-1
inhibitors.12,169 Studies of short duration involving
small numbers of patients with aspirin-induced
asthma have shown that the COX-2 inhibitors,
celecoxib and rofecoxib, do not exacerbate asth-
ma.240-242 In addition, acetaminophen at a dose of
less than 1g, sodium salicylate, choline salicy-
lamide, and magnesium trisalicylate have not been
shown to exacerbate asthma because of their lack
of effect on the COX-1 enzyme. In some patients
with NSAID-induced asthma, desensitization to
aspirin or other NSAIDs has been achieved.243
Rapid desensitization protocols for patients with
cardiovascular disease requiring aspirin have also
been described.244
Radiocontrast Media
Pseudoallergic reactions associated with radiocon-
trast agents are largely prevented by the use of pre-
treatment regimens, as noted in Table 6–8. In
addition, administration of a low-osmolarity agent
in conjunction with pretreatment has been shown to
lower the risk of reactivity to approximately 1%.245
MANAGEMENT
Recommended treatment regimens for drug allergy
vary based on the signs and symptoms of the reac-
tion and the type of allergic syndrome. Reactions
mediated by pseudoallergic mechanisms are treat-
ed in a manner similar to those of true hypersensi-
tivity reactions, with the choice of therapy based
on the patient’s signs and symptoms. Table 6–9
provides a summary of recommended treatments
for a variety of allergic syndromes.
In 2005, the Joint Task Force of the American
Academy of Allergy, Asthma and Immunology
75
(AAAI) and the American College of Allergy,
Asthma, and Allergy (ACAAA) updated the
Practice Parameter on the Diagnosis and
Management of Anaphylaxis.170 On the basis of
these guidelines, patients with stridor, respiratory
distress, wheezing, hypotension, cardiac arrhyth-
mias, shock, or loss of consciousness require
immediate treatment. Life-threatening conditions
may also develop in patients with non-life-threat-
ening symptoms on initial presentation (e.g.,
localized urticaria) .170 Table 6–9 summarizes the
Joint Task Force’s guidelines for treatment of ana-
phylaxis. The mainstays of therapy are epineph-
rine 1:1,000 dilution administered subcutaneously
or intramuscularly, a histamine H1-receptor block-
er administered intravenously, and aggressive
intravenous fluid replacement. In studies of adults
and children not experiencing anaphylaxis, epi-
nephrine has been shown to be most efficiently
absorbed when administered intramuscularly,
rather than subcutaneously.246 In adults, the pre-
ferred intramuscular site of injection is the antero-
lateral thigh, because of a higher rate of
absorption.247 In patients with hypotension that is
refractory to epinephrine and intravenous fluid
replacement, the addition of a histamine H2-recep-
tor blocker is advised. Patients receiving long-term
␤-blocker therapy by either oral or topical routes
usually require higher doses of epinephrine.170 In
these patients, anaphylaxis is often severe and
associated with profound hypotension or brady-
cardia that are unresponsive to epinephrine.
Glucagon may be used in these patients for its
inotropic and chronotropic effects that occur
independently of ␤-receptor responsiveness.
Corticosteroids have no role in the acute treat-
ment of anaphylaxis, except for patients with a
history of asthma or idiopathic angioedema; how-
ever, they are used adjunctively to prevent the
late-phase reaction. Patients treated long term
with ACE inhibitors may also require aggressive
treatment for hypotension associated with ana-
phylaxis. In these patients, the release of
angiotensin II as a normal compensatory mecha-
nism will be blunted.
Treatment of immune complex diseases is high-
ly variable and dependent on the patient’s presen-
tation. In many cases, discontinuation of the
causative drug is the only treatment required.
Supportive therapy may include a mild
analgesic/antipyretic, such as acetaminophen, for
flu-like symptoms. An oral antihistamine should be
considered in patients with pruritus associated with
an urticarial, maculopapular, or mixed skin rash. In
some patients, a short course of a low-dose oral cor-
ticosteroid such as methylprednisolone may be
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76 SECTION II • Drug-Induced Dermatologic Diseases

TABLE 6–9 Management of Drug Allergy

Anaphylaxis164,165,170
• Discontinuation of the offending agent
• Establish and maintain airway
• Place patient in a recumbent position
• lower extremities
• Oxygen 4–10 L/min
• Administer IV fluids (0.9% sodium chloride or Ringer’s lactate 1–2 L initially) for hypotension
• Epinephrine (adults) 0.2–0.5 mL of a 1:1,000 (1 mg/mL) dilution SC or IM every 5 min as needed to maximum of 1 mg
per dose
• Epinephrine (children): 0.01 mg/kg of body weight (up to a maximum of 0.3 mg per dose, or 0.3 mL) of a 1:1,000
(1 mg/mL) dilution every 5 min SC or IM for 2 doses, then every 4 hr as needed
• Diphenhydramine 1–2 mg/kg body weight or 25–50 mg per dose IM/IV; then 25–50 mg orally every 4–6
hr; maximum daily dose of 300 mg (children) and 400 mg (adults)
• Corticosteroids (methylprednisolone 1–2 mg/kg IV every 4–6 hr (adults) for 24 hr; 1–2 mg/kg (maximum, 125 mg ) IV
or orally every 6 hr for 24 hr (children); then 1–2 mg/kg/day IV or orally
• Ranitidine 50 mg (adults) or 12.5–50 mg (1 mg/kg) in children, diluted in D5W to a volume of 20 mL
administered IV over 5 minutes; given every 6–8 hr
• Glucagon 1–5 mg (20-30 ␮g/kg) given IV over 5 min followed by an IV infusion of 5–15 mcg/min
• Nebulized albuterol 2.5–5 mg in 3 mL saline every 20 min for 3 doses; in children, 0.15 mg/kg via nebulizer every 20
min for 3 doses.
• Dopamine 400 mg in 500 mL; 2–5 ␮g/kg/min initially, then titrated to response
Angioedema
• Discontinue the causative agent.
• Establish and maintain airway.
• Treatment is based on the extent and severity of the clinical presentation. Treatment may include:
• Histamine H1 antihistamines (see “Urticaria,”)
• Epinephrine (see “Anaphylaxis”)
• Corticosteroids (see “Anaphylaxis”)
• Nebulized ␤2-agonists (see “Anaphylaxis”)
Urticaria248
• Discontinue the causative agent.
• First-line therapy: nonsedating antihistamines such as cetirizine 5–20 mg daily or in divided doses; loratidine
5–10 mg daily in morning; fexofenadine 180 mg daily or 60 mg twice a day
• Second-line therapy: hydroxyzine hydrochloride 10–100 mg daily at bedtime or in divided doses, diphenhydramine 12.5 to
100 mg per dose every 4 to 6 hr as needed
• Third-line therapy: doxepin 25–100 mg/day (adults); 25–50 mg/day initially up to a maximum of 100 mg/day (adoles-
cents); 1–3 mg/kg/day (children)
• Combinations of antihistamines is also recommended.
Serum sickness–like disease55,175
• Short course of methylprednisolone
• Corticosteroids (1–2 mg/kg prednisone or equivalent) once daily or administered in 2 divided doses for 5 days (if
severe systemic event)
Vasculitis69-71
• Discontinue the offending agent.
• Histamine H1-receptor antagonist (diphenhydramine or hydroxyzine) for pruritus
• Corticosteroids (1 mg/kg prednisone or equivalent) in divided doses for 7–14 days or bolus IV therapy with 15
mg/kg/day for 3 days followed by 1 mg/kg/day orally
Hypersensitivity Syndrome174
• Discontinue the offending agent.
• Systemic corticosteroids (ⱖ 0.5 mg/kg/day prednisone or equivalent)
D5W = 5% dextrose in water; IM = intramuscularly; IV = intravenously; SC = subcutaneously.
TisdaleC06_49-97 1/20/10 10:54 PM Page 77
CHAPTER 6 • Drug Allergy, Pseudoallergy, and Cutaneous Diseases
used for treatment of a diffuse erythematous, mac-
ulopapular skin rash. High-dose corticosteroids (i.e.,
prednisone 40 to 60 mg/day) should be reserved for
patients with systemic events involving the kidney
or liver, patients with drug hypersensitivity syn-
dromes, or patients with vasculitis.175 The presence
of mucosal involvement (i.e., SJS or TEN) often pre-
cludes the use of systemic corticosteroids because of
the risk of infectious complications.175
INFORMATION FOR PATIENTS
Patients in whom an allergic reaction to a drug
develops should be educated as to the name of the
specific drug, the terminology used to describe the
reaction, and the likelihood of having a similar or
more severe reaction upon reexposure to the drug.
If the reaction was severe (e.g., anaphylaxis, SJS),
the patient should be advised to wear a Medic-Alert
tag or bracelet describing the reaction. In the case
of a severe anaphylactic or anaphylactoid reaction
to a drug or chemical, the patient may be pre-
scribed injectable epinephrine in an easily
injectable form (e.g., EpiPen or EpiPen Jr.) for use
in an emergency situation. Such patients should be
advised to have at least two doses of epinephrine in
their possession, particularly if they live in a rural
area without direct access to emergency care. In
addition, these patients must be counseled regard-
ing the appropriate administration technique to
ensure rapid absorption (i.e., intramuscularly into
the anterolateral thigh).
Patients with a history of allergy to a drug or
multiple drugs should be encouraged to ask ques-
tions about newly prescribed medications. For
example, a patient allergic to a sulfa drug should be
advised to question whether any newly prescribed
medication is considered a “sulfa medication.”
Patients with aspirin-induced asthma or reactions to
excipients should be encouraged to read the labels
of nonprescription medications to identify ingredi-
ents of concern. In addition, patients should be edu-
cated regarding the avoidance of the causative drug
and other cross reactive drugs in the future.
CUTANEOUS DISEASES
The spectrum of adverse cutaneous reactions
ranges from the commonly occurring, often self-
limiting erythematous rash to the rare, life-threat-
ening severe cutaneous adverse reactions (SCARs).
Approximately 30 different drug-mediated cuta-
neous reaction patterns have been described.252
This section will address drug-induced acne, ery-
77
thematous reactions, fixed drug eruptions, psoria-
sis, and the SCARs (DRESS, SJS, TEN, warfarin tissue
necrosis). The previous section provides discussion
of urticaria, angioedema, and skin reactions associ-
ated with immune complex diseases. Chapter 8
provides a review of drug-induced photosensitivity.
Standard terms are used to describe the mani-
festations of drug-induced cutaneous reactions. A
listing of these terms and their definitions is pro-
vided in Table 6–10.252,253
TABLE 6–10 Glossary of Terms for Drug-Induced
Cutaneous Diseases252, 253
• Bullae
• Vesicle filled with serous fluid, >1 cm
• Comedone (open)
• Blackhead; dilated hair follicle filled with sebum
and bacteria with a blackened mass of skin debris
at the surface
• Comedone (closed)
• Whitehead; dilated hair follicle filled with sebum
and bacteria with an obstructed opening to the skin
• Macule
• Circumscribed, nonpalpable, red, flat lesion, <1 cm
• Nodule
• Papule that is firm and with depth, 0.5–2 cm
• Papule
• Solid, palpable, red elevated lesion, <1 cm
• Patch
• Group or cluster of macules
• Plaque
• Solid, palpable, elevated solid lesion, 0.5 cm
• Pustule
• Vesicle filled with purulent material
• Typical target or iris lesion253
• Lesion <3 cm in diameter, regular round shape,
well-defined border with at least three different
zones (two concentric rings around a central area);
one ring consists of palpable edema, paler than
the central area
• Target lesion (flat, atypical)253
• Round lesions with only two zones and/or a
poorly defined border and nonpalpable, with the
exception of a potential central blister
• Wheal
• Central blister, irregular, pink in color, superficial
area of skin edema
• Vesicle
• Circumscribed, elevated lesion filled with serous
fluid, 0.5 cm
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78 SECTION II • Drug-Induced Dermatologic Diseases
CAUSATIVE AGENTS
Identifying the most likely cause of a potential
drug-induced cutaneous reaction is complicated by
the fact that almost all drugs have been associated
with rash as described in the product literature. To
streamline the assessment of causality, it is impor-
tant to consider that antimicrobial agents have
been consistently identified as the most frequent
offenders in cutaneous eruptions, followed in fre-
quency by the NSAIDs.166,254,255
Based largely on reports of single cases, more
than 100 drugs have been implicated as causative
of SJS or TEN.253,254 In a large international
case–control study, Roujeau et al.254 attempted to
quantify the association between the use of specif-
ic medications and the development of SJS and
TEN. Cases (n = 245) were patients admitted to the
hospital with a diagnosis of SJS or TEN, and con-
trols (n = 1,147) were patients admitted to the
same hospital for an elective procedure or treat-
ment of an acute condition not deemed to be drug-
related. Of the drugs used for short periods,
sulfonamides were the most strongly associated
with TEN (crude relative risk [RR], 172; 95% CI,
75–396], with trimethoprim–sulfamethoxazole
accounting for 69% of these cases.254 Thiazide
diuretics and sulfonylureas were not associated
with increased risk. In descending order of fre-
quency, other major drug offenders were
chlormezanone (crude RR, 62; 95% CI, 21–188),
cephalosporins (crude RR, 14; 95% CI, 3.2–59),
quinolones (crude RR, 10; 95% CI 2.6–38), tetracy-
clines (crude RR, 8.1, 95% CI, 1.5–43), aminopeni-
cillins (crude RR, 6.7; 95% CI, 2.5–18), and
imidazole antifungals (crude RR, 24; 95% CI,
5.5–104).254 Of the drugs administered for a dura-
tion of months to years, significantly increased
risks were associated with carbamazepine, pheno-
barbital, phenytoin, valproic acid, the oxicam
NSAIDs, allopurinol, and corticosteroids. The first
2 months of long-term drug administration was
identified as the highest-risk period. In 2007, the
results of the Euro-SCAR study offered an update
on the risks of SJS/TEN with newly marketed med-
ications.256 In this international, multicenter
case–control study, 379 patients with SCAR and
1,505 controls were enrolled. The results of this
study confirmed the high associated risks previous-
ly identified with the use of antiinfective sulfon-
amides, allopurinol, carbamazepine,
phenobarbital, phenytoin, and the oxicam
NSAIDs.256 An increased risk of SJS/TEN was also
identified with the use of nevirapine (RR, >22) and
lamotrigine (RR, >14), with weaker associations
identified with sertraline (RR, 11; 95% CI, 2.7–46),
pantoprazole (RR, 18; 95% CI, 3.9–85), and tra-
madol (RR, 20; 95% CI, 4.4–93).256 The majority of
SCAR cases occurred within 8 weeks of drug initia-
tion. Onset of the SCAR within 4 to 28 days after
drug initiation was most suggestive of the drug as
the cause.
The medications most commonly associated
with the development of skin eruptions are listed
in Table 6–11.147,175,228,229,253,254,256-281 In addition to
prescription medications, it is important to consid-
er that SCARs have been associated with the use of
nonprescription drugs (e.g., pseudoephedrine),
and traditional Chinese herbal medications.282
EPIDEMIOLOGY
Cutaneous and mucocutaneous events are the
most commonly reported adverse reactions to
medications. Based on the results of the Boston
Collaborative Drug Surveillance program conduct-
ed in the 1970s and 1980s, it is estimated that a
drug-related skin rash develops in 2% to 3% of all
hospitalized patients.179 In this prospective study
of 37,000 hospitalized patients, the majority of the
skin reactions were exanthematous (94%) and
urticarial (5%). Approximately 2% of the reactions
were fatal.179 Epidemiologic studies conducted in
the 1990s focused on estimating the incidence of
SCARs. Compared to exanthematous reactions,
SCARs appear to be relatively rare. In 1995,
Roujeau et al.175 estimated that serious cutaneous
drug events including SJS and TEN occur in 1 of
every 1,000 hospitalized patients.
Estimates of the prevalence of drug-induced
cutaneous events have been determined from
prospective studies of hospitalized patients, outpa-
tients, patients receiving systemic drug therapy,
and those exposed to medications via any route of
administration.179,255,283 The estimates have varied
based on the type of cutaneous event investigated,
the definition used to describe the dermatologic
condition, and the population studied. In a 6-
month prospective study conducted in 2000–2001,
all suspected allergic cutaneous reactions that led
to hospitalization or occurred during hospitaliza-
tion were identified by practitioners and subse-
quently assessed by a dermatologist.255 Causality
was evaluated retrospectively by a group of derma-
tologists and pharmacologists. A total of 48 cases
were identified, resulting in an estimated preva-
lence of 3.6 of 1,000 hospitalized patients.255 The
majority of the allergic reactions were exanthema-
tous (56%), and the prevalence was significantly
higher (P<0.001) in medical patients (0.5%) as
TisdaleC06_49-97 1/20/10 10:54 PM Page 79

CHAPTER 6 • Drug Allergy, Pseudoallergy, and Cutaneous Diseases 79

TABLE 6–11 Agents Implicated in Drug-Induced Cutaneous Diseases

Drug Incidence Level of Evidence
(see page xii for explanation)

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)
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80 SECTION II • Drug-Induced Dermatologic Diseases

TABLE 6–11 Agents Implicated in Drug-Induced Cutaneous Diseases (Continued)

Drug Incidence Level of Evidence

DRESS (Continued)
Minocycline175,253 NK C
NSAIDs175,253 NK C
Phenytoin175,253 NK C
Phenobarbital175,253 NK C
Sulfonamides175,253 NK B
Teicoplanin269 NK C
Vancomycin269 NK C
PSORIASIS
ACE inhibitors270,271 NK C
␤-Blockers270,271 NK B
Chloroquine270,271 NK C
Etanercept273 NK C
Granulocyte colony-stimulating factor272 NK C
272
Growth hormone NK C
Hydroxychloroquine270,271 NK B
Imatinib270 NK C
Infliximab273,274 NK C
Interferon-alfa and interferon-⌼270,271 NK C
Lithium270,271 NK B
NSAIDs270,271 NK C
Tetracyclines270,271 NK C
Terbinafine270,271 NK C
STEVENS–JOHNSON SYNDROME/TOXIC EPIDERMAL NECROLYSIS275
Allopurinol276 NK B
Aminopenicillins175 NK B
Celecoxib228 NK C
Cephalosporins175 NK B
Ciprofloxacin256 NK C
Imidazole antifungal agents254,256 NK B
Lamotrigine256 NK B
Levofloxacin277 NK C
Mesalamine278 NK C
Modafinil279 NK C
Nevirapine256 NK B
Pantoprazole256 NK B
Phenobarbital175 NK B
Phenytoin175 NK B
Piroxicam256 NK B
Sertraline256 NK B
Tramadol256 NK C
(Continued)
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CHAPTER 6 • Drug Allergy, Pseudoallergy, and Cutaneous Diseases
TABLE 6–11 Agents Implicated in Drug-Induced Cutaneous Diseases
Drug
STEVENS–JOHNSON SYNDROME/TOXIC EPIDERMAL NECROLYSIS275
Trimethoprim–sulfamethoxazole175,254
Valdecoxib229
Valproic acid256
Voriconazole280
SKIN NECROSIS
Warfarin175,257,281
a = prevalence; ACE = angiotensin-converting enzyme; DRESS = drug rash with eosinophilia and systemic symptoms; HHV-6 = human
herpesvirus 6; NK = not known; NSAIDs = nonsteroidal antiinflammatory drugs.
compared to surgical patients (0.01%).255 Thirty-
four percent of cases were deemed serious on the
basis of being responsible for the hospitalization
(18%), increasing the duration of hospital stay
(14%), or being life-threatening (2%).255 Compared
to other studies reporting an incidence of cuta-
neous drug reactions of 2% in hospitalized
patients, the lower prevalence determined in this
study can be attributed to the restricted focus on
allergic-mediated skin reactions and on systemic
drug exposures.255
TEN is estimated to occur in 0.4 to 1.3 cases per
million person-years, while SJS occurs in 1 to 6
cases per million person-years.253,275 The variability
in these estimates of incidence can be attributed to
differences in the diagnostic criteria for SJS and
TEN. The prevalence or incidence of other cuta-
neous skin disorders is less well described. The inci-
dence of DRESS is highly variable, occurring in 1 of
1,000 to 1 of 10,000 patients exposed to anticon-
vulsants and sulfonamides, and the mortality rate
has been estimated to be approximately 10%.253
The wide variability in the reported incidence of
DRESS can be attributed to the variable presenta-
tion of the condition. Fixed drug eruptions occur
more frequently, with reported incidences of 2.5%
to 22%.268 Tissue necrosis has been reported in 1 of
10,000 patients treated with warfarin and in 0.01%
to 0.12 % of patients treated with all oral anticoag-
ulants including the coumarin products.175,281
MECHANISMS
Cutaneous reactions to drugs can result from both
allergic and nonallergic mechanisms (i.e., direct
pharmacologic effects, pseudoallergy, idiosyncrasy).
Hypersensitivity is the underlying mechanism in
50% of the events, including most cases of urticaria,
81
(Continued)
Incidence Level of Evidence
NK B
NK C
NK C
NK C
1 in 10,000a B
angioedema, serum sickness–like syndrome with
maculopapular rash, fixed drug eruptions, vasculi-
tis, and the SCARs, including DRESS, SJS, and TEN.
The skin is a target for immunologically mediated
reactions because it possesses APCs such as the cuta-
neous Langerhans’ cells. The presence of monooxy-
genases, cytochromes, and transport-associated
proteins in the keratinocytes allow for transforma-
tion of low-molecular-weight drug haptens into
reactive, immunogenic metabolites.284
T cells play a major role in the pathophysiology
of drug-related cutaneous reactions. An extensive
review of the role of the T lymphocyte in the medi-
ation of a variety of drug-induced eruptions
has been provided by Naisbett.285 Based on
immunohistologic studies, allergy-mediated macu-
lopapular rashes have been shown to involve the
recruitment of CD4 cells and co-presentation of the
drug hapten with MHC class II molecule HLA-
DR.285 Maculopapular rashes are also associated
with the secretion of high levels of IL-5 and eotax-
in, two cytokines involved in the recruitment and
differentiation of eosinophils. Bullous reactions are
more likely to be associated with the recruitment of
CD8+ cells and co-presentation of the haptenic
drug or reactive metabolite with MHC class I mole-
cules.285 Cell studies of blister fluid from patients
who survived TEN also support a dominant role for
T lymphocytes, particularly CD8+ cells, in the
pathogenesis of this SCAR. In patients with TEN,
activation of cytotoxic T lymphocytes ultimately
results in dermal-cell apoptosis, which is believed to
be triggered via activation of the perforin/granzyme
or the Fas–Fas ligand pathways. In addition to cyto-
toxic T lymphocytes, other mediators of TEN
include monocytes, macrophages, and tumor
necrosis factor ␤ (TNF-␤). Overexpression of TNF-␤,
interferon-␤, IL-2, and IL-5 has been reported in
skin lesions of patients with SJS and TEN.253
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82 SECTION II • Drug-Induced Dermatologic Diseases
Mechanisms by which many drugs cause skin
eruptions are not known. Pharmacologic effects
may be the underlying mechanism by which most
drugs cause acneiform eruptions and provocation
of psoriasis. Androgenic drugs (e.g., anabolic
steroids, danazol, methyltestosterone) aggravate
preexisting acne or cause acneiform eruptions by
activating sebaceous-gland hypertrophy and
increasing sebum production. The high incidence
of acneiform eruptions associated with the use of
epidermal growth factor receptor (EGFR) inhibitors
may also be explained in part by the known phar-
macology of these agents. EGFRs are overexpressed
in many solid tumors, explaining the effectiveness
of EGFR inhibitors in the treatment of refractory
colorectal and lung cancers. EGFRs are also
expressed in the basal layer of the epidermis and in
the hair follicle.261,262 Although the mechanism by
which EGFR inhibitors cause acne-like rashes is not
entirely known, the dose-related incidence may be
related to inhibition of EGFR signaling on epider-
mal epithelium leading to impaired cell growth
and differentiation.261 Provocation of psoriasis by
nonselective ␤-blockers such as propranolol may
be explained in part by blockade of epidermal ␤2-
receptors, resulting in a decrease in intraepidermal
cyclic adenosine monophosphate and an increase
in epidermal-cell turnover.270 Cyclooxygenase
inhibitors such as indomethacin may induce psori-
asis by inhibiting prostaglandin synthesis, thereby
shunting the metabolism of arachidonic acids to
the lipoxygenase pathway. The resultant increase
in leukotriene concentrations may contribute to
the exacerbation of psoriasis in patients treated
with COX inhibitors.271 Studies support that
leukotriene concentrations are 7 to 11 times high-
er in psoriatic lesions as compared with normal
skin.270
CLINICAL PRESENTATION AND
DIFFERENTIAL DIAGNOSIS
The discriminating features of specific drug erup-
tions are provided in Table 6–12 and the condi-
tions to consider in the differential diagnoses are
provided in Table 6–13.
The most common type of drug-induced skin
eruption is the exanthematous or maculopapular
rash. This red, inflamed cutaneous reaction usually
appears as a mixture of discrete macules and
papules on the trunk or dependent areas of the
body (e.g., lower extremities of an ambulating
patient, middle to lower back of a bedridden
patient). The lesions typically spread outward in a
bilateral, symmetrical pattern to involve the neck,
upper and lower extremities, and potentially the
face.257,286 The rash is often described as “dot-like”
in appearance, or measles (morbilliform)-like, and
may or may not be associated with fever and pruri-
tis. The discrete lesions typically coalesce over days
into patches with large areas of confluence. The
rash usually occurs within 4 to 14 days after the
initiation of therapy with the causative drug or
within 1 to 2 days after drug discontinuation.286
This reaction is usually self-limited, with resolution
in 1 to 2 weeks after drug discontinuation. Upon
reexposure to the drug, the rash may reappear
within hours. In rare instances, a maculopapular
rash may be the initial sign of a severe cutaneous
event such as SJS. Therefore, all patients who pres-
ent with a maculopapular rash should be assessed
for hallmark signs of a more severe, progressive
reaction. Lesions in the mucous membranes (e.g.,
conjunctiva, oral cavity, naries, genitalia) are evi-
dent in more than 90% of serious cutaneous events
and extension of the rash to the palms and soles
often portends a more protracted course.175,253
A commonly encountered clinical challenge is
differentiation of a maculopapular rash from an
urticarial lesion. Unlike maculopapular lesions,
urticarial lesions are typically asymmetrical, pink
rather than red, and irregular in shape. These
superficial wheals, largely confined to the epider-
mis, are often described as geographic in shape
(i.e., similar in shape to the continent of Africa or
Asia). Urticarial lesions are highly pruritic, vary in
size from 1 mm to several centimeters in diameter,
and typically develop on the chest, face or neck
within minutes to 48 hours after drug exposure.257
Differentiation of a maculopapular rash from
urticaria is important, because the latter often indi-
cates IgE-mediated mast-cell degranulation. In a
patient with drug-related IgE-mediated urticaria,
continuation of the causative drug may lead to a
more severe reaction, including angioedema or
anaphylaxis. Urticaria may also be caused by foods,
insect bites/stings, and environmental factors such
as sunlight, cold, and heat.257
Fixed drug eruptions (FDEs) are the second
most commonly occurring drug- related cutaneous
reaction.252 FDEs present as solitary lesions or mul-
tiple well-demarcated lesions occurring anywhere
on the body, but favoring the face, lips, hands, feet,
and genitalia. The lesions are round or oval in
shape and range in size from 1 to 20 cm in diame-
ter.252,257 The color of the lesions may vary from
dusky red, to blue-gray or violaceous. Patients typ-
ically describe a burning sensation or itching, or
both, associated with the development of lesions.
In some patients, the center of the lesion may
become bullous and result in denuding of skin. The
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CHAPTER 6 • Drug Allergy, Pseudoallergy, and Cutaneous Diseases 83

TABLE 6 –12 Signs and Symptoms Associated with Cutaneous Diseases

Acne257
• Papules and pustules on face and upper trunk
• Limited number of comedones to no comedones
Erythematous rash166,286
• Symmetrical distribution of macules and papules starting on upper trunk or legs
• Rash may progress to entire body including face
• Pruritus (50%)
DRESS253,287
• High fever (38–40°C)
• Diffuse, symmetrical maculopapular rash with pruritus (90%)
• Facial and periorbital edema
• Enlarged lymph nodes at at least two sites (cervical and inguinal)
• Involvement of at least one internal organ (hepatitis, pneumonitis, pancreatitis)
• Conjunctivitis
• Eosinophilia
• Atypical lymphocytosis
Fixed drug eruption166,252
• Initial burning sensation or itching of skin
• Round or oval dusky red to violaceous lesions, 1–20 cm in diameter, favoring the face, lips, hands, feet, perineal area,
genitalia
• Blistering of lesions
• Anorexia and malaise (infrequent)
• High fever (infrequent)
• Hyperpigmentation in the area of the lesion following recovery
Psoriasis
• Red or salmon-pink plaques covered by silvery scales symmetrically distributed on elbows, knees, scalp and lum-
bosacral region
SJS/TEN175,253,275
• Prodrome of nausea, vomiting, sore throat, cough, arthralgias, myalgias for 2–8 days before rash development
• Widespread erythematous, purpuric rash with flat atypical target lesions
• Burning and painful sensation of the skin
• Fever (10–30% of cases of SJS, 100% of cases of TEN)
• Facial edema
• Mucosal lesions of the mouth, lips, nasal cavity, conjunctivae, genitalia (92–100% of cases of SJS; 85–95% of cases of TEN);
• Epidermal detachment (<10% of body-surface area with SJS; >30% of body-surface area with TEN)
• Positive Nikolsky sign (TEN)
• Neutropenia (30% of cases of SJS and TEN)
• Lymphopenia (90% of cases of TEN)
• Thrombocytopenia (15% of cases of TEN)
• Prerenal azotemia (TEN)
• Elevated aspartate and alanine aminotransferases (50% of cases of SJS and TEN)
• Hypopigmentation or hyperpigmentation (88% of cases of TEN)
• Keratitis and corneal erosions
Warfarin-Induced Skin Necrosis175,257,281
• Poorly demarcated, painful red plaques with soft-tissue edema
• Pain
• Petechial hemorrhages that coalesce into large hemorrhagic bullae with areas of gangrenous tissue
• Lesions usually distributed in areas of fatty tissue (buttocks, breasts, hips)
DRESS = drug rash with eosinophilia and systemic symptoms; SJS = Stevens–Johnson syndrome; TEN = toxic epidermal necrolysis.
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84 SECTION II • Drug-Induced Dermatologic Diseases

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
lesion in the same anatomical location after drug
rechallenge.268 Both topical and oral provocation
tests have been performed to confirm the diagno-
sis. However, oral challenge is more likely to lead
to the development of generalized bullous
lesions.268 Following resolution of lesions, the
affected tissue may remain hyperpigmented for an
extended period. As the name implies, the sole
cause of FDE are drugs. Therefore, a complete drug
history with attention to prescription, nonpre-
scription and herbal remedies must be obtained to
identify the causative agent. Drugs most common-
ly associated with FDE are listed in Table 6–11.
Acneiform eruptions are an infrequent drug-
induced adverse event, accounting for only 1% of
all drug-related cutaneous reactions.257 Unlike acne
vulgaris, drug-related acneiform eruptions consist
primarily of papules and pustules with limited to
no comedones. Similar to those associated with
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CHAPTER 6 • Drug Allergy, Pseudoallergy, and Cutaneous Diseases
acne vulgaris, the eruptions are typically confined
to the face and upper trunk.257 The classic drug
offenders are corticosteroids, adrenocorticotropic
hormone, anabolic steroids, combination oral con-
traceptives, danazol, bromides, iodides, isoniazid,
lithium, and azathioprine. Corticosteroids admin-
istered orally, parenterally, topically, or by inhala-
tion have been shown to provoke acneiform
eruptions or exacerbate underlying conditions of
acne.258,259,260 Steroid-induced acne is common and
usually appears within 14 days after initiation of
systemic or topical therapy. An acne-like reaction
has also been described in association with the use
of the EGFR inhibitors (e.g., cetuximab, panitu-
mumab, erlotinib, gefitinib) used in the treatment
of colorectal and non-small-cell lung cancer. The
acne-like rash is pruritic, with a predominance of
pustules and an absence of open or closed come-
dones.261,262 The rash is typically mild to moderate
in severity, occurs most frequently on the face and
V-shaped areas of the chest, back, or both and
appears within 10 to 14 days after drug therapy ini-
tiation. The severity of the rash has been shown to
correlate with both increasing drug dose and the
antitumor activity of the agent.262 Some data sup-
port a relationship between the occurrence of rash
and the increased likelihood of patient survival.261
In patients with severe rashes, particularly those
involving more than 50% of the body-surface area,
dose modification or interruption of EGFR
inhibitor therapy is recommended.261,262 The rash
is typically reversible following discontinuation of
therapy.
Psoriasis is a chronic, immunologically mediat-
ed skin disease that is characterized by red or
salmon-pink plaques covered by silvery or white
scales surrounded by normal skin.270 The plaques
are symmetrically distributed on the elbows, knees,
scalp and lumbosacral region. Several clinical phe-
notypes of psoriasis exist, including pustular, ery-
throdermic, and nail psoriasis. However, 90% of
cases present as plaque psoriasis (psoriasis vul-
garis). This chronic condition involves the activa-
tion of T lymphocytes with overexpression of a
number of cytokines, including tumor necrosis fac-
tor ␤, interferon-␤, IL-6, IL-2, and IL-8. Drugs can
exacerbate preexisting lesions (e.g., ␤-blockers,
lithium, synthetic antimalarial drugs), provoke the
development of new plaques on the normal skin of
patients with psoriasis (e.g., ␤-blockers, lithium),
and cause psoriasis in patients with no history or
familial predisposition (e.g., growth hormone).270-
273
Most cases of drug-induced psoriasis are clinical-
ly indistinguishable from psoriasis from
non-drug-induced causes. In some cases, the
offending drug can cause a lichenoid pattern of
85
disease or a transformation to the pustular form of
psoriasis.270 The latency period from initiation of
therapy with the offending drug to the exacerba-
tion or appearance of psoriatic lesions varies wide-
ly. Mean latency periods of 3 weeks, 6 weeks, and
33 weeks have been described for psoriasis induced
by the synthetic antimalarial drugs, ACE
inhibitors, and lithium, respectively.270 ␤-Blockers
have been associated with a latency period ranging
from days to weeks after initiation of therapy.
Drugs used to treat psoriasis, including topically
applied agents (e.g., coal tar) and systemically
administered agents (e.g., etretinate, etanercept,
infliximab) can also aggravate the condition. The
tumor necrosis factor ␣ agents infliximab and etan-
ercept have aggravated psoriasis in patients under-
going treatment for psoriatic arthritis and have
provoked psoriasis in patients treated for Crohn’s
disease, ankylosing spondylitis, rheumatoid arthri-
tis, and ulcerative colitis.273 In patients treated with
infliximab or etanercept, new psoriatic lesions
developed as soon as after the second injection.273
Serious cutaneous adverse reactions include
DRESS, SJS, TEN, and warfarin tissue necrosis.
DRESS is a distinct clinical syndrome previously
described by the more general term, drug hyper-
sensitivity syndrome.84,92,287 DRESS is characterized
by the triad of high fever, rash, and internal organ
involvement.175,287 Compared with immune com-
plex diseases such as SSLD, DRESS is associated
with a more delayed onset of symptoms, ranging
from 3 to 8 weeks after drug initiation, and a more
consistent pattern of internal-organ involve-
ment.84,287 The initial manifestation of DRESS is dif-
fuse, symmetrical maculopapular eruptions on the
upper trunk and face. This rash can extend to
include the lower extremities and is typically asso-
ciated with facial and periorbital edema. The
edema may lead to gross distortion of the patient’s
features.253 Organs affected by this syndrome
include the kidney, liver, pancreas, lungs, and
hematologic system. A high degree of interpatient
variability exists with regard to the targeted organ
and the severity of organ involvement. Both the
anticonvulsant hypersensitivity syndrome and the
allopurinol hypersensitivity syndrome are classic
examples of DRESS. Anticonvulsant hypersensitivi-
ty syndrome, associated with the aromatic anticon-
vulsants (e.g., phenytoin, phenobarbital,
carbamazepine) is characterized by the triad of
fever (38–40°C), rash (papular, pruritic, often asso-
ciated with facial or periorbital edema), and lym-
phadenopathy occurring within 3 months after the
initiation of therapy.87,233 Other diagnostic criteria
include hematologic abnormalities (leukocytosis,
eosinophilia), myalgias, pharyngitis, and hepatitis
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86 SECTION II • Drug-Induced Dermatologic Diseases
or other multisystem involvement (e.g., interstitial
nephritis, rhabdomyolysis, pneumonitis).87,233
Allopurinol hypersensitivity syndrome is associat-
ed with a mean (±SD) onset of 47±109 days92 and
also presents with high fever, eosinophilia, and
skin rash that may be severe (e.g., SJS or TEN).
Kidney failure, hepatomegaly, and abnormalities in
liver-function tests are also frequently noted. This
reaction, attributed to the active metabolite oxy-
purinol, has been described as a vasculitic immune
complex disease.91,92
SJS and TEN are related mucocutaneous disor-
ders that are considered by many as severe variants
of erythema multiforme. Like erythema multi-
forme, both SJS and TEN are associated with the
widespread development of multiple types of skin
lesions, including macules, blisters, purpuric
lesions, and the hallmark target iris lesions. The
target lesion is discrete, round, <3 cm in diameter,
and identified by its central zone of epidermal
necrosis surrounded by two concentric rings of
edema and erythema.288 SJS and TEN are progres-
sive bullous disorders that are considered dermato-
logic emergencies.288 Unlike erythema multiforme,
which is usually self-limiting and related to recur-
rent herpes simplex viral infections, both SJS and
TEN are usually drug-related and extend from dif-
fuse erythematous reactions to include mucous
membrane erosion and epidermal detachment.
Drugs are the cause of SJS and TEN in 50% and
80% of cases, respectively.252,289
Both SJS and TEN typically occur within the
first 4 weeks of drug therapy. Before skin lesions
become evident, both SJS and TEN are associated
with a prodromal syndrome of nausea, vomiting,
sore throat, diarrhea, myalgias, and arthralgias. In
patients with TEN, high fevers and a burning sen-
sation of the skin are also frequently reported prior
to the eruption of skin lesions. Mucous membrane
involvement, typically of the mouth and lips, nasal
cavity, and conjunctivae, tends to precede the
development of skin lesions by 1 to 3 days.252,290
The initial lesions are erythematous and appear on
the face and upper trunk, after which they rapidly
evolve into blisters and target lesions on the face,
trunk, and limbs.290 Full-thickness epidermal
detachment occurs within days after the onset of
skin lesions. Rather than being thought of as two
distinctly different syndromes, SJS and TEN are
often described as a continuous spectrum of a dis-
ease, with TEN as the more severe form.288 The
extent of epidermal detachment has been used to
distinguish between SJS and TEN. SJS is described
by the presence of mucosal erosions with wide-
spread purpuric macules and epidermal detach-
ment of <10% of body-surface area, whereas TEN
involves widespread purpuric macules and epider-
mal detachment of >30% of body-surface
area.288,291 The term SJS–TEN overlap is used to
describe cases in which evidence of epidermal
detachment is present on 10% to 30% of the body-
surface area.288,291 Although regrowth of the epider-
mis begins within days after the onset of epidermal
loss, TEN is often complicated by the development
of acute kidney disease, respiratory failure, neu-
tropenia, electrolyte abnormalities, and sepsis.
Long-term sequelae of SJS and TEN may include
temporary nail loss, permanent visual impairment,
cutaneous scarring, and irregular pigmentation. A
severity-of-illness scoring system for TEN, known
as SCORTEN, has been described and evaluated as
a prognostic indicator.292 With the use of this sys-
tem, seven independent risk factors, determined
within 24 hours of patient presentation with TEN,
are used as patient outcome indicators.292
Warfarin-induced skin necrosis (WISN) is a
severe cutaneous reaction that typically begins
within 10 days after initiation of warfarin therapy,
with a peak occurrence between days 3 and 6.257
WISN initially presents with red, poorly demarcat-
ed painful plaques usually in areas of high adipose
tissue (e.g., breasts, hips, buttocks). The plaques
can progress to hemorrhagic blisters and eventual-
ly become necrotic, requiring surgical debride-
ment.175,257 WISN occurs as a result of an
imbalance between the concentrations of the
endogenous vitamin K–dependent anticoagulant,
protein C, and the vitamin K–dependent clotting
factors.175,257 The half-life of protein C is much
shorter (8 hours) as compared with those of clot-
ting factors II, IX, and X (24 to 48 hours). After
warfarin initiation, a rapid decline in the concen-
tration of protein C may lead to a hypercoagulable
state, resulting in WISN. This theory is supported
by the fact that WISN is more likely to occur in
patients who receive excessive starting doses of
warfarin and have an underlying protein C defi-
ciency. Patients with a deficiency of protein S, the
cofactor for protein C activity, may also be at
greater risk of WISN. WISN can be fatal if not
treated.
RISK FACTORS
Female sex,179 concomitant viral infection with
HIV190 or EBV,189 and the presence of autoim-
mune disease have routinely been identified as
risk factors for cutaneous drug eruptions. In a
prospective study of 48 patients with allergic-
mediated skin reactions, identified risk factors
were HIV (19% of patients), connective-tissue
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CHAPTER 6 • Drug Allergy, Pseudoallergy, and Cutaneous Diseases 87

disease (10% of patients), and viral or autoim-

mune hepatitis (12% of patients).255 In another TABLE 6–14 Risk Factors for Drug-Induced
prospective cohort study of hospitalized patients Cutaneous Diseases
with adverse cutaneous drug reactions, those Abacavir
with systemic lupus erythematosus had a relative • HHV-6192,193
risk of 4.68 (95% CI, 1.79–12.18) and patients Allopurinol
with acquired immunodeficiency syndrome had • Doses >200 mg per day276
a relative risk of 8.68 (95% CI, 2.18–33.19).293 • Kidney disease92,93
Studies have also been performed to identify pre-
dictors of skin rash associated with specific drugs Amoxicillin and Ampicillin
or drug classes. In the antiepileptic drug class, an • EBV38,189
increased risk of drug rash was identified in Aromatic Anticonvulsants (Carbamazepine,
women of reproductive age and in those with Phenobarbital, Phenytoin)
history of a rash induced by another antiepilep- • Previous rash in response to an antiepileptic
tic medication.294,295 The likelihood of rash asso- agent294,295
ciated with an antiepileptic medication was • Women of reproductive age294
shown to be significantly lower in patients with Carbamazepine
learning disabilities (OR, 0.41; 95% CI, • HLA-B* 1502297
0.20–0.78; P = 0.004).295 Other risk factors associ- Lamotrigine
ated with specific drugs, drug eruptions, or both • Age <16 yr296
are provided in Table 6–14. • Exceeding the recommended initial dose296
The initial dose, rate of dose titration, and con- • Coadministration with valproic acid296
comitant administration of interacting drugs can
be risk factors for cutaneous drug eruptions. Both Nevirapine
lamotrigine and nevirapine have been identified as • Female sex256
strongly associated with SJS/TEN in the EuroSCAR • Lack of adherence with recommendation for 14-day
study.256 In addition to female sex, lack of adher- lead-in dosing256
ence with the 14-day lead-in period of dosing of Penicillins
nevirapine may increase the risk of SCARs.256 • HIV190
Factors that have been shown to increase the risk Sulfonamides
of rash associated with lamotrigine include age <16 • HIV190
years, history of rash caused by another antiepilep- Warfarin
tic drug, exceeding the recommended initial dose, • Female sex281
exceeding the recommended rate of dose escala- • Hereditary protein C or S deficiency281
tion, and coadministration with valproic acid.296 In • Large initial doses281
the EuroSCAR study, daily allopurinol doses ≥200 • Obesity281
mg were associated with a higher risk of SJS/TEN
(OR, 36; 95% CI, 17–76) as compared with lower EBV = Epstein-Barr virus; HIV = human immunodeficiency virus;
daily doses (OR, 3.0; 95% CI, 1.1–8.4).256 In other HLA = human leukocyte antigen; HHV-6 = human herpesvirus 6.
analyses, both kidney disease and the lack of dose
adjustment in patients with impaired kidney func-
tion have been identified as risk factors for allop-
urinol-induced DRESS, SJS, or TEN.92 Excessive the allele.297 This allele occurs almost exclusive-
starting doses of warfarin, female sex, and obesity ly in patients of Asian and South Asian Indian
have all been identified as risk factors for ancestry. Preliminary data suggest a possible
WISN.175,257 association between the HLA-B*1502 allele and
Genetic susceptibility has always been sus- the risk of SJS/TEN associated with both fos-
pected as a risk factor for allergic-mediated cuta- phenytoin and phenytoin therapy. 298,299
neous disorders, and evidence has become Presence of the HLA-B*5701 allele has been
available to support this hypothesis. The HLA- shown to increase the risk of abacavir hypersen-
B*1502 allele has been strongly linked to the risk sitivity,183 and studies in Han Chinese suggest
of SJS/TEN associated with carbamazepine. In a that the HLA-B*5801 allele may be a genetic
study of Han Chinese patients, all of whom marker for allopurinol-induced SJS and TEN.282
developed SJS/TEN during carbamazepine thera- Preliminary evidence also suggests a higher fre-
py had the HLA-B*1502 allele, whereas only 3% quency of FDEs in association with the HLA-B22
of the patients who tolerated carbamazepine had and HLA-C1 antigens.268
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88 SECTION II • Drug-Induced Dermatologic Diseases
MORBIDITY AND MORTALITY
Using four national databases, Stern283 quantified
hospitalizations and visits to office-based physi-
cians and hospital clinics for a primary diagnosis of
a skin condition. The U.S. Census estimates for
2000 were used to calculate the rates of hospitaliza-
tion or office visits for a diagnosis of SJS/TEN, drug
eruption, drug allergy and urticaria/angioedema.
Overall, 0.06% of hospital admissions were attrib-
uted to a skin condition related to drug use.283
Approximately 5,000 hospitalizations per year
resulted from a diagnosis of erythema multiforme,
SJS, or TEN, 35% of which were attributed to drug
use.283 The rates of hospitalization for a primary
diagnosis of SJS/TEN and drug eruptions were cal-
culated as 16 and 21 admissions per million per-
son-years, respectively. During the 6 years of study
(1995–2000), there were 650,000 office visits with
a primary diagnosis of erythema multiforme, SJS,
or TEN and 1 million visits with a primary diagno-
sis of drug eruption.283 Urticaria, angioedema, and
anaphylaxis were the most frequent diagnoses
associated with outpatient visits, accounting for
three times as many visits as SJS/TEN, drug rash,
and drug allergy combined.283 When the data were
annualized, more than 500,000 office visits per
year were attributed to drug eruptions and drug
allergies including a dermatologic component.
Although rare in occurrence relative to other
dermatologic conditions, SJS and TEN are associated
with substantial morbidity, with the potential for
lasting disabilities and complications (e.g., corneal
ulcers, corneal neovascularization, skin grafts, coag-
ulopathies, hepatitis, glomerulonephritis) in 30% to
45% of patients.275 Moreover, estimates of mortality
associated with SJS and TEN range from 1% to 5%
and 10% to 70%, respectively.275 In at least one
study, the death rate associated with SJS and TEN
was found to positively correlate with age, and was
10 times higher in patients >65 years old.283 In cases
of SJS and TEN, the most common causes of death
are sepsis, pulmonary embolism, gastrointestinal
bleeding, and hypovolemia.
PREVENTION
Advances in genetic testing allow for prospective
screening for the HLA-B*1502 and the HLA-B*5701
alleles, biomarkers of an increased risk of severe
hypersensitivity reactions to carbamazepine and
abacavir, respectively. Screening for the presence of
these and other biomarkers may ultimately lead to
the prevention of allergy-mediated severe cuta-
neous reactions. Genetic tests for HLA-B*1502 and
HLA-B*5701 are currently available.
Other preventive measures include the avoid-
ance of drugs with a propensity to cause cutaneous
diseases in high-risk populations (Table 6–15),
adherence with recommended dosing guidelines
specifically for dosing titration, and avoidance of
drug–drug interactions. Patients who have experi-
enced a SCAR associated with a specific drug
should be counseled to avoid the use of that drug
and any structurally related drug for the rest of
their lives. When initiating therapy with a medica-
tion known to present a high risk of a severe cuta-
neous reaction, counseling should be provided
regarding the initial warning signs and symptoms
(i.e., burning sensation of skin, mucous membrane
involvement).
MANAGEMENT
Table 6–16 provides recommended treatment
methods for the drug eruptions presented in this
section. Of note, maculopapular rashes are usually
self-limited and usually do not require treatment.
If associated with pruritus, oral antihistamines are
advised. Topical corticosteroid creams such as 1%
hydrocortisone may be used in patients with non-
diffuse, limited areas of involvement. In patients
with a diffuse maculopapular rash and evidence of
systemic symptoms (e.g., arthralgias, muscle pain
or weakness), an oral, self-tapering, low-dose
steroid regimen (e.g., methylprednisolone) may be
appropriate. The recommended treatment of drug-
induced urticaria and angioedema is provided in
Table 6–9.
Drug-induced psoriasis is usually resistant to
treatment and requires discontinuation of the
offending agent (e.g., ␤-blockers, lithium, synthet-
ic antimalarial drug). However, in one case series,
50% of the patients in whom psoriasis associated
with either infliximab or etanercept developed
were able to continue therapy and their lesions
responded favorably to treatment with topical
steroids.273
Treatment of SJS and TEN is focused on sup-
portive therapy (nutritional support, pain man-
agement, fluid replacement) and the prevention
of complications such as acute kidney disease
and sepsis. Depending on the extent of blistering
and epidermal detachment, patients may require
treatment in an intensive care or burn unit.
Recommended treatment methods for SJS and
TEN are provided in Table 6–16. In particular, the
topical administration of silver sulfadiazine
should be avoided, because of the high risk of SJS
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CHAPTER 6 • Drug Allergy, Pseudoallergy, and Cutaneous Diseases
TABLE 6–15 Approaches to Help Prevent Drug-Induced Cutaneous Diseases
Drug Condition
Abacavir DRESS
Allopurinol DRESS /SJS/TEN
Aromatic anticonvulsants SJS, TEN
(carbamazepine, phenytoin, phenobarbital)
Carbamazepine SJS, TEN
Lamotrigine SJS/TEN
Nevirapine SJS/TEN
Warfarin WISN
DRESS = drug rash with eosinophilia and systemic symptoms; SJS = Stevens–Johnson syndrome; TEN = toxic epidermal necrolysis; WISN
= warfarin-induced skin necrosis.
and TEN associated with sulfonamides and the
potential for cross reactivity with sulfadiazine.252
The use of systemic corticosteroids remains con-
troversial.175,252,288 To date, there are no large ran-
domized, controlled studies to support the
concept that systemic corticosteroids either
reduce the time to recovery or prevent the devel-
opment of complications. High dose intravenous
immunoglobulin (IVIG), administered as 0.4 to
1.0 g/kg/day for 3 to 4 consecutive days, has
emerged as a potential treatment of SJS and TEN
in children and adults.300-303 IVIG is postulated to
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
of disease, and mortality.300-303 Controlled clini-
cal trials are needed to determine the effective-
ness of IVIG versus that of standard therapies for
SJS and TEN, in addition to the optimal dosage
regimen, formulation, and duration of therapy.
INFORMATION FOR PATIENTS
Patients in whom a drug-induced adverse cuta-
neous event develops should be educated as to the
89
Prevention
Test for HLA-B* 5701.183
Adjust dose in patients with kidney disease.92
Avoid concomitant therapy with thiazide
diuretics.93
Avoid use in patients with history of severe
rash caused by another aromatic
anticonvulsant.
Test for HLA-B*1502.297
Adhere to recommended dose and
dose-escalation recommendations.296
Avoid concomitant therapy with valproic
acid.296
Adhere to 14-day lead-in dosing
recommendation.
Avoid loading or large initial doses.
In patients with protein C or S deficiency or
previous history of WISN, overlap therapy
with heparin for at least 5 days and initiate
warfarin with low doses.281
name of the specific offending drug, the terminol-
ogy used to describe the rash, and the likelihood of
the occurrence of a similar or more severe reaction
following reexposure to the drug. If the reaction
was allergic-mediated, the patient should be
instructed to question all newly prescribed medica-
tions regarding similarity to the offending agent in
chemical structure or chemical class. Patients with
underlying skin conditions such as acne or psoria-
sis should be instructed to question whether any
newly prescribed medication may aggravate the
condition.
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90 SECTION II • Drug-Induced Dermatologic Diseases

TABLE 6 –16 Management of Drug-Induced Cutaneous Diseases

Disease Recommended treatment
Acne257-267 May or may not require discontinuation of the offending agent
Topical benzoyl peroxide or retinoids
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Sunscreen for 6 mo to 1 yr if areas of hyperpigmentation
DRESS175,287 Discontinue offending agent.
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SJS and TEN175,288,289,291 IV fluid replacement (saline or lactated Ringer’s solution)
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WISN175,281 Discontinue warfarin
Vitamin K or fresh-frozen plasma to restore protein C or S
Initiate heparin to prevent further thrombosis
Protein C concentrate if patient has known protein C deficiency
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drugs. Neurology. 2007;68:1701-1709.
97
295. Alvestad S, Lydersen S, Brodtkorb E. Rash from
antiepileptic drugs: influence by gender, age and learning
disability. Epilepsia. 2007;48(7):1360-1365.
296. Hirsch LJ, Weintraub DB, Buchsbaum R et al. Predictors
of lamotrigine-associated rash. Epilepsia. 2006;47(2):318-
322.
297. Chung WH, Hung SI, Hong HS, et al. A marker for
Stevens Johnson syndrome. Nature. 2004;428:486.
298. Man CBL, Kwan P, Baum L, et al. Association between
HLA-B* 1502 and antiepileptic drug-induced cutaneous
reactions in Han Chinese. Epilepsia. 2007;48:1015-
1018.
299. FDA Information for Health Care Professionals.
Phenytoin and fosphenytoin. Available at:
http://www.fda.gov/CDER/Drug/InfoSheets/HCP/phenyt
oin_fosphenytoinHCP.htm. Accessed March 3, 2009.
300. Metry DW, Jung P, Levy ML. Use of intravenous
immunoglobulin in children with SJS and TEN: seven
cases and review of the literature. Pediatrics.
2003;112:1430-1436.
301. Ruetter A, Luger TA. Efficacy and safety of IV
immunoglobulin for immune-mediated skin disease. Am
J Clin Dermatol. 2004;5:153-160.
302. Bachot N, Roujeau JC. Intravenous immunoglobulins in
the treatment of severe drug eruptions. Curr Opin Allergy
Clin Immunol. 2003;3:269-274.
303. Stella M, Clemente A, Bollero D, et al. Toxic epidermal
necrolysis (TEN) and Stevens-Johnson syndrome (SJS):
experience with high-dose intravenous immunoglobulins
and topical conservative approach: a retrospective
analysis. Burns. 2007;33:452-459.
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CHAPTER 7
Systemic Lupus Erythematosus—
like Syndrome
I diopathic systemic lupus erythematosus (SLE) is
an autoimmune disease of unclear etiology and
pathogenesis. Clinical and laboratory findings char-
acterizing SLE involve various organs of the body,
including the musculoskeletal system, skin, kid-
neys, and the central nervous system.1-4 Certain
drugs have been reported to cause signs and symp-
toms that closely mimic the presentation of SLE,
and this drug-induced syndrome is often referred to
with terms such as drug-induced lupus, drug-relat-
ed lupus, drug-induced lupus-like syndrome, drug-
induced lupus erythematosus, lupus erythematosus
medicamentosus, and drug/medication-induced
SLE.1,5 For the purpose of this chapter, this syn-
drome will be referred to as drug-induced lupus.
CAUSATIVE AGENTS
Drugs that have been reported to cause drug-
induced lupus are listed in Table 7–1.6-192 Since sul-
fadiazine was first reported to cause drug-induced
lupus in 1945, over 80 medications have been asso-
ciated with the disease.191 Although drug-induced
lupus has been reported as an adverse effect in clin-
ical trials, most of the literature is in the form of
case reports.
EPIDEMIOLOGY
The incidence of drug-induced lupus is approxi-
mately 15,000–30,000 cases per year.193,194
Approximately 30,000–50,000 people in the
United States are afflicted by this drug-induced dis-
ease.6 It is estimated that 5–10% of cases of SLE are
98
Karen W. Lee and Marie M. Wenzel
drug-induced. The true incidence of drug-induced
lupus may in fact be much higher, as some patients
may experience mild symptoms that remain unrec-
ognized and undiagnosed.
The incidence of drug-induced lupus associated
with specific agents is presented in Table 7–1.6–192
Since the literature associating many medications
with drug-induced lupus is primarily in the form of
case reports, the incidence associated with individ-
ual medications is largely unknown or assumed to
be less than 1%.84 It is challenging to determine
the incidence of drug-induced lupus associated
with newer agents. However, drugs such as pro-
cainamide and hydralazine have been strongly
associated with drug-induced lupus, and the inci-
dence of drug-induced lupus associated with these
drugs is more easily estimated. Growing evidence
supports a strong association between lupus-induc-
ing capabilities and other drugs, such as chlorpro-
mazine, isoniazid, methyldopa, quinidine, and
minocycline.75,195
MECHANISMS
Possible mechanisms of drug-induced lupus are
summarized in Table 7–2. The mechanisms of
drug-induced lupus involve alterations in
immunologic pathways or drug metabolism.
Although exact mechanisms are unknown, several
hypotheses have been proposed, including one or
often a combination of the following mechanisms
for a given lupus-inducing agent: molecular mim-
icry, nucleic acid alterations, immunoregulatory
alterations, interference in the complement path-
way, and predisposing genetic factors.
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CHAPTER 7 • Systemic Lupus Erythematosus—like Syndrome 99

TABLE 7–1 Agents Implicated in Drug-Induced Lupus

Drug Incidence Level of Evidence
(see page xii for explanation)

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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100 SECTION II • Drug-Induced Dermatologic Diseases

TABLE 7–1 Agents Implicated in Drug-Induced Lupus (Continued)

Drug Incidence Level of Evidence

Cardiovascular agents (Continued)
Pindolol16,104 NK C
Practolol6,105 NK C
Prazosin6,16,106 NK C
Propafenone16,84 NK C
Propranolol107 NK C
Reserpine14 NK C
Ticlopidine109 NK C
Timolol (ophthalmic)16,84 NK C
Triamterene101 NK C
Antibacterial/antifungal
Cefuroxime110 NK C
Ciprofloxacin111 NK C
Doxycycline37 NK C
6,112,113
Griseofulvin NK C
Nafcillin114 NK C
Nitrofurantoin6,16,115,116 NK C
Para-aminosalicylic acid6,75 NK C
Penicillin6,117 NK C
Streptomycin118 NK C
Sulfasalazine16,34,119-131 NK C
Sulfonamides14,20,117,132 NK C
Terbinafine133 NK C
Tetracycline37,134 NK C
Central nervous system agents
Chlorprothixene6,10,16,135 NK C
Clobazam75,136 NK C
Clozapine137,138 NK C
Lithium6,16,139,140 NK C
Phenelzine6,16,84 NK C
Valproate141-143 NK C
Other
Adalumimab144 NK C
Allopurinol14 NK C
Aminoglutethimide6,84 NK C
Bupropion146 NK C
D-Penicillamine6 18,34,146-152 0.4–2% C
Estrogens153 NK C
Etanercept154-159 NK B
(Continued)
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CHAPTER 7 • Systemic Lupus Erythematosus—like Syndrome 101

TABLE 7–1 Agents Implicated in Drug-Induced Lupus (Continued)

Drug Incidence Level of Evidence

Other (Continued)
Flutamide160 NK C
Gold salts6,75 NK C
Hydrazine6,162 NK C
Hydroxyurea161 NK C
Infliximab154,155-158,162-163 NK B
Interferon alpha6,16,165-172 NK C
Interleukin-2173-175 NK C
Leuprolide acetate6,176 NK C
Levodopa6,16,84 NK C
Mesalamine178 NK C
Methysergide6 NK C
Oral contraceptives6,14,178-187 NK C
Phenylbutazone6,16,189,190 NK C
Sulfadiazine190 NK C
Tocainide75,191 NK C
HMG-CoA = 3-hydroxy-3-methylglutaryl-coenzyme A; NK = not known.

Molecular mimicry involves the interaction
between an implicated medication and a nucleic
acid. Drugs or drug metabolites with structures that
are similar to the structure of a particular nucleic
acid may stimulate the production of autoantibod-
ies to that nucleic acid, the drug, or its metabolite.
This hypothesis has been supported by several
studies showing structural similarities between
hydralazine and the nucleic acid adenosine.17,196
The nucleic acid alteration hypothesis suggests
that the offending drug or its metabolite may
somehow alter the immune process, increasing the
immunogenicity of nuclear antigens. Alternatively,
the drug or metabolite may couple with an antigen
to form a hapten, triggering the formation of
autoantibodies. The drug or its metabolites may
also damage deoxyribonucleic acid (DNA), which
also may result in the formation of autoantibod-
ies.17,75,208 For drugs that undergo hepatic acetyla-
tion, acetylator phenotype may affect response to
this damage. Fast acetylators require less DNA
repair, suggesting that less damage to DNA occurs
in patients with this phenotype.17,75,208
Defective methylation of DNA in T cells has
been suggested in the pathogenesis of idiopathic
SLE and may also contribute to the development of
drug-induced lupus. Hypomethylation of DNA in T
cells alters T-cell gene expression and function.193
Both procainamide and hydralazine inhibit DNA
methylation, which may be an important compo-
nent of the development of drug-induced lupus
associated with these drugs.
The immunoregulatory alteration hypo-
thesis suggests that drug or drug metabolites may
alter the function of immunoregulatory cells via
direct cytotoxicity. Studies examining this
hypothesis have produced inconsistent results.210
Procainamide alters the function of T lymphocytes
in vitro, enhancing or suppressing the prolifera-
tive response in a concentration-dependent
fashion; high concentrations of procainamide
suppress lymphocyte response, whereas low
concentrations enhance this response.202
Macrophages and mononuclear cells may also be
involved in immunoregulation. It is proposed that
during drug metabolism, these cells may release a
variety of oxygen free radicals, which may be
directly cytotoxic to lymphocytes. This cytotoxic-
ity may lead to the loss of T suppressor cells, stim-
ulation of B cells, and increased antibody
production.17,197 Drugs or drug metabolites may
bind to the major histocompatibility antigens on
monocytes, rendering them immunogenic.17,211
The drug or the metabolite may also bind to his-
tone antibodies, stimulating the production of
antihistone antibodies.17,212 Anti–tumor necrosis
factor ␣ (anti-TNF␣) therapies have been shown to
down regulate a mechanism involved in control-
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102 SECTION II • Drug-Induced Dermatologic Diseases

TABLE 7–2 Mechanisms of Drug-Induced Lupus

Drug Theorized Mechanism(s)
Most Common
Chlorpromazine75 Direct cytotoxicity due to formation of reactive metabolite(s)
Hydralazine17,75,193,196-200 Interaction between hydralazine and nucleic acid adenosine leading to an increase in
immunogenicity of nuclear antigens and/or formation of autoantibodies; inhibition
of covalent binding reactions between C3 and C4 leading to prohibited clearing of
immune complexes; slow acetylation and/or presence of certain HLA alleles; inhibi-
tion of DNA methylation; direct cytotoxicity due to formation of reactive metabolite(s).
Isoniazid75,199-200 Inhibition of covalent binding reactions between C3 and C4 leading to prohibited
clearing of immune complexes; slow acetylation; direct cytotoxicity due to forma-
tion of reactive metabolite(s)
Methyldopa NK
Minocycline49,190,201 Genetic predisposition due to presence of certain HLA alleles; incomplete inhibition
of apoptosis pathways resulting in autoimmunity
Procainamide75,193,198-199,202-206 Alters function of immunoregulatory cells, including the interference of T-cell
maturation, via direct cytotoxicity due to formation of the procainamide-
hydroxylamine reactive metabolite; inhibition of covalent binding reactions between
C3 and C4 leading to prohibited clearing of immune complexes; slow acetylation;
inhibition of DNA methylation
Quinidine75 Direct cytotoxicity due to formation of reactive metabolite(s)
Anticonvulsant Agents
Carbamazepine NK
Ethosuximide NK
Lamotrigine NK
Mephenytoin NK
Phenytoin NK
Primidone NK
Trimethadione NK
Troxidone NK
Valproate NK
Antithyroid Drugs
Methimazole NK
Methylthiouracil NK
75
Propythiouracil Direct cytotoxicity due to formation of reactive metabolite(s)
Thiamazole NK
Cardiovascular Agents
Acebutolol NK
Amiodarone NK
Atenolol NK
Calcium-channel blockers NK
(diltiazem, nifedipine, verapamil)
Captopril NK
Chlorthalidone NK
Clonidine NK
(Continued)
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CHAPTER 7 • Systemic Lupus Erythematosus—like Syndrome 103

TABLE 7–2 Mechanisms of Drug-Induced Lupus (Continued)

Drug Theorized Mechanism(s)

Cardiovascular Agents (Continued)
Disopyramide NK
Enalapril NK
Gemfibrozil NK
Guanoxan NK
HMG-CoA reductase inhibitors NK
(atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin)
Hydrochlorothiazide NK
Labetalol NK
Lisinopril NK
Minoxidil NK
Pindolol NK
Practolol NK
Prazosin NK
Propafenone NK
Propranolol NK
Reserpine NK
Thiazide diuretics NK
Ticlopidine NK
Timolol (ophthalmic) NK
Triamterene NK
Antibacterial/Antifungal Agents
Cefuroxime NK
Ciprofloxacin NK
Doxycycline NK
Griseofulvin NK
Nafcillin NK
Nitrofurantoin NK
Para-aminosalicylic acid NK
Penicillin NK
Streptomycin NK
Sulfasalazine NK
Sulfonamides199 Slow acetylation
Terbinafine NK
Tetracycline NK
Central Nervous System Agents
Chlorprothixene NK
Clobazam NK
Clozapine NK
Lithium NK
Phenelzine NK
(Continued)
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104 SECTION II • Drug-Induced Dermatologic Diseases

Table 7–2 Mechanisms of Drug-Induced Lupus (Continued)

Drug Theorized Mechanism(s)

Other Agents
Adalumimab NK
Allopurinol NK
Aminoglutethimide NK
Bupropion NK
D-Penicillamine NK
Estrogens NK
Etanercept207 Down regulation in control of B-cell hyperactivity
Flutamide NK
Gold salts NK
Hydrazine NK
Hydroxyurea NK
Infliximab207 Down regulation in control of B-cell hyperactivity
Interferon alfa NK
Interleukin-2 NK
Leuprolide acetate NK
Levodopa NK
Mesalamine NK
Methysergide NK
Oral contraceptives NK
Phenylbutazone NK
Sulfadiazine NK
Tocainide NK
DNA = deoxyribonucleic acid; HLA = human leukocyte antigen; HMG = 3-hydroxy-3-methyl-glutaryl-coenzyme A; NK = not known.

ling B-cell hyperactivity, which may induce lupus
in some patients.207
Another immunoregulatory alteration hypoth-
esis involves the interference of T-cell maturation
in the thymus by a reactive metabolite of pro-
cainamide—procainamide-hydroxylamine. These
T cells are then exported to the periphery and are
reactive to chromatin. The T cells help autoreactive
B cells already in the periphery to stimulate an
autoantibody response.203-206
It is well established that hereditary deficien-
cies in complements 1, 2, and 4 (C1, C2, and C4)
predispose patients to idiopathic lupus and other
autoimmune diseases.17 One of the roles of the
complement system is to scavenge immune com-
plexes, promoting their clearance from the body.213
Drug-induced lupus may occur as a result of inter-
ference in the complement pathway. Some drugs
or drug metabolites may inhibit C3 activation, pre-
venting complement from clearing immune com-
plexes and possibly stimulating autoimmune
processes. Isoniazid, hydralazine, and the hydroxy-
lamine metabolite of procainamide have been
shown to inhibit covalent binding reactions
between C3 and C4.17,198
It has been proposed that genetic factors may
play a role in the development of drug-induced
lupus. The term lupus diathesis refers to a predispo-
sition to idiopathic lupus. Patients with lupus
diathesis are those with a personal or family histo-
ry of arthritis, myalgia, drug reaction, pleuritic
pain, epilepsy, or leukopenia.197,214 In patients with
lupus diathesis, certain drugs may cause the clini-
cal expression of the disease; in contrast, medica-
tions known to cause drug-induced lupus may be
used in patients with idiopathic SLE without exac-
erbating disease.197,214 Other genetic factors may be
important in the development of drug-induced
lupus. The incidence of lupus induced by
hydralazine and, to a lesser extent, procainamide is
TisdaleC07_98-116 1/12/10 2:30 PM Page 105
CHAPTER 7 • Systemic Lupus Erythematosus—like Syndrome
higher in slow acetylators.197,199 This is most likely
due to the metabolism of hydralazine resulting in
the formation of an active metabolite. Other genet-
ic factors have also been associated with the devel-
opment of drug-induced lupus, including the
presence of certain human leukocyte antigen
(HLA) alleles. HLA-DR4 is found in 73% of patients
with hydralazine-induced lupus, which is higher
than the rate in patients with SLE (25%).200 HLA-
DR2 and the HLA-DQB1 allele have also been
found in patients with minocycline-induced
lupus.201 The presence of null alleles for the fourth
component of complement (C4) has been associat-
ed with drug-included lupus.193,215 A newer, less
established, hypothesis suggests that minocycline-
induced lupus may occur as a result of incomplete
inhibition of apoptosis pathways, leading to
autoimmunity.49
CLINICAL PRESENTATION AND
DIFFERENTIAL DIAGNOSIS
Signs and symptoms associated with drug-induced
lupus are listed in Table 7–3. Signs and symptoms
of drug-induced lupus typically present within 3
weeks to 2 years after initiation of therapy with the
suspected agent.5,19,193 Patients typically present
with prodromal symptoms of arthralgia and arthri-
tis before progression to a lupus-like syndrome,
potentially affecting numerous organs.19 Arthralgia
is present in up to 90% of patients with drug-
induced lupus.194,216 Patients typically present with
only one or two symptoms. Initial presentation
usually involves articular symptoms characterized
by polyarticular and symmetric joint involve-
ment.20,217 Constitutional symptoms associated
with drug-induced lupus include fever, malaise,
musculoskeletal symptoms (i.e., myalgia, arthral-
gia, arthritis), serositis (i.e., pleurisy, pericarditis,
pleural effusion, pulmonary infiltrate),
hepatomegaly, splenomegaly, and skin manifesta-
tions, including the signature “butterfly rash” asso-
ciated with SLE.5,17,19,20,34,217 Weight loss has also
been reported in association with drug-induced
lupus.20,21,50 Autoimmune hepatitis has been
reported with an incidence of 32–54% in patients
with minocycline-induced lupus.1,39,40 Pulmonary
involvement with pleuropericarditis and pul-
monary infiltrates is most commonly reported
with lupus induced by procainamide.16,19,50,57,58,218
Cutaneous involvement is generally less frequent
in drug-induced lupus, though certain skin mani-
festations are actually more common as compared
with idiopathic SLE, including purpura, erythema
nodosum, and erythematous papules. Cutaneous
105
TABLE 7–3 Signs and Symptoms Associated
with Drug-Induced Lupus
• Malaise
• Myalgia
• Arthralgia
• Arthritis
• Pleuritis
• Pericarditis
• Pleural effusion
• Fever
• Pulmonary infiltrate
• Hepatosplenomegaly
• Skin manifestations
• Renal involvement
• Antinuclear antibodies
• Lupus erythematosus cells
• Antihistone antibodies
• Anti-ssDNA
• Anti-dsDNA
• Anti-Sm antibodies
• Anemia (serum hemoglobin <11.5 g/dl)
• Erythrocyte sedimentation rate
• Leukopenia (white-cell count <4000/mm3)
• Hypergammaglobulinemia
• Positive Coombs’ test
• Weight loss
DNA = deoxyribonucleic acid; dsDNA = double-stranded DNA;
Sm = Smith nuclear antigen; ssDNA = single-stranded DNA.
manifestations occur in up to 39% of patients with
quinidine- and hydralazine-induced lupus, but are
rarely associated with lupus induced by minocy-
cline or procainamide.1,84,219 Certain drugs may
induce characteristic skin manifestations unique to
the medication.5,220
Serologic evidence in patients with drug-
induced lupus typically includes a positive antinu-
clear antibody (ANA) test, lupus erythematosus
cells, antihistone antibodies, and the absence of
antibodies to DNA.1,20,119,217,221 It is important to
note that some drugs cause a positive ANA test
without evidence of clinical disease.34,221,222
Likewise, patients taking either quinidine or
minocycline and exhibiting rheumatologic symp-
toms of lupus may not present with a positive ANA
test.16 Depending on the drug, antibody formation
may be directed toward individual histones (i.e.,
H1, H2A, H2B, H3, H4) and/or histone complexes
(i.e., H2A–2B, H3–4).20,223,224 The antibodies pres-
ent as either immunoglobulin G (IgG) or
IgM.17,19,20 Binding to single-stranded DNA has
been reported in a few cases, but binding to dou-
ble-stranded DNA has not been reported.17,212
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106 SECTION II • Drug-Induced Dermatologic Diseases
Antiphospholipid antibodies have been reported
predominantly in cases of lupus induced by chlor-
promazine, but also in association with lupus
induced by other drugs, such as hydralazine, pro-
cainamide, quinidine, valproic acid, amoxicillin,
propranolol, and streptomycin.20,225,226 Antibodies
against Smith nuclear antigen (anti-Sm) are not
commonly present in patients with drug-induced
lupus.2,19,20,221,227
Elevations in the erythrocyte sedimentation rate
(ESR) are very common, indicative of an inflamma-
tory process.1,16,17,19,193,217,221 Serum complement
concentrations are generally normal; however, sev-
eral reports of transient lowering of serum comple-
ment concentrations (i.e., C3 and C4) have been
published.16,17,19,20,217,221,228,229 Anemia, leukopenia,
thrombocytopenia, and hypergammaglobulinemia
are less common and are usually mild.16,17,19,20,217 A
positive Coombs’ test has been reported in cases of
lupus induced by methyldopa, procainamide, and
hydralazine.19,20,50,230-234 Circulating lupus anticoag-
ulants, due to binding of autoantibodies to phos-
pholipids and proteins associated with the cell
membrane, have been reported with chlorpro-
mazine use; however, an association of these lupus
anticoagulants with the diagnosis and prognosis of
drug-induced lupus is unclear.221,235
Drug-induced lupus is less likely to involve
the central nervous system or the kidneys than is
idiopathic SLE.5,17,20,119,117,221 Nonetheless, neu-
ropathy has been reported in patients diagnosed
with lupus induced by procainamide or
hydralazine, 17,236,237 and mild and reversible
renal involvement, particularly glomeru-
lonephritis, has been noted in cases of drug-
induced lupus caused by D-penicillamine,
hydralazine, griseofulvin, procainamide, propy-
lthiouracil, quinidine, and anticonvul-
sants. 5,14,17,19,20,119,217,221,238-243 The signs and
symptoms of idiopathic SLE and drug-induced
lupus are compared and contrasted in Table
7–4.1,2,17,19,50,84,193-194,216,219,221,236,244-248
No specific diagnostic criteria for drug-induced
lupus exist.1,17,34 However, several investigators
have identified cases of drug-induced lupus based
on four patient criteria: (1) adequate exposure
(dose and duration) of a drug suspected of induc-
ing lupus, (2) temporal association of clinical man-
ifestation upon drug ingestion with no history of
idiopathic SLE prior to drug administration, (3)
positive ANA test with at least one clinical symp-
tom of SLE, and (4) remission of clinical symptoms
and gradual fall in serum ANA concentrations on
drug discontinuation.5,14,16-17,19,216,221 At least one
clinical symptom of SLE must be present for diag-
nosis because many patients can convert from
ANA-negative to ANA-positive with no clinical
signs or symptoms of lupus.17 Recurrence of lupus
symptoms after a rechallenge with the implicated
drug strengthens the probability that the syn-
drome is drug-induced, although rechallenge is sel-
dom performed.1,38
To confirm a case of drug-induced lupus, one
must recognize key differences between the clinical
and laboratory findings characteristic of idiopathic
SLE and those of drug-induced lupus. Although the
presentation of SLE and drug-induced lupus appear
similar on initial assessment, the underlying char-
acteristics of each condition are not the same. The
two conditions differ in terms of known risk fac-
tors, affected organs, serologic features, and severi-
ty. The diagnosis of SLE is based on the presence of
four clinical or laboratory findings in a variety of
organs according to guidelines compiled by the
American College of Rheumatology.2 However, no
specific diagnostic criteria have been adopted for
drug-induced lupus.
Idiopathic SLE presents in a younger popula-
tion, ranging from 15 to 40 years of age, with an
average age at presentation of 29 years.
Idiopathic SLE is reported more commonly in
females.5,17,248 Unlike drug-induced lupus, idio-
pathic SLE often presents with antibodies to dou-
ble-stranded DNA, and is less likely to be
associated with antibodies to antihistones. 1
Antihistone antibodies are present in 25% of SLE
cases, whereas 90% of drug-induced lupus cases
present with antihistone antibodies. 5,20,217
Anemia, leukopenia, and thrombocytopenia are
more common and usually more severe in idio-
pathic SLE as compared with drug-induced
lupus.217 Other symptoms, such as butterfly rash,
alopecia, discoid lesions, and mucosal ulcers are
more common in idiopathic SLE.5,221
Because lupus-like syndrome is characterized
by a multisystem presentation, a broad spectrum of
illnesses must be ruled out during a differential
diagnosis. Viral or bacterial conditions must be
ruled out because of the common presentation of
fever and malaise. Because patients with lupus
induced by certain drugs (e.g., procainamide) may
present with pleuropulmonary involvement, other
pulmonary diseases (e.g., pneumonia, pulmonary
embolus) must be ruled out.17 Refer to Table 7–5 for
conditions to consider in the differential diagnosis
of drug-induced lupus.
Other physical and chemical agents and envi-
ronmental toxins may contribute to a lupus-like
syndrome and must be ruled out. Such factors
include exposure to hydrazines (e.g., mushrooms,
tobacco, tobacco smoke), aromatic amines (e.g.,
hair-coloring solutions), eosin (ingredient in cos-
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CHAPTER 7 • Systemic Lupus Erythematosus—like Syndrome 107

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-
cide, and heavy metals (e.g., mercury, cadmi-
um).5,17,251
Two other forms of drug-induced lupus include
drug-induced subacute cutaneous lupus erythe-
matosus (SCLE) and drug-induced chronic cuta-
neous lupus erythematosus (CCLE). Drugs
including terbinafine, hydrochlorothiazide, acebu-
tolol, bupropion, and certain calcium-channel
blockers have been associated with drug-induced
SCLE, in addition to 3-hydroxy-3-methylglutaryl
coenzyme A reductase inhibitors (statins) and
interferons alfa and beta. 82,99,133,146,252,253 This con-
dition appears to be more common in females than
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108 SECTION II • Drug-Induced Dermatologic Diseases
TABLE 7–5 Conditions to Consider in the
Differential Diagnosis of Drug-Induced Lupus
• Idiopathic systemic lupus erythematosus
• Systemic sclerosis
• Scleroderma
• Connective-tissue diseases
• Antiphospholipid antibody syndrome
• Fibromyalgia
• Rheumatoid arthritis
• Vasculitis (Wegener’s granulomatosis)
• Viral/bacteriologic conditions
• Pleuropulmonary conditions (pneumonia, pulmonary
embolus)
in males, and anti-Sjögren syndrome A/B (also
known as anti-Ro/La), antihistone, and ANA anti-
bodies have been detected. Fluorouracil agents
have been associated with drug-induced CCLE.
Limited information regarding these types of drug-
induced lupus exists.216
RISK FACTORS
Risk factors for drug-induced lupus are listed in
Table 7–6 and are often specific to the causative
agent. Patient characteristics that influence drug
metabolism have been associated with drug-
induced lupus.19 In the past, investigators identi-
fied lupus diathesis, or family history of lupus, as a
risk factor for drug-induced lupus. However, this
has not been proven.
Many reported cases of drug-induced lupus are
in older patients (mean age, 62 years).5,17,34,217 This
may be because patients who take these drugs, typ-
ically prescribed for cardiac and other diseases,
tend to be older.17,27,34,243 However, cases of anti-
convulsant-induced lupus have been reported
most commonly in children.19,20,72,253,254
According to case reports published in the
United States, white patients are six times more
likely to be affected by drug-induced lupus as com-
pared with blacks.6,20,21,34,255 The ratio of occur-
rence of idiopathic SLE in blacks versus whites is
2.7:1. However, this ratio is 0.3:1 for procainamide-
induced lupus and 0.2:1 for hydralazine-induced
lupus.17
Idiopathic SLE occurs more commonly in
females, with a reported female-to-male ratio of
9:1.20 Conversely, drug-induced lupus tends to
affect both sexes equally, although females may
still be at a slightly increased risk; female-to-male
ratios range from 1:1 to 1.6:1.1,17,20,246-248,253,256 An
exception to this trend is observed in patients with
minocycline-induced lupus, with which women
are 14 times more likely than men to be affected.1
It has been hypothesized that women may often
have a higher risk of minocycline-induced lupus
because of the estrogen-related increase of cal-
cineurin activity causing enhanced T-cell activa-
tion.257
The biochemical structure of a drug may influ-
ence the potential for drug-induced lupus.5,212,217 A
common structural feature shared by many drugs
associated with lupus is the presence of a nitrogen
or sulfur heteroatom in a functional group such as
the aromatic amine, hydrazine, sulfhydryl, or
thiono-sulfur. Many of the drugs that have been
implicated in drug-induced lupus produce chemi-
cally reactive metabolites; these drugs include aro-
matic amines (e.g., procainamide, dapsone,
sulfadiazine, aminosalicylic acid, aminog-
lutethimide, sulfasalazine, practolol, acebutolol),
hydrazines (e.g., hydralazine, isoniazid,
phenelzine, hydrazine), or drugs containing a
sulfhydryl or thiono group (e.g., propylthiouracil,
methimazole, penicillamine, and captopril). Drugs
characterized as hydantoin anticonvulsants (e.g.,
phenytoin, mephenytoin, ethosuximide, trimetha-
dione) may also cause drug-induced lupus because
of their similar reactive metabolites. The associa-
tion between the production of reactive metabo-
lites based on the biochemical structure of a drug
and its potential to induce lupus is merely theo-
rized. Lithium is a drug that is associated with
lupus but undergoes no metabolism at all.
Many cases of drug-induced lupus occur after
prolonged administration of the causative agent
for 1 month or longer.75 Drugs such as antiepilep-
tics, antiarrhythmics (procainamide), and other
medications (e.g., hydralazine, isoniazid, chlorpro-
mazine) cause lupus in a dose-dependent man-
TABLE 7–6 Risk Factors for Drug-Induced Lupus
• Older age (mean age, 62 years)
• White race
• Female sex
• Certain drug exposures (aromatic amines, hydrazines,
agents with a sulfhydryl or thiono group).
• High dose singly or cumulatively dose of drug
• Duration of drug use (3 wk to 2 yr)
• Slow acetylator phenotype
• Presence of null alleles for fourth component of
complement (C4)
• Certain human leukocyte antigen (HLA) allele expres-
sion (HLA-DR2, HLA-DR4, HLA-DQB1)
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CHAPTER 7 • Systemic Lupus Erythematosus—like Syndrome
ner.5,17,19,117 This dose relationship may correlate to
the accumulation of unacetylated drug in the
body.17,19 Hydralazine doses greater than 200
mg/day or cumulative doses of more than 100 g
have been associated with lupus-like syn-
drome.20,255,258
Certain drugs undergo acetylation to be inacti-
vated. Patients who are slow acetylators often are
at a higher risk of adverse effects from these drugs
because of the potential for accumulation of the
active drug. For instance, sulfasalazine is metabo-
lized into sulfapyridine and 5-aminosalicylic acid;
the sulfapyridine component is typically acetylated
in the liver by the enzyme N-acetyltransferase 2
(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
higher concentrations of the active sulfapyridine
component rather than its inactivated form.259
Slow acetylators of procainamide experience lupus-
like symptoms four times faster than fast acetyla-
tors, and positive ANA tests develop at lower
cumulative drug doses in slow acetylators than in
fast acetylators.217,260 Other drugs that are acetylat-
ed in the liver through NAT2 include hydralazine,
isoniazid, and sulfonamides.5,17,20,212,217
The severity of lupus induced by hydralazine is
greatly influenced by acetylator phenotype. One
study reported that 60% of slow acetylators taking
less than 400 mg of hydralazine had a positive
ANA test, whereas 0% of fast acetylators taking the
same dose of hydralazine showed positive serum
ANA titers.259 On the other hand, although the
incidence of procainamide-induced lupus is higher
in slow acetylators, the severity of procainamide-
induced lupus is influenced minimally by acetyla-
tor type.201,259 Because both fast and slow
acetylators may experience procainamide-induced
lupus, it has been hypothesized that a reactive,
nonacetylated metabolite of procainamide may be
responsible for the syndrome.260 The influence of
the acetylator phenotype is supported by the evi-
dence that no cases of drug-induced lupus associat-
ed with the administration of the acetylated form
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
exclusive to certain drugs (see Table 7–2). It is also
important to note that acetylator status does not
influence idiopathic SLE.261
Various human leukocyte antigen (HLA) types,
especially HLA-DR2 and DR4, are associated with
SLE.20 However, only HLA-DR4, which is associated
with slow acetylation, has been shown to be
strongly associated with hydralazine-induced
109
lupus.5 For example, in one study, 73% of patients
with hydralazine-induced lupus had HLA-DR4.213
The presence of a null allele for C4 is also a risk fac-
tor for drug-induced lupus.193,215
MORBIDITY AND MORTALITY
Drug-induced lupus usually resolves within weeks
to months after discontinuation of the offending
drug, although the ANA test may remain positive
for months to years.5,20 It is fatal only in extremely
rare circumstances, usually as a result of kidney
failure.5
PREVENTION
Monitoring parameters for prevention and detec-
tion of drug-induced lupus are presented in Table
7–7. Drug-induced lupus is an idiosyncratic drug
reaction that may not be explained by the known
pharmacologic actions of the specific drug. To pre-
vent drug-induced lupus, the drug known to cause
the lupus-like syndrome should be avoided.
However, avoidance of certain drugs may not be an
option in many medical circumstances. The lupus-
inducing potential of only a select number of drugs
has been substantiated with results from prospec-
tive studies. The potential for other drugs to cause
lupus is supported only by spontaneous, and often
single, case reports. As a routine screening process,
baseline serum ANA concentrations should be
determined when initiating a medication docu-
mented to induce lupus.34 Periodic ANA testing
should be initiated based on clinical judgment,
remembering that serum ANA concentrations
alone are not diagnostic of drug-induced lupus. A
common recommendation is to obtain a complete
blood count, ANA concentration, and ESR every 3
months in a patient receiving a drug with the
potential to cause lupus.20 Periodic assessment of
constitutional signs and symptoms associated with
the syndrome helps guide the clinical decision to
TABLE 7–7 Approaches to Help Prevent
Drug-Induced Lupus
Monitor the following at baseline and every
3 months during therapy:
• Serum antinuclear antibody titers
• Complete blood count
• Erythrocyte sedimentation rate
• Signs and symptoms of drug-induced lupus
TisdaleC07_98-116 1/12/10 2:30 PM Page 110
110 SECTION II • Drug-Induced Dermatologic Diseases
continue or discontinue the implicated drug. There
are no data to support cross-sensitivity between
medications implicated in drug-induced lupus;
therefore, it is not possible to say with certainty
that patients experiencing drug-induced lupus
after taking a certain medication will have the
same reaction to another medication implicated in
the disease. However, careful clinical decision mak-
ing is necessary when considering treatment with
such medications. Patients should be followed
carefully and appropriate baseline testing should
be done to ensure patient safety during the course
of treatment.
MANAGEMENT
Strategies for managing drug-induced lupus are
presented in Table 7–8. Symptoms of drug-induced
lupus do not subside with continued administra-
tion of the offending agent, although they are
reversible on discontinuation of the drug.19,217,221
Therefore, discontinuation of the offending drug is
required. Clinical and laboratory findings associat-
ed with drug-induced lupus typically disappear
within weeks. Rarely, clinical and laboratory find-
ings may take years to resolve after the termination
of the lupus-inducing drug.5,19,20,118,253 Although
symptoms often resolve quickly, serum ANA con-
centrations may fall gradually over several months
to 2 years.5,34,193 Clinical symptoms of lupus never
develop in most asymptomatic patients with posi-
tive ANA serum concentrations, and drug discon-
tinuation is not required in these cases.8,193
Patients often improve dramatically without
treatment. Patients experiencing musculoskeletal
and mild constitutional symptoms (e.g., pyrexia,
arthralgia, myalgia) may be treated with antiin-
flammatory agents such as aspirin and nons-
TABLE 7–8 Management of Drug-Induced Lupus
Sign/Symptom
Positive antinuclear antibody only
Any lupus-like symptoms
Persistent constitutional symptoms and/or
musculoskeletal symptoms
Pleurisy, pericarditis, renal involvement
Skin and joint manifestations, and constitutional
symptoms including fever, malaise, and fatigue
teroidal antiinflammatory drugs if there are no
contraindications to their use.17,19,20,218,222
However, patients presenting with more severe
symptoms (e.g., pleurisy, pericarditis, renal
involvement) require treatment with empirical,
short-term low-dose systemic corticosteroids (e.g.,
prednisone 0.5–1.0 mg/kgd) tapered over 1 week
to several months.5,16-17,19-20,217,246-247,253 Patients
presenting with lupus-induced skin manifesta-
tions have been treated with antimalarial agents
(i.e., chloroquine–hydroxychloroquine). 5,221
Several case reports describe rechallenge of the
offending agent in the patient; lupus symptoms
promptly reappeared on reinitiation of the
drug.38,217
INFORMATION FOR PATIENTS
When patients are initiated on a drug that is
strongly associated with drug-induced lupus, the
health care professional should counsel the patient
regarding the fact that symptoms of arthralgia or
arthritis may occur at any time during the thera-
py—up to and including 2 years after the first dose.
Regardless of whether or not the patient has an
arthritis-related medical condition before the initi-
ation of the drug, symptoms of fever, malaise, and
skin manifestations of unknown origin should be
reported promptly. The patient should also be
counseled regarding other specific symptoms asso-
ciated with the implicated drugs (e.g., pulmonary
symptoms with procainamide, symptoms of hepa-
totoxicity with minocycline). The health care pro-
fessional must educate the patient regarding the
importance of reporting symptoms because of: (1)
the progression of the syndrome if ignored and (2)
the reversibility of the syndrome on cessation of
the implicated drug.
Management
Continue drug if asymptomatic
Discontinue drug immediately
Discontinue drug immediately. Treat symptoms with
aspirin or nonsteroidal antiinflammatory drugs
Discontinue drug immediately
Initiate low-dose corticosteroids (e.g., prednisone 0.5–1.0
mg/kg daily) tapered over 1 wk to several months
Initiate hydroxychloroquine at 200 mg twice a day and
continue indefinitely
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CHAPTER 7 • Systemic Lupus Erythematosus—like Syndrome
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case with LE cells antemortem and postmortem, and
pulmonary, renal, splenic, and muscular lesions of
disseminated lupus erythematosus. J Lab Clin Med.
1955;46:806.
239. Bendersky G, Ramirez C. Hydralazine positioning. JAMA.
1960;173:1789-1794.
240. Whittingham S, Mackay IR. Systemic lupus
erythematosus induced by procainamide. Aust Ann Med.
1970;19:358-361.
241. Whittle TS, Ainsworth SK. Procainamide-induced
systemic lupus erythematosus-renal involvement with
deposition of immune complexes. Arch Pathol Lab Med.
1976;100:469-474.
242. Rallison ML, Carlisle JW, Lee RE Jr, et al. Lupus
erythematosus and the Stevens-Johnson syndrome:
occurrence as reactions to anticonvulsant medication.
Am J Dis Child. 1961;101:725-738.
243. Stokes MB Foster K, Markowitz GS, et al. Development of
glomerulonephritis during anti-TNF alpha therapy for
rheumatoid arthritis. Nephrol Dial Transplant.
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244. Hess EV. Introduction to drug-induced lupus. Arthritis
Rheum. 1981;24:6-9.
245. Harmon CE, Portanova JP. Drug-induced lupus-clinical
and serological studies. Clin Rheum Dis. 1982;8:121-135.
246. Hess EV, Mongrey AB. Drug-induced lupus: the same or
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Systemic Lupus Erythematosus. New York, NY: Churchill-
Livingstone; 1992:893-904.
247. Rich MW. Drug-induced lupus. Postgrad Med.
1996;100:299-308.
248. Stratton MA. Drug-induced systemic lupus
erythematosus. Clin Pharm. 1985;4:657-663.
249. Kale SA. Drug-induced lupus erythematosus-
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250. Burry JN. Lipstick and lupus erythematosus. N Engl J Med.
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251. Farhi D, Viguier M, Cosnes A, et al. Terbinafine-induced
subacute cutaneous lupus erythematosus. Dermatology
2006;212:59-65.
252. Srivastava M, Rencic A, Diglio G, et al. Drug-induced,
Ro/SSA-positive cutaneous lupus erythematosus. Arch
Dermatol. 2003;139:45-49.
253. Ansell BM. Drug-induced systemic lupus erythematosus
in childhood. Lupus 1993;2:139-140.
254. Jacobs JC. Drug-induced lupus. In: Pediatric Rheumatology
for the Practitioner. New York, NY: Springer-Verlag;
1982:365-367.
255. Mansilla-Tinoco R, Harland SJ, Ran PJ. Hydralazine,
antinuclear antibodies and the lupus syndrome. Br Med J.
1982;284:936-939.
256. Krohn K, Bennett R. Drug-induced autoimmune disorders.
Immunol Allergy Clin North Am. 1998;18:897-911.
257. Rider V, Abdou NI. Gender differences in autoimmunity:
molecular basis for estrogen effects in systemic lupus
erythematosus. Int Immunopharmacol. 2001;1:1009-1024.
258. Hildreth EA, Biro CE, McCreary TA. Persistence of the
“hydralazine syndrome”—a follow-up study of eleven
cases. JAMA. 1960;173:657-660.
259. Perry HM Jr, Tan EM, Carmody S, et al. Relationship of
acetyl transferase activity to antinuclear antibodies and
toxic symptoms in hypertensive patients treated with
hydralazine. J Lab Clin Med. 1970;76:114-125.
260. Woolsey RL, Drayer DE, Reidenberg MM, et al. Effect of
acetylator phenotype on the rate at which procainamide
induces antinuclear antibodies and the lupus syndrome.
N Engl J Med. 1978;298:1157-1159.
261. Morris RJ, Freed CR, Kohler PF. Drug acetylation
phenotype unrelated to development of spontaneous
systemic lupus erythematosus. Arthritis Rheum.
1978;21;192-195.
TisdaleC08_117-134 1/15/10 9:43 AM Page 117
CHAPTER 8
Photosensitivity
D rug-induced photosensitivity is a term used to
describe an undesirable pharmacologic reac-
tion to light irradiation.1,2 Drug-induced photosen-
sitivity reactions are quite common today, as a
result of an increased number of photosensitizing
chemicals found in many drug products.1 Drug-
induced photosensitivity reactions are typically
classified as either photoallergic or phototoxic
effects.
CAUSATIVE AGENTS
Several drugs and drug classes have been implicat-
ed in causing clinically significant photosensitivity
reactions (Table 8–1).3-319 Drugs that have been
reported to cause phototoxic reactions include
nonsteroidal antiinflammatory drugs (NSAIDs),
coal tar, tetracyclines, sulfonamides, fluoro-
quinolones, phenothiazines, thiazide diuretics,
and amiodarone.2,13-16,319 Drugs that may cause
photoallergic reactions include tetracyclines, sul-
fonamides, thiazide diuretics, phenothiazines, and
antihistamines.319 It is important to note, however,
that many of these drugs may contribute to the
development of both types of photosensitivity (i.e.,
phototoxic and photoallergic) reactions.
EPIDEMIOLOGY
It is assumed that the incidence of drug-induced
photosensitivity reactions may be too low to be
detected in most clinical trials, and as a result, data
from postmarketing surveillance must be relied on
to determine this information. Although there are
many case reports describing drug-induced photo-
Julie M. Koehler
sensitivity reactions, it is difficult to estimate the
true incidence of such reactions, given the difficul-
ty in distinguishing between sunburn and a mild
drug-induced photosensitivity reaction and the
resultant potential for bias or inaccuracy in report-
ing. This is further confounded by the fact that
individual patients may be able to control the
occurrence of photosensitivity reactions by taking
protective action against sunlight exposure.318
Although the exact incidence of drug-induced pho-
tosensitivity in the general population has not
been defined, results from a retrospective review
from a skin-treatment referral center in Singapore
indicated that 11.3% of all cases of photoder-
matoses were the result of drug-induced photosen-
sitivity.320 In another report describing the types of
drug eruptions treated by dermatologists at a
Finnish hospital, photosensitivity accounted for
3% of all cases.321 In general, drug-induced photo-
toxic reactions occur more commonly than pho-
toallergic reactions,322 and phototoxic reactions
may occur in almost any person who receives a
high enough dose of the offending agent coupled
with a sufficient amount of exposure to light irra-
diation.323 The occurrence of drug-induced photo-
toxicity reactions can thus be dependent on the
concentration (or amount) of the sensitizing agent
(drug) and the amount of light exposure.323 The
recorded incidence, where known, of photosensi-
tivity associated with the administration of specif-
ic drugs is also included in Table 8–1.3-317
MECHANISMS
Photosensitivity reactions can be classified accord-
ing to the underlying mechanism or pathogenesis
117
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118 SECTION II • Drug-Induced Dermatologic Diseases

TABLE 8–1 Agents Implicated in Drug-Induced Photosensitivity3-319

Drug Incidence Level of Evidence
(see page xii for explanation)

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)
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CHAPTER 8 • Photosensitivity 119

TABLE 8–1 Agents Implicated in Drug-Induced Photosensitivity3-319 (Continued)

Drug Incidence Level of Evidence

Dacarbazine3,69 <0.1% B
Dantrolene70 NK C
Dapsone71,72 NK C
Demeclocycline73 NK C
Desipramine74 NK C
Desoximetasone75 NK C
Dibucaine76,77 NK C
Dichlorphenamide78 NK C
Diclofenac3,79 3%a B
Diflunisal80,81 NK C
Diltiazem3,82 <2% B
Diphenhydramine83-85 NK C
Doxycycline86-89 NK C
Efavirenz90,91 NK C
Enalapril3,91,92 0.5–1% B
Enoxacin94 NK B
Epirubicin95 NK C
Estrogen/ progestin96-99 NK C
Ethionamide100 NK C
Felodipine101 NK C
Fenofibrate102,103 NK C
Flucytosine104 NK C
Fluorouracil105,106 NK C
Fluoxetine107 NK C
Fluphenazine108 NK C
Flutamide109-114 NK C
Fluvastatin115 NK C
Fosinopril3 0.2–1% B
Furosemide116-118 NK C
Ganciclovir119 <1% A
Glimepiride3 NK C
Glyburide120 NK C
Gotu kola121 NK C
Griseofulvin122-125 NK C
Haloperidol126 NK C
Hexachlorophene127 NK C
Hydrochlorothiazide41,129-131 NK B
Hydrocortisone132 NK C
Hydroxyurea133 NK C
Ibuprofen134,135 5.3% B
Imatinib136,137 0.1–1% B
Imipramine138 NK C
(Continued)
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120 SECTION II • Drug-Induced Dermatologic Diseases

TABLE 8–1 Agents Implicated in Drug-Induced Photosensitivity3-319 (Continued)

Drug Incidence Level of Evidence

Indapamide139 NK C
Isotretinoin140-143 NK C
Itraconazole144 NK C
Ketoconazole145 NK C
Ketoprofen3,146-154 <1% B
Leflunomide155 NK C
Lemon oil28 NK B
Levofloxacin156 <0.1% A
Lime oil28 NK B
Lisinopril3 NK C
Lomefloxacin157-159 NK A
Loratadine160 NK C
Losartan161 <1% A
Lovastatin3 NK C
Maprotiline3,162 0.1–1% B
Mequinol/tretinoin163,164 NK C
Methazolamide3 NK C
Methotrexate166-174 3–10% B
Methoxsalen175 NK C
Methyldopa176 NK C
Methylene blue177,178 NK C
Minocycline3,89,179,180 NK C
Mirtazapine181 0.1–1% A
Mitomycin C182 NK C
Moexipril183 <1% B
Moxifloxacin184,185 <0.1% A
Nabumetone3,186 <1% A
Nalidixic acid187-197 NK B
Naproxen198-202 <1% B
Nifedipine3,203,204 <1% A
Norfloxacin205 NK C
Ofloxacin3,206,207 <1% A
Olanzapine3,208 0.1–1% A
Oxaprozin209 <1% A
Paclitaxel210 NK C
Panitumumab211 NK B
Pantoprazole212,213 NK C
Paroxetine3,214 0.1–1% A
Pentostatin3,215 <3% A
Phenelzine216 NK C
Piroxicam3,217-222 <1% B
Porfimer3,223-229 ~20%b A
(Continued)
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CHAPTER 8 • Photosensitivity 121

TABLE 8–1 Agents Implicated in Drug-Induced Photosensitivity3-319 (Continued)

Drug Incidence Level of Evidence

Promethazine195,230 NK C
Protriptyline231 NK C
Pyrazinamide3,100,232,233 <0.1% B
Pyridoxine12,234-238 NK C
Pyrimethamine239 NK C
Quinethazone43 NK C
Quinidine240-247 NK C
Quinine248-253 NK C
Ramipril254 <1% A
Ranitidine255,256 NK C
Risperidone257 <1% A
Ritonavir258 <2% A
Saquinavir259,260 <2% A
Selegiline261 NK C
Sertraline3,262 0.1–1% A
Shitake mushroom263 NK C
Simvastatin264,265 NK C
Sotalol266 <0.1% B
Sparfloxacin267-272 2–7.9% A
Spironolactone273 NK C
St. John’s wort274-286 NK B
Sulfisoxazole287,288 NK C
Sulindac3 <1% A
Tacrolimus3,289,290 NK A
Tetracycline100,291-294 NK C
Thioridazine3,295,296 <0.1% B
Tolbutamide297 NK C
Torsemide298 NK C
Triamterene299,300 NK C
Trimethoprim301 NK C
Valacyclovir302 NK B
Valproic acid303 NK C
Valsartan304 NK C
Venlafaxine3,305 0.1–1% A
Verteporfin3,306-309 1–10% A
Vinblastine310 NK C
Voriconazole311-315 7% A
Zaleplon316 <1% A
Zolpidem3 <0.1% A
NK = not known; information either not reported or provided via case reports only
a
Incidence reported is for topical gel only.
b
Incidence varies according to type of cancer being treated.
TisdaleC08_117-134 1/15/10 9:43 AM Page 122
122 SECTION II • Drug-Induced Dermatologic Diseases
Ultraviolet
Radiation
Phototoxin
Excited State
(Drug/Chromophore)
Energy
Absorption
FIGURE 8–1 Mechanism of Drug-Induced Phototoxicity319
of the reaction. Specifically, photosensitivity reac-
tions are the result of either phototoxicity or pho-
toallergy. Of the two types of drug-induced
photosensitivity reactions, phototoxic reactions
represent the most common form, and photoaller-
gic reactions are generally uncommon.
Phototoxic reactions are a type of nonim-
munologic reaction. During phototoxic reactions,
the drug, after either ingestion or topical applica-
tion, is believed to potentiate solar energy by act-
ing as a chromophore, causing absorption of
ultraviolet (UV) light and yielding damage to skin
tissues.1 In contrast to photoallergic reactions,
drug-induced phototoxic reactions typically occur
on first exposure to the drug, and are often dose-
related.1,2,323 Figure 8–1 illustrates the underlying
mechanism of drug-induced phototoxic reac-
tions.319
Unlike phototoxic reactions, drug-induced
photoallergic reactions are the result of an
immunologic response. The proposed mechanism
of photoallergic reactions is that of a type IV cell-
mediated hypersensitivity response.1 Specifically, it
is postulated that when UV light reacts with either
the drug or the drug’s metabolites in the skin, this
induces a structural change in the drug so that it
behaves as a hapten,1,322 which then combines
with proteins in the skin (a tissue antigen) to form
a hapten–protein complex (complete antigen). On
subsequent exposure to the drug, a hypersensitivi-
ty response is elicited.322 Once the patient is “sen-
sitized” to the drug, subsequently only minimal
amounts of drug exposure are required to produce
a photoallergic reaction.1 In general, photoallergic
reactions occurring in sensitized patients are not
Ultraviolet
Radiation
Excited
Phototallergen
Photoallergen
(drug or drug’s
(hapten)
metabolites)
FIGURE 8–2 Mechanism of Drug-Induced Photoallergy319
Reactive
Oxygen Tissue Damage
Energy Intermediates
Transfer
dose-dependent.2 Because photoallergic reactions
involve the immune system, there is typically a
delay between the time of exposure to the drug and
the actual onset of the skin eruption.1 Figure 8–2
illustrates the underlying mechanism of drug-
induced photoallergic reactions.319
Although the general underlying mechanisms
of drug-induced photoallergy and phototoxicity
are well-described in the literature, information
regarding the exact mechanisms of photosensitivi-
ty associated with specific drug classes and individ-
ual agents are not as well understood. Table 8–2
summarizes possible underlying mechanisms of
drug-induced photosensitivity reactions for select-
ed agents.
Diuretics and Phenothiazines
Diuretics such as hydrochlorothiazide, chlorthali-
done, and furosemide and phenothiazines such as
chlorpromazine and promethazine contain chlo-
rine substituents within their chemical structure. It
has been postulated that UV light exposure causes
dissociation of the chlorine substituents, which is
believed to lead to free radical formation, produc-
ing a photosensitivity reaction.318 Complement,
proteases, and histamine have also been suggested
to play a role in phenothiazine-induced phototox-
icity, however, suggesting a nonoxidative mecha-
nism.319
NSAIDs
Many NSAIDs have been reported to cause photo-
sensitivity reactions. Within the NSAID class, drugs
Subsequent
Protein Drug
(tissue antigen) Exposure
Hapten-Protein
Hypersensitivity
Complex
Response
(complete
antigen)
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CHAPTER 8 • Photosensitivity 123

TABLE 8–2 Mechanisms of Drug-Induced Photosensitivity

Drugs Mechanism(s)
Chlorothiazide Dissociation of chlorine substituent on ultraviolet light exposure,
Chlorthalidone causing free radical formation318
Furosemide
Hydrochlorothiazide
Indapamide
Quinethazone
Torsemide
Chlorpromazine Dissociation of chlorine substituent on ultraviolet light exposure, causing
Fluphenazine free radical formation318
Promethazine Complement, proteases and histamine may also play a role319
Thioridazine
Diclofenac Decarboxylation reaction on ultraviolet light exposure, causing free radical
Diflunisal formation318,319,323
Ketoprofen
Naproxen
Nabumetone
Oxaprozin
Piroxicam
Sulindac
Demeclocycline Oxidative reaction on ultraviolet light exposure, causing free radical
Doxycycline formation
Minocycline Polymorphonuclear cells and complement may also serve as inflammatory
Tetracycline mediators319
Methoxsalen Possible alteration of DNA synthesis and direct inflammatory effect, leading
to increased melanin production and an erythemogenic effect319,324
Porfimer Free radical formation on ultraviolet light exposure
Verteporfin
DNA = Deoxyribonucleic acid

such as ketoprofen, naproxen, and nabumetone, thought to play a role.319 Polymorpho-nuclear

which contain a 2-aryl propionic acid group, are
thought to be the most photoactive.318,319 It is
believed that a decarboxylation reaction occurs on
exposure to UV light, resulting in free radical for-
mation and a subsequent photosensitivity reac-
tion. NSAIDs lacking the 2-aryl propionic acid
group, such as ibuprofen, have also been reported
to cause photosensitivity, however, via a less well-
understood mechanism.318,323
Antibacterials
Many antibacterial agents are known to elicit a
high degree of photosensitivity. Tetracyclines, flu-
oroquinolones, and sulfonamides are believed to
be the most photoactive.318 Although the under-
lying phototoxic mechanisms of these drug class-
es (particularly the tetracyclines) have been
extensively studied, they have yet to be fully elu-
cidated. Within the tetracycline class, oxidative
reactions involving free radical formation are
cells and complement have also been identified as
potential inflammatory mediators involved in the
mechanism of tetracycline-induced photosensi-
tivity.319
Psoralens
Psoralen derivatives, such as methoxsalen, repre-
sent a unique class of drugs in that their inherent
photosensitizing mechanism is used therapeutically
in combination with controlled UV light exposure
to produce a melanogenic effect in the treatment of
disorders such as idiopathic vitiligo.319,324 Thus, the
photosensitizing potential of such agents is a
known and, for the most part, intended effect.
Methoxsalen, when activated by UVA light,
becomes highly erythemogenic and melanogenic.
Although the exact mechanism by which these
agents induce phototoxic reactions is not complete-
ly known, it is believed that psoralen-induced pho-
totoxicity involves non–oxygen-dependent
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124 SECTION II • Drug-Induced Dermatologic Diseases
pathways and may be linked most closely to the
alteration of DNA synthesis and direct induction of
an inflammatory skin reaction to enhance melanin
formation.319,324
Photosensitizing Agents
Porfimer and verteporfin represent drugs that are
used therapeutically because of their known pho-
tosensitizing properties. Both of these agents are
used in photodynamic therapy, for which UV light
exposure is required for pharmacologic activation.
On exposure to UV light, these photosensitizers
become activated in the presence of oxygen, and
free radicals are generated, enhancing the potential
for phototoxicity.319,324
CLINICAL PRESENTATION AND
DIFFERENTIAL DIAGNOSIS
Classic signs and symptoms associated with drug-
induced photosensitivity are listed in Table 8–3.317
Symptoms of drug-induced photosensitivity reac-
tions are very similar to those of a sunburn. Typical
photosensitivity reactions may result in the devel-
opment of erythema, edema, and papules, and in
severe cases, may also progress to the development
of plaque-like urticarial lesions and possible vesicle
formation.1,325 When differentiating between pho-
tosensitivity and other types of skin eruptions, the
clinician should note that photosensitivity erup-
tions classically manifest on areas of the skin that
are most routinely exposed to sunlight (e.g., nose,
cheeks, tops of the ears, neck, forearms, backs of
the hands).1,325 In general, sharp lines of demarca-
tion between sunlight-exposed and uninvolved
TABLE 8–3 Signs and Symptoms Associated with
Drug-Induced Photosensitivity317
• Pain
• Erythema
• Pruritus
• Swelling
• Edema
• Papules
• Wheals
• Vesicles
• Scarring
• Scaly patches
• Petechiae
• Hyperpigmentation
• Erythroderma
TABLE 8–4 Conditions to Consider in the
Differential Diagnosis of Drug-Induced
Photosensitivity317
• Sunburn
• Plant-induced photosensitivity reaction
(phytophotodermatitis)
• Solar urticaria
• Polymorphic light eruption
• Actinic prurigo
• Hydroa vacciniforme
• Erythropoietic protoporphyria
• Systemic lupus erythematosus
skin are noted.325 In some cases, however, the skin
eruptions can appear on areas of the skin that
receive little to no sun exposure and may be gener-
alized over the entire body. In general, while differ-
entiation between drug-induced photosensitivity
and other adverse skin reactions to sunlight may
be somewhat challenging (Table 8–4), differentia-
tion between cases of drug-induced phototoxicity
and photoallergy can also be difficult, given that
many drugs have been implicated in causing both
types of reactions.2,319 Differences between the
characteristics of phototoxic and photoallergic
reactions are highlighted in Table 8–5.2,319
Examples of the clinical appearance of drug-
induced phototoxic and photoallergic reactions are
presented in Figure 8–3.
Cases of drug-induced phototoxic reactions are
associated with a much more rapid onset (e.g.,
within 30 minutes to several hours after exposure
to UV light) than cases of drug-induced photoaller-
gy.2 In general, phototoxic reactions are less severe
than photoallergic reactions and resemble an exag-
gerated sunburn.2 Phototoxic reactions are associ-
ated with erythema and pain, and occasionally
may progress to blistering and vesicle formation.325
Within several days of the onset of the reaction,
the damaged skin may begin to desquamate.323
In the long term, epidermal thickening, elastosis,
telangiectasia, and pigmentary changes (hyperpig-
mentation or hypopigmentation) may occur in asso-
ciation with phototoxic reactions.1 Pigmentary
changes occur quite commonly as a manifestation of
photosensitivity in patients receiving long-term,
high-dose amiodarone therapy.319,326-330 Specifically, a
blue-gray discoloration commonly develops on areas
of the skin that are subjected to unprotected light
exposure because of the deposition of amiodarone
and its metabolites within the dermis.319,326,327,329
The skin damage that occurs in phototoxic
reactions is typically confined to areas of exposed
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CHAPTER 8 • Photosensitivity 125

TABLE 8–5 Differentiating Characteristics of Phototoxicity and Photoallergy2,319

Characteristic Phototoxicity Photoallergy
Frequency of occurrence Common Uncommon
Mechanism Non-immune-mediated Immune-mediated
Onset after exposure to drug Immediate (minutes to hours) May be delayed
and sunlight to drug and (hours to days)
sunlight after exposure
Distribution Usually confined to exposed skin May affect unexposed skin
Potential for pigmentary changes High Low
Dose-dependency Yes No
Potential for cross reactivity No Yes
Potential for persistent light reaction No Yes

skin only. Occasionally, the nails may also be
affected. This phototoxic effect is a well-known
phenomenon known as photoonycholysis.2,325
Histologically, dermal edema, dyskeratosis, and
keratinocytic necrosis may be observed.325
Cases of drug-induced photoallergic reactions
are typically associated with an onset ranging from
24 to 48 hours to up to 14 days after initial expo-
sure to the sun. The initial eruption is usually
described as a papulovesicular, intensely pruritic,
eczematous rash.323,325 In some cases, the rash has
been reported to involve lichenoid, urticarial, bul-
lous, or purpuric lesions. Histopathologic findings
in cases of drug-induced photoallergy are typically
similar to those found in cases of contact dermati-
tis.1 In general, photoallergic reactions involve only
areas directly exposed to the sun, but in severe
cases, these reactions may also affect areas that are
normally protected from UV light. It is important
to note that after discontinuation of therapy with
the offending agent, the clinical effects of drug-
induced photoallergy may persist for some time.
Over time, the eruptions may even become hyper-
pigmented or hypopigmented.319

FIGURE 8–3 Drug-Induced Phototoxicity and Photoallergy317

The photo on the left depicts a case of drug-induced phototoxicity secondary to demethylchlorte-
tracycline use for treatment of acne. The woman was wearing a hat that protected her face and neck
from sunlight exposure, but her hands were exposed to sunlight while holding a railing at a sporting
event. The photo on the right depicts a case of drug-induced photoallergy secondary to trimetho-
prim–sulfamethoxazole use for Pneumocystis jiroveci pneumonia prophylaxis. Eczema and hyperpig-
mentation of the sun-exposed areas are noted. (Photos reprinted with permission from Wolff K,
Johnson RA, Suurmond D. Fitzpatrick’s Color Atlas and Synopsis of Clinical Dermatology: Common
and Serious Diseases. 5th ed. New York, NY: McGraw-Hill; 2005:226-269.) (See color section.)
TisdaleC08_117-134 1/15/10 9:43 AM Page 126
126 SECTION II • Drug-Induced Dermatologic Diseases
RISK FACTORS
There are several potential risk factors that may
increase a person’s susceptibility to a drug-induced
photosensitivity reaction (Table 8–6).2,319,322,325 For
any patient who is taking a known photosensitiz-
ing agent, use of sunscreens and protective cloth-
ing is warranted to help minimize the risk of a
photosensitivity reaction. It should be noted, how-
ever, that occasionally sunscreens themselves can
act as photosensitizing agents. Sunscreens contain-
ing para-aminobenzoic acid (PABA) contain a sulfa
moiety, which may actually aggravate photoder-
matitis in sensitized individuals. Thus, sunscreens
containing PABA should generally be avoided in
susceptible individuals.319,325
In cases of phototoxicity, the dose of the pho-
tosensitizer itself may be a risk factor. For example,
dose-related increases in the incidence of light
eruptions have been reported in association with
doxycycline.331 Reduction of the dose of the
offending agent during phototoxic reactions has
been shown to yield symptom and reaction resolu-
tion in some cases,332,333 supporting the theory that
dose can be an important risk factor.
In cases of photoallergy, the patient’s immune
status may be an important risk factor to consider.
Photosensitivity reactions have been reported to
occur more frequently in patients who are
immunocompromised because they have acquired
immunodeficiency syndrome.2,334
Drug–drug interactions involving photosensi-
tizing agents may play a role in photosensitivity.
Concomitant administration of photosensitizing
agents such as porfimer, verteporfin, or psoralens
(e.g., methoxsalen) and other agents reported to
cause photosensitivity reactions (see Table 8–1),
such as tetracyclines, phenothiazines, thiazide
diuretics, sulfonamides, NSAIDs, and others may
produce additive photosensitizing effects, thereby
increasing the potential for a photosensitivity reac-
tion.324 In cases of amiodarone-induced photosen-
TABLE 8–6 Risk Factors for Drug-Induced
Photosensitivity Reactions2,319,322,323,325
• Lack of protection against sunlight exposure
• Use of sunscreens containing para-aminobenzoic
acid
• Light skin (types I and II)/fair complexion
• High drug dose (phototoxic reactions only)
• Drug–drug interactions
• Immunocompromised state
sitivity, coadministration of pyridoxine has been
demonstrated to worsen the photosensitivity reac-
tion, possibly because of a metabolic effect result-
ing in damage to the skin’s structural integrity.12
Thami et al.335 have reported a reactivation of pho-
todermatitis caused by the concomitant adminis-
tration of haloperidol and methotrexate in a
patient with psoriasis. Although both drugs have
been reported to cause photosensitivity reactions, a
possible drug interaction between haloperidol and
methotrexate was suggested to play a role in the
development of the adverse reaction in this case.
With respect to phototoxicity, for which the dose
of the drug may be an important factor, any drug
interaction that may cause a significant increase in
the plasma concentration of the photosensitizing
drug may contribute to the development of photo-
sensitivity reactions.
MORBIDITY AND MORTALITY
In general, drug-induced photosensitivity reactions
rarely involve significant morbidity or mortality,
and most reactions are reversible after discontinua-
tion of the offending agent.2 However, in 5 to 10%
of patients who experience photoallergy, a chronic
condition known as “persistent light reaction”
(PLR) may develop; this is also occasionally
described as “chronic actinic dermatitis.”325 In such
patients, the photosensitivity reaction persists after
drug discontinuation, and relapse of the reaction
occurs on minimal exposure to UV light in the
absence of the offending agent. Although PLR may
occur in patients sensitized to systemic photosensi-
tizing agents, it is thought to occur more common-
ly in patients sensitized to topical photosensitizers.2
PREVENTION
Some possible methods for preventing drug-
induced photosensitivity reactions are listed in
Table 8–7.325 In the case of both photoallergic and
phototoxic reactions, the best means of prevention
includes both the avoidance of sunlight and the
use of broad-spectrum sunscreens that block both
UVA and UVB sunlight.325 In addition, the use of
protective clothing is also helpful in preventing
adverse reactions to light exposure. Of note, for
patients who are receiving photodynamic therapy
with agents such as porfimer and verteporfin,
opaque sunscreens such as zinc oxide should be
used, as nonopaque sunscreens are ineffective for
prevention of the photosensitivity induced by
these agents.227,307 Because of their potential to
TisdaleC08_117-134 1/15/10 9:43 AM Page 127
TABLE 8–7 Approaches to Help Prevent Drug-
Induced Photosensitivity325
• Avoid sunlight
• Use broad-spectrum sunscreens that block both
ultraviolet A and B sunlight (sun protection factor
>15)
• Avoid sunscreens containing para-aminobenzoic acid
• Use protective clothing (e.g., wide-brimmed hats,
sunglasses, and long-sleeved shirts)
• Use dietary supplements containing antioxidantsa
a reactions are listed in Table 8–8.1,2,319,324,325,328,
Further study is needed to confirm the efficacy of this
method.
cause or aggravate photodermatitis, sunscreens
containing PABA should be avoided.
Based on the underlying mechanism of photo-
sensitivity reactions, it has also been suggested that
dietary supplementation with antioxidants may
help prevent adverse cutaneous photoreactions.318
However, further study is needed to validate this
method of prevention.
MANAGEMENT
The appropriate treatment of drug-induced photo-
sensitivity reactions depends somewhat on the
type of reaction (i.e., photoallergic or phototoxic).
Treatment of patients with phototoxic reactions is
similar to that of patients with routine sunburn.
Discontinuation of the offending drug often accel-
erates resolution. In some cases of phototoxicity,
reducing the dose of the offending agent (rather
than drug discontinuation) may result in resolu-
tion of the reaction.319,328,332,333 In cases of amio-
darone-induced photosensitivity in which
blue-gray discoloration of the skin has occurred,
dose reduction has resulted in gradual disappear-
ance of the pigmentary changes.328 Systemic corti-
costeroids have failed to demonstrate efficacy in
the management of drug-induced phototoxici-
ty.1,336 Similarly, topical antihistamines have also
been shown to be ineffective.1
For patients experiencing a photoallergic reac-
tion, both antihistamines and corticosteroids may
be prescribed to assist with symptom relief. Oral
prednisone in doses of 1 mg/kg/day administered
as a short burst (e.g., for 3 to 10 days) or tapered
over the course of 3 weeks has been shown to be
highly effective in symptomatic patients suffering
from photoallergy.1,325 Topical corticosteroids (e.g.,
betamethasone valerate 0.1% cream) or NSAIDs
(e.g., indomethacin 25 mg three times daily) may
CHAPTER 8 • Photosensitivity 127
help to reduce pain and inflammation.325 The use
of NSAIDs or corticosteroids should be avoided,
however, in cases in which such medications have
been identified as the potential causative agent of
the photoreaction. In patients with photoallergic
reactions, discontinuation of the offending drug is
almost always necessary.2,337 For both types of pho-
tosensitivity reactions, the use of ice packs or cold-
water compresses may occasionally provide
symptomatic relief.325 Treatment options that may
be used in the management of photosensitivity
332,333,336
INFORMATION FOR PATIENTS
Patients to whom medications that have been
reported to cause photosensitivity reactions are
prescribed should be informed of the potential for
this adverse effect prior to the initiation of thera-
py. During the course of therapy with the poten-
tially photosensitizing agent, patients should be
encouraged to avoid excessive exposure to sun-
light, particularly from the hours of 10.A.M. to
4.P.M. and especially in the absence of protection
against UV light. Protective clothing (e.g., wide-
brimmed hats, sunglasses, long-sleeved shirts)
should be worn and broad-spectrum sunscreens
with a minimum sun protection factor of 15
should be used by the patient throughout the
duration of therapy.325 Zinc oxide, although cos-
metically less acceptable, may provide the best
protection against sunlight exposure. In general,
sunscreens containing PABA contain a sulfa moi-
ety and should be avoided in sensitized patients
because of the potential to aggravate or worsen
photodermatitis.319,325
TABLE 8–8 Treatment Options for Drug-Induced
Photosensitivity1,2,319,324,325,328,332,333,336
• Discontinuation of the offending drug
• Reduction in dose of the offending druga
• Systemic corticosteroidsb
• Topical corticosteroidsb
• Antihistaminesb
• Nonsteroidal antiinflammatory drugs
• Ice packs or cold water compresses
a
May be effective only in certain cases of phototoxicity.
Photoallergy reactions require discontinuation of the offend-
ing agent.
b
Only shown to be effective in cases of photoallergy.
TisdaleC08_117-134 1/15/10 9:43 AM Page 128
128 SECTION II • Drug-Induced Dermatologic Diseases
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2005;52(5 Suppl 1):581-585.
314. Rubenstein M, Levy ML, Metry D. Voriconazole-induced
retinoid-like photosensitivity in children. Pediatr
Dermatol. 2004;21:675-678.
315. VFEND(r) [package insert]. New York, NY: Pfizer, Inc; 2002.
316. Sonata [package insert]. Philadelphia, PA: Wyeth
Laboratories Inc; 2007.
317. Wolff K, Johnson RA, Suurmond D. Fitzpatrick’s Color
Atlas and Synopsis of Clinical Dermatology: Common and
Serious Diseases. 5th ed., New York, NY: McGraw-Hill;
2005:226-269.
318. Moore DE. Drug-induced cutaneous photosensitivity:
incidence, mechanism, prevention and management.
Drug Saf. 2002;25:345-372.
319. Gould JW, Mercurio MG, Elmets CA. Cutaneous
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324. Envoy GK, et al., eds. AHFS Drug Information 2004.
Bethesda, MD: American Society of Health-System
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325. Bondi J, Jegasothy B, Lazarus G. Dermatology, Diagnosis
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326. Heger JJ, Prystowsky EN, Zipes DP. Relationships between
amiodarone dosage, drug concentrations, and adverse
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327. Jafari-Fesharaki M, Scheinman MM. Adverse effects of
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dependent appearance and disappearance of
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329. Matheis H. Amiodarone pigmentation. Dermatologica.
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330. Cordarone [package insert]. Philadelphia, PA: Wyeth-
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331. Layton AM, Cunliffe WJ. Phototoxic eruptions due to
doxycycline–a dose-related phenomenon. Clin Exp
Dermatol. 1993;18:425-427.
332. Wainwright NJ, Collins P, Ferguson J. Photosensitivity
associated with antibacterial agents. Drug Saf.
1993;9:437-440.
333. Johnson BE, Ferguson J. Drug and chemical
photosensitivity. Semin Dermatol. 1990;9:39-46.
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335. Thami GP, Kaur S, Kanwar AJ. Delayed reactivation of
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TisdaleC09_135-176 1/12/10 2:33 PM Page 135
CHAPTER 9
Alopecia, Hirsutism, and
Hypertrichosis
ALOPECIA
Alopecia is hair loss due to a disturbance of the hair
growth cycle and may be manifested as total or
partial hair loss. Although the scalp is most often
involved, the disorder can affect all hair-bearing
areas of the body.1-3 Most cases are caused by
androgenic alopecia, also known as male pattern
baldness, secondary to hormonal and genetic fac-
tors. A relatively small percentage of alopecia cases
are drug-induced.4 Although drug-induced alope-
cia is not an extremely common event, it is quite
distressing to the patient, and therefore important
to recognize.5
The three phases of hair growth are anagen,
catagen, and telogen.6 The anagen, or growth,
phase is the most active phase of the growth cycle
and lasts from several months to years. During this
phase, the hair follicle produces hair continuously.
Intense mitotic activity occurs, and follicles are
highly susceptible to noxious events.6 The catagen
cycle, or transition period, lasts only 2 to 3 weeks.
During this phase, the inferior portion of the hair
follicle significantly thins. The third and final phase
of hair growth is the telogen, or resting, phase. This
phase usually lasts 2 to 4 months, after which the
follicle re-enters the anagen phase. At any given
time, 80% to 90% of the follicles of the typical scalp
are in the anagen phase and 10% to 15% of follicles
are in the telogen phase. Hair is shed during the tel-
ogen phase; telogen follicles usually shed between
40 and 100 hairs daily.7 Follicles in the telogen and
catagen phases, unlike those in the anagen phase,
typically are not sensitive to noxious agents, such
as cancer chemotherapy drugs, because of their
inconsistent mitotic and metabolic activity.6
Kristine E. Keplar
Androgenic alopecia, or “male pattern bald-
ness,” is hair thinning that occurs in an M-shaped
pattern, during which hair loss occurs on the
crown and temple areas of the head but spares the
back and sides of the head. It is termed “andro-
genic alopecia” because it generally follows the dis-
tribution of androgen-sensitive hair follicles.
Androgenic hair loss is often familial, and is
thought to involve a physiologic process incited in
genetically predisposed hair follicles under the
influences of androgens. Drugs with androgenic
activity can also induce this type of hair loss.8-11
CAUSATIVE AGENTS
The primary medications that may induce alope-
cia are anticoagulants, androgenic agents, hor-
mone therapy, psychotropic drugs, thyroid
medications, antiretroviral drugs, and cancer
chemotherapy agents.12 Drugs known to induce
alopecia are listed in Table 9–1.13-151
Anticoagulants
Heparin and heparinoid drugs primarily affect
scalp hairs. The hair loss usually occurs approxi-
mately 3 months after the initiation of treatment.
In one report, the onset of hair loss varied from 1
week to 3 months after the last dose of heparin.21
Although unfractionated heparin has been the pri-
mary anticoagulant linked to drug-induced alope-
cia, low-molecular-weight heparins and warfarin
have also been implicated as causative agents.4,8,9,
22,152,153
Warfarin typically induces mild, diffuse
alopecia with an onset between 3 and 20 weeks
135
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136 SECTION II • Drug-Induced Dermatologic Diseases

TABLE 9–1 Agents Implicated in Drug-Induced Alopecia

Drug Incidence Level of Evidence
(see page xii for explanation)

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)
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CHAPTER 9 • Alopecia, Hirsutism and Hypertrichosis 137

TABLE 9–1 Agents Implicated in Drug-Induced Alopecia (Continued)

Drug Incidence Level of Evidence

ANTICONVULSANTSd (Continued)
Lamotrigine8 1–5% C
Levetiracetam31 NK C
Phenobarbitol32 1.2% C
Pregabalin33 0.1–1% C
Primidone32 1.5% A
Tiagabine19 >1% C
Topiramate34,35 0.1–2% A
Valproic acid19,28,29,36,37,38,39 2.6–13% A
24–28% with higher doses8,39 A
ANTIDEPRESSANTS29
Bupropion40 <0.1% C
Venlafaxine41 NK C
Monoamine oxidase inhibitors:
Tranylcypromine29,42 NK C
9,28
Selective serotonin reuptake inhibitors:
Citalopam43 <1% B
Escitalopam44 <1% C
Fluoxetine23 NK C
Fluvoxamine45 <1% B
Paroxetine46 <1% B
Sertraline47 <1% B
Tricyclic antidepressants:28,9
Amitriptyline23 NK C
Amoxapine23 NK C
Clomipramine23 NK C
Desipramine23 NK C
Doxepine23 NK C
Imipramine48 0.01% C
Nortriptyline23 NK C
Protriptyline23 NK C
Trimipramine23 NK C
ANTIVIRALSe
Acyclovir9,19 1–5% C
Atazanavir19,49 NK C
Didanosine19,50 NK C
Indinavir19 NK C
Lamivudine19 NK C
Saquinavir19 NK C
Valacyclovir19,51 NK C
Zalcitabine19 <1% C
Zidovudine19 NK C
(Continued)
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138 SECTION II • Drug-Induced Dermatologic Diseases

TABLE 9–1 Agents Implicated in Drug-Induced Alopecia (Continued)

Drug Incidence Level of Evidence

BENZODIAZEPINES
Clonazepam28 NKc C
␤-BLOCKERS
Acebutolol19 NK C
Atenolol19 NK C
Betaxolol19 <2% C
Carvedilol19,52 ≤1% B
Metoprolol19 NK C
Nadolol19 NK C
Propranolol19,53 NK C
Timolol9,19 >5% C
CALCIUM-CHANNEL BLOCKERS
Nifedipine9 1–5% C
Verapamil9 <1% C
CANCER CHEMOTHERAPY AGENTS
Altretamine54,55 <1 % A
Amsacrine12,23 >10 % C
Anastrozole23 1–13% C
Bleomycin9,56,f 50% C
Busulfan9,12,57 >10% C
Carboplatin9,58 3–17% A
Cetuximab59 4% C
Cisplatin9,60-62 >10 % A
Cyclophosphamide9,60-62 40–60% C
Dactinomycin63, f >30% C
Daunorubicin9,64 >10% C
Docetaxel65-67, g 38% A
Dasatinib68 1–<10% A
Doxifluridine69 9–10% C
Doxorubicin9,23,60-62,64,70,71, f 16–100% A
Edatrexate72 Up to 35% C
Efaproxiral73 28 % C
Epirubicin12,74 25-100 % C
Erlotinib75 NK C
Estramustine76 1% A
Etoposide56,60-62,77,78,f 44 % B
Exemestane23,79,80 2–15% A
Fluorouracil9 >10% C
Gemcitabine58,81-83 10–61% A
Gefitinib84 10–11% A
Idarubicin85 1–10% B
(Continued)
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CHAPTER 9 • Alopecia, Hirsutism and Hypertrichosis 139

TABLE 9–1 Agents Implicated in Drug-Induced Alopecia (Continued)

Drug Incidence Level of Evidence

Ifosfamide23,77 75–100% C
Imatinib86 1–10% C
Irinotecan12,87,88 24–33% A
Ixabepilone86,89,90 43–92% A
Lobaplatin91 26–33% C
Methotrexate7,12,23,77,92,95,h ≥10% A
Mitomycin23,96 4% B
Mitoxantrone12,128 0.4–11% B
Nilotinib86,98 1–10% C
Oxaliplatin23 3% C
Paclitaxel12,58,70,99,100,i 87–92% A
Panitumumab59 4–9% C
Pemetrexed102 6–11% A
Pirarubicin103-105 12–94% C
Sorafenib86,106-108 14–38% A
Sunitinib109 5% A
Tamoxifen110-112 <1–5% A
Temozolomide113 9% C
Teniposide23,77,114 9% A
Thiotepa12,77 NKc C
Topotecan12,70,115-120 49–77% A
10% (oral)
Vinblastin9,12 >10% C
Vincristine9,12,56 20–70% C
Vindesine12,121,122 6–92 % B
Vinorelbine12,82,123-125 1–15% A
CHOLESTEROL-LOWERING AGENTS
Atorvastatin126 <2% C
Cholestyramine126 NK C
Clofibrate126 NK C
Lovastatin9 1–5% C
Pravastatin9 <1% C
DOPAMINE AGONISTS
Bromocriptine12,127 <1% C
Cabergoline12,127 <1% C
Dopamine12,127 <1% C
Levodopa12,127 <1% C
Pergolide12,127 <1% C
Ropinirole12,127 <1% C
GONADOTROPIN-RELEASING HORMONE–RELEASING AGONISTS
Gosereline12,128 NK C
(Continued)
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140 SECTION II • Drug-Induced Dermatologic Diseases

TABLE 9–1 Agents Implicated in Drug-Induced Alopecia (Continued)

Drug Incidence Level of Evidence

GOUT MEDICATIONS
Allopurinol12,13,23,129 NK C
Colchicine13,23,129 1–10% C
HISTAMINE2-RECEPTOR ANTAGONISTS
Cimetidine19,130 NK C
HEAVY METALS/TOXINS:
Arsenic, bismuth, lead, mercury, thallium131,132 NKj C
IMMUNOSUPPRESSANTS
Azathioprine9 <1% C
Cyclosporine9 1–5% C
Gold9,133 1–5% C
Leflunomide12,134 9–17% A
Methotrexate7,12,23,77,92,94,135 0.5–10% A
Mycophenolate23 3–20% C
Sulfasalazine19,134,136 6% A
Tacrolimus12,137 28% C
INTERFERONS6,19,138
Interferon alfa-N3 2–30% A
Interferon alfacon-1 2–30% A
Interferon alfa-2a, recombinant 2–30% A
Interferon alba-2b 2–30% A
Peginterferon alfa-2a and alfa-2b 14–44% A
ORAL CONTRACEPTIVES
All agents with high progesterone content11,14,126,133,139,140 NKb B
ANTIANXIETY/ANTIPSYCHOTIC MEDICATIONS
Aripiprazole86,141 <1% A
Buspirone8,9 1–5% C
Haloperidol8,126 <1% C
Lithium3,12,29,142-144,k 12–20% A
Olanzapine28,145,146 0.1–1% A
Quetiapine28,146 NK C
Risperidone88,146 NK C
Ziprasidone147 0.1–1% B
RETINOIDS
Acitretin6,12,13,148 20–30% C
Etretinate6,12,13,148 20–30% C
Isotretinoin6,12,13,148 20–30% C
Retinoic acid6,12,13,148 20–30% C
THYROID MEDICATIONS
Carbimazole9,149,150 3.5–10% C
Levothyroxine9,23,149,150 NKl C
(Continued)
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CHAPTER 9 • Alopecia, Hirsutism and Hypertrichosis 141

TABLE 9–1 Agents Implicated in Drug-Induced Alopecia (Continued)

Drug Incidence Level of Evidence

THYROID MEDICATIONS (Continued)
Liothyronine9,23,149,150 NKl C
Methimazole9,23,150 NKl C
Propylthiouracil9,86,149,150 NKc C
MISCELLANEOUS AGENTS
Aminoglutethimide19 NK C
Cetirizine9 1–5% C
Naproxen9 <1% C
Vasopressin9,12 >10% C
NK = Not known
a
Weight loss may play a role in amphetamine-induced hair loss.
b
Although the incidence is not known, it is believed to occur commonly.
c
Although the incidence is not known, it is believed to occur rarely.
d
“Perming” effects may be observed with valproic acid.36
e
Combinations of indinavir plus ritonavir may be associated with severe hair loss.12 Thoracic, axillary, pubic, thigh, and leg hair loss are
also frequently effects of indinavir.
f
Bleomycin, dactinomycin, doxorubicin, and etoposide may caused delayed alopecia.9,23,56,60-63
g
With docetaxel, hair loss is sudden in onset (usually during the third week after the first 1-hour infusion) and complete in many
patients, including loss of axillary and pubic hair, eyelashes, and eyebrows.64
h
Methotrexate causes dose-related alopecia.7,23,77,89,92
i
Paclitaxel has been reported to cause loss of all body hair.12,92
j
Degree and incidence of alopecia depends on dose and time of exposure.131,132
k
Changes in hair texture, such as loss of curl or wave, often may occur at significantly higher hair lithium concentrations.142
l
All thyroid replacement agents implicated, since hyperthyroidism and hypothyroidism are associated with hair loss.9,23,149,150

after the initiation of therapy. Most cases of hair
loss secondary to warfarin or heparinoid drugs go
unnoticed by the patient. Only 20% of those who
experience hair loss associated with these drugs
exhibit clinically evident alopecia. Scalp hair is the
primary target, but eyebrows, axillary, and pubic
hair also may be affected. Total alopecia is extreme-
ly rare.13
Retinoids
Vitamin A, or retinol, is often prescribed for the
treatment of hair disorders. However, alopecia of
the telogen effluvium type can occur in association
with ingestion of vitamin A in doses greater than
50,000 IU daily (whether dietary, such as cod liver
oil, or pharmaceutical) over a period of several
months.12 Other retinoids such as acitretin, etreti-
nate, and isotretinoin also cause hair loss.19
Alopecia associated with these agents usually
occurs after 3 to 8 weeks of therapy. Alopecia may
occur after exposure to lower doses, but the onset
is longer than 8 weeks. Alopecia is diffuse and
involves not only the scalp, but also eyelashes, eye-
brows, and pubic and axillary hair.13 Alopecia is
quickly reversible when the dose is decreased or
vitamin A supplementation is discontinued. Hair
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
Immunosuppressants
Medications used for rheumatoid arthritis, notably
disease-modifying antirheumatic drugs (DMARDs),
have been associated with mild, reversible alope-
cia.9,19,133 Gold therapy may cause exfoliative der-
matitis leading to alopecia. There is a case report of
scarring alopecia following gold therapy.9,19,133
Methotrexate-induced alopecia is thought to be
TisdaleC09_135-176 1/12/10 2:33 PM Page 142
142 SECTION II • Drug-Induced Dermatologic Diseases
dose-dependent.77,92 Other DMARDs that may
cause alopecia include leflunamide and sul-
fasalazine. Cyclosporine, tacrolimus, and
mycophenolate, which are often used following
organ transplantation, have also been associated
with hair loss.12,137
Dopamine Agonists
Dopamine agonists implicated in alopecia include
bromocriptine, levodopa, pergolide, pramipexole,
and ropinirole. Alopecia caused by these agents is
considered to be a rare side effect. Hair loss is
reversible following discontinuation of thera-
py.12,154
Interferons
No correlation has been established between inter-
feron dose and the onset or severity of hair loss. In
some patients, alopecia resolves despite continued
treatment.6 Transient localized alopecia has been
noted at the injection site in patients treated with
interferon alfa. There are also reports of hair-shape
and hair-color changes associated with interferon
use.12
Thyroid Agents
Antithyroid medications, including iodine, propy-
lthiouracil, carbimazole, and methimazole can
cause iatrogenic hypothyroidism leading to alope-
cia. Papadopoulos and Harden149 reported that
carbimazole, an agent similar in structure to
methimazole, induced alopecia in a small percent-
age of patients. However hair regrowth occurred in
all cases after carbimazole therapy was discontin-
ued.149 This reversible type of hair loss is telogen
effluvium and is associated with dry scalp and dry
and brittle hair.4,6 In a few case reports, carbima-
zole-induced alopecia occurred in euthyroid
patients.149 Sometimes the hair loss terminates
despite continuation of therapy with carbimazole
and methimazole.13 Thyroid replacement medica-
tions can also cause drug-induced alopecia.155,156
In general, maintaining patients’ euthyroid status
will aid in preventing antithyroid-induced alope-
cia.156
Antiepileptics
Several antiepileptic drugs have been associated
with alopecia.13 Of these, valproic acid is associated
with the highest incidence of hair loss, reported to
be between 2.6% and 12%. Alopecia occurs within 3
months after initiating therapy, and is believed to be
of the telogen effluvium type. The hair loss is usual-
ly transient and may terminate even if the medica-
tion is continued.13 Valproic acid can also affect hair
by causing a “perming” effect or “diffuse curliness of
the hair.” One report stated that this curliness
occurred while taking valproic acid for approximate-
ly 1 year. The curliness persisted for approximately
30 months of therapy and subsided within approxi-
mately 6 months after discontinuation of the thera-
py.36 Carbamazepine may also cause hair loss.6,28,29,34
Other antiepileptic medications that have been
associated with hair loss have all been implicated via
case reports. In one case, alopecia developed after 2
months of topiramate therapy in a 15-year-old
female. Hair loss resolved after discontinuation of
therapy and recurred upon reinitiation of topira-
mate treatment.34
Psychotropics
Psychotropic drug–induced alopecia tends to be
associated with transient mild to moderate hair
loss and is reversible upon discontinuation of ther-
apy.3 In some cases, improvement has occurred
spontaneously despite continuation of lithium
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-
ated with lithium use. This effect reversed upon
discontinuation of lithium therapy.29 Lithium-
induced hair loss may be a result of lithium-
induced hypothyroidism; resolution of the
hypothyroid state may reverse the hair loss.142
Antidepressant agents such as the tricyclic antide-
pressants, selective serotonin reuptake inhibitors,
new-generation antidepressants and the antianxi-
ety agent buspirone have all been implicated as
causing alopecia, although this occurs rarely.29
Atypical and typical antipsychotic agents have also
been reported to induce hair loss, which usually
occurs several months after the initiation of thera-
py and is characterized as nonscarring, diffuse
alopecia with generalized or localized hair loss
commonly affecting the scalp. The alopecia is
reversible, usually within 2 to 5 months after dis-
continuation of therapy.157
Hormones/Androgens
Two types of oral contraceptive–induced hair loss
have been identified. In the first type, hair loss
occurs 3 months after discontinuation of therapy
with oral contraceptives. This type of alopecia is
similar to postpartum hair loss, in which increased
telogen loss is a consequence of the higher percent-
age of anagen hair maintained during pregnancy.
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CHAPTER 9 • Alopecia, Hirsutism and Hypertrichosis 143

Although hair shedding can appear dramatic, it

usually is not noticeable.6,152 The androgenic
effects of progestin are responsible for the second
type of oral contraceptive–induced alopecia. In
these cases, modifying therapy to an oral contra-
ceptive with a lower dose of progestin often results
in resolution of the alopecia. The incidence of this
type of drug-induced alopecia is decreasing because
of the lower progestin content of new formulations
of oral contraceptives.152,158,159
Any medication containing androgens or ana-
bolic steroids can produce or aggravate alopecia in
women.9,19,160 For instance, androgenic alopecia
occurs in a small percentage of women receiving
hormone-replacement therapy.12 Methyltestos-
terone and progestin derivatives such as medrox-
yprogesterone and norethindrone may, in rare
instances, aggravate scalp alopecia. Estrogen also
has been associated with increased hair shed-
ding.158 A review of hormone-replacement therapy
with esterified estrogen 1.25 mg and methyltestos-
terone 2.5 mg as well as esterified estrogen 0.625
mg and methyltestosterone 1.25 mg in 2,556
patients over 13 years verified the occurrence of FIGURE 9–1 Diffuse alopecia caused by 5-fluorouracil.13
drug-induced alopecia associated with both contra- Reprinted with permission from Bork K, ed. Cutaneous Side
ceptive combinations.140 Effects of Drugs. Philadelphia, PA: Saunders; 1988:249-258.
Antiestrogens and aromatase inhibitors such as
tamoxifen and letrozole and gonadotropin-releas-
ing hormone agonists may also be associated with
androgenic alopecia.12 Other androgen-induced apy, and hair regrowth tends to occur rapidly.
hair loss may be caused by anabolic steroids such However, the texture and color of regrown hair may
as testosterone and nandrolone.19,150 be different.12 In rare cases associated with exposure
to cancer chemotherapy over a long period, atrophy
of the hair bulb may occur. However, most believe
Cancer Chemotherapy that this atrophy is always reversible after discontin-
Cancer chemotherapy–induced alopecia occurs uation of therapy with the causative agent.13,126
commonly.6,9,60,155 The agents that are most com- Permanent alopecia may occur after condition-
monly implicated include bleomycin, cisplatin, ing regimens used commonly in hematopoietic
cyclophosphamide, daunorubicin, doxorubicin, stem-cell transplantation and in association with
fluorouracil, methotrexate, and vincristine. 6,9,60,155 certain chemotherapy agents administered in high
Figure 9–1 depicts a patient with alopecia induced doses (e.g. carboplatin).57,161 Combinations of cer-
by fluorouracil.13 Hair loss typically begins after the tain cancer chemotherapy agents, such as
first or second cycle. Consequently, hair shedding cyclophosphamide combined with thiotepa and
occurs approximately 4 to 8 weeks after treatment carboplatin and cyclophosphamide combined with
has been initiated. Roughly 25% of hair has been busulfan have also been documented as causes of
lost after 6 to 8 weeks of therapy, at which time permanent alopecia.161,162
clinically apparent alopecia is observed. Hair may
appear patchy or patterned, and typically falls out
spontaneously or with brushing or combing.4,12,126
Poisoning and Nonmetal Elements
Antineoplastic drug–induced alopecia can result Poisoning with arsenic, bismuth, copper, lead,
in loss of hair from other parts of the body in addi- mercury, or thallium can also result in pronounced
tion to the scalp. The majority of male patients with hair loss, which occurs relatively quickly after
cancer chemotherapy–induced alopecia report that exposure.4,6,131 Hair loss associated with thallium,
the frequency of shaving is reduced to one to three gold, arsenic, and bismuth usually begins 2 to 4
times a week.126 Chemotherapy-induced alopecia weeks after exposure.11,104 Thallium can affect not
almost always resolves after discontinuation of ther- only the scalp but also the eyelashes, eyebrows (lat-
TisdaleC09_135-176 1/12/10 2:33 PM Page 144
144 SECTION II • Drug-Induced Dermatologic Diseases
eral aspects), arms, and legs. Total epilation may
occur approximately 1 month after the initiation
of therapy.4,6 Severe hair shedding usually occurs
only in association with the cytotoxic agents.
Noncytotoxic drug-induced hair loss rarely results
in total hair loss, and is normally reversible upon
discontinuation of the offending drug.12
EPIDEMIOLOGY
Drug-induced alopecia is not uncommon,
although the exact incidence is not known. The
incidence of alopecia associated with specific
drugs, where known, is presented in Table 9–1.13-151
Alopecia associated with chemotherapy and
cytotoxic drugs, whether noticed or unnoticed,
occurs nearly in 100% of patients who do not
undergo prophylaxis against the hair loss. The
prevalence and severity depend on the drug as well
as on individual predisposition. Hair loss can occur
in association with some drugs when administered
in usual doses, while other drugs are unpredictable
and produce drug-induced alopecia only occasion-
ally.6,9,12,60 Heparin and heparinoid drugs can lead
to telogen effluvium, with an incidence that varies
from 0 to >50%.21 Vitamin A (retinol)–induced
alopecia has been reported in approximately 20%
to 30% of patients.6,13 The incidence of DMARD-
induced alopecia ranges from 1% to 10%.11,20,21
Alopecia caused by dopamine agonists occurs rarely
and is more common in females.12,154 Nearly 20% to
30% of patients receiving interferon experience
alopecia of the telogen effluvium type.6 One review
of case reports found the incidence of alopecia
induced by carbimazole to be low, ranging from
3.5% to 10%.149 The overall incidence of hair loss
induced by antiepileptic medications is 0.01% to
12%, with valproic acid therapy leading to the
highest incidence (2.6% to 12%).13,34 Alopecia asso-
ciated with carbamazepine has been reported to be
a very rare adverse event in some case reports, while
others have documented it as “common.”6,28,29,34
The incidence of lithium-induced hair loss has been
reported to be 12% to 17%.3 Hormone-replacement
therapy with esterified estrogen 1.25 mg with
methyltestosterone 2.5 mg or with esterified estro-
gen 0.625 mg and methyltestosterone 1.25 mg
induces alopecia with a reported incidence of
8.8%.140 Cytostatic agents have been reported to
cause total scalp-hair loss in roughly 10% of
patients. Hair loss was reversed after therapy with
the agent was discontinued.4,13,126,163
The onset of drug-induced hair loss occurring
in telogen effluvium is delayed by several months;
consequently, it may be difficult to determine the
causative agent. It may be equally difficult to deter-
mine whether it was drug treatment or another
event that was the cause of the hair loss.6,163-165
MECHANISMS
Mechanisms of drug-induced alopecia are listed in
Table 9–2.5,6,166 Drugs that induce alopecia can be
classified according to their effects on the phases of
the hair growth cycle (Figure 9–2).1,63 There are two
patterns of drug-induced alopecia; anagen effluvi-
um and telogen effluvium.5,163
During anagen effluvium, drugs may partially
or completely suppress mitosis and cause metabol-
ic impairment of hair growth. This leads to failure
to form a hair shaft or the formation of a thinned,
weakened hair shaft.5,166 Eighty-five percent of hair
follicles on the scalp are in the anagen phase.
Therefore, this is a major target for drugs that cause
alopecia. Hair loss also can be manifested in axil-
lary, pubic, and other body regions. Cytotoxic
agents such as cancer chemotherapy drugs and
toxic plasma concentrations of certain metals
cause drug-induced alopecia by affecting follicles
during the anagen phase of hair growth. Since the
anagen phase duration is the main determinant of
the length of the hair, the maximum length of the
new anagen hair is shorter than that of the hair it
is replacing. Eventually, the anagen phase is short-
ened to the point at which the hair cannot reach
the skin surface. At this point, the only visible part
of the hair cycle on the skin is the pore, as the hair
follicle can no longer be seen.7 In patients with
anagen alopecia, hair loss is almost always
reversible when therapy with the offending agent
is terminated. However, since hair grows at a rate
of only about 1 cm per month, several months is
required for complete reversal of the hair loss.6 The
medications most commonly associated with ana-
gen effluvium are cancer chemotherapy agents.5
Drug-induced hair loss is primarily considered
telogen effluvium hair loss, since the majority of
drugs that induce hair loss disrupt the telogen efflu-
vium growth phase. In telogen effluvium, drugs
induce hair loss by causing premature termination
of the anagen, or growing, phase of the hair cycle,
resulting in an increased number of shed hairs. This
type of hair loss often can be identified by the pres-
ence of a clubbed root on shed hair. Hair loss is typ-
ically diffuse rather than patchy, and patients often
are asymptomatic. Telogen effluvium is primarily
noted on the scalp; however, it sometimes may be
detected in other locations.1,5,6,28
Alopecia in patients with telogen effluvium is
usually subclinical and rarely involves more than
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CHAPTER 9 • Alopecia, Hirsutism and Hypertrichosis 145

TABLE 9–2 Mechanisms of Drug-Induced Alopecia5,6,166

Drug Mechanism
AMPHETAMINES
All agents implicated Telogen effluvium
ANABOLIC STEROIDS/ANDROGENS
All agents implicated Androgenic alopecia
ANESTHETICS
Halothane Telogen effluvium
ANGIOTENSIN-CONVERTING ENZYME INHIBITORS
Benazepril Telogen effluvium
Captopril
Enalopril
Lisinopril
Quinapril
Ramipril
ANTIARRHYTHMICS
Amiodarone Telogen effluvium
ANTICOAGULANTS
Heparin Telogen effluvium
Low-molecular-weight heparins
Warfarin
ANTICONVULSANTS
Carbamazepine Telogen effluvium
Felbamate
Gabapentin
Lamotrigine
Levetiracetam
Phenobarbital
Pregabalin
Primidone
Tiagabine
Topiramate
Valproic acid
ANTIDEPRESSANTS
Bupropion Telogen effluvium
Venlafaxine
Monoamine oxidase inhibitors
Selective serotonin reuptake inhibitors
Tricyclic antidepressants
ANTIVIRALS Telogen effluvium
Acyclovir
Atazamavir
Didanosine
Indinavir
Lamivudine
Saquinavir
Valacyclovir
Zalcitabine
Zidovudine
(Continued)
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146 SECTION II • Drug-Induced Dermatologic Diseases

TABLE 9–2 Mechanisms of Drug-Induced Alopecia5,6,166 (Continued)

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)
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CHAPTER 9 • Alopecia, Hirsutism and Hypertrichosis 147

TABLE 9–2 Mechanisms of Drug-Induced Alopecia5,6,166 (Continued)

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)
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148 SECTION II • Drug-Induced Dermatologic Diseases

TABLE 9–2 Mechanisms of Drug-Induced Alopecia5,6,166 (Continued)

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-
induced alopecia is often delayed for months.21 As
the hair loss is mild and often occurs long after
therapy with the offending agent is initiated, this
condition can be easily overlooked. In telogen
effluvium, the hair root is not damaged and hair
will spontaneously regrows once therapy with the
offending drug is discontinued. The condition also
may be reversed following a reduction in the dose
of the causative agent.6,163-165
Telogen hair loss often occurs secondary to events
such as severe illness, childbirth, fever, and hemor-
rhage. It can be caused by drugs including heparin,
warfarin, low-molecular-weight heparins, lithium,
certain ␤-blockers (metoprolol, nadolol, propranolol),
and alpha- and gamma-interferon. A few cytotoxic
agents also may cause telogen effluvium by shifting
the hair follicles into a premature resting cycle.166
Drugs also may induce hair loss by increasing
androgen activity. Hair loss occurring by this mech-
anism is termed “androgenic alopecia” or “androge-
netic alopecia,” also known as “male pattern bald-
ness.” Women with androgenic alopecia have
higher plasma concentrations of 5␣-reductase
(which converts testosterone to dihydrotestos-
terone), lower plasma concentrations of cytochrome
P-450 (which converts testosterone to estrogen), and
greater density of androgen receptors. However,
these patients do not have higher plasma concentra-
tions of androgens and tend to have normal fertili-
ty, menses, and endocrine function.167 Androgenic
alopecia often presents as a bitemporal recession of
the hairline, as thinning of the frontal and vertex
areas of the scalp, or as complete baldness and loss
of all hair except the occipital and temporal
fringes.1,5,63,168 In women, androgenic alopecia often
manifests as a diffuse thinning over the top of the
scalp with preservation of the anterior hairline.
Drugs implicated in androgenic alopecia include
danazol, metyrapone, estrogen receptor antagonists,
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CHAPTER 9 • Alopecia, Hirsutism and Hypertrichosis 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
is not reversible upon discontinuation of therapy
with the offending agent.5
CLINICAL PRESENTATION AND
DIFFERENTIAL DIAGNOSIS
Signs and symptoms associated with drug-induced
alopecia are listed in Table 9–3.4-6,10,11,12,63,167,169
Features of different types of drug-induced alopecia
are compared in Table 9–4.6,9,10,12,63,167,169 Patients
with drug-induced anagen alopecia present with
hair that is thin and fragile, and shed hairs are nar-
row, broken, and have no roots.5 Hair loss usually
occurs within days to weeks after the initiation of
therapy with the offending medication and often
is very severe. Microscopic examination of hair
from patients with cancer chemotherapy–induced
alopecia reveals fragmentation, trichorrhexis,
decreased diameter, and depigmentation of the
hair shaft. Hair is fragile, thin, and breaks off near-
ly as quickly as it issues from the hair follicle.166,170
Patients with drug-induced telogen alopecia typ-
ically present with mild, diffuse hair loss. Shed hair
is typically found to have clubbed roots; miniatur-
ized hairs are generally not found.1,5,6,28,165 Although
presentation depends on the percentage of hair fol-
licles involved, hair loss in patients with drug-
induced telogen alopecia often does not become evi-
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
each successive growth cycle, hair follicles become
smaller and produce shorter, finer hairs that poorly
cover the scalp. Miniaturization of hairs with vari-
ous lengths and diameters is a classic sign of andro-
genic alopecia.5,168 Evaluation of plasma
testosterone concentrations is of value in these
patients; testing for drug-induced alopecia is expect-
ed to yield normal or low results in the absence of
other features consistent with androgen excess (e.g.,
hirsutism, acne, or irregular menses).9,167,171 Biopsy
of the scalp in women with androgenic alopecia
shows increased aromatase activity as compared to
that in men with androgenic alopecia.158
Patients should be evaluated for the presence
of shedding or fragile hair (or both), slowed rate of
hair growth, inability to regenerate new hair, and
any related local or systemic disorders. In addition
to a visual inspection, specific diagnostic proce-
dures such as the hair-pull test, hair plucks, micro-
scopic examination of hair and scalp, as well as
cultures and biopsies may be used.1 The hair-pull
test is one of the easiest tests used to evaluate
alopecia. Patients are advised not to shampoo the
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150 SECTION II • Drug-Induced Dermatologic Diseases

TABLE 9–3 Signs and Symptoms Associated with Drug-Induced Alopecia4-6,10,11,12,63,167,169

Anagen Effluvium Alopecia
• Acute severe hair shedding with onset of days to weeks after the initiation of therapy
• Often >200 hairs are shed daily.
• May cause loss of hair from entire scalp, eyebrows, and eyelashes.
• Hair loss elsewhere is less common.
• Positive hair-pull test
• Photograph/visualization of scalp reveals diffuse thinning, which may progress to entire scalp hair loss.
• Trichogram/trichoscan reveals weakening and thinning of hair shaft, hair shaft breaks easily at the base with minimal
trauma, and/or dystrophic hair (toxically damaged hair).
Telogen Effluvium Alopecia
• Hair loss occurs often within 2–4 months after the initiation of therapy.
• Increased hair shedding can vary from day to day, but often ~100–150 hairs per day
• Hair loss is usually diffuse and mild. Many times, it is not noticeable at all.
• Occasional loss of pubic or body hairs can occur.
• Trichogram/trichoscan often reveals that scalp and hair shafts appear normal.
• Shed hair has clubbed roots.
• Positive hair-pull test
• Photograph/visualization of scalp reveals diffuse thinning; may progress to entire scalp hair loss.
Androgenetic Alopecia
• Preservation of the follicular ostia is observed.
• The hair loss is nonscarring.
• Trichogram/trichoscan reveals shorter, finer, and often lighter-colored hair shafts.
• Hair-pull test reveals (+) high telogen count.
• Photograph and/or visualization of scalp reveals diffuse thinning, specific areas of hair loss, progression of hair loss in
androgenic pattern.
• Scalp biopsy (possible histologic features) reveals fraction of terminal hair is decreased, nonspecific focal perivascular
basophilic degeneration of the lower third of the connective-tissue sheath of otherwise normal anagen follicles, peri-
follicular lymphocytic infiltrate at the level of the sebaceous duct, and/or fibrotic streamers present.
Male Androgenetic Alopecia
• Hair loss begins at the frontal hairline and causes a receding hairline and possibly thins the hair at the crown, then can
spread.
• The hair loss is nonscarring.
• Preservation of the follicular ostia is observed.
Female Androgenetic Alopecia
• Diffuse thinning typically occurs at vertex, but can spread to the crown.
• For the most part, the frontal hair line is preserved.

hair for 24 hours prior to the test.167 The clinician
grasps approximately 60 hairs using the thumb
and index and middle fingers. The hairs are gently
but firmly pulled. The test is considered positive
for active shedding when more than six hairs are
pulled free. If on microscopic exam a white bulb is
found on the shaft of extracted hair, the test is con-
sidered positive for telogen effluvium.8
When a definitive diagnosis is needed or if the
routine testing is inconclusive, a scalp biopsy can
be performed. The scalp biopsy provides histologic
features, the number of anagen and telogen hairs,
and the number of terminal and vellus hairs per
area, which provides a more definitive analysis of
the hair loss. A scalp biopsy leaves a small scar on
the patient’s scalp, as it is an invasive procedure.
Patients may refuse the biopsy because of the scar
if the hair loss is potentially irreversible. A scalp
biopsy is usually not necessary for routine diagno-
sis of hair loss.10
Drug-induced androgenic alopecia may be sus-
pected in patients taking an androgenic drug and
in whom the hair loss is mediated by the presence
of androgen dihydrotestosterone, the hair loss is
male-pattern type (no effects on nonscalp hair),
the shedding is usually not severe, and the hair
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CHAPTER 9 • Alopecia, Hirsutism and Hypertrichosis 151

TABLE 9–4 Comparison of Features of Drug-Induced Alopecia6,9,10,12,63,167,169

Feature
Onset of hair loss
Description of hair loss
Evaluation of the hair follicle
Results if causative drug
is discontinued
Anagen Effluvium
Within days to weeks
Extensive or severe hair
loss can occur. Sometimes
complete hair loss can
occur, especially with
certain cancer
chemotherapy agents.
Weakening and thinning of
hair shaft; breaks easily at
the base with minimal
trauma.
Usually resolves; however,
if long-term exposure to
drug, may result in a
scarring alopecia (which
does not resolve with
discontinuation of therapy)
Telogen Effluvium
Becomes evident
within 2–4 mo
Usually mild and diffuse,
often not noticed at all
Scalp and hair shafts often
appear normal. Shed hair
has clubbed roots
Nearly always resolves with
discontinuation or lower
doses of the causative
drug.
Androgenic Alopecia
First appears as telogen
effluvium then pro-
ceeds to androgenic
alopecia if drug is
continued.
In males, primarily
bitemporal recession of
the hairline; in women,
a diffuse thinning over
the scalp with more
noticeable thinning in
the frontal and parietal
areas with preservation
of the anterior hairline
Shorter, finer, and often
lighter-colored hair
shafts often present.
In many cases, it is not
reversible upon
discontinuing the
causative agent.

comes out by the roots.9,12,19,155,167,168 In those with

telogen effluvium hair loss, the hair comes out by
the roots and the inducing drug was usually initi-
ated 2 to 4 months before the onset of alopecia and
the onset of hair shedding is abrupt and promi-
nent. Severe shedding is uncommon and occurs
exclusively in association with interferons, anti-
retroviral drugs, heparin and heparinoids, and, on
occasion, cancer chemotherapy agents.12 Hair
regrowth normally occurs within 2 to 6 months
after discontinuing therapy with the causative
agent.9,12,19,155 Anagen effluvium alopecia usually
develops within 7 to 14 days after the initiation of
therapy with the causative agent, and the hair
shedding is acute, severe, and may produce loss of
most of the scalp hair, eyelashes, and eyebrows.
This type of alopecia occurs almost exclusively in
association with cytotoxic drugs such as cancer
chemotherapy agents. Normally, hair regrowth
occurs rapidly if therapy with the causative agent is
discontinued and minimal damage to the hair fol-
licles occurred.12,13,125,155 Conditions to consider in
the differential diagnosis of drug-induced alopecia
are listed in Table 9–5.4,8
RISK FACTORS
Risk factors for drug-induced alopecia are listed in
Table 9–6.148,152,155 A number of factors may
increase a patient’s risk for drug-induced alopecia.
Route of administration has been shown to influ-
ence the risk of alopecia associated with some
drugs. Cancer chemotherapy agents administered
intravenously may cause complete alopecia within
a short time, whereas oral therapy tends to be asso-
ciated with a lower risk of alopecia, regardless of
the total dose administered. Drug combinations,
higher doses, and longer duration of drug therapy
also can contribute to the risk of alopecia.166 For
example, lithium-induced changes in hair texture,
such as a loss of a natural wave or curl, are more
likely to occur in patients with significantly higher
hair lithium concentrations than in those who do
not experience hair changes.142 The risk of antico-
agulant-induced hair loss is not related to age, but
appears to be dose-related, and seems to be more
frequent in women than in men.6,13 Alopecia
caused by dopamine agonists is also more com-
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152 SECTION II • Drug-Induced Dermatologic Diseases
TABLE 9–5 Conditions to Consider in the
Differential Diagnosis of Drug-Induced Alopecia4,8
Alopecia areata, cicatricial alopecia, telogen
effluvium:
• Systemic/chronic illness (e.g., autoimmune disorder,
cancer)
Cicatricial alopecia, telogen effluvium, tinea
capitis:
• Infection (systemic or local)
Telogen effluvium; anagen effluvium:
• Serious illness within previous 3– 4 mo
Trichotillomania:
• If taking psychoactive medication, also consider
telogen effluvium, as both types of alopecia could
be occurring simultaneously
• Psychiatric disorder (e.g., psychosis, anxiety, obses-
sive–compulsive disorder)
Telogen effluvium:
• Physical stress (e.g., surgery, pregnancy, malnutrition)
• Life-threatening psychological stress
Traction alopecia:
• Tight braids
• “Pulled-back” hairstyle
Androgenic alopecia (women):
• Hirsutism (combined hirsutism/alopecia in polycys-
tic ovary disease)
• Amenorrhea
• Infertility
Alopecia areata, telogen effluvium:
• Hypothyroidism
• Other endocrinopathies
mon in women than in men.12,154 Vitamin A
(retinol)–induced alopecia occurs more frequently
in women receiving higher doses. Vitamin E, taken
concurrently with vitamin A, may potentiate vita-
min A toxicity.6,13 Patients with preexisting thyroid
disease, polycystic ovary disease, inflammatory dis-
eases such as seborrheic dermatitis, psoriasis, mal-
nutrition, or certain metabolic disorders are at risk
for alopecia.1 Concomitant systemic and chronic
illness such as autoimmune disorders and cancer
may also increase the risk. Stress, crash dieting,
infection, fever, and childbirth are other factors
that can lead to telogen effluvium.4,8 Women with
androgen alopecia who take a progestin with high
androgenic activity for oral contraception or hor-
mone-replacement therapy are at increased risk for
further hair loss. Consequently, a progestin with
little or no androgenic activity such as norgesti-
mate or ethynodiol diacetate is preferable.
Testosterone and related substances such as dehy-
TABLE 9–6 Risk Factors for Drug-Induced
Alopecia148,152,155
Risk factors related to drug administration:
• Higher doses
• Intravenous route of administration
• Longer duration of exposure
• Combination therapy
Disease states:
• Endocrine abnormalities
• Autoimmune disease
• Polycystic ovary disease
• Inflammatory diseases (i.e., seborrheic dermatitis,
psoriasis)
• Hyperandrogenic disorders
• Hypothyroidism or hyperthyroidism
• Illness/fevers/infection
• Iron deficiency anemia
• Parturition; increased blood loss
• Poor nutritional status/crash diets (low serum iron
or ferritin concentrations or deficiency of protein,
zinc, selenium)
• Family history of androgenic alopecia
• Recent surgery
• Stress
droepiandrosterone (DHEA) should be avoided in
women with androgen alopecia because of the
increased risk for worsening the condition.168
Postoperative alopecia is the temporary or per-
manent loss of hair that occurs following pro-
longed immobilization during general anesthesia
and intubation.172 Localized pressure-induced
ischemia is the likely cause. Patients at highest risk
for permanent hair loss include those undergoing
cardiac or gynecologic surgical procedures for
which the combined intraoperative and postopera-
tive intubation time exceeds 24 hours.
MORBIDITY AND MORTALITY
Although drug-induced hair loss is usually
reversible, it can be quite traumatic for both men
and women.77 In one study, cancer chemothera-
py–induced alopecia ranked third on patients’ lists
of distressing symptoms, behind nausea and vom-
iting.173 Patients sometimes refuse cancer
chemotherapy for fear of hair loss.77 It is important
that clinicians appreciate their patients’ views
regarding the social impact of hair loss, even in
cases in which patients experience only hair thin-
ning. Understanding patients’ feelings regarding
hair loss and openly discussing the matter may
TisdaleC09_135-176 1/12/10 2:33 PM Page 153
reduce the risk that they will abruptly discontinue
medications and suffer potentially serious health
consequences as a result.29
PREVENTION
Avoiding therapy with medications that may cause
alopecia is the best method of prevention, but in
many cases this approach is not feasible. In situa-
tions in which drug-induced alopecia may occur,
continuation of therapy may be necessary, particu-
larly with cancer chemotherapy agents, anticoagu-
lants, or psychiatric medications. In such cases,
clinicians should use the lowest possible dose of
the potentially causative agents and avoid, when
possible, the use of multiple drugs with the poten-
tial to cause hair loss. In addition, the duration of
exposure should be limited, and the oral, rather
than intravenous, route should be used whenever
possible.159,166 Delivery of anthracyclines via lipo-
somes significantly reduces the risk of hair loss as
compared with other routes of administration.56
Avoiding drug interactions that lead to increased
plasma concentrations of alopecia-inducing drugs
is also important, especially if the alopecia is dose-
dependent. Approaches to help prevent drug-
induced alopecia are presented in Table
9–7.6,8,9,56,158,159,166,174-177
Other preventive measures include ensuring
proper nutritional status and management of
stress. Stress and anxiety are often present in
patients who are taking psychotropic medications
and are also symptoms in patients with malnutri-
tion. Stress, anxiety, and malnutrition are each
well-documented causes of hair loss. Therefore,
patients taking drugs known to cause alopecia may
experience hair loss due to the medication, stress,
anxiety, or any combination of these factors.
Consequently, helping the patient cope and gain
better control of his or her disease state may reduce
stress and anxiety and may decrease the risk or
severity (or both) of hair loss induced by psy-
chotropic medications.9,19
Diseases or conditions that can cause or exacer-
bate hair loss, such as infections, fever, malnutri-
tion, polycystic ovary disease, hyperinsulinemia,
inflammatory diseases, and autoimmune disorders
should be identified and managed appropriately
and corrected, if possible. Prior to the initiation of
therapy with drugs known to cause alopecia,
assessment of plasma iron and ferritin concentra-
tions and thyroid function, identifying any family
history of androgenic alopecia, and detection of
conditions associated with androgen excess, such
as hirsutism, amenorrhea, or infertility may allow
CHAPTER 9 • Alopecia, Hirsutism and Hypertrichosis 153
TABLE 9–7 Approaches to Help Prevent Drug-
Induced Alopecia6,8,9,56,158,159,166,174-177
• Avoid drugs with potential to induce alopecia.
• Use the lowest possible dose of potentially causative
agents.
• Avoid, when possible, the use of multiple drugs with
the potential to cause hair loss.
• Limit duration of exposure to potentially causative
agents.
• Use oral route rather than intravenous route when-
ever possible.
• Avoid drug interactions that could increase plasma
concentrations of potentially causative agents associ-
ated with dose-dependent alopecia.
• Monitor kidney and/or hepatic function in patients
taking renally eliminated or hepatically metabolized
drugs known to cause dose-dependent alopecia.
• Maintain proper nutritional status.
• Manage stress.
• Identify and manage comorbid diseases and condi-
tions that can cause or exacerbate hair loss, such as
infections, fevers, malnutrition, polycystic ovary dis-
ease, hyperinsulinemia, inflammatory diseases, and
autoimmune diseases.
• Check plasma iron and ferritin concentrations and
thyroid function at first sign of hair loss.
• Identify any family history of androgenic alopecia,
hirsutism, amenorrhea, or infertility prior to initiation
of therapy with medications known to cause hair
loss; this may be allow the clinician to identify and
correct potential risk factors for alopecia.
• Recognize patients at high risk for alopecia or deal
with existing alopecia to allow the either the admin-
istration of preventive therapy (such as with topical
minoxidil for prevention of drug-induced hair loss) to
avoidance of the alopecia-inducing medication.
• For patients undergoing cancer chemotherapy, con-
sider scalp cooling or hypothermia.
• Patients with breast cancer or lymphoproliferative
disorders should be warned of the potential for
interference with drug delivery. Scalp cooling should
be avoided in patients with hepatic dysfunction.
• Risk of hair loss is significantly lower with liposomal
delivery of the anthracyclines.
the clinician to identify and correct potential risk
factors for alopecia.8,9,158 Methotrexate-induced
alopecia may be prevented with folic acid supple-
mentation.77,92 There are a few reports that valproic
acid–induced hair loss may be prevented with zinc
and selenium supplementation, dose reduction, or
both.29 The risk of postoperative alopecia may be
reduced with frequent intraoperative and postop-
erative head repositioning.172
TisdaleC09_135-176 1/12/10 2:33 PM Page 154
154 SECTION II • Drug-Induced Dermatologic Diseases
Patients with a family history of androgenic
alopecia are at high risk for androgen-induced
alopecia associated with certain oral contracep-
tives. In these patients, selection of an oral contra-
ceptive with little to no androgenic effects may
reduce the risk of alopecia.148 Prophylactic therapy
with topical minoxidil can be prescribed when a
patient with a family history of androgenic alope-
cia requires long-term therapy with a medication
known to induce androgenic alopecia. However,
minoxidil is not effective for prevention of cancer
chemotherapy–induced alopecia.178
Scalp cooling and hypothermia are of question-
able efficacy for the prevention of cancer
chemotherapy-induced alopecia. Scalp cooling
involves applying a cooling turban around the
scalp with a tourniquet pressure ranging from 30 to
50 mm Hg above systolic blood pressure 10 minutes
prior to drug administration, followed by removal
30 minutes after drug administration application.
Hypothermia involves cooling the scalp to at least
24°C for 5 minutes before, during, and 20 minutes
after the infusion of cancer chemotherapy.6,56 Some
investigators have raised concerns that, in some
cases, these methods may be detrimental because of
a possible reduction of delivery of chemotherapy
drugs to intended areas, or when chemotherapy is
being used for generalized hematogenic metastases
or there is a high likelihood of metastasis to the
scalp, such as in patients with breast cancer or lym-
phoproliferative disorders.56,174 Liver dysfunction
may also impair the potential efficacy of these pre-
ventive measures, as it inhibits the metabolism of
some chemotherapy agents, thereby allowing drug
concentrations to persist beyond the protective
time frame of induced scalp hypothermia.175-177
MANAGEMENT
For patients with drug-induced telogen alopecia,
hair growth returns when the causative agent is
discontinued or the dose is decreased.
Consequently, additional treatment is usually not
necessary.6,162,164,165 When discontinuation or dose
adjustment is not possible, a trial with topical
minoxidil is suggested (Table 9–8).1,6-9,11,56,152,
165,167,168,174-177,179-181
Use of minoxidil for the pre-
vention and treatment of chemotherapy-induced
alopecia has been found to reduce the severity or
shorten the duration of the disorder. Minoxidil can
be used for the management of any type of drug-
induced hair loss; the American Academy of
Dermatology guidelines recommend minoxidil as
first-line treatment for androgenetic alopecia in
men or women.182 Minoxidil is the only topical
agent with proven efficacy for androgenic alopecia
and is the only drug that is approved by the Food
and Drug Administration (FDA) for hair loss for
both men and women. The drug works by affecting
the hair cycle, causing premature termination of
the telogen phase, and may also prolong the ana-
gen phase.183 A 2% strength is available for both
men and women and a 5% strength is approved
only for men.9,10 For women who do not respond
to the 2% strength, the 5% strength can be used, as
it has been shown to provide greater patient satis-
faction in one study.9 However, the incidence of
hypertrichosis and scalp contact dermatitis were
higher in association with the 5% strength as com-
pared with the 2% strength.9 Minoxidil solution or
minoxidil foam should be applied twice daily to a
dry scalp. If the solution is used, a dropper or
extended-spray applicator must be used to apply
the solution directly to the scalp.168 A capful of the
foam product should be applied directly to the
scalp with the hands. Patients should be told that
at least 4 to 6 months of treatment is necessary
before the effects of minoxidil become evident,
and maximum effects may not occur for approxi-
mately 1 year.10,152 Adverse effects of tachycardia
and low blood pressure are very rare (0.001%).10
Minoxidil treatment may be required indefi-
nitely, unless therapy with the alopecia-inducing
drug is discontinued. However, if minoxidil treat-
ment is discontinued, all of the regained hairs are
shed within 3 months.10,165 Minoxidil has been
reported to cause scalp irritation, although the
incidence is lower in association with the new
foam product. In addition, the foam product con-
tains much less propylene glycol, which is thought
to be the cause of the contact dermatitis.150
Oral medications are also available for andro-
gen-induced alopecia. However, these drugs have
not been studied for the management of drug-
induced alopecia. Finasteride and dutasteride work
by inhibiting 5␣-reductase type 2, which results in
a decrease in plasma dihydrotesterone (DHT) con-
centrations. Finasteride has been documented to
decrease plasma prostate-specific antigen (PSA) con-
centrations by 50% in older men. Consequently,
when monitoring older men for prostate dysfunc-
tion, the serum PSA concentration range may need
to be doubled.184 Finasteride has been on the mar-
ket for years and has been widely used for the man-
agement of androgenic alopecia in men, whereas,
dutasteride, a newer agent, is relatively new for the
treatment of androgenic alopecia. A study by Olsen
et al.185 found that dutasteride 2.5 mg daily was
superior to finasteride 5 mg daily in increasing scalp
hair growth in men. The difference may be that
finasteride inhibits only one isoenzyme of 5␣-
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CHAPTER 9 • Alopecia, Hirsutism and Hypertrichosis 155

TABLE 9–8 Treatment Options for Drug-Induced Alopecia1,6-9,11,56,152,165,167,168,174-177,178-180

Treatment Dosage and Administration Comments
TOPICAL TREATMENT
Minoxidil 2% solution (men and women), Solution: A dropper or extended-spray
apply twice daily applicator must be used to apply the
5% solution (men only), solution directly to the scalp.
apply twice daily
5% foam (men only), Foam: Place a capful in hand and apply
apply twice daily foam directly to the scalp.
Monitor for hypertrichosis and skin irritation.
Wait 4 hr before washing or swimming.
After applying, do not allow scalp to get
wet from the rain.
Should not be used in pregnant or nursing
women.
ORAL TREATMENT
5␣-Reductase inhibitors Finasteride: 1–5 mg orally daily Benefits not evident for 4 mo or longer.
Dutasteride: 0.5–2.5 mg orally daily May be combined with minoxidil.
For women: rule out pregnancy before use;
use contraception, if applicable.
Spironolactone 100–300 mg orally daily (often Rule out pregnancy before use; use contra-
(for use in women only) need ≥200 mg/day) ception, if applicable. May be used with
minoxidil.
Monitor serum potassium concentrations,
hypotension, dizziness.
Cyproterone (not available 50 mg orally daily OR Rule out pregnancy before use; use
in the United States) 50–100 mg for 10 days /mo contraception, if applicable. May be
if premenopausal used with minoxidil.
Monitor for dyslipidemias, weight gain,
depression.
Flutamide 250–500 mg orally daily Reserved for refractory disease due to
(doses of 250–375 mg may be less hepatotoxicity.
hepatotoxic)
Oral contraceptives Ethinyl estradiol + drospirenone Efficacy studies are lacking.
(for use in women only) Ethinyl estradiol + norgestimate Often combined with spironolactone.
Ethinyl estradiol + ethynodiol diacetate
1 tablet orally at bedtime
(low-androgenic-activity progestin)
PRIOR TO CANCER CHEMOTHERAPY
Scalp cooling Involves applying a cooling turban These methods may detrimental because
around the scalp with tourniquet of a possible reduction of distribution of
pressure ranging from 30–50 mm Hg chemotherapy to intended areas or when
above systolic blood pressure 10 min chemotherapy is being used for general-
prior to drug administration and then ized hematogenic metastases or if there is
removed 30 minutes after drug a high likelihood of metastasis to the scalp
administration. such as in breast cancer or lymphoprolifer-
ative disorders
(Continued)
TisdaleC09_135-176 1/12/10 2:33 PM Page 156
156 SECTION II • Drug-Induced Dermatologic Diseases
TABLE 9–8 Treatment Options for Drug-Induced Alopecia1,6-9,11,56,152,165,167,168,174-177,178-180
Treatment Dosage and Administration
Hypothermia therapy Cool the scalp to at least 24°C for 5 min
before, during, and 20 min after the
infusion of chemotherapy
COSMETIC OPTIONS
Hairpiece, wig, hairstyling
SURGICAL OPTIONS
Hair transplantation Cylindrical grafts
Elliptical grafts
Minigrafts and micrografts
Scalp reduction
Transposition flap
Soft-tissue expansion
reductase, which results in a reduction of serum
DHT concentrations by approximately 70%, while
dutasteride inhibits both type 1 and type 2 isoen-
zymes and can reduce serum DHT concentrations
by 94% to 95%.186 Despite initial failures of finas-
teride for treatment of women with androgen
alopecia, more recent data have demonstrated clin-
ical efficacy of finasteride in women. One case
found that dutasteride 0.5 mg orally daily provided
clinical improvement, accompanied by an increase
in mean hair diameter, reduction in variability of
hair diameter, and normalization of trichogram
results in a 46-year-old female.186 Dutasteride was
noted to also be well tolerated.186 Dutasteride may
have the potential for efficacy in the management
of androgen alopecia in women as well as men if
large, long-term studies provide similar results.
For women, other oral antiandrogens that can
be used to treat androgen-induced alopecia include
spironolactone, cyproterone acetate (which is not
available in the United States), and flutamide.
However, flutamide is associated with hepatic toxi-
city and is rarely used.8,9 Spironolactone, an aldos-
terone antagonist with antiandrogenic effects, is
commonly used in females with androgenic alope-
cia at doses of 100 to 300 mg daily.11 In patients tak-
ing spironolactone, periodic serum potassium
concentrations should be determined, as the drug
can cause hyperkalemia. In an open-label trial of 80
women taking spironolactone 200 mg daily or
cyproterone acetate either 50 mg daily (or 100 mg
for 10 days/mo in women who were pre-
menopausal), 85% of women in both groups expe-
rienced no worsening of female pattern hair loss.
If oral antiandrogens such as finasteride or spiro-
nolactone are prescribed to females of reproductive
(Continued)
Comments
Often used by patients faced with tempo-
rary or permanent alopecia
Can be expensive
For more extensive balding, more than one
method is necessary
age, pregnancy should be ruled out prior to use and
oral contraceptive therapy or other methods of con-
traception should be prescribed concomitantly, as
these agents are known teratogens.9,11 Oral antian-
drogens have been used alone or in combination
with topical minoxidil in men and women.8,10,187
Some trials in men have shown superior efficacy
when minoxidil is combined with finasteride.10
Newer oral contraceptives with antiandrogenic
effects such as ethanyl estradiol in combination
with drospirenone, norgestimate, or ethynodiol are
potential treatments for female alopecia.188 Some
premenopausal female patients taking antiandro-
gens are using these newer low-dose progesterone
oral contraceptives to prevent pregnancy (since
antiandrogens are teratogenic) while benefiting
from their antiandrogenic effects. Unfortunately,
the use of topical and oral antiandrogens such as
progestins and estrogens for the treatment of
alopecia has not been studied in large trials, and
the safety and efficacy of these agents are
unknown. These agents are not used in men
because of the potential for sexual side effects.19
Cosmetic treatments are also available for
addressing drug-induced alopecia and are applica-
ble to both men and women. Common cosmetic
treatment options for temporary or permanent
drug-induced alopecia include wigs, hair pieces,
hair extensions, and hair weaves. There are also
dyes now available that can be sprayed or applied
onto the scalp that aid in camouflaging balding
areas. Special hairstyling techniques also can be of
benefit. These cosmetic measures often can pro-
duce satisfactory results.8
Surgical procedures are rarely needed for patients
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
severe or in situations in which therapy with the
offending drug cannot be discontinued. Hair restora-
tion is a permanent and successful treatment for
qualifying candidates.10 There are several surgical
options for patients with baldness, and these proce-
dures currently are performed routinely and provide
a definitive correction of the alopecia. The degree of
alopecia often dictates the surgical technique to be
used. If the baldness is extensive, more than one
method is usually required.152 Table 9–81,6-
9,11,56,152,165,167,168,174-177,178-180
provides a list of the var-
ious treatment options for drug-induced alopecia.
INFORMATION FOR PATIENTS
Patients experiencing hair loss, whether perma-
nent or temporary, should be informed that it is
safe for them to style, blow dry, and tease the hair
and use hair spray, hair color, and permanents.
This helps patients deal with the cosmetic effects of
alopecia.167-168 Patients with alopecia often
decrease the frequency of shampooing because
they associate it with increased hair shedding.
Patients should be taught about the hair growth
cycle and should understand the cumulative
nature of hair loss. With once-weekly shampooing,
patients may experience 7 days’ cumulative hair
loss at one time, while daily shampooing allows a
more realistic assessment of the actual daily hair
loss and improves scalp health.152,158
If significant alopecia occurs, head coverings,
wigs, and hairpieces should be encouraged and
patients should be assured that these cosmetic
devices will not interfere with hair regrowth. Use
of these cosmetic aids may improve patients’
morale.5 Patients also may benefit from use of a
wide-toothed comb or soft-bristled brush and
should be instructed to comb hair gently and to
avoid excessive brushing, especially if undergoing
cancer chemotherapy. Baby shampoo or a protein-
enriched shampoo may be optimal in patients with
alopecia, and use of a satin pillowcase will mini-
mize friction. If alopecia is excessive, short hair-
styles tend to disguise hair thinning, but enough
length should be left to possibly allow for arrange-
ment of hair to cover areas of baldness. If hair loss
becomes pronounced, some patients prefer to
shave the head, which may promote regrowth
once the treatment is stopped. If a wig is worn, care
should be taken to ensure that the lining is com-
fortable and not irritating. Applying baby oil, min-
eral oil, or ointment containing petrolatum and
lanolin with some mineral oil and cod liver oil
(which contain vitamins A and D) and massaging
the scalp may reducing itching and keep the skin
CHAPTER 9 • Alopecia, Hirsutism and Hypertrichosis 157
soft. Avoiding sun exposure helps protect the
scalp.77
Patients should be educated regarding the risk
of alopecia when a potentially causative agent is
prescribed. A study by Edelstyn et al.77,189 demon-
strated that although patients found hair loss to be
disturbing, the alopecia was tolerable, provided that
wigs were available and advance warning regarding
hair loss was provided. Patients should also be
informed that hair regrowth following chemother-
apy may involve new hair that is coarse and has a
changed color. Hair also may be thinner than it was
prior to the chemotherapy.77,166 Patients should be
counseled regarding proper nutrition, such as
dietary protein intake, and should avoid fad or
crash dieting while receiving medications with the
potential to induce alopecia.158
Patients using topical minoxidil should be
warned of its primary adverse effect, which is hyper-
trichosis or excessive hair growth. Hypertrichosis
primarily occurs above the eyebrows, in the malar
region, and on the lateral cheek area. Occasionally,
hair growth is also noted above the lip and on the
chin.167 Some rare hair growth on the limbs has
been noted in association with the 5% solution.
Local adverse effects from irritation and contact der-
matitis also have been reported with continued
use.165 Switching to the foam product may help
minimize the risk of these adverse effects. Patients
should be told that an increase in scalp hair shed-
ding may occur during the first months of therapy
as the follicles cycle from the telogen to the anagen
phase. Patients should be informed that 4 to 6
months may be required before the effects of
minoxidil become evident, and up to 1 year may be
required for maximum effects.10 Patients should be
warned that if minoxidil treatment is discontinued
and the alopecia-inducing agent is still present, that
the hair loss will return.10,11,155 After each use of the
topical solution, the hands should be washed to
avoid getting solution on other parts of the body.
The topical product should stay on the scalp for at
least 4 hours before showering or shampooing.10
When appropriate, it is important to assure patients
that once the drug causing alopecia is discontinued,
the alopecia tends to resolve.
Patients taking 5␣-reductase inhibitor therapy
may experience decreased libido or impotence during
therapy. To prevent pregnancy in a partner of child-
bearing age, men should use barrier contraceptives
(even though the risk is negligible) and women of
childbearing age should be told to use contraception,
since these medications can lead to fetal abnormali-
ties.10,11,184 Women who are prescribed antiandro-
genic medications should be warned, if applicable,
not to become pregnant, since these medications are
teratogenic.9 Effects on libido and changes in men-
TisdaleC09_135-176 1/12/10 2:33 PM Page 158

158 SECTION II • Drug-Induced Dermatologic Diseases

strual patterns may occur. Patients with heart failure
should be instructed to have their serum potassium
concentrations and kidney function measured at 3
days and 1 week after initiating therapy with spirono-
lactone and with every increase in dose, then every 2
to 4 weeks for 3 months, then every 3 months for a
year, then every 6 months thereafter.23
HIRSUTISM AND HYPERTRICHOSIS
Both hirsutism and hypertrichosis are patterns
of excessive hair growth that may be highly dis-
tressing to patients. Hirsutism occurs only in
women and involves excessive growth of hair
with masculine characteristics or “male-like”
pattern of hair growth on the body and face.
This usually occurs as a result of excessive andro-
genic stimulation. In contrast, hypertrichosis is
excessive hair growth that is independent of
androgen influence. Hypertrichosis describes
hair growth on any part of the body that is in
excess of the amount that is usually present in
persons of the same race, sex, and age. The hair
growth is manifested by the uniform and super-
fluous growth of vellus (nonterminal) hair over
the body, particularly in nonsexual areas. Unlike
hirsutism, hypertrichosis can occur in both men
and women. Hirsutism can be induced by drugs
that lead to an interaction between the serum
androgen concentration and the sensitivity of
the hair follicle to androgen. Unlike drug-
induced hirsutism, drug-induced hypertrichosis
usually is not associated with androgen produc-
tion.1,6,148,190,191
CAUSATIVE AGENTS
Hirsutism
By definition, hirsutism is induced by androgenic
agents (Table 9–9).12,17,18,158,179,180,191-199 Androgenic
agents such as danazol, testosterone, adrenocorti-
cotropic hormones, and glucocorticoids are com-
mon agents associated with hirsutism.6,179
Anabolic steroids and medications containing
androgens or that can directly or indirectly cause
an increase in androgen activity or serum andro-
gen concentrations may induce hirsutism.160
Hirsutism has been reported in 0.1% of women
taking oral contraceptives. Hair growth has been

TABLE 9–9 Agents Implicated in Drug-Induced Hirsutism

Drug Incidence Level of Evidence
(see page xii for explanation)
192
Acetazolamide NK C
Fluoxymesterone12,158,180,191-194 NKa C
Danazol195 NK A
Dehydroepiandrosterone (DHEA) NK C
Methyltestosterone NK C
Nandrolone NK C
Oxandrolone NK C
Oxymetholone NK C
Progesterone17 NK C
Stanozolol NK C
Testolactone18 NK C
Testosterone NK C
Oral contraceptives/hormones with androgenic activity12,17,158,180,191,193,194 NKa C
Corticotropin (adrenocorticotropic hormone)12 NK C
Cyclosporine194-196-198 21–50% A
Metoclopramide179 NK C
Valproic acid180,199 NK C
a
Believed to be common in susceptible women. NK = Not known
TisdaleC09_135-176 1/12/10 2:33 PM Page 159
reported on the face and is most likely caused by
the progestin component.200 Using an agent with a
lower progestin content may be of benefit. It may
take some time for the hair growth to resolve fol-
lowing discontinuation. Hormone-replacement
therapies containing moderate to high amounts of
progestin are more likely to induce hirsutism.158
Valproic acid has been shown in one prospec-
tive trial in Indian women to increase serum testos-
terone concentrations and lead to polycystic
ovarian syndrome. The incidence of hirsutism was
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
for a list of drugs reported to induced hirsutism.
Hypertrichosis
Drugs associated with hypertrichosis are listed in
Table 9–10.12-14,132,164,191,194,201-216 The primary drugs
known to cause hypertrichosis are cyclosporine,
phenytoin, and oral minoxidil. Other agents report-
ed to induce hypertrichosis include diazoxide, oral
chlorobenzene, erythropoietin, penicillamine, and
psoralens.12,191 Ophthalmic prosta- glandin analogs
and topical minoxidil have been well documented
to cause hypertrichosis.211 Drug-induced hyperpro-
lactinemia can induce unwanted hair growth.217
Cyclosporine-induced hypertrichosis usually
occurs within the first 3 months of therapy and
involves excessive hair growth on the trunk, back,
neck, shoulders, nose, and fingers. The hair growth
may worsen over the first 6 months and then
remain constant. The condition is reversible upon
discontinuation of therapy, with hair growth ceas-
ing over 1 or more months.6,218
Long-term phenytoin therapy has been well
documented as a cause of hypertrichosis (Figure
9–3),13 which typically occurs approximately 2 to 3
months after the initiation of therapy. The limbs
and sometimes the face and trunk are the most com-
monly affected areas. Hypertrichosis is reversible
upon discontinuation of the drug. Dose reduction,
when possible, may stop abnormal hair growth.218
Both oral and topical minoxidil cause hypertri-
chosis that primarily affects the malar areas, forehead,
and sides of the face. Facial hypertrichosis is believed
to be due to a systemic effect or via the transfer of the
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
lead to hypertrichosis that is often is observed within
a few weeks of initiating therapy and is more severe
on the face and limbs. Diazoxide-induced hypertri-
chosis is reversible, but resolution can take as long as
CHAPTER 9 • Alopecia, Hirsutism and Hypertrichosis 159
2 years.6,218 Erythropoietin, when used in patients
with chronic kidney disease, can induce hypertri-
chosis. Erythropoietin-induced hypertrichosis is
reversible upon discontinuation of therapy.6
Ophthalmic agents used to treat glaucoma that
contain prostaglandin F analogs such as latano-
prost, bimatoprost, and travoprost can induce tri-
chomegaly of the eyelashes and can also darken
the eyelashes. In one case report, latanoprost pro-
moted the regrowth of eyelashes in a patient suffer-
ing eyelash loss due to alopecia.211
EPIDEMIOLOGY
The overall incidence of drug-induced hirsutism
and hypertrichosis is unknown. The incidence of
hirsutism and hypertrichosis associated with specif-
ic drugs, when known, is presented in Tables
9–912,17,18,158,179,180,191-199 and 9–10.12-14,132,164,191,194,
201-216
Although neither is considered to be a com-
mon event, they are well-recognized complications
associated with drugs such as anabolic steroids,
cyclosporine, and minoxidil.218 When minoxidil is
taken orally for at least 1 month, over 80% of
patients experience reversible hypertrichosis.6
Topical minoxidil has been reported to cause hyper-
trichosis in 3% to 5% of women using the 2% solu-
tion and more than 5% of those using the 5%
solution. Erythropoietin has been reported to cause
hypertrichosis in 13% of patients with chronic kid-
ney disease. With the lower cyclosporine doses used
in the treatment of dermatologic diseases, the risk
of hypertrichosis declines to approximately 3%.6
Hirsutism is known to affect 5% to 15% of women,
but drugs are not a frequent cause of that disor-
der.179 The incidence of drug-induced hypertri-
chosis associated with diazoxide in children treated
for idiopathic hypoglycemia is nearly 100%. Two
investigators reported incidences of hypertrichosis
of 2% and 6% in children receiving phenytoin.
Another study found that 35% of children experi-
enced hair growth; however, this report included
cases in which only moderate hypertrichosis
occurred.219 Drug-induced hypertrichosis appears to
be less common than hirsutism except in the treat-
ment of organ transplantation, during which hir-
sutism is manifested in 30% to 60% of patients.
MECHANISMS
Hirsutism
Terminal hair (coarse, longer, pigmented hair) is
found primarily on the scalp and eyebrows. Vellus
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160 SECTION II • Drug-Induced Dermatologic Diseases

TABLE 9–10 Agents Implicated in Drug-Induced Hypertrichosis

Drug Incidence Level of Evidence
(see page xii for explanation)

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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CHAPTER 9 • Alopecia, Hirsutism and Hypertrichosis 161

TABLE 9–10 Agents Implicated in Drug-Induced Hypertrichosis (Continued)

Drug Incidence Level of Evidence

OPHTHALMIC AGENTS WITH PROSTAGLANDIN ANALOGSb
Latanoprost12,191,211,212 Up to 77% C
Bimatoprost12,191,211,212 Up to 77% C
Travoprost12,191,211,212 Up to 77% C
PRENATAL EXPOSURE INVOLVING
Alcohol abuse202 NK C
Hydrantoin202 NK C
Minoxidil202 NK C
PSYCHIATRIC DRUGS
Citalopram132 < 0.1% B
Phenothiazines12 NK C
Sertraline164 < 0.1% B
RETINOIDS
Tretinoin (retinoic acid) 12 NK C
VACCINES
Diphtheria–pertussis–tetanus213,214 NK C
Measles213,215 NK C
Smallpox213,216 NK C
MISCELLANEOUS AGENTS
Diazoxide12,13 NK C
Psoralens12 NK C
Streptomycin12 NK C
a
Hypertrichosis reported in children using inhaled corticosteroids; b Eyelash trichomegaly; NK = Not known

hair is the short fine, unpigmented hair found in
all other areas. As androgen concentrations
increase during puberty, the vellus hair of andro-
gen-sensitive follicles is converted to terminal hair.
Exposure to exogenous androgens such as testos-
terone can also cause vellus hair to be converted to
terminal hair. Excessive growth of terminal hair
induced by androgenic drugs is known as “drug-
induced hirsutism”199 (Table 9–1112,158,179,180,191-
194,196,197,199
). Hirsutism is commonly associated
with hormonal abnormalities associated with poly-
cystic ovary syndrome. Hirsutism involving viril-
ization, especially in women over 25 years of age,
is commonly associated with an androgen-produc-
ing tumor. Drugs that induce androgenic stimula-
tion of hair follicles are a less common cause of
hirsutism.32,63,220-223 Hyperinsulinemia can also
lead to hirsutism via inhibition of aromatase, the
enzyme that converts testosterone to estrogen.
Valproic acid can cause hirsutism as a result of
inducing hyperinsulinemia.220
Hypertrichosis
Although the mechanism of hypertrichosis is not
well understood, it is, by definition, not associated
with androgen excess or exposure to androgenic
agents. The disorder is not common and describes
an increase in nonsexual hair. Hypertrichosis may
be congenital (e.g., Hurler’s syndrome, fetal alco-
hol syndrome, or trisomy 18 syndrome), or associ-
ated with anorexia nervosa, malnutrition,
hypothyroidism, porphyria, epidermolysis bullosa,
dermatomyositis, or following skin trauma. It also
can be caused by drugs that stimulate hair
growth.217,218 Hair growth induced by erythropoi-
etin may be caused by a decrease in plasma cortisol
concentrations. At higher serum concentrations,
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162 SECTION II • Drug-Induced Dermatologic Diseases
FIGURE 9–3 Hypertrichosis caused by phenytoin.13
Reproduced with permission from Bork K, ed. Cutaneous Side Effects
of Drugs. Philadelphia, PA: Saunders; 1988:249–258.
cortisol has been shown to inhibit follicular activi-
ty. Many antipsychotic agents are known to cause
hyperprolactinemia, which can indirectly cause
hypertrichosis.
Several underlying pathologic conditions are
associated with acquired generalized hypertri-
chosis, such as acquired immunodeficiency syn-
drome (AIDS). Patients with AIDS can experience
eyelash trichomegaly or a generalized form of
hypertrichosis. The pathogenesis remains
unknown, but may be multifactorial, associated
with malnutrition, metabolic changes, and
immunologic dysregulation, such as elevated
serum interferon concentrations. In addition,
TABLE 9–11 Mechanisms of Drug-Induced Hirsutism12,158,179,180,191-194,196,197,199
Drugs
Androgens/anabolic steroids12,158,180,191,193,194
Valproic acid180,199
Contraceptives/hormones with androgenic activity12,158,180,191,193,194
Corticotropin (adrenocorticotropic hormone)12
Metoclopramide179
Cyclosporine194,196,197
Acetazolamide192
drugs such as interferon and zidovudine may con-
tribute to hypertrichosis.191
Hypertrichosis can appear after a head injury
or other cerebral disturbances. Hypertrichosis
was originally attributed to phenytoin therapy
administered following head injury, but hypertri-
chosis has also occurred in patients with head
injury who have not received phenytoin.
Malnutrition and anorexia nervosa may, in rare
instances, lead to hypertrichosis. Excessive hair
growth of the limbs and trunks has been record-
ed in children with celiac disease as well as in
young women on low-carbohydrate diets. 190
These acquired conditions as well as conditions
such as juvenile hypothyroidism and malignancy
as mentioned above, are rare causes of hypertri-
chosis, and the mechanism is not fully under-
stood.
CLINICAL PRESENTATION AND
DIFFERENTIAL DIAGNOSIS
Hirsutism
Signs and symptoms associated with drug-induced
hirsutism and hypertrichosis are listed in Table
9–12.180,191 Women with drug-induced hirsutism
present with excessive hair growth in a somewhat
masculine pattern, such as the appearance of coarse
facial hair in the upper lip or chin area. The chest,
lower abdomen, back, and limbs also may be affect-
ed.169 Patients with hirsutism often present with
other dermatologic symptoms of virilization, such
as acne, androgenic alopecia, and seborrhea oleosa.6
A physical examination typically facilitates dif-
ferentiation between hirsutism and hypertrichosis.
The Ferriman–Gallwey scoring system for hir-
sutism (Figure 9–4),180 which evaluates hair growth
in nine body areas, can be helpful.180,224 The nine
body areas that are androgen-sensitive are graded
from 0 (no terminal hair) to 4 (frankly virile) to
Mechanism
Androgenic activity
Androgenic activity
Androgenic activity
Androgenic activity
Androgenic activity
Androgenic activity
Androgenic activity
TisdaleC09_135-176 1/12/10 2:33 PM Page 163
TABLE 9–12 Signs and Symptoms Associated with
Drug-Induced Hirsutism or Hypertrichosis180,191
Hirsutism
• The development of larger, curlier, and darker hair in
a male pattern
• Examples of sexual hair: mustache, beard, inner
thighs, chest, back, buttocks area, and/or abdomen
found on women.
• Ferriman–Gallwey scale:a
• Score of 8 or higher
• May be associated with:
• Elevated serum testosterone concentration. The
normal upper limit for total plasma testosterone
concentrations in women varies from 70 to 90
ng/dL.
• A total plasma testosterone concentration that is
normal or marginally elevated (within approxi-
mately 20 ng/dL of the upper limits of normal) in
the absence of other features of concern (polycys-
tic ovary syndrome, risk of neoplasm, risk of
endocrinopathy, thyroid dysfunction, metabolic
syndrome) probably indicates idiopathic hirsutism
or idiopathic hyperandrogenism.
• Pelvic ultrasonogram: Polycystic ovaries or neoplasm
• Menstrual irregularities
• Insulin resistance
• Metabolic syndrome (central obesity, hypertension,
glucose abnormalities, and dyslipidemias)
Hypertrichosis
• Hair growth is distributed in a generalized, nonsexual
pattern on men or women. The hair involved may be
vellus, lanugo, or terminal hair.
• Hair growth normally involves face, limbs (front and
back), eyelashes, elbows, pinnae auris, elbows, anteri-
or or posterior neck, lumbosacral region or trunk.
• Ferriman–Gallwey scale:a
• Score of <8
• No elevation in free testosterone concentrations fol-
lowing start of hypertrichosis-inducing agent
• No laboratory evaluation work required
a
See Figure 9–4 for the Ferriman–Gallwey Scoring System for
hirsutism180
obtain a total score. A normal score is less than
8.180,219,224 A careful medication history should be
obtained and patients should be questioned
regarding the onset and progression of hair
growth, family history of similar disorders, expo-
sure to skin irritants, menstrual and reproductive
history, presence of hair loss, acne, and any
changes in extremity or head size, facial contour,
or weight.32,180,219
CHAPTER 9 • Alopecia, Hirsutism and Hypertrichosis 163
During evaluation of hirsutism, it is important
to rule out nondrug causes such as polycystic ovary
syndrome, ovarian tumor, adrenal tumor, hyper-
prolactinemia, congenital adrenal hyperplasia,
Cushing’s syndrome, diabetes, and thyroid dis-
ease.32,180,219,225 In women with epilepsy who pres-
ent with hirsutism, polycystic ovary–like syndrome
should be excluded. Polycystic ovary syndrome is
characterized by hyperinsulinemia due to insulin
resistance, which promotes androgen production.
Women with epilepsy have a higher incidence of
polycystic ovary syndrome and higher plasma
androgen concentrations, which may be further
exacerbated by medications. Laboratory evaluation
for patients with hirsutism should include meas-
urement of serum total and unbound testosterone,
DHEA, DHEA sulfate (DHEA-S), follicle-stimulating
hormone, luteinizing hormone, and prolactin con-
centrations. An ovarian tumor is considered when
the total serum testosterone concentration is
greater than 200 ng/dL in the presence of a mildly
elevated DHEA-S concentration.158 Drug-induced
hirsutism should be suspected in female patients
with hair growth exhibiting masculine characteris-
tics who have been exposed to drugs known to
have androgenic effects. Conditions to consider in
the differential diagnosis of drug-induced hir-
sutism and hypertrichosis are listed in Table
9–13.217,225,226 In addition, specific diagnostic tests
that can be used to differentiate drug-induced hir-
sutism from other causes of hirsutism are listed in
Table 9–14.217,219
Hypertrichosis
In patients with hypertrichosis, the excessive hair
growth involves terminal and/or vellus hair and a
non–male pattern of hair growth is noted on areas
of the body where the hair is normally short.
Hypertrichosis may be generalized or circum-
scribed and is independent of hormone stimula-
tion.6 An example of hypertrichosis in a male
patient includes hair in the forehead area or coars-
er, prominent hair on one area of the shoulder or
forearm.169 Hypertrichosis should be suspected in
male or female patients who exhibit abnormal
growth of nonsexual hair (non–androgen-depend-
ent hair) and who are taking potentially causative
drugs that are not associated with increased andro-
genic activity.218,225 Hypertrichosis usually becomes
apparent after a few weeks of therapy. However,
phenytoin-induced hypertrichosis may not appear
until after 3 months of therapy, while hypertri-
chosis induced by cyclosporine may not manifest
until as long as 6 months after initiating thera-
py.12,190,193,201-206
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164 SECTION II • Drug-Induced Dermatologic Diseases

FIGURE 9–4 The

Ferriman–Gallwey scoring sys-
tem for hirsutism.180
Reproduced with permission from
BMJ Publishing Group from refer-
ence 181: Rosenfield RL. Hirsutism.
N Engl J Med. 2005;353:2578-2588.

eases, as compared with patients taking higher

RISK FACTORS
Women already at risk for hirsutism from other
causes, such as menopause, pregnancy, excessive
ovarian androgen production, family history of
hirsutism, and Mediterranean origin, may be at
greater risk for hirsutism or experience more pro-
nounced hirsutism when exposed to medications
with androgenic effects.169,190,225 Risk factors for
drug-induced hirsutism are summarized in Table
9–15.158,169,180,191,217,218,226
Drug dose and duration of therapy can be risk
factors for drug-induced hirsutism and hypertri-
chosis, as some drugs induce hair growth only at
higher doses and following long-term exposure.
For instance, the risk of hypertrichosis associated
with cyclosporine is lower in patients taking small-
er doses for the management of dermatologic dis-
doses for other indications.6 The addition of
tretinoin solution to topical minoxidil therapy
leads to increased absorption of minoxidil and
associated increased risk of hypertrichosis.184
Children and adolescents appear to be at greater
risk for hypertrichosis than adults. Concomitant
administration of two or more drugs known to
cause abnormal hair growth increases the risk.218
Table 9–1612,169,191,218 summarizes risk factors for
drug-induced hypertrichosis.
MORBIDITY AND MORTALITY
Drug-induced hirsutism and hypertrichosis, while
often unpleasant, are not associated with increased
morbidity and mortality.

TABLE 9–13 Conditions to Consider in the
Differential Diagnosis of Drug-Induced Hirsutism
or Drug-Induced Hypertrichosis217,225,226
• Congenital adrenal hyperplasia
• Polycystic ovary syndrome
• Ovarian tumor
• Adrenal tumor
• Idiopathic
• Familial
PREVENTION
Drug-induced hair growth is best prevented by
avoiding the use of agents known to cause hir-
sutism or hypertrichosis, especially in patients
with preexisting risk factors. Patients should not be
exposed to two or more drugs with a known poten-
tial to cause abnormal hair growth. Lower doses
and shorter periods of exposure to potentially
causative drugs are also advised.218 The potential
for minoxidil-associated hypertrichosis is increased
if the topical solution is accidentally transferred to
the face from the hands or from residual minoxidil
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CHAPTER 9 • Alopecia, Hirsutism and Hypertrichosis 165

TABLE 9–14 Clinical and Diagnostic Evaluation of Hirsutism217,219

Additional
Diagnosis Testosterone 17-OHP LH/FSH Prolactin DHEA-S Cortisol Testing
Congenital Normal to Increased Normal/ Normal Normal to Normal to ACTH stim-
adrenal increased increased decreased ulation may be
hyperplasia normal necessary to
make diagnosis
Polycystic Normal to Normal Normal to Normal to Normal to Normal Primarily a
ovary increased increased increased Increased clinical
syndrome LH and diagnosis.
decreased Consider lab
to normal testing and
FSH ultrasonogra-
phy of ovaries
to rule out
other disor-
ders/tumors.
Consider
screening lipids,
glucose.
Ovarian Increased Normal Normal/ Normal Normal Normal Ultrasound or
tumor normal CT to image
tumors
Adrenal Increased Normal Normal/ Normal Increased Normal to Ultrasound or
tumor normal increased CT to image
tumors
Drugs Normal Normal Normal/ Normal Normal Normal Withdrawal of
normal offending agent
recommended.
Idiopathic Normal Normal Normal/ Normal Normal Normal Onset is shortly
Normal after puberty
and slowly
progresses.
Familial Normal Normal Normal/ Normal Normal Normal
Normal
ACTH = adrenocorticotropic hormone; CT = computed tomography; DHEA-S = dehydroepiandrosterone sulfate; FSH = follicle-stimu-
lating hormone; LH = luteinizing hormone; 17-OPH = 17-hydroxyprogesterone.
Plasma prolactin concentrations may be high if drug-induced (e.g., risperidone) hyperprolactinemia is present.
Source: Adapted from Hunter MH, Carek PJ. Evaluation and treatment of women with hirsutism. Am Fam Physician. 2003;67:2565–2572217.

on pillows, bed sheets, and garments. Topical

minoxidil also may be distributed via local
intravascularization, but this is not normally pre-
ventable.167,190 Avoiding drug interactions that lead
to increased serum concentrations of drugs that
cause hirsutism or hypertrichosis is also important
especially if the hirsutism or hypertrichosis is dose-
dependent. Table 9–1712,169,191,218,219 provides some
approaches to help prevent drug-induced hir-
sutism and drug-induced hypertrichosis.
MANAGEMENT
Hirsutism
Medications for managing hirsutism include those
that inhibit androgen action at the hair follicles
and suppress androgen production. Response to
these medications is very slow, and desired effects
may not be evident for 6 months or more; conse-
quently, hair-removal techniques may also be war-
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166 SECTION II • Drug-Induced Dermatologic Diseases

TABLE 9–15 Risk Factors for Drug-Induced

Hirsutism158,169,180,191,217,218,226
• Female sex
• Drug administration:
• Higher doses
• Intravenous route
• Longer duration of exposure
• Combination of two or more drugs that can cause hair
growth
• Female patients already at risk for hirsutism
• Genetic predisposition
• Hormonal abnormalities, such as menstrual irregu-
larity, endometrial cancer, polycystic ovaries, infer-
tility
• Metabolic abnormalities, such as metabolic syn-
drome often involving central obesity, hypertension,
glucose abnormalities, and dyslipidemia
• Endocrine abnormalities, such as polycystic ovary
syndrome, insulin resistance,
• Cushing’s syndrome, hyperprolactinemia,
acromegaly, thyroid dysfunction, and tumors
TABLE 9–17 Approaches to Help Prevent Drug-
Induced Hirsutism or Hypertrichosis12,169,191,218,219
• Avoid drugs with potential to induce hirsutism or
hypertrichosis, when possible.
• Use the lowest possible dose of the potentially
causative agent.
• Avoid, when possible, the use of multiple drugs with
the potential to cause hirsutism or hypertrichosis.
• Limit the duration of exposure.
• Use the oral route rather than the intravenous route
whenever possible.
• Avoid drug interactions that could increase serum
concentrations of drugs with the potential to cause
dose-dependent hirsutism or hypertrichosis
• Adjust appropriately the doses of renally eliminated
or hepatically metabolized drugs with the potential
to cause hirsutism or hypertrichosis in patients with
kidney or liver disease, respectively.
• Identify any family history of androgenic alopecia,
hirsutism, amenorrhea, or infertility prior to starting
therapy with medication known to cause hirsutism
or hypertrichosis to allow the clinician to identify
and correct potential risk factors.

TABLE 9–16 Risk Factors for Drug-Induced

Hypertrichosis12,169,191,218
A detailed list of the topical and nonpharmaco-
• Drug administration: logic procedures for the treatment of both hir-
• Higher doses sutism and hypertrichosis is provided in Table
• Intravenous route 9–18.180,191,227,228 Systemic agents used for the treat-
• Longer duration of exposure ment of hirsutism are listed in Table
• Combination of two or more drugs that can cause 9–19.148,163,179,180
hair growth If the offending medication can be discontin-
• Children and adolescents are at higher risk ued, then no treatment is needed if the excess hair
• Acquired immunodeficiency syndrome growth is mild. Discontinuation of therapy with
• Familial trait or congenital some drugs (e.g., cortisol) usually leads to resolu-
• Head injuries and other cerebral disturbances tion of hirsutism.25 However, drug-induced hir-
• Hepatic porphyria caused by chemical exposure such sutism is not always reversible, and resolution,
as hexachlorbenzene when it does occur, may require longer than 6
• Juvenile hypothyroidism months after discontinuation of the drug. In this
• Juvenile dermatomyositis case, if the hair growth is moderate to severe, or if
• Malnutrition the patient cannot tolerate even mild hirsutism,
• Anorexia nervosa short-term use of cosmetic procedures, topical
• Malignancy pharmacologic treatment for hair removal, or both
may be desirable.
If the causative agent cannot be discontinued,
a variety of treatment options exist. Nonsystemic
ranted. Clinical management of hirsutism includes drug treatment is appropriate for mild hirsutism.
discontinuing the causative agent, if possible; For patients with moderate to severe hirsutism or
administering topical pharmacological treatment; those mild hirsutism who desire more-aggressive
using cosmetic procedures for hair removal; using treatment, systemic therapy should be considered
light sources and lasers for hair removal; and along with nonpharmacologic and topical treat-
administering oral systemic pharmacologic treat- ments.
ment (oral contraceptives, antiandrogens, 5␣- Oral contraceptives containing lower amounts
reductase inhibitors).191 of androgenic progestins (e.g., norgestimate deso-
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CHAPTER 9 • Alopecia, Hirsutism and Hypertrichosis 167

TABLE 9–18 Cosmetic Measures for Management of Hypertrichosis and Hirsutism180,191,227,228

Cosmetic Measure Information
Bleaching Commercial products contain persulfate to boost peroxide bleach, but can lead
to anaphylaxis.
Home product: 40 ml hydrogen peroxide + 7 ml 20% ammonia
Apply to hair and leave on hair until the color is removed (average time is 5–10 min).
Duration of effect: up to 4 wk
Disadvantages: does not work for dark-skinned patients; skin irritation
Trimming Does not accelerate hair regrowth
Good option for young children with either local or generalized hypertrichosis.
Duration of effect: ~24 hr or longer
Disadvantage: hypertrichosis may still be noticeable
Shaving Does not affect the rate or width of regrowth; it will, however, result in stubble that grows
out without the softer and finer unshaven hair tip.
Duration of effect: 24 hr
Disadvantages: requires daily shaving; skin irritation
Plucking Appropriate for targeting only small areas, as it is painful, slow, and tedious.
Duration of effect: up to 2 wk
Adverse effects: hyperpigmentation; folliculitis, distorted hair follicles, scarring
Risk of metaplastic ossification
Waxing Cold, warm, or hot wax is applied to the area of unwanted hairs. Then the wax is stripped
off, thus epilating the embedded hairs.
Target: any vellus hairs in all areas of the body
Duration of effect: 2–6 wk
Disadvantage: poor results when attempting removal of short hair
Adverse effects: pain, skin irritation, folliculitis
Chemical depilatories Chemicals that damage the hair leading to breakage at the skin’s surface
Thioglycolates are commonly used in concentrations of 2–4% and act within 5–15 min.
Duration of effect: ~1 wk
Disadvantage: potent skin irritant. Not for use in children unless for small localized sites to
avoid toxicity from systemic thioglycolate absorption.
Adverse effects: skin irritation, allergic contact dermatitis, and, with inadvertent eye
contact, corneal alkali burns
Electrosurgical epilation 3 types of electrolysis: galvanic electrolysis; thermolysis electrolysis; blend method of
electrolysis (considered the most effective)
Considered a permanent mode of hair removal
Target: localized coarse hair
Duration of effect: hair regrows in 20–40% of the follicles treated.
Disadvantage: expensive, painful, requires multiple treatment sessions and is time-consuming
Adverse effects: hyperpigmentation or hypopigmentation, perifollicullar inflammation,
punctate scarring.
(Continued)
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168 SECTION II • Drug-Induced Dermatologic Diseases

TABLE 9–18 Cosmetic Measures for Management of Hypertrichosis and Hirsutism180,191,227,228 (Continued)

Cosmetic Measure Information

Light source and
laser treatments
Topical hair growth retard-
ant (cell-cycle inhibitor)
Several effective systems available: ruby laser, alexandrite laser, diode laser,
neodymium:yttrium–aluminum–garnet (Nd:YAG) laser, and intense pulsed-light sources
(590 to 1200 nm)
Longer pulse durations and longer wavelength lasers such as the Nd:YAG laser should be
used on dark skin to lessen risk of scarring or dyspigmentation. These lasers are less effica-
cious but involve less risk to skin.
Duration of effect: Permanent hair removal occurs in patients with dark hair and fair skin.
Patients with blond, red, or white hair may not have permanent hair removal but the
regrowing hairs are thinner and more lightly pigmented.
Disadvantages: cost and rare adverse reaction of thermal damage-related cutaneous side
effects (blistering, crusting, scabbing, pigmentary alteration, scarring). If occurs, this usually
requires treatment with topical corticosteroid or topic antibiotic.
Adverse effects: pain/discomfort (icing treated areas postprocedure is helpful); immediate
perifollicular edema and mild erythema, which lasts ~ minutes to hours following treatment.
Eflornithine hydrochloride, 13.9%; topical cream applied twice daily. Slows excessive hair
growth but does not remove excessive hair. Patients must use hair-removal methods.
Clinical trials have shown efficacy for facial hirsutism improvement
Target: facial areas of unwanted hair growth
Contraindications: pregnancy, breast feeding
Disadvantages: expensive; hair grows back after discontinuation; must use hair-removal
techniques
Adverse effects: burning, stinging, acne, rash may occur at application site

gestrel, ethynodiol diacetate, gestrodene, and
norethindrone acetate) are preferable for the man-
agement of mild-to-moderate hirsutism. This
treatment should reduce the need for shaving by
50% and can usually stop the progression of hir-
sutism, but will not reverse it.180 Women with clin-
ically significant hirsutism may require therapy
with an androgen-inhibiting agent either as
monotherapy or in addition to oral contraceptive
treatment.180,219,222,227 The addition of the oral
contraceptive will help ensure menstrual cycling
and minimize the risk of pregnancy, as antiandro-
gens and ␣2-reductase inhibitors are teratero-
genic.180 It has been reported that combined
therapy with an oral contraceptive and an andro-
gen-receptor inhibitor may produce clinical
improvement in up to 75% of women with hir-
sutism.217
Antiandrogenic drugs include spironolac-
tone, flutamine, and cyproterone. Spironolac-
tone and flutamine are the most widely used and
are equally effective. Spironolactone is an aldos-
terone antagonist and appears to be the safest
androgen-receptor blocker. Flutamide may cause
hepatotoxicity, and liver function should be
monitored in patients receiving this agent.
Cyproterone is not available in the United States.
The use of spironolactone or cyproterone often
provides significant attenuation of hirsutism
within 6 months and maximum benefit within 9
to 12 months.180
Other hormonal therapies include finas-
teride—a 5␣-reductase inhibitor that has been
shown to be effective for the treatment of hir-
sutism. However, finasteride is teratogenic, causing
feminization in male infants, and is therefore con-
traindicated in many women. Like oral antiandro-
gens, finasteride therapy should be reserved for
severe or refractory cases of hirsutism. Once initiat-
ed, treatment should be continued for at least 2
years for maximum benefit.217,221 Combination
therapy with spironolactone and finasteride is an
option for some patients.226 Dutasteride, also a 5␣-
reductase inhibitor, has not been extensively stud-
ied for the management of hirsutism. Other
hormonal therapies include glucocorticoids and
gonadotropin-releasing hormone agonists. The
efficacy of glucocorticoids for drug-induced hir-
TisdaleC09_135-176 1/12/10 2:33 PM Page 169

CHAPTER 9 • Alopecia, Hirsutism and Hypertrichosis 169

TABLE 9–19 Common Medications Used for Treatment of Hirsutism148,163,179,180

Contraindications/ Major Adverse
Variable Agent Dose Precautions Effects
Androgen Ethinyl estradiol + 1 tablet orally at Breast cancer, Irregular vaginal
suppression drospirenone OR bedtime (the larger smoking, history of bleeding, venous
Ethinyl estradiol + estrogen doses may blood clots, thrombosis, bloating
norgestimate OR be necessary in cardiovascular
Ethinyl estradiol + heavier women for disease,
ethynodiol diacetate menstrual regularity) uncontrolled
(all low androgenic hypertension
activity)
Androgen Spironolactone 50–100 mg orally Lack of Teratogenic; irregular
inhibition twice daily contraception, menstrual bleeding
(300 mg daily for kidney disease, unless oral contracep-
pronounced hirsutism liver failure tive administered;
or for obese patients) decreased libido;
nausea; hyperkalemia;
hypotension; liver dys-
function
Cyproterone Induction: 50–100 Lack of contraception Teratogenic; irregular
(not available in mg orally at bedtime, menstrual bleeding
the United States) days 5–15 unless estrogen
Maintenance: 5 mg administered cyclical-
orally at bedtime, ly; decreased libido;
days 5–15 nausea
Flutamide 125–250 mg orally Lack of contraception; Teratogenic; reserved
twice daily liver disease for severe hirsutism
because of hepatotox-
icity
5␣-Reductase Finasteride 1–5 mg orally daily Lack of contraception Teratogenic; minimal
inhibitors side effects in females
Dutasteride 0.5–2.5 mg orally Lack of contraception Teratogenic; limited
daily data on dutasteride
use in hirsutism;
minimal side effects
in females
Other hormones Glucocorticoids Example: Prednisone Uncontrolled Changes typical of
5–7.5 mg orally at diabetes; obesity Cushing’s syndrome;
bedtime adrenal atrophy
Gonadotropin- Leuprolide acetate, Osteoporosis Osteoporosis without
releasing agonists depot suspension estrogen–progestin
7.5 mg monthly replacement
intramuscularly, with
25–50 mcg transdermal
estradiol
Cosmetic measures See Table 9–14
Adapted from Rosenfield. RL. Hirsutism. N Engl J Med. 2005;353:2578-2588.181
TisdaleC09_135-176 1/12/10 2:33 PM Page 170
170 SECTION II • Drug-Induced Dermatologic Diseases
sutism is unknown. Gonadotropin-releasing hor-
mone agonists are considered alternatives to oral
contraceptives.180
Treatment with eflornithine, a topical hair
growth inhibitor, has been shown to reduce rates
of hair growth. Eflornithine therapy results in the
reduction of the frequency of use of other methods
of hair removal. Eflornithine is indicated for facial
hirsutism and is marketed as an 11.5% topical
cream that is applied twice daily. The cream is
effective for slowing excessive hair growth, but not
for removing excess hair. The cream must remain
on the skin for at least 4 hours. Unfortunately, if
therapy is discontinued, hair growth will likely
return.158,191,227
Information regarding cosmetic procedures for
hair removal for patients with either hirsutism or
hypertrichosis is provided in the next section.
Hypertrichosis
Although drug-induced hypertrichosis nearly
always resolves after discontinuation of therapy
with the causative agent, reversal of hair growth
takes time. During that period, cosmetic methods
for hair removal are suggested and are effec-
tive.191,219,222 Consequently, the management of
drug-induced hypertrichosis includes discontinua-
tion of the offending agent, if possible; cosmetic
procedures for removal of excess hair; hair removal
using light sources and lasers; and only topical
pharmacologic treatment.191 Systemic agents such
as antiandrogens or oral contraceptives should not
be used. Treatment with eflornithine may be effec-
tive for hypertrichosis.
Treatment options for drug-induced hypertri-
chosis are provided in Table 9–18.180,191,227,228
Cosmetic measures include bleaching, wax strip-
ping, shaving, plucking (tweezing), using hair-
removal creams (depilatories), and electrolysis.
The FDA has approved electrolysis as a permanent
option for hair removal, because it has been asso-
ciated with a 30% reduction in the number of hair
follicles. Laser therapy is a newer development,
and several types are available, including the
ruby, alexandrite, pulsed diode, and Q-switched
yttrium–aluminum–garnet (YAG) lasers. Pulsed-
diode lasers are often more reliable and less
expensive than other laser sources for hair
removal. Q-switched YAG lasers work best for
darker-skinned patients. Unfortunately, laser
therapy is not always effective for long-term hair
removal. After a single laser treatment, hair
growth is delayed for 2 to 6 months, and hair
removal is permanent in some patients after mul-
tiple treatments. The cost of these approaches is
sometimes an issue, since most patients require
repeated treatments.158,219,222
INFORMATION FOR PATIENTS
Patients should have realistic expectations regard-
ing the time frame for the resolution of drug-
induced hirsutism and hypertrichosis, and must
understand that it may take a long time for these
conditions to resolve even after the causative agent
is discontinued. When certain medications are
used to treat hirsutism, hormonal suppression for 6
months or longer may be necessary before reduc-
tion of hair growth becomes evident.222 When oral
drug therapy is used to manage hirsutism, patients
should be instructed that treatment must continue
during therapy with the causative agent. For
patients with drug-induced hypertrichosis, when
the offending drug is discontinued, resolution of
excess hair growth may require several months to
1 year, depending on the hair-cycling characteris-
tics of the site of hypertrichosis. For example, it
takes an average of 3 months for hypertrichosis res-
olution if the excess hair growth is on the face, but
an average of 1 year if the excessive hair growth is
on the arms.191
Patients with drug-induced hirsutism or hyper-
trichosis should be counseled regarding the poten-
tial benefit of cosmetic measures, and these can be
encouraged even if oral therapy is prescribed.
Patients should be informed of the cosmetic
options available, their adverse effects, duration,
effectiveness, and cost. Patients should be
informed that although shaving can lead to a stub-
ble-like hair, it does not worsen hirsutism.
Depilating agents, though effective, can cause
chronic skin irritation and may even worsen hair
growth if used excessively or indiscriminately.
Waxing or plucking in androgenized skin may lead
to folliculitis and trauma to the hair shaft, and
does not kill the hair follicles. Methods that can
permanently destroy the hair follicle, such as elec-
trolysis and laser, often work well, but require time
to be effective. These methods may also be costly
and usually require repeated treatments.180,217,222
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175. Dorr, VJ. A practitioner’s guide to cancer-related alopecia.
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183. Messenger AG, Rundegren J. Minoxidil mechanisms of
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186. Olszewaska M, Rudnicka L. Case reports: effective
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188. Millikan L. Hirsutism, postpartum telogen effluvium, and
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191. Trueb RM. Causes and management of hypertrichosis.
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192. Weiss IS. Hirsutism after chronic administration of
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194. Sakiyama R. Approach to patients with hirsutism. West J
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195. Barbieri RL, Evans S, Kistner RW. Danazol in the
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204. Livingston S, Peterson D, Boks LL. Hypertrichosis
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206. Guerreiro MM, Vigonius U, Pohlmann H, et al. A double-
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212. Demitsu T, Manabe M, Harima N. Hypertrichosis induced
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219. Azziz R. The evaluation and management of hirsutism.
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227. Dawber RPR, Rundegren J. Hypertrichosis in females
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228. Battle EF Jr., Hobbs LM. Laser-assisted hair removal for
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SECTION III

DRUG-INDUCED
NEUROLOGICAL DISEASES

CHAPTER 10 Seizures

CHAPTER 11 Stroke

CHAPTER 12 Movement Disorders

CHAPTER 13 Peripheral Neuropathy

CHAPTER 14 Visual Disturbances

CHAPTER 15 Delirium

CHAPTER 16 Sleep Disorders

CHAPTER 17 Cognitive Disorders

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TisdaleC10_177-189 1/20/10 11:00 PM Page 179
CHAPTER 10
Seizures
S eizures, including those induced by drugs, are
serious neurologic events; without prompt and
proper recognition, diagnosis, and treatment,
seizures can result in neurologic impairment. It is
important to recognize drug-induced seizures in
the clinical setting rapidly and to provide immedi-
ate, effective treatment.
CAUSATIVE AGENTS
Numerous drugs have been identified as possible
causes of seizures. Since drug-induced seizures are
relatively rare events, it is difficult to determine
causality for many drugs. Most reports of drugs
causing seizures are based on individual cases,
epidemiologic studies, and very few prospective
studies. A list of drugs associated with seizures is
presented in Table 10–1.1-31
Drugs can induce seizures in a number of clin-
ical situations. The scenario that most people rec-
ognize is the setting of an intentional or
unintentional overdose. Seizures can also occur as
an adverse effect of a drug even when administered
at therapeutic doses. These events are not pre-
dictable and may occur even in patients with no
history of or risk factors for seizures. Abrupt with-
drawal of therapy with some drugs can also result
in a seizure. Many illicit drugs are associated with
this type of seizure. In addition, ethanol, baclofen,
antiepileptic drugs, and benzodiazepines may be
associated with withdrawal seizures. Caution must
be exercised when using an antagonist to one of
these drugs because of the potential for precipitat-
ing a seizure.
Timothy E. Welty
EPIDEMIOLOGY
First-time seizures from all causes occur with an
incidence of 70 to 100 per 100,000 patients annu-
ally.32 Of these, 23 to 61 per 100,000 are single
events in patients in whom epilepsy does not
develop. The mortality rate associated with a first
unprovoked seizure is 1% to 4%. There are few data
available regarding the incidence of drug-induced
seizures. It is likely that seizures as an adverse event
of drug therapy are a small percentage of the over-
all number of first-time seizures.
The precise incidences of seizures induced by
specific drugs are unclear. One of the first reported
studies on drug-induced seizures by the Boston
Collaborative Drug Surveillance Program found a
rate of 0.08% in 32,812 patients.33 Another review
of emergency cases of status epilepticus showed
that ethanol ingestion and drug overdose were
responsible for 13% <5%, respectively, of these
cases.34 Twenty-five percent of the seizures related
to a drug overdose were fatal. A review of 1993 data
from the California Poison Control System showed
that cyclic antidepressants, stimulants, antihista-
mines, theophylline, and isoniazid were the most
common causes of drug-induced seizures.35 A fol-
low up to this study 10 years later showed that the
most common causes of drug-induced seizures
were bupropion, diphenhydramine, cyclic antide-
pressants, tramadol, amphetamines, isoniazid, and
venlafaxine.36 Of patients included in this series,
68% had a single seizure, 27% had more than one
seizure, and 3.6% experienced status epilepticus.
However, these data are derived only from calls to
poison centers or admissions to an emergency
department, and do not account for drug-induced
179
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180 SECTION III • Drug-Induced Neurological Diseases

TABLE 10–1 Agents Implicated in Drug-induced Seizures

Drug Incidence Level of Evidence
(see page xii for explanation)

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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CHAPTER 10 • Seizures 181

TABLE 10–1 Agents Implicated in Drug-induced Seizures (Continued)

Drug Incidence Level of Evidence

ANTIPSYCHOTIC DRUGS (Continued)
Haloperidol1 NK B
ASTHMA DRUGS
Theophylline1 NK B
CONTRAST MEDIA
Iodinated and noniodinated1 0.2–0.5% B
15%c
HERBALS
Ephedra (Ma Huang)27 NK B
Eucalyptus28,29 NK C
Gingko28,29 NK C
Ginseng28,29 NK C
Pennyroyal28 NK C
Sage28 NK C
Shankhapusphi (Ayurveda)28 NK C
Star anise28 NK C
Star fruit28 NK C
IMMUNOSUPPRESSANTS
Cyclosporine1 0.5–3.9% B
STIMULANT DRUGS FOR ADHD
Atomoxetene30,31 NK C
Methylphenidate30,31 NK C
ADHD = attention deficit/hyperactivity disorder; NK = not known.
a
Used alone.
b
Used in combination with other antibiotics.
c
In patients with brain metastases.

seizures that occur outside these settings. Most
likely, the incidence of drug-induced seizures is
greater than is reflected in these reports. Even so,
drug-induced seizures are relatively rare events that
typically occur as a single, isolated seizure.
Analgesics
Tramadol, a non-narcotic analgesic, is associated
with drug-induced seizures. In a review of 190 cases
of tramadol toxicity reported to a poison control
center, 13.7% of patients experienced a seizure.4 A
similar study reported that 55% of patients with
tramadol intoxication experienced a seizure.5
Ninety percent of these seizures were single events,
and 84% occurred within 24 hours of ingesting a
toxic dose. Chronic use of tramadol predisposed
this group of patients to a seizure. Most cases are
associated with toxic doses or prolonged chronic
use, but seizures are possible at therapeutic doses,
especially in patients with underlying epilepsy.4,5
Anesthetics
While propofol is used in the treatment of refractory
status epilepticus, it is also associated with drug-
induced seizures. Several case series have suggested
that 24% to 40% of patients receiving propofol expe-
rience seizures or epileptiform electroencephalogram
(EEG) activity during induction, emergence, and
recovery from anesthesia.1
Sevoflurane is associated with a high incidence
of drug-induced seizures. Studies of EEG activity
during the induction of anesthesia have shown
TisdaleC10_177-189 1/20/10 11:00 PM Page 182
182 SECTION III • Drug-Induced Neurological Diseases
epileptiform activity in 50% to 60% of children and
adults,6,7 and this increases to nearly 100% of
patients when combined with hyperventilation and
hypocapnia.7 Additional study of EEGs in patients
receiving sevoflurane has demonstrated a dose-
dependent relationship in the EEG change.8 At a 1.5
minimum alveolar concentration, epileptiform EEG
discharges were present in 100% of patients.
Antibiotics
Carbapenems have been reported to cause seizures.
Approximately 0.9% of patients taking imipenem
as monotherapy experience a seizure.9 The inci-
dence of seizures in patients taking imipenem in
combination with other antibiotics is 2% to 3%. In
one study, 28% of children treated with imipenem
for bacterial meningitis experienced a seizure.37 In
contrast, meropenem caused no seizures in a study
of adult patients with bacterial meningitis.38 In
another study, 12% of children receiving therapy
with meropenem experienced a seizure.39
Antidepressants
Overdose with tricyclic antidepressants is responsi-
ble for over 40% of seizures encountered in the
emergency department.12 Most of these seizures are
generalized tonic–clonic seizures, but partial
seizures may occur in individuals with a history of
epilepsy.36,40
Other antidepressant agents can cause seizures
in the setting of an overdose. Approximately 2% of
patients with an overdose of a selective serotonin
reuptake inhibitors experience a seizure.41
Overdose of bupropion is also associated with a
high incidence of seizures.10
Antidepressant drugs may also cause seizures at
therapeutic doses. The incidence varies from
approximately 0.1%, with lower doses of
imipramine, to over 2%, with higher doses of
bupropion.11 The risk of seizures appears lowest
with trazadone, fluoxetine, and fluvoxamine. In
contrast, the risk of seizures is highest in associa-
tion with maprotiline, amoxapine, and bupropion,
and these drugs should be avoided in patients with
epilepsy. The risk of antidepressant-associated
seizures is dose-dependent; for example, the inci-
dence of seizures associated with bupropion at
doses above 400 mg/day is 2% to 4%, while at
lower doses the incidence is 0.5% to 1.0%.
Antipsychotics
Among older antipsychotic agents, chlorpro-
mazine is associated with the greatest risk of
seizures, with an incidence of 2.1%.22 At chlorpro-
mazine doses <200 mg/day, the incidence of
seizures is 0.3%, at doses of 200 to 900 mg/day
0.7%, and at doses >900 mg/day 9%.23
Concomitant treatment with other psychoactive
agents increases the risk of seizures caused by
chlorpromazine.23 Other older antipsychotic
agents are associated with a much lower risk of
seizures than chlorpromazine.24
Of the newer, atypical antipsychotic agents,
clozapine is associated with the greatest risk of
seizures. The cumulative risk of seizures with cloza-
pine over nearly 4 years of treatment has been esti-
mated at 10%.25 At clozapine doses <300 mg/day,
the incidence of seizures is approximately 1%,
which increases to 4% at doses >600 mg/day.26
Antineoplastic Agents
Seizures are common among patients undergoing
treatment for cancer. Approximately 13% of
patients with cancer experience a seizure, and
seizures account for 5% of neurologic complica-
tions.42 Children with cancer are especially suscep-
tible to seizures, which occur with a much higher
incidence than that in adults.43 The causes of
seizures among patients with cancer vary greatly
and include primary brain tumors, brain metas-
tases, metabolic derangements, and medications.19
Drug-induced seizures are more common during
intensive cancer chemotherapy, in patients with
liver or kidney disease, or when high doses of anti-
neoplastic agents are used, such as those recom-
mended in protocols for bone marrow
transplantation.
Stimulant Drugs for Attention
Deficit/Hyperactivity Disorder (ADHD)
Drugs such as methylphenidate and atomoxetine
have been implicated as a cause of seizures in
cases of overdose and abuse.30,31 Early reports of
seizures associated with drugs for ADHD in chil-
dren were complicated by the fact that children
with ADHD are at a higher risk for seizures. Two
studies indicate that these drugs do not increase
the risk of seizures for children with ADHD.44,45
In one of these studies, children with epilepti-
form discharges on EEG were studied separately
from those with normal EEG recordings. 44
Stimulant medications did not increase the risk
of seizures in children with normal EEGs. A
greater risk of seizures was seen in children with
epileptiform discharges, but this could not be
attributed to stimulant use. These data indicate
that stimulant medications may be safely used in
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CHAPTER 10 • Seizures 183

children with ADHD with little added risk of
seizures.
MECHANISMS
Seizures are acute neurologic events resulting from
hypersynchronous and hyperactive discharges of
neurons. The precise mechanisms that result in
this type of neuronal activity are poorly under-
stood, partly because there are multiple causes of
hypersynchronous activity. Proposed mechanisms
of action of antiepileptic drugs involve excitatory
neurotransmitters, ion channels (sodium, potassi-
um, and calcium), and inhibitory neurotransmit-
ters, providing limited understanding of the
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
understood, there is some limited insight regarding
potential mechanisms of seizures induced by some
drugs. Proposed mechanisms by which specific
drugs induce seizures are summarized in Table
10–2.1,46-58 Meperidine is a well-documented
causative agent in drug-induced seizures, most like-
ly as a result of accumulation of the active metabo-
lite normeperidine. Penicillin is a direct neurotox-
in that results in seizures. The mechanism of
carbapenem-induced seizures is believed to be inhi-
bition of the inhibitory neurotransmitter gamma-
aminobutyric acid,48 which is also the likely
mechanisms of seizures induced by tricyclic antide-
pressants.12 Seizures caused by theophylline over-
dose in children, adults, and the elderly may occur
as a result of saturation of hepatic metabolism of
the drug, resulting in progressive theophylline
accumulation. Premature infants may be some-
what protected from theophylline-induced seizures
because of the different metabolic pathways for
theophylline in immature hepatic enzyme sys-
tems.59
CLINICAL PRESENTATION AND
DIFFERENTIAL DIAGNOSIS
A major problem with drug-induced seizures is
accurate detection and diagnosis. The clinical pres-
entation of seizures may be variable, ranging from
decreased levels of consciousness to a major gener-

TABLE 10–2 Mechanisms of Drug-Induced Seizures

Drug Mechanism
5-Fluorouracil46 Genetic polymorphism of dihydropyrimidine dehydrogenase
leading to accumulation
Bupropion47 Increases noradrenergic activity
Carbapenems48 GABA antagonist
NMDA agonist
Cisplatin49 Hypomagnesemia, hypokalemia, hyponatremia
Clozapine1 Anticholinergic activity and reduced affinity for striatal
dopaminergic receptors
Cyclosporine50 Direct neurotoxin
Fluoroquinolones51 Displacement of GABA from receptors
Interferon-alfa52 Increases neuronal excitability
Isoniazid53,54 Disruption of pyridoxine metabolism
Maprotiline55 Increases noradrenergic activity
Meperidine1 Accumulation of metabolite, normeperidine, with CNS
excitation activity
Methotrexate56 Mineralizing microangiopathy of cerebral vasculature
Penicillins1 GABA antagonist
Phenothiazines57 Dopamine antagonist activity
Theophylline54 Disruption of pyridoxine metabolism
Tricyclic antidepressants58 Increases noradrenergic activity
CNS = central nervous system; GABA = gamma-aminobutyric acid; NMDA = N-methyl-D-aspartic acid.
TisdaleC10_177-189 1/20/10 11:00 PM Page 184
184 SECTION III • Drug-Induced Neurological Diseases
TABLE 10–3 Signs and Symptoms Associated
with Drug-Induced Seizures
• “Blacking out” spells, lapses in memory, or sudden
alteration in consciousness
• Daydreaming
• Falling
• Shaking or convulsions of all limbs
• Jerks, shoulder shrugs
• Sudden episodes of various stereotypical sensations
or automatic, uncontrolled movements
alized tonic–clonic event (Table 10–3). Symptoms
of a seizure can be extremely subtle, and unless
caregivers are aware of the various presentations of
seizures, these symptoms can be overlooked or
misdiagnosed. In addition, seizures are usually
brief and unpredictable events, complicating
detection and diagnosis. Caregivers of individuals
who are at increased risk for drug-induced seizures
and who are receiving medications known to cause
seizures should be trained regarding the typical
symptoms of a seizure, including alteration of con-
sciousness and uncontrolled muscle movement of
part or all of the body.
Rarely, drug-induced seizures can last >5 to 10
minutes, developing into status epilepticus, which
requires immediate medical intervention. Patients
with status epilepticus may not necessarily experi-
ence convulsions, but may present only with
decreased levels of consciousness. When a patient
experiences unexplained alterations in conscious-
ness, seizures should be considered as a possible
diagnosis.
While the clinical presentation of a seizure is the
primary method of detection, a definitive diagnosis is
only possible with an EEG. Many other disorders are
associated with clinical presentations that are similar
those of seizures (Table 10–4). The EEG should
TABLE 10–4 Conditions to Consider in the
Differential Diagnosis of Drug-Induced Seizures
• Anxiety or panic attack
• Cardiac arrhythmia
• Complicated migraine headache
• Hypoglycemia
• Psychogenic events
• Seizures from other causes
• Stroke
• Syncope
• Tics
• Transient ischemic attack
demonstrate abnormal neuronal activity that is con-
sistent with a seizure. An EEG is preferably performed
during a seizure to ensure that the abnormal activity
is recorded, but the brief duration of most seizures
makes this difficult to accomplish. Between seizures,
the EEG can be completely normal, and is not help-
ful in determining whether the patient had a seizure.
However, an abnormal EEG between seizures is
indicative of an ongoing propensity for further
seizures. The EEG should be performed by a skilled
EEG technician and interpreted by a neurologist.
It is particularly important to distinguish drug-
induced seizures from seizures from other causes in
patients with cancer, who may have brain metas-
tases. Seizures that occur because of antineoplastic
drug therapy may not be ongoing, and can often be
treated or prevented by dose adjustments of
chemotherapy agents. Criteria have been developed
to assist in determining whether seizures are drug-
induced or from a different cause.20,60 These criteria
include development of encephalopathy and
seizures soon after administration of a chemothera-
py agent, exclusion of metabolic and structural
causes, and exclusion of seizures due to other drugs.
RISK FACTORS
Precise risk factors for drug-induced seizures have
not been clearly identified. Possible risk factors for
drug-induced seizures are listed in Table 10–5.
Drugs known to cause seizures at therapeutic doses
should be used with caution in patients with a his-
tory of epilepsy or seizures. However, a history of
epilepsy is not an absolute contraindication to
receiving drugs that may be associated with
seizures, and treatment decisions should be made
on an individual basis. Patients with compromised
kidney or liver function are at risk for the accumu-
lation of renally eliminated or hepatically metabo-
lized drugs. For example, the risk of
meperidine-induced seizures is increased sevenfold
in patients with kidney disease.1 In other patients,
disorders or infections that compromise the
blood–brain barrier may allow excessive penetra-
tion of a drug into the central nervous system and
result in seizures. Finally, drugs known to cause
metabolic disruptions such as hyponatremia or
hypoglycemia could produce seizures, and serum
sodium and/or glucose concentrations should be
carefully monitored when using these drugs.
Antiepileptic drugs can cause seizures when a
drug is improperly chosen for management of a
seizure or epilepsy syndrome. Juvenile myoclonic
epilepsy is an example of a seizure syndrome that
can be exacerbated by the use of the incorrect
TisdaleC10_177-189 1/20/10 11:00 PM Page 185
TABLE 10–5 Risk Factors for Drug-Induced
Seizures
• Cancer
• Compromised blood–brain barrier
• Concomitant use of central nervous system stimulant
drugs
• History of epilepsy or seizures
• Impaired metabolism of hepatically metabolized
potentially seizure-inducing drugs in patients with
liver disease
• Impaired elimination of renally eliminated potentially
seizure-inducing drugs in patients with kidney disease
antiepileptic drug. Carbamazepine and oxcar-
bazepine have been shown to increase the risk of
myoclonic and absence seizures patients with juve-
nile myoclonic epilepsy.13,14,17 Accurate diagnosis of
seizures and proper selection of an antiepileptic drug
therapy are essential to prevent worsening of seizures
in this patient population. In addition, discontinua-
tion of antiepileptic drugs can precipitate seizures,
especially in patients with epilepsy. This typically
occurs in association with abrupt discontinuation of
an antiepileptic drug, but seizures can occur even
during controlled withdrawal of therapy.15,16
Withdrawal seizures have been reported in associa-
tion with discontinuation of therapy with carba-
mazepine, oxcarbazepine, phenobarbital, phenytoin,
felbamate, and benzodiazepines. Seizures resulting
from the discontinuation of antiepileptic drugs can
be severe or result in status epilepticus.
Seizures associated with antiepileptic drugs
may occur when administered at toxic doses or
concentrations. For example, serum phenytoin
concentrations >30 µg/mL have been associated
with seizures. Topiramate has been reported to
cause seizures at supratherapeutic doses.61 In addi-
tion, drug-induced metabolic disturbances such as
hyponatremia induced by carbamazepine or oxcar-
bazepine result in seizures.
Seizures associated with fluoroquinolones are
relatively uncommon, and often occur in patients
with a prior diagnosis of epilepsy, neurotrauma, or
anoxia.62 Some evidence exists that concomitant
use of nonsteroidal anti-inflammatory agents
increases the risk of fluoroquinolone-induced
seizures.62 There appears to be a relationship
between the chemical structure of the fluoro-
quinolone and the propensity to cause seizures.
Compounds that contain the 7-piperazine or 7-
pyrrolidine moieties (e.g., ciprofloxacin, enoxacin,
norfloxacin, tosufloxacin, clinafloxacin) have an
increased potential to cause seizures.63 The majori-
ty of reported cases of carbapenem-induced sei-
CHAPTER 10 • Seizures 185
zures have occurred in patients with kidney disease
or a compromised blood–brain barrier, allowing
greater penetration of the drug into the brain.
Theophylline-induced seizures can occur at
any dose. Older children, adults, and the elderly
are particularly vulnerable to seizures associated
with theophylline, especially in overdose. In one
case series, seizures related to theophylline devel-
oped in 6% of elderly patients.64
MORBIDITY AND MORTALITY
Drug-induced seizures are typically single events of
short duration that are associated with a low risk of
morbidity or mortality. However, during these
events, an individual may experience an injury,
such as lacerations or broken bones from falling, or
may injure others if the seizure occurs while driv-
ing a motor vehicle or operating equipment or
machinery. It is unlikely that typical drug-induced
seizures result in repeated seizures, as may occur in
patients with epilepsy.
Status epilepticus occurs rarely as a result of drug-
induced seizures, but it is associated with increased
morbidity and mortality. Uncontrolled, prolonged
seizures can result in permanent neurologic damage
and increase the risk of ongoing seizures.
PREVENTION
As the mechanisms and causes of drug-induced
seizures are diverse, it is difficult to describe specif-
ic plans for prevention (Table 10–6). Caution
should be exercised when using medications
known to cause seizures in patients with a history
of epilepsy or seizures. Efforts should be made to
ensure proper dose adjustments of drugs in
patients with kidney or liver disease. Increased
monitoring of metabolic function parameters may
TABLE 10–6 Approaches to Help Prevent
Drug-induced Seizures
• Appropriate dose adjustment of potentially seizure-
inducing drugs in patients with liver or kidney disease
• Appropriate monitoring of laboratory values (e.g.,
serum electrolytes, kidney function, liver function,
serum glucose concentrations)
• Avoidance of concomitant use of drugs that are cen-
tral nervous system stimulants
• Avoidance of abrupt discontinuation of drugs with
central nervous system activity
TisdaleC10_177-189 1/20/10 11:00 PM Page 186
186 SECTION III • Drug-Induced Neurological Diseases
be helpful in preventing seizures due to drug
effects on serum chemistry and homeostasis.
Premedication and combination anesthesia
may reduce the risk of seizures associated with
sevoflurane. To minimize the risk of seizures, pre-
treatment with benzodiazepines and/or narcotics
and concomitant use of nitrous oxide have been
suggested.65 In addition, hypocapnia should be
avoided and a maximum of 1.5 minimum alveolar
concentration should be used during anesthesia to
prevent sevoflurane-induced seizures.
To reduce the risk of withdrawal seizures, ther-
apy with antiepileptic drugs should be withdrawn
over 1 to 2 months, unless potentially life-threat-
ening adverse effects are occurring, in which case
more rapid discontinuation of therapy is warrant-
ed. Care should be taken to ensure proper doses
and laboratory monitoring of antiepileptic drug
therapy, including serum antiepileptic drug con-
centrations, serum electrolyte concentrations, and
kidney and liver function tests.
Appropriate dose adjustment of penicillins
and carbapenems in patients with kidney disease
or a compromised blood–brain barrier is the best
method of preventing seizures associated with
these agents. These drugs and fluoroquinolone
antibiotics should be used with caution in
patients with a history of seizures. Similarly,
other drugs, such as hydroxychloroquine66 and
antipsychotic agents,67 should be used with cau-
tion in patients with a history of epilepsy. Some
have suggested initiating therapy with an
antiepileptic drug in patients in whom therapy
with clozapine is initiated in an attempt to pre-
vent seizures.22
Many of the reported cases of seizures associat-
ed with ephedra or ma huang occurred in patients
without a history of epilepsy, and often occurred
with the co-administration of other stimulant
drugs, like phenylpropanolamine or caffeine.27
Clearly, stimulant drugs should not be adminis-
tered in combination with ephedra.
MANAGEMENT
Because drug-induced seizures can occur through a
variety of mechanisms, treatment strategies should
be approached carefully and individualized. The
first step is to immediately discontinue the
causative agent, or in the case of abrupt discontin-
uation, to initiate therapy with the discontinued
medication. If the risk of a second acute seizure
appears to be low, then pharmacologic interven-
tions to treat seizures are probably not necessary.
However, if the risk for another acute seizure is
high, then seizures should be treated aggressively.
In either case, there is no evidence that drug-
induced seizures produce epilepsy. The focus of
treatment is prevention of additional acute
seizures.
Some drugs induce seizures by altering metab-
olism leading to disorders such as hypoglycemia or
hyponatremia. In these cases, the underlying meta-
bolic problem should be identified and corrected
before the initiation of therapy with drugs com-
monly used to treat seizures. Antiepileptic drugs
are associated with numerous adverse drug reac-
tions, and indiscriminate use should be avoided.
Management of drug-induced seizures is some-
what dependent on the causative agent. For some
drugs that induce seizures, there are specific treat-
ment guidelines or recommendations regarding
drugs to avoid. With other causative drugs, a gen-
eral treatment approach to seizures can be used. In
either case, the key to treatment and prevention of
additional seizures is rapid identification of the
causative agent, and rapid implementation of the
appropriate treatment plan. When the likelihood
of repeated acute seizures is low, more time is avail-
able to discontinue the offending agent or take
alternative actions.
The acute treatment of seizures typically
involves the use of a drug to immediately control
the seizures and a drug to provide sustained control
of seizures. Usually a benzodiazepine, such as
lorazepam or diazepam, is administered to provide
rapid control of seizures. This should be followed by
the administration of an antiepileptic drug, usually
phenytoin, to provide sustained control of seizures.
Most patients respond to these measures. If seizures
are not controlled or recur, administration of a ben-
zodiazepine can be repeated and additional pheny-
toin may be administered. In the very rare
situations in which patients do not respond to addi-
tional doses of a benzodiazepine and phenytoin,
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
specific drugs should be used in the place of this
general treatment approach to seizures.
Benzodiazepines are usually effective in treat-
ing and preventing carbapenem-induced seizures,
because of the benzodiazepine-associated enhance-
ment of gamma-aminobutyric acid activity.68 For
patients with seizures induced by tricyclic antide-
pressants, benzodiazepines are the preferred drugs
for treatment.12 In this situation, phenytoin should
be avoided, because of its lack of efficacy and the
possibility of enhancing the arrhythmogenic
TisdaleC10_177-189 1/20/10 11:00 PM Page 187
effects of tricyclics. Benzodiazepines are recom-
mended for the management of seizures induced
by antimalarial drugs.69 However, benzodiazepines
may not be as effective for the management of
theophylline-induced seizures.70 Theophylline may
antagonize the effects of benzodiazepines, render-
ing them less effective. Therefore, barbiturates are
the preferred drugs for treating theophylline-
induced seizures. Loading doses of phenobarbital
or pentobarbital, 5 to 15 mg/kg, should be admin-
istered, with additional loading doses given until
seizures terminate.71 Caution should be exercised
when administering intravenous doses of barbitu-
rates because of the respiratory and cardiovascular
adverse effects of these agents.
If it is determined that seizures are induced by
an antineoplastic agent, the general recommenda-
tion not to treat the seizures, when possible, but
rather to adjust the doses and chemotherapy regi-
men.19 Care should also be taken to address under-
lying metabolic changes associated with anti-
neoplastic drugs that can result in seizures.
However, if there are other potential causes of the
seizures, especially central nervous system tumors,
ongoing use of antiepileptic drugs are indicated.
INFORMATION FOR PATIENTS
As drug-induced seizures are rare events and are
usually very short in duration, education of all
patients regarding the seizure risk when receiving
potentially seizure-inducing drugs may not be pro-
ductive. Individuals who are at an increased risk for
seizures should be advised regarding the signs and
symptoms of seizures. Caregivers should be
instructed concerning first aid for seizures. If a
seizure occurs, caregivers should protect the
patient from self-injury or injuring others by lay-
ing the person on his or her side, placing a pillow
under the head, making sure the airway remains
clear, and helping the individual become reorient-
ed once the seizure subsides. In addition, timing of
the duration of the seizure with a clock is impor-
tant, and emergency medical care should be called
if a seizure lasts longer than 10 minutes for patients
with a history of seizures, or when a seizure occurs
in an individual without a history of seizures.
Forcing objects into the patient’s mouth or
restraining the patient should never be attempted.
In addition to instruction on managing
seizures, individuals with a history of epilepsy
should be advised to avoid medications that may
cause seizures, particularly nonprescription drugs
and herbal products, and to avoid abrupt discon-
tinuation of antiepileptic agents.
CHAPTER 10 • Seizures 187
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61. Anand JS, Chodorowski Z, Wisniewski M. Seizures
induced by topiramate overdose (letter). Clin Toxicol
(Phila). 2007;45:197.
62. Owens RC Jr, Ambrose PG. Antimicrobial safety: focus on
fluoroquinolones. Clin Infect Dis. 2005;41(suppl 2):S144-
S157.
63. Owens RC Jr, Ambrose PG. Clinical use of the
fluoroquinolones. Med Clin North Am. 2000;84:1447-
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64. Sessler CN. Theophylline toxicity: clinical features of 116
consecutive cases. Am J Med. 1990;88:567-576.
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65. Constant I, Seeman R. Inhalational anesthetics in
pediatric anesthesia. Curr Opin Anaesthesiol. 2005;18:277-
281.
66. Fish DR, Espir ML. Convulsions associated with
prophylactic antimalarial drugs: implications for people
with epilepsy. BMJ. 1988;297:526-527.
67. Koch-Stoecker S. Antipsychotic drugs and epilepsy:
indications and treatment guidelines. Epilepsia.
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68. Koppel BS, Hauser WA, Politis C, et al. Seizures in the
critically ill: the role of imipenem. Epilepsia.
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CHAPTER 10 • Seizures 189
69. Marquardt K, Albertson TE. Treatment of
hydroxychloroquine overdose. Am J Emerg Med.
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70. Yoshikawa H. First-line therapy for theophylline-
associated seizures. Acta Neurol Scand Suppl. 2007;186:57-
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71. Willmore LJ. Epilepsy emergencies: the first seizure and
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TisdaleC011_190-210 1/12/10 2:35 PM Page 190
CHAPTER 11
Stroke
S troke refers to a sudden onset of focal neurolog-
ic deficit and is the third leading cause of death
in the United States (U.S.).1 There are two main
types of stroke: ischemic and hemorrhagic. Drugs
should always be considered as a possible etiology
of either ischemic or hemorrhagic stroke.
ISCHEMIC STROKE
CAUSATIVE AGENTS
Drugs that have been reported to cause ischemic
stroke are listed in Table 11–1.2-52 Many of the
agents listed in the table have been associated with
both ischemic and hemorrhagic stroke. For many
agents, an association with drug-induced stroke is
controversial.
There is substantial controversy as to whether
oral contraceptives are a cause of stroke. Many
studies have attempted to assess the possible rela-
tionship between oral contraceptives and stroke,
but the results are contradictory. Higher-dose for-
mulations have been shown to increase the risk of
stroke in specific subgroups of patients: those who
smoke, those with hypertension, those older than
35 years, those with a history of stroke, those with
hyperlipidemia, and those with a history of
migraine headaches. Although the risk of stroke
appears to be reduced with lower-dose formula-
tions of oral contraceptives, meta-analyses have
reported conflicting results.27,53 Therefore, oral
contraceptives should be used with caution in
women at risk for stroke.28-29,54 The rate of ischemic
stroke among users of the Ortho EVRA contracep-
tive patch was 13.6 per 100,000 woman-years,
which is similar to the stroke incidence in users of
190
Denise H. Rhoney
norgestimate-containing oral contraceptives (11.3
per 100,000 woman-years).55
Data from studies of postmenopausal women
receiving hormone-replacement therapy with
estrogen may provide some additional informa-
tion regarding the risk of stroke in patients taking
oral contraceptives. In the Women’s Health
Initiative, a randomized trial of 16,500 generally
healthy postmenopausal women, the combina-
tion of estrogen and progestin increased the rela-
tive risk of ischemic stroke by 41%, with an
absolute stroke risk of 8 more strokes per 10,000
person-years.31 Although the patients in this trial
were relatively healthy, they were substantially
older than typical patients receiving therapy with
oral contraceptives. Therefore, it may not be
appropriate to draw inferences from these results
regarding the overall risk of stroke associated with
oral contraceptive therapy.
In December 2004, the Food and Drug
Administration (FDA) issued a health advisory con-
cerning the use of nonsteroidal antiinflammatory
agents (NSAIDs) and cyclooxygenase (COX)-2
selective inhibitor drugs,49 and meta-analyses have
since reinforced this concern. There is evidence
that these agents increase the risk of myocardial
infarction and stroke when used for extended peri-
ods or in high-risk settings (such as immediately
after cardiac surgery) and in higher doses.50
Rofecoxib and valdecoxib were withdrawn from
the U.S. market in 2004 and 2005, respectively. A
National Institutes of Health (NIH) clinical trial of
celecoxib was suspended because of an increased
incidence of cardiovascular events, but the drug
was not removed from the U.S. market. However,
the FDA recommends the use of other agents or
administration of the lowest effective dose, and
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CHAPTER 11 • Stroke 191

TABLE 11–1 Agents Implicated in Drug-Induced Ischemic Stroke

Agent Incidence Level of Evidence
(see page xii for explanation)
2-8
Cocaine NK C
Amphetamines2,9 NK C
Heroin2 NK C
Methylphenidate2 NK C
Ecstasy2,10 NK C
Nicotine12 25% (Relative risk 1.8) A
Alcohol abuse (⭌ 5 drinks/day)13 Relative risk 1.69 B
Sumatriptan18 NK C
Intravenous immunoglobulin20 NK C
Isometheptene mucate15 NK C
Marijuana22 NK C
Risperidola,23 4% C
Olanzapinea,24 Relative risk 3.1 C
Intranasal phenoxazoline or oxymetazoline26 NK C
30
Oral contraceptives (women age 25-44 years > 50 mcg estradiol) 0.9-10/100,000
Relative risk 2.8 B
33
Hormone replacement in postmenopausal women Relative risk 1.4 A
Recombinant factor VIIa35,36 NKb B
Selective serotonin reuptake inhibitorsc,37-39 NK B
Serotonin-norepinephrine reuptake inhibitorsc,39 NK B
Cisplatin40-46 0.137% B
Tamoxifen47,48 Relative risk 1.49 B
Non-steroidal antiinflammatory agents49-52 Relative risk 1.99 B
NK = not known
a
Primarily reported in patients with dementia
b
A total of 151 thromboembolic events reported with rFVIIa in FDA Adverse Event Reporting System; recent clinical trial reported a
higher incidence of arterial events in patients receiving 80 mcg/kg
c
Primarily reported with high doses
d
Data from World Health Organization adverse reaction database as of July 12, 2002
e
Data from a retrospective database of over 10,000 chemotherapy patients

has added a “black box” warning to the labeling. In
addition, the NIH halted a trial conducted in
patients with Alzheimer’s disease, which showed
an increased risk of cardiovascular events in
patients receiving naproxen, but not in those
receiving celecoxib.51 The extended follow-up data
from the Adenomatous Polyps Prevention with
VIOXX (APPROVe) study revealed an increased risk
of ischemic stroke with rofecoxib as compared
with placebo, and found that 7 of the 18 ischemic
strokes occurred after rofecoxib therapy had been
discontinued. This finding raised concern regard-
ing the risk of stroke in patients who have previ-
ously been exposed to rofecoxib.50
The results of the Rotterdam Study indicated
that in the general population the risk of stroke
was greater in association with the use of nonse-
lective NSAIDS (e.g., naproxen, ibuprofen) and
COX-2 selective NSAIDs (e.g., celecoxib), with the
most pronounced risk of stroke related to the use
of COX-2 selective NSAIDs.52 The public health
advisory issued by the FDA is as follows49: (1)
Physicians prescribing COX-2 selective agents
should consider this emerging information when
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192 SECTION III • Drug-Induced Neurological Diseases

weighing the benefits against risks for individual
patients. Patients who are at a high risk of gas-
trointestinal bleeding, have a history of intoler-
ance to non-selective NSAIDs, or are not doing
well on non-selective NSAIDs may be appropriate
candidates for COX-2 selective agents. (2)
Individual patient risk for cardiovascular events
and other risks commonly associated with NSAIDs
should be taken into account for each prescribing
situation. (3) Consumers are advised that all non-
prescription pain medications, including NSAIDs,
should be used in strict accordance with the label
directions. If an NSAID is needed for longer than
10 days, a physician should be consulted. The
American Heart Association (AHA) has recom-
mended a stepped-care approach for the manage-
ment of musculoskeletal symptoms in patients
with risk factors or known cardiovascular dis-
ease.51
EPIDEMIOLOGY
The most common type of non-drug-induced
stroke is ischemic, which accounts for 85% of all
cases. Of ischemic strokes, 65% are atherothrom-
botic, with the remainder cardioembolic in origin.
The overall incidence of drug-induced stroke is
unknown, but is generally considered to be low. In
young adults (<50 years of age) drug-related etiolo-
gies can be identified in 15–38% of ischemic
strokes.2,56 Use of illicit drugs, particularly cocaine,
is commonly implicated in younger patients who
lack other known vascular risk factors. Since the
emergence of the more potent alkaloidal cocaine
(“crack”) there has been a significant increase in
case reports of cocaine-induced stroke.57 The inci-
dence of all drug-induced stroke may be on the
rise.2 See Table 11–1 for the incidence of stroke
associated with specific agents.
MECHANISMS
There are many proposed mechanisms for drug-
induced strokes. Mechanisms by which drugs
result in stroke may be multifactorial, and are pre-
sented in Table 11–2.
Embolic Mechanisms
Embolism can result in a stroke when a clot,
plaque, platelet aggregate, or foreign body

TABLE 11–2 Mechanisms of Drug-Induced Ischemic Stroke

Drug Mechanism
Intravenous drugs of abuse (e.g., heroin) Cerebral embolism
Cocaine
Methylphenidate (from injection of oral product)
Tamoxifen
Cocaine Vasoconstriction/ vasospasm
Amphetamines
Methylphenidate
Sumatriptan
Selective serotonin reuptake inhibitors
Serotonin–norepinephrine reuptake inhibitors
Amphetamines Acute hypertension
Cocaine
Alcohol
Caffeine
Cigarette smoking
Heroin Vasculitis
Cocaine
Amphetamines
Nonsteroidal antiinflammatory agents Induces direct vascular damage and subsequently promotes
Cisplatin platelet aggregation and vasoconstriction
Cocaine Clotting derangements (platelet aggregation)
Cigarette smoking
Atypical antipsychotic agents (risperidone, olanzapine) Orthostatic hypotension
TisdaleC011_190-210 1/12/10 2:35 PM Page 193
breaks off into the circulation and obstructs an
artery. Intravenous drugs of abuse (e.g., heroin)
can be associated with infarction due to embolic
vessel occlusion, infective endocarditis, or hem-
orrhage caused by the rupture of a septic
(mycotic) aneurysm. Stroke is a complication in
about 20% of patients with infective endocardi-
tis. Cocaine and other drugs may cause heart dis-
ease resulting in release of emboli to the brain.
Foreign body emboli, primarily from talc fillers,
have been reported after the injection of agents
intended for oral administration (i.e.,
methylphenidate).58 Foreign substances injected
into the systemic circulation may embed in the
lung, resulting in granulomatous reactions that
ultimately provide a path for this foreign materi-
al to reach the brain. Tamoxifen may be associ-
ated with a paradoxical embolism (emboli
originating in the venous system migrating to
the arterial system as a result of abnormal com-
munication within the heart) and subsequent
cerebral venous thrombosis.59-60
Vasoconstriction/Vasospasm
Systemic vasoconstriction can lead to hyperten-
sion and intracerebral hemorrhage (ICH), where-
as cerebral vasoconstriction can lead to
infarction. Vasoconstriction may be transient or
prolonged. Vasospasm with subsequent cerebral
infarction may occur in association with
cocaine, amphetamines, phenylpropanolamine,
ephedrine, and methylphenidate. 61 Cocaine
temporarily causes vasoconstriction, thus reduc-
ing blood supply to various brain regions. It also
may potentiate the effects of serotonin by block-
ing its reuptake, resulting in vasoconstriction.62
In addition, cocaine exerts direct effects on cal-
cium channels, leading to the release of intracel-
lular calcium in cerebral vascular smooth-muscle
cells.57 Other possible mechanisms of cocaine-
induced vasospasm are via endothelin-1 and
reuptake of dopamine at presynaptic nerve ter-
minals. There appears to be a cumulative effect
of cocaine exposure and the risk of stroke.57 The
use of selective serotonin reuptake inhibitors
and serotonin–norepinephrine reuptake
inhibitors can cause vasoconstrictive stroke
(Call–Fleming syndrome) or vasospasm. 37,39
Underlying atherosclerosis may augment this
vasoconstriction. Sumatriptan binds to a partic-
ular subpopulation of 5-hydroxytryptamine (5-
HT1) receptors in the pia and dural vessels,
leading to vasconstriction. 14 Subcutaneous
administration of sumatriptan has been shown
to result in vasoconstriction of the middle cere-
CHAPTER 11 • Stroke 193
bral and internal carotid arteries within 30 min-
utes.63 There have been case reports of stroke
associated with triptan use. However, patients
with migraine are also at increased risk of
stroke.18
Acute Hypertension
The primary mechanism of drug-induced acute
hypertension is related to the effects of drugs on
neurotransmitters. Many drugs increase cate-
cholamine release from central noradrenergic
nerve terminals (e.g., amphetamines, ephedra,
nonprescription sympathomimetics), inhibit
reuptake of catecholamines into adrenergic
nerve terminals (e.g., cocaine), or increase plas-
ma catecholamine concentrations (e.g., ethanol,
cocaine). Hypertension related to drug use may
disrupt cerebral autoregulation, promote reper-
fusion of brain tissue, or damage cerebral arteri-
oles, which may eventually rupture. Cigarette
smoking acutely elevates blood pressure and
reduces cerebral blood flow.64-66 Alcohol acutely
and chronically increases blood pressure because
of the increased adrenergic activity and the
increased plasma concentrations of cortisol,
renin, aldosterone, and vasopressin.67-69
Vasculitis
Inflammation of small, medium, and large
intracranial arteries and subsequent develop-
ment of arteritis is another reported mechanism
of stroke induced by drugs such as heroin,
amphetamines, cocaine, ephedra, and pseu-
doephedrine.70 These agents are associated with
an inflammatory vasculopathy and vessel-wall
necrosis.71
Clotting Derangements
Platelets play an important role in the develop-
ment of thrombosis. With endothelial damage,
vessel collagen can be exposed to blood and acts as
a triggering mechanism for platelet activation,
resulting in release of adenosine diphosphate from
the platelets, which causes platelets to aggregate.
Thromboxane A2 is produced, which also pro-
motes platelet aggregation and vasoconstriction.
Cocaine may stimulate platelet aggregation and
inhibit prostacyclin.72 Cigarette smoking aggra-
vates atherosclerosis and increases arterial wall
stiffness, ultimately increasing the likelihood of
plaque formation. Cigarette smoking increases
platelet reactivity and inhibits prostacyclin forma-
tion.73 Alcohol consumption may elevate blood
TisdaleC011_190-210 1/12/10 2:35 PM Page 194
194 SECTION III • Drug-Induced Neurological Diseases
pressure and cause thrombocytopenia and platelet-
function defects, and long-term use may result in
coagulation abnormalities due to liver impairment.
Nonsteroidal antiinflammatory agents act primari-
ly via inhibition of COX, which consists of 2 major
isoenzymes—COX-1 and COX-2. Experimental
evidence suggests that inhibition of COX-2 results
in a shift in the prothombotic/antithrombotic bal-
ance toward thrombosis. The differential biologic
effects of these agents are a result of the degree of
selectivity for COX-2 versus COX-1.51 Cisplatin
induces direct endovascular damage and also indi-
rect damage via free radical–induced lipid peroxi-
dation. Direct endovascular damage can lead to the
accumulation of mediators that promote platelet
aggregation and vasoconstriction.74 In addition,
cisplatin may reduce the activity of the anticoagu-
lant protein C and may elevate plasma concentra-
tions of von Willebrand factor.44
Orthostatic Hypotension
A potential mechanism for atypical antipsychotic
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
by these agents may also result in the promotion of
platelet aggregation.75
CLINICAL PRESENTATION AND
DIFFERENTIAL DIAGNOSIS
Clinically, it is difficult to distinguish drug-induced
stroke from non-drug-induced stroke. The diagno-
sis of drug-induced stroke is often made by exclu-
sion of other causes, or through serum or urine
testing for drugs. The typical stroke patient pres-
ents with an abrupt onset of neurologic deficits,
which can include hemiparesis, speech distur-
bance, hemisensory loss, monocular or visual field
loss, and/or ataxia. The clinical presentation of
both ischemic stroke and ICH is dependent on the
anatomical location of the stroke. It is not possible
to distinguish an ischemic stroke from ICH based
on clinical examination alone, although several
characteristics are more indicative of ICH:
headache, impaired level of consciousness, nausea
and vomiting, and extreme elevations of blood
pressure. Subarachnoid hemorrhage must be sus-
pected in a patient who experiences a sudden new
severe headache. Drug-induced stroke can occur at
any time during therapy with a potentially
causative agent. Common signs and symptoms of
drug-induced ischemic stroke are presented in
Table 11–3.
Drug-induced stroke must be distinguished
from stroke due to other etiologies. Conditions to
consider in the differential diagnosis of drug-
induced stroke are presented in Table 11–4. It is dif-
ficult to distinguish between drug-induced and
non-drug-induced causes of stroke unless symp-
toms are temporally related to the ingestion of sub-
stances of abuse or agents with surrogate
monitoring parameters (e.g., drug screen) that can
be quantitatively assessed.
The diagnosis of stroke consists of a thorough
evaluation of patient history, clinical examina-
tion, laboratory evaluation, and imaging studies,
including computed tomography (CT) scan, cere-
bral angiography, and magnetic resonance imag-
ing (MRI). Laboratory studies should consist of
serum electrolyte and glucose concentrations,
complete blood count, coagulation parameters,
and drug screen evaluation. A CT scan is essential
to differentiate between ischemic and hemor-
rhagic stroke.
TABLE 11–3 Signs and Symptoms Associated with
Drug-Induced Ischemic Stroke
Anterior cerebral artery blockage
• Contralateral hemiparesis
• Confusion
• Gait apraxia
Middle cerebral artery blockage
• Contralateral hemiparesis
• Dysarthria
• Hemianesthesia
• Contralateral homonymous hemianopia
• Aphasia
• Apraxia
Posterior cerebral artery blockage
• Unilateral cortical blindness
• Memory loss
• Contralateral homonymous hemianopia
• Unilateral third-cranial-nerve palsy
Ophthalmic artery blockage
• Monocular loss of vision
Vertebrobasilar system blockage
• Unilateral or bilateral cranial-nerve deficits
(e.g. nystagmus, vertigo, dysphagia, dysarthria,
diplopia, blindness)
• Coma
• Ataxia
• Impaired consciousness
TisdaleC011_190-210 1/12/10 2:35 PM Page 195
TABLE 11–4 Conditions to Consider in the
Differential Diagnosis of Drug-Induced Ischemic
Stroke
• Seizure disorder (with postictal paralysis)
• Migraine headache
• Metabolic encephalopathy (hypoglycemia, diabetic
ketoacidosis, hyperosmolar coma, hepatic
encephalopathy, kidney disease, hypercapnia, sepsis)
• Syncope
• Peripheral neuropathy
• Malingering/somatization
• Brain tumor
• Cerebral abscess
• Encephalitis
• Meningitis
• Psychiatric symptoms
• Post–cardiac arrest ischemia
• Cerebral hemorrhage
• Cranial trauma
• Antiphospholipid syndromes
• Genetic factors (i.e., deficiencies in protein
factors C and S, factor V Leiden, Moya moya, Fabry’s
disease, CADASIL [cerebral autosomal dominant
arteriopathy with subcortical infarcts and
leukoencephalopathy])
RISK FACTORS
Risk factors for drug-induced stroke have been
identified and are presented in Table 11–5. An
underlying history of hypertension is one of the
most common risk factors. In addition, any patient
with risk factors for stroke is at a higher risk for
drug-induced stroke. The Framingham study iden-
tified five factors that placed the general popula-
tion at increased risk of ischemic stroke: elevated
systolic blood pressure, elevated serum cholesterol
concentration, glucose intolerance, cigarette smok-
ing, and left ventricular hypertrophy as shown on
an electrocardiogram.76 Risk factors for ischemic
stroke have been outlined in recent guidelines
from the American Stroke Association (ASA) and
the AHA.54
MORBIDITY AND MORTALITY
Stroke is one of the most devastating diseases, yet
one of the most preventable. The overall direct and
indirect economic impact of stroke is approximate-
ly $40.9 billion annually.77 Stroke is the third lead-
CHAPTER 11 • Stroke 195
TABLE 11–5 Risk Factors for Drug-Induced
Ischemic Stroke54
• Elderly
• Previous stroke
• Polydrug use
• Hypertension
• Migraine headaches with aura
• Pregnancy
• Diabetes
• Concurrent caffeine use
• Dementia
• Concurrent tobacco use
• Use of higher than recommended doses of potentially
causative agents
• Exposure to drugs of abuse
• Physical inactivity
• History of vascular events
ing cause of death in the U.S. and a leading cause
of disability in hospitalized patients. Long-term
sequelae of a stroke, whether induced by drugs or
other etiologies, include memory loss, depression,
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.
PREVENTION
The most effective means of preventing drug-
induced stroke is avoidance of agents known to
be associated with stroke, especially in high-risk
patients. Strategies for prevention of drug-
induced ischemic stroke are listed in Table
11–6.54 Drug-induced stroke may also be prevent-
ed by minimizing other ischemic stroke risk fac-
tors (e.g., hypertension, hyperlipidemia,
smoking, diabetes). However, the mainstay of
prevention is patient education and identifica-
tion of risk factors, particularly in patients who
are at high risk.
MANAGEMENT
The treatment of any patient has many phases:
prevention of additional strokes or other vascular
disease, supportive and medical management dur-
ing the acute phase, measures to mitigate the
ongoing pathologic process, and rehabilitation. In
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196 SECTION III • Drug-Induced Neurological Diseases

TABLE 11–6 Approaches to Help Prevent Drug-Induced Ischemic Stroke54

Drug Prevention
All agents Control of hypertension
Glucose control
Cholesterol-lowering therapy
Weight management
Atrial fibrillation management
Sleep apnea management
Physical activity
Discontinue drugs known to be associated with stroke in patients at high risk
Cigarette smoking Encourage patient and family to stop smoking
Provide counseling, nicotine replacement and formal programs
Alcohol Men should consume no more than 2 drinks/day and nonpregnant women should
consume no more than 1 drink/day
Control hypertension
Oral contraceptive use Avoid in those at high risk
Inform patients about stroke risk and encourage alternative forms of birth control
among women who smoke cigarettes, have migraines (especially with older age or
smoking), are ⱖ35 years of age, or have had prior thromboembolic events
Drug abuse Cessation
Rehabilitation program
Hormone-replacement therapy Avoid use for primary prevention of stroke
If used for other indications the patient should be informed of vascular risks
SSRI/SNRI Use lowest effective dose for all indications
NSAID Refer to scientific statement for stepped-care approach recommendations51
Stepwise approach to pharmacologic therapy for musculoskeletal symptoms in
patients with or at risk for cardiovascular disease (administer in following order):
1. Acetaminophen, tramadol, narcotic analgesics (short-term)
2. Nonacetylated salicylates
3. Non-COX-2 selective NSAIDs
4. NSAIDs with some COX-2 activity
5. COX-2 selective NSAIDs
COX = cyclooxygenase; NSAID = nonsteroidal antiinflammatory drug; SNRI = serotonin–norepinephrine reuptake inhibitor; SSRI =
selective serotonin reuptake inhibitor.

addition, discontinuation of the offending agent
(if identified) is essential.
Approaches to treatment of drug-induced acute
ischemic stroke are similar to those of stroke due to
other etiologies (refer to treatment guidelines pub-
lished for the acute management of ischemic
stroke78). Hospital admission is indicated for any
patient presenting with an acute stroke. Neurologic
progression and cardiac sequelae are common in
the early stages of a stroke. Preventing and recog-
nizing secondary complications such as aspiration
pneumonia and pulmonary embolism are essen-
tial. The only proven specific treatment for acute
ischemic stroke at present is the thrombolytic
agent recombinant tissue plasminogen activator
(rt-PA). In appropriately selected patients, rt-PA sig-
nificantly increases the likelihood of a good neuro-
logic recovery.79 To be eligible for rt-PA therapy,
patients should have a well-described time of
symptom onset within 3-4.5 hours before the initi-
ation of treatment. The dose of rt-PA for stroke is
0.9 mg/kg IV over 1 hour, 10% as an initial bolus.
The maximum total dose is 90 mg. During the first
24 hours after treatment, therapy with antithrom-
botic agents such as heparin and aspirin should be
withheld, blood pressure should be strictly main-
tained at <180/105 mm Hg, and neurologic and
cardiac function should be closely monitored in an
intensive care unit or stroke unit. Some evidence
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-
out intravenous galactose-based microbubbles aug-
ments intravenous rt-PA recanalization. This
technique is currently being tested in clinical tri-
als.80 Therapy with intraarterial thrombolysis for
patients with middle cerebral artery occlusions pre-
senting within 6 hours of the onset of stroke symp-
toms appears promising.81 Angioplasty and
stenting of cerebral arteries may also have a thera-
peutic role for patients with acute ischemic strokes.
In 2004 the FDA approved the MERCI (mechanical
embolus removal in cerebral ischemia) Retrieval
System. This “corkscrew-type” device is designed to
restore blood flow by engaging, capturing, and
removing blood clots. Most recently (2008), anoth-
er mechanical device, the Penumbra System,
designed to reduce clot burden, was approved by
the FDA. These might represent treatment options
for patients who do not present within the 3-4.5
hour time window necessary for administration of
thrombolysis, as the clinical trials enrolled patients
within 8 hours of symptom onset.80
Fever and hyperglycemia should be treated
aggressively in patients with acute stroke, because
both conditions exacerbate cerebral ischemia and
may worsen neurologic outcome. The appropriate-
ness of treating acute hypertension is less clear,
except in the patient who has undergone throm-
bolysis. In fact, lowering blood pressure excessive-
ly may contribute to cerebral ischemia. In most
patients, blood pressure probably should not be
lowered during the first 24–48 hours after the
stroke unless blood pressure exceeds 220/120 mm
Hg.78
If antihypertensive therapy is needed in the
acute stage, intravenous agents should be used,
particularly those for which doses can be easily
titrated. Current ASA/AHA guidelines suggest the
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
achieved. Labetalol should be avoided in patients
with contraindications to ␤-blockers. Nicardipine
therapy may be initiated as an intravenous infu-
sion of 5 mg/hr, and the infusion rate can be
adjusted to achieve the desired blood pressure.78
After the acute phase of a stroke, risk-factor
management is essential.82 The appropriate specif-
ic preventive agent in patients with other risk fac-
tors may be aspirin, clopidogrel, ticlopidine, or
warfarin. Of these, aspirin is the most frequently
prescribed. There is a lack of consensus regarding
the optimal dose for stroke prevention. Doses of
50–325 mg have been shown to be effective.
Warfarin is indicated for stroke prevention in most
patients with atrial fibrillation, acute myocardial
CHAPTER 11 • Stroke 197
infarction, or dilated cardiomyopathy. The stan-
dard target range for the international normalized
ratio (INR) is 2.0–3.0. Patients with mechanical
prosthetic valves require a higher INR (2.5–3.5),
but this places them at increased risk for ICH. In
addition, any other risk factor that may be present
(e.g., hyperlipidemia, hypertension, diabetes)
should be managed aggressively. Refer to second-
ary prevention guidelines for specific recommen-
dations.82
INFORMATION FOR PATIENTS
Risk factor assessment of patients is essential in the
prevention of drug-induced stroke. Because many
of the drugs that are known to cause stroke are not
obtained by patients at pharmacies, it is extremely
important that patients at risk are counseled to
consult health care professionals before purchasing
nonprescription drug products. For example,
patients with hypertension should be advised that
cough and cold products or herbal products might
contain sympathomimetic drugs that could place
them at increased risk for drug-induced stroke.
Patients should be instructed to inform their
health professionals of all medications and herbal
products that they are taking, to facilitate a full
evaluation of potential agents that may be associ-
ated with drug-induced stroke. Since a large num-
ber of recreational drugs of abuse may cause stroke,
appropriate counseling on the risk of these agents
should be performed, and referral to rehabilitation
programs should be considered. In addition, all
patients should be counseled regarding the signs
and symptoms of ischemic stroke and risk factors,
and should be instructed to seek medical attention
at the onset of symptoms.
INTRACEREBRAL
HEMORRHAGE (ICH)
CAUSATIVE AGENTS
Drugs that have been reported to cause hemorrhag-
ic stroke are listed in Table 11–7.2-3,8,25,38,79,81,83-136
Many of the agents that are associated with ICH
are used as therapeutic agents for other disease
states. Symptomatic ICH is one of the most feared
complications associated with the use of rt-PA for
ischemic stroke and occurs in approximately 6% of
treated patients. It is estimated that for every 100
patients treated with rt-PA, 1 will experience severe
disability or death associated with symptomatic
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198 SECTION III • Drug-Induced Neurological Diseases

TABLE 11–7 Agents Implicated in Drug-Induced Intracerebral Hemorrhage

Drug Incidence Level of Evidence
(see page xii for explanation)

Thrombolytic agents for management of 0.46–1.9% A

acute myocardial infarction83,84
rt-PA for management of ischemic stroke79 6–9% A
Intraarterial thrombolytic agents (urokinase, rt-PA) for 10–15% A
management of stroke81,85
Warfarin86-92 0.3–1%/yr A
Heparin86,91,93 0.3% A
Cocaine2,3,8,94-95 NK B
Heavy alcohol use (>60 g/day)96-100 NK B
Amphetamines101 NK C
Nicotine102 Twofold to fourfold A
increased risk
Aspirin103,104 12 events/10,000 A
105
Aspirin + clopidogrel 0.4% /yr A
Ephedra-containing products (32mg/day)106-109,a NK B
25
Pseudoephedrine NK C
110-114
Phenylpropanolamine B
In dietary supplements NK
In cough and cold preparations NK
2,115
Heroin NK C
Nicotine116,117 NK C
118-121
Low-molecular-weight heparins NK A
122
Abciximab in ischemic stroke 5.5% B
123-125
Glycoprotein IIb/IIIa inhibitors B
With heparin 0.12%
Without heparin 0.07%
Herbal energy drinks (adaptogenic blend Eleutherococcus senticosus, NK C
Schisandra, Panax species)126
Selective serotonin reuptake inhibitor38,127-128 NK B
129-133
High-dose statin Relative risk 1.6 B
134-136,b
Drotrecogin alfa (activated) 3.5% B
NK = not known; rt-PA = recombinant tissue plasminogen activator.
a
Including the herbal source ma huang.
b
Reported in patients with severe sepsis presenting with purpura fulminans, meningitis, or meningococcal disease.

ICH.137 Most of the patients who experience this
devastating complication have more severe base-
line infarcts.137,138 Other risk factors for sympto-
matic ICH associated with rt-PA will be discussed
later in the chapter.
Warfarin is highly effective therapy for the pre-
vention of ischemic stroke among patients with
atrial fibrillation. Despite its proven efficacy, one
study found underutilization of warfarin, primarily
due to the perceived bleeding risk.139 An estimated
3,000 of the 60,000 ICH cases occurring annually
in the U.S. are caused by warfarin, with an associ-
ated mortality rate as high as 67%.90,105 Warfarin
increases the risk of progressive bleeding and sub-
sequent clinical deterioration in these patients.
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
2.0–4.5. The incidence of ICH increases by a factor
of 1.37 for each 0.5-unit increase in the INR.
Unfortunately, the prevalence of atrial fibrillation
is expected to triple by the year 2050, so the inci-
dence of warfarin-associated ICH is expected to
increase.90,105,140-141
Alcohol abuse remains an important risk factor
for ICH, with the risk related to the quantity con-
sumed. Consumption of 41–120 g is associated
with a 4.6 times higher risk of ICH as compared
with that in nondrinkers, and the risk is 11.3-fold
higher in those who consume 121 g or more.142
Other drugs of abuse have also been implicated in
causing ICH. Cocaine and other sympathomimet-
ics have been implicated in both ischemic stroke
and ICH.71
Both epidemiologic and clinical trials have
suggested that very low cholesterol concentrations
(total cholesterol <160 mg/dL) achieved with
high-dose statin therapy is associated with ICH.129-
133
It has been suggested that adequate plasma
cholesterol concentrations are necessary to main-
tain the integrity of the small vessels to prevent
rupture.143 In the Heart Protection Study, patients
who had a previous history of stroke or transient
ischemic attack showed a trend toward a higher
incidence of ICH after treatment with simvastatin
as compared with placebo.144 The Stroke
Prevention by Aggressive Reduction in Cholesterol
Levels (SPARCL) trial was the first study to specifi-
cally evaluate the effect of high-dose statin (ator-
vastatin) in patients with prior stroke or transient
ischemic attacks but without a history of coronary
artery disease or hypercholesterolemia. Patients
randomly assigned to atorvastatin had a higher
rate of ICH as compared with those who received
placebo (hazard ratio, 1.66; 95% confidence inter-
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
ICH, so it is reasonable to conclude that the
majority of patients with ischemic stroke are like-
ly to receive benefit from statin therapy. The effect
of cholesterol concentrations or the use of statins
and incidence of ICH is unclear; this observation
needs to be further evaluated in larger prospective
studies.
There are many drugs that may theoretically
increase the risk of hemorrhagic stroke, although,
for some, such an association has not been report-
ed in the literature. Direct thrombin inhibitors
such as hirudin or bivalirudin have not been
shown to increase the risk of hemorrhagic stroke in
clinical trials, and the risk of bleeding associated
with these drugs is lower than that associated with
CHAPTER 11 • Stroke 199
heparin.145 However, clinicians should be aware of
the possibility of ICH associated with these agents,
especially when used in combination with other
antiplatelet drugs such as the glycoprotein IIb/IIIa
receptor antagonists. Activated protein C
(drotrecogin alfa activated) promotes fibrinolysis
and inhibits thrombosis and inflammation and has
been associated with serious bleeding events in
clinical trials involving severe sepsis.135-136
However, these trials have not found an increased
intracranial bleeding rate. One analysis of four
clinical studies found a higher rate of ICH in
patients with severe sepsis presenting with purpu-
ra fulminans, meningitis, or meningococcal dis-
ease who received drotrecogin alfa.134 Intracranial
bleeding events have been reported in association
with glycoprotein IIb/IIIa receptor antagonists,
especially when used in combination with heparin,
and these events are associated with increased mor-
tality.123 The Abciximab in Emergency Treatment
of Stroke Trial (AbESTT-II), which was prematurely
halted, was designed to evaluate the impact of
abciximab on outcome following ischemic stroke.
This study found an increased rate of symptomatic
or fatal ICH, without improved efficacy, in patients
who were treated with abciximab.122 Conflicting
information has been reported regarding the risk of
bleeding complications associated with the use of
enoxaparin for the prevention of venous throm-
boembolism in patients undergoing neurosurgery,
but concern has been expressed regarding the use
of low-molecular-weight heparins in this popula-
tion.118-119 There has also been concern regarding
the risk of ICH associated with the use of non-
aspirin nonsteroidal antiinflammatory drugs
(NANSAIDs). However, one multicenter case–con-
trol study did not find an increase in the risk of
ICH associated with NANSAIDs.146
EPIDEMIOLOGY
Intracerebral hemorrhage is defined as bleeding
into the brain parenchyma with possible extension
into the ventricular system or subarachnoid space.
Approximately 37,000–52,000 people suffer from
ICH annually (approximately 8–13% of all strokes)
in the U.S.147 Although ICH accounts for only a
small proportion of all strokes, it is associated with
the highest mortality rate. Drug-related etiologies
can be identified in 14–27% of intracerebral hem-
orrhages.2,56 The incidence of drug-induced stroke
may be on the rise.2 Anticoagulant therapy is
implicated in about 10% of all cases of ICH. The
incidence of stroke associated with specific agents
is presented in Table 11–7.
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200 SECTION III • Drug-Induced Neurological Diseases
MECHANISMS
There are many proposed mechanisms for drug-
induced hemorrhagic strokes. Mechanisms by which
drugs result in intracerebral hemorrhage may be
multifactorial and are discussed below and presented
in Table 11–8.
Acute Hypertension
Acute hypertension is often an underrecognized
mechanism, particularly for drug-induced ICH.
The primary mechanism is related to the effects of
drugs on neurotransmitters. Many drugs increase
catecholamine release from central noradrenergic
nerve terminals (i.e., amphetamines, ephedra,
nonprescription sympathomimetics), inhibit
reuptake of catecholamines into adrenergic nerve
terminals (i.e., cocaine), or increase plasma cate-
cholamine concentrations (i.e., ethanol, cocaine).
Hypertension related to drug use may disrupt cere-
bral autoregulation, promote reperfusion of brain
tissue, or damage cerebral arterioles, which may
eventually rupture.
Ephedra products increase sympathomimetic
activity, leading to acute hypertension. In combi-
nation with caffeine, ephedrine 20 mg increases
systolic blood pressure by 14 mm Hg.148 Caffeine
acts by competitively antagonizing adenosine
receptors, thus inhibiting adenosine-mediated
dilatation, resulting in vasoconstriction. Caffeine
TABLE 11–8 Mechanisms of Drug-Induced Intracerebral Hemorrhage
Drug
Alcohol abuse
Ephedra
Pseudoephedrine
Phenylpropanolamine
Cocaine
Nicotine
Amphetamines
High-dose statin
Warfarin
Heparin
Low-molecular-weight heparin
Aspirin
Glycoprotein IIb/IIIa inhibitors
Thrombolytics
Selective serotonin reuptake inhibitors
also augments the release of catecholamines, aug-
menting the effects of ephedra.149-150 Cigarette
smoking acutely elevates blood pressure and
reduces cerebral blood flow.64-66 Alcohol acutely
and chronically increases blood pressure related to
increased adrenergic activity and increased plasma
concentrations of cortisol, renin, aldosterone, and
vasopressin.67-69
Bleeding Diathesis
The mechanism by which anticoagulants increase
the incidence of ICH is unclear. Anticoagulants
may cause spontaneous subclinical hemorrhages
that eventually become clinically significant.
Drugs that cause thrombocytopenia (platelet
count, <50,000⫻109/L), such as heparin, may
increase the risk for drug-induced ICH. Drugs that
cause severe hepatic failure or hepatitis may cause
derangements in clotting and a subsequent risk of
ICH. Cocaine and heroin may also result in an ill-
ness similar to autoimmune thrombocytopenic
purpura, which places patients at higher risk of
stroke. Selective serotonin reuptake inhibitors
(SSRIs) may place patients at increased risk of ICH
through antiplatelet effects.151 Serotonin concen-
tration in platelets is essential for the maintenance
of hemostatic functioning, and SSRIs may cause a
depletion of serotonin storage in platelets, leading
to attenuation of platelet activity.152 The
antiplatelet effects of SSRIs are considered to be
dose-dependent.127-128
Mechanism
Acute hypertension
Bleeding diathesis (including antiplatelet effects,
thrombocytopenia, or defects in coagulation system)
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CHAPTER 11 • Stroke 201

CLINICAL PRESENTATION AND TABLE 11–10 Conditions to Consider in the

DIFFERENTIAL DIAGNOSIS
It is not possible to distinguish an ischemic stroke
from ICH based on clinical examination alone,
although several characteristics are more indicative
of ICH, including headache, impaired level of con-
sciousness, nausea and vomiting, and extreme ele-
vations of blood pressure. Drug-induced
hemorrhagic stroke can occur at any time during
therapy with a potentially causative agent.
Common clinical features of drug-induced ICH are
presented in Table 11–9.
Drug-induced hemorrhagic stroke must be dis-
tinguished from stroke due to other etiologies.
Conditions to consider in the differential diagnosis
of drug-induced ICH are presented in Table 11–10.
It is difficult to distinguish between drug-induced
and non-drug-induced causes of stroke unless
symptoms are temporally related to the ingestion
of substances of abuse, specific drugs can be identi-
fied via quantification drug concentration (i.e.,
illicit-drug screen), or surrogate monitoring param-
eters associated with specific potentially causative
agents (e.g., warfarin or heparin) can be quantita-
tively assessed.
Differential Diagnosis of Drug-Induced
Intracerebral Hemorrhage
• Seizure
• Hemorrhagic conversion of ischemic infarct
• Trauma
• Ischemic stroke
• Arteriovenous malformation
• Cerebral aneurysm
• Hypertensive encephalopathy
• Central nervous system infection/brain abscess
• Arterial dissection
• Encephalitis
• Metabolic encephalopathy
• Intracranial tumors
• Thrombotic thrombocytopenic purpura
• Hemolytic–uremic syndrome
The diagnosis of hemorrhagic stroke consists of
a thorough evaluation of patient history, clinical
examination, laboratory evaluation, and imaging
studies, including CT scan, cerebral angiography,
and MRI. Laboratory studies should include serum
electrolyte and glucose concentrations, complete
blood count, coagulation parameters, and drug
screen evaluation. A CT scan is essential to differ-
entiate between ischemic and hemorrhagic stroke.

TABLE 11-9 Signs and Symptoms Associated with

Drug-Induced Intracerebral Hemorrhage
RISK FACTORS
Increased intracranial pressure Risk factors for drug-induced ICH are listed in
• Sudden headache Table 11–11. Thrombolysis has become a main-
• Nausea/vomiting stay of therapy for both acute myocardial infarc-
• Loss of consciousness tion and acute ischemic stroke. Although this
Lobar hemorrhage therapy improves morbidity and mortality in
• Seizure patients with these conditions, it inherently car-
• Aphasia ries the risk of ICH. Risk factors for ICH associat-
• Neglect ed with thrombolytic therapy following acute
• Hemianopia myocardial infarction include age > 65 years,
• Gaze deviation female sex, African-American ethnicity, systolic
• Contralateral sensory-motor deficits blood pressure ≥160 mm Hg, diastolic blood pres-
sure ≥100 mm Hg, previous stroke, recombinant
Brainstem hemorrhage
tissue plasminogen activator (r-tPA) dose >1.5
• Altered consciousness
mg/kg, and low body weight (< 65 kg).155 The risk
• Ataxia
of thrombolysis-related ICH in patients with
• Diplopia
acute ischemic stroke include NIH Stroke Scale
• Coma
score >20, age >70 years, thrombocytopenia, early
• Difficulty breathing
infarct signs on pretreatment CT scan, increased
• Disconjugate gaze
time to treatment, history of heart failure, serum
• Nystagmus
glucose >200 mg/dL, low plasminogen activator
• Dysmetria
inhibitor concentrations (< 21.4 ng/mL), history
TisdaleC011_190-210 1/12/10 2:35 PM Page 202

TABLE 11–11 Risk Factors for Drug-Induced Intracranial Hemorrhage

General Risk Factors
• Age >70 yr
• History of hypertension
• Amyloid angiopathy
• Cigarette smoking
• Sedentary lifestyle
• Coagulation disturbances
• Thrombocytopenia
Warfarin-Induced ICH153
• Age >85 yr
• Previous cerebral ischemic event
• Cerebral amyloid angiopathy
• Addition of aspirin
• Intensity of anticoagulation
• Duration of therapy
• History of bleeding
• Drug interactions
Thrombolytic-Induced ICH154
• Severity of neurologic deficit at time of presentation (measured by National Institutes of Health Stroke Scale score >20)
• Thrombolytic dose used for ischemic stroke
• Early signs of infarction with brain edema or mass effect on imaging studies
• Age >80 yr
• Hypertension
• Timing of revascularization therapy (i.e., longer stroke onset-to-treatment times)
• Hyperglycemia (glucose >200 mg/dL) or history of diabetes
• Coadministration of antithrombotic agents
• History of heart failure
• Thrombocytopenia
Aspirin-Induced ICH103
• History of stroke
• Hypertension
• Age >75 yr
• Black race
• Dose ≥ 650 mg/day
• Amyloid accumulation
• Epistaxis
• Concurrent anticoagulant use
• Neoplasm
• Vascular malformations or aneurysms
Low-Molecular-Weight Heparin and Glycoprotein IIb/IIIa Inhibitor–Induced ICH
• Kidney disease
• Age >75 yr
• Thrombocytopenia
Heparin-Induced ICH
• Hypertension
• Use of bolus dosing
• Thrombocytopenia
• Magnitude of stroke
Selective Serotonin Reuptake Inhibitor–Induced ICH38
• Heavy alcohol use
• Cigarette smoking
• Vulnerability to bleeding diathesis
High-Dose Statin–Induced ICH129,132
• Advanced age (each 10-yr increment in age increases risk)
• Stage 2 hypertension
• Middle age (in men)
• Previous ischemic stroke or transient ischemic attack
ICH = Intracranial hemorrhage
TisdaleC011_190-210 1/12/10 2:35 PM Page 203
of diabetes mellitus and cardiac disease, increas-
ing stroke severity, advancing age, use of
antiplatelet agents other than aspirin, elevated
pretreatment mean blood pressure, and lower
platelet counts.138,154 In addition, the use of r-tPA
in patients who do not meet the inclusion criteria
or meet exclusion criteria detailed in the National
Institutes of Neurological Diseases Study (espe-
cially administration of r-tPA to patients that
present >3 hours from the onset of symptoms) or
both increases the risk of ICH in patients with
acute ischemic stroke.156-157
Phenylpropanolamine was marketed in combi-
nation with caffeine as a weight-loss aid and was
banned by the FDA after the occurrence of numer-
ous cardiovascular and central nervous system
adverse events.112 Used in combination, these
drugs have an additive effect on blood pressure.158
Women between the ages of 18 and 49 years who
use phenylpropanolamine as an appetite suppres-
sant are 17 times more likely to experience an ICH
as compared with women of that age group who
do not take this medication.110 The risks associated
with cough and cold preparations are less clear.
The risks in men taking phenylpropanolamine are
also unclear, because the case–control study
included too few men from which to make conclu-
sions.112 The association between sympathomimet-
ic drugs and ICH appears to be dose-related and
additive when used in combination with other
agents with similar activity. ICH was three times
more likely to develop in patients receiving
phenylpropanolamine in cough and cold prod-
ucts.112,159 Herbal preparations that contain
ephedra or ma huang also increase the risk of ICH
in a dose-related fashion. The risk of ICH is four-
fold greater in patients receiving ephedra doses >32
mg/day.107-108,160 This is an important issue with
respect to counseling patients regarding the use of
nonprescription drugs or herbal supplements/ener-
gy drinks that may have sympathomimetic effects.
Anticoagulant therapy is used commonly to
treat many thromboembolic disorders, particularly
in the elderly population. Patients with an INR >3.0
or an activated partial thromboplastin time (aPTT)
>80–90 seconds are at increased risk of ICH associ-
ated with warfarin and heparin, respectively.
Factors that increase the risk of anticoagulant-relat-
ed ICH includes older age, level of anticoagulation,
prior stroke, and hypertenson.89,91,153 The risk for
ICH with warfarin therapy particularly increases at
ages ≥85 years. An INR <2.0 is not associated a with
lower risk of ICH as compared with an INR of
2.0–3.0, but the risk is increased with an INR >3.5,
which should be avoided.88,91,153 Therefore, for pre-
vention of recurrent ischemic stroke, anticoagula-
CHAPTER 11 • Stroke 203
tion management should focus on maintaining the
INR between 2.0 and 3.0.91 The risk of anticoagu-
lant-related bleeding is highest during the first
month of therapy.161 Other factors that increase the
risk of anticoagulant-induced ICH include atrial fib-
rillation, diabetes, concomitant use of antiplatelet
agents, amyloid angiopathy, fibrinoid degeneration
of arterioles, head trauma, acute alcohol intoxica-
tion, and migraine headaches.89 There is an
increased rate of cerebral bleeding associated with
intermittent intravenous heparin therapy as com-
pared with that associated with continuous intra-
venous infusion. Subcutaneous heparin is
associated with bleeding rates similar to those due
to continuous intravenous infusion.91,93 Increased
bleeding incidences (cerebral and noncerebral)
have been reported in patients who have an aPTT
that is prolonged to more than twice the upper
limit of the therapeutic range in at least 50% of the
tested samples. For every 10-second increase in the
aPTT, major bleeding complications increase by
7%.91
Patients with kidney disease (serum creatinine,
>2.0 mg/dL) are at greater risk of bleeding associat-
ed with low-molecular-heparins or glycoprotein
IIb/IIIa receptor antagonists than patients with
normal kidney function.162,163 Many of these
agents are excreted renally and may accumulate in
patients with kidney disease, and therefore dose
adjustments are necessary. Patients ≥75 years of age
have a higher rate of ICH after treatment with gly-
coprotein IIb/IIIa receptor antagonists.125
The use of aspirin for both primary and sec-
ondary prevention of vascular events, including
ischemic stroke, has been associated with increased
risk of ICH (relative risk, 1.35).103 Since significant
benefit is achieved with the use of aspirin, evalua-
tion of possible risk factors for ICH may assist in
assessing whether the risk exceeds the benefit. Risk
factors for ICH include age >75 years, African-
American race, hypertension, amyloid accumula-
tion, history of epistaxis, dose ⱖ650 mg/day,
bleeding disorders, and neoplasm.103
Use of combinations of agents, such as
antiplatelet drugs, anticoagulants, and throm-
bolytics, may provide additive beneficial effects in
patients with heart disease or stroke, but these
combinations also increase the risk of ICH.
Concomitant use of aspirin with warfarin or
heparin and glycoprotein IIb/IIIa antagonists is
associated with an increased incidence of bleed-
ing.91 The use of combinations of oral antiplatelet
agents for secondary prevention of stroke or acute
coronary syndromes has become a common prac-
tice. However, a study that evaluated the combina-
tion of aspirin and clopidogrel for prevention of
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204 SECTION III • Drug-Induced Neurological Diseases
recurrent stroke or transient ischemic attack
reported an absolute increased risk of life-threaten-
ing bleeding of 1.3%. The combination therapy
was not associated with a reduction in vascular
events, so the risks of the combination therapy
appeared to outweigh the benefits.164 In addition,
the Prevention Regimen for Effectively avoiding
Second Strokes (PRoFESS) trial showed similar
recurrent ischemic stroke rates with extended
release dipyridamole plus aspirin as compared with
clopidogrel. However, major bleeding events and
intracranial bleeds were more frequently observed
in those who received extended-release dipyri-
damole plus aspirin. The overall risk:benefit was
not significantly different between the two regi-
mens.165
MORBIDITY AND MORTALITY
ICH accounts for only a small percentage of all
stroke cases but is associated with the highest inci-
dence of mortality. Therefore, although the mortal-
ity rates associated with drug-induced ICH are
unknown, it is reasonable to assume that they may
be high.
PREVENTION
The most effective means of prevention of drug-
induced stroke is avoidance of agents known to be
associated with ICH, especially in high-risk
patients. Strategies for the prevention of drug-
induced stroke are listed in Table 11–12. Patients
receiving anticoagulant therapy should be closely
monitored for intensity of anticoagulation and the
possibility of drug interactions. Careful selection of
patients with ischemic stroke who receive intra-
venous rt-PA is also important. However, the main-
stay of prevention is patient education and
identification of risk factors, particularly in
patients who are at high risk.
MANAGEMENT
The treatment of any patient with ICH includes
many phases: prevention of additional ICH, sup-
portive and medical management during the acute
phase, measures to mitigate the ongoing patholog-
ic process, and rehabilitation. In addition, discon-
tinuation of the offending agent (if identified) is
essential.
All patients with acute drug-induced ICH
should be hospitalized, and most will require care
in an intensive care unit. Guidelines for the man-
agement of patients with ICH have been pub-
lished previously.166 Patients with ICH often
present with severe acute hypertension. There is
no consensus regarding the ideal target range for
blood pressure control. The decision regarding
the appropriate target lower blood pressure is a
balance between limiting an increase in
hematoma volume and preventing ischemic
changes. Surgical evacuation of the hematoma
may be necessary in some patients. General med-
ical management and supportive care are indicat-
ed in all patients to prevent complications (i.e.,
intracranial hypertension).
If ICH occurs in association with thrombolytic,
anticoagulant, or antiplatelet therapy, immediate
cessation of the causative agent is indicated, with
rapid reversal of the impaired clotting profile.
Patients with ICH who are receiving unfractionat-
ed heparin or low-molecular-weight heparin
should receive protamine sulfate (1 mg/100 units
of heparin or 1 mg of enoxaparin). The dose of pro-
tamine should be adjusted according to the time
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
60–120 minutes, the protamine dose should be
0.375–0.5 mg/100 units of heparin; finally, if the
heparin infusion is discontinued for more than 120
minutes, the protamine dose should be 0.25–0.375
mg/100 units of heparin. Protamine sulfate should
be administered intravenously over 10 minutes in
doses not to exceed 50 mg, because of the potential
risk of severe systemic hypotension.166 Patients
with bleeding caused by platelet dysfunction
should receive platelet transfusions (6 units)
and/or a single dose of desmopressin (0.3 mcg/kg).
For treatment of ICH related to thrombolysis, the
currently recommended therapy is platelet infu-
sion (6–8 units) and cryoprecipitate that contains
factor VIII.166
The clotting factor inhibition in patients who
are receiving warfarin and experiencing ICH
should be reversed immediately with fresh frozen
plasma (15 mL/kg) or prothrombin-complex con-
centrates (15–30 units/kg) and vitamin K (5–10
mg). Therapy should never be withheld to check
coagulation profiles because normalization of the
INR with some of these approaches may take sev-
eral hours. Administration of prothrombin-com-
plex concentrate normalizes the INR more
rapidly than fresh-frozen plasma and can be
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CHAPTER 11 • Stroke 205

TTABLE 11–12 Approaches to Help Prevent Drug-Induced Intracranial Hemorrhage

Drug Prevention
All agents Control of hypertension
Discontinue drugs known to be associated with stroke in patients at high risk
Antithrombotic therapy105 Assess risk benefit and monitor patients closely
Maintain INR <3.0
Control of hypertension
Caution in elderly patient who are at highest risk
Combination of aspirin and clopidogrel may accentuate ICH risk
Avoid combinations of warfarin with antiplatelet agents
Evaluate for potential drug interactions
Thrombolytic therapy Assess risk benefit and monitor patients closely
Follow recommended inclusion/exclusion selection criteria outlined in acute
ischemic stroke guidelines78
Substance abuse Cessation
Rehabilitation program
Cigarette smoking Encourage patient and family to stop smoking
Provide counseling, nicotine replacement, and formal programs
Alcohol Men should consume no more than 2 drinks/day and nonpregnant women should
consume no more than 1 drink/day
Control hypertension
ICH = Intracranial hemorrhage; INR = International normalized ratio

administered in smaller volumes, thus decreasing

the risk of heart failure exacerbation that may
occur in association with fresh-frozen plasma.
Some reports have described the use of recombi-
nant activated factor VII (rFVIIa) for rapid war-
farin reversal. A single intravenous dose of rFVIIa
(doses reported ranged from 10 to 90 mcg/kg)
normalized the INR within minutes, nearly four-
fold faster than fresh-frozen plasma and vitamin
K alone with only 50% of the volume of fresh
frozen plasma required.167,168 The use of rFVIIa
should be considered as adjuvant therapy to vita-
min K and coagulation factor replacement
because the effects with those agents only last for
several hours. A difficult decision after anticoag-
ulation-induced ICH is whether to reinitiate anti-
coagulant therapy. There are no strict guidelines
regarding the length of time to withhold antico-
agulation therapy. However, it is generally
accepted that warfarin should be discontinued
for a period of 7–10 days after ICH. The balance
between risk and benefit must be assessed in each
patient. It may not be appropriate to reinitiate
therapy in patients with severe disability but safe
to restart anticoagulation in a patient with ICH
with less severe disability due to a markedly ele-
vated INR.166
INFORMATION FOR PATIENTS
Risk factor assessment of patients and drug-profile
review for potential drug interactions is essential in
the prevention of drug-induced ICH. Since many of
the drugs that are known to cause ICH are not
obtained by patients at pharmacies, it is extremely
important that patients at risk are counseled to con-
sult their health care professionals before purchas-
ing nonprescription drugs or herbal products. For
example, patients with hypertension should be
advised that cough and cold products or herbal
products, including energy drinks may contain
sympathomimetic agents that could place them at
increased risk for drug-induced ICH. Patients receiv-
ing combinations of agents that are known to cause
stroke (such as warfarin and aspirin) should be
informed regarding the increased risk. Patients
should be instructed to inform their health care
professionals of all medications that they are tak-
ing, to facilitate a full evaluation of potential agents
that may be associated with drug-induced stroke. It
is important for patients to closely adhere to the
regimens prescribed, including scheduled laborato-
ry monitoring, in order to minimize the risk associ-
ated with the use of some of these agents.
TisdaleC011_190-210 1/12/10 2:35 PM Page 206
206 SECTION III • Drug-Induced Neurological Diseases
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140. Flaherty ML, Kissela B, Woo D, et al. The increasing
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141. Miyasaka Y, Barnes ME, Gersh BJ, et al. Secular trends in
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142. Juvela S, Hillbom M, Palomaki H. Risk factors for
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145. Weitz JI, Buller HR. Direct thrombin inhibitors in acute
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146. Choi NK, Park BJ, Jeong SW, et al. Nonaspirin
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148. Haller CA, Jacob P 3rd, Benowitz NL. Pharmacology
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150. Robertson D, Frolich JC, Carr RK, et al. Effects of caffeine
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TisdaleC012_211-235 1/12/10 2:36 PM Page 211
CHAPTER 12
Movement Disorders
I n the United States and across the globe, drug-
induced movement disorders are a significant
iatrogenic burden among selected patient popula-
tions,1 such as those receiving psychotropic agents
for psychiatric disorders or antiemetic drugs (e.g.,
droperidol, metoclopramide, prochlorperazine) for
gastrointestinal disorders. The term drug-induced
movement disorder (DIMD) refers to a variety of
distinct, treatment-emergent, involuntary move-
ments, including akathisia, tardive dyskinesia
(TDk), dystonia, and parkinsonism, which may
interfere with medication adherence, performance
of motor tasks, and psychosocial interactions. In
patients with psychiatric disorders, DIMDs are a sig-
nificant source of distress and discomfort resulting
in medication nonadherence or refusal, subsequent
relapse and rehospitalization, and increased use of
health care resources.2 In one study, patients with
schizophrenia or schizoaffective disorder in whom
antipsychotic-induced DIMD developed were 40
times more likely to discontinue maintenance med-
ication therapy.3 DIMDs are underrecognized iatro-
genic conditions. In one study, resident physicians
failed to detect or recognize more than 50% of cases
of TDk and drug-induced parkinsonism.4
The onset of DIMDs can be classified as acute,
subacute, or tardive. Acute DIMDs (e.g., acute
akathisia, acute dystonia) occur within hours to
days after exposure. Subacute DIMDs (e.g., parkin-
sonism) appear within weeks. Tardive (i.e., delayed
onset) DIMDs (e.g., tardive akathisia, TDk, tardive
dystonia) occur months to years after drug expo-
sure. Patients with DIMDs commonly present with
two or more coexistent movement disorders.5,6
Examples of DIMD combinations include TDk with
parkinsonism, TDk with tardive dystonia, and TDk
with akathisia.
Jack J. Chen and David M. Swope
Soon after the introduction of conventional
antipsychotics in the 1950s, it became obvious that
these agents were a cause of iatrogenic movement
disorders. These DIMDs were termed “extrapyrami-
dal symptoms or side effects” (EPS), which implies
the involvement of extrapyramidal regions (i.e.,
basal ganglia and thalamus) as opposed to the cor-
ticospinal pyramidal motor system. Subsequently,
as induction of EPS became viewed as a typical and
expected correlate to antipsychotic efficacy, the
term neuroleptic (“seize the nerves”) was coined.7
The introduction of clozapine, an antipsychotic
nearly devoid of EPS, in the late 1980s demonstrat-
ed that development of EPS was not a requisite for
antipsychotic efficacy, and thus the newer antipsy-
chotics are referred to as “atypical.” It is important
to note that the term EPS is not synonymous with
DIMDs. The former refers collectively to drug-
induced dystonia, parkinsonism, and TDk. Drug-
induced akathisa is considered a DIMD but not an
EPS.
It has been clearly established that atypical
antipsychotics are associated with a significantly
lower risk of DIMDs as compared with convention-
al neuroleptics (with or without concurrent
antimuscarinic prophylaxis).8-13 Among the atypi-
cal antipsychotics, clozapine and quetiapine are
associated with a very low risk of EPS, while arip-
iprazole is associated with moderate risk. The haz-
ard associated with these atypical agents appears to
be independent of dose. The risk of EPS associated
with iloperidone also appears to be very low.
Olanzapine and ziprasidone are associated with a
moderate risk of EPS, especially at higher doses
(e.g., olanzapine 20 mg daily). Among the atypical
antipsychotic agents, paliperidone and risperidone
are associated with the highest risk of dose-depend-
211
TisdaleC012_211-235 1/12/10 2:36 PM Page 212
212 SECTION III • Drug-Induced Neurological Diseases
ent EPS. Risperidone at doses >6 mg daily or
administered concurrently with cytochrome P-450
2D6 or 3A4 inhibitors, which can result in accumu-
lation of risperidone’s active moiety (9-hydrox-
yrisperidone or paliperidone), predispose to
occurrence of DIMDs. EPS induction occurs more
frequently at paliperidone doses >9 mg daily.
Movement disorders are also associated with
other psychotropic drugs, such as lithium, selective
serotonin reuptake inhibitors (SSRIs), psychostim-
ulants, and tricyclic antidepressants (TCAs).
Tremor commonly occurs with lithium treatment,
which also occasionally causes chorea.14 Treatment
with SSRIs may cause akathisia and tremor, but
rarely induces dyskinesia, dystonia, or parkinson-
ism.15,16 Psychostimulants (e.g., amphetamine,
methylphenidate, pemoline) have occasionally
been reported to produce a variety of movement
disorders such as dyskinesias, dystonia, stereotypic
behavior, and tics.17 The most common movement
disorders associated with TCAs are 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.
Carbamazepine, ethosuximide, felbamate, gaba-
pentin, phenobarbital, and phenytoin have rarely
been associated with dyskinesia or dystonic reac-
tions.20 For many years, chorea has been recog-
nized as a complication of estrogen- and pro-
gesterone-containing products (e.g., oral contra-
ceptives).21 Antiemetics that block central dopa-
mine receptors (i.e., droperidol, metoclopramide,
prochlorperazine) are also commonly implicated
in the various DIMDs.22-25
Drug-induced tremor, although not uncom-
mon, will not be discussed in this chapter, and
readers are referred elsewhere for further reading.26
Readers are also referred elsewhere for discussions
on drug-induced myoclonus (abrupt, brief, and
sudden “shock-like” involuntary movements), lev-
odopa-induced dyskinesias, neuroleptic malignant
syndrome, restless legs syndrome, and motor
tics.27-32 The primary topics that will be covered in
this chapter are drug-induced akathisias, tardive
dyskinesia, dystonias, and parkinsonism.
AKATHISIA (ACUTE AND TARDIVE)
The term akathisia is derived from Greek (“not sit-
ting still”), and was initially used at the turn of the
20th century to describe the restlessness and pac-
ing observed in patients diagnosed with hysteria
and neuroses. The term akathisia is now used
extensively to describe the restlessness and pacing
behavior induced by neuroleptics and other drugs.
Akathisia induced by psychotropic agents can be a
distressing adverse effect, resulting in poor treat-
ment adherence and, consequently, an increased
risk of relapse or exacerbation of the underlying
psychiatric disorder.
CAUSATIVE AGENTS
Agents implicated in drug-induced akathisia are
listed in Table 12–1.24,25,33-43 Conventional neu-
roleptics and antidopaminergic antiemetics are the
most commonly implicated drugs in acute and tar-
dive akathisia. Several atypical antipsychotics also
induce akathisia, albeit at lower rates as compared
with conventional neuroleptics. The SSRIs and the
serotonin–norepinephrine reuptake inhibitor mir-
tazapine are also commonly implicated in acute
akathisia, but rarely in tardive akathisia.
EPIDEMIOLOGY
Acute akathisia occurs in 8% to 76% of patients tak-
ing conventional neuroleptics.33,34 However, the
most consistently reported incidence of acute
akathisia associated with conventional neuroleptics
is 20% to 30%,35 and the incidence of tardive
akathisia is approximately 30%. The atypical
antipsychotics (i.e., aripiprazole, clozapine, iloperi-
done, olanzapine, paliperidone, quetiapine, risperi-
done, ziprasidone) also induce akathisia, although
the risk is lower than that associated with conven-
tional neuroleptics. In one study, the point preva-
lences of akathisia associated with clozapine,
risperidone, and conventional neuroleptics were
7.3%, 13%, and 23.8%, respectively.36 However, at
daily doses >6 mg, the frequency of risperidone-
induced akathisia increases significantly. The inci-
dence of akathisia in iloperidone-treated patients is
low and similar to that of placebo.37,38
Akathisia is also induced by SSRIs and TCAs.
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-
ulating SSRIs (e.g., fluoxetine, paroxetine).
Treatment-emergent anxiety, agitation, and restless-
ness are commonly reported in association with
antidepressants (especially within the first 2 weeks
of initiating treatment) and it is possible that a sub-
set of these patients are experiencing akathisia.
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CHAPTER 12 • Movement Disorders 213

TABLE 12-1 Agents Implicated in Drug-Induced Akathisia

Drug Incidence Level of Evidence
(see page xii for explanation)

ANTIEMETICS / GASTRIC MOTILITY AGENTS

Droperidol24 20-30% B
Metoclopramide24,25 20-30% B
Prochlorperazine24 20-30% B
ANTIEPILEPTICS
Carbamazepine40 NK C
PSYCHOTROPICS
Amoxapine41 NK C
Atypical antipsychoticsa,36-38 5-15% A
Conventional neurolepticsb,33-36 20-30% A
Lithium42 NK C
Selective serotonin-reuptake inhibitorsc,39 5% B
Tricyclic antidepressantsd,43 5% C
NK = not known
a = aripriprazole, olanzapine, paliperidone, risperidone, ziprasidone
b = chlorpromazine, fluphenazine, haloperidol, loxapine, molindone, perphenazine, thiothixene, thioridazine, trifluoperazine
c = citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline
d = amitriptyline, clomipramine, desipramine, doxepin, imipramine, nortriptyline

Akathisia also frequently occurs in association
with antidopaminergic antiemetics. In one study,
acute, transient akathisia occurred in 71.4%, 25%,
35.3%, and 11.1% of patients treated with droperi-
dol, metoclopramide, prochlorperazine, and place-
bo, respectively.24 Bolus intravenous infusion of
metoclopramide is associated with higher rates of
akathisa as compared with slow infusion.25
MECHANISMS
The pathophysiologic mechanism of drug-induced
acute akathisia is not well understood, but involves
altered dopaminergic and serotoninergic activity
(Table 12–2). This model is supported by the obser-
vation that akathisia is a well-recognized effect of
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
higher the incidence of akathisia.44 Serotoninergic
and noradrenergic input in the ventral tegmental
area exerts an inhibitory effect on mesocortical
dopamine transmission. This is supported by the
observation that akathisia may be caused by sero-
toninergic agents, such as SSRIs, and the positive
therapeutic response to 5-hydroxytryptophan
(serotonin) type 2 (5-HT2) receptor blockers (e.g.,
cyproheptadine) and the noradrenergic ␤-receptor
blocker propranolol (which also possess antisero-
tonergic activity). In addition, the atypical antipsy-
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-
pared to those of conventional neuroleptics. Iron
deficiency has been implicated as a component of
the pathophysiologic mechanism for akathisia, but
the data are inconsistent.45 The mechanism under-
lying the tardive form of akathisia is less well
understood, but is probably distinct from that of
acute akathisa.
CLINICAL PRESENTATION AND
DIFFERENTIAL DIAGNOSIS
According to the Diagnostic and Statistical Manual of
Mental Disorders (DSM-IV), neuroleptic-induced
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214 SECTION III • Drug-Induced Neurological Diseases
TABLE 12–2 Mechanisms of Drug-Induced Akathisia
Drug
Amoxapine
Atypical antipsychoticsa
Conventional neurolepticsb
Droperidol
Metoclopramide
Prochlorperazine
Promethazine
Selective serotonin reuptake inhibitorsc
Tricyclic antidepressantsd
Carbamazepine
Lithium
Reserpine
a
Aripiprazole, olanzapine, paliperidone, risperidone, ziprasidone
b
Chlorpromazine, fluphenazine, haloperidol, loxapine, molindone, perphenazine, thiothixene, thioridazine, trifluoperazine
c
Citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline
d
Amitriptyiline, clomipramine, desipramine, doxepin, imipramine, nortriptyline
akathisia is comprised of both a subjective and an
objective component.46 The core features are sub-
jective symptoms of restlessness (commonly refer-
able to the legs) and at least one of the following
objective findings: fidgety movements or leg
swinging while seated, marching on the spot while
standing, rocking from one foot to another, pacing
to relieve subjective restlessness, or an inability to
sit or stand still for several minutes (Table 12–3).
Subjective dysphoria is a major component of neu-
roleptic-induced akathisia and includes apprehen-
sion, an inner sense of restlessness (often in the
legs), anxiety, and the urge to move. Significant
mental distress is experienced if the patient is
asked to not move or is restrained from moving.
Drug-induced akathisia can easily be mistaken for
anxiety, psychotic agitation, or restless legs syn-
drome (Table 12–4). Unlike most movement disor-
ders, which are involuntary, the movements
associated with akathisia (e.g., fidgeting, leg or
body shifting, toe tapping, walking) are voluntary,
and occur in response to the subjective feeling of
restlessness or discomfort. As with other move-
ment disorders, anxiety or stress exacerbates preex-
isting akathisia.
Symptoms of acute akathisia may occur with-
in an hour (as with intravenously administered
antidopaminergic antiemetics) to within several
weeks of initiating or increasing the dose of the
offending drug, and may also develop after neu-
Mechanism
Postsynaptic blockade of dopamine type 2 receptors in the
mesocortical pathway
Stimulation of 5-hydroxytryptophan (serotonin) type 2
receptors in the ventral tegmental area, resulting in
hypofunction of the dopaminergic mesocortical pathway
Unknown
roleptic therapy cessation or dose reduction (i.e.,
withdrawal akathisia). Occasionally, the discon-
tinuation of therapy with a concurrent anti-
akathisia agent (e.g., propranolol) may unmask
akathisia. Although the temporal criteria for tar-
dive akathisia are debatable, an onset of symp-
toms after 3 months of stable drug therapy is
considered tardive. Tardive akathisia can also
occur several months after drug therapy discon-
tinuation or dose reduction. Concurrent symp-
toms of parkinsonism, TDk, dystonia, or tremor
are not uncommon.
Drug-induced akathisia may resemble agitation
and anxiety presenting as a component of a psy-
chiatric disorder or from drug withdrawal syn-
dromes. Acute drug-induced akathisia should be
suspected if symptoms develop soon after the initi-
ation of therapy with potentially causative drugs
and in the absence of other conditions associated
with restlessness. In contrast to restless legs syn-
drome, patients with akathisia may report
improvement when lying down or sleeping,
absence of lower extremity paresthesias, absence of
diurnal pattern, and absence of periodic leg move-
ments in sleep. Tardive akathisia may be suspected
in the absence of other conditions associated with
restlessness. The symptoms of tardive akathisia are
similar to those of acute akathisia, except that
patients with tardive akathisia tend to report less
distressing subjective symptoms and are able to
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CHAPTER 12 • Movement Disorders 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

suppress movements or remain still for longer peri-

ods. The Barnes Akathisia Rating Scale (BARS) may
be used for akathisia detection and assessment.46
The BARS is a clinician-rated assessment tool, com-
posed of four items, used to assess the presence and
severity of drug-induced akathisia. The BARS rates
both objective items (e.g., observed restlessness)
and subjective items (e.g., patients’ awareness of
restlessness and related distress), in addition to a
global clinical assessment of akathisia.
RISK FACTORS
Risk factors for drug-induced akathisia are not well
described, but include older age, concurrent affec-
tive disorder, cognitive impairment, female sex,
history of akathisia, iron deficiency,47 mental retar-
dation, presence of negative symptoms of schizo-
phrenia,35 use of high-dose neuroleptics,36 rapid
neuroleptic dose escalation, and use of high-poten-
cy neuroleptics (Table 12–5).
MORBIDITY AND MORTALITY
When left untreated, the symptoms of acute, drug-
induced akathisia may gradually subside or may
fluctuate over time. In some patients, acute
akathisia may become chronic and persist for
TisdaleC012_211-235 1/12/10 2:36 PM Page 216
216 SECTION III • Drug-Induced Neurological Diseases
TABLE 12–5 Risk Factors for Drug-Induced
Akathisia
• Advanced age
• Affective disorder
• Cognitive impairment
• Female sex
• High dose neuroleptic therapy
• High potency neuroleptic therapy
• History of akathisia
• Iron deficiency
• Mental retardation
• Presence of negative symptoms of schizophrenia
• Rapid neuroleptic dose escalation
months or years. Acute akathisia has been associat-
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
the underlying akathisia. Although tardive
akathisia may slowly remit upon drug discontinu-
ation, it often persists.
PREVENTION
Approaches to help prevent drug-induced akathisia
are summarized in Table 12–6. As with most drug-
induced adverse effects, prevention is very impor-
tant. Primary prevention aided by knowledge and
recognition of risk factors is a key factor for mini-
mizing the burden of akathisia. The necessity of
short- or long term use of potentially causative
agents should be carefully evaluated. If indicated,
the lowest effective dose should be used and
patients should undergo regular evaluations for
emergence of akathisia. Standardized titration of
doses of antipsychotic agents to avoid excessive
dose escalation and the use of atypical antipsy-
chotics are successful means of prevention.
Although iron deficiency has been associated with
acute and tardive akathisia, routine iron supple-
mentation as a preventive or treatment interven-
tion is not supported by the available evidence.51
However, it is reasonable to correct an underlying
iron deficiency or to administer oral iron supple-
mentation to patients with akathisia that is unre-
sponsive to standard measures. In patients at high
risk of akathisia (e.g., history of akathisia), concur-
rent administration of an antimuscarinic agent or
␤-blocker is reasonable.
TABLE 12–6 Approaches to Help Prevent Drug-
Induced Akathisia
Amoxapine, atypical antipsychotics, conventional neu-
roleptics, lithium, metoclopramide
• Use lowest effective dose,
• Use standardized dose titration to avoid excessive
dose escalation.
• Correct underlying iron deficiency .
• If high risk for akathisia (e.g., prior history of akathisia)
exists, concurrent administration of an antimuscarinic
agent or ␤-blocker is recommended.
Droperidol, prochlorperazine, promethazine, selective
serotonin reuptake inhibitors, tricyclic antidepressants
• Use lowest effective dose.
Carbamazepine, reserpine
• None known
MANAGEMENT
Early detection is a key factor in the probability of
eventual remission of drug-induced akathisia. If
treatment with an implicated agent has been
extended for 3 months or longer, the patient
should be periodically examined to determine the
presence of subjective and objective features of
akathisia. When akathisia is detected, several
management approaches can be initiated (Table
12–7).
For patients with acute akathisia, the
causative agent should be discontinued, if possi-
ble. For neuroleptic-treated patients, a switch to
an atypical antipsychotic or alternative agent
should be considered. In patients in whom
causative agents have been discontinued, the
akathisia may promptly resolve, only to be
replaced with increased agitation and anxiety.
Care should be taken to differentiate these symp-
toms from those of persistent akathisia.
Administration of a lipophilic ␤-blocker, such as
propranolol, is effective and well-tolerated.52 ␤2-
receptor inhibition appears to be crucial for effica-
cy, as ␤1-receptor selective agents are less
effective.53 However, a trial of a cardioselective,
␤1-receptor blocker is reasonable if ␤2-blockade is
undesirable. The hydrophilic ␤-blockers (e.g.,
atenolol, nadolol) do not appear to be effective. ␤-
blockers should be avoided in patients with a his-
tory of cardiac conduction blocks, orthostatic
hypotension, or reactive airway disease.
Administration of antimuscarinic agents (e.g.,
TisdaleC012_211-235 1/12/10 2:36 PM Page 217
TABLE 12–7 Management of Drug-Induced
Akathisia
• Discontinue or reduce dose of causative agent
• If due to neuroleptic, switch to an atypical antipsy-
chotic
• Trial of antimuscarinic agent or ␤-blocker (i.e. propra-
nolol)
• Miscellaneous other agents may be effective (amanta-
dine, benzodiazepine, clonidine, cyproheptadine,
mianserin, mirtazapine).
benztropine, diphenhydramine), benzodi-
azepines, or antiserotoninergic agents (cyprohep-
tadine) is also effective and may be preferable if
sedation is desired.52,54-56 However, these agents
should be used with caution in elderly patients
with cognitive impairment. Less commonly used
agents include amantadine, amitriptyline, cloni-
dine, mianserin, mirtazapine, and mild opioids
(e.g., codeine or propoxyphene).57-62
Treatment of drug-induced tardive akathisia is
difficult, as no pharmacologic intervention consis-
tently provides benefit. If possible, therapy with
the suspected agent should be discontinued, or
modification of therapy from a conventional neu-
roleptic to an atypical antipsychotic should be per-
formed. Antimuscarinic agents and ␤-blockers may
be considered. However, as compared with their
use in patients with acute akathisia, improvement
is less likely to occur.
INFORMATION FOR PATIENTS
Before initiating therapy with antipsychotic
agents, clinicians should inform patients regard-
ing the potential risk of DIMDs. It is important to
inform patients about the purpose of antipsychot-
ic treatment and the potential risk of movement
disorders, such as akathisia, and to document that
this counseling has been performed. Informed
consent is recommended by some clinicians, and
should be updated yearly or when there is a
change in antipsychotic therapy. The patient’s
family members or caregivers can play a role in
monitoring and reporting any abnormal move-
ments. Patients and caregivers should be educated
regarding the symptoms of akathisia and the
importance of timely reporting, because early
detection reduces the risk of irreversible abnormal
movements.
CHAPTER 12 • Movement Disorders 217
TARDIVE DYSKINESIA
CAUSATIVE AGENTS
Tardive dyskinesia is a persistent DIMD that devel-
ops after at least 1 month of treatment with
DRBAs. Agents implicated in TDk are listed in Table
12–8.9-13,23,63 The term tardive dyskinesias empha-
sizes the delayed or tardive onset of choreoa-
thetoid, stereotypic movements.
EPIDEMIOLOGY
Since the initial reports in the late 1950s and early
1960s, TDk has become one of the most recognized
DIMDs.64-66 In the early 1970s, product labeling for
all antipsychotic drugs was revised to include
information regarding TDk. Although symptoms
may initially be mild, many patients develop pro-
gressively severe TDk, resulting in meaningful dis-
ability. In a study of antipsychotic-naive patients
with first-episode schizophrenia, the incidence of
persistent TDk increased with longer duration of
treatment.67 The cumulative incidence of TDk was
4.8% after 1 year, 7.2% after 2 years, and 15.6%
after 4 years. Increasing antipsychotic drug dose
was associated with a modestly increased risk of
TDk, with each 100-mg chlorpromazine equivalent
unit increase associated with a 5% increase in the
risk of TDk. In the Hillside Hospital TDk study,
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
other prospective studies.12 The authors concluded
that, at the end of 5 years, approximately one in
four patients treated with neuroleptics were at risk
for TDk. It is important to note that peculiar, chor-
eiform orofacial movements were observed in
patients with schizophrenia before the advent of
conventional neuroleptic therapy and that dyski-
nesias may be an intrinsic motor feature of schizo-
phrenia.69 Although spontaneous dyskinesias
occur, the data provide strong evidence demon-
strating an increased incidence of TDk associated
with neuroleptic drug exposure.
The incidence of TDk associated with neu-
roleptic drug therapy has been extensively studied
and ranges from 0.5% to 70%.70,71 This range
reflects differences in diagnostic criteria, duration
of follow-up, sampled population, and study
design. Overall, TDk develops in approximately
20% to 30% of patients treated with conventional
TisdaleC012_211-235 1/12/10 2:36 PM Page 218
218 SECTION III • Drug-Induced Neurological Diseases
TABLE 12–8 Agents Implicated in Drug-Induced Tardive Dyskinesia
Drug
ANTIEMETICS/GASTRIC-MOTILITY AGENTS
Metoclopramide23
Prochlorperazine23
PSYCHOTROPICS
Amoxapine63
Atypical antipsychotics9-11,13
Conventional neuroleptics12,13
NK = not known.
neuroleptics.70,71 On the basis of studies in young
patients, estimates of incidence suggest that TDk
develops in about 5% of patients with each year of
neuroleptic exposure.72 The highest incidence and
prevalence of TDk appears to occur in the geropsy-
chiatric population. In a study of elderly psychi-
atric patients who had never previously received
neuroleptic agents, 35.4% had TDk during neu-
roleptic treatment.73 In a prospective study of pre-
viously neuroleptic-naive patients 55 years of age
or older, the cumulative incidence of TDk was
25%, 34%, and 53% after 1, 2, and 3 years, respec-
tively, of antipsychotic therapy.74 In another study
of middle-aged and elderly patients, the cumula-
tive incidence of neuroleptic-induced TDk was
26%, 52%, and 60% after 1, 2, and 3 years, respec-
tively.75
Neuroleptic-induced TDk is a class effect
among the conventional neuroleptics. Although
debatable, the risk appears to be similar for all
agents within the class regardless of formulation
(e.g., oral or depot). However, the risk of TDk is
lower in association with atypical antipsychotics,
regardless of prior neuroleptic exposure.9-13 In one
review of 11 long term studies that were pub-
lished between 1999 and 2002 (n > 2,700
patients), the atypical antipsychotics (olanzapine,
quetiapine, risperidone, ziprasidone) were associ-
ated with a mean annual incidence of new-onset
TDk of 0.8% in adults, as compared with 5.4%
treated with haloperidol.9 Despite the fact that
most patients had been exposed to conventional
neuroleptics before treatment with an atypical
antipsychotic, the incidence of TDk was lower
compared with that in haloperidol-treated
patients. In this study, the risk of TDk associated
with atypical antipsychotics was one-fifth that of
Incidence Level of Evidence
(see page xii for explanation)
12–40% B
NK C
NK C
5–15% A
20–30% A
conventional neuroleptics. A subsequent system-
atic review of 12 newer long term studies that
were published between 2004 and 2006 (n >
30,000 patients) confirmed that atypical antipsy-
chotics are associated with a significantly lower
incidence of TDk as compared with conventional
neuroleptics.10
Long term use of antidopaminergic antiemet-
ics or gastric-motility agents is also associated
with a significant risk of TDk. In one study of 434
patients diagnosed with TDk in a movement dis-
orders clinic, the causative agent was metoclo-
pramide in 39.4% of patients, followed by
prochlorperazine and promethazine in 11.8%
and 9.4% of patients, respectively.23 In 2009, the
Food and Drug Administration issued a mandate
that metoclopramide product labeling regarding
TDk must be strengthened to a “black box” warn-
ing.
MECHANISMS
The pathophysiologic basis of drug-induced TDk
remains speculative, but various neurochemical
hypotheses have been proposed, including stri-
atal dopaminergic hypersensitivity,76 cholinergic
deficiency within the basal ganglia,77 dysfunc-
tion of striatonigral ␥-aminobutyric acid
(GABA)-mediated neurons,78 glutamate-induced
excitotoxicity, and oxidative stress.79,80 Support
for some of these hypotheses is derived from
observations that antimuscarinic agents worsen
TDk, whereas agents with GABAergic, antigluta-
matergic, and antioxidant activity suppress TDk.
Other mechanistic factors may include attenua-
tion of nitric oxide–mediated neuromodulation
TisdaleC012_211-235 1/12/10 2:36 PM Page 219
in the striatum,81 genetic polymorphisms of
dopamine and serotonin receptor genes,82-85 and
neuroleptic-induced neuronal apoptosis. 86 Ex
vivo data from animal models of TDk suggest
that presynaptic areas such as the substantia
nigra are involved.87 The most popular mecha-
nistic hypothesis for TDk involves long term
blockade of striatal dopamine D2 receptors
resulting in receptor upregulation and hypersen-
sitization. A postmortem study in neuroleptic-
treated patients with schizophrenia was unable
to detect significant differences in striatal
dopamine D1 or D2 receptors between patients
with and those without TDk.88 However, an in
vivo study using radioligand positron-emission
tomography demonstrated that patients with
the highest degree of dopamine D2 receptor
upregulation had severe TDk.89 Within the stria-
tum, GABA and glutamate are the major neuro-
transmitters that modulate the motor circuit.
Evidence suggests that GABA deficiency
enhances dyskinesia and excess glutamate is
implicated in neuronal toxicity. Given that sev-
eral hypotheses are plausible, the pathophysiol-
ogy of TDk most likely involves multiple
mechanisms and events. A unifying hypothesis
can be proposed: use of DRBAs results in
increased dopamine turnover followed by excess
free radical production and subsequent damage
to striatal GABAergic fibers and reduced
inhibitory activity on motor circuits.
Concurrently, long term blockade of dopamine
receptors results in excessive glutamate activity
and resultant excitotoxicity. Likewise, long term
dopamine receptor blockade results in receptor
supersensitivity and persistent changes within
the basal ganglia motor circuit.
CLINICAL PRESENTATION AND
DIFFERENTIAL DIAGNOSIS
Symptoms of drug-induced TDk are characterized
by a combination of involuntary choreiform
(rapid, jerky, nonrepetitive), athetoid (slow, sinu-
ous, writhing), and stereotypic (rhythmic, repeti-
tive) movements (Table 12–3). Regions of the
mouth and face (i.e., oral, buccal, lingual, mastica-
tory) are most commonly affected, followed by
upper and lower limbs. Choreiform movements
commonly affect the proximal muscles, whereas
athetoid movements affect the distal muscles.
Frequently, TDk occurs in the presence of other
movement disorders such as akathisia, dystonia, or
CHAPTER 12 • Movement Disorders 219
parkinsonism. The onset of drug-induced TDk is
insidious, and symptoms are initially mild and
often unnoticeable to patients. The vast majority
of TDk cases are associated with antipsychotic
treatment. Patients receiving long term metoclo-
pramide or phenothiazine antiemetic treatment
are also at risk for TDk. Rarely, TDk may occur in
association with other agents, such as antiepilep-
tics, lithium, oral contraceptives, and SSRIs. If the
offending drug is not discontinued, remission of
TDk is rare. Occasionally, TDk may also occur after
discontinuation of long term DRBA treatment.
This is reported most commonly in children90 but
in one study, 34% of adult patients with no prior
evidence of TDk in whom neuroleptic therapy was
withdrawn developed emergent dyskinesia within
3 weeks.72 In general, withdrawal dyskinesia
improves within 3 months. Also, latent TDk may
be “unmasked” during a reduction in neuroleptic
dose and during a switch to an atypical antipsy-
chotic.
When assessing a patient presenting with
TDk symptoms, the clinician should keep in
mind that orofacial dyskinesias can be a feature
of several other conditions, including
Huntington’s disease, hyperthyroidism, lev-
odopa-induced dyskinesias, neuroacanthocytosis
(choreoacanthocytosis), Sydenham’s chorea, and
Wilson’s disease (Table 12–4). In addition, orofa-
cial dyskinetic-like movements may be observed
in edentulous individuals as well as patients with
schizophrenia who are DRBA-naive.91,92 In one
large study of over 2,000 subjects, spontaneous
dyskinesia was reported in 1.3% of healthy elder-
ly individuals, 4.8% of medical geriatric inpa-
tients, and up to 2% of neuroleptic-naive
psychiatric patients.72
The diagnosis of drug-induced TDk is straight-
forward in most cases. For assessment purposes,
the Abnormal Involuntary Movement Scale (AIMS)
developed by the National Institute of Mental
Health is commonly used, particularly in the psy-
chiatric field.93 The AIMS rates dyskinetic move-
ments in seven body regions and includes
assessments for global severity, functional impair-
ment, and self-awareness of symptoms. Orofacial
features include involuntary blinking, chewing
and lower jaw movements, grimacing, lip pucker-
ing and smacking, tongue protrusion and twisting,
and facial tic-like movements. Many patients also
experience concurrent choreoathetoid or stereo-
typic movements of the feet, hands, limbs, trunk,
head, and neck. Movements of the fingers may
appear as though the patient is playing an invisible
guitar or piano. Occasionally, patients exhibit
TisdaleC012_211-235 1/12/10 2:36 PM Page 220
220 SECTION III • Drug-Induced Neurological Diseases
pelvic rocking or “copulatory dyskinesia” and
grunting or moaning due to respiratory and pha-
ryngeal dyskinesia.94 Factors associated with exac-
erbation of TDk symptoms include administration
of antimuscarinics or sympathomimetic stimulants
and emotional extremes. Symptoms of TDk can be
suppressed for brief periods. Distraction during vol-
untary movements of unaffected body parts (e.g.,
finger-tapping test) or during performance of men-
tal tasks (e.g., arithmetic) unmasks latent dyskine-
sia in other body parts. As with most dyskinesias,
symptoms subside during sleep and, in mild cases,
patients may be unaware of the movements.
Rabbit syndrome is a rare and peculiar subacute
EPS that involves a slow, rhythmic, vertical-only
tremor of the perioral region that resembles the
chewing motions of a rabbit. Rabbit syndrome is
very specific to the buccal region only and differs
from orofacial TDk in that tongue involvement is
absent. Rabbit syndrome is associated predomi-
nantly with neuroleptics, with a incidence ranging
from 2.3% to 4.4%.95 Some clinicians consider rab-
bit syndrome to be a form of drug-induced parkin-
sonism.
RISK FACTORS
In general, if patients do not have TDk during the
initial 5 years of neuroleptic treatment, the risk of
TDk developing during later years of therapy is
reduced. Risk factors for the development of TDk
include older age, 96,97 affective symptomatol-
ogy,98,99 alcoholism or substance-use disorder,100
concomitant anticholinergic use,97,100 conven-
tional (as opposed to atypical) neuroleptic
use,97,101 daily drug dose,67,102 diabetes melli-
tus,103,104 duration of treatment,67,101 previous
electroconvulsive treatment,74 female sex, history
of EPS,101,105 intermittent (as opposed to continu-
ous) neuroleptic treatment,106 iron deficiency,107
mental retardation,108 and organic brain disor-
der109 (Table 12–9). Older age is a well-established
risk factor. The risk of TDk is at least five times
greater in elderly patients as compared with that
in young individuals.110 Not only is TDk more
common in the elderly, but TDk also tends to be
more severe and irreversible in this age group. If
multiple risk factors are present, an additive effect
on risk potential is observed. For example, elderly
women are very susceptible to TDk. Interestingly,
diabetes has been associated as a risk factor for
TDk in patients with schizophrenia. 103,104
Diabetics treated with metoclopramide are also at
increased risk of TDk, as compared with metoclo-
TABLE 12–9 Risk Factors for Drug-Induced
Tardive Dyskinesia
• Advanced age
• Affective symptomatology
• Alcoholism or substance abuse disorder
• Anticholinergic use
• Daily neuroleptic dose
• Diabetes mellitus
• Duration of neuroleptic treatment
• Female sex
• History of electroconvulsive therapy
• History of extrapyramidal symptoms
• Intermittent neuroleptic treatment
• Iron deficiency
• Mental retardation
• Organic brain disorder
pramide-treated nondiabetic patients. 111
However, although some atypical antipsychotics
may induce glucose intolerance and diabetes mel-
litus, the overall risk of TDk remains low as com-
pared with that of conventional neuroleptics. The
presence of an affective disorder has also been
implicated as a risk factor for TDk, although sup-
portive data are equivocal.112,113
MORBIDITY AND MORTALITY
Once TDk develops, remission rates are low if ther-
apy with the antipsychotic drug is continued. In
one study, only 11% of patients improved over the
course of 5 years with continued therapy.114 If
treatment is discontinued upon early detection,
remission rates are favorable, especially in the
younger population, but complete remission may
require several months to years. However, discon-
tinuation of antipsychotic therapy for the purpose
of treating TDk is associated with risks, primarily
psychotic decompensation. Mild cases of TDk are
often associated with social impairment such as
employment difficulties, social isolation, and stig-
ma. Anxiety and stress further exacerbate symp-
toms. In more severe cases, functional impairment
occurs. Patients experience difficulties with chew-
ing, speaking, and swallowing. Orofacial dyskine-
sias may also result in dental problems, denture
displacement, and damage to the soft tissues with-
in the oral cavity. Gait abnormality associated with
lower-extremity dyskinesia may result in falls and
injury.
TisdaleC012_211-235 1/12/10 2:36 PM Page 221
PREVENTION
Approaches to help prevent drug-induced TdK are
summarized in Table 12–10. Primary prevention
aided by knowledge and recognition of risk factors
is key to minimizing the burden of TDk. The neces-
sity for long term therapy with DRBAs such as con-
ventional neuroleptics, metoclopramide, and
antidopaminergic antiemetics should be carefully
evaluated. Standardized titration to avoid excessive
dose escalation and the use of atypical antipsy-
chotics, rather than conventional antipsychotics,
are successful means of prevention. Other strate-
gies include use of lowest effective DRBA dose and
eliminating unnecessary, prolonged drug therapy.
Although the use of intermittent antipsychotic
treatment (or drug holidays), as compared with
continuous treatment, may seem like a logical
strategy for reducing TDk risk, it is actually associ-
ated with an increased risk of TDk and higher rates
of psychosis relapse and rehospitalization.106,115
The American Psychiatric Association has pub-
lished specific indications for short and long term
antipsychotic drug treatment.116
MANAGEMENT
Early detection of drug-induced TDk is impera-
tive, as remission rates are inversely correlated
TABLE 12–10 Approaches to Help Prevent Drug-
Induced Tardive Dyskinesia
Amoxapine, metoclopramide, prochlorperazine
• Carefully evaluate the necessity for long term admin-
istration.
• Avoid unnecessary, prolonged drug therapy.
Atypical antipsychotics
• Carefully evaluate the necessity for long term admin-
istration.
• Use standardized dose titration to avoid excessive
dose escalation.
• Use lowest effective dose.
Conventional neuroleptics
• Carefully evaluate the necessity for long term admin-
istration.
• Use standardized dose titration to avoid excessive
dose escalation.
• Use lowest effective dose.
• Consider use of atypical antipsychotic agent.
CHAPTER 12 • Movement Disorders 221
with duration and severity of TDk. For patients
with dyskinesias induced by non-DRBAs (e.g.,
antiepileptics, lithium, oral contraceptives,
SSRIs), the movements generally reverse or
improve within weeks after discontinuation of
the offending drug. For neuroleptic-induced TDk,
the movements may improve (generally within
weeks) in up to 50% of patients after discontinu-
ation of the causative agent. Thus, routine assess-
ment for TDk (approximately every 3 months) is
recommended. Management approaches for drug-
induced TDk are summarized in Table 12–11. A
meta-analysis of evidence from more than 500
randomized, controlled trials evaluating over 90
different interventions117 identified no definitive
information regarding the optimal manner in
which to treat drug-induced TDk. Given the lack
of strong evidence, emphasis should be placed on
primary prevention, prompt recognition, and
management of early and potentially reversible
causes of TDk.
In the 1960s and 1970s, the most common
method of suppressing symptoms of TDk was to
continue therapy with neuroleptics.118 However,
with the advent of atypical antipsychotic agents,
continuation of conventional neuroleptic thera-
py is now considered inappropriate. Strategies
for treatment of drug-induced TDk vary, and
include drug discontinuation, switching to or
initiating therapy with an atypical antipsychot-
ic, 119 discontinuing anticholinergic agents
(except in patients with tardive dystonia), and
initiating treatment with adjunctive vitamin E
or benzodiazepines. Anxiety often exacerbates
TDk and should be treated appropriately.
Discontinuation of therapy with DRBAs may
result in noticeable improvement or remission,
TABLE 12–11 Management of Drug-Induced
Tardive Dyskinesia
• Discontinue or reduce dose of causative agent.
• Discontinue concurrent antimuscarinic agents.
• If due to neuroleptic, switch to an atypical antipsy-
chotic.
• Use tetrabenazine
• Use botulinum toxin for focal dyskinesias.
• Miscellaneous agents (amantadine, baclofen,
branched-chain amino acids, donepezil, gabapentin,
levetiracetam, melatonin, ondansetron, pregabalin,
verapamil, vitamin B6, vitamin E) may be used.
• Use deep brain stimulation (subthalamic nucleus,
globus pallidus).
TisdaleC012_211-235 1/12/10 2:36 PM Page 222
222 SECTION III • Drug-Induced Neurological Diseases
particularly if TDk is recognized early. However,
complete and long-lasting resolution is uncom-
mon. 120 The most consistent predictor of
improvement after discontinuation of neurolep-
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
TDk and the elderly. In patients on stable neu-
roleptic maintenance therapy, a modification to
a low or intermittent dose regimen may occa-
sionally provide relief, but is associated with a
risk of relapse and potential exacerbation of
TDk. Modifying therapy to an atypical antipsy-
chotic often results in significant improvement,
and is the most appropriate approach if mainte-
nance antipsychotic treatment is indicated for
an underlying psychiatric disorder. Increasing
the neuroleptic dose may suppress the dyskine-
sias but, with the advent of atypical antipsy-
chotics, is considered inappropriate. For mild
cases of drug-induced TDk, therapy with benzo-
diazepines may be helpful, and may also reduce
concomitant anxiety. Vitamin E 1,600 IU daily
has also been found to be effective, particularly
in patients with mild TDk for a duration of less
than 5 years.121,122 Dopamine-depleting drugs,
such as reserpine and tetrabenazine, are also
effective. In young patients, tetrabenazine tends
to induce depression, whereas older patients
tend to experience parkinsonism. The use of
reserpine for TDk is limited by the development
of depression and dose-related hypotension.
Trials of several other agents, including amanta-
dine, baclofen, branched-chain amino acids, cal-
cium-channel blockers (e.g., verapamil),
donepezil, gabapentin, levetiracetam, mela-
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
a pallidotomy may be considered.123,124
Occasionally, discontinuation of DRBA thera-
py results in emergence of dyskinesia (i.e., with-
drawal dyskinesia), particularly if therapy with
the DRBA is withdrawn abruptly. Withdrawal
dyskinesias are generally self-limiting within 3
months. In general, reintroduction of the
causative agent followed by a slow taper alleviates
the dyskinesias.
Treatment of rabbit syndrome involves reduc-
tion of the neuroleptic dose as much as possible.
However, in most cases, complete discontinuation
of neuroleptic therapy may not be possible because
of the risk of relapse or worsening of the underly-
ing psychiatric condition. Therapy with an
antimuscarinic agent may be attempted. This con-
trasts with orofacial TDk, for which addition of an
antimuscarinic agent tends to exacerbate the
movements.
INFORMATION FOR PATIENTS
Before initiating therapy with antipsychotics,
clinicians should inform patients about the
potential risk of TDk. 125 It is important to
inform patients about the purpose of antipsy-
chotic treatment and the potential risk of TDk
and to document that this counseling has been
performed. Some clinicians believe that such
discussion concerning the risk of TDk should
occur after the patient’s acute psychiatric condi-
tion has been stabilized, and at the time that
treatment for longer than 3 months is being
considered.126 Informed consent is recommend-
ed and should be updated yearly or when there
is a change in antipsychotic medication.127 The
benefits and need for long term treatment with
antipsychotics should be discussed, and patients
should be informed that long term treatment
can result in TDk, especially with the conven-
tional neuroleptics. Patients should under-
stand that movement disorders may also occur
in association with the atypical antipsychotics,
but are much less common. Patients should also
understand that early detection of any antipsy-
chotic movement disorder is important and
reduces the risk of irreversible abnormal move-
ments. The patient’s family members or care-
givers can play a role in monitoring and
reporting any abnormal movements.
DYSTONIA (ACUTE AND TARDIVE)
CAUSATIVE AGENTS
Agents implicated in drug-induced dystonia are
listed in Table 12–12.11,13,36,128-132,134-137
EPIDEMIOLOGY
The reported incidence of drug-induced acute dys-
tonia (DIAD) varies widely, from 2% to 94% of
patients treated with conventional neuroleptics.128-
130
This variance may be attributed to the study
method, the study setting (e.g., inpatient or outpa-
tient), and the characteristics of the study popula-
TisdaleC012_211-235 1/12/10 2:36 PM Page 223
TABLE 12–12 Agents Implicated in Drug-Induced Dystonia
Drug
ANTIEMETICS/GASTRIC-MOTILITY AGENTS
Metoclopramide132
Prochlorperazine131
PSYCHOTROPICS
Atypical antipsychotics11,13,36
Conventional neuroleptics13,36,128-130,134-137
tion, including age, concurrent use of antimus-
carinic agents, and type of neuroleptic agent.
Other DRBAs (e.g., metoclopramide, prochlorper-
azine) are also associated with DIAD.131,132 A
prospective study of neuroleptic-treated psychi-
atric patients reported a prevalence of acute dysto-
nia of 8.5% in those not receiving concurrent
therapy with antimuscarinic agents.133 The preva-
lence of acute dystonia was lower (2.8%) in
patients concurrently taking an antimuscarinic
drug. In the same study, DIAD was more common-
ly associated with butyrophenone antipsychotics
(e.g., haloperidol) as compared with phenothiazine
antipsychotics (e.g., chlorpromazine). In an analy-
sis of pooled data from nine studies, the overall
incidence of antipsychotic-induced acute dystonia
in patients not receiving antimuscarinic prophy-
laxis was 14.8%.134 However, in patients receiving
high-potency neuroleptics (e.g., haloperidol), the
incidence was 51.2%. One retrospective study of
159 patients found the incidence of neuroleptic-
induced dystonia to be 15.7%.135 Another retro-
spective study reported an incidence of 31% in
young patients.136 A prospective, 14-day study
reported a 33% rate of acute dystonia associated
with haloperidol treatment in young inpatients
with psychosis not receiving concurrent therapy
with antimuscarinic agents.137
Tardive dystonia is distinct from TDk,
although the two often coexist. Originally
termed “dystonia tarda,” tardive dystonia is
defined as an involuntary movement predomi-
nated by dystonia and associated with the use of
a DRBA.138,139 Tardive dystonia occurs in approx-
imately 2% to 4% of patients treated with con-
ventional neuroleptics.140,141 However, the true
incidence may be much greater. In one study of
inpatient veterans receiving long term neurolep-
tic treatment, the prevalence of tardive dystonia
was 21.6%.142
CHAPTER 12 • Movement Disorders 223
Incidence Level of Evidence
(see page xii for explanation)
1–5% B
1–5% B
1–5% A
1–50% A
MECHANISMS
The mechanisms of acute and tardive dystonias are
unclear. Dopaminergic hypofunction within the
basal ganglia with subsequent overactivity of the
cholinergic system has been proposed, and this
hypothesis is supported by the antidystonia activi-
ty of antimuscarinic agents. A contrasting hypoth-
esis implicates striatal dopaminergic hyperactivity.
In addition, other neurotransmitter systems such
as GABA and serotonin may also contribute.
CLINICAL PRESENTATION AND
DIFFERENTIAL DIAGNOSIS
The onset of DIAD is sudden and occurs within
hours to several days of the initiation of therapy
with DRBAs or, less commonly, after an increase
in the dose of the DRBA or a reduction in the
dose of a concomitant antimuscarinic agent. The
risk of DIAD appears to be greater in younger
patients and in those receiving DRBAs via the
parenteral route. Symptoms include sustained
muscular contractions or spasms that result in
abnormal fixed postures or positions of the jaw,
neck, shoulders, trunk, and extremities (Table
12–3). The severity of symptoms and anatomic
distribution varies, but the classic clinical presen-
tation is characterized by the three O’s: oculo-
gyric crisis (conjugate deviation of the eyes
upward or laterally), opisthotonos or extensor
axial dystonia (involuntary posturing in which
the head, neck, and spine are arched backward),
and oromandibular dystonia (forceful contrac-
tions of the jaw causing difficulty in opening or
closing the mouth). Blepharospasm (involuntary
eyelid closure), trismus (jaw-closing dystonia),
TisdaleC012_211-235 1/12/10 2:36 PM Page 224
224 SECTION III • Drug-Induced Neurological Diseases
laryngeal spasm, tongue protrusion, and respira-
tory stridor may be also be present. Symptoms
are usually painful and can interfere with walk-
ing, breathing, speaking, swallowing, and seeing.
In severe cases (e.g., laryngeal spasm), DIAD may
be life-threatening. Rhabdomyolysis due to sus-
tained muscle contraction may also occur. The
occurrence of acute dystonia is not only painful
and frightening to the patient but the bizarre
posturing may be mistaken for hysterical conver-
sion by observers. If acute dystonia occurs in the
presence of fever, generalized rigidity, altered
level of consciousness, and autonomic instabili-
ty, a diagnosis of neuroleptic malignant syn-
drome should be considered (Table 12–4).
Dystonia may also resemble catatonia because of
the underlying psychiatric disorder. However, in
contrast to catatonic patients, those in whom
dystonia develops report anxiety and discomfort
and seek treatment. Because of the discomfort
associated with DIAD, patients are at higher risk
for medication nonadherence.
Tardive dystonia develops after months to
years during treatment with a DRBA or within 3
months after discontinuation of therapy, and
often coexists with TDk. Remission of tardive
dystonia is uncommon. DRBAs are most com-
monly implicated in tardive dystonia. SSRIs have
been rarely implicated.16 In general, the diagno-
sis of tardive dystonia can be made based on the
presence of persistent dystonia (for longer than
1 month), a documented history of DRBA use,
and the absence of a general medical or neuro-
logic condition that may account for dystonia
(e.g., genetic forms of dystonia, stiff person syn-
drome). In contrast to DIAD, symptoms of tar-
dive dystonia develop insidiously over weeks to
months. Symptoms may or may not be painful
and can be isolated to one body part (e.g., jaw,
cervical area) or may spread to contiguous body
parts (segmental dystonia) or even generalize to
multiple body parts. Patients often report that
anxiety and stress transiently exacerbate symp-
toms, resulting in daily variations of symptoma-
tology. The clinical presentation of tardive
dystonia resembles that of an idiopathic focal,
segmental, or generalized dystonia. Cervical tar-
dive dystonia resembles that of idiopathic cervi-
cal dystonia. In patients with cervical dystonia,
the neck muscles contract involuntarily and sus-
tained contractions cause abnormal head and
neck posturing (Figure 12–1), whereas periodic
muscular spasms cause jerky head movements
that may resemble head tremors. The abnormal
posturing may vary from mild to severe, pain
FIGURE 12–1 Cervical dystonia. Upper left: rotational;
upper right: retrocollis; lower right: anterocollis; lower left:
laterocollis.
may or may not be present, and a dystonic head
tremor may be present. The concurrent presence
of oromandibular dystonia with blepharospasm
resembles Meige’s syndrome. Blepharospasm
affects both eyelids and should not be mistaken
for hemifacial spasm, which is a peripheral nerve
disorder that is generally unilateral and involves
twitching or myoclonic spasms affecting the eye-
lids, cheeks, and mouth regions. Tardive oro-
mandibular dystonia is associated with
persistent difficulty in opening or closing the
mouth and affects chewing, speech, and swal-
lowing. Bruxism may also accompany jaw-clos-
ing dystonia.
Pisa syndrome is a form of axial dystonia
that is most commonly associated with neu-
roleptic treatment and is characterized by sus-
tained truncal lateroflexion. 143 Drug-induced
Pisa syndrome is more common in elderly
patients, females, those receiving combination
antipsychotics, or patients who have organic
brain pathology (e.g., dementia).144 The onset of
Pisa syndrome may be acute or tardive.
Treatment consists of administering antimus-
carinic agents and discontinuing or reducing
daily doses of the causative agent. As with tar-
dive dystonia, Pisa syndrome responds more
favorably to antimuscarinic treatment than TDk.
However, unlike tardive dystonia, symptoms of
Pisa syndrome generally abate after discontinua-
tion of therapy with the causative agent. Thus,
Pisa syndrome may be considered an atypical
TisdaleC012_211-235 1/12/10 2:36 PM Page 225
subtype of tardive dystonia. Rarely, patients with
tardive dystonia may experience “status dyston-
icus,” a life-threatening condition associated
with severe dystonic spasms resulting in rhab-
domyolysis, myoglobinuria, and kidney failure.
In addition to idiopathic dystonia, other con-
ditions, such as atlantoaxial rotary subluxation,
conversion reaction, dopa-responsive dystonia,
inherited dystonias (e.g., DYT1), Huntington’s
disease, and Wilson’s disease must be ruled out
(Table 12–4). Other conditions that cause a twist-
ed neck, such as orthopedic or congenital prob-
lems of the neck, ophthalmologic conditions
resulting in head tilt to compensate for double
vision, stiff neck, arthritis, or wry neck should
also be considered.
RISK FACTORS
Risk factors for the development of acute dysto-
nia include young age,136 previous electroconvul-
sive therapy, male sex, mental retardation, and
use of high-potency neuroleptics (Table 12–13).
As with other DIMDs, the presence of multiple
risk factors exerts an additive effective on risk; for
example, young men are very susceptible to dys-
tonic reactions.133 An inverse relationship exists
between the incidence of DIAD and age. In con-
trast to TDk, dystonia is uncommon in older
patients. In one retrospective study, antipsychot-
ic-induced acute dystonia was 15 times more
common in patients under 35 years of age as
compared with patients older than 35 years (31%
vs. 2%, respectively).136 The highest risk popula-
tion is young male patients receiving high-poten-
cy neuroleptics.145
Patients with affective disorders may be at
greater risk of DIAD. In a study of 181 male
patients with mania or schizophrenia treated
with conventional neuroleptics, a significantly
higher proportion of the manic patients (26.1%)
TABLE 12–13 Risk Factors for Drug-Induced
Dystonia
• Affective symptomatology
• High-potency neuroleptics
• History of electroconvulsive therapy
• Male sex
• Mental retardation
• Young age
CHAPTER 12 • Movement Disorders 225
had acute dystonia as compared with those with
schizophrenia (5.9%).146 However, subsequent
studies failed to find a significant difference
between manic and schizophrenic patients in
the prevalence of DIAD. In a prospective study
of 31 patients, neuroleptic-induced dystonia
occurred in 62.5% of the patients with mania
and 66.7% of the patients with schizophrenia.147
In another prospective study of 83 male patients,
neuroleptic-induced acute dystonia was reported
in 24% of patients with mania and 15% of
patients with schizophrenia.148 Manic patients
received higher peak doses of neuroleptics dur-
ing the risk period for dystonia, and analysis
revealed that peak neuroleptic dose and younger
age were strongly related to the occurrence of
dystonia.
Risk factors for tardive dystonia overlap with
some of the risk factors for DIAD and include
young age, male sex, and the presence of TDk.
Children are at particularly high risk for drug-
induced tardive dystonia. Duration of therapy is
not consistently correlated with the risk of drug-
induced tardive dystonia, which may develop
after a relatively short duration of therapy or after
years of treatment. In some cases, drug-induced
tardive dystonia may develop following a dose
increase despite a long stable period of treat-
ment.16
MORBIDITY AND MORTALITY
Although drug-induced dystonia generally does
not affect mortality, except in rare cases of laryn-
geal spasm or status dystonicus, patients are at
higher risk for medication nonadherence or refusal
because of the discomfort that accompanies a dys-
tonic reaction. In moderate to severe cases of tar-
dive dystonia, task-specific impairment can occur,
the likelihood of which depends on the affected
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
can damage dentition.
PREVENTION
Approaches to help prevent drug-induced dysto-
nia are summarized in Table 12–14. Primary pre-
vention aided by knowledge and recognition of
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226 SECTION III • Drug-Induced Neurological Diseases
TABLE 12–14 Approaches to Help Prevent Drug-
Induced Dystonia
Amoxapine, metoclopramide, prochlorperazine
• Carefully evaluate the necessity for short- or long-
term therapy.
• Use standardized dose titration to avoid excessive
dose escalation.
• Administer lowest effective dose.
Atypical antipsychotics
• Carefully evaluate the necessity for short or long
term therapy.
• Use standardized dose titration to avoid excessive
dose escalation.
• Administer lowest effective dose.
• Short-term administration of oral antimuscarinic
agent (e.g., benztropine, diphenhydramine, tri-
hexyphenidyl) may be considered for young patients
receiving high-dose olanzapine, paliperidone, or
risperidone.
Conventional neuroleptics
• Carefully evaluate the necessity of short- or long-
term therapy.
• Use standardized dose titration to avoid excessive
dose escalation.
• Administer lowest effective dose.
• Consider use of atypical antipsychotic agent.
• Short-term administration of oral antimuscarinic
agent (e.g., benztropine, diphenhydramine, tri-
hexyphenidyl) may be considered, especially in
young patients receiving high-potency neuroleptics.
risk factors is key to minimizing the burden of
drug-induced dystonia. The necessity of short or
long-term use of potentially causative DRBAs
such as conventional neuroleptics, metoclo-
pramide, and antidopaminergic antiemetics
should be carefully evaluated. If indicated, the
lowest effective dose should be used and patients
should undergo regular evaluations for the emer-
gence of dystonic posturing. Standardized titra-
tion to avoid excessive dose escalation and the
use of atypical antipsychotics are successful
means of prevention.
Several studies comparing the incidence of
neuroleptic-induced acute dystonia report that
administration of concurrent antimuscarinic
agents (e.g., benztropine, diphenhydramine, tri-
hexyphenidyl) reduces the overall rate of dystonia
by at least 2-fold.133,134,137 In patients treated with
high-potency neuroleptics (e.g., haloperidol), the
risk reduction is even greater (5- to 11-fold).134,149
Because the greatest risk of neuroleptic-induced
acute dystonia occurs within the first week of drug
treatment, short-term administration of an oral
antimuscarinic agent should be considered, espe-
cially in young patients receiving high-potency
antipsychotics.145,150,151
The efficacy of antimuscarinic prophylaxis
appears to be inversely related to age.134 Because of
reduced prophylactic efficacy and undesirable
antimuscarinic adverse reactions (e.g., cognitive
impairment, sedation), the use of antimuscarinic
agents in elderly patients for the primary preven-
tion of DIAD is disfavored. Although antimus-
carinic agents reduce the severity of EPS, these
agents are also associated with adverse effects, such
as blurred vision, cognitive impairment, constipa-
tion, dry mouth, sexual dysfunction, and urinary
retention. Currently, the practice of primary pro-
phylaxis of drug-induced dystonia with antimus-
carinic agents is controversial, but appears to be
reasonable in patients at high risk for dystonia
(e.g., young men receiving conventional neurolep-
tics).
MANAGEMENT
Management approaches for drug-induced dys-
tonia are summarized in Table 12–15. Acute dys-
tonia can be relieved effectively with a short
course of therapy with a potent antimuscarinic
agent (e.g., benztropine, diphenhydramine)
TABLE 12–15 Management of Drug-Induced
Dystonia
Acute dystonia
• Discontinue causative agent.
• Administer antimuscarinic agent.
Tardive dystonia
• Discontinue or reduce dose of causative agent.
• If due to neuroleptic, switch to an atypical antipsy-
chotic.
• A trial of an antimuscarinic agent may be used.
• Use tetrabenazine
• Use botulinum toxin for focal dystonias.
• A trial of muscle relaxant (e.g., baclofen) may be used.
• Miscellaneous agents (amantadine, clonidine, leve-
tiracetam, pregabalin) may be used.
• Use deep brain stimulation (globus pallidus) or palli-
dotomy.
TisdaleC012_211-235 1/12/10 2:36 PM Page 227
administered orally, intramuscularly, or intra-
venously. If drug-induced dystonia is life-threat-
ening (e.g., stridor due to laryngospasm),
intravenous administration of antimuscarinic
drugs is warranted and supportive measures such
as tracheostomy may be required.
Benzodiazepines may be administered (to relieve
anxiety) in conjunction with antimuscarinic
therapy.
Symptoms of tardive dystonia also may be
improved with antimuscarinic therapy. In addi-
tion, atypical antipsychotics (e.g., clozapine, queti-
apine), benzodiazepines, muscle relaxants (e.g.,
baclofen), and dopamine-depleting drugs, such as
tetrabenazine, are also effective. Less commonly
used drugs include amantadine, ␤-blockers, benzo-
diazepines, clonidine, dantrolene, levodopa, and
antiepileptics such as levetiracetam, pregabalin,
tiagabine, and zonisamide.
For patients with symptoms of focal dystonia
(e.g., cervical, mandibular), local injections of bot-
ulinum toxin are highly effective and are preferred
because of a low incidence of systemic adverse
effects. In refractory and severe cases, intrathecal
baclofen and deep brain stimulation of the globus
pallidus or ablative pallidotomy should be consid-
ered.124,152,153
INFORMATION FOR PATIENTS
Before initiating DRBAs, clinicians should inform
patients regarding the potential risk of a dystonic
reaction. It is important to inform patients regard-
ing the purpose of treatment and the potential risk
of dystonia and to document that this counseling
has been performed. If long term treatment with a
DRBA is anticipated, informed consent is recom-
mended and should be updated yearly. Patients
should also understand that early detection of any
DRBA-induced movement disorder is important
and reduces the risk of irreversible abnormal move-
ments. The patient’s family members or caregivers
can play a role in monitoring and reporting any
abnormal movements.
PARKINSONISM
CAUSATIVE AGENTS
After idiopathic Parkinson’s disease, drug-
induced parkinsonism (DIP) is considered the
CHAPTER 12 • Movement Disorders 227
second most common form. DIP is associated
with up to 15% of all cases of parkinsonism
worldwide. In one study of elderly patients, 51%
of newly referred cases of parkinsonism were
believed to be caused by drugs.154 Agents impli-
cated in drug-induced parkinsonism are listed in
Table 12–16.6,36,155-165 The DRBAs are the most
commonly implicated agents, and are responsi-
ble for 70% to 80% of DIP cases worldwide.
Valproate is a common cause of DIP. 159
Valproate-induced parkinsonism is often charac-
terized by concurrent cognitive and hearing
impairments and is underreported because of its
insidious onset. The SSRIs are rarely associated
with DIP, although SSRI-induced tremor is com-
mon.
EPIDEMIOLOGY
In patients treated with conventional neuroleptics,
the prevalence of DIP ranges from 20% to
66%.6,155,156 The prevalence of parkinsonism associ-
ated with atypical antipsychotics is much lower. In
one study, the prevalence of parkinsonian rigidity
associated with clozapine, risperidone, and con-
ventional neuroleptics was 4.9%, 17.4%, and
35.7%, respectively.36
MECHANISMS
The mechanism of DRBA-induced parkinsonism
involves occupancy and blockade of striatal
dopamine receptors (Table 12–17).166-168 However,
mitigating factors include D2 receptor binding
affinity and dissociation and 5-HT2A receptor
activity. Traditional thinking has been that block-
ade of approximately 65% of mesolimbic
dopamine receptors and 80% of nigrostriatal
dopamine receptors is required to elicit antipsy-
chotic and parkinsonism (or other EPS) reactions,
respectively.169 Relative to the conventional neu-
roleptics, the affinity of atypical antipsychotic
agents for striatal dopaminergic receptors is
lower, which helps to explain the dose-dependent
incidence of parkinsonism induced by conven-
tional neuroleptics and some of the atypical
antipsychotics, such as olanzapine, paliperidone,
and risperidone. However, receptor affinity and
dissociation also play a role, and rapid dissocia-
tion from dopamine D2 receptors (i.e., “fast-off-
D2”) plays a role in mitigating EPS risk.170,171
According to the fast-off-D2 model, atypical
TisdaleC012_211-235 1/12/10 2:36 PM Page 228

228 SECTION III • Drug-Induced Neurological Diseases

TABLE 12–16 Agents Implicated in Drug-Induced Parkinsonism

Drug Incidence Level of Evidence
(see page xii for explanation)

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.

antipsychotics bind loosely to dopamine D2 dopamine “false transmitters” (e.g., ␣-methyldopa)

receptors, resulting in a short duration of binding,
which is sufficient to produce antipsychotic activ-
ity without inducing EPS. Conventional neu-
roleptics bind tightly to dopamine D2 receptors
and thus produce antipsychotic activity, but with
an increased risk of inducing EPS. Furthermore,
among the atypical antipsychotics, fast-off-D2
occurs more readily with low-potency agents as
compared with high-potency agents. For exam-
ple, EPS is rarely associated with clozapine (an
agent that requires higher mg doses for efficacy)
compared with risperidone (an agent that
requires lower mg doses). In addition, the atypical
antipsychotics also block 5-HT2A receptors that
project to the presynaptic aspect of nigrostriatal
dopamine neurons. Since activation of 5-HT2A
receptors inhibits dopamine release, blockade of
these 5-HT 2A receptors enhances dopamine
release sufficiently to mitigate the risk of EPS.
In addition to the DRBAs (e.g., antipsychotics,
metoclopramide), drugs that deplete presynaptic
dopamine (e.g., reserpine, tetrabenazine) or act as
can also induce parkinsonism.
CLINICAL PRESENTATION AND
DIFFERENTIAL DIAGNOSIS
In general, the clinical features of DIP are indistin-
guishable from those of idiopathic parkinsonism
and include at least two of the following: tremor
(rest or postural), rigidity, and bradykinesia (Table
12–3). In the absence of an accurate drug history,
DIP can be easily mistaken for idiopathic
Parkinson’s disease. Recognition of DIP may be dif-
ficult, as symptoms such as reduced facial expres-
sion, reduced energy and motivation, and
bradykinesia can mimic negative symptoms of
schizophrenia as well as psychomotor retardation
associated with depressive disorders (Table 12–4).
Tremor is often the most visible feature of DIP, but
the presence of tremor in the absence of bradykine-
sia or rigidity is not parkinsonism. Symptoms of
TisdaleC012_211-235 1/12/10 2:36 PM Page 229

CHAPTER 12 • Movement Disorders 229

TABLE 12–17 Mechanisms of Drug-Induced Parkinsonsism

Drug Mechanism
Amoxapine Blockade of striatal D2 receptors
Atypical antipsychoticsa
Cinnarizine
Conventional neurolepticsb
Flunarizine
Metoclopramide
Prochlorperazine
Methyldopa Neuronal dopamine depletion
Reserpine
Tetrabenazine
Valproate Unknown
a
Aripiprazole, olanzapine, paliperidone, risperidone, ziprasidone
b
Chlorpromazine, fluphenazine, haloperidol, loxapine, molindone, perhpenazine, thiothixene, thiroidazine, trifluoperazine

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.,
TisdaleC012_211-235 1/12/10 2:36 PM Page 230
230 SECTION III • Drug-Induced Neurological Diseases
smallest degree of impairment of activities of daily
living, as compared with bradykinesia.
PREVENTION
Approaches to help prevent drug-induced parkin-
sonism are summarized in Table 12–19. Primary
prevention aided by knowledge and recognition of
risk factors is key to minimizing the burden of DIP.
The necessity for long term use of potentially
causative DRBAs such as conventional neurolep-
tics, metoclopramide, and antidopaminergic
antiemetics should be carefully evaluated. If indi-
cated, the lowest effective dose should be used and
patients should undergo regular evaluations for
emergence of symptoms of parkinsonism.
Standardized titration to avoid excessive dose
escalation and the use of atypical antipsychotics
are successful means of prevention. In practice,
some clinicians routinely use antimuscarinic
agents for primary prophylaxis of DIP, but this
approach is controversial, especially for elderly
patients.
TABLE 12–19 Approaches to Help Prevent Drug-
Induced Parkinsonism
Amoxapine, atypical antipsychotics, cinnarizine, flu-
narizine, metoclopramide, prochlorperazine, tetra-
benazine
• Carefully evaluate the necessity for long term
therapy.
• Use standardized dose titration to avoid excessive
dose escalation.
• Administer the lowest effective dose.
Conventional neuroleptics
• Carefully evaluate the necessity for long term
therapy.
• Use standardized dose titration to avoid excessive
dose escalation.
• Administer the lowest effective dose.
• Consider use of atypical antipsychotics.
• Initiation of therapy with antimuscarinic agent for
primary prevention is controversial, especially for the
elderly.
Methyldopa, reserpine, valproate
• No known means of prevention
MANAGEMENT
Strategies for the management of DIP include dis-
continuation of the causative agent, reducing the
dose of the causative agent, changing therapy from
a conventional neuroleptic to an atypical antipsy-
chotic agent, and the use of antiparkinsonism
drugs such as amantadine, antimuscarinics, car-
bidopa–levodopa, and dopamine agonists (Table
12–20). For symptom management, dopamine ago-
nists and carbidopa–levodopa are effective, but a
severe neuroleptic-induced parkinsonian tremor
may be resistant. Alternatively, antimuscarinic
agents can be used and are better tolerated in
younger patients. Amantadine is another alterna-
tive and is better tolerated than anticholinergic
drugs in the elderly.
INFORMATION FOR PATIENTS
Before initiating therapy with DRBAs, clinicians
should inform patients regarding the potential risk
of DIP. It is important to inform patients regarding
the purpose of treatment and the potential risk of
DIP and to document that this counseling has been
performed. If long term treatment with a DRBA is
anticipated, informed consent is recommended
and should be updated yearly. Patients should also
understand that early detection of any DRBA-
induced movement disorder is important and
reduces the risk of irreversible abnormal move-
ments. The patient’s family members or caregivers
can play a role in monitoring and reporting any
abnormal movements.
References
1. Weiden PJ, Mann JJ, Haas G, et al. Clinical
nonrecognition of neuroleptic-induced movement
disorders: a cautionary study. Am J Psychiatry.
1987;144:1148-1153.
2. Perkins DO. Predictors of noncompliance in patients
with schizophrenia. J Clin Psychiatry. 2002;63:1121-1128.
TABLE 12–20 Management of Drug-Induced
Parkinsonism
• Discontinue or reduce dose of causative agent.
• If due to neuroleptic, switch to an atypical antipsy-
chotic.
• Use a trial of antimuscarinic, amantadine, dopamine
agonist, or levodopa.
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CHAPTER 13
Peripheral Neuropathy
P eripheral neuropathy is defined as a dysfunc-
tion or lesion in the peripheral nervous system
that is usually characterized by pain, abnormal
sensory symptoms, or both. Although this syn-
drome is most commonly a complication of chron-
ic illnesses such as diabetes mellitus, alcoholism, or
human immunodeficiency virus (HIV) infection, it
may also be drug-induced.
CAUSATIVE AGENTS
Many drugs have been associated with peripheral
neuropathy. The most common agents that have
been implicated include antineoplastic and anti-
retroviral drugs. Drugs known to cause peripheral
neuropathy are listed in Table 13–1.1-97
EPIDEMIOLOGY
The exact incidence of drug-induced peripheral
neuropathy is unknown. Despite few epidemiolog-
ic data, it seems likely that, although many agents
have been implicated, the overall occurrence of
drug-induced peripheral neuropathy is low.98 The
incidence varies depending on the agent in ques-
tion, as well as its duration of use and dose, and
patient-specific factors. The risk of peripheral neu-
ropathy is notably high in association with certain
drug classes. Cancer chemotherapeutic agents
(platinum derivatives, taxanes, vinca alkaloids)
and antiretroviral drugs (nucleoside reverse-tran-
scriptase inhibitors) are commonly associated with
peripheral neuropathy. The incidence of peripher-
al neuropathy has been reported to be as high as
85% to 100% in patients receiving higher doses of
236
Dennis Parker Jr.
cisplatin or oxaliplatin and 30% to 80% in patients
with HIV who receive zalcitabine.26,35,99-101 Most
other associations of peripheral neuropathy with
drugs are limited to case reports or small case
series. Some population-based cohort studies
examining the risk of peripheral neuropathy asso-
ciated with lipid-lowering agents such as statins
have been published. In one large cohort, Gaist et
al.102 found the incidence of peripheral neuropathy
to be higher in users of statin medications as com-
pared with nonusers. The same group performed a
subsequent study in 166 patients and found a 4- to
14-fold increased risk of idiopathic polyneuropa-
thy in those who used statins for long-term treat-
ment (median, 2.8 years).102 A subsequent analysis
of four cohort trials estimated the incidence of
neuropathy associated with statin use to be low (12
per 100,000 person-years).103
MECHANISMS
Peripheral neuropathy is associated with damage
to the peripheral nervous system, namely the dor-
sal-root ganglia and dorsal roots. The cell bodies of
sensory neurons lie in the dorsal-root ganglia,
which also give rise to the dorsal roots (axons). It is
postulated that drugs may affect the peripheral
nervous system selectively because these anatomi-
cal structures have a somewhat porous
blood–nerve barrier, thus allowing access of harm-
ful toxins.98,104 Others have pointed out that
increased access to sensory neurons alone could
not explain susceptibility, as autonomic neurons
also lack a blood–brain barrier but autonomic dys-
function is commonly absent in patients with
drug-induced peripheral neuropathy.37
TisdaleC013_236-249 1/12/10 2:38 PM Page 237

CHAPTER 13 • Peripheral Neuropathy 237

TABLE 13–1 Agents Implicated in Drug-Induced Peripheral Neuropathy

Drug Incidence Level of Evidence
(see page xii for explanation)

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)
TisdaleC013_236-249 1/12/10 2:38 PM Page 238

238 SECTION III • Drug-Induced Neurological Diseases

TABLE 13–1 Agents Implicated in Drug-Induced Peripheral Neuropathy (Continued)

Drug Incidence Level of Evidence

Clofibrate61 NK C
Disopyramide62 NK C
Enalapril63,64 NK C
Hydralazine65,66 NK C
Indomethacin67 NK C
Pravastatin59,60 NK C
Propafenone25 NK C
Rosuvastatin59,60 NK C
Simvastatin59,60 NK C
MISCELLANEOUS
Acetazolamide68,69 NK C
Allopurinol70 NK C
Colchicine71 NK C
Cyclosporine72-74 NK C
Disulfiram75-78 NK C
Gold salts*79-81 1% C
Interferons alfa 2A and 2B82-84 NK C
Infliximab85 NK C
Leflunomide86,87 3–10% B
Lithium88 NK C
Nitrous oxide48,89 NK C
Penicillamine90 NK C
Phenelzine91,92 NK C
Phenytoin93,94 NK C
Pyridoxine92,95 NK C
Sulfasalazine96 NK C
Tacrolimus97 NK C
* Sodium aurothiomalate.

Although mechanisms by which drugs induce
peripheral neuropathy have not been fully eluci-
dated, the general pathogenesis of drug-induced
peripheral neuropathy involves primarily axonal
or cell-body degeneration, demyelination, or both.
Axonal degeneration is often associated with the
“dying back” phenomenon, in which the most dis-
tal portion of the axon degenerates and the myelin
sheath begins to break down more proximally
toward the cell body.105
For some drugs with well-established associa-
tions with peripheral neuropathy, several cellular
pathways have been identified using in vitro meth-
ods and animal models (Table 13–2).106-109 The
therapeutic mechanism of action of some drugs is
also associated with detrimental consequences to
sensory neurons. Nucleoside reverse-transcriptase
inhibitors cause peripheral neuropathy by deplet-
ing mitochondrial deoxyribonucleic acid (DNA) in
neurons. These agents exert a therapeutic effect on
HIV reverse-transcriptase DNA but are also sub-
strates for gamma DNA polymerase, which is
responsible for replication of mitochondrial DNA
in neurons.99 Vinca alkaloids destroy cancer cells
by binding with tubulin to prevent microtubular
formation, which disrupts mitosis. Axonal trans-
port is dependent on microtubular function.
Dysfunction of axoplasmic transport has been
demonstrated in animal models.36,110,111 Other
drugs can affect important mediators of metabolic
TisdaleC013_236-249 1/12/10 2:38 PM Page 239
TABLE 13–2 Mechanisms of Drug-Induced Peripheral Neuropathy
Drug
Nucleoside reverse-transcriptase inhibitors
Taxanes and vinca alkaloids
Platinum compounds
Oxaliplatin (acute)
Thalidomide
Bortezomib
Isoniazid
Linezolid
Statins
DNA = deoxyribonucleic acid; HMG-CoA = hydroxymethylglutaryl coenzyme A.
function. Isoniazid inhibits phosphorylation of
pyridoxine, which causes neuronal cellular dys-
function.112 Paradoxically, pyridoxine overdose is
also associated with peripheral neuropathy.113
CLINICAL PRESENTATION AND
DIFFERENTIAL DIAGNOSIS
A wide spectrum of clinical features can be
observed in patients with drug-induced peripheral
neuropathy. Symptoms are most often sensory or
sensorimotor in nature, and patients present in a
similar fashion to those afflicted with peripheral
neuropathy due to other causes. The clinical syn-
drome may be dependent on many factors. Drugs
that affect large myelinated axons (e.g., paclitaxel)
cause disturbances of proprioception, vibration,
and light touch. Others, such as cisplatin, are
more selective for small fibers and may cause pain
or dysfunction in temperature sensation.26,35
Patients with sensorimotor neuropathy present
with sensory as well as motor symptoms such as
weakness or muscle cramps. The onset and severi-
ty of these symptoms vary. Most commonly, neu-
rotoxicity is a dose-related phenomenon that
occurs after a prolonged, cumulative exposure to
the offending agent (weeks to months). In some
instances, however, acute symptoms may appear
after a single exposure to the drug (e.g., oxali-
platin, paclitaxel).35 Oxaliplatin induces a unique
CHAPTER 13 • Peripheral Neuropathy 239
Mechanism
Depletion of mitochondrial DNA in neurons
Disruption of neuronal axonal transport
Cross-linkage of DNA strands to impair cell division;
demyelination and axonal swelling in dorsal-root ganglia
Interaction with ion channels in dorsal root to enhance
Na++ transmission; chelation of Ca++ ions. Overall shift to
more negative membrane potential
Down regulation of the production of tumor necrosis
factor ␣ and inhibition of nuclear factor-␬␤ leading to
reduced nerve growth factor–mediated neuron survival
Inhibition of phosphorylation of pyridoxine, which leads to
neuronal cellular dysfunction
May disrupt neuronal mitochondrial protein synthesis
Inhibition of HMG-CoA leading to reduced cholesterol syn-
thesis, which is necessary for maintenance of cell-mem-
brane integrity in neurons
form of acute neuropathy in a majority of
patients.34 Patients afflicted experience paresthe-
sias in the extremities. Rarely, pharyngolaryngeal
dysesthesia may occur, which is manifested as
unusual sensations in the mouth or throat and dif-
ficulty in swallowing or breathing. Symptoms may
begin during the infusion of the drug or shortly
thereafter. This syndrome usually resolves sponta-
neously within days of onset but can recur with
subsequent infusions.
Patients may experience a syndrome known as
“coasting,” in which symptoms begin to occur
some time after the drug has been discontinued.114
This has been reported in association with neuro-
toxic antiretroviral drugs, with which symptoms
may actually worsen for a period of 1 to 2 months
after the offending agent is discontinued. Some
drugs known to cause peripheral neuropathy also
cause autonomic or optic neuropathies or purely
motor abnormalities. Signs and symptoms associ-
ated with drug-induced peripheral neuropathy are
listed in Table 13–3.
Identifying the cause of peripheral neuropathy
can be challenging. Even with extensive investiga-
tion, the exact cause is often elusive. In a small
study of patients with sensory neuropathy, nearly
50% were categorized as having an idiopathic
cause.104 It follows, therefore, that distinguishing
drug-induced peripheral neuropathy from non-
drug causes can be a daunting task. Drug-induced
peripheral neuropathy is often a diagnosis of exclu-
TisdaleC013_236-249 1/12/10 2:38 PM Page 240
240 SECTION III • Drug-Induced Neurological Diseases
TABLE 13–3 Signs and Symptoms Associated with
Drug-Induced Peripheral Neuropathy*
• Orthostatic hypotension (autonomic neuropathy)
• Reduced sensation (vibration, pinprick)
• Reduced (abnormal) reflexes in affected area
• Reduced nerve action potential amplitude (nerve
conduction studies)
• Paresthesias
• Burning sensations
• Shocklike sensations
• Decreased sensations or numbness
• Shooting or stabbing pain
• Radiating pain
• Ataxia
*Symptoms are typically distal and symmetrical in nature.
sion, because numerous causes of peripheral neu-
ropathy exist, many of which present in a fashion
similar to those that are drug-related. A careful
medical history and physical exam are important
for diagnosis, and additional tests may be required
to establish the most likely cause of a patient’s neu-
ropathy.
It is important that clinicians inquire specifi-
cally about the frequency, quality, and duration of
symptoms of peripheral neuropathy. Knowledge of
the onset and duration of symptoms is particularly
helpful in discerning the cause of neuropathy,
because drug-induced peripheral neuropathy usu-
ally presents as a subacute process over several
weeks to months. The medical history should be
assessed for trauma, infectious diseases (especially
HIV), diseases such as diabetes mellitus, kidney or
liver disease, cancer, and family history of neuropa-
thy. The patient should also be evaluated for alco-
hol abuse and for exposure to other potentially
neurotoxic chemicals or medications.
On physical exam, drug-induced peripheral
neuropathy is usually distal, symmetrical, and sen-
sorimotor in nature. The neurologic exam may
reveal a reduced sensation on pinprick as well as
reduced vibratory sense bilaterally in the extremi-
ties. The reduction in sensation may result in sub-
sequent formation of ulcers. In some cases,
hyperesthesia or allodynia may be present.
Weakness or clumsiness may be observed in
patients with motor involvement secondary to
neuropathy. Deep tendon reflexes may be absent
or reduced in affected areas.
Grading scales for neuropathy (particularly
chemotherapy-induced) are widely used by clini-
cians to assess the scope and severity of drug-
induced peripheral neuropathy as a part of patient
monitoring and during clinical trials. The most
widely used scales are the National Cancer Institute
of Canada Common Toxicity, Eastern Cooperative
Oncology Group, and World Health Organization
grading scales. These scales generally classify
patients from 0 (no symptoms) to up to 4 or 5
(severe, disabling symptoms). Although these tools
are helpful, a substantial amount of variability
exists between examiners using these scales
because of the subjective nature of some classifica-
tion schemes. More in-depth descriptions of these
scales are published elsewhere.115,116
Nerve-conduction studies (NCS) and elec-
tromyography (EMG) are the primary tools used in
electrodiagnostic studies. These tests are usually
performed in concert to identify disorders occur-
ring in the nerves, muscle, or both. EMG (needle
examination) is used to study the electrical activity
of muscles, whereas NCS assess motor and sensory
function of the nerves. EMG and NCS are per-
formed by generating a small electrical current via a
stimulator placed on the skin along a nerve.
Electrical activity is recorded using either surface
electrodes (NCS) or needle electrodes inserted into
muscles (EMG) and is visualized as waveforms on a
monitor. The amplitude of the waveform estimates
the amount of electrically active tissue. Conduction
velocity is a measurement of how quickly neurons
are propagating impulses. Both amplitude and con-
duction velocity data generated during NCS can aid
in the determination of the level of peripheral
nerve disease (i.e., demyelination versus axonal
degeneration). In general, axonal destruction pro-
duces a reduction in amplitude. This represents the
most common consequence of neuropathy due to
medications. In contrast, demyelination is associat-
ed with a reduction in conduction velocity, as may
occur in patients who receive amiodarone.
Although electophysiologic testing may be useful in
identifying the presence of peripheral neuropathy
in some patients, many investigators have found a
poor correlation between performance on NCS and
clinical symptoms of the disease.117,118 Furthermore,
it has yet to be shown that NCS are useful in pre-
dicting the future development of peripheral neu-
ropathy in those receiving potentially neurotoxic
drugs. Mileshkin et al.118 studied the utility of serial
NCS in 75 patients receiving thalidomide for
relapsed or refractory multiple myeloma in an
effort to identify patients at risk for developing
peripheral neuropathy. Electrophysiologic monitor-
ing was found to be no better than clinical assess-
ment for identifying patients at risk for developing
peripheral neuropathy. Therefore, the utility of the
routine use of NCS to identify patients at risk for
peripheral neuropathy remains unclear.
TisdaleC013_236-249 1/12/10 2:38 PM Page 241
Conditions to consider in the differential diag-
nosis of drug-induced peripheral neuropathy are
listed in Table 13–4. A wide variety of systemic dis-
eases, particularly diabetes mellitus, kidney disease,
and thyroid disease may play a role in producing
neuropathy. Therefore, complete blood count,
fasting blood glucose, blood urea nitrogen and cre-
atinine, and thyroid-stimulating hormone concen-
trations should be evaluated. Serum vitamin B12
concentrations can also be easily obtained and
should be included in the patient evaluation. A
serum concentration of 100 pg/mL or less with
symptoms is usually indicative of vitamin B12 defi-
ciency. Malignancy has also been associated with
peripheral neuropathy, which is a common pre-
senting feature in patients with small-cell lung can-
cer.104 In these patients, symptoms of sensory
neuropathy often occur rather abruptly, a presenta-
tion that differs from the more common subacute
presentation of drug-induced peripheral neuropa-
thy. Therefore, a routine cancer evaluation includ-
ing chest radiography and measurement of anti-Hu
antibodies should be performed in any patient pre-
senting with acute symptoms of neuropathy.
Cerebrospinal fluid evaluation may be useful in
screening patients for immune-related causes such
as Guillain–Barré syndrome and chronic inflamma-
tory demyelinating polyradiculoneuropathy
(CIDP), as elevated plasma protein concentrations
may be found in patients with these illnesses.
Nerve biopsy, which involves removing and exam-
ining nerve tissue, is generally poorly tolerated and
TABLE 13–4 Conditions to Consider in the
Differential Diagnosis of Drug-Induced
Peripheral Neuropathy
• Immune-related disorders
• Guillain–Barré syndrome
• Sjögren’s syndrome
• Chronic inflammatory demyelinating polyradicu-
loneuropathy
• Infectious diseases
• Human immunodeficiency virus
• Herpes simplex
• Metabolic/systemic diseases
• Nutritional deficiency
• Diabetic neuropathy
• Hypothyroidism
• Traumatic injury
• Hereditary sensory neuropathies
• Idiopathic sensory neuropathy
• Paraneoplastic neuropathy
CHAPTER 13 • Peripheral Neuropathy 241
can cause complications of neuropathy. Therefore,
this technique is reserved for patients for whom
the diagnosis of neuropathy cannot be determined
by other means.104,105,119
RISK FACTORS
Risk factors for the development of drug-induced
peripheral neuropathy are listed in Table 13–5. For
the most part, cumulative drug exposure increases
the risk of peripheral neuropathy, and repeated
exposure to an agent that has caused peripheral
neuropathy places patients at a higher risk.
However, some data demonstrate that some
patients can be safely rechallenged with cisplatin.120
For many anticancer drugs, the risk of neurotoxici-
ty appears to be related to both the amount of drug
given in each individual dose and the cumulative
dose. Postma et al.121 studied the effect of dose-
dependent neurotoxicity in 227 patients with can-
cer receiving paclitaxel in doses ranging from 135
to 300 mg/m2 every 3 weeks. The incidence of neu-
ropathy was higher in patients who had received
both a higher cumulative dose and a higher dose
per cycle. Similar effects have been noted in
patients receiving high doses of oxaliplatin, cis-
platin, and vincristine. Therefore, it appears that
both total drug exposure and dose intensity can
influence chemotherapy-induced neuropathy.122
Infusion time appears to affect the incidence of
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
Combinations of neurotoxic HIV medications
may result in a substantial increase in the risk of
TABLE 13–5 Risk Factors for Drug-Induced
Peripheral Neuropathy
• High drug doses
• Prolonged drug administration
• Human immunodeficiency virus
• Diabetes mellitus
• Alcohol abuse
• Hypothyroidism
• Preexisting neuropathy
• Concomitant administration of agents known to
cause neuropathy
• Possible genetic predisposition
• Impaired hepatic or renal drug metabolism/elimina-
tion
• Rapid infusion of some antitumor agents
TisdaleC013_236-249 1/12/10 2:38 PM Page 242
242 SECTION III • Drug-Induced Neurological Diseases
peripheral neuropathy.99 In addition, HIV infec-
tion itself is associated with peripheral neuropathy,
and the incidence is higher in patients with a high
viral load or low CD4 count.124
Genetics appear to play a role in the develop-
ment of drug-induced peripheral neuropathy in
many patients. The risk of peripheral neuropathy
associated with isoniazid and hydralazine may be
higher in patients who are slow acetylators.
Acetylation status also be of importance with
respect to thalidomide-induced peripheral neu-
ropathy.117
Diabetes mellitus and alcohol abuse both pose
a significant risk for the development of peripheral
neuropathy. Therefore, caution must be used when
prescribing potentially neurotoxic medications to
these patients. Nutritional deficiencies and hepatic
or kidney disease may also cause damage to nerves,
and patients with these disorders are at a higher
risk for drug-induced peripheral neuropathy.
MORBIDITY AND MORTALITY
Drug-induced peripheral neuropathy can produce
symptoms ranging from mild, annoying paresthe-
sias to painful sensations that can exert a signifi-
cant impact on the quality of life. Fortunately, the
majority of patients demonstrate at least partial
improvement in symptoms following discontinua-
tion of the offending agent, and many patients
experience complete recovery.36 The coasting phe-
nomenon may occur, however, in some patients
after the drug is discontinued. The time to
improvement in symptoms after discontinuing
some agents may take as long as several months to
years. Resolution is dependent on underlying
mechanisms and the duration and extent of neu-
ronal damage. Recovery from axonal damage may
be prolonged, whereas recovery from a demyelinat-
ing process may be more rapid.119
PREVENTION
The most effective means for preventing drug-
induced peripheral neuropathy is avoidance of use
of drugs known to cause peripheral neuropathy in
patients with known risk factors (Table 13–6).
Clinicians should be cognizant of the neurotoxic
potential of medications so that patients can be
screened for risk factors before initiating therapy.
Medications with a potential for causing peripher-
al neuropathy should be administered in the small-
est effective dose for the shortest possible duration,
TABLE 13–6 Approaches to Help Prevent Drug-
Induced Peripheral Neuropathy
• Limit/monitor for potential predisposing risk factors
• Use lowest dose possible to achieve desired effect
• Monitor blood urea nitrogen and serum creatinine
concentration in patients taking renally eliminated
drugs. Adjust dose appropriately if kidney disease
occurs.
• Monitor liver function in patients taking hepatically
eliminated agents. Adjust dose if hepatic impair-
ment occurs.
• Monitor for signs/symptoms of peripheral neuropathy
• Educate patients about potential symptoms of neu-
ropathy
• Routine clinical neurologic assessment
• Electrophysiologic testing may be useful
• Drugs
• Routine pyridoxine therapy in patients receiving
drugs that may induce vitamin B12 deficiency (e.g.,
isoniazid).
and doses should be adjusted properly for patients
with kidney or liver disease.119 Drugs that can
potentially induce vitamin B deficiency, such as
isoniazid, should be coadministered with pyridox-
ine, 100 to 150 mg/day.
Although cancer chemotherapy–induced
peripheral neuropathy is predictable and well
established, pharmacologic measures to prevent
this complication have generally been disappoint-
ing. Although no drugs are currently approved for
the prevention or treatment of chemotherapy-
induced peripheral neuropathy, several strategies
have been used to attempt to reduce the risk of this
complication (Table 13–7). Growth factors such as
nerve growth factor (NGF) and insulin-like growth
factor have both been reported to reduce the inci-
dence of peripheral neuropathy in animals
exposed to anticancer agents.141,142 The adrenocor-
ticotropic hormone-(4-9) analog ORG 2766
demonstrated efficacy in attenuating cisplatin-
induced peripheral neuropathy in patients with
ovarian cancer.143 Unfortunately, subsequent stud-
ies in patients with ovarian cancer and lymphoma
showed no benefit associated with the prophylac-
tic use of this agent.144,145 Glutamine and glu-
tathione have shown promise in preliminary
clinical trials, but the role of these agents must be
further evaluated in large randomized stud-
ies.115,135,136,138
Acute neuropathy associated with oxaliplatin
occurs commonly. Symptoms may be triggered by
exposure to cold, and consequently patients
TisdaleC013_236-249 1/12/10 2:38 PM Page 243

CHAPTER 13 • Peripheral Neuropathy 243

TABLE 13–7 Experimental Pharmacologic Approaches to Prevent Drug Induced Neuropathy

Drug Clinical Condition Proposed Mechanism
Acetyl-L-carnitine125-128 CIPN and antiretroviral- • Antioxidant effects, and stimulates
induced PN mitochondrial DNA synthesis.
• Facilitates expression of nerve-growth
factor
Amifostine31,115,128-130 CIPN • Free radical scavenger
Calcium and magnesium salts31,128,131 Oxaliplatin-induced PN • Combats chelation of calcium and
magnesium, thus preventing neuronal
voltage-gated sodium channelopathy
Carbamazepine/oxcarbazepine31,106,109,132-134 Oxaliplatin- induced PN • Sodium-channel blockade to combat
oxaliplatin-induced channelopathy
Erythropoeitin115 CIPN • Erythropoietin receptor activation in
neurons stimulates an anti-apoptotic
effect
Glutamine109,115,135-137 CIPN • May upregulate or downregulate nerve-
growth factor, thus converting glutamine
to the excitatory neurotransmitter
glutamate
Glutathione115,128,138 CIPN • Neuroprotective “detoxifying” effects in
neuronal tissues
• May prevent accumulation of platinum
adducts in neurons
ORG 2766128,129 CIPN • Neurotrophic effects*
Vitamin E31,128,129,139 CIPN • Reduction of oxidative stress induced by
chemotherapy
Xaliproden115,140 Oxaliplatin induced PN • Serotonin agonist that promotes
increased neuronal survival
CIPN = chemotherapy-induced peripheral neuropathy; DNA = deoxyribonucleic acid; PN = peripheral neuropathy.
* Promotes survival of neurons.

should be instructed to avoid extremes in temper- in affecting electrophysiologic studies or provid-

atures and cold beverages. Long-term exposure
can also cause cumulative toxicity similar to that
associated with other platinum compounds. It is
postulated that neurotoxicity after oxaliplatin
exposure is the result of hyperexcitability due an
interaction with ion channels (channelopathy)
that results in a relative increase of the sodium
current. This is likely a result of calcium ion chela-
tion by oxaliplatin or its oxalate metabolite.109
Some data suggest that prophylactic administra-
tion of the sodium-channel blocker carba-
mazepine may prevent acute oxaliplatin
neurotoxicity. Results of an unblinded trial
showed that neuropathy was less severe in
patients who received carbamazepine combined
with oxaliplatin as compared with historical con-
trols.132 Conversely, in another study, prophylactic
carbamazepine failed to offer a significant benefit
ing symptomatic relief.146 Much attention has
been devoted to the use of calcium and magne-
sium to prevent chelation and thus reduce oxali-
platin-induced excitation, based on theoretical
beneficial effects. Many clinicians advocated the
use of prophylactic infusions of calcium and mag-
nesium salts, particularly after the publication of a
retrospective study of 161 patients with colorectal
cancer, which reported that calcium and magne-
sium was effective for reducing the incidence and
severity of oxaliplatin-induced neuropathy.131
However, a more recent prospective trial was halt-
ed early at an interim analysis, because investiga-
tors found no effect on tumor burden in patients
treated with calcium and magnesium.31,147 These
results raise serious concerns regarding the use of
calcium and magnesium to prevent oxaliplatin-
induced neuropathy in the future.
TisdaleC013_236-249 1/12/10 2:38 PM Page 244
244 SECTION III • Drug-Induced Neurological Diseases
MANAGEMENT
Unfortunately, pharmacologic measures to reliably
prevent or treat drug-induced peripheral neuropa-
thy have not been identified. The severity of symp-
toms of peripheral neuropathy can vary widely.
Thus, although neuropathy may occur commonly
in association with many drugs, it is often a pre-
dictable and tolerable occurrence, such that dis-
continuation of the causative drug is unnecessary.
However, if symptoms are severe, initial treatment
of drug-induced peripheral neuropathy should
include discontinuation, or at least a reduction in
the dose, of therapy with the offending agent.
After discontinuation of therapy, pharmacologic
measures to treat neuropathic pain should be used
if symptoms are persistent. In cases such as cancer
or HIV treatment, in which drug discontinuation is
not possible, other approaches may be helpful.
Strategies widely used for patients with peripheral
neuropathy induced by antineoplastic regimens
include reduction in dose intensity, extending
drug-free intervals, and prolonging infusion
times.100,122,148
Discontinuation of antiretroviral agents may
cause a loss of HIV virologic control, and dose
reduction is generally undesirable. Similarly, anti-
tuberculosis regimens including isoniazid and
ethambutol can cause drug-induced peripheral
neuropathy, but clinicians may resist modifying
the dosage regimen because of concerns regarding
the potential for the development of multidrug-
resistant tuberculosis (MDR-TB). Shin et al.149
reviewed the management of peripheral neuropa-
thy in patients undergoing treatment for MDR-TB.
Antituberculosis medications were not discontin-
ued in any of the 10 patients with presumed drug-
induced peripheral neuropathy. The addition of
amitriptyline therapy resulted in a favorable
response in most patients. Therefore, medications
to treat drug-induced peripheral neuropathy can
be effective in reducing the frequency or severity of
symptoms even if current neurotoxic medications
are continued.
Unfortunately, although there are several med-
ications that have shown promise in open-label
studies of drug-induced peripheral neuropathy or
in anecdotal reports, evidence from randomized
trials demonstrating efficacy is sparse. Acetyl-L-car-
nitine (ALC) may be the most promising agent,
based on results in both chemotherapy and anti-
retroviral toxic neuropathy. Two small open-label
studies in patients experiencing chemotherapy-
induced peripheral neuropathy (CIPN) have found
ALC to be of benefit at reducing pain scores for up
to 1 year, and therapy appeared to be well tolerat-
ed.125,150 One placebo-controlled trial in patients
with HIV suffering from antiretroviral-induced
neuropathy found a reduction in pain scores as
compared to placebo in patients treated acutely
with intramuscular ALC, as well as improvements
in symptoms during follow-up therapy with oral
ALC.126 Larger studies are necessary to confirm the
results of these preliminary data.
NGF-1 therapy was associated with encourag-
ing results in patients with HIV-related neuropa-
thy. Results of a double-blind study and the
long-term (48-week) follow-up study showed a
reduction in pain symptoms associated with sub-
cutaneous NGF, although pain severity was not
consistently reduced.151-154 Unfortunately, phase
III studies in patients with diabetic neuropathy
were negative, which limited further large-scale
studies with this agent.124 It must be reiterated that
results from clinical studies regarding treatment of
drug-induced peripheral neuropathy are often con-
founded by the fact that disease state itself (HIV,
cancer) often plays a role in causing neuropathy.
Other measures to treat pain or other neurolog-
ic manifestations are limited to symptomatic treat-
ments used in other types of neuropathic pain,
such as diabetic neuropathy or postherpetic neu-
ralgia. Simple analgesics such as nonsteroidal anti-
inflammatory drugs or acetaminophen often have
limited efficacy but they are safe and inexpensive.
Other drugs that are generally more effective for
neuropathic pain tend to be either more costly or
carry the burden of undesirable toxicities or drug
interactions.
Tricyclic antidepressants have been used for
several years and have been proved effective in
clinical trials in patients with painful neuropathy.
The results of two placebo-controlled trials, howev-
er, could demonstrate only a nonsignificant trend
toward efficacy.155,156
Gabapentin is often used for the treatment of
neuropathic pain. It is associated with few serious
adverse effects or drug interactions and has been
proven effective in randomized clinical trials in
patients with diabetic neuropathy and postherpet-
ic neuralgia.157,158 Small studies have noted that
gabapentin may be effective for the management
of both HIV and cancer-related pain. An unblinded
trial in 20 patients with cancer and neuropathy
revealed that gabapentin not only reduced pain
scores but also reduced the need for rescue pain
medication.159 In a small study in patients with
HIV with sensory neuropathy, both pain and sleep
scores improved in gabapentin-treated patients as
compared with those receiving placebo.160 The
incidence of gabapentin-induced somnolence was
TisdaleC013_236-249 1/12/10 2:38 PM Page 245
notably high in this particular cohort (80%), but
otherwise this agent was generally well tolerated.
In contrast, however, a phase III trial of gabapentin
in 115 patients with CIPN proved disappointing.
After 6 weeks of therapy with either gabapentin or
matching placebo, the severity of pain scores was
not improved in the treatment group.161
Lamotrigine has also been studied for the treat-
ment of neuropathic pain syndromes, and has
demonstrated some benefit for the treatment of
peripheral neuropathy in patients with HIV. In a
double-blind, randomized trial, Simpson et al.162
studied the effects of lamotrigine versus placebo in
patients with HIV who were afflicted with periph-
eral neuropathy. Patients were stratified according
to whether or not they were receiving neurotoxic
antiretroviral agents. Pain scores were significantly
improved in lamotrigine-treated patients who were
currently receiving neurotoxic HIV medications.
Other antiepileptic drugs, such as carbamazepine,
topiramate, and valproic acid, can be used if other
treatments fail. These agents may inhibit the
metabolism of drugs metabolized via the
cytochrome P-450 system. Topical preparations
such as capsaicin and lidocaine are associated with
a low incidence of systemic side effects and have
been shown to be effective in treating neuropathic
pain. Results with these agents, unfortunately,
have been generally disappointing in patients with
HIV-associated neuropathy, and thus their use
should be restricted to adjunctive therapy if other
options are ineffective.151,153 Opioid analgesics and
tramadol are also options in patients experiencing
inadequate relief or intolerable side effects with
other agents.
INFORMATION FOR PATIENTS
Patients for whom potentially neurotoxic drugs
are prescribed should be instructed regarding the
signs and symptoms of drug-induced peripheral
neuropathy. Patients should understand that for
many drugs, symptoms might not appear until
late in therapy or even after therapy has been
completed or discontinued. Patients should be
instructed to consult their pharmacist or physi-
cian as soon as they begin to experience abnormal
sensations or pain occurring in the extremities so
that peripheral neuropathy can be identified early
enough to permit intervention. Finally, patients
should make their pharmacist and physician
aware of all medications they are taking to pre-
vent the occurrence of drug interactions that may
predispose them to drug-induced peripheral neu-
ropathy.
CHAPTER 13 • Peripheral Neuropathy 245
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111. Shiraishi S, Le Quesne PM, Gajree T. The effect of
vincristine on nerve regeneration in the rat: an
electrophysiological study. J Neurol Sci. 1985;71:9-17.
112. Siskind MS, Thienemann D, Kirlin L. Isoniazid-induced
neurotoxicity in chronic dialysis patients: report of three
cases and a review of the literature. Nephron.
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113. Schaumburg H, Kaplan J, Windebank A, et al. Sensory
neuropathy from pyridoxine abuse: a new megavitamin
syndrome. N Engl J Med. 1983;309:445-448.
114. Berger AR, Schaumburg HH, Schroeder C, et al. Dose
response, coasting, and differential fiber vulnerability in
human toxic neuropathy: a prospective study of
pyridoxine neurotoxicity. Neurology. 1992;42:1367-1370.
115. Bhagra A, Rao RD. Chemotherapy-induced neuropathy.
Curr Oncol Rep. 2007;9:290-299.
116. Hausheer FH, Schilsky RL, Bain S, et al. Diagnosis,
management, and evaluation of chemotherapy-induced
peripheral neuropathy. Semin Oncol. 2006;33:15-49.
117. Hess CW, Hunziker T, Kupfer A, et al. Thalidomide-
induced peripheral neuropathy: a prospective clinical,
neurophysiological and pharmacogenetic evaluation. J
Neurol. 1986;233:83-89.
118. Mileshkin L, Stark R, Day B, et al. Development of
neuropathy in patients with myeloma treated with
thalidomide: patterns of occurrence and the role of
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2006;24:4507-4514.
119. Olesen LL, Jensen TS. Prevention and management of
drug-induced peripheral neuropathy. Drug Saf.
1991;6:302-314.
120. van den Bent MJ, van Putten WL, Hilkens PH, et al.
Retreatment with dose-dense weekly cisplatin after
previous cisplatin chemotherapy is not complicated by
significant neuro-toxicity. Eur J Cancer. 2002;38:387-391.
121. Postma TJ, Vermorken JB, Liefting AJ, et al. Paclitaxel-
induced neuropathy. Ann Oncol. 1995;6:489-494.
122. Verstappen CC, Heimans JJ, Hoekman K, et al.
Neurotoxic complications of chemotherapy in patients
with cancer: clinical signs and optimal management.
Drugs. 2003;63:1549-1563.
123. Eisenhauer EA, ten Bokkel Huinink WW, Swenerton KD,
et al. European-Canadian randomized trial of paclitaxel
in relapsed ovarian cancer: high-dose versus low-dose
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1994;12:2654-2666.
124. Simpson DM. Selected peripheral neuropathies associated
with human immunodeficiency virus infection and
antiretroviral therapy. J Neurovirol. 2002;8 Suppl 2:33-41.
125. Bianchi G, Vitali G, Caraceni A, et al. Symptomatic and
neurophysiological responses of paclitaxel- or cisplatin-
induced neuropathy to oral acetyl-L-carnitine. Eur J
Cancer. 2005;41:1746-1750.
126. Youle M, Osio M. A double-blind, parallel-group,
placebo-controlled, multicentre study of acetyl L-
carnitine in the symptomatic treatment of antiretroviral
toxic neuropathy in patients with HIV-1 infection. HIV
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127. Flatters SJ, Xiao WH, Bennett GJ. Acetyl-L-carnitine
prevents and reduces paclitaxel-induced painful
peripheral neuropathy. Neurosci Lett. 2006;397:219-223.
128. Stillman M, Cata JP. Management of chemotherapy-
induced peripheral neuropathy. Curr Pain Headache Rep.
2006;10:279-287.
129. Albers J, Chaudhry V, Cavaletti G, et al. Interventions for
preventing neuropathy caused by cisplatin and related
compounds. Cochrane Database Syst Rev. 2007:CD005228.
130. Openshaw H, Beamon K, Synold TW, et al.
Neurophysiological study of peripheral neuropathy after
high-dose paclitaxel: lack of neuroprotective effect of
amifostine. Clin Cancer Res. 2004;10:461-467.
131. Gamelin L, Boisdron-Celle M, Delva R, et al. Prevention
of oxaliplatin-related neurotoxicity by calcium and
magnesium infusions: a retrospective study of 161
patients receiving oxaliplatin combined with 5-
fluorouracil and leucovorin for advanced colorectal
cancer. Clin Cancer Res. 2004;10:4055-4061.
132. Eckel F, Schmelz R, Adelsberger H, et al. [Prevention of
oxaliplatin-induced neuropathy by carbamazepine: a
pilot study]. Dtsch Med Wochenschr. 2002;127:78-82.
133. Argyriou AA, Chroni E, Polychronopoulos P, et al.
Efficacy of oxcarbazepine for prophylaxis against
cumulative oxaliplatin-induced neuropathy. Neurology.
2006;67:2253-2255.
134. von Delius S, Eckel F, Wagenpfeil S, et al. Carbamazepine
for prevention of oxaliplatin-related neurotoxicity in
patients with advanced colorectal cancer: final results of
a randomised, controlled, multicenter phase II study.
Invest New Drugs. 2007;25:173-180.
135. Vahdat L, Papadopoulos K, Lange D, et al. Reduction of
paclitaxel-induced peripheral neuropathy with
glutamine. Clin Cancer Res. 2001;7:1192-1197.
136. Wang WS, Lin JK, Lin TC, et al. Oral glutamine is
effective for preventing oxaliplatin-induced neuropathy
in colorectal cancer patients. Oncologist 2007;12:312-319.
137. Stubblefield MD, Vahdat LT, Balmaceda CM, Troxel AB,
Hesdorffer CS, Gooch CL. Glutamine as a
neuroprotective agent in high-dose paclitaxel-induced
peripheral neuropathy: a clinical and electrophysiologic
study. Clin Oncol (R Coll Radiol). 2005;17:271-276.
138. Cascinu S, Catalano V, Cordella L, et al. Neuroprotective
effect of reduced glutathione on oxaliplatin-based
chemotherapy in advanced colorectal cancer: a
randomized, double-blind, placebo-controlled trial. J Clin
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139. Argyriou AA, Chroni E, Koutras A, et al. Vitamin E for
prophylaxis against chemotherapy-induced neuropathy:
a randomized controlled trial. Neurology. 2005;64:26-31.
140. Susman E. Xaliproden lessens oxaliplatin-mediated
neuropathy. Lancet Oncol. 2006;7:288.
141. Apfel SC, Arezzo JC, Lipson L, et al. Nerve growth factor
prevents experimental cisplatin neuropathy. Ann Neurol.
1992;31:76-80.
142. Contreras PC, Vaught JL, Gruner JA, et al. Insulin-like
growth factor-I prevents development of a vincristine
neuropathy in mice. Brain Res. 1997;774:20-26.
143. van der Hoop RG, Vecht CJ, van der Burg ME, et al.
Prevention of cisplatin neurotoxicity with an ACTH(4-9)
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1990;322:89-94.
144. Koeppen S, Verstappen CC, Korte R, et al. Lack of
neuroprotection by an ACTH (4-9) analogue: a
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145. Roberts JA, Jenison EL, Kim K, et al. A randomized,
multicenter, double-blind, placebo-controlled, dose-
finding study of ORG 2766 in the prevention or delay of
cisplatin-induced neuropathies in women with ovarian
cancer. Gynecol Oncol. 1997;67:172-177.
146. Wilson RH, Lehky T, Thomas RR, et al. Acute oxaliplatin-
induced peripheral nerve hyperexcitability. J Clin Oncol.
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147. Hochster HS, Grothey A, Childs BH. Use of calcium and
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neurotoxicity. J Clin Oncol. 2007;25:4028-4029.
148. Markman M. Managing taxane toxicities. Support Care
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149. Shin SS, Hyson AM, Castaneda C, et al. Peripheral
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150. Maestri A, De Pasquale Ceratti A, et al. A pilot study on
the effect of acetyl-L-carnitine in paclitaxel- and
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151. Estanislao L, Carter K, McArthur J, et al. A randomized
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152. McArthur JC, Yiannoutsos C, Simpson DM, et al. A phase
II trial of nerve growth factor for sensory neuropathy
associated with HIV infection. AIDS Clinical Trials Group
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153. Paice JA, Ferrans CE, Lashley FR, et al. Topical capsaicin
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154. Schifitto G, Yiannoutsos C, Simpson DM, et al. Long-
term treatment with recombinant nerve growth factor
for HIV-associated sensory neuropathy. Neurology.
2001;57:1313-1316.
155. Kieburtz K, Simpson D, Yiannoutsos C, et al. A
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156. Shlay JC, Chaloner K, Max MB, et al. Acupuncture and
amitriptyline for pain due to HIV-related peripheral
CHAPTER 13 • Peripheral Neuropathy 249
neuropathy: a randomized controlled trial. Terry Beirn
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157. Backonja M, Beydoun A, Edwards KR, et al. Gabapentin
for the symptomatic treatment of painful neuropathy in
patients with diabetes mellitus: a randomized controlled
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158. Rowbotham M, Harden N, Stacey B, et al. Gabapentin for
the treatment of postherpetic neuralgia: a randomized
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159. Lossignol DA, Plehiers B, Body JJ. [Gabapentin
(Neurontin) and cancer pain: a pilot study]. Rev Med
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160. Hahn K, Arendt G, Braun JS, et al. A placebo-controlled
trial of gabapentin for painful HIV-associated sensory
neuropathies. J Neurol. 2004;251:1260-1266.
161. Rao RD, Michalak JC, Sloan JA, et al. Efficacy of
gabapentin in the management of chemotherapy-
induced peripheral neuropathy: a phase 3 randomized,
double-blind, placebo-controlled, crossover trial (N00C3).
Cancer. 2007;110:2110-2118.
162. Simpson DM, McArthur JC, Olney R, et al.
Lamotrigine for HIV-associated painful sensory
neuropathies: a placebo-controlled trial. Neurology.
2003;60:1508-1514.
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CHAPTER 14
Visual Disturbances
O ver 20 classes of drugs have been associated
with the development of visual disturbances
and ocular toxicities. The reported ocular effects
range from benign and transient to very severe.
Health care practitioners should be aware of these
in order to assess the cause of specific and some-
times serious ocular problems associated with
drugs.
CAUSATIVE AGENTS
Drugs and herbal supplements that have been report-
ed to cause or exacerbate visual disturbances are list-
ed in Table 14–1.1-150 A wide array of medications can
cause visual disturbances through various mecha-
nisms. These ocular problems can occur despite
administration at the recommended daily dose.
Many drug classes, such as the antihistamines,
antipsychotics, and tricyclic antidepressants, pos-
sess anticholinergic properties that are known to
induce visual disturbances. Some medications with
strong anticholinergic effects may cause mydriasis,
the basis of photophobia that may occur in
patients using these agents. Often, these visual dis-
turbances are associated with overdose (e.g.,
diphenhydramine) or topical or accidental intro-
duction into the eye (e.g., scopolamine patch).
Anticholinergics may also precipitate angle-closure
glaucoma and aggravate open-angle glaucoma.
Cycloplegia occurs to a lesser extent.1-3,28
Amiodarone, a widely used antiarrhythmic
medication, is known to cause bilateral corneal
deposition, especially when used long term at
higher doses. Only minimal deposits develop in
patients taking 100 to 200 mg/day. However, at
doses exceeding 400 mg/day, corneal deposits
250
Yaman Kaakeh and Steven R. Abel
develop in nearly 100% of patients. The majority
of patients are unaffected by these deposits; only
4% to 9% of users report visual disturbances.
Anterior subcapsular lens opacities and halo vision
have been associated with amiodarone therapy,
although to a lesser extent. One serious complica-
tion is optic neuropathy, which is relatively rare
but can gradually progress to blindness. Because of
its long half-life, amiodarone-induced optic neu-
ropathy may progress even after discontinua-
tion.1,2,5,12,22-35
The antimalarials chloroquine and hydroxy-
chloroquine are known to cause ocular distur-
bances, although the latter to a lesser extent.1,2 Like
amiodarone, these drugs can cause corneal deposits
in nearly all patients, even at therapeutic doses.
The majority of adverse ocular effects associated
with these drugs are dose- and time-dependent.
Maculopathy and retinopathy are rare and most
commonly associated with long-term, high-dose
therapy. Maculopathy is very serious, and is
reversible only if it is diagnosed in its early phase.
Macular changes may progress even after therapy
with the drug is discontinued. Serious retinal toxi-
city associated with chloroquine can develop in
association with cumulative doses exceeding 100 g.
Retinopathy may develop after 1 to 3 years, but
case reports have described onset in as little as 6
months. In contrast, the total daily dose, rather
than the cumulative dose, appears to be more
important with hydroxychloroquine. The risk of
retinopathy is much smaller when the daily dose is
6.5 mg/kg or less for up to 10 years. Blurred vision
is rare and usually associated with high doses
(500–700 mg/day). Cases of nyctalopia (night
blindness) and oculogyric crisis have been reported
in association with chloroquine.2
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CHAPTER 14 • Visual Disturbances 251

TABLE 14–1 Agents Implicated in Drug-Induced Visual Disturbances

Drug Effect(s) Incidence Level of Evidence
(see page xii for explanation)
1-4,a
Acetazolamide Angle-closure glaucoma NK C
Myopia NK B
Albuterol1,4,b Mydriasis NK C
Alendronate5-13 Blurred vision NK B
Conjunctivitis NK B
Ocular pain NK B
Scleritis NK B
Uveitis NK B
Alfuzosin5 Amblyopia NK B
Blurred vision NK B
Floppy iris syndrome NK B
Allopurinol1,14-18 Cataracts NK B
Amantadine1,4,19-21,c Corneal edema 0.1–1%d A
Corneal lesions 0.1–1%d A
Decreased vision 0.1–1%d A
Keratitis NK B
Mydriasis NK B
Oculogyric crises NK B
Optic nerve palsy 0.1–1% A
Photosensitivity 0.1–1% A
Visual hallucinations NK B
Amiodarone1,2,5,12,22-35,e Blurred vision NK B
Corneal deposits 69–100% A
Halo vision 1.4–40%d B
Lens opacities 22–60% A
Optic neuropathy 1.3–1.8% A
Photophobia NK B
Amphetamine1,2,4,f Decreased vision NK B
Disturbed color vision NK B
Mydriasis NK B
Visual hallucinations NK B
Anidulafungin36 Blurred vision <2% A
Ocular pain <2% A
Anticholinergics1-3,28,g Cycloplegia NK B
Decreased accommodation NK B
Decreased vision NK B
Mydriasis NK B
Photophobia NK B
Aspirin1,3,28,37 Aggravation of sicca NK C
Blurred vision NK C
Intraocular hemorrhage NK C
Myopia (transient) NK C
Periorbital edema NK C
Superficial punctate keratitis NK C
Atorvastatin3,38-40 Amblyopia <2% A
Dry eyes <2% A
Eye hemorrhage <2% A
Glaucoma <2% A
(Continued)
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252 SECTION III • Drug-Induced Neurological Diseases

TABLE 14–1 Agents Implicated in Drug-Induced Visual Disturbances (Continued)

Drug Effect(s) Incidence Level of Evidence

Atorvastatin3,38-40 Ophthalmoplegia NK C
(Continued) Ptosis of eyelid NK C
Barbiturates1,2,h Disturbed ocular movement NK B
Miosis NK B
Mydriasis NK B
Ptosis NK B
Bishop’s weed Phototoxicity NK C
(Ammi visnaga)41,42
Bitter orange Phototoxicity NK C
(Citrus aurantium)41,42
Black mustard Eye irritation NK C
(Brassica nigra)41-43
Bromocriptine34,44 Blurred vision NK C
Myopia NK C
Burning bush Phototoxicity NK C
(Dictamnus albus)41,42
Busulfan1,31,45-47, i Cataracts 12–47% B
Calcium-channel Blurred vision NK B
blockers1,2, j Transient blindness NK B
Canthaxanthine5,12,41,42,48 Crystalline retinopathy NK C
Retinal depositsd NK C
Carbamazepine1,34,37,49-51,k Blurred vision Up to 5%d B
Conjunctivitis NK C
Diplopia Up to 17%d B
Lens opacities NK C
Oculogyric crises NK C
Retinopathy NK C
Carmustine1-3,34,37,52,53,l Arterial narrowing NK C
Blurred vision NK C
Conjunctivitis NK C
Intraretinal hemorrhage NK C
Neuroretinitis NK B
Ocular pain NK C
Retinal infarction NK C
Celecoxib12,13,54-60 Blurred vision 0.1–1.9% A
Chromatopsia NK C
Conjunctivitis 0.1–1.9% A
Glaucoma 0.1–1.9% A
Ocular pain 0.1–1.9% A
Celery (Apium Phototoxicity NK C
graveolens)41,42
Cetirizine8,35,61,62 Blindness <2% A
Blurred vision NK C
Keratoconjunctivitis sicca NK C
Oculogyric crises NK C
Pupillary changes NK C
Xerophthalmia <2% A
(Continued)
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CHAPTER 14 • Visual Disturbances 253

TABLE 14–1 Agents Implicated in Drug-Induced Visual Disturbances (Continued)

Drug Effect(s) Incidence Level of Evidence

Chamomile Allergic conjunctivitis NK C
(Matricaria chamomilla)5,12,41-43
Chaulmoogra Visual disturbances NK C
(Hydrocarpus species)41,42
Chloramphenicol1,3,28,m Optic neuritis NK B
Retrobulbar neuritis NK B
Chlorella41,42 Photosensitivity NK C
Chloroquine5,12,28,31,34,63-67,n Blurred vision NKd A
Corneal deposits Up to 95%d A
Maculopathy <1%d A
Nyctalopia NK C
Oculogyric crises NK C
Retinopathy <1%d A
Chlorpheniramine1-3,o Blurred vision 1% B
Decreased lacrimation NK B
Mydriasis NK B
Chlorpromazine1,3,28,31,34,68,p Cataracts/lens deposits NK B
Conjunctival pigmentation Up to 46% B
Corneal deposits Up to 95% B
Epithelial keratopathy NK C
Eyelid pigmentation NK B
Pupillary changes NK B
Retinal pigment deposits NK C
Cimetidine1,2,4 Decreased vision NK B
Mydriasis NK B
Photophobia NK B
Visual hallucinations NK B
Ciprofloxacin69 Blurred vision <1% A
Decreased vision <1% A
Diplopia <1% A
Disturbed color vision <1% A
Ocular pain <1% A
Clomiphene1-3,70,q Blurred vision 1.5–10%d A
Mydriasis 5–10%d B
Optic neuropathy NK B
Visual field changes 5–10%d B
Visual sensations 5–10%d B
Clonidine1,2,r Dry, itchy eyes NK B
Miosis NK B
Contrayerva Phototoxicity NK C
(Dorstenia contrayerva)41,42
Corticosteroids1,2,25,28,31,34,47,71, s Cataracts 10–40%d A
Decreased vision NK B
Exophthalmos NK C
Increased IOP 30%d A
Mydriasis NK B
Myopia NK B
Optic neuropathy NK C
Papilledema NK B
Pseudotumor cerebri NK B
(Continued)
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254 SECTION III • Drug-Induced Neurological Diseases

TABLE 14–1 Agents Implicated in Drug-Induced Visual Disturbances (Continued)

Drug Effect(s) Incidence Level of Evidence

Cyclophosphamide1,2,37,47,t Blepharoconjunctivitis NK B
Blurred vision Up to 17% B
Keratoconjunctivitis sicca Up to 50% B
Optic neuropathy NK C
Pinpoint pupils NK B
Cyclosporine3,34,72,73 Conjunctivitis <2% A
Cortical blindness NK B
Optic disk edema 2.5% A
Cypress spurge Conjunctivitis NK C
(Euphorbia Corneal defects NK C
cyparissias)41-43 Eyelid swelling NK C
Cytarabine3,43,74,75,u Blurred vision NK B
Corneal toxicity Up to 80% A
Keratoconjunctivitis Up to 100% A
Ocular burning NK B
Photophobia NK B
Datura Mydriasis NK C
(D. stramonium,
D. wrightii)5,12,41,42
Dextroamphetamine1,2,4,f Decreased vision NK B
Mydriasis NK B
Visual hallucinations NK B
Diazepam1,4,30,50,76 Blurred vision NK B
Conjunctivitis NK B
Diplopia NK B
Nystagmus NK B
Diazoxide1,2,v Epiphora Up to 20% B
Diclofenac28,54,77 Abnormal vision Up to 2% B
Corneal infiltrates NK C
Photosensitivity NK C
Digitalis1-3,28,34,78,w Blurred vision 16–20%d B
Decreased visual acuity 16–20%d B
Disturbed color vision 16–20%d B
Halo vision 16–20%d B
Retrobulbar neuritis NK C
Dimethyl sulfoxide41,42 Ocular burning NK C
Docetaxel3,4,31,79,80 Conjunctivitis 1.1–5.1% A
Epiphora Up to 10% A
Open-angle glaucoma NK C
Doxazosin5,81 Amblyopia NK B
Blurred vision <1% B
Floppy iris syndrome <1% B
Doxorubicin1,2,47, x Blurred vision NK B
Conjunctivitis NK B
Epiphora Up to 25% B
Duloxetine82 Blurred vision 3% A
Echineacea Purpurea5,12,41,42 Conjunctivitis NK C
(Continued)
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CHAPTER 14 • Visual Disturbances 255

TABLE 14–1 Agents Implicated in Drug-Induced Visual Disturbances (Continued)

Drug Effect(s) Incidence Level of Evidence

Ethambutol1,2,5,12,25,28,31,34,83,y Retrobulbar neuritis 1–50%d B
Ethanol1,3 Decreased accommodation NK B
Diplopia NK B
Disturbed color vision NK B
Mydriasis NK B
Nystagmus NK B
Etidronate5-8,12,13 Blurred vision NK B
Conjunctivitis NK B
Etodolac52,84 Blurred vision 1–3% A
Conjunctivitis NK C
Fluorouracil1,2,34,47,z Cicatricial ectropion NK C
Conjunctivitis NK C
Corneal erosions NK C
Epiphora NK C
Optic nerve atrophy NK C
Periorbital edema NK C
Photophobia NK C
Fluoxetine1,3,4,85,86,aa Abnormal vision 2% A
Conjunctivitis 0.1–1% A
Dry eyes 0.1–1% A
Eye tics NK C
Mydriasis 0.1–1% A
Photophobia 0.1–1% A
Fluvoxamine4 Amblyopia 3% A
Mydriasis NK C
Furosemide1 Blurred vision NK B
Xanthopsia NK B
Gabapentin1,87 Amblyopia 2.7– 4.2% A
Diplopia 1.2–5.9% A
Nystagmus 1–8.3% A
Visual hallucinations 0.1–1% A
Gentamicin1,2,bb Pseudotumor cerebri NK B
Ginkgo biloba5,12,41,42 Spontaneous hyphema NK C
Retinal hemorrhage NK C
Retrobulbar hemorrhage NK C
G Conjunctivitis NK C
(Andira araroba)41-43
Gold1,3,28,34,cc Cornea l /conjunctival deposits Up to 80% A
Lenticular deposits 36–55% A
Ophthalmoplegia NK C
Guanethidine1,2,dd Blurred vision Up to 17% A
Conjunctivitis NK B
Miosis NK B
Ptosis NK B
Haronga Phototoxicity NK C
(Haronga madagascariensis)41,42
Henbane Impaired accommodation NK C
(Hyoscyamus niger)41,42 Mydriasis NK C
(Continued)
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256 SECTION III • Drug-Induced Neurological Diseases

TABLE 14–1 Agents Implicated in Drug-Induced Visual Disturbances (Continued)

Drug Effect(s) Incidence Level of Evidence

Heparin34 Subconjunctival hemorrhage NK C
Herb Paris Miosis NK C
(Paris quadrifolia)41,42
Hogweed Phototoxicity NK C
(Heracleum sphondylium)41,42
Horse chestnut Visual disturbances NK C
(Aesculus hippocastanum)41,42
Huperzine A41,42 Blurred vision NK C
Hydrochlorothiazide1,4,28,37,a Angle-closure glaucoma NK B
Decreased lacrimation NK B
Myopia NK B
Photosensitivity NK C
5-Hydroxytryptophan41,42 Blurred vision NK C
Mydriasis NK C
Hydroxychloroquine Blurred vision NK B
1-3,5,12,28,31,34,35,63-65,88,ee
Corneal deposits Up to 100%d A
Diplopia NK C
Maculopathy <1%d A
Retinopathy <1%d A
Visual-field defects NK B
Ibandronate13,43,89 Conjunctivitis NK B
Scleritis NK C
Uveitis NK C
Ibuprofen3,28,34,54,90-94,ff Amblyopia <1% C
Blurred vision <1% C
Decreased vision <1% C
Diplopia NK C
Disturbed color vision <1% C
Scotomata <1% C
Uveitis NK C
Visual field defects <1% C
Vortex keratopathy NK C
Imatinib35,43,95-98 Blurred vision 1–10% A
Conjunctivitis 1–10% A
Dry eyes 0.1–1% A
Epiphora 7–18% A
Glaucoma <0.1% A
Macular edema <0.1% A
Periorbital edema Up to 74% A
Vitreous hemorrhage <0.1% A
Indomethacin3,28,34,54,gg Blurred vision NK C
Corneal deposits NK C
RPE changes NK C
Retinopathy NK C
Retinopathy of prematurity NK C
Interferon1,3,25,47 Conjunctivitis NK B
Decreased vision NK B
Disk edema NK C
Retinopathy Up to 57% B
(Continued)
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CHAPTER 14 • Visual Disturbances 257

TABLE 14–1 Agents Implicated in Drug-Induced Visual Disturbances (Continued)

Drug Effect(s) Incidence Level of Evidence

Interleukin-21,2,99,hh Diplopia NK C
Palinopsia NK C
Visual field defects NK C
Isoniazid1,12,ii Optic neuritis NK B
Isotretinoin3,8,12,13,28,35,43,100-106 Blepharoconjunctivitis 20–43% B
Blurred vision 16–27% B
Cataracts NK C
Corneal deposits 5–7% B
Decreased vision 5.9% B
Dry eyes 14–33% B
Impaired dark adaptation 8% B
Intracranial hypertension 10% B
Myopia NK C
Optic neuritis 1.9% C
Photophobia 5% B
Subconjunctival hemorrhage 1.4% C
Superficial punctate keratitis Up to 22% B
Kava kava Impaired accommodation NK C
(Piper methysticum)41,42
Ketorolac107 Abnormal vision <1% A
Blurred vision <1% A
Lamotrigine1,13,50,108,109 Blurred vision 11–25% A
Conjunctivitis NK B
Diplopia 24–49% A
Nystagmus < 5% B
Licorice5,12,41,42 Decreased vision NK C
Visual disturbances NK C
Lily of the valley Disturbed color perception NK C
(Convallaria majalis)41,42
Linezolid31,jj Optic neuropathy NK C
Lithium1-3,37 Blurred vision NK B
Decreased accommodation Up to 10% B
Exophthalmos 11% B
Nystagmus NK B
Ocular teratogenesis NK B
Oculogyric crises NK C
Papilledema NK C
Photophobia NK C
Lorazepam1 Blurred vision NK B
Conjunctivitis NK B
Diplopia NK B
Nystagmus NK B
Lovage Phototoxicity NK C
(Levisticum officinale)41,42
Lovastatin3,33,110,111 Blurred vision 1% A
Mandrake Mydriasis NK C
(Mandragora officinarum)41,42
(Continued)
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258 SECTION III • Drug-Induced Neurological Diseases

TABLE 14–1 Agents Implicated in Drug-Induced Visual Disturbances (Continued)

Drug Effect(s) Incidence Level of Evidence

Marijuana3,5 Blurred vision NK C
Dry eyes NK C
Mydriasis NK C
Photophobia NK C
Nystagmus (with overdose) NK C
Masterwort Phototoxicity NK C
(Peucedanum ostruthium)41,42
Mechlorethamine2,3,47 Necrotizing uveitis 25% B
Methamphetamine1,2,4,f Decreased vision NK B
Mydriasis NK B
Visual hallucinations NK B
Methotrexate1,3,28,47 Blurred vision NK B
Conjunctivitis 10–19% B
Periorbital edema 20–49% B
Optic neuropathy NK B
Metronidazole34,37 Myopia NK C
Oculogyric crises NK C
Optic neuritis NK C
Photophobia NK C
Visual field defects NK C
Midazolam1,3 Blurred vision <1% B
Conjunctivitis NK B
Decreased accommodation <1% B
Diplopia <1% B
Miosis <1% B
Nystagmus <1% B
Mountain laurel Temporary loss of vision NK C
(Kalmia latifolia)41,42
Nalidixic acid1,2,kk Papilledema NK B
Visual loss NK B
Visual sensations NK B
Naproxen1,3 Cataracts NK C
Corneal opacities <1% B
Decreased vision <5% B
Optic disk edema <1% B
Optic neuritis <1% B
Optic papillitis <1% B
Narcotics1,2,ll Decreased accommodation NK B
Diplopia NK B
Epiphora NK B
Irregular pupils NK B
Miosis NK B
Niacin5,12,41,42,112 Blurred vision 25% B
Dryness 20% B
Eyelid edema 10% B
Cystoid macular edema NK B
(Continued)
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CHAPTER 14 • Visual Disturbances 259

TABLE 14–1 Agents Implicated in Drug-Induced Visual Disturbances (Continued)

Drug Effect(s) Incidence Level of Evidence

Oral contraceptives1,3,25,34,mm Disturbed color vision NK B
Optic neuritis NK B
Pseudotumor cerebri NK B
Retrobulbar neuritis NK B

Paclitaxel1,3,4,31 Decreased vision 20%d B

Open-angle glaucoma NK C
Scintillating scotoma 43%d B
Vision loss NK C
Pamidronate3,5-8,12,13,113,114 Blurred vision NK B
Conjunctivitis <1% B
Episcleritis <1% B
Nerve palsy NK C
Ocular pain NK B
Photophobia NK B
Ptosis NK C
Retrobulbar neuritis NK C
Scleritis <1% B
Uveitis (anterior) NK B
Xanthopsia NK C
Paroxetine3,4,115 Anisocoria <0.1% A
Blurred vision 2–5% A
Conjunctivitis 0.1–1% A
Mydriasis 0.1–1% A
Optic neuritis NK B
Parsnip (Pastinaca sativa)41,42 Photosensitivity NK C
Phenmetrazine1,2,4,nn Cataracts NK C
Decreased vision NK B
Mydriasis NK B
Retinal venous thrombosis NK B
Visual hallucinations NK B
Phenylbutazone1,2,oo Conjunctivitis NK B
Decreased vision NK B
Optic neuritis NK C
Retinal hemorrhage NK B
Phenytoin28,34,pp Cataracts NKd B
Diplopia NK B
Disturbed color vision NK B
Nystagmus NK B
Ophthalmoplegia NK C
Pimpinella Photosensitivity NK C
(Pimpinella major)41,42
Pregabalin116 Abnormal vision Up to 5%d A
Blurred vision 1–12%d A
Diplopia Up to 12%d A
Propofol3,34,117,qq External ophthalmoplegia NK C
Conjunctival chemosis NK C
Propolis41,42 Conjunctivitis NK C
(Continued)
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260 SECTION III • Drug-Induced Neurological Diseases

TABLE 14–1 Agents Implicated in Drug-Induced Visual Disturbances (Continued)

Drug Effect(s) Incidence Level of Evidence

Psyllium Allergic conjunctivitis NK C
(Plantago ovata, P. afra)41-43
Pyrethrum Irritative conjunctivitis NK C
(Chrysanthemum Keratitis NK C
cinerarifolium)41,42
Quetiapine5,rr Cataracts <0.1% C
Ranitidine1,2,4 Decreased vision NK B
Disturbed color vision NK C
Mydriasis NK B
Photophobia NK B
Visual hallucinations NK B
Reserpine1,2,ss Conjunctivitis NK B
Miosis NK B
Risedronate5-8,12,13 Blurred vision NK B
Conjunctivitis NK B
Ocular pain NK B
Scleritis NK B
Uveitis NK B
Risperidone118 Abnormal vision 1 –7% A
Conjunctivitis <1% A
Rue Photosensitivity NK C
(Ruta graveolens)41,42
Scopolia41,42 Impaired accommodation NK C
Sildenafil3,5,12,31,35,119-125,tt Blurred vision 3-50%d A
Disturbed color vision 3-50%d A
Increased brightness 3-50%d A
NAION NK B
Other ocular effects in clinical trialsuu <2% A
Ocular effects in postmarketing phasevv NK B
Solifenacin126 Blurred vision 3.8– 4.8%d A
Dry eyes 0.3–1.6%d A
Spironolactone1 Decreased vision NK B
Myopia NK B
St. John’s wort Photosensitivity NK C
(Hypericum perforatum)41,42
Strophanthus Disturbed color perception NK C
(Strophanthus kombe) 41,42
Sulfamethoxazole– Angle-closure glaucoma NK B
trimethoprim2,4,37,127 Myopia NK B
Uveitis NK B
Sulfonamides1,4,13,34,37,127-129,ww Decreased vision NK B
Myopia NK B
Optic neuritis NK B
Photosensitivity NK B
Uveitis NK C
(Continued)
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CHAPTER 14 • Visual Disturbances 261

TABLE 14–1 Agents Implicated in Drug-Induced Visual Disturbances (Continued)

Agent Effect(s) Incidence Level of Evidence

Tadalafil3,5,12,124,130,131,d Blurred vision <2% A
Conjunctivitis <2% A
Disturbed color vision <0.1% A
Eyelid edema <2% A
Increased lacrimation <2% A
NAION NK B
Ocular pain <2% A
Retinal artery occlusion NK B
Retinal vein thrombosis NK B
Visual field defect NK B
Tamoxifen1,3,5,12,28,31,34,132-134,xx Cataracts 8% A
Corneal opacities 1–11% B
Disturbed color vision NK B
Optic neuritis <2% B
Retinopathy 1–6.3% B
Tamsulosin1,135 Amblyopia NK B
Blurred vision Up to 2% A
Floppy iris syndrome NK B
Terazosin5,136 Amblyopia Up to 1.3% A
Blurred vision Up to 1.6% A
Floppy iris syndrome <1% B
Tetracyclines1,3,34,37,yy Conjunctival deposits NK B
Diplopia NK B
Disturbed color vision NK B
Myopia NK B
Papilledema NK B
Pseudotumor cerebri NK B
Scleral discoloration NK B
Thioridazine1,28,31,34,137,138,d,zz Oculogyric crises NK C
Retinopathy NKd B
Tiagabine3,12 Amblyopia 4–9%d A
Disturbed color vision 50% B
Tiludronate7,139 Cataracts 3% A
Conjunctivitis 3% A
Glaucoma 3% A
Scotoma NK C
Tolu balsam Phototoxicity NK C
(Myroxylon balsamum)41,42
Topiramate4,5,8,12,35,140,141 Abnormal/blurred vision Up to 13% A
Conjunctivitis 1–2% A
Diplopia Up to 14%d A
Eye pain At least 1% A
Glaucoma NK B
Myopia NK A
Nystagmus Up to 15% A
Tricyclic Cycloplegia NK B
antidepressants1,2,4,34,aaa Decreased vision NK B
Mydriasis NK B
(Continued)
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262 SECTION III • Drug-Induced Neurological Diseases

TABLE 14–1 Agents Implicated in Drug-Induced Visual Disturbances (Continued)

Drug Effect(s) Incidence Level of Evidence

Trimethadione1,2,bbb Diplopia NK B
Photophobia NK B
Visual glare NK B
Valerian Mydriasis NK C
(Valeriana officinalis)41,42
Vardenafil3,5,12,124,142,143,d Blurred vision <2% A
Chromatopsia <2% A
Conjunctivitis <2% A
Dim vision <2% A
Disturbed color vision <2% A
Glaucoma <2% A
NAION NK B
Ocular pain <2% A
Photophobia <2% A
Reduced visual acuity NK B
Retinal vein occlusion NK B
Venlafaxine3,4,144,145 Blurred vision 4–6% A
Glaucoma NK B
Mydriasis >1% A
Vigabatrin1,3,12,146,147 Diplopia 2% B
Visual field constriction 0.1–52% B
Vinca alkaloids1,2,3,34,48,ccc Blindness NK C
Diplopia Up to 32%d B
Extraocular muscle paresis Up to 50%d B
Optic neuropathy NK B
Ptosis 32–78%d B
Voriconazole3,148,149,ddd Abnormal vision 21–33% A
Blurred vision 21–33% A
Disturbed color vision 21–33% A
Photophobia 21–33% A
Visual hallucinations 16.7% B
Wafer ash Phototoxicity NK C
(Ptelea trifoliata)41,42
Warfarin1-4,25 Angle-closure glaucoma NK C
Decreased vision NK C
Ocular hemorrhage 5–11% B
Ocular teratogenic effect NK B
Wormseed Visual disturbances NK C
(Artemisia cina)41,42
Yellow jasmine Abnormal eye movements NK C
(Gelsemium Diplopia NK C
sempervirens)41,42 Heavy eyelids NK C
Zoledronic acid3,5,6,13,35,150 Blurred vision NK B
Conjunctivitis NK B
Eye irritation NK B
Mydriasis NK C
Scleritis NK B
Uveitis NK B
(Continued)
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TABLE 14–1 Agents Implicated in Drug-Induced Visual Disturbances (Continued)

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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264 SECTION III • Drug-Induced Neurological Diseases

TABLE 14–1 Agents Implicated in Drug-Induced Visual Disturbances (Continued)

u Corneal toxicity and conjunctivitis have been reported with high-dose (3 g/m2) therapy.
v Increased lacrimation may continue after drug is discontinued.
wA glare phenomenon and a snowy appearance in objects have been associated primarily with digitalis intoxication. In a small num-
ber of cases, reversible reduction in visual acuity has been noted. Also associated with changes in the visual fields.
x Effects may last for several days after discontinuation of treatment.
y At doses of 15 mg/kg/day, virtually devoid of ocular side effects. Such effects are rare at doses of 25 mg/kg/day for a duration of a
few months. Patients treated for prolonged periods should undergo routine visual examinations including visual fields. Most effects are
reversible after therapy is discontinued.
z Ocular effects are reversible and seldom interfere with continued therapy.
aaAdministration of 20–40 mg/day has been associated with paroxysmal contractions of the muscles around the lateral aspect of the
eye. This effect occurred 3–4 wk after initiation of fluoxetine therapy and resolved within 2 wk of discontinuation.
bb Rare, but has been well documented with secondary papilledema and visual loss.
ccDeposition in the conjunctiva and superficial cornea more common than in the lens or deep cornea. Incidence in cornea of 40–80%
in total doses of ≥1.5 g. Lens deposits observed in 36–55% of patients on long-term therapy (>3 yr; lowest cumulative dose, 2.5 g). Visual
acuity is unaffected and deposits resolve 3–12 mo after discontinuation of therapy.
dd Sporadically documented. One study reported a 17% incidence of blurred vision in patients taking 70 mg/day.
eeSee chloroquine comments (n). Incidence of corneal deposits up to 100% after 4 or more years of therapy. At <4 yr incidence is
~1–28%, much lower than that associated with chloroquine.
ff Rare; blurred vision has been reported in patients taking from four 200-mg tablets/wk to six tablets/day. Changes in color vision have

rarely been reported.

gg Rare; changes in color vision have rarely been reported.
hh Visual complications have occurred during the first or second treatment cycle, usually within 5–6 days after initiation of therapy.
Ocular symptoms included diplopia, binocular negative scotomata (isolated areas of varying size and shape in which vision is absent
or depressed. These are not perceived ordinarily but may be apparent upon completion of a visual-field examination), and palinopsia
(abnormal recurring visual imagery). In most cases, treatment was continued for the entire planned duration of therapy. Symptoms
resolved after discontinuation of therapy.
ii
Prevalence not well defined, but appears to be significantly less common than peripheral neuritis. Evaluation difficult because most
patients are malnourished, chronic alcoholics, or receiving multiple medications. Preexisting eye disease does not appear to be a pre-
disposing factor.
jj
Only 12 reported cases of optic neuropathy associated with extended use (>28 days). Duration of therapy ranged from 5–11 mo before
development of optic neuropathy.
kkVisual sensations are most common. Main feature: a brightly colored appearance of objects, occurring soon after the drug is taken.
Although quinolone antibiotics are nalidixic acid derivatives, they have rarely been associated with these ocular side effects. Visual loss
appears to be temporary; lasting between 30 min and 72 hr. Papilledema can also occur, secondary to increased intracranial pressure,
primarily in infants and young children. This is reversible upon discontinuation.
ll
Miosis often with morphine in normal doses; slight with other agents. The effect is secondary to central nervous system action on
the pupilloconstrictor center. Other effects are associated with narcotic withdrawal.
mm Optic neuritis is quite rare. In patients with retinal vascular abnormalities, use of oral contraceptives may not be prudent. Numerous
other possible ocular adverse effects are associated with these agents, and further documentation is required.
nn Ocular effects reported with high doses; can induce or exacerbate narrow-angle glaucoma. There have only been a few case reports

linking phenmetrazine with cataracts; further documentation is needed.

ooDecreased vision is the most common ocular side effect; may be caused by increased lens hydration. Conjunctivitis is less prevalent
and may be associated with development of Stevens–Johnson syndrome or an allergic reaction.
pp
Nystagmus in patients with high plasma concentrations (>20 mcg/mL); rarely occurs with other hydantoins. Cataracts may occur
rarely with prolonged therapy.
qqIn 6 of 50 patients undergoing ear, nose, and throat procedures using standardized anesthesia with propofol there was inability to
open their eyes either spontaneously or in response to verbal commands. This effect lasted between 3 and 20 min after the end of
anesthetic administration. Complete loss of ocular motility occurred in two patients. This was a transient, myasthenia-like weakness.
rrThere have been only 34 cases of cataracts reported with use of quetiapine. At this time, the association remains classified as “unlike-
ly,” since cataract development in these patients may have been due to other, causes such as age-related lens changes. A causal rela-
tionship has not been established.
(Continued)
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TABLE 14–1 Agents Implicated in Drug-Induced Visual Disturbances (Continued)

ssConjunctivitis is common and secondary to dilation of conjunctival blood vessels. Miosis can result, although the symptoms are gen-
erally mild and can last up to 1 wk after a single dose.
ttColor vision alterations are mild to moderate. Blurred vision does not impair visual acuity. Visual alterations usually subside within
4 hr after the dose.
uuOcular effects of sildenafil identified in premarketing clinical trials occurring in <2% of patients: cataracts, conjunctivitis, dry eyes,
eye hemorrhage, mydriasis, ocular pain, and photophobia.
vv Ocular effects of sildenafil identified in postmarketing phase (incidence not known): decreased vision, diplopia, increased intraocu-
lar pressure, ocular burning, ocular redness, ocular swelling/pressure, retinal vascular disease, vitreous detachment/traction.
ww Myopia is the most common ocular effect (acute and reversible). Optic neuritis can occur even in association with low doses,
although it is usually reversible with complete recovery of vision.
xx Generally occur in patients taking higher-than-normal doses for 12–18 months.
yy Myopia appears to be acute, transient, and rare. Papilledema is also rare; more prevalent in children and adolescents.
zzPigmentary retinopathy is primarily associated with maximal daily doses or average doses >1000 mg. Daily doses up to 600 mg are
relatively safe; the risk associated with daily doses of 600–800 mg is uncertain, but rarely suspected. If doses >800 mg/day are used,
periodic ophthalmoscopic examinations may uncover problems before visual acuity is compromised.
aaaMydriasis is the most common ocular adverse effect. Cycloplegia is rare. Precipitation of angle-closure glaucoma has been report-
ed.
bbb
A prolonged glare or dazzle occurs when eyes are exposed to light. The glare is reversible, occurs at the retinal level, and is more
common in adolescents and adults; rare in young children.
cccOnset of extraocular muscle paresis/paralysis may be seen as early as 2 weeks. Dose-related. Most recover fully when therapy is
discontinued.
dddTransient; onset within 30 minutes and usually persist for 30 minutes. Most common in first week of therapy, resolving with contin-
ued drug administration. May be dose-related.

Ocular adverse effects associated with the
antiepileptic medications are not uncommon.
Blurred vision, diplopia, and nystagmus are well-
documented adverse effects of carbamazepine and
phenytoin.109 Downbeat nystagmus has been
described as a consequence of lamotrigine therapy
in two patients. In both cases, plasma lamotrigine
concentrations were supratherapeutic and the nys-
tagmus was reversible upon correction of plasma
concentrations.108 There have also been numerous
case reports linking topiramate with acute, second-
ary bilateral angle-closure glaucoma.140
The bisphosphonates have been linked to a
number of ocular inflammatory side effects,
including nonspecific conjunctivitis and anterior
uveitis. They are currently the only drugs reported
to cause scleritis.6,7,113 While this is a rare occur-
rence, scleritis is a serious condition associated
with ocular pain and may lead to vision loss.6
Selective phosphodiesterase-5 inhibitors, such as
sildenafil, tadalafil, and vardenafil, are commonly
associated with transient visual disturbances,
namely changes in color perception, blurred
vision, and photophobia. These effects are largely
dose-dependent. Sildenafil appears to carry the
greatest dose-dependency, with impaired color per-
ception observed at the standard 50 mg dose (3%),
and increasing in incidence to 11% and 40% to
50% in association with the 100-mg and 200-mg
doses, respectively. There are also reports of nonar-
teritic anterior ischemic optic neuropathy (NAION)
in patients using selective phosphodiesterase-5
inhibitors. However, a causal relationship cannot
yet be confirmed, as other risk factors may have
been involved.5,119,121,123
Other drug classes associated with ocular
adverse effects include analgesics, anticoagulants,
antidepressants, antiinfectives, antihyperlipi-
demics, antineoplastic agents, barbiturates, benzo-
diazepines, ␤-adrenergic blockers, calcium-channel
blockers, corticosteroids, hypouricemics, immune
modulators, and oral contraceptives.1,2 Numerous
visual disturbances have also been reported in asso-
ciation with the use of herbal products and nutri-
tional supplements.3,5,12,41-43,48
EPIDEMIOLOGY
The exact incidence of drug-induced visual distur-
bances is not known. Numerous factors including
the specific medication, frequency of administra-
tion, cumulative dose, genetics, and route of
administration may influence the occurrence of
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266 SECTION III • Drug-Induced Neurological Diseases
visual disturbances. For example, 5% of the popu-
lation receiving therapy with topical corticos-
teroids experience an increase in intraocular
pressure of 16 mm Hg or greater, while 30% of the
population experiences an increase of 6 to 15 mm
Hg following 4 weeks or more of treatment.151,152
Further assessment documented that primary
open-angle glaucoma developed in 13% of high
corticosteroid responders (defined as >15-mm-Hg
increase) and ocular hypertension occurred in
63.8%. Open-angle glaucoma developed in no low-
responders (<5-mm-Hg increase) and ocular hyper-
tension occurred in only 2.4%.153
Corneal opacities occur in 70 to 100% of
patients receiving amiodarone, while optic neu-
ropathy develops in approximately 2%. The anti-
convulsant lamotrigine causes diplopia and
blurred vision with incidences of 22% and 15%,
respectively.1 Agents used for erectile dysfunction
(sildenafil, vardenafil, tadalafil) are associated with
dose-dependent changes in color vision, blurred
vision, increased light perception, and visualiza-
tion of flashing lights in 3% to 50% of patients.1
High-dose cytarabine has been associated with
blurred vision and keratitis in 100% of treated
patients. Decreased visual acuity, diplopia, and
color vision defects have been reported with nons-
teroidal antiinflammatory drugs even in patients
taking small doses infrequently.1 The known inci-
dences of visual disturbances associated with spe-
cific drugs are provided in Table 14–1.
MECHANISMS
The pathogenesis of drug-induced visual distur-
bances appears to be multifactorial. Cumulative or
daily dose, duration of therapy, properties of spe-
cific medications, and site of drug action all appear
to play a role. While we are knowledgeable about
mechanisms of visual disturbances associated with
some drugs, mechanisms have yet to be described
for the majority of medications. Known mecha-
nisms can be divided into direct and indirect drug
effects on the ocular structures (Table 14–2).
The blood aqueous barrier and posterior
blood–retinal barrier serve to naturally defend the
intraocular structures of the eye from exogenous
compounds or toxins. However, some compounds
may penetrate the tight junctional areas between
retinal pigment epithelium (RPE) cells and within
the retinal capillary endothelium. Over time, this
can lead to a number of ocular problems, such as
epithelial keratopathy or pigmentary deposition.
Medications may also interact directly with RPE
cells, resulting in retinotoxicity. For example, the
antimalarial drugs chloroquine and hydroxychloro-
quine have high affinity for melanin in RPE and
may induce photoreceptor degradation, leading to
the development of a “bulls-eye” maculopathy.33,154
Amphophilic compounds, such as amiodarone,
accumulate in lysosomes and cannot be eliminated
effectively. This leads to the accumulation of the
drug in intracytoplasmic lamellar bodies in the eye.
The resulting complex with cellular phospholipids
on the epithelium cannot be metabolized by lysoso-
mal phospholipids, and corneal deposits occur.
These deposits are dose- and duration-related and
resemble chloroquine-induced keratopathy.32,33,154
Amiodarone also causes optic neuropathy, although
the mechanism is less clear. It is thought that a vas-
cular occlusion from a decrease in axoplasmic flow
may be involved. This may result in optic disk edema
that progresses to optic neuropathy.30,32
Amiodarone-induced optic neuropathy is sometimes
difficult to distinguish from NAION, since patients
may already have underlying vascular disease.5
The mechanism of ethambutol-induced optic
neuropathy remains incompletely understood. It is
postulated that ethambutol chelates retinal-cell
copper, which acts as a cofactor for mitochondrial
functioning in the optic nerve. As a result, axonal
transport in the optic nerve may be compromised,
leading to optic neuropathy. These effects appear
to be dose- and time-dependent.12
An increase in intraocular pressure, caused by
certain medications such as corticosteroids, can
exacerbate open-angle glaucoma. Mydriatics and
mydriatic/cycloplegics could exacerbate angle-clo-
sure glaucoma, because this is an anatomical event.
Drugs that cause mydriasis also have the potential
to exacerbate angle-closure glaucoma. Secretion of
medications through the lacrimal gland can lead to
blurred vision, eye and contact-lens discomfort,
dry eye symptoms, and conjunctivitis.
Drug-induced ocular effects are time-depend-
ent, suggesting that tissue accumulation likely plays
a role in the pathophysiology.32 Visual disturbances
can also result from the indirect actions of certain
medications on nonocular structures. Blurred
vision is a common side effect of anticholinergic
medications and benzodiazepines. Phenytoin may
cause cerebellar degeneration and eventually lead
to irreversible cerebellar deficits. Vision changes
may be an indication of toxic plasma drug concen-
trations.1 Drugs that lead to hypertension, metabol-
ic abnormalities, sedation, or dehydration may also
lead to visual problems. Nystagmus induced by car-
bamazepine and phenytoin may be due to cere-
bellovestibular dysfunction.49
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CHAPTER 14 • Visual Disturbances 267

TABLE 14–2 Mechanisms of Drug-Induced Visual Disturbances

Effect Mechanisms
Angle-closure glaucoma Associated with mydriasis, which causes closure of the anterior chamber angle,
preventing elimination of aqueous humor from the eye. May also result from
swelling of the lens or other ocular tissues
Blepharoconjunctivitis Drug concentrating in the tears causing irritation and subsequent inflammation of
the eyelids and conjunctiva
Blurred vision Direct ocular effects (see: Dry eyes, Keratoconjunctivitis sicca, Mydriasis) or
indirect effects in nonocular areas (central nervous system depression,
cranial-nerve damage, hypertension, etc.)
Cataracts/lens opacities Medications may precipitate as fine granules, typically in the superficial cortex of
the lens and in the anterior capsule
Color vision disturbances Impairment of retinal-cell dysfunction through direct effect of medications on
the ocular tissues. May occur at therapeutic plasma drug concentrations
Conjunctival pigmentation Direct deposition of medication in cysts within conjunctival epithelium
Corneal deposits Accumulation of the drug in the intracytoplasmic lamellar bodies in the eye.
These bodies form complexes with cellular phospholipids that cannot be
metabolized by lysosomal phospholipids, and corneal deposits result. May be
time- or concentration-dependent, or both.
Diplopia See: Dry eyes, Keratoconjunctivitis sicca, Mydriasis
Dry eyes Secretion of medication by lacrimal gland, leading to local eye irritation.
Medications may also indirectly lead to inadequate tear production and
subsequent irritation.
Epiphora Excessive lacrimation due to local irritation of the eye or obstruction of tear
ducts, thus preventing the drainage of tears
Exophthalmos Unknown
Extraocular muscle paresis Cranial-nerve palsy, which may lead to dysfunction in one or more extraocular
muscles
Floppy iris syndrome ␣1-adrenergic blocking effect (alfuzosin, terazosin, etc.) may also selectively block
receptors in the iris dilator muscle, leading to atrophy of the iris dilator smooth
muscle
Halo vision Unknown
Intraocular pressure increases See: Angle-closure glaucoma
Keratoconjunctivitis sicca Secretion of medication by lacrimal gland, leading to local eye irritation. Medications
may also lead indirectly to inadequate tear production and subsequent irritation.
Mydriasis Sympathetic stimulation may cause contraction of the radial muscle, and
subsequent dilation of the iris. Mydriasis may precipitate or exacerbate angle-
closure glaucoma
Necrotizing uveitis Medications may cause uveitis through direct toxicity or indirect mechanisms,
including stimulation of the immune system to develop antidrug antibodies; drug
combining with melanin and inducing uveitis by reducing the pigment’s free radi-
cal scavenger properties; antibiotics stimulating the immune system by liberating
antigens from dead microorganisms.
Nystagmus Cerebellovestibular dysfunction. Dose-related, potentially irreversible cerebellar
deficits.
Optic neuropathy Decrease in axoplasmic flow may lead to vascular occlusion, resulting in optic disk
edema that progresses to optic neuropathy; compromised axonal transport in
optic nerve that leads to optic neuropathy. May be time- or concentration-
dependent, or both.
Continued
TisdaleC14_250-274 1/12/10 2:39 PM Page 268

268 SECTION III • Drug-Induced Neurological Diseases

TABLE 14–2 Mechanisms of Drug-Induced Visual Disturbances (Continued)

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

Docetaxel and paclitaxel have also been associ-

CLINICAL PRESENTATION
AND DIFFERENTIAL DIAGNOSIS
Signs and symptoms of drug-induced visual distur-
bances are listed in Table 14–3. The onset of signs
and symptoms is largely time-dependent, meaning
that they are more likely to occur later in therapy. In
some cases, drug-induced visual disturbances may
mimic the signs and symptoms of other diseases,
requiring clinicians to carefully evaluate each con-
tributing factor that might result in visual distur-
bances experienced by their patients. Table 14–4 lists
conditions that should be considered in the differ-
ential diagnosis of drug-induced visual disturbances.
Hypersensitivity reactions including dermatitis
are most likely to affect the eyelids. Quinolones may
cause hyperpigmentation of the eyelids, while 5-flu-
orouracil is associated with blepharitis and conjunc-
tivitis involvement.31 Keratoconjunctival disorders
present mainly as conjunctival hyperemia (red eye)
with or without superficial corneal involvement.31
Medications structurally related to sulfonamides
may induce swelling of the ciliary body leading to
the development of angle-closure glaucoma.31
Agents that dilate the pupil (adrenergics, anti-
cholinergics) may cause blurred vision or precipi-
tate angle-closure glaucoma in patients with
narrow anterior chamber angles. Angle-closure
glaucoma is a medical emergency. Symptoms
include swelling of the eye, clouding of the cornea,
and severe pain. Corticosteroids can increase
intraocular pressure (IOP) in genetically predis-
posed patients, resulting in ocular hypertension of
open-angle glaucoma.151,152 Although corticos-
teroid-induced increases in IOP are associated most
frequently with topical ophthalmic preparations,
systemic corticosteroids may cause a similar
response, although with a lesser magnitude.156
ated with the development of open-angle glauco-
ma.31 Unlike angle-closure glaucoma, ocular
hypertension and open-angle glaucoma are silent
diseases that are frequently symptom-free until
there has been significant damage to the optic
nerve, resulting in a reduction of the visual field.
Patients may describe a loss of central or peripher-
al vision.
Corticosteroids, allopurinol, phenothiazines,
and busulfan have been reported to cause
cataracts. 31 Symptoms of cataracts include a
reduction in visual clarity and a reduced ability to
see in low light or darkness. Many drugs adminis-
tered systemically reach the retina via the sys-
temic circulation. Phenothiazines may bind to
melanin, causing a severe phototoxic retinopa-
thy.31 Amiodarone appears to cause a bilateral
optic neuropathy that is similar to nonarteritic
ischemic optic neuropathy, a condition also asso-
ciated with the use of cyclic guanosine
monophosphate (cGMP)–specific phosphodi-
esterase-5 inhibitors for erectile dysfunction.31
Amiodarone has also been associated with lens
deposits and keratopathy due to corneal alter-
ations related to a drug-induced lipid storage dis-
order.157 Symptoms of keratopathy include glare
and photophobia.
RISK FACTORS
In some instances, the risk of visual disturbances
associated with medications is genetically prede-
termined. An example of this was previously
described in the discussion related to the propen-
sity for topical corticosteroids to cause increases
in intraocular pressure. Myocilin is a gene linked
TisdaleC14_250-274 1/12/10 2:39 PM Page 269
TABLE 14–3 Signs and Symptoms Associated
with Drug-Induced Visual Disturbances155
• Blepharitis
• Blindness
• Blurred vision
• Cataracts
• Color vision alterations
• Conjunctivitis
• Decreased vision (miosis, mydriasis)
• Diplopia
• Glaucoma
• Halos around lights
• Hallucinations
• Hazy vision
• Increased intraocular pressure
• Keratopathy
• Night blindness
• Optic neuropathy
• Photophobia
• Pseudotumor cerebri
• Scleritis
• Tunnel vision
• Vertigo
• Visual field constriction
to the most common form of glaucoma (open-
angle). Overexpression of myocilin due to corti-
costeroid administration augments the pressure
response.158 There are other studies that suggest
that individuals who are at medium risk are het-
erozygotes while higher risk patients are homozy-
gotes. 159 Unfortunately, there is no reliable
genomic test to assess individuals prior to treat-
ment to determine the likelihood for exaggerated
and potentially adverse response to these medica-
tions.
In other cases, the risk for visual disturbances
is increased with the daily drug dose, the cumula-
tive drug dose, or both, as well as the use of com-
binations of medications associated with the
development of visual disturbances. Underlying
disease states may predispose patients taking cer-
tain medications to visual disturbances. The risk
for corticosteroid-induced ocular hypertension is
greater in patients with high myopia, diabetes
mellitus, or connective-tissue disease (particularly
rheumatoid arthritis).156 The best approach to
minimize the risk of drug-induced visual distur-
bances involves accurate diagnosis, including all
underlying disease states and preexisting drug
therapy (prescription and nonprescription drugs
and natural remedies), past therapeutic response
to medications, including adverse events, and
CHAPTER 14 • Visual Disturbances 269
TABLE 14–4 Conditions to Consider in the
Differential Diagnosis of Drug-Induced Visual
Disturbances30,33,155
• scular accident
• Concussion
• Dehydration
• Encephalopathy
• Exposure to environmental toxins
• Drug intoxication
• Glaucoma
• Head trauma
• Hypertension
• Intracranial lesions/infarction
• Macular degeneration
• Medication history
• Migraine
• Metabolic disorders
• Neoplasm
• Psychiatric disease
• Retinal disease /detachment
• Seizures
• Trauma
• Vitreous detachment
careful patient monitoring based on the benefit-
to-risk ratio of medications administered.
Practitioners must also recognize that some ocular
disorders will occur regardless of careful prescrib-
ing or monitoring practices. Ocular symptoms can
occur within the therapeutic range, often fre-
quently. The effects may be more marked at high-
er plasma concentrations.160 For example, while
age-related cataracts are slowly progressive, the
potential for their development exists in everyone,
depending upon longevity. Table 14–5 lists other
risk factors associated with drug-induced visual
disturbances.
MORBIDITY AND MORTALITY
Drug-induced visual disturbances pose a relatively
small risk of mortality. Conceivably, drug-induced
loss of vision could result in a situation associated
with bodily harm or death (i.e., personal or motor
vehicle accident).
Left untreated, acute emergencies such as drug-
induced angle-closure glaucoma could result in the
loss of sight in one or both eyes. Any acute or
chronic reduction in visual acuity, as well as clini-
cally significant reactions such as conjunctivitis
could be associated with the perception of dimin-
ished quality of life.
TisdaleC14_250-274 1/12/10 2:39 PM Page 270
270 SECTION III • Drug-Induced Neurological Diseases
TABLE 14–5 Risk Factors for Drug-Induced Visual
Disturbances
• Anatomic predisposition (e.g., narrow anterior cham-
ber angles)
• Concomitant use of multiple drugs, including herbal
therapies, that may cause visual disturbances (see
Table 14–1)
• Cumulative dose (e.g., chloroquine, >100 g )
• Daily dose (e.g., hydroxychloroquine 500–700 mg/day)
• Genetics (e.g., myocilin and topical ophthalmic corti-
costeroids)
• Underlying disease states/conditions (see Table 14–4)
PREVENTION
Some topically administered ocular medications are
associated with systemic toxicities that can include
visual disturbances. Topical atropine has been associ-
ated with blood pressure changes that affect vision.
The use of punctal occlusion minimizes systemic
absorption of the topically administered medication
and therefore reduces, but does not eliminate, the
associated risk. Punctal occlusion involves the appli-
cation of pressure to the inner canthus with the
index finger following topical administration of oph-
thalmic medication. Ideally, pressure should be
applied for approximately 2 minutes. However, use
of this technique, even for shorter periods will reduce
the potential for systemic absorption of the topically
administered medication.
The development of visual disturbances associ-
ated with systemic medications is frequently related
to the average daily dose administered, the duration
of treatment, and the cumulative dose of the med-
ication. Prescribers are encouraged to consider the
potential for visual disturbances associated with pre-
scribed medications and to appropriately monitor
patients for the occurrence of such effects. Health
providers may consider avoiding certain agents,
such as phosphodiesterase-5 inhibitors, in patients
already at high risk for certain ocular diseases, such
as NAION. Although there are only case reports link-
ing these agents to NAION, these patients may
already have compromised optic nerves due to vas-
cular disease. It is postulated that these medications
can lead to further neural function damage.
In some situations, visual disturbances occur in
association with medications that may be moni-
tored via the assessment of serum concentrations
(e.g., phenytoin). In such cases, therapeutic drug
monitoring is suggested as appropriate based on
clinical management of the patient and the poten-
tial for or suspicion of visual disturbances associat-
ed with the medication.
Routine ophthalmic examinations should be
completed in all individuals. The usual frequency for
examinations in patients without risk is every 2 years
for individuals 18 to 60 years of age, and yearly there-
after. Patients with risk factors, including medica-
tions, that may be associated with visual disturbances
should be seen more frequently, at least annually. In
addition, patients should be educated regarding the
necessity for follow-up visits if they receive medica-
tions that might be associated with the development
of visual disturbances. Prescribers should carefully
consider any underlying conditions that might make
a patient more prone to visual disturbances associat-
ed with medications. Product information is another
valuable tool in enabling individuals to assess the
potential for a medication to induce visual distur-
bances. Approaches to help prevent drug-induced
visual disturbances are outlined in Table 14-6
MANAGEMENT
Relatively little information exists regarding the
effective management of visual disturbances and
ocular toxicities. The decision to discontinue,
change, or even continue therapy with the offend-
ing agent is dependent on multiple factors (risk vs.
benefit, availability of alternative agents, severity
of disease). The key to appropriate management is
early identification.
Nonprescription or prescription medications
(decongestants, artificial tears, nonsteroidal antiin-
flammatory drugs) may be used to manage mild
visual disturbances, such as blurred vision or con-
junctivitis. Discontinuation of the offending agent
is usually necessary to ameliorate drug-induced
visual disturbances. This is especially true for more
serious ocular problems, such as retinopathy or
maculopathy. Discontinuation of bisphosphonates
is necessary for resolution of scleritis. Visual effects
associated with cyclooxygenase-2 inhibitors typi-
cally resolve within 72 hours of drug discontinua-
tion. Ocular adverse effects induced by phenytoin
often resolve with discontinuation or dose reduc-
tion, although in some cases nystagmus may per-
sist for 20 months or longer.1 Intraocular pressure
elevation, such as that caused by corticosteroids, is
an indication to taper the medication. Left uncon-
trolled, significant increases in intraocular pressure
could result in blindness. The antimalarial medica-
tions chloroquine and hydroxychloroquine may
produce retinopathy and maculopathy. These
effects are usually irreversible unless identified in
the very early stage. Progression may occur and
TisdaleC14_250-274 1/12/10 2:39 PM Page 271
TABLE 14–6 Approaches to Help Prevent Drug-
Induced Visual Disturbances
• Be aware of the potential for visual disturbances
• Discontinue therapy prior to reaching total cumula-
tive dose associated with visual disturbances
• Use punctal occlusion (for topical ophthalmic medica-
tions with the potential for systemic adverse effects)
• Restrict daily dose to minimize risk of visual distur-
bances
• Routine ophthalmic examinations
management may be limited to interventional
pharmacology or surgical intervention.
In situations in which discontinuation of the
medication is not always feasible (i.e., amio-
darone), reducing the dose may help attenuate
some of the visual disturbances. This is especially
true for obese patients, who may be receiving
above-normal doses of certain medications, such as
gentamicin.
INFORMATION FOR PATIENTS
Appropriate patient education is the key to pre-
venting the occurrence or reducing the impact of
drug-induced visual disturbances. The use of punc-
tal occlusion when administering topical oph-
thalmic medications reduces the potential
incidence of systemic side effects. The risks and
benefits of a particular therapy should be thor-
oughly conveyed to the patient. Routine oph-
thalmic examinations are central to eye health
assessment, and patients should have follow-up
examinations at the recommended frequency.
Patients should be advised to disclose all prescrip-
tion, nonprescription, and herbal medications to
their health care provider. Any rapid or sudden
changes in visual acuity should also be reported.
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93. Tullio CJ. Ibuprofen-induced visual disturbance. Am J
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99. Friedman DI, Hu EH, Sadun AA. Neuro-ophthalmic
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100. Fraunfelder FT, LaBraico JM, Meyer SM. Adverse ocular
reactions possibly associated with isotretinoin. Am J
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associated intracranial hypertension. Ophthalmology.
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effects possibly associated with isotretinoin usage. Am J
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103. Caffery BE, Josephson JE. Ocular side effects of
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104. Ellies P, Dighiero P, Legeais JM, et al. Persistent corneal
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CHAPTER 14 • Visual Disturbances 273
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106. Milson J, Jones DH, King K, et al. Ophthalmological
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120. Egan RA, Fraunfelder FW. Viagra and anterior ischemic
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125. Fraunfelder FW, Shults T. Non-arteritic anterior ischemic
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128. Flach AJ. Photosensitivity to sulfisoxazole ointment. Arch
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129. Flach AJ. Photosensitivity to topically applied
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130. Escaravage GK Jr, Wright JD Jr, Givre SJ. Tadalafil
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132. Heier JS, Dragoo RA, Enzenauer RW, et al. Screening for
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133. Pavlidis NA, Petris C, Briassoulis E, et al. Clear evidence
that long-term, low-dose tamoxifen treatment can
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134. Noureddin BN, Seoud M, Bashshur Z, et al. Ocular
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154. Hollander DA, Aldave AJ. Drug-induced corneal
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155. Fraunfelder FW. Ocular and systemic side effects of drugs.
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Asbury’s General Ophthalmology. New York, NY: The
McGraw Hill Companies; 2008.
156. Tripathi RC, Parapuram SK, Tripathi BJ, et al.
Corticosteroids and glaucoma risk. Drugs Aging.
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157. D’Amico DJ, Kenyon KR, Ruskin JN. Amiodarone
keratopathy: drug-induced lipid storage disease. Arch
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158. Wentz-Hunter K, Xiang S, Kazushiro O, et al.
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159. Kersey JP, Broadway DC. Corticosteroid-induced
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160. Plaa GL. Acute toxicity of antiepileptic drugs. Epilepsia.
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TisdaleC15_275-292 New 1/12/10 2:40 PM Page 275
CHAPTER 15
Delirium
D elirium is a common and sometimes fatal dis-
order characterized by a disturbance of con-
sciousness and a change in cognition that develops
over a short time.1 The disorder may have numer-
ous causes, including drugs.
CAUSATIVE AGENTS
Drug-induced delirium may be caused by a wide
array of drugs. However, there are a few agents that
are consistently associated with the development
of the disorder.2-6 These include high-risk drugs
that possess anticholinergic properties, such as
low-potency antipsychotics, tricyclic antidepres-
sants, older antihistamines, sedative hypnotics,
corticosteroids, and narcotics (Table 15–1).7-93
Other agents vary in their propensity for caus-
ing delirium. For instance, exposure to opiates has
been shown to increase the risk of delirium in
patients with cancer. However, it has been reported
that effectively using opiates to treat pain in post-
operative patients may actually reduce the risk of
delirium.17,94,95 The incidence of postoperative
delirium is approximately 50%.
In a meta-analysis, the association between
psychoactive medications and the development of
delirium in hospitalized patients was assessed.96
This meta-analysis reviewed 28 studies that
included several classes of psychotropic medica-
tions such as antiparkinsonians, anticonvulsants,
anticholinergics, antiemetics, antidepressants,
antipsychotics, benzodiazepines, corticosteroids,
histamine2–receptor antagonists, nonsteroidal
antiinflammatory drugs (NSAIDS), and opioid
analgesics. Only psychoactive medications
(grouped together) were found to be associated
Matthew A. Fuller and Mary C. Borovicka
with the development of delirium. No individual
medication was significantly associated with delir-
ium.
EPIDEMIOLOGY
Delirium is very common and has been reported in
14% to 24% of patients at hospital admission and
in up to 56% of hospitalized patients.97 Most
patients have multiple causes rather than a single
cause of delirium, especially if they are burdened
with medical problems or are elderly.
Although the majority of cases are thought to
be multifactorial, medications, particularly in the
case of patients taking multiple drugs (polyphar-
macy), have been cited as the single cause of delir-
ium in 12% to 39% of cases.4 Aside from
drug-induced causes, other frequently identified
causes of delirium include sensory and environ-
mental issues (poor vision and hearing), infection,
and fluid and electrolyte disturbances.98
MECHANISMS
There is a paucity of data describing mechanisms
of drug-induced delirium. Some mechanisms have
been determined through electrophysiological and
biochemical studies and brain scans (Table 15–2).99
The presence of anatomical lesions may lead to the
development of delirium. Symptoms are related to
the location of the lesion.
Acetylcholine has been implicated as the major
neurotransmitter involved in the development of
delirium. Despite various locations of lesions or
other neurochemical changes, acetylcholine
275
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276 SECTION III • Drug-Induced Neurological Diseases

TABLE 15–1 Agents Implicated in Drug-Induced Delirium

Drug Incidence Level of Evidence
(see page xii for explanation)

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)
TisdaleC15_275-292 New 1/12/10 2:40 PM Page 277

CHAPTER 15 • Delirium 277

TABLE 15–1 Agents Implicated in Drug-Induced Delirium (Continued)

Drug Incidence Level of Evidence

Doxepin40 NK C
Fluoxetine41 NK C
Paroxetine42 NK C
Sertraline12 NK C
Bupropion43 NK C
Venlafaxine44 NK C
Mirtazapine45 NK C
MONOAMINE OXIDASE INHIBITORS
Phenelzine47 NK C
Tranylcypromine46 NK C
DOPAMINERGIC AGENTS
Amantadine48 NK C
Levodopa49 NK C
Bromocriptine50 NK C
BENZODIAZEPINES
Lorazepam51 NK C
Diazepam52 NK C
Clonazepam53 NK C
Alprazolam54 NK C
Triazolam55 NK C
Clorazepate56 NK C
NONSTEROIDAL ANTIINFLAMMATORY DRUGS
Diclofenac58 NK C
Ibuprofen59 NK C
Ketoprofen60 NK C
Sulindac61 NK C
Indomethacin62 NK C
Salicylic acid63 NK C
CYCLOOXYGENASE-II INHIBITORS
Celecoxib64 NK C
ANGIOTENSIN-CONVERTING ENZYME INHIBITORS65
Enalapril NK C
Captopril NK C
Lisinopril NK C
MISCELLANEOUS ANTIHYPERTENSIVES65
Reserpine NK C
Clonidine NK C
(Continued)
TisdaleC15_275-292 New 1/12/10 2:40 PM Page 278

278 SECTION III • Drug-Induced Neurological Diseases

TABLE 15–1 Agents Implicated in Drug-Induced Delirium (Continued)

Drug Incidence Level of Evidence

Methyldopa NK C
CALCIUM-CHANNEL BLOCKERS
Nifedipine67 NK C
Verapamil66 NK C
␤-BLOCKERS
Atenolol69 NK C
Metoprolol70 NK C
Propranolol68 NK C
ANTIMICROBIALS
Tobramycin71 NK C
Azithromycin72 NK C
Clarithromycin73 NK C
Cephalexin74 NK C
Cephalothin75 NK C
76
Cefazolin NK C
Piperacillin/ tazobactam77 NK C
Ciprofloxacin78 NK C
Gatifloxacin79 NK C
Ofloxacin80 NK C
Levofloxacin81
Chloramphenicol82 NK C
Trimethoprim–sulfamethoxazole83 NK C
Linezolid84 NK C
HISTAMINE-2-RECEPTOR ANTAGONISTS
Cimetidine85 NK C
Ranitidine86 NK C
Nizatidine87 NK C
Famotidine88 NK C
ANTICHOLINERGICS89
Atropine90 NK C
Benztropine91 NK C
Scopolamine92 NK C
Tolterodine93 NK C
OTHER
Digoxin26,27 NK B
Alcohol withdrawal22 NK B
CI = confidence interval; NK = Not known; RR = relative risk; OR = odds ratio.
TisdaleC15_275-292 New 1/12/10 2:40 PM Page 279

CHAPTER 15 • Delirium 279

TABLE 15–2 Mechanisms of Drug-Induced Delirium

Drug Mechanism
Amitriptyline Decreased acetylcholine function
Atropine
Benztropine
Clomipramine
Clozapine
Desipramine
Doxepin
Imipramine
Olanzapine
Protriptyline
Quetiapine
Scopolamine
Thioridazine
Tolterodine
Amantadine Excess dopamine function
Levodopa
Bromocriptine
Prednisone Excess glucocorticoid activity
Alprazolam GABA dysfunction
Clonazepam
Clorazepate
Diazepam
Lorazepam
Triazolam
Fluoxetine Serotonin dysfunction
Paroxetine
Sertraline
GABA = gamma-aminobutyric acid

appears to be the final common pathway involved
in delirium.100 This is consistent with the acetyl-
choline hypothesis of cognitive impairment in
dementias such as Alzheimer’s disease. An age-
related decrease in acetylcholine reserve develops
in elderly patients, making them more vulner-
able to acute changes in plasma acetylcholine con-
centrations. Further support for this theory is the
relationship between the administration of anti-
cholinergic drugs and cognitive deficits, particular-
ly reduction in the ability to focus or maintain
attention and short-term memory deficits. Tune
and Egeli100 studied 91 patients meeting criteria for
delirium (n = 47) or dementia (n = 41) and found
that patients with delirium were taking a signifi-
cantly larger number of anticholinergic medica-
tions than the control group with dementia. It is
unlikely that acetylcholine is the sole neurotrans-
mitter involved in the development of delirium,
given its interaction with dopamine transmis-
sion.101 Dopamine exerts an inhibitory effect on
the release of acetylcholine.
Glucocorticoid excess also has been implicated
in the development of delirium.102 Preclinical and
clinical data support the hypothesis that increases
in plasma glucocorticoid concentrations associated
with various disorders, including depression,
dementia, and Cushing’s disease, lead to cognitive
impairment. Even modest increases in plasma glu-
cocorticoid concentrations over a period of 5 to 6
TisdaleC15_275-292 New 1/12/10 2:40 PM Page 280
280 SECTION III • Drug-Induced Neurological Diseases
years have led to reduced hippocampus-dependent
memory and hippocampus volumes. There also
may be a decrease in the hypothalamic–
pituitary–adrenal axis negative feedback loop in
response to elevated plasma glucocorticoid con-
centrations as well as an increased sensitivity to
adrenocorticotropic hormone stimulation.
Other possible neurotransmitters involved in
the pathogenesis of delirium include gamma-
aminobutyric acid, glutamate, ␤-endorphins, and
serotonin.103 Cerebrospinal fluid sampling in elder-
ly patients with delirium revealed diminished
somatostatin-like immunoreactivity and ␤-endor-
phin–like immunoreactivity. Therefore, while
acetylcholine most commonly has been implicated
in the development of delirium, the complete
pathogenesis remains unknown, but is likely mul-
tifactorial.
CLINICAL PRESENTATION AND
DIFFERENTIAL DIAGNOSIS
The Diagnostic and Statistical Manual on Mental
Disorders, Fourth Edition, Text Revision (also known
as DSM-IV-TR) characterizes delirium as a distur-
bance in consciousness and change in cognition
that occurs over a brief period of time.1 Symptoms
of drug-induced delirium do not differ from those
associated with delirium from other causes (Table
15–3).1,2,5 There may be a prodromal syndrome of
anxiety, changes in sleep patterns, disorientation,
irritability, and restlessness 1 to 3 days prior to the
full onset of delirium. Following the prodromal
syndrome, disturbances of consciousness, cogni-
tion, psychomotor function, and perhaps sleep
patterns develop. These disturbances advance over
a short period of time (hours to days) and the
symptoms fluctuate throughout the course of
the day, making recognition of the disorder
difficult.5,97 Patients may be easily distracted
and have a decreased awareness of their environ-
ment. Cognitive deficits such as disorientation
to place and time, dysarthria, and loss of recent
memory are common. In some patients, perceptu-
al disturbances develop, such as delusions, illu-
sions, or hallucinations. Psychomotor activity may
present as hyperactive, hypoactive, or mixed types.
Hyperactivity is characterized by agitation, restless-
ness, and emotional lability. Hypoactivity is char-
acterized by withdrawal, flat affect, lethargy, and
decreased responsiveness. Hypoactivity occurs
more frequently than hyperactivity, and is often
unrecognized in as many as 66% to 84% of hospi-
talized patients.104 In a study of patients in an
intensive care unit (ICU), 1.6%, 43.5%, and 54.1%
TABLE 15–3 Signs and Symptoms Associated
with Drug-Induced Delirium
• Autonomic activation (dilated pupils, dry mouth,
flushing, sweating, tachycardia)
• Coma
• Decreased ability to sustain or focus attention
• Disorientation to time or place
• Dysarthria
• Dysgraphia
• Dysnomia
• Easily distractible
• Electroencephalographic abnormalities
• Emotional disturbances (anger, anxiety, fear, eupho-
ria, apathy, depression)
• Emotional lability
• Hallucinations
• Hyperactivity (picking at things, trying to get out of
bed)
• Illusions
• Memory deficit (recent memory)
• Misinterpretations/misperceptions
• Neurologic abnormalities
• Rambling, pressured, or incoherent speech
• Restlessness
• Sleep disturbances
• Sluggishness or lethargy
• Stupor
of patients were diagnosed with hyperactive,
hypoactive, and mixed delirium, respectively.104
Patients with mixed psychomotor symptoms fluc-
tuate between hypoactive and hyperactive symp-
toms throughout the day. The sleep–wake cycle is
often disrupted, and patients may experience
insomnia, drowsiness during the day, or a com-
plete reversal of the sleep cycle. Emotional distur-
bances such as anxiety, depression, fear, anger,
irritability, aggression, or euphoria commonly
occur.
The incidence of delirium is very high in cer-
tain populations, including older postoperative
patients (15–53%), those in an ICU (70–87%) or
nursing home (60%), and patients at the end of life
(up to 83%).97 Geriatric, oncologic, pediatric, and
psychiatric patients are also at significant risk for
delirium.96,99
Any evaluation of a patient for drug-induced
delirium must include a careful and thorough med-
ication history. One must assess patients’ use of
nonprescription medications and drugs of abuse,
as both have been implicated in producing deliri-
um. Furthermore, a social history that includes
alcohol or illicit-drug use should alert the clinician
TisdaleC15_275-292 New 1/12/10 2:40 PM Page 281
to the potential for delirium, which may occur in
association with drug or alcohol withdrawal.2,105 In
the majority of cases, a multitude of causes exists,
including drugs, and all possibilities must be
explored.
The diagnosis of drug-induced delirium is pure-
ly clinical, as there are no laboratory tests that can
definitively diagnose the disorder. Along with the
medical history and clinical observation, the use of
rating scales may assist in confirming the diagno-
sis. A simple screening tool for delirium, the
Confusion Assessment Method,106 can be complet-
ed by clinicians in just a few minutes and has been
adapted to other settings, such as the ICU.107 The
Mini–Mental State Examination (MMSE) may also
be used to screen patients for delirium. Other
scales, such as the Delirium Rating scale108 and the
Memorial Delirium Assessment Scale,109 are used to
monitor symptoms over time. Differentiating delir-
ium from other disorders may be difficult as symp-
toms may overlap considerably. Delirium is also
frequently underdiagnosed. Studies report that
delirium occurring in patients on general medical
units is not diagnosed in 32% to 67% of cases.110 It
may also be difficult to distinguish drug-induced
delirium from delirium occurring as a result of
other causes. Conditions to consider in the differ-
ential diagnosis of drug-induced delirium are listed
in Table 15–4.
Patients with drug-induced delirium usually
have symptoms during intoxication, over an
TABLE 15–4 Conditions to Consider in the
Differential Diagnosis of Drug-Induced Delirium
• Dehydration
• Delirium not caused by drugs
• Dementia
• Depression
• Drug/alcohol use or withdrawal
• Fever
• Heart failure
• Hepatic insufficiency
• Hypercalcemia
• Hypoglycemia
• Hyponatremia or hypernatremia
• Hypoxia
• Infection
• Intoxication
• Mania
• Metabolic disturbances
• Kidney disease
• Shock
• Uremia
CHAPTER 15 • Delirium 281
extended period of time with continuous drug use,
or during drug or alcohol withdrawal. Delirium
during acute intoxication presents within minutes
to hours after ingestion of the substance (e.g.,
cocaine, hallucinogens).111 The potential for
delirium is increased if additional agents with
anticholinergic activity also are ingested. Drug-
induced delirium also may develop secondary to
the accumulation of a drug or its metabolite over
an extended period (e.g., barbiturates, alcohol)
or as a result of a combination of a suspect medi-
cation and a preexisting medical condition.1,112
Withdrawal delirium may last a few hours to sever-
al weeks, depending on the half-life of the
causative agent. This type of delirium results from
lower tissue and body fluid concentrations than
those to which the body has become accustomed.
Withdrawal delirium may also be precipitated by a
drug interaction, lowering the dose of a medica-
tion, or increased drug clearance.113
Most underlying causes of delirium often can
be easily ruled out. However, the diagnosis of
dementia is often confused with that of deliri-
um.1,5,112 Although memory impairment is com-
mon to both delirium and dementia, delirium is
associated with impairment in consciousness dur-
ing which patients are not alert or oriented to time
or place. In addition, symptoms that develop rap-
idly and fluctuate throughout the day are more
consistent with delirium than dementia.
Differentiation between the two disorders is impor-
tant and may require a more complete history
from family or caregivers (Table 15–5).114
RISK FACTORS
Specific risk factors for delirium have been identi-
fied (Table 15–6). It is unknown whether the risk
factors for drug-induced delirium are different
from those for delirium secondary to other causes.
A decrease in the metabolism or elimination of
psychoactive drugs is a risk factor for drug-induced
delirium. In some patients, decreased metabolism
may be linked to drug interactions, heart failure,
hepatic insufficiency, or kidney disease (or all of
these). The anticholinergic effects of psychoactive
compounds may to contribute to delirium through
increased neuronal excitability and rate of neu-
ronal adenosine triphosphate consumption,
release of dopamine and glutamate, and stimula-
tion of the sympathetic nervous system. The post-
operative state is also a risk factor for delirium
(moderate pain: odds ratio [OR], 2.2; 95% confi-
dence interval (CI), 1.2–4.0; severe pain: OR, 3.7;
95% CI, 1.5–9.0].95
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282 SECTION III • Drug-Induced Neurological Diseases
TABLE 15–5 Clinical Features That Distinguish Delirium and Dementia114
Clinical Feature Delirium
Onset Sudden
Course Fluctuating
Attention Disordered
Cognition Disordered
Consciousness Reduced
Delusions Fleeting
Hallucinations Usually visual
Involuntary movements Asterixis or course tremor
Orientation Usually impaired
Physical illness or drug toxicity Present
Psychomotor activity Altered
Speech Often incoherent
A number of medical conditions are recognized
as potential risk factors for delirium and may pos-
sibly increase the risk of drug-induced delirium. A
diagnosis of dementia or cognitive impairment has
been identified as a risk factor for delirium.5,115
Disorders that affect neuronal functioning may
cause delirium, including cerebral infarction,
seizures, head trauma, vascular disease, Parkinson’s
disease, and dementia.2,5,115 Various metabolic
abnormalities may contribute to the development
of delirium, including electrolyte disturbances, kid-
ney disease, hepatic insufficiency, edema from
heart failure, thiamine deficiency, and acid–base
imbalance.2,111 Conditions that lead to a change in
the delivery of oxygen or nutrients to the central
nervous system—myocardial infarction, cardiac
arrhythmias, heart failure, respiratory failure,
chronic obstructive pulmonary disease, anemia,
hypoxia, or shock—also may predispose patients to
delirium. Patients with a history of alcohol abuse,
hypertension, and higher Acute Physiology and
Chronic Health Evaluation (also known as
APACHE) II scores have been identified as being at
an increased risk for delirium.116
Infection and fever also are risk factors for
delirium. Hyperthermia causes a central release of
norepinephrine, glutamate, and dopamine, which
may predispose the patient to a delirious
episode.111 Patients with the human immunodefi-
ciency virus infection may have delirium caused by
viral infection of neuronal tissue, opportunistic
infection of the central nervous system, or meta-
bolic encephalopathy.117,118 Antibiotics, antivirals,
or antifungals may be involved in drug interac-
tions contributing to the potential for delirium.
Dementia
Insidious
Stable
Normal
Impaired
Clear
Usually absent
Usually absent
Usually absent
Often impaired
Often present
Normal
Word-finding difficulty and perseveration
Cancer increases the risk of delirium, possibly
because of associated hepatic or renal failure, prer-
enal azotemia, hyperosmolality, dehydration, med-
ications (e.g., opioids), hypoxia, disseminated
intravascular coagulation, recent surgery, metasta-
sis to the brain or other areas of the central nerv-
ous system, and infection.119,120 In addition,
patients undergoing treatment for cancer are often
receiving therapy with complex medication regi-
mens associated with drug interactions that
increase the potential for delirium.
The increased risk of delirium in postoperative
patients appears to be linked to common occur-
rences such as infection, hypoxia, myocardial
ischemia, metabolic derangement, decreased
mobility, and exposure to anticholinergic
drugs.113,121 The increased risk in this population
does not correlate with the number of previous sur-
geries, the duration of the surgical procedure, the
type of anesthesia used, or the surgical technique
used.
Conditions of deprivation, including both
sleep and sensory deprivation (hearing loss, visual
impairment, immobility) such as that which
occurs in an ICU have been found to be risk factors
for delirium.122 An interventional study of patients
with deprivation as a risk factor for delirium found
that nonpharmacologic interventions such as pro-
viding a relaxing nighttime environment, hearing
aids, glasses or magnifying glasses, large-print
materials, other forms of communication, and
exercise all may lower the incidence of delirium.122
Advanced age is considered to be a risk factor
for delirium, because elderly patients are more like-
ly to have multiple predisposing risk fac-
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CHAPTER 15 • Delirium 283

ed with higher rates of long-term care placement

TABLE 15–6 Risk Factors for Drug-Induced and increased mortality rates.122 Medical complica-
Delirium tions such as immobility, skin breakdown, falls,
• Acid–base imbalance and aspiration pneumonia occur more commonly
• Advanced age in delirious patients.5,124 These additional medical
• Anemia problems lead to prolonged hospitalizations, an
• Cardiac arrhythmias increased rate of functional decline necessitating
• Concomitant alcohol use institutionalization, and increased mortali-
• Concomitant use of multiple drugs that may cause ty.5,122,125-130 Drug-induced delirium is an unfortu-
delirium nate event that leads to increased health care costs
• Heart failure that are almost completely avoidable.122
• Dementia In the months to years after an episode of delir-
• Fever ium, patients are at risk for delayed recovery and
• Fluid/electrolyte abnormality poor functional status.104,131 Of 126 patients who
• Head trauma were diagnosed with delirium in one study, 64%
• Hepatic insufficiency reported the same number of delirium symptoms 1
• Hypoalbuminemia week later, and 12% had a larger number of symp-
• Hypoglycemia toms.131 Patients with persistent delirium had
• Hypoxia lower activities of daily living scores than those in
• Impaired physical function whom delirium did not develop. Another study of
• Infection 77 elderly patients on medical, surgical, and geri-
• Kidney disease atric hospital units, indicated that frailty (OR, 2.0
• Myocardial infarction 95% CI, 1.2–3.5) and poor recognition of delirium
• Neoplasm (OR, 18.2 95% CI, 2.2–153.2) were associated with
• Pain increased risk of poor outcome including function-
• Parkinson’s disease al decline or death.132
• Respiratory failure Other serious outcomes of delirium are persist-
• Seizure disorder ent or worsening cognitive function and an
• Sensory deprivation increased risk of dementia.104 Rockwood and col-
• Severe illness leagues examined the risk of dementia and death
• Shock over a 3-year period in previously hospitalized
patients over the age of 65 years.126 After adjusting
for age, sex, and comorbid illnesses, there was a sig-
tors.1,3,101,111-113,122 Physiologic changes in the elder- nificantly increased risk of dementia after an
ly may alter drug transport across the blood–brain episode of delirium (OR, 5.97; 95% CI, 1.83–19.54).
barrier, making them more vulnerable to central Delirium was also associated with an increased risk
nervous system effects. It has been reported that of death (OR, 1.71; 95% CI, 1.02–1.87). Kelly and
the presence of at least one copy of the apolipopro- colleagues reported that 18% of elderly nursing
tein ⑀4 allele on chromosome 19 increased the risk home residents who were hospitalized for acute
of postoperative delirium in elderly patients (OR, medical illness and in whom delirium developed
3.64; 95% CI, 1.51–8.77).123 In addition, there may died during their inpatient stay.130 Of those who
be age-related changes in metabolism or elimina- were discharged, an additional 18.4% died within
tion that lead to drug accumulation in the elder- 1 month, and another 13.3% died within 3
ly.105 As patients age, the number of concomitant months. The cumulative mortality in this study
medical conditions and medications generally was 46.6% at 3 months after hospital discharge.
increases. These factors, along with a potential In a prospective, cohort study of 243 patients
increased sensitivity to some of the psychoactive with delirium and 118 controls, delirium was asso-
medications, may contribute to the increased inci- ciated with a twofold increase in mortality during
dence of drug-induced delirium in this age group. a 12-month period following hospitalization (haz-
ard ratio, 2.11; 95% CI, 1.18–3.77).133 The 1-year
mortality rate associated with delirium is 40% to
MORBIDITY AND MORTALITY 63%.99,133 It is likely that these same outcomes
could be expected in patients with drug-induced
Few data are available regarding morbidity and delirium.
mortality specifically associated with drug-induced Delirium has been reported to be responsible
delirium. However, delirium in general is associat- for 49% of all hospital days for elderly patients.97 It
TisdaleC15_275-292 New 1/12/10 2:40 PM Page 284
284 SECTION III • Drug-Induced Neurological Diseases
accounts for an estimated $38 billion to $152 bil-
lion in annual health care expenditures.134 Mean
(±SD) daily costs were 2.5 times higher in delirium
survivors as compared with those in whom deliri-
um did not develop ($461±$570 vs. $166±$570;
P<0.001). Prolonged hospital stays account for a
portion of these costs, but expenses are compound-
ed by the need for rehabilitation, long-term care,
and home health care.122,134
PREVENTION
There are few studies of the primary prevention of
drug-induced delirium.122,135 However, methods of
prevention of delirium in general may also be
effective for prevention of drug-induced delirium
(Table 15–7). A prospective, controlled trial was
conducted in which standardized protocols were
implemented for managing specific risk factors for
delirium, such as cognitive impairment, sleep dep-
rivation, immobility, visual and hearing impair-
ments, and dehydration in a group of hospitalized
patients.122 Risk-factor management in the treat-
ment group reduced the incidence of delirium as
compared with that in the control (usual-care)
group (9.9% vs. 15%; P = 0.02). Risk-factor manage-
ment was also associated with significantly fewer
days of delirium and a smaller number of delirium
episodes. Those in the risk-factor management
group who were most adherent to the prevention
protocol carried a significantly lower risk of deliri-
um (adjusted OR, 0.69; 95% CI, 0.56–0.87).135
These techniques for the prevention of delirium
may also be applied to those at risk for drug-
induced delirium.
Prophylactic low-dose haloperidol (1.5
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-
sion and continued for up to 3 days after surgery.
TABLE 15–7 Approaches to Help Prevent Drug-
Induced Delirium
• Avoid anticholinergic, sedative/hypnotic, and opioid
medications in the elderly.
• Obtain a careful medication history and perform
periodic reviews of all drug therapy.
• Perform a brief mental status exam on acutely ill
patients at admission to assist in the detection of
drug-induced delirium.
• Avoid medications known to cause drug-induced
delirium.
The incidence of delirium was not different in the
haloperidol (15.1%) or placebo-treated groups
(16.5%); (RR, 0.91; 95% CI, 0.59–1.44). Delirium in
haloperidol-treated patients was less severe, of
shorter duration, and associated with a shorter
duration of hospital stay as compared with those in
the placebo group.
Nursing staff on an orthopedic unit were edu-
cated regarding the appropriate use of pharmaco-
logic and nonpharmacologic interventions to
prevent and treat delirium.137 Suggestions regard-
ing medication use included avoiding or minimiz-
ing the routine use of anticholinergics to prevent
or treat nausea, prescribing morphine in the lowest
doses for the shortest possible duration after sur-
gery, and using antipsychotic agents for manage-
ment of psychotic symptoms of delirium.
Medication use was evaluated in the 6 months
before and after the education session. There was a
significant decrease in the use of anticholinergic
medications, but the use of opiates and antipsy-
chotics did not change significantly. Data regard-
ing the rates of delirium were incomplete. Effective
treatment of pain with opiates led to a decreased
risk of delirium (OR, 0.4; 95% CI, 0.2–0.7).95
Since delirium is likely the result of multiple
issues, including drugs, management of nondrug
risk factors is important for the prevention of drug-
induced delirium. Anticholinergic, hypnotic/seda-
tive, and opioid medications should be avoided
whenever possible in elderly patients.6 A careful
medication history should be obtained from
patients at risk and periodic reviews of all drug
therapy should be performed. All elderly patients
who present with an acute illness should be
screened for the presence of drug-induced deliri-
um.
MANAGEMENT
Principles of management of drug-induced delirium
are presented in Table 15–8. Management of drug-
induced delirium requires that clinicians recognize
the presence of delirium and consider that it may
be caused by drugs.5,6 This can be extremely diffi-
cult, particularly in intubated patients in the ICU or
in those with underlying dementia.138,139 The most
critical step in the diagnosis is a careful medication
history. The clinician must carefully consider any
new medications that the patient is taking and the
time to onset of signs and symptoms. Other steps in
diagnosis include a physical exam and a toxicology
screen, which may help in identifying the drug(s)
involved. Determination of serum concentrations
of suspected drugs may be helpful, although some
TisdaleC15_275-292 New 1/12/10 2:40 PM Page 285
TABLE 15–8 Management of Drug-Induced
Delirium
• Identify the causative agent:
• Medication history
• Physical exam
• Toxicology screen
• Plasma concentrations
• Discontinue or reduce the dose of the causative
agent. If possible, substitute with another drug that
does not cause delirium.
• Identify and eliminate any other contributors to the
drug-induced delirium.
• Use a specific antidote, if available.
• Use nonpharmacologic methods:
• Provide support and orientation.
• Provide an unambiguous environment.
• Maintain competency.
• Use pharmacologic methods:
• Haloperidol
• Benzodiazepines
• Atypical antipsychotics
agents may cause drug-induced delirium even at
therapeutic concentrations.2,5 When a particular
medication is determined to be the causative agent,
it should be discontinued or the dose should be
reduced whenever possible.111 A drug that is less
likely to cause delirium should be substituted if pos-
sible.2
Management of drug-induced delirium should
include supporting and maintaining basic vital
functions, including adequate oxygenation, hydra-
tion, nutrition, and body temperature. Specific
pharmacologic and/or physiologic precipitants
should be identified and discontinued or reversed
whenever possible. After treatment is initiated,
careful monitoring for signs and symptoms of
recovery as well as for treatment-associated adverse
effects is important. Any medications used in the
treatment of drug-induced delirium should be
tapered to discontinuation as soon as possible after
recovery to minimize the risk of further complica-
tions.111 Care should be taken to prevent dehydra-
tion, falls, decubitus ulcers, and aspiration during
treatment of these patients.94
The management of drug-induced delirium can
include both pharmacologic and nonpharmaco-
logic treatments.6 Basic nonpharmacologic inter-
ventions should always be initiated first because
of the ease with which they can be implemented
and their proven efficacy.139 Nonpharmacologic
approaches to managing delirium include ensuring
CHAPTER 15 • Delirium 285
that patients have their eyeglasses, hearing aids,
and dentures; arranging for all treatments to be
completed during the daytime to permit the maxi-
mum amount of sleep at night; reducing nighttime
noise; placing familiar objects from the patient’s
home in the room; ensuring clear and concise
communications; and encouraging patients to par-
ticipate in their care and perform their own activi-
ties of daily living. The use of physical restraints
should be avoided unless patients are likely to
harm themselves or others, as deaths have been
reported in association with their use.2,5,138
Constant staff observation in a specialized delirium
unit or observation by a sitter or family member
are preferable to physical restraint.139 Often, dis-
continuation of the causative agent alone is not
sufficient, and drug therapy must be used to con-
trol symptoms of agitation and psychosis after
nonpharmacologic measures have been imple-
mented.6,140
Psychotropic agents, typical and atypical
antipsychotics, and the benzodiazepines are the
most frequently prescribed classes of medication
for the management of delirium. Guidelines from
the American Psychiatric Association recommend
psychotropic agents as adjunctive therapy.2
However, these drugs have also been linked to the
development of delirium.96 There are no medica-
tions that are approved by the Food and Drug
Administration for the management of drug-
induced delirium. Psychotropic agents should be
considered after nonpharmacologic measures have
been implemented, after suspected offending
drug(s) have been discontinued, and when control
of severe agitation is required for the patient’s safe-
ty or for the safety of others.
Benzodiazepines may be considered for the
treatment of drug-induced delirium, particularly in
hyperactive or agitated patients.141 However, there
is little evidence to support the use of benzodi-
azepines as monotherapy. One study comparing
haloperidol, chlorpromazine, and lorazepam in
patients with the acquired immunodeficiency syn-
drome and delirium reported that lorazepam was
less effective than either antipsychotic drug.142 It is
appropriate to initiate benzodiazepine therapy in
cases of delirium associated with alcohol or seda-
tive withdrawal or in combination with an antipsy-
chotic, like haloperidol, when a patient cannot
tolerate increases in antipsychotic doses.
Lorazepam is the most commonly used benzo-
diazepine in patients with delirium, because of its
rapid onset of action, short half-life, and availabil-
ity in various dosage forms.140 This agent is rela-
tively safe for use in patients with hepatic
dysfunction, as it has no active metabolites.141
TisdaleC15_275-292 New 1/12/10 2:40 PM Page 286
286 SECTION III • Drug-Induced Neurological Diseases
Lorazepam can be administered orally, intramuscu-
larly, or intravenously in doses ranging from 0.5 to
2 mg.143 This dose also can be repeated or doubled
every 30 to 60 minutes, depending on the patient’s
degree of agitation and sedation. Diazepam is rec-
ommended as an alternative to physostigmine in
patients with anticholinergic toxicity because of its
longer duration of action and more favorable
adverse effect profile.6 Haloperidol and phenoth-
iazines should be avoided in this situation.
When benzodiazepines are administered par-
enterally, they may cause respiratory depression
and arrhythmias, and therefore cardiopulmonary
function must be monitored.140 There also is the
potential for the occurrence of a paradoxical reac-
tion, in which the patient becomes more agitated
with continued benzodiazepine administration.
Paradoxical reactions tend to occur more often in
the elderly, in those with liver dysfunction, and in
patients with low plasma albumin concentrations.
Caution should be exercised when using benzodi-
azepines as they may worsen delirium and cause
excessive sedation in some patients.144
In a small case series study, melatonin 2 mg
was administered to two postoperative patients for
3 to 4 nights. One patient received melatonin for
the prevention of delirium and the other for the
treatment of delirium. In both cases, melatonin
effectively reduced the severity of delirium symp-
toms or prevented delirium. No adverse events
were reported.145
Haloperidol is the most widely used antipsy-
chotic medication for the symptomatic manage-
ment of delirium, despite few prospective studies of
its effectiveness for agitation and hallucinations in
this setting. Haloperidol offers several advantages
over the low-potency antipsychotics, including a
relative absence of anticholinergic activity, ␣-adren-
ergic blockade, and sedation.6,141 In nonelderly
patients, haloperidol oral doses of 2 mg may be
given for mild agitation, 5 mg for moderate agita-
tion, and 10 mg for severe agitation.146 In elderly
patients, recommended haloperidol doses are 0.5
mg for mild agitation, 1 mg for moderate agitation,
and 2 mg for severe agitation.147 Response may
occur in 10 to 30 minutes. The dose may be repeat-
ed every 30 to 60 minutes until the patient is sedat-
ed or calm. In some cases, the dose may be doubled
until the agitation is controlled. Haloperidol thera-
py can be continued on a tapering schedule for 3 to
5 days.146 The goal is to use the lowest possible
haloperidol dose for the shortest possible duration.
In cases in which agitation is severe, the
patient is at serious risk of self-injury or is unable
or unwilling to take medications orally, haloperi-
dol may be administered intramuscularly or intra-
venously (IV).140 Doses vary greatly, from as low as
0.25 mg intramuscularly or as high as 10 mg in a
single IV dose. A continuous IV infusion of
haloperidol may be administered at rates ranging
from 2 to 10 mg per hour.148 Intravenous adminis-
tration of haloperidol has been shown to produce
a lower incidence of extrapyramidal adverse
effects, presumably due to lower concentrations of
the pyridium metabolite. However, intravenous
haloperidol is associated with a risk of prolonga-
tion of the corrected QT (QTc) interval and, in
some cases, torsades de pointes.140,149 Patients
receiving treatment with IV haloperidol should
undergo baseline electrocardiography to determine
the QTc interval. Prolongation of the QTc interval
to longer than 0.45 second or more than 25%
above baseline is cause for concern, and the rela-
tive risks and benefits of continued therapy must
be carefully considered.
The use of high-dose haloperidol for the treat-
ment of delirium is not without controversy.
Dopamine-D2 receptor blockade in the mesolimbic
region is believed to be the main mechanism of
action; a threshold of 60% of D2 receptor blockade
is necessary for antipsychotic effects. Some argue
that very high doses of haloperidol are unlikely to
be more effective than lower doses, since 53% to
85% of D2 receptors are occupied by haloperidol at
doses of 2 to 20 mg/day.150 Therefore, large doses
should offer no additional benefit, with the poten-
tial for a higher incidence of adverse effects. In fact,
there are numerous reports of extrapyramidal
symptoms (EPS), including pseudoparkinsonism,
acute or tardive dystonia, dyskinesias, and
akathisia associated with high-dose IV haloperidol
or withdrawal from haloperidol therapy.151,152
Worsening symptoms may be the result of EPS,
especially akathisia, which often goes unrecog-
nized and is sometimes inappropriately managed
by increasing haloperidol doses.
Some clinicians prefer to use droperidol in the
critical care setting, as it is a more potent, fast-act-
ing antipsychotic that is more sedating than
haloperidol and is reportedly associated with a
lower incidence of extrapyramidal effects.153 Bolus
IV injections of droperidol have been associated
with hypotension, tachycardia, and torsades de
pointes.153 Baseline QTc-interval assessment and
cardiac monitoring are necessary when administer-
ing high doses of droperidol, since prolongation of
the QTc interval can occur. This drug should be
reserved for use only in the ICU setting, where
patients are closely monitored and resuscitation
equipment is immediately available.
Newer antipsychotic agents including aripipra-
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
the management of delirium. The use of aripipra-
zole for the management of delirium was reported
in a small case series of two patients.154 One
patient’s MMSE score improved from 5 to 28, while
his Delirium Rating Scale (DRS) score decreased
from 28 to 6. The second patient’s MMSE score
improved from 7 to 27, while her DRS score
decreased from 18 to 6. In another series of 14
patients with delirium treated with aripiprazole, 12
had a reduction of greater than 50 percent in the
DRS score and 13 showed improvement on the
Clinical Global Impressions scale scores.155 There
was a low incidence of adverse effects. Olanzapine
has been reported to be effective for delirium in
several clinical trials. One study enrolled medically
ill patients whose mean age was 46 years.156 The
mean maximum dose of olanzapine was 8.8 mg per
day, and the mean time to response was 3.8 days.
In another study, patients with cancer (mean age,
61 years) were enrolled.157 The mean maximum
dose was only 6.3 mg per day. Approximately 76%
of patients responded within 4 to 7 days. However,
patients older than 70 years had a lower response
rate (42%). Sipahimalania and Masand conducted
a retrospective medical record review of 22 mixed
medical–surgical patients.158 Five of 11 patients
treated with olanzapine (mean dose, 8.2 mg daily)
showed a significant improvement in their DRS
score as compared with 6 of 11 patients in the
haloperidol group. In a prospective, randomized,
single-blind study, the efficacy of therapy with
olanzapine (n = 28) was compared with that of
haloperidol (n = 45) in a mixed group of critically
ill medical–surgical patients.159 Delirium index
scores improved similarly in both groups and the
need for rescue therapy did not differ between
groups. Six patients receiving haloperidol experi-
enced mild EPS, as compared with no patients in
the olanzapine group.
Several case reports indicate that quetiapine
may be a reasonable choice for the management of
delirium.160-162 Sasaki et al. reported the effect of
quetiapine therapy in 12 patients with delirium of
multiple causes.163 Patients were treated for a mean
(±SD) of 4.8±3.5 days with a flexible dose of queti-
apine (mean maximum dose, 63.5 mg per day).
Delirium rating scale scores improved significantly,
and no patient experienced significant adverse
events. In a retrospective review of the medical
records of 22 mixed medical–surgical patients, que-
tiapine (median dose, 211 mg daily) was as effec-
tive as haloperidol in increasing DRS score by more
than 50% from baseline.164 One patient receiving
quetiapine experienced mild to moderate sedation,
and two patients receiving haloperidol developed
CHAPTER 15 • Delirium 287
EPS. In another study, the efficacy of therapy with
quetiapine at doses of 25 to 100 mg daily for 7 days
was assessed in 22 patients with delirium.165 The
DRS and Clinical Global Improvement (CGI) scores
on days 2 to 7 were significantly lower than those
on day 0. Mild tremor developed in 2 patients
(9.1%).
Risperidone at mean doses of 0.75 to 1.7 mg
daily has been reported to be effective for the man-
agement of delirium.166,167 In an unblinded study, 64
medically ill hospitalized patients with delirium
received oral risperidone in daily doses of 1.85 to
2.97 mg (mean daily dose, 2.6±3.3 mg).168
Risperidone was effective in 58 of 64 patients and
significantly improved all symptoms measured by
DRS, Positive and Negative Symptom Scale, MMSE,
and CGI during a period of 7 days. The comparative
efficacy of risperidone and haloperidol for treatment
of delirium was assessed in a prospective, random-
ized, double-blind study of acutely ill inpatients.169
The Memorial Delirium Assessment Scale improved
significantly in both groups at 7 days, and there was
no significant difference in efficacy between the
groups. In another study, the relationship between
response and genetic polymorphisms in the
dopamine transporter was studied in 42 patients
receiving either haloperidol or risperidone for the
management of delirium.170 There was no difference
in efficacy between the groups. Interestingly,
dopamine transporter polymorphisms did not play
a significant role in the effects of the antipsychotics.
In a randomized, double-blind study of 126 patients
undergoing cardiac surgery with cardiopulmonary
bypass,171 patients were randomly assigned to
receive risperidone 1 mg or placebo sublingually.
The incidence of postoperative delirium was signifi-
cantly lower in the risperidone group. Miyaji et al.
compared the adverse effects of risperidone with
those of haloperidol in a retrospective study of 266
Japanese inpatients treated for delirium. The inci-
dence of adverse effects was significantly lower in
risperidone-treated patients.172 Ziprasidone has also
been used for the treatment of delirium.173,174 This
drug is associated with a low risk of sedation and
EPS. However, in a case report of the use of ziprasi-
done for delirium, the drug was effective, but the
patient exhibited QTc-interval prolongation requir-
ing drug discontinuation.173
Overall, haloperidol and atypical antipsy-
chotics appear to be equally efficacious for the
treatment of delirium in acutely ill hospitalized
patients.175,176 However, this statement must be
tempered by the fact that placebo-controlled, ran-
domized trials supporting the efficacy of these
agents for the treatment of delirium are lacking. In
addition, all antipsychotic agents include a boxed
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288 SECTION III • Drug-Induced Neurological Diseases
warning in their labeling regarding an increased
risk of mortality in elderly patients treated for
dementia-related psychosis. Clinicians should
weigh the benefits and risks associated with
antipsychotic drug therapy prior to prescribing
these agents for the management of drug-induced
delirium.177 Further studies are required to deter-
mine the role of antipsychotics in the management
of delirium.
Pharmacologic strategies for the manage-
ment of drug-induced delirium should be imple-
mented after nonpharmacologic measures have
been attempted, after suspected offending
drug(s) have been discontinued, when control of
severe agitation is required for the patient’s safe-
ty or for the safety of others, and when psychosis
is present.
INFORMATION FOR PATIENTS
Patients taking medications implicated in causing
delirium and their caregivers should be instructed
to be vigilant for early signs and symptoms of the
disorder. In addition, they should be taught about
available nonpharmacologic treatment approaches
and be instructed to implement these measures
should signs or symptoms develop.6 Early recogni-
tion and intervention may prevent or ameliorate
this disabling condition.
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174. Young CC, Lujan E. Intravenous ziprasidone for
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TisdaleC16_293-300 1/12/10 2:41 PM Page 293
CHAPTER 16
Sleep Disorders
S leep is an essential part of life; we spend
approximately one third of our life sleeping.1
Drug-induced sleep disorders, such as insomnia,
may be reported as difficulty in falling asleep, not
feeling rested despite adequate time to sleep,
and/or daytime sleepiness. While sleep distur-
bances may be caused by a variety of medical or
psychiatric conditions, drugs always must be care-
fully considered as a potential cause of these symp-
toms.
CAUSATIVE AGENTS
Altered patterns of sleep and wakefulness may be
caused by drugs that affect the central nervous sys-
tem. These effects may be present immediately
upon initiation of therapy with the drug or during
periods of withdrawal. In addition, drugs may
exacerbate existing primary sleep disorders. Drugs
that have been reported to cause sleep disorders are
listed in Table 16–1.2-51
EPIDEMIOLOGY
Insomnia is reported in approximately one third of
adults in the United States, and it is considered to
be a serious problem in about 50% of those afflict-
ed.52-54 The overall incidence of drug-induced sleep
disturbances in the general population is not
known, but individual agents are associated with a
corresponding incidences ranging from 1% to 55%
(Table 16–1).55
Lisa L. Forsyth
MECHANISMS
Humans, along with most mammals, undergo two
phases of sleep: rapid-eye-movement (REM) and
non–rapid-eye-movement sleep (NREM).56 NREM
sleep is subdivided into four distinct stages, 1
through 4. A full cycle of NREM and REM sleep
requires approximately 90 minutes, and this cycle
is repeated approximately four to six times
throughout the night. Researchers do not yet fully
understand all the functions of REM and NREM
sleep and their relationship to the symptoms of
sleep disturbance. The elderly experience alter-
ations in their sleep patterns manifested typically
as a decrease in REM, stages 3 and 4 of NREM, and
total sleep time. These changes have been found to
correspond to added awakenings and total time
spent awake at night.57,58
Several neurotransmitters are responsible for
the sleep cycle.59 The neurochemistry responsible
for sleepiness and wakefulness has not been fully
elucidated, and it is unknown whether one or
more neurotransmitters is responsible for sleeping
and awakening.60 A primary function of the norep-
inephrine-containing neurons is to regulate the
sleep pattern. Wakefulness is thought to be mediat-
ed by norepinephrine, dopamine, acetylcholine,
and serotonin.61
There are three main mechanisms for drug-
induced sleep disturbances (Table 16–2).62,63 First,
the desired effects of a drug may affect the neuro-
transmitters or receptor sites responsible for sleepi-
ness. Second, the sedative effects of drugs used to
treat insomnia may carry over into the daytime
293
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294 SECTION III • Drug-Induced Neurological Diseases

TABLE 16–1 Agents Implicated in Drug-Induced Sleep Disorders

Drug Incidence Level of Evidence
(see page xii for explanation)
2,a
MAO inhibitors NK B
SSRIs
Fluoxetine3-7 Insomnia: 5–19% B
Daytime sedation: 5–18%
Paroxetine3,4,7-9 Insomnia: 8–14% B
Daytime sedation: 2–21%
Sertraline3,4 Insomnia: 7–16% B
Daytime sedation: 7–13%
Fluvoxamine3,4,10 Insomnia: 10–15% B
Daytime sedation: 14–26%
Citalopram5 NK C
Duloxetine11,12 12.6% B
Escitalopram12 4.9% B
Venlafaxine3,13-16 Insomnia: 8% B
Sedation: 13–31%
Bupropion3,17,18 5–19% B
19-22
␤-Antagonists 2–4.3% B
(lipophilic)
␣2-Agonists22 30–75% B
Clonidineb
Methyldopab,c
␤-Antagonists with:
␣-blocking activity23,24 B
Carvedilol 3–11%
Labetalol 1 –4%
Lovastatin25,26 NK C
Corticosteroids27-37 NK B
Stimulants30,38,39 46–55% B
Anticonvulsants40-43 NK B
Antiparkinsonian agents44-50
Levodopa–carbidopa 75% B
Selegiline 10–32% B
Pergolide, bromocriptine 42% B
Amantadine 14% B
Trihexyphenidyl, benztropine NK C
Entacapone 30% B
Alcohol51 NK (withdrawal) C
MAO = monoamine oxidase; NK = not known; SSRI = selective serotonin reuptake inhibitor.
a
Daytime sleepiness
b
Sedation, nightmares
c
Insomnia
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CHAPTER 16 • Sleep Disorders 295

TABLE 16–2 Mechanisms of Drug-Induced Sleep Disorders

Drug Mechanism (Neurotransmitter & PSG data)
MAO inhibitors2 Inhibits MAO enzyme that degrades norepinephrine,
serotonin, dopamine, 2REM, 1wakefulness, 2TST
SSRIs3-12 Serotonin uptake inhibition, 1wakefulness, 2TST
Venlafaxine3,13,16 Serotonin, norepinephrine uptake inhibition, weak effects on dopamine uptake
1wakefulness, 2TST
Bupropion3,18 Dopamine uptake inhibition, minimal PSG data
␤-Antagonists19-21 ␤-Adrenergic inhibition, 1wakefulness, 2TST, 1S1,
(lipophilic agents) 2REM
␣2-Agonists22 ␣2-Adrenergic agonist, no PSG studies available
␤-Antagonists with ␤ - and ␣-antagonism, no PSG studies available
␣-blocking activity23,24
Lovastatin25-26 Mechanism unknown, minimal PSG data, 1wakefulness
Corticosteroids27-37 Mechanism unknown, 1wakefulness, 1S2, 2REM
Stimulants38,39 Release of various neurotransmitters, 1wakefulness, 2TST
Antiparkinsonian agents44-50 Effect on various neurotransmitters, 1wakefulness,2TST
Alcohol51 Mechanism unknown, occurs upon withdrawal, 1wakefulness, 2TST
MAO = monoamine oxidase; PSG = polysomnography, REM = rapid eye movement; SSRI = selective serotonin reuptake inhibitor; TST =
total sleep time, S1 = stage 1 sleep, S2 = stage 2 sleep.

hours. Third, effects of withdrawal of therapy with
a drug may produce a sleep disturbance.
CLINICAL PRESENTATION AND
DIFFERENTIAL DIAGNOSIS
The prevalence of sleep disturbance, specifically
insomnia, is much greater in women and in elderly
patients.64,65 Patients suffering from sleep distur-
bance often report an inability to fall asleep, to stay
asleep, or both, or of not feeling rested after having
time to sleep.62 Often these conditions are followed
by daytime sleepiness and an inability to concen-
trate. The common signs and symptoms of sleep dis-
orders are listed in Table 16–3. A number of medical
and psychiatric conditions (Table 16–4) are known to
TABLE 16–3 Signs and Symptoms Associated
with Drug-Induced Sleep Disorders55,56,66
• Inability to fall asleep
• Inability to maintain sleep
• Not feeling rested following adequate sleep duration
• Excessive daytime sleepiness
• Poor cognitive performance
• Lack of concentration
affect sleep, and these must be considered when eval-
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
incorporates an electroencephalogram, electro-ocu-
logram, and electromyelogram.63 Other measures of
sleep include sleep latency (time to fall asleep), REM
latency (time to first REM sleep), number of awaken-
ings, and the number of stage shifts during sleep.68
The effects of drugs on sleep are often identified
and characterized based on subjective data, PSG
measures, objective evidence of sleepiness and alert-
ness from a Multiple Sleep Latency Test, and/or by
objective performance data. Evidence of disturbance
during sleep on the PSG does not always correlate
with patients’ subjective symptoms.62,63 Venlafaxine
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
other agents listed in Table 16–1 is highly variable.
Patient assessment should start with a medica-
tion history and physical examination. Further
psychiatric assessment should be undertaken if
indicated. When a drug-induced sleep disorder is
suspected, patients should be questioned specifi-
cally regarding the use of medications known to
affect neurotransmitters, the frequency and timing
of drug administration, and any recent discontinu-
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296 SECTION III • Drug-Induced Neurological Diseases

age (beginning in middle-aged adults) and female

TABLE 16–4 Conditions to Consider in the sex are known risk factors for insomnia, but it is
Differential Diagnosis of Drug-Induced Sleep not known whether they also are risk factors for
Disorders56,63,67 drug-induced sleep disorders.55,56 Most studies that
Medical have attempted to evaluate drug effects on sleep
• Neurologic have been conducted in healthy individuals, most-
• Delirium ly men, who may respond differently from the
• Epilepsy intended treatment population.55 In addition, the
• Parkinson’s disease treatment population may already have sleep dis-
turbances or impaired daytime performance before
• Respiratory
the initiation of drug therapy. It is known that
• Asthma
both age and drug dose contribute to the frequen-
• Obstructive sleep apnea
cy of sleep disturbance associated with ␤-antago-
• Cardiovascular nists.55 Potential risk factors for sleep disorders are
• Arrhythmias listed in Table 16–5.
• Heart failure In addition to directly causing sleep distur-
• Gastrointestinal bances, drugs may exacerbate symptoms and
• Gastroesophageal reflux increase the risk of primary sleep disorders. One
• Peptic ulcer disease example is obstructive sleep apnea, which is char-
• Endocrine acterized by loud snoring and gasping or apneic
• Diabetes mellitus episodes during sleep. Patients with sleep apnea
• Hyperthyroidism typically experience excessive daytime sleepiness
and poor performance. A patient’s apneic
• Chronic pain
episodes may worsen with the use of
• Pregnancy sedative/hypnotic agents, and daytime symptoms
Psychiatric may become more severe.55,62 In addition, the
menopausal symptom of “hot flashes” during
• Mood disorders
nighttime hours has been reported as a cause of
• Depression
insomnia following the discontinuation of hor-
• Mania
mone-replacement therapy.
• Anxiety disorders
• Generalized anxiety disorder
• Obsessive–compulsive disorder
• Panic MORBIDITY AND MORTALITY
• Substance
• Alcohol abuse Sleep disorders may impair quality of life beyond
• Sedative/hypnotic withdrawal causing excessive daytime sleepiness. It has been
reported that those who suffer insomnia receive
Situational fewer career promotions, demonstrate poor pro-
• Work or financial ductivity, and have a higher rate of absen-
• Interpersonal conflict teeism.69,70 In addition to poor performance during
• Major life events the daytime hours at work, there is an increased
• Jet lag risk of motor vehicle accidents reported in patients
• Shift work who experience insomnia.71 Nearly 70 million
Americans suffer from a sleep disorder that may

ation of medication.62 The utility of sleep studies in

the diagnosis and characterization of drug-induced TABLE 16–5 Risk Factors for Drug-Induced Sleep
sleep disturbance has not been determined. Disorders55,56
• Female sex
• Older age
RISK FACTORS • Combination therapy with two or more agents with
central nervous system effects
Specific risk factors for drug-induced sleep disor-
• Drug interactions
ders have not been definitively elucidated. Older
TisdaleC16_293-300 1/12/10 2:41 PM Page 297
have negative consequences on their overall health
and well-being.72 It is estimated that the direct
costs of insomnia range from $1.8 billion to $3 bil-
lion annually. 73
Obstructive sleep apnea has been associated
with hypertension the primary mechanism of
which is sympathetic hyperactivity.74 In addition,
sleep deprivation experienced for one night has
been linked to hypertension in the ambulatory
care setting.75,76 The suggested mechanism also
relates to an increase sympathetic outflow.
Decreased sleep duration may impair glucose
tolerance and insulin sensitivity.77-80 It is postulat-
ed that insulin resistance, like elevated blood pres-
sure, is linked to increased sympathetic outflow
associated with reduced duration of sleep. One
investigation that spanned 10 years suggests that a
sleep duration of 5 hours or less may be a signifi-
cant risk factor in the development of diabetes.77
Currently, there are no data regarding the inci-
dence of morbidity or mortality specifically associ-
ated with drug-induced sleep disorders.
PREVENTION
Ultimately, prevention of drug-induced sleep disor-
ders requires a better understanding of the basic
functions and different stages of sleep. Basic and
clinical research is necessary in order to allow clini-
cians to anticipate possible sleep disturbances
based on pharmacologic properties of specific
drugs. Nonpharmacologic measures to improve
sleep hygiene (Table 16–6) are useful and have
been shown to improve sleep patterns in 70% to
80% of patients.56,81,82
MANAGEMENT
Because sleep disturbances may affect all aspects of
an individual’s life, all symptoms should be inves-
tigated carefully. Management of drug-induced
sleep disorders requires a thorough understanding
of the pharmacology, especially the neurotransmit-
ter activity, of each medication taken by the
patient. It also is important to consider drug com-
binations with possible additive central nervous
system effects and drug interactions that may
potentiate drug effects by altering pharmacokinet-
ics or pharmacodynamics. The first step in man-
agement involves discontinuation of agents with
the potential to cause drug-induced sleep disorders
(Tables 16–1 and 16–6). The time frame for resolu-
tion of symptoms following drug discontinuation
CHAPTER 16 • Sleep Disorders 297
TABLE 16–6 Approaches to Help Prevent Drug-
Induced Sleep Disorders56,81
Sleep hygiene
• Establish a regular bedtime and wake-up time,
including weekends
• Sleep only as much as necessary
• Go to bed only when sleepy, using the bed only for
sleep and intimacy
• Avoid long periods of wakefulness while in bed
• Avoid trying to force sleep; after 30 minutes, leave
the bed to do something relaxing (watch television,
listen to music, or read)
• Avoid daytime naps
• Do not take your worries to bed
• Exercise regularly (three to four times weekly); how-
ever, exercising near bedtime may cause arousal
• Create comfortable sleeping environment (steady
temperature, lack of light source)
• Reduce or discontinue the use of alcohol, caffeine,
or nicotine
• Avoid hunger or fullness at bedtime
• Avoid drinking large amounts of liquids in the
evening to prevent trips to the bathroom at night
• Engage in a relaxing or enjoyable activity before
bedtime
Pharmacologic Approaches
• Discontinue agents with potential to cause drug-
induced sleep disturbances when possible
• If unable to discontinue potentially causative
agents:
• Change time of administration to earlier in the
day
• Reduce dose to decrease symptoms (e.g.,
selegiline)
is a function of the causative agent’s elimination
half-life.
In some cases, such as in patients with seizure
disorders, discontinuation of the potentially
causative agent may not be possible, and alterna-
tive measures are required. Changing the time of
administration to earlier in the day may help
reduce symptoms for some patients. With some
drugs (e.g., selegiline) symptoms are reported most
often with the use of higher doses, and dose reduc-
tion may be helpful.
It is reasonable to use drug therapy for insom-
nia when all other measures to resolve a drug-
induced sleep disorder have failed. For insomnia
requiring short-term treatment, there is no differ-
ence in efficacy between benzodiazepines, antide-
pressants, and sedative–hypnotic agents.83 Patients
TisdaleC16_293-300 1/12/10 2:41 PM Page 298
298 SECTION III • Drug-Induced Neurological Diseases
with difficulty falling asleep or with excessive day-
time sleepiness may benefit from therapy with a
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
sleep or have trouble awakening may benefit from
an intermediate-acting benzodiazepine such as
estazolam or temazepam. The long-acting benzodi-
azepines (flurazepam and quazepam) may be help-
ful when there is daytime anxiety in addition to a
sleep disturbance. There is no rationale, however,
for the combined use of two benzodiazepines for
the treatment of insomnia and anxiety. In every
case, the lowest effective drug dose should be given
for the shortest possible period of time. Tolerance
can develop in as little as 2 weeks with continual
use of some benzodiazepines.56 One strategy used
to help prevent tolerance involves the administra-
tion of benzodiazepines for 3 to 4 days per week
rather than daily.
When long-term treatment of insomnia is
required, antidepressants are among potential
options.83 Trazodone may be effective at doses of
50 to 100 mg for antidepressant-induced insomnia
associated with fluoxetine and bupropion.87 An
advantage of trazodone is its lack of anticholiner-
gic activity. Doxepin has also shown promise in
treating antidepressant-induced insomnia, and
maintains normal melatonin secretion at night.83
Several other agents, such as antipsychotics, anti-
histamines and melatonin have been used for the
long-term treatment of insomnia, but the data are
limited, and these agents are associated with
adverse effects.
Most patients initially seek a nonprescription
remedy for the treatment of sleep symptoms.
Unfortunately, there are limited data regarding the
efficacy of these drugs.88 Of the many options
available, melatonin is the only agent that has
undergone extensive evaluation for its circadian
effects and hypnotic properties. Limited and con-
tradictory evidence is available for the efficacy of
histamine H1-receptor antagonists and valerian.
Other alternative agents for which some data exist
include passionflower, chamomile, St. John’s Wort,
kava, wild lettuce, patrinia root, and vitamins and
supplements (calcium, vitamin A, nicotinamide,
magnesium, vitamin B12).88
When treatment is initiated for a sleep disor-
der, the lowest effective dose should be pre-
scribed. Ideally, these medications should be used
for the shortest amount of time possible, but this
may not be feasible for patients who require a
longer duration of therapy. Patients under treat-
ment for drug-induced sleep disorders should be
routinely monitored to assess the effectiveness of
drug therapy and to ensure the resolution of
symptoms.
INFORMATION FOR PATIENTS
Patients who are prescribed medications that are
known to cause sleep disorders should be instruct-
ed to contact their health care provider if they
experience difficulty falling asleep, do not feel rest-
ed after having adequate time to sleep, or are exces-
sively tired during the day. Patients should be
advised to consult with their physician or pharma-
cist before beginning treatment with any nonpre-
scription medication to avoid interactions that
could precipitate sleep disturbances. Finally,
patients should be warned not to change the dose
or administration times of prescribed medications
without consulting their physician or pharmacist.
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TisdaleC17_301-314 1/12/10 2:42 PM Page 301
CHAPTER 17
Cognitive Disorders
C ognitive function is a multidimensional con-
cept for higher-order mental functions and
processes.1,2 Cognitive function encompasses
many domains, including attention, memory,
learning, planning, problem solving, language pro-
cessing, visuospatial ability, and psychomotor per-
formance. Medications have often been implicated
as a cause of alterations to these processes.
CAUSATIVE AGENTS
Drugs that have been implicated as causes of cog-
nitive disorders are listed in Table 17–1.3-26 Effects
from some medications, such as sedation from opi-
ates, are experienced acutely. Effects of other med-
ications are subtle and are often recognized only
with long-term use. An example is slowing of cog-
nitive processing speed in children leading to
attention and memory deficits associated with
phenobarbital.27,28
EPIDEMIOLOGY
It is difficult to determine the relative frequency of
drug-induced cognitive disorders because of the
diversity of drugs capable of causing cognitive
impairment and the divergent demographic char-
acteristics of study populations.5 In one study, 22%
of 229 consecutive hospitalized patients over 70
years of age were reported to be experiencing delir-
ium.29 Drug toxicity was identified as the most
Michele Y. Splinter
common definite cause of delirium and was the
third most probable contributor, after infection
and fluid and electrolyte imbalance. In another
prospective study, 7% of 1500 hospital neurologic
consultations were for delirium, 17% of which
were attributed to drugs.30
In an outpatient study of 308 patients older
than 60 years of age with global cognitive impair-
ment, 35 (11.4%) were found to have experienced
adverse drug reactions contributing to cognitive
dysfunction.31 Upon follow-up 1 year after enroll-
ment, it was determined that medications were the
sole cause of the cognitive changes in 10 of these
patients, and in the remaining 25, cognitive func-
tion improved after discontinuation of the offend-
ing agent.
Reported incidences of cognitive disorders
depend on the domain investigated and the instru-
ment used to measure the disorder.32 More than 80
instruments have been used to assess the different
domains of cognitive function of patients with
cancer. Self-reports of cognitive decline do not
always correlate with formal assessments.1 Several
challenges to using cognitive assessments in cancer
research have been identified: baseline data may
not reflect function before the cancer diagnosis,
moderating variables (education, race, age, sex)
may affect comparisons between groups or estab-
lished norms, tests may be subject to practice and
learning effects, and a valid comparison group is
difficult to identify because cancer treatment is
specific to diagnosis, stage, and biological factors
characteristic of the specific type of cancer.
301
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302 SECTION III • Drug-Induced Neurological Diseases

TABLE 17–1 Agents Implicated in Drug-Induced Cognitive Disorders

Drug Class/Medication Incidence Level of Evidence
(see page xii for explanation)
3 a
Anticholinergics 18–20% B
Antiarrhythmics (amiodarone, digoxin, lidocaine)4,5 NK C
Antibiotics5,6 NK C
Antifungals5,6 NK C
Antiretrovirals5,6 NK C
Anticonvulsants
Phenobarbital7 NK B
Topiramate8,9 35%b A
7–71%c B
Valproic acid10 22%d B
Antineoplastic agents11,12 4–75%e A
(cyclophosphamide, thiotepa, carboplatin)1,4 25%f A
Antipsychotics13,14 NK B
Antiparkinsonian agents4,5,15 NK C
Benzodiazepines (chronic)16 22.2% B
Glucocorticosteroids5 NK C
Histamine2-receptor antagonists17 0.2% (outpatient) B
1.6–1.9% (inpatient)
Interferon-alpha18-20 30–77 % B
Lithium21 NK B
Nonnucleoside reverse transcriptase inhibitors22,23 18.9–23 % B
Nonsteroidal antiinflammatory drugs24 NKa B
Opioids25 20–70%g B
Selective serotonin reuptake inhibitors26 0.5% B
NK = not known.
a
Elderly.
b
Healthy volunteers.
c
Obese children—memory (71%), psychomotor speed (36%), language (29%), attention (29%), visual–spatial perception (14%), and intel-
ligence (7%).
d
Children of epileptic mothers who took valproate scoring 69 and below on verbal IQ.
e
Varies depending on medication, regimen, population, stage of cancer, domain measured, time of measurement.
f
High-risk patients with breast cancer receiving high-dose chemotherapy (cyclophosphamide, thiotepa, and carboplatin after receiving
standard-dose chemotherapy).
g
Varies depending on population (healthy, patient with cancer, or patient with nonmalignant pain—and whether tolerant to medication).

and antispasmodics and have been associated

MECHANISMS
There are several neuronal processes in the brain
that are associated with states of awareness.33 It
has been proposed that neural pathways mediat-
ed by acetylcholine regulate conscious awareness
and its degree of intensity. Anticholinergic agents
are used as antiemetics, antiparkinsonian agents,
with cognitive impairment.4,15,34-36 In addition,
drugs in many other classes possess anticholiner-
gic properties, including tricyclic antidepressants,
antipsychotics, antihistamines, and antiarrhyth-
mics.4,37 The cholinergic system is distributed in
various nuclei, including two major groups, the
basal forebrain and the pedunculopontine nuclei,
which have bidirectional connections to the cor-
TisdaleC17_301-314 1/12/10 2:42 PM Page 303
tex and thalamus. Memory loss in patients with
Alzheimer’s disease or Parkinson’s disease with
prominent dementia has been associated with a
significant decline of cortical cholinergic innerva-
tion due to cell loss in the nucleus basalis.38 High-
frequency oscillations that unite information
related to different aspects of a perceived object
from widely distributed cortical neurons appear
to emanate from the thalamus.33 The action of
acetylcholine in the cortex and thalamus and the
interactions between the neurotransmitters
acetylcholine, gamma-aminobutyric acid (GABA),
and glutamate appear to be central to the mainte-
nance of conscious awareness. Rebound insomnia
and anxiety have been reported in association
with benzodiazepine and barbiturate withdrawal,
and hallucinations and delirium have been asso-
ciated with barbiturate withdrawal.39 Down-regu-
lation of high-affinity GABA receptors occurs
during benzodiazepine and barbiturate therapy,
and the withdrawal syndrome probably reflects a
state of GABA underactivity in conjunction with
a surge in output of excitatory neurotransmitters
normally inhibited by GABA. There also appears
to be a noradrenergic mechanism contributing to
consciousness, because
2-receptor antagonists
and variations in norepinephrine concentration
alter anesthetic dose requirements.33 In addition,

2-receptor agonists increase the depth of anes-
thesia.
Antiepileptic medications diminish neuronal
irritability, and therefore may inhibit neuronal
excitability and impair cognitive function.27,40
High serum concentrations of valproate have been
shown to affect both function and morphology of
the brain.41 Hypothesized mechanisms include an
interference with pituitary adrenal function,
hyperammonemia, or changes in blood–brain bar-
rier permeability. Histologic examination of brains
of rats aged 3 to 30 days who had received pheny-
toin, phenobarbital, valproate, vigabatrin,
diazepam, and clonazepam revealed apoptotic neu-
rodegeneration.42,43
The hippocampus, which is critical for the
formation of new memories, possesses the high-
est concentration of corticosteroid-binding sites
in the brain.44 Glucocorticoids inhibit glucose
transport into cells by 25% to 30%, thereby accel-
erating the usual decline in adenosine triphos-
phate concentrations after ischemia or
hypoglycemia.45 This lessens the cell’s ability to
inhibit neuronal insults, leading to neuronal
death. In several studies involving children with
acute lymphoblastic leukemia, those treated with
dexamethasone performed less well on cognitive
testing than did children treated with pred-
CHAPTER 17 • Cognitive Disorders 303
nisone.46,47 It has been hypothesized that dexam-
ethasone may be more neurotoxic than pred-
nisone because of a lesser degree of plasma
protein binding and because of the presence of a
fluoride atom in its chemical structure.46 Altered
brain membrane lipid content and synaptic
transmission in hippocampal neurons have been
associated with fluoride anions.46
Acute changes in mental status can occur
with the use of selective serotonin reuptake
inhibitors, because of hyponatremia secondary to
the syndrome of inappropriate antidiuretic hor-
mone (ADH) secretion.26,48,49 This syndrome may
also be caused by other medications, including
carbamazepine, tricyclic antidepressants,
monoamine oxidase inhibitors, and neurolep-
tics.49 These classes of medications may facilitate
the secretion of ADH or increase renal respon-
siveness to ADH.49
A decline in cognitive function has been found
to be significant in studies of some cancers, partic-
ularly breast cancer.1 It has been hypothesized that
two distinct pathways are involved: psychological
and social factors associated with the diagnosis of
cancer and a physiologic effect of cancer treat-
ment, especially with medications that cross the
blood–brain barrier. Other confounders include
dose intensity, duration of treatment, concomitant
medications, radiation therapy and other toxicities
of the treatment, including anemia, vascular injury
and neurotoxicity.
Specific mechanisms of cognitive disorders
associated with several classes of medications are
summarized in Table 17–2.25,27,37,39,40,42,43,45,48-54
CLINICAL PRESENTATION AND
DIFFERENTIAL DIAGNOSIS
The clinical presentation of patients with drug-
induced cognitive disorders is diverse and may
involve acute or chronic changes in states of wake-
fulness, attention, or memory.55 Anticholinergic
drugs have been associated with memory impair-
ment, confusion, hallucinations, sedation, and
dysphoria.15 The most common cognitive effects
associated with anticonvulsants are psychomotor
slowing, reduced vigilance, and impairment in
memory and mood.28 In contrast, many patients
receiving corticosteroids exhibit mood elevation,
and some may experience euphoria, insomnia,
restlessness, and increased motor activity.56 Others
become anxious, depressed, or psychotic.
Common central nervous system adverse signs and
symptoms caused by medications are listed in
Table 17–3.
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304 SECTION III • Drug-Induced Neurological Diseases
TABLE 17–2 Mechanisms of Drug-Induced Cognitive Disorders
Drug
Anticholinergics37
Antiepileptic drugs 27,40,42
Antineoplastic agents50,51
Antipsychotics52
Barbiturates 39,43
Benzodiazepines39
Glucocorticosteroids45,53
Interferon-alpha54
Opioids25
Selective serotonin reuptake inhibitors48,49
Tricyclic antidepressants39
DNA = Deoxyribonucleic acid; GABA = gamma-aminobutyric acid.
Central nervous system effects of benzodi-
azepines include sedation, hypnosis, decreased
anxiety, muscle relaxation, anterograde amnesia,
and anticonvulsant activity.57 As the dose is
increased, sedation progresses to hypnosis and
then to stupor. There have been reports of delirium
in hospitalized patients receiving benzodiazepines,
more often associated with long-acting benzodi-
azepines and higher doses of all benzodiazepines.4
Long-term use of benzodiazepines in the elderly
has been associated with a higher risk for cognitive
decline than with episodic, recurrent, or no use of
benzodiazepines.16
Cases of a reversible pseudoatrophy of the
brain and mental deterioration have been report-
ed in association with valproate in children.41 In
these reports, the serum valproate concentration
Mechanisms
Age-related loss of acetylcholine and cholinergic cell
bodies in nucleus basalis of Meynert
Reduction of neuronal excitability; decrease in the expres-
sion of neurotrophins and -estradiol causing dose-
dependent apoptotic neurodegeneration in fetal brains
Leucoencephalopathy, direct cytotoxic effects, cytokine-
induced inflammatory response, chemotherapy-induced
anemia and menopause; genetic risk factors (low-efficiency
efflux pumps, deficits in DNA-repair mechanisms),
ened telomere length, genetically modulated neural repair
deficits and decreased neurotransmitter activity
Decreased cholinergic enzyme choline acetyltransferase;
decreased nicotinic and muscarinic acetylcholine receptors
due to antagonist activity at dopaminergic-D2 receptors;
decreased nerve growth factor and brain-derived growth
factor
Enhancement of GABA, decreased calcium uptake by
neuronal membranes depressing excitability; reduces
number of fetal neurons and the length and branching
frequency of dendrites
Enhancement of GABA activity
Hippocampal cell loss
Inhibition of dopaminergic activity
Inhibition of the cholinergic system
Hyponatremia secondary to inappropriate antidiuretic
hormone secretion
Anticholinergic and antihistaminic effects
was near or above 100 mcg/mL, magnetic reso-
nance imaging documented pseudoatrophy, and
there was a loss of 18 to 26 IQ points as tested on
the Wechsler Intelligence Scale for Children-III.
Some of these reports also mentioned the simul-
taneous presence of other overdose symptoms,
such as tremor, weight gain, alopecia, ataxia, and
nystagmus.
Differentiating between cognitive dysfunction
that is drug-induced with that due to a non-drug-
induced disease process can be complex. This is
especially true in patients with disorders such as
epilepsy, Parkinson’s disease and human immun-
odeficiency virus (HIV).15,59,60 The “five foes” of
mental competence in patients with epilepsy have
been described as heredity, brain damage, seizures,
antiepileptic medications, and psychosocial
TisdaleC17_301-314 1/12/10 2:42 PM Page 305
TABLE 17–3 Signs and Symptoms Associated with
Drug-Induced Cognitive Disorders1,4,15,21-23,28,44,50,56-58
• Sedation/drowsiness
• Insomnia
• Decreased attention
• Impaired concentration
• Memory disorders
• Confusion
• Myoclonus
• Hallucinations
• Delirium
• Seizure disorders
• Impaired performance on assessment instruments
(e.g., Wechsler Adult Intelligence Scale, Digit
Span/Digit Symbol, CogHealth, Hopkins Verbal
Learning Test) to assess executive function, attention,
concentration, intelligence, memory and recall, psy-
chomotor ability, processing verbal ability, vigilance,
and visuospatial and visuomotor ability
• Seizure activity on electroencephalogram
• Magnetic resonance imaging changes (e.g., cerebral
atrophy, diffuse white matter hyperintensities, ven-
tricular enlargement, cortical calcifications)
issues.59 Neuropsychiatric problems of Parkinson’s
disease—such as hallucinations, memory loss, con-
fusion, and dementia—can be aggravated by
antiparkinsonian medications.15 Cognitive and
motor impairment occurs in 20% of patients with
advanced HIV.60 Robertson and colleagues con-
ducted a prospective study of HIV-positive patients
enrolled in randomized antiretroviral trials and
found that a history of immunosuppression (nadir
CD4 cell count less than 200 cells/mm3) was asso-
ciated with an increase in neurocognitive impair-
ment.60 Forty-four percent of the 458 patients who
were classified as having mild impairment at base-
line improved while receiving highly active anti-
retroviral therapy.
The differential diagnosis of a patient with
altered mental status can be quite lengthy.4,58,61
The patient may not be able to provide an accurate
history. Therefore, interviews of family members
or care providers may be essential to determine
the patient’s baseline mental status.6 It is impor-
tant to determine the timeline of development of
the cognitive dysfunction, which may be
described as either acute or insidious. The rate of
drug absorption and penetration into the brain
determines the speed of onset of acutely occurring
drug-induced events.39 A careful history of current
CHAPTER 17 • Cognitive Disorders 305
prescription and nonprescription medication use,
as well as the use of herbal or other remedies is
essential and should include information regard-
ing any recent alterations in drug, dose, or adher-
ence.4
The most common causes of cognitive disor-
ders are Alzheimer’s disease, vascular dementia,
alcoholism, Parkinson’s disease, and drug intoxica-
tion.61 Dementia associated with chronic alco-
holism may be linked to the associated
malnutrition and deficiency of the B vitamins or to
withdrawal syndromes. Thiamine (vitamin B1)
deficiency can lead to Wernicke’s encephalopathy,
which in turn can progress to irreversible
Korsakoff’s psychosis and death. Vitamin B12 defi-
ciency, in addition to damaging peripheral nerves
and causing sensory loss, can damage cerebral
myelinated fibers, thereby inducing dementia.
Another insidious cause of memory loss is chronic
metal intoxication, such as with lead, mercury, and
aluminum poisoning.
Acute and chronic infections can cause cogni-
tive disorders.61 Chronic diseases such as tubercu-
losis, cryptococcosis, advanced stages of HIV
infection and neurosyphilis must be considered.
Prion illnesses such as Creutzfeldt–Jakob disease
and bovine spongiform encephalopathy are rare.
Elderly patients may experience delirium in associ-
ation with acute infections such as urinary tract
infections and pneumonia.60
Acute changes in mental status can serve as an
alert for an underlying life-threatening medical
problem.24 Metabolic and endocrine disorders,
including dehydration, hyperammonemia, hyper-
calcemia, hyponatremia, hypothyroidism, kidney
disease, liver failure, and hypoxemia should be
considered in the differential diagnosis.61-63
Withdrawal from certain agents, including alcohol,
barbiturates, benzodiazepines, and tricyclic antide-
pressants, can also cause cognitive distur-
bances.39,55
Psychiatric diseases must also be considered in
the differential diagnosis. Some patients with
severe depression have expressed that they are con-
fused and cannot perform routine tasks.61
Cognitive dysfunction has been experienced by
patients with schizophrenia or with a conversion
disorder (mental disorders presenting as physical
illnesses but without a physiologic basis). In
patients with conversion disorders, psychometric
testing does not confirm memory loss.
Schizophrenia is usually associated with delusions
and hallucinations and initially with an intact
memory, but an unexplained progressive dementia
develops in some patients late in life.
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306 SECTION III • Drug-Induced Neurological Diseases

Table 17– 4 provides a list of conditions to con-

TABLE 17–4 Conditions to Consider in the sider in the differential diagnosis of drug-induced
Differential Diagnosis of Cognitive Disorders55,61,62 cognitive disorders. Diagnostic tests that can be
Neoplastic disease performed to confirm or assist in the diagnosis are
• Primary brain tumor listed in Table 17–5.57,58,61-63
• Metastatic brain tumor
Central nervous system disorder
• Extradural hemorrhage RISK FACTORS
• Chronic subdural hematoma
• Vascular dementia Certain situations may increase the risk of experi-
• Postanoxia encing drug-induced cognitive dysfunction (Table
• Normal-pressure hydrocephalus 17–6). Predisposing characteristics include age,
• Stroke cerebral damage, chronaic illness, functional
impairment, genetics, polypharmacy and underly-
Metabolic disorder ing cognitive impairment.4,27,62 Precipitating fac-
• Dehydration tors include acute illness, infection, metabolic
• Hyperammonemia disturbance, dehydration, acute urinary retention,
• Hypercalcemia malnutrition, environmental and psychosocial fac-
• Hyperglycemia/hypoglycemia tors, surgery, drug interactions, and dose–response
• Hypoadrenalism relationships.4,27,36,55,64,65
• Hyponatremia In one study, altered mental status was pres-
• Hypothyroidism/hyperthyroidism ent in 40% of patients older than 70 years of age
• Kidney disease who presented to the emergency department.55
• Liver failure There are a number of pharmacokinetic changes
• Hypoxemia in the elderly that place them at higher risk of
Infections cognitive dysfunction. In elderly patients there is
• Central nervous system infection (meningitis, a lesser degree of gastric acid secretion, reduced
encephalitis, brain abscess) gastrointestinal blood flow, and a diminished rate
• Human immunodeficiency virus of gastric emptying, translating to reduced ioniza-
• Neurosyphilis tion and solubility of certain drugs and a delay in
• Prion (Creutzfeldt–Jakob disease) drug absorption.66 As a person ages, there is a
• Acute infection/sepsis decrease in lean body mass and an increase in
Vitamin deficiencies
• Thiamine (B1) (Wernicke’s encephalopathy)
• B12 (pernicious anemia)
• Nicotinic acid (pellagra) TABLE 17–5 Tests for Evaluation of Patients with
Toxic disorders Cognitive Dysfunction57,58,61-63
• Intoxication with drugs of abuse and/or prescription
• Thyroid function
medications
• Vitamin B12
• Heavy metal intoxication
• Complete blood count
• Dialysis dementia (aluminum)
• Electrolytes
• Organic toxins
• Computed tomography/magnetic resonance imaging
Psychiatric disorders • Venereal Disease Research Laboratory (VDRL) test
• Conversion disorder • Human immunodeficiency virus
• Depression • Chest x-ray
• Schizophrenia • Lumbar puncture
Recurrent nonconvulsive seizures • Kidney function
Degenerative disorders • Liver function
• Alzheimer’s disease • Serum ammonia concentration
• Diffuse Lewy body disease • Urine toxin screen
• Frontotemporal dementia • Urine heavy metals
• Parkinson’s disease • Psychometric testing
• Multiple sclerosis • Electroencephalogram
TisdaleC17_301-314 1/12/10 2:42 PM Page 307
TABLE 17–6 Risk Factors for Drug-Induced
Cognitive Disorders4,27,35,55,62,64,65
Predisposing characteristics
• Elderly
• Children
• Genetic predisposition
• Underlying cognitive impairment
• Chronic illness
• Cerebral damage
• Functional impairment
• Polypharmacy
Precipitating factors
• Acute illness
• Acute infections/sepsis (brain abscess, encephalitis,
meningitis pneumonia, urinary tract infection)
• Metabolic disturbances (hyperammonemia, hypercal-
cemia, hyperglycemia or hypoglycemia, hyponatremia,
hypothyroidism, hypoxemia)
• Dehydration
• Acute urinary retention
• Malnutrition
• Environmental (heavy metal intoxication, organic tox-
ins, aluminum toxicity associated with dialysis)
• Psychosocial factors (drug abuse, depression)
• Surgery
• Drug interactions leading to elevated serum concen-
trations of causative agents and/or additive pharma-
codynamic effects
• Dose–response relationships
body fat. These changes affect the distribution
and volume of distribution of lipophilic and
hydrophilic drugs. Binding to serum albumin and

1-acid glycoprotein is a determinant of drug dis-
tribution and the fraction of drug available for
activity. Albumin primarily binds with acidic and
some basic drugs; albumin concentrations
decrease with increasing age. Conversely,
1-acid
glycoprotein binds to basic and neutral drugs;
there is either no change or an increase in the
1-
acid glycoprotein concentration with advancing
age. In addition, serum drug concentrations may
be increased in patients with infection, trauma,
myocardial infarction, and chronic disease.
Hepatic metabolic activity—especially phase 1
reactions, including oxidation, reduction, and
hydrolysis—is reduced in the elderly. 67
Glomerular filtration rate, creatinine clearance,
and tubular secretion and absorption all decrease
in elderly patients. Older patients may also be
more sensitive to the effects of some medications
CHAPTER 17 • Cognitive Disorders 307
because of pharmacodynamic changes.4,66,67 There
may be reduced cholinergic transmission and
decreases in receptor numbers and sensitivity.4,67
Younger age has also been implicated as a risk
factor for specific drug-induced alterations of cog-
nitive function. Phenobarbital has been shown to
slow cognitive processing speed as compared with
carbamazepine and valproate in children. 7,27
There is concern that minor detriments to atten-
tion and memory caused by antiepileptic medica-
tions may impact long-term neurodevelopment
in children.28
Genetic polymorphisms (deoxyribonucleic
acid sequence variation) are responsible for
inherited differences in drug metabolism and dis-
position and the resulting effects.68 In addition,
polymorphism in genes encoding drug trans-
porters and targets cause modifications in drug
response. Genetic variability affects the sensitivi-
ty to opioid analgesia and may determine a pre-
disposition to adverse effects.62 In studies of the
addition of topiramate or valproate to carba-
mazepine therapy, a subgroup of patients who
are particularly sensitive to the cognitive side
effects of topiramate was identified. 69,70
Galimberti and colleagues identified a mitochon-
drial mutation in the MTATP8 gene of a child
who developed reversible mental deterioration
with brain pseudoatrophy while receiving val-
proate therapy. 71 Womack and Heilman
described the case of a 46-year-old woman in
whom memory loss and abnormal memory test
results developed, but who improved upon dis-
continuation of tolterodine therapy. 35 The
authors suggested that she might be one of the
7% of the population lacking the cytochrome P-
450 2D6 enzyme responsible for converting
tolterodine to the active 5-hydroxymethyl
metabolite. In poor metabolizers, the more
lipophilic parent compound predominates and
crosses the blood–brain barrier more easily than
the metabolite, which is more hydrophilic.
Cognitive adverse effects of many medications
occur more commonly in association with higher
serum concentrations and with polypharmacy.28,65
Therapeutic serum concentration ranges have been
identified for many “narrow-therapeutic index”
medications, including phenytoin (10–20 mg/L),
carbamazepine (4–12 mg/L), phenobarbital (15–40
mg/L), valproic acid (50–100 mg/L), lithium (0.5–1.5
mEq/L), digoxin (0.9–2.2 ng/ml), theophylline
(10–20 mg/L), lidocaine (1–5 mg/L), amitriptyline
(75–175 ng/ml), and nortriptyline (50–150 ng/ml).65
Many patients experience cognitive adverse events
TisdaleC17_301-314 1/12/10 2:42 PM Page 308
308 SECTION III • Drug-Induced Neurological Diseases
when the upper limit of the therapeutic range is
exceeded. Doses must be individualized for efficacy
and to prevent toxicity. Some patients may not be
able to tolerate the medication at a lower serum con-
centration, while others may tolerate much higher
concentrations. Additive effects are often observed
when sedative or hypnotic medications are taken
concurrently.57 Tolerance may develop to some
effects of medications, but other effects may linger.
With benzodiazepines, patients report subjectively
that drowsiness subsides after a few days, but toler-
ance to the impairment of some measures of psy-
chomotor performance, such as visual tracking, does
not occur.
Adverse central nervous system reactions have
been attributed to histamine2-receptor block-
ers.17,72-73 Slugg and colleagues determined that
ranitidine-induced adverse central nervous sys-
tem reactions are more likely to occur in patients
with estimated creatinine clearances <50 mL/min
than in those with estimated creatinine clear-
ances >50 mL/min.72 Patients with creatinine
clearances <50 mL/min had higher peak plasma
concentrations, higher average plasma concentra-
tions, and larger areas under the plasma concen-
tration:time curve than patients who did not
have kidney disease.
Postoperative confusion occurs commonly,
with a reported incidence between 5% and 45% in
the elderly.74 Common causes include opioids,
benzodiazepines, and anticholinergics.22,74 Short-
term and long-term postoperative cognitive dys-
function has been evaluated in both elderly and
middle-aged patients.73,74 Postoperative cognitive
dysfunction was present in 25.8% and 9.9% of
1218 patients ≥60 years of age at 1 week and 3
months after surgery, respectively, as compared
with 3.4% and 2.8% in control subjects (P<0.0001
and P = 0.0037).75 Risk factors were increasing age,
duration of anesthesia, minimal education, a sec-
ond operation, postoperative infections, and respi-
ratory complications. In a study investigating
patients 40 to 60 years of age who were undergoing
surgery, cognitive dysfunction was reported in
19.2% at 1 week postoperatively, as compared with
4% of control subjects (P<0.001).76 The major risk
factors for this group of patients at 7 days was sup-
plementary epidural analgesia and reported avoid-
ance of alcohol consumption.
MORBIDITY AND MORTALITY
There are few published data regarding the influ-
ence of drug-induced cognitive impairment on
morbidity or mortality. However, in one prospec-
tive study of hospitalized elderly patients, delirium
prolonged the duration of hospitalization from 7.2
days to 12.1 days, and increased mortality from 1%
to 8%.29
PREVENTION
A number of strategies have been used to reduce
the likelihood of the occurrence of drug-induced
cognitive disorders. These include adjusting drug
doses in patients with liver or kidney disease,
limiting the total dose of medications with
known dose–toxicity relationships, monitoring
plasma concentrations, slowly titrating the dose,
using alternative agents, limiting the total num-
ber of medications, and using consensus criteria.
Table 17–7 provides a summary of measures that
can be taken to prevent drug-induced cognitive
disorders.
Adjusting the dose and/or the dosing interval
in patients with liver or kidney disease is not only
important when initiating therapy, but it is also
critical in patients with severe illness in which
organ function may decline suddenly and precipi-
tously. Histamine2-receptor blockers are an exam-
ple of a class of medications for which careful dose
adjustment is necessary.72 Other medications
should be avoided altogether in patients with liver
or kidney disease. Meperidine, for example, has a
neurotoxic active metabolite, normeperidine, that
accumulates after repeated doses in patients with
kidney disease.77
Another strategy is to limit the total dose of a
potentially offending agent for which a known
dose–toxicity relationship exists.62 In patients
requiring pain management with opioids, for
example, the addition of a nonopioid co-analgesic
or an adjuvant analgesic and around-the-clock
administration can decrease the total required opi-
oid dose.62,77 Proper management of pain is impor-
tant, as was demonstrated in a study of
postoperative patients 50 to 80 years of age, which
found that pain, not analgesic intake, predicted a
decline in mental status during the first 5 days after
surgery.78 Other pain management approaches to
consider include the use of a therapy targeting the
cause of pain (antitumor therapies such as radio-
therapy, chemotherapy, and surgery) or use of a
regional anesthetic or neuroablative interven-
tion.62
Medications such as anticonvulsants and lithi-
um require routine plasma concentration monitor-
ing to maintain concentrations within specified
ranges.65 For some medications, minor adverse
effects often appear as the plasma concentrations
TisdaleC17_301-314 1/12/10 2:42 PM Page 309
TABLE 17–7 Approaches to Help Prevent Drug-
Induced Cognitive Disorders28,31,65,72,77-80
• Adjust dose for patients with renal and hepatic im-
pairment where applicable
• Limit total dose for medications with dose–toxicity
relationships
• Use concomitant medications with same indications
• Use adjunctive medications
• Use around-the-clock regimen
• Perform routine plasma concentration monitoring of
medications with defined ranges for efficacy and toxicity
• On initiation of medications, use a slow titration to
target range
• Use alternative medications with less association for
cognitive adverse events
• Use consensus guidelines for safe medication use in
specific populations
rise before major cognitive toxicities are experi-
enced. To an astute clinician, these minor adverse
effects serve as a warning that more serious cogni-
tive impairment may be imminent. For example,
gastrointestinal distress may be an early symptom
of valproic acid toxicity, while fatigue may be an
early indicator of impending toxicity associated
with phenytoin or topiramate. Patients become
tolerant to some of the adverse cognitive effects of
some medications when doses are slowly titrated
upward. This is the case with the anticonvulsant
topiramate, for which therapy should be initiated
at a low dose and titrated to the target dose over a
period of 1 to 2 months.69
Another strategy for the prevention of cogni-
tive disturbances involves the use of medications
with lower associated risk. Of the anticonvulsants,
phenobarbital and benzodiazepines cause the
highest incidence of cognitive adverse effects.28 In
contrast, tiagabine and vigabatrin are associated
with a lower incidence of cognitive adverse effects.
Among newer anticonvulsant medications, topira-
mate is associated with the highest incidence of
adverse cognitive effects. Residual daytime seda-
tion has been associated with the use of benzodi-
azepines. However, psychomotor assessment has
shown that the newer benzodiazepine-receptor
agonist hypnotics zolpidem and zaleplon are not
associated with undesirable residual morning-after
effects.79
The potential for drug interactions and addi-
tive pharmacodynamic effects should be consid-
ered as new medications are added to a patient’s
treatment regimen. The relative odds for experi-
encing adverse drug reactions, adjusted for age and
CHAPTER 17 • Cognitive Disorders 309
duration of symptoms, were shown to increase as
the number of drugs used increased in an elderly
population.31 Compared to patients taking no pre-
scription medications or only one, the relative
odds of adverse drug reactions for those taking two
or three medications was 2.7 (95% confidence
interval [CI], 0.9–7.8), compared with 9.3 (95% CI,
3.3–26.6) for those taking four or five medications,
and 13.7 (95% CI, 3.6–51.9) for those taking six or
more medications.31 In a prospective study of 72
children with epilepsy, in which siblings of 45 of
the children served as controls, investigators found
that 11% of children with a persistent decrease in
IQ score had a higher incidence of toxic plasma
drug concentrations, took a larger number of med-
ications simultaneously, had seizures that were
more difficult to control, had a higher total num-
ber of seizures, and began to have seizures at a
younger age.59 All of these factors were statistically
interrelated, except for the younger age at onset.
Federal regulations have been enacted to pro-
tect the elderly, a population that is at increased
risk for the development of adverse events due to
medications. The Omnibus Budget Reconciliation
Act of 1987 (OBRA-87) contained the Federal
Nursing Home Reform Bill, which gave the right of
long-term care residents to be free from unneces-
sary physical and chemical restraints.81 Reportable
quality measures, such as the Minimum Data Set
(MDS) for nursing home residents, improve quali-
ty for residents by providing regular organized
assessments of each resident’s physical and mental
status.82 The Beers criteria, first published in 1997
and updated in 2003, provide a consensus state-
ment of medications that are potentially inappro-
priate in general populations of older adults and in
older adults with common medical conditions.80,83
The Beers criteria were accepted by the Centers for
Medicare and Medicaid Services (CMS) for nursing
home regulation in 1999.83
MANAGEMENT
A summary of management strategies for drug-
induced cognitive disorders is provided in Table
17–8. Management of drug-induced cognitive dis-
orders may include discontinuation of the offend-
ing agent with or without adjuvant medications,
dose reduction, substitution of a sustained-release
formulation, symptomatic treatment, and/or cog-
nitive rehabilitation.17,21,62,84 In some instances,
such as in patients with epilepsy or bipolar disease,
it may be necessary to substitute another medica-
tion before therapy with the offending agent can
be discontinued.21,28 Use of a sustained-release for-
TisdaleC17_301-314 1/12/10 2:42 PM Page 310
310 SECTION III • Drug-Induced Neurological Diseases
Table 17–8. Management of Drug-Induced
Cognitive Disorders13,22,56,70,76,82
• Distinguish between medication effects and symp-
toms caused by comorbid conditions
• Discontinue the offending agent and use alternative
medications
• Reduce the dose of the offending agent
• Where available, use a sustained-release formulation
to prevent peak serum concentrations associated
with adverse events
• Provide symptomatic treatment
• Provide cognitive rehabilitation
• Provide supportive measures
mulation that may ameliorate toxicity associated
with peak plasma concentrations has been recom-
mended for patients with cognitive impairment
induced by lithium.21
Discontinuation of some medications, such as
benzodiazepines, may cause a withdrawal reac-
tion.84 These reactions occur more often in patients
receiving higher daily doses, with agents having
shorter half-lives, those with a longer duration of
daily drug therapy, and in association with more
rapid rates of tapering. Other predictors of poor out-
come following discontinuation of benzodiazepines
include a diagnosis of panic, higher levels of anxiety
or depression before tapering, higher levels of per-
sonality psychopathology, and concomitant alcohol
and/or substance dependence or abuse. Tapering of
therapy has been recommended for patients receiv-
ing daily doses of >10 mg of diazepam or its equiva-
lent (2 mg lorazepam, 1 mg alprazolam) after
patients’ psychopathology levels have been reduced.
After maintenance of a benzodiazepine dose at a
minimum level of 10 mg daily of diazepam or its
equivalent for several months, final tapering can be
initiated. Therapy with carbamazepine, imipramine,
valproate, and trazodone has been shown to
improve benzodiazepine tapering success rates, but
has not been shown to decrease withdrawal severity.
Psychostimulant agents have been shown to
antagonize opioid-induced sedation and cognitive
impairment in postsurgical patients and patients
with chronic cancer.62 However, these agents can
also cause cognitive adverse effects, including hallu-
cinations, delirium, and psychosis, as well as
noncognitive adverse events such as decreased
appetite and tachycardia. A short-acting benzodi-
azepine such as lorazepam is often administered for
severe agitation, and neuroleptic drugs such as
haloperidol are often administered for the treatment
of patients with delirium. Several studies have
shown that opioid rotation, also referred to as “opi-
oid switching” or “opioid substitution,” can mini-
mize delirium or agitated confusion. Dose
conversion tables should be used cautiously as
guidelines. Because of incomplete cross-tolerance to
opioids in tolerant patients, it has been recommend-
ed to decrease the dose of the new opioid by 30 to
50%. Cherny and colleagues have published
detailed instructions regarding the manner in which
to perform opioid rotation.62 The use of 25 to 50
mcg per day of liothyronine was found to improve
cognitive functioning in patients receiving lithium,
even in the absence of hypothyroidism.21
Cognitive rehabilitation approaches may sig-
nificantly improve patient functioning.85 One
approach is for caregivers and family members to
orient confused patients to person, place, and
time.77 Supportive measures include convenient
arrangement of the home or work environment,
use of notes, and avoidance of distractions.11
The pharmacokinetic properties of a medica-
tion will most often determine the duration of
adverse cognitive effects.39 The duration may be
affected by redistribution from the brain into other
tissues, as occurs with highly lipid-soluble drugs
such as diazepam. With other central nervous sys-
tem depressants, drug metabolism and elimination
determine the duration of effect of the parent drug
and any active or toxic metabolites. These factors
may be influenced by age, disease, genetics, and
concomitant medications.
INFORMATION FOR PATIENTS
Patients and/or their caregivers should be informed
that the prescribed medication has been known to
cause cognitive dysfunction, and they should be
informed of associated signs and symptoms.
Patients should be warned regarding the potential
hazards of driving or using machinery and should
be aware that alcohol could have additive effects
when used concurrently. Patients and their care-
givers should be informed that health care providers
should be contacted if the prescribed therapy causes
intolerable cognitive effects so that appropriate
changes in therapy can be implemented.
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47. Kingma A, Van Dommelen RI, Mooyaart EL, et al. No
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51. Ahles TA, Saykin AJ. Candidate mechanisms for
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59. Bourgeois BF. Antiepileptic drugs, learning, and behavior
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CHAPTER 17 • Cognitive Disorders 313
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SECTION IV

DRUG-INDUCED
PSYCHIATRIC DISEASES

CHAPTER 18 Depression

CHAPTER 19 Anxiety

CHAPTER 20 Psychosis
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TisdaleC18_315-332 1/20/10 11:07 PM Page 317
CHAPTER 18
Depression
D epression is one of the most common psychiatric
illnesses, and it may interfere significantly with a
patient’s daily functioning and quality of life.
Untreated depression is associated with substantial
morbidity and increases the risk of suicide and death.
An estimated 15% of mood disorders end in suicide.1
Depression is a biologic illness with an unknown
cause. Depression occurring secondary to medica-
tions is similar in presentation to endogenous depres-
sion and carries similar risks of morbidity and
mortality. While the overall prevalence is unknown,
drug-induced depression poses a significant challenge
for practitioners, as it may undermine the effective-
ness of much-needed treatment. The risk of treat-
ment-emergent suicidality (e.g., suicidal ideation and
behavior) has more recently been characterized inde-
pendently, although it often occurs with mood
changes and poses significant risks to the patient.
CAUSATIVE AGENTS
Depression has been associated with many drugs,
including antiinfective agents, cardiovascular agents,
central nervous system (CNS) drugs, dermatologic
agents, hormonal treatments, and immunologic and
chemotherapeutic drugs. The Diagnostic and
Statistical Manual of Mental Disorders, 4th edition, Text
Revision (DSM-IV-TR)1 defines substance-induced
depression as a prominent and persistent disturbance
of mood that occurs during use of a medication
causally related to depression, or within 1 month of
intoxication or withdrawal of therapy with a medica-
tion. Symptoms must be severe enough to result in
clinically significant distress in social, occupational,
or other areas of functioning. The clinical features of
substance-induced depression may be similar to
Sheila Botts and Melody Ryan
those of major depressive disorder (MDD), but do
not have to meet full diagnostic criteria. In the eval-
uative literature, depression may be characterized as
a specific symptom (i.e., depressed mood), or a clus-
ter of depressive symptoms, or as a diagnostic entity
(MDD), though the latter is less common. For the
purposes of this chapter, depression is defined as the
presence of any one of these three characterizations
severe enough to cause a disruption in daily func-
tion. Suicide and suicidality are often associated with
depression. Suicidality associated with antidepres-
sants, antipsychotics, and anticonvulsants is defined
as suicidal thoughts or behaviors or suicide.
All drugs associated with inducing depression
for which evaluative support is available in the lit-
erature are reviewed in this chapter. The literature
supporting an association of drugs with depression
is largely comprised of case reports, postmarketing
surveillance and retrospective observational stud-
ies, making the case for causality difficult. There
are few prospective, controlled trials with objective
assessments of depressive symptoms or diagnostic
criteria. When available, these data are discussed
for each agent. A list of drugs that have been asso-
ciated with depression and the estimated incidence
for each agent are presented in Table 18–1.2-120
EPIDEMIOLOGY
The estimated lifetime prevalence of depression in
the general population is approximately 17%.
Depression occurs at a much higher rate in patients
with chronic illnesses, such as diabetes and cardio-
vascular disease.121 While many drugs have been
associated with depression, few have been ade-
quately studied to identify the risk that they
317
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318 SECTION IV • Drug-Induced Psychiatric Diseases

TABLE 18–1 Agents Implicated in Drug-Induced Depression

Drug Incidence Level of Evidence
(see page xii for explanation)

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
the population of patients with disease.
Several literature sources suggest a possible causal
association between isotretinoin and depression.
There has been a relatively large number of reports of
serious depression (37 cases of suicide and 394 cases
of depression between 1982 and 2000) associated
with isotretinoin submitted to the Food and Drug
Administration (FDA). These reports have document-
ed a temporal relationship between use of the drug
and onset or worsening of depression. In addition,
cases of positive dechallenge with discontinuation of
isotretinoin therapy and initiation of psychiatric
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
the risk of depression in patients treated with
isotretinoin in Quebec revealed a relative risk of 2.68
(95% confidence interval [CI], 1.10–6.48).6 Another
retrospective study from Saskatchewan and the
United Kingdom (U.K.) compared patients treated
with isotretinoin to those treated with antibiotics for
acne.7 There was no increased risk of depression or
suicide in patients treated with isotretinoin. A
prospective, case–control study compared 100 sub-
jects treated with isotretinoin to 100 subjects treated
with topical cream or oral antibiotics.8 This study
used two depression scales and collected information
on the severity of acne, social support, stress, and
family history as potential confounders. Depression
developed in two patients treated with isotretinoin,
but the overall difference between the two groups
was not statistically significant.8 Another prospective
study administered depression inventories to 33 sub-
jects at various times during isotretinoin treatment.
In this study, patients’ depression scores improved as
their acne improved, although improvements were
not statistically significant.9 Despite the lack of con-
sensus in the literature, many health care providers
prescribe isotretinoin with caution and consider
depression a substantial risk associated with this
drug.
Antihypertensive agents, including angiotensin-
converting enzyme (ACE) inhibitors, ␤-blockers,
calcium-channel blockers, anti-adrenergic agents
(e.g., reserpine, methyldopa, guanethidine, and
clonidine), and thiazide diuretics have been impli-
cated in causing depression in case reports. With
the exception of anti-adrenergic agents and ␤-
blockers, little empirical evidence exists to support
this association. Reserpine, methyldopa, and
guanethidine increase patients’ risk of depression,
but these agents are no longer commonly used.10-14
The association between clonidine and depression
is supported by case-report data. However, larger
evaluative studies suggest that the incidence of
depression in patients taking clonidine is similar to
that in the general population.15 The risk of depres-
sion associated with ␤-blocker therapy remains
somewhat controversial. In addition to case reports,
two epidemiologic studies support an association
with depression, but this association was not con-
firmed in two prospective studies.16-19 It has been
suggested that true depressive disorders rarely
develop in patients treated with ␤-blockers, but that
these patients experience typical ␤-blocker adverse
effects, which leads to misdiagnosis of depression.
Studies that have incorporated diagnostic criteria
for depressive disorders have failed to identify an
association between ␤-blockers and depression.20,21
Digoxin also has been associated with depres-
sion in case reports and two small prospective stud-
CHAPTER 18 • Depression 319
ies.21-23 In a community sample, Palinkas reported
that elderly women taking digoxin had higher rates
of significant depressive symptoms than women
not taking digoxin (10.5% vs. 6.5%), although this
difference was not statistically significant.22 In a
second study, digoxin exposure was associated with
an increased risk of depression in patients with a
history of myocardial infarction.20 Psychiatric
adverse effects have been reported in association
with most antibiotics, but are still considered rela-
tively rare events.21 Depression has been observed
in patients taking fluoroquinolones and the antitu-
bercular agents cycloserine and ethionamide.25-27
These data, however, are limited to case reports, and
the overall prevalence is unknown.
Both non-nucleoside reverse transcriptase
inhibitors (NNRTIs) and protease inhibitors have
been associated with depression. The NNRTI
efavirenz appears to confer the greatest risk. In over
1,000 patients treated with efavirenz in clinical tri-
als for an average of 1.6 years, severe depression was
reported with an incidence of 1.6%, and suicidal
ideation occurred in 0.6% of patients.28 The risk of
depression and suicidal ideation increased to 2% in
patients with a history of psychiatric disorders. In
contrast, a 48-week randomized, controlled trial of
patients receiving a protease inhibitor–containing
regimen or efavirenz-containing once-daily regi-
men failed to find a difference in the risk of depres-
sion during maintenance treatment.29 In addition,
nevirapine, abacivir, and indinavir have been noted
in clinical case reports to cause depression.30-32
The prevalence of drug-induced depression asso-
ciated with hormonal agents ranges from 1% to 54%.
Agents that affect sex-hormone production appear to
be associated with significant risks for inducing
depression. Gonadotropin-releasing hormone
(GnRH) agonists induce a profoundly hypoestro-
genic state and are associated with significant depres-
sive symptoms in approximately 50% of patients.33-37
Tamoxifen, an antiestrogenic agent, does not appear
to confer the same risk. Depression as an adverse
effect of tamoxifen was not supported by early place-
bo-controlled trials in patients with breast cancer.39
However, several published reports suggest that
depression may occur in up to 15% to 20% of tamox-
ifen-treated patients with breast cancer and that it is
often overlooked or erroneously attributed to the ill-
ness.40-42 These reports do not control for confound-
ing factors, such as the effects of the illness,
diagnosis, or adverse effects of chemotherapy, and
may overestimate the incidence of tamoxifen-
induced depression. The Breast Cancer Prevention
(P-1) Study of the National Surgical Adjuvant Breast
and Bowel Project provided additional controlled
data regarding the association between tamoxifen
and depression.43 The P-1 study was a multicenter
TisdaleC18_315-332 1/20/10 11:07 PM Page 320
320 SECTION IV • Drug-Induced Psychiatric Diseases
randomized, double-blind, placebo-controlled
chemoprevention trial in which a total of 11,064
women were assigned to receive tamoxifen or place-
bo for 5 years. The frequency of depression, as
assessed by the Center for Epidemiological
Studies–Depression was similar in both groups dur-
ing the first 36 months of the trial.43 However, the
presence of risk factors at baseline including history
of depression, current or previous treatment with an
antidepressant, or extended periods of dysphoric
mood (≥12 months) was associated with significant
depressive symptoms regardless of treatment arm.44
Although depression is the most commonly
cited reason for discontinuing therapy with oral con-
traceptives (OCs), the literature does not contain
overwhelming evidence of significant OC-induced
depression.45 The Royal College of General
Practitioners’ Oral Contraception Study reported
that depression occurred at a rate of 70 per 1,000 per-
son-years in women taking OCs. This is similar to the
expected rate of affective disorders in females in the
United States (U.S.)-based Epidemiologic Catchment
Area studies.122 Moreover, the rate of depression in
women receiving low-dose estrogen (ⱕ35 mcg) was
similar to that observed in the control group, sug-
gesting that commonly used low-dose preparations
do not carry an increased risk of depression. More
recent evaluations have focused on affective changes
rather than on identifying a depressive syndrome or
disorder. Oinonen and Mazmanian reviewed 13 con-
trolled, prospective studies evaluating affective
changes during OC treatment and concluded that
women taking OCs have less variability in affect
across the menstrual cycle and experience less nega-
tive affect during the time of menstruation.46
Drugs that affect the hypothalamic–pituitary–
adrenal (HPA) axis are associated with depression.
Corticosteroids have been associated with significant
psychiatric adverse effects, including depression,
mania, and psychosis.47 The occurrence of severe
depression in patients taking corticosteroids is sup-
ported by case reports.48,49 Data from case series,
observational studies, and controlled trials also sup-
port an association with depression. However, many
of these reports fail to quantify the prevalence of sig-
nificant depressive symptoms.47,50,51 The largest
observational study, the Boston Collaborative Drug
Surveillance Program, found that severe psychiatric
symptoms, including depression, were relatively
uncommon (1.3%) in patients without a psychiatric
history who were taking low doses of corticosteroids
(<40 mg/day prednisone equivalents).52 However, the
incidence increased to 18% in patients taking >80
mg/day prednisone equivalents. A cross-sectional
study comparing self-reported depression in steroid-
using and non–steroid-using patients with chronic
obstructive pulmonary disease reported significantly
higher depression scores in the steroid-using group.50
Furthermore, in a short-term prospective cohort
study of medical inpatients, corticosteroid exposure
was associated with a threefold increased risk of inci-
dent depressive symptoms.53
Several CNS-acting drugs have been associated
with depression, including anti-epileptic drugs
(AEDs), benzodiazepines, physostigmine, and 5-
hydroxytryptophan (HT)1 agonists (triptans). The
AEDs levetiracetam, phenobarbital, primidone,
phenytoin, tiagabine, topiramate, and vigabatrin
have been reported to cause depression. Conversely,
many of the AEDs may be used to stabilize patients
with mood disorders. Sodium valproate, carba-
mazepine and lamotrigine have FDA-approved indi-
cations for bipolar disorder. In addition, several AEDs
including phenytoin and carbamazepine have
demonstrated effectiveness in the management of
unipolar depression.54,55 It is important to note that,
because of ethical considerations, very few of the AED
epilepsy trials are strictly placebo-controlled. Because
of the various CNS activities of the AEDs used as com-
parators, it is difficult to judge the exact prevalence of
depression caused by these agents. Also, the rate of
depression in patients with epilepsy is very high
(32–48%) and the lifetime prevalence of suicide and
suicide attempts is 5% to 14% in this population.56
Therefore, this increase in the incidence of mood dis-
orders can be only partially attributed to the AEDs. All
of the AEDs, particularly at higher doses, are associat-
ed with lethargy, fatigue, drowsiness, and asthenia,
which may mimic depression. In January 2008, the
FDA issued an alert regarding suicidality related to
AEDs.57 Data from 199 placebo-controlled trials of 11
AEDs (carbamazepine, felbamate, gabapentin, lamot-
rigine, levetiracetam, oxcarbazepine, pregabalin,
tiagabine, topiramate, valproate, zonisamide) were
analyzed, and the investigators reported suicidal
ideation or behavior in 0.43% of patients taking AEDs
as compared with 0.22% of those taking placebo. The
relative risk of suicidal behavior or ideation in
patients taking AEDs for epilepsy was 3.53 (95% CI,
1.28–12.1) as compared with 1.51 (95% CI,
0.95–2.45) for those taking AEDs for psychiatric rea-
sons and 1.87 (95% CI, 0.81–4.76) for those taking
AEDs for other reasons.57 No specific AED or demo-
graphic group appeared to be at greater risk.
Of the AEDs, the barbiturates are most strong-
ly associated with depression in both adult and
pediatric populations.58-61 In one cross-sectional
sample of adult patients in Mexico City, pri-
madone use was strongly associated with depres-
sion, with an odds ratio of 4.089 (95% CI,
2.094–7.985). In this sample, 70% of the patients
treated with primadone were depressed.61 In
another study, phenobarbital was associated with
an incidence of depression of 40%.60 Data relating
TisdaleC18_315-332 1/20/10 11:07 PM Page 321
phenytoin use to depression are much less con-
vincing. There are case reports of two patients with
epilepsy who had supratherapeutic serum pheny-
toin concentrations (22.7 mcg/mL and 25.5
mcg/mL) who also had depressive symptoms.
When the phenytoin dose was decreased or the
medication was discontinued, the symptoms
resolved.62 A prospective study of 277 subjects in
whom tiagabine or placebo was added to baseline
AED therapy found depression in 3% of those
treated with tiagabine.63 Topiramate treatment has
been associated with new-onset depression in 5%
to 10% of patients.64 Depression was reported in
4% of levetiracetam-treated subjects as compared
with 2% in those treated with placebo.65 A retro-
spective case series and an additional case report
have also implicated levetiracetam as a cause of
depression.66,67 Vigabatrin-associated depression
occurred in 12.1% of patients treated in double-
blind, placebo-controlled clinical trials (P<0.001).68
Depression often is cited as an adverse effect of
benzodiazepines, both during therapy and after dis-
continuation.69 However, the literature supporting
incident depression in patients taking benzodi-
azepines is not robust, and depression is reported
infrequently in controlled clinical trials. Case
reports and observational studies have identified an
increased risk of depression in patients taking ben-
zodiazepines.70-73 These reports, however, do not
control for confounding variables, such as history
of depression, presence of comorbid depression, or
concomitant medications, and are therefore diffi-
cult to interpret. Depression and anxiety are highly
comorbid syndromes, and the emergence of depres-
sion during benzodiazepine therapy may occur
from a relapse or as a coincidental finding.
Moreover, alprazolam administered in higher doses
has been shown to have an antidepressant effect.74
Physostigmine was associated with immediate
depressive symptoms in nine normal volunteers
administered high intravenous doses.75 Whether
the results of this study apply to patients with
myasthenia gravis who take oral physostigmine,
with relatively low bioavailability, is unknown.
Only a single epidemiologic study exists to
implicate triptans as causative agents for depression.
A cohort analysis of the West Midlands General
Practice Research Database in the U.K. examined the
incidence of depression in migraineurs receiving
any oral triptan, sumatriptan, or the more lipophilic
medications (naratriptan or zolmitriptan).76 A larger
proportion of the 1,062 patients (23.2%) receiving
any oral triptan were diagnosed with depression, as
compared with 16.8% of 18,033 patients not receiv-
ing an oral triptan (P<0.001). When specific medica-
tions were compared, no difference in the number
of patients diagnosed with depression after their first
CHAPTER 18 • Depression 321
prescription was found between those receiving
sumatriptan (4.2%) and those receiving naratriptan
or zolmitriptan (3.9%) (P = 0.87).
Several medications used in immunotherapy and
chemotherapy, including interferon-alfa, interferon-
␤, and interleukin (IL)-2 have demonstrated associa-
tions with depression. In addition, the immuno-
suppressant agent mycophenolate was reported to
cause depression in a patient using the drug for myas-
thenia gravis.77 Multiple types of alfa interferons
(INF␣) are available: recombinant INF␣2a; recombi-
nant INF␣2b; INF␣n3, a mixture of at least 15 differ-
ent interferon subtypes produced from human
leukocytes; peginterferon ␣2a, a combination of
recombinant INF␣2a and an inert 40kD polyethylene
glycol polymer; peginterferon ␣2b, a combination of
recombinant INF␣2b and an inert 12-kD polyethyl-
ene glycol polymer; and INF alfacon-1 (consensus
INF), a recombinant, synthetic product. Depression
has been reported in association with each type of
INF␣.78-86 Several trials investigating the relationship
of depression and the various INF␣s have been con-
ducted, with treatment-emergent depression reported
in 16% to 96%78-80 of patients. Although none of
these trials were placebo-controlled, many used stan-
dardized instruments to assess depression. One study
examined the effect of INF␣ over time and found
decreased numbers of patients with depression after 6
months of therapy (8–33%) as compared with 1
month (79–96%; P = 0.03).80
Two ␤ interferons are available in the U.S. for
treatment of multiple sclerosis (MS). Interferon-beta
(INF␤) 1a is available for intramuscular or subcuta-
neous injection and INF␤1b is administered subcuta-
neously. The data regarding INF␤-precipitated
depression are less clear than those for depression
induced by INF␣. Two controlled trials suggest an
increased risk of depression associated with INF␤1a,
with incidences ranging from 20% to 33%.105,106 Two
other studies of INF␤1a have not revealed an
increased prevalence of depression as compared with
that associated with placebo.107,108 Only one trial
compared the two commercially available formula-
tions of INF␤1a. The Evidence for Interferon Dose-
Effect: European-North American Comparative
Efficacy (EVIDENCE) study assigned 677 subjects to
receive either INF␤1a 44 mcg subcutaneously three
times weekly or INF␤1a 30 mcg intramuscularly
weekly for 24 weeks.91 No difference in depression
between the two treatment groups was reported
(17% vs. 18%).
A long-term seminal trial of INF␤1b demonstrat-
ed higher rates of depression with the clinically-used
8 MU dose compared with those associated with
placebo at each yearly timepoint.92 Two trials have
been conducted to specifically examine rates of
depression associated with INF␤1b. One study report-
TisdaleC18_315-332 1/20/10 11:07 PM Page 322
322 SECTION IV • Drug-Induced Psychiatric Diseases
ed depression in a mean (±SD) 13±4% of patients,
though no formal testing for depression was per-
formed.93 Another small study found a decreasing rate
of reported depression over the 1-year study period,
ranging from 21.4% of subjects at baseline to 6.3% of
subjects at 12 months.94 Only one study comparing
two of the INF␤ products examined depressive symp-
toms. The Independent Comparison of Interferon
(INCOMIN) trial noted depression in 22% of subjects
(18 of 88) given INF␤1a 30 mcg intramuscularly week-
ly and in 19% of subjects (18 of 94) given INF␤1b 8
mcg subcutaneously every other day (P = 0.68).95 A
prospective cohort of 182 patients started on any
INF␤ treatment were administered the Hamilton
Rating Scale for Depression and the Beck Depression
Inventory at baseline and after a mean treatment
duration of 65.6 months. There was no increase in the
number of patients demonstrating depression over
this time.96 A Canadian database analysis of antide-
pressant prescription claims for patients with multiple
sclerosis failed to detect a significant difference in the
percentage of patients receiving antidepressant pre-
scriptions between INF-treated and glatiramer
acetate–treated patients. However, the percentage of
patients in all cohorts receiving antidepressant med-
ications was high (40%).97
IL-2 also has been reported to cause depression.
In two studies of patients with metastatic carcinoma,
patients administered IL-2 were found to be signifi-
cantly more likely to have depression than those not
receiving IL-2 therapy.98,99 The association between
other chemotherapeutic agents and depression is
more tenuous. One trial examined two regimens for
the treatment of small-cell carcinoma of the lung in
77 patients.100 Regimen 1 consisted of methotrexate,
doxorubicin, lomustine, and cyclophosphamide.
Regimen 2 comprised cyclophosphamide, doxoru-
bicin, vincristine, and lomustine. Subjects were test-
ed with the Profile of Mood States at baseline and
after completion of therapy. Increased depression rat-
ings following therapy were reported in 30% (not
statistically significant as compared with baseline) of
those receiving regimen 1 and 48% (P = 0.03 as com-
pared with baseline) of those receiving regimen 2.
The authors speculated that the larger proportion of
patients with increased depression rating scores in
patients who received regimen 2 can be attributed to
vincristine. A case report also implicates vincristine
as a cause of depression.101 A patient treated for acute
myoblastic leukemia who received vincristine 10 mg
instead of 1 mg had severe depression with uncon-
trollable crying. The symptoms dissipated over a 3-
week period.
Other drugs that have been implicated in depres-
sion in case reports include 3-hydroxy-3-methyl-
glutaryl coenzyme A reductase inhibitors, histamine2-
receptor blockers, amiodarone, nonsteroidal antiin-
flammatory drugs, metoclopramide, ondansetron,
and psychostimulants.102-116 However, cause–effect
relationships have not been established for any of
these agents. Similarly, postmarketing adverse event
reporting largely from case reports identified a risk of
neuropsychiatric adverse events including depression
and suicidality associated with the nicotine-receptor
agonist varenicline and the leukotriene antagonist
montelukast. These reports prompted the FDA to
require stronger warning language in the product
information.117-119 In placebo-controlled trials of
4,400 patients, varenicline was associated with high-
er risk of depression than no treatment. However,
patients with a history of psychiatric disorders were
excluded from these trials. Postmarketing surveillance
revealed severe neuropsychiatric events, including
suicide, occurring during and after treatment with
varenicline. While smoking cessation may be associ-
ated with nicotine withdrawal symptoms including
depression and agitation, there appears to be an
increased risk of these symptoms associated with
varenicline, as some of these cases occurred while
patients were still smoking.117,118
Antidepressant medications would not be expect-
ed to cause drug-induced depression. However, anti-
depressant drugs are associated with an increased risk
of suicidality in patients younger than 25 years of
age.120 Pooled analyses of 24 short-term placebo-con-
trolled antidepressant trials in over 4,400 children
and adolescents with MDD, obsessive–compulsive
disorder, or other psychiatric disorders showed that
these drugs increased the risk of suicidality, although
no suicides were reported. Antidepressant treatment
in patients younger than 18 years of age resulted in
an additional 14 cases of suicidality per 1,000 patients
treated. The pooled analyses of 295 short-term place-
bo-controlled studies in over 77,000 adults aged 18 to
24 years with MDD or other psychiatric disorders
showed an additional 5 cases of suicidality per 1,000
patients treated. There was no increased risk in adults
aged 25 to 64 years, and there was a reduced risk in
adults ≥65 years (6 fewer cases per 1,000 patients). All
antidepressant medications, including antipsychotics
with an FDA indication for MDD (e.g., aripiprazole
and quetiapine), have a boxed warning for suicidality
in the product information. This risk should be care-
fully considered when choosing a treatment interven-
tion for MDD.
MECHANISMS
Drug-induced depression occurs through several
mechanisms, including direct alteration of
bioamine function, disturbance of HPA axis func-
tion, dramatic hormonal changes, and elevation of
cytokine production (Table 18–2).
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CHAPTER 18 • Depression 323

TABLE 18–2 Mechanisms of Drug-Induced Depression

Drug Mechanism
Reserpine Depletes neuronal norepinephrine, serotonin, and dopamine
Guanethidine Depletes neuronal norepinephrine
Methyldopa Partial agonism of norepinephrine receptor
Clonidine Reduces norepinephrine output via ␣2-adrenergic receptor agonism
Digitalis Inhibits central nervous system synthesis of norepinephrine
Isotretinoin Alters dopaminergic, serotonin, and possibly norepinephrine systems
Leuprolide Reduces both estrogen and androgen production
Tamoxifen Reduces estrogen function via antagonizing estrogen receptors
Cortisone Elevates plasma co oncentrations
Phenobarbital Reduces plasma unbound tryptophan, which influences plasma serotonin concentrations
Topiramate Increases the amount of GABA available
Tiagabine Increases the amount of GABA available
INF␣ Increases interleukin-6 production
Vincristine Prevents the conversion of dopamine to norepinephrine
Varenicline ␣4␤2-nicotinic receptor agonist, indirectly modulates dopamine
GABA = ␥-aminobutyric acid.

The antihypertensive agents reserpine, guanethi-
dine, and methyldopa all likely induce depression by
depleting CNS bioamine activity.123 Guanethidine
and reserpine deplete norepinephrine at the synapse.
Methyldopa is transformed into ␣-methyl norepi-
nephrine, which is less active than norepinephrine
and replaces it at the sympathetic nerve endings,
thus acting as a false neurotransmitter. Notably, the
norepinephrine depletion caused by reserpine gener-
ated one of the early theories of the pathogenesis of
depression (e.g., the monoamine hypothesis).124,125
Clonidine also reduces central norepinephrine out-
put via stimulation of ␣2-adrenergic receptors.126
␤-blockers exert a specific centrally-mediated
effect on both ␤-adrenergic and serotonin recep-
tors. Chronic ␤-receptor blockade results in
increased ␤-receptor binding, an effect opposite to
that associated with antidepressants. This reduces
␤-receptor binding and receptor density.127,128
The mechanism of digoxin-induced depression
is unknown, although alteration of CNS norepi-
nephrine synthesis is suspected. In animal models,
digitalis has been shown to inhibit CNS synthesis of
norepinephrine and to decrease norepinephrine
uptake by CNS tissue, with an apparent overall acti-
vation of CNS noradrenergic function. Altered activ-
ity of CNS dopaminergic and serotonergic systems
also has been demonstrated, particularly with high
digitalis doses.24 Similarly, the mechanism of
isotretinoin-induced depression is not clear, but ani-
mal studies suggest alterations in the dopaminergic,
serotonin, and possibly norepinephrine systems.129
GnRH agonists induce a hypogonadal state,
resulting in a significant reduction in both estrogen
and androgen production. Significant fluctuation
in serum estrogen concentrations and low estro-
genic states have been associated with substantial
mood symptoms in patients with premenstrual dys-
phoric disorder and during menopause. The signif-
icant decline in estrogen production associated
with GnRH agonist therapy is believed to be the
cause of depressive symptoms in these patients.
Estrogen may affect mood in several ways, such as
by increasing the availability of neurotransmitters,
including serotonin, by enhancing the degradation
of monoamine oxidase.130 Estrogen modulates sero-
tonin in other ways, including regulation of trypto-
phan, a serotonin precursor, and increasing the
number of serotonin transport sites.131 Tamoxifen,
an estradiol receptor antagonist, also may produce
depressive symptoms caused by a decline in estro-
gen function. However, raloxifene, a selective estra-
diol receptor antagonist, without CNS activity, does
not appear to induce depression.132
A number of mechanisms have been proposed
regarding the mood effects of OCs. Estrogen may
induce a pyridoxine deficiency resulting in a decrease
in serotonin and ␥-aminobutyric acid (GABA) con-
centrations in the CNS. Vitamin B6 has been suggest-
ed as an effective treatment.133 Other possible
mechanisms include an estrogen- and progesterone-
mediated augmentation of GABA’s inhibition and
suppression of glutamate and a progesterone-mediat-
ed increase in monoamine oxidase activity.130,134
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324 SECTION IV • Drug-Induced Psychiatric Diseases
Corticosteroids are thought to induce mood
symptoms by elevating plasma cortisol concentra-
tions. Patients with Cushing’s disease have been
reported to have high rates of depressive symp-
toms.135 Moreover, abnormalities of the HPA axis
with hypercortisolemia are found in patients with
MDD.136 It is of interest that corticosteroids are as
likely to induce mania as depression, suggesting a
complex interaction.48
The mechanism of AED-induced depression
likely involves GABA, an inhibitory neurotransmit-
ter, alterations in serotonin activity or a combina-
tion of these. Some evidence suggests that
antidepressant agents enhance activity at GABA-B
receptors and decrease activity at GABA-A recep-
tors.137 Therefore, agents that primarily act at the
GABA-A receptors, such as phenobarbital, tiagabine,
or topiramate, or indiscriminately increase the
amount of GABA available to both receptors, such as
tiagabine, may be associated with greater potential
for inducing depression. Both phenobarbital and
phenytoin reduce unbound plasma tryptophan con-
centrations, which influences serotonin turnover.138
In addition, the enzyme-inducing AEDs can cause a
folate deficiency. Decreases in plasma folate concen-
trations may reduce methylation reactions involv-
ing neurotransmitters and monoamines, which may
be implicated in depression induction.139
The mechanisms of depression caused by the
immunologic agents have not been elucidated com-
pletely. Most work in this area has been conducted
with INF␣, and several mechanisms have been pro-
posed that may be applicable to INF␤ and IL-2. INF␣
induces the production of proinflammatory
cytokines, such as IL-6, which may lead to depres-
sion.81 An increase in the Montgomery–Asberg
Depression Rating Scale scores was significantly and
positively correlated with increases in serum IL-6
concentrations.70 INF␣ affects the serotonergic sys-
tem to increase serotonin transporter messenger
ribonucleic acid and uptake activity, suppress sero-
tonin concentrations in brain or serum, and induce
the catabolism of tryptophan.81 The net effect of
these alterations in the serotonin system is to
decrease the amount of serotonin at the active recep-
tor sites and potentiate depression. INF␣ administra-
tion is also associated with activation of the HPA,81
which has been associated with depression and with
increases in serum IL-6 concentrations.140,141 A deple-
tion of tryptophan, the amino acid precursor to sero-
tonin, caused by INF␣ administration has also been
hypothesized.142 A polymorphism (C1019G) on the
allele coding for the 5-HT1A receptor (HTR1A) has
also been implicated in the development of INF␣-
induced depression. The HTR1A receptor is the
major autoreceptor on the serotonergic raphe neu-
rons. Alterations in this receptor can lead to
decreased secretion of serotonin. This polymorphism
is relatively common, with approximately 48% of
people having at least one C1019G allele. This find-
ing may help explain the very common occurrence
of depression in patients treated with INF␣.142
Vinca alkaloids have been shown to inhibit the
transport of dopamine hydroxylase, thereby pre-
venting the conversion of dopamine to norepi-
nephrine,101 the resultant effect of which could be
depression. The mechanism of varenicline-induced
depression is unknown, but the partial ␣4␤2-nico-
tinic receptor agonist indirectly modulates
dopamine,143 which may in turn modulate mood.
CLINICAL PRESENTATION AND
DIFFERENTIAL DIAGNOSIS
Drug- or substance-induced depression is defined
by DSM-IV as a prominent and persistent distur-
bance of mood that occurs during use or within 1
month of intoxication or withdrawal of therapy
with a medication.1 The key feature of diagnosis is
the temporal association between the development
of depressive symptoms and the use of a causative
drug. The disturbance of mood or presence of
depression should be severe enough to result in
impairment of daily function. In addition, the clini-
cian must rule out the possibility of preexisting
depression and the influence of the disease state
being treated, particularly psychological stressors.
Symptoms associated with drug-induced depres-
sion (Table 18–3) are similar to those observed in
patients with MDD, with few exceptions. More severe
symptoms including suicidal ideation and psychotic
symptoms have been reported in association with
INF␣, corticosteroids, and varenicline.48,52,82,117,118
With most agents, the onset of depression generally
occurs during the first weeks of treatment. The medi-
an onset of symptoms in FDA-reported cases of
isotretinoin-associated depression during the first
course of therapy was 30 days, and the median recov-
ery time was 4.5 days.5 During the rechallenge course,
TABLE 18–3 Signs and Symptoms Associated
with Drug-Induced Depression
• Depressed mood
• Diminished interest or pleasure in most activities
• Sleep changes (insomnia or hypersomnia)
• Appetite increase or decrease
• Hopelessness/helplessness
• Suicidal ideation
• Fatigue
• Decreased concentration
• Psychomotor agitation or retardation
TisdaleC18_315-332 1/20/10 11:07 PM Page 325
the time to onset of symptoms was shorter.144 Patients
treated with GnRH agonists have depressive symp-
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-
ment, depressive symptoms are transient and less
severe.38 However, during sustained treatment for
endometriosis, depressive symptoms appear to be
persistent and generally more severe, sometimes
resulting in the need for discontinuation of treat-
ment.35,39,145 Drug-induced suicidality is temporally
associated with initiation of treatment and represents
a marked change in thoughts and behavior from
baseline.120 Suicidality associated with anticonvul-
sants and antidepressants occurs early in treatment,
and must be distinguished from the underlying mood
disorder for which they have been prescribed.
Conditions and diseases associated with depres-
sion must be ruled out in order to arrive at a diagno-
sis of drug-induced depression (Table 18–4). The
incidence of depression in patients with epilepsy
ranges from 4% to 62%, depending on the method
of diagnosis and the population studied.146,147 One
study found that patients with hypertension were
three times more likely to have depression than nor-
motensive patients.148 Many chronic health condi-
tions for which immunologic agents are used have
been associated with high rates of depression. The
prevalence of depression in patients with chronic
hepatitis C is 11% to 30%,149 while the prevalence of
depression in patients with cancer is 28%.150
Multiple sclerosis is also associated with a 15% to
30% point prevalence of depression and a lifetime
depression incidence of 40% to 60%.151 Fatigue, a
symptom common to all of the disease states in this
category, often can be confused with depression.
Alternatively, depression may be underdiagnosed
because of the expectation that patients will present
with fatigue. Other conditions that may cause mis-
diagnosis of depression include hyperthyroidism
TABLE 18–4 Conditions to Consider in the
Differential Diagnosis of Drug-Induced Depression
• Substance-use disorder
• Preexisting mood disorder
• General medical conditions
• Endocrine
• Infectious
• Deficiency state
• Collagen disorders
• Metabolic disorders
• Neurologic disorders
• Cardiovascular disease
• Malignant disease
CHAPTER 18 • Depression 325
and hypothyroidism and unrealistic expectations,
leading to discouragement and frustration.152
RISK FACTORS
Female sex, family history of mood disorder, child-
hood abuse, anxiety disorders, sleep disorders, and
neurologic disorders are known risk factors for MDD.1
It is unclear, however, whether these factors also
increase the risk of drug-induced depression. Much of
the literature regarding drug-induced depression aris-
es from case reports, database evaluations, and obser-
vational studies, which are not designed to identify
risk factors. Factors that appear to increase the risk of
drug-induced depression are listed in Table 18–5.
A history of depression or another psychiatric
disorder is the most consistently identified risk fac-
tor for depression associated with most of the
causative drugs. In addition, the presence of psy-
chological stressors has been noted to increase the
risk. While increased stress may be expected in
patients with serious medical illnesses, it is unclear
whether increased stress increases the risk of
depression associated with drugs such as immuno-
logic or cancer chemotherapeutic agents. Patients
with a history of drug-induced depression are like-
ly to be at greater risk upon repeated exposures.15
Dose may be an important risk factor for
depression associated with some agents.
Depression is more likely to occur when higher
doses of corticosteroids are used (>80 mg/day pred-
nisone equivalents).53 It is unclear whether multi-
ple courses of corticosteroids increase the risk of
depression. However, patients with a history of
steroid-induced depression should be monitored
closely. Likewise, oral contraceptives with higher
estrogen content are more commonly associated
with depression. Some open-label data suggest that
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
>2.74 µg/L.153
Several factors have been specifically associated
with an increased risk of treatment of emergent
depression or negative affect in patients taking OCs
(Table 18–5). Whereas the overall risk for depression
caused by these drugs is considered low, patients pre-
senting with any of these factors should be consid-
ered at greater risk. The risk may vary with the type
of OC used. Monophasic OCs exert greater mood-sta-
bilizing effects than triphasic products. In addition,
patients with premenstrual mood symptoms may
have an increased risk of negative mood effects with
OCs containing low amounts of progesterone or a
low progesterone-to-estrogen ratio. Women without
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326 SECTION IV • Drug-Induced Psychiatric Diseases
TABLE 18–5 Risk Factors for Drug-Induced
Depression
Risk Factors Common to All Drugs
• History of major depressive disorder or prior depres-
sion episode
• History of drug-induced depression
• Psychosocial stressors (e.g., financial, relationship, or
job stress)
Risk Factors Associated with Specific Drugs
• Corticosteroids
• Dose (>80 mg/day prednisone equivalents)
• Efavirenz
• Plasma concentrations >2.74 mcg/L during long-
term treatment
• Topiramate
• Dose (higher starting dose of 50 mg/day, titration
of 50 mg/day every 2 wk)
• Temporal-lope epilepsy with hippocampal
sclerosis
• Presence of cognitive adverse effects
• Family history of epilepsy
• History of febrile seizures
• Interferon-alfa
• Homozygous for the HTR1A-1019G allele
• Increased immune activation (e.g., increased solu-
ble IL-2 receptor, IL-6, and IL-10 serum concentra-
tions) prior to treatment for hepatitis C
• Oral contraceptives
• History of premenstrual depression or pregnancy-
related depression
• History of dysmenorrhea
• Family history of depression while taking oral con-
traceptives
• Predisposition to vitamin B6 deficiency
• High degree of psychological distress prior to oral-
contraceptive use
• Age <20 yr experience negative affect more often
• High estrogen/ progesterone content
IL = interleukin.
premenstrual mood symptoms appear to have
increased risk with a higher progesterone content.47
A retrospective study of patients with temporal-
lobe epilepsy who were initiated on topiramate ther-
apy revealed that those with hippocampal sclerosis
in association with temporal-lobe epilepsy were sig-
nificantly more likely to have depression than those
without hippocampal sclerosis. Patients without
hippocampal sclerosis who had cognitive adverse
effects such as psychomotor slowing or word-find-
ing difficulties associated with topiramate were also
more likely to be diagnosed with depression.154 A
case series of patients started on topiramate therapy
found that a higher starting dose (50 mg daily) and
a faster titration schedule (increase of 50 mg/day
every 2 weeks) as well as the presence of cognitive
adverse effects caused by topiramate increased the
odds of any psychiatric adverse events, including
depression. Other related factors were family or per-
sonal history of psychiatric conditions, family histo-
ry of epilepsy and a history of febrile convulsions.64
Risk factors for depression associated with INF␣
treatment include hepatitis C and an increase in
vegetative symptoms of depression on the Zung
depression rating scale after 4 weeks of treat-
ment.155,156 Patients who were homozygous for the
HTR1A-1019G allele had an approximate threefold
risk increase of depression induced by INF␣ treat-
ment.157 One small study of 16 patients undergoing
treatment with various INF␣ regimens for hepatitis
C found that patients with higher levels of immune
activation as demonstrated by increased soluble IL-
2 receptor, IL-6, and IL-10 serum concentrations
prior to treatment were more likely to have major
depressive disorder as measured by DMS-IV criteria
and the Montgomery–Asberg Depression Rating
Scale score.158
The risk for suicidality associated with antide-
pressants is inversely related to age, with patients
<18 years at greatest risk, and adults 18 to 24 years
at greater risk than older adults (25 to 64 years).120
Antidepressant selection, dose, or indication do
not significantly change the risk of suicidality
within the stratified age groups. Conversely,
patients receiving an AED for epilepsy are 3.4 times
more likely to experience suicidality than patients
with psychiatric disorders.
MORBIDITY AND MORTALITY
Drug-induced depression can be associated with sig-
nificant morbidity and mortality. Many drugs associ-
ated with depressive symptoms are used to treat
chronic medical disorders or are components of life-
saving or prolonging therapeutic regimens. Patients
experiencing significant depressive symptoms as a
result of their treatment may be less likely to adhere
to therapy and may be less optimistic about potential
treatment benefits. Furthermore, the development of
severe depressive symptoms may necessitate the dis-
continuation of lifesaving treatments.
The presence of depression or severe depressive
symptoms may increase the risk of suicide or suicidal
ideation. Whereas the prevalence of suicide risk in
patients with drug-induced depression is unknown,
up to 15% of patients with severe MDD die as a result
of suicide.1 Moreover, patients with MDD have
decreased physical, social, and role functioning as
well as increased pain and physical illness.159 The risk
TisdaleC18_315-332 1/20/10 11:07 PM Page 327
of suicidality associated with antidepressant treat-
ment must be balanced with the much greater risk of
suicidality in patients with untreated depression.
PREVENTION
There is very little information available regarding
preventive strategies for drug-induced depression.
However, some interventions may prove useful
(Table 18–6). Identifying patients with risk factors
(e.g., history of depressive episode) and implement-
ing a prospective monitoring plan seems prudent,
but will not prevent drug-induced depression.
Careful monitoring and early detection may, howev-
er, minimize the negative sequelae associated with
depression. Treating psychosocial stressors with
interventions such as counseling and education may
also prove beneficial, but this strategy has not been
systematically evaluated. Pretreatment or prophylax-
is for depressive symptoms may be useful in some
cases. Sabet reported the successful pretreatment
(with lithium and protriptyline) of an individual
with a history of steroid-induced depression.160 In a
retrospective review of patients receiving leuprolide
for treatment of endometriosis, concomitant treat-
ment with sertraline minimized the emergence of
depressive symptoms.158 Convincing evidence exists
regarding the benefit of pretreatment for depression
in patients with melanoma receiving INF␣.
Musselman et al.161 randomly assigned 40 patients
with melanoma to receive pretreatment with parox-
etine (n = 20) or placebo (n = 20) 2 weeks prior to and
throughout the 12-week INF␣ regimen. The risk of
developing depression was lower in the paroxetine
group (11% vs. 35%; relative risk, 0.24; 95% CI,
0.08–0.93) and pretreated patients were less likely to
discontinue INF␣ because of depressive symptoms
(5% vs. 35%; relative risk, 0.14; 95% CI, 0.05–0.85).
A small group (n = 10) of patients with hepatitis C
who had a history of major depression were admin-
istered escitalopram preventively during treatment
with peg-INF␣2a and ribavirin. Only one patient
TABLE 18–6 Approaches to Help Prevent Drug-
Induced Depression
• Assess patient for history of depressive episodes or
history of drug-induced depression at baseline
• If Yes:
• Consider individual risk–benefit of drug therapy
• Select alternative drug within therapeutic category,
if possible
• Pretreatment with selective serotonin reuptake
inhibitor if undergoing therapy with interferon or
gonadotropin-releasing hormone agonist
CHAPTER 18 • Depression 327
from this group had depression (Hamilton Rating
Scale for Depression, >17) during the course of 24 to
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
peg-INF␣2a and ribavirin for hepatitis C. As com-
pared with the control group, amantadine-treated
subjects were significantly less likely to have depres-
sion by week 24 of treatment.163
MANAGEMENT
Appropriate management (Table 18–7) of drug-
induced depression begins with prompt recognition
of the emergence of depressive symptoms. In some
cases, depressive symptoms may be transient or
mild, as in patients receiving GnRH agonist therapy
as part of in vitro fertilization treatment.38 For many
patients, education and support may be the only
intervention needed. Psychological interventions or
psychotherapy prove beneficial for patients with
mild-to-moderate symptoms of MDD, but the bene-
fit of psychotherapy in patients with drug-induced
depression is unclear. For more severe or persistent
depressive symptoms, therapy with the offending
agent will likely have to be discontinued or antide-
pressant treatment may need to be initiated, and in
some cases, both strategies are required. Children,
adolescents, and young adults (18–24 years) receiv-
ing antidepressants for depression or other psychi-
atric disorders should be monitored frequently
(weekly to biweekly) during the first few weeks for
treatment-emergent suicidality or worsening of
depression. The emergence of suicidal ideation or
psychotic symptoms should always be considered
serious, and these patients should receive immediate
intervention, including hospitalization.
There are insufficient data to recommend spe-
cific doses of antidepressant therapy for the treat-
ment of drug-induced depression, although in
most reports doses similar to those used in patients
with endogenous depression have been adminis-
tered. Duration of therapy should be based on
patient response and clinical judgment. In cases in
which it would be best for a patient to continue to
TABLE 18–7 Management of Drug-Induced
Depression
• Discontinue the offending agent, if possible
• Substitute medication within therapeutic class
• Counseling or supportive therapy for mild depressive
symptoms
• Initiate antidepressant therapy for persistent or mod-
erate-to-severe depressive symptoms
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328 SECTION IV • Drug-Induced Psychiatric Diseases
receive therapy with the causative agent, clinicians
should consider factors such as severity of presen-
tation, current mood, and level of psychological
stress before deciding to discontinue drug therapy.
While not always possible, in some cases substi-
tuting another medication in the same drug or ther-
apeutic class but with a lower risk of causing
depression may represent the best management
strategy. For example, patients experiencing ␤-block-
er-induced depression may benefit from receiving a
hydrophilic ␤-blocker or an antihypertensive drug
from a different class (e.g., ACE inhibitor or diuret-
ic).164 Similarly, patients experiencing OC-induced
depression may benefit from an OC with a lower
estrogen content or different estrogen:progesterone
ratio. Patients with varenicline-induced neuropsy-
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.
Discontinuation of therapy is sometimes considered,
but remission of depression does not always occur
simultaneously with the discontinuation of interfer-
on.147 For patients with hepatitis C, selective sero-
tonin reuptake inhibitors may be the best choice, as
they are well tolerated by patients with liver disease,
whereas tricyclic antidepressants with significant
anticholinergic effects may increase the cognitive
dysfunction that occurs in these patients.147 Gleason
et al.165 conducted a study using citalopram to treat
depression in patients with hepatitis C. Of the 15
subjects participating in the trial, four had previous-
ly taken INF␣ and four were currently receiving INF␣
therapy. Citalopram 10 to 40 mg/day was adminis-
tered to all subjects, with a resultant improvement in
mood. In another study, 13 patients on therapy with
INF␣ had depression, 85% of whom were responsive
to treatment with citalopram.166 Similar results were
achieved with citalopram in another study.157 There
are case reports of patients with INF␣-induced
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.
For patients with suicidal tendencies, INF␣n3 is pre-
ferred; for patients experiencing depersonalization,
INF␣2a is suggested; patients with paranoia may
experience fewer symptoms with INF␣2a or INF␣2b;
and those patients exhibiting obsessive or compul-
sive symptoms may improve during treatment with
INF␣n1.82 However, these recommendations are
based on relatively small numbers of individuals and
the symptoms expressed by those individuals in a
clinical trial, and require evaluation in a prospective
trial. Sertraline has proven effective for the manage-
ment of depressive symptoms associated with GnRH
agonists.34,35,152 Lithium, selective serotonin reuptake
inhibitors, and electroconvulsive therapy have been
used to manage steroid-induced depression.48
There is inherent difficulty in recommending
antidepressant therapy for patients with epilepsy
because of the epileptogenic potential of most anti-
depressant drugs. Bupropion may exert proconvul-
sant properties in persons without epilepsy,
particularly in doses >450 mg/day.169 Tricyclic anti-
depressants also may have epileptogenic potential,
particularly amoxapine, clomipramine, maproti-
line, and mianserin.139 Although selective sero-
tonin-reuptake inhibitors are generally preferred in
patients with epilepsy, they have been associated
with seizures in case reports. This may be caused,
in part, by an increased incidence of hyponatrem-
ia, which may induce seizures.170
INFORMATION FOR PATIENTS
Patients should be informed regarding the possibil-
ity of the emergence of depressive symptoms when
prescribed a drug associated with depression. They
should be instructed to report any symptoms of
depressed mood or extreme irritability, anxiety,
anhedonia, difficulty sleeping, fatigue, feelings of
hopelessness or helplessness, change in appetite or
weight, or thoughts of death. Patients with a histo-
ry of depression may be at greater risk for experi-
encing drug-induced depression. Patients should
be encouraged to inform their provider of any his-
tory or treatment of any psychiatric disorder.
The FDA requires pharmacists to distribute
medication guides to patients receiving medica-
tions with specific warnings of suicidality or other
severe neuropsychiatric side effects. Medication
guides are intended to inform patients about a
known serious side effect of a drug. These guides
are available at http://www.fda.gov/cder/offices/
ods/medication_guides.htm.
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CHAPTER 19
Anxiety
E ach individual, no matter how healthy, has
experienced anxiety at some point in his or her
life. Minor anxiety can be helpful, as it prompts
one to avoid dangerous situations, such as walking
alone at night in a high-crime area. Occasional,
low-level anxiety can motivate an individual to
prepare for an examination or professional presen-
tation. In contrast, persistent anxiety at a moder-
ate-to-severe level can impair functioning and, if
left untreated, it may lead to other conditions,
such as depression or alcohol abuse.1-4 Whenever a
person presents with anxiety symptoms, a careful
clinical assessment must include an evaluation to
determine whether a primary anxiety disorder is
present, whether the symptoms are situational, or
whether the symptoms are drug-induced. A combi-
nation of these factors is also possible.1,4
CAUSATIVE AGENTS
Drugs that may induced anxiety are listed in Table
19–1.4-49 Anxiety is a well-known effect of stimulat-
ing substances such as caffeine, nasal decongestants
(e.g., pseudoephedrine), and amphetamines.1,4-
6,17,37
Stimulant medications including dextroam-
phetamine, mixed amphetamine salts,
methylphenidate, and dexmethylphenidate have
been associated with new-onset or worsening anxi-
ety in susceptible individuals.4-8,33 Anxiety is
uncommon when these agents are used at recom-
mended doses. In fact, some studies show improve-
ments in symptoms of anxiety when patients with
attention deficit/hyperactivity disorder are treated
with methylphenidate.33
Antidepressants, particularly the selective sero-
tonin reuptake inhibitors, venlafaxine, and some
Julie A. Dopheide
tricyclic antidepressants, are effective treatments
for anxiety and depressive disorders when used at
recommended doses for longer than 4 weeks. It is
important to recognize that new-onset or worsen-
ing anxiety is possible during the initiation of
treatment, during a dose increase, or after abrupt
discontinuation of therapy. Anxiety is common
when central nervous system (CNS)–active agents
such as barbiturates, benzodiazepines, gabapentin,
selective serotonin reuptake inhibitors, or other
antidepressants are discontinued abruptly after
long-term use.4,12,13,27,38
Benzodiazepines relieve anxiety via potentia-
tion of ␥-aminobutyric acid, an inhibitory neuro-
transmitter.4,23 After 2 to 4 weeks of treatment with
benzodiazepines, receptors become dependent on
the anxiolytic effects of these agents and signifi-
cant withdrawal symptoms can occur when a dose
is missed or when therapy is discontinued.13,14
Anxiety associated with benzodiazepine withdraw-
al is frequently described as worse than the pre-
treatment anxiety for which therapy was initiated.
Abrupt discontinuation of high-dose benzodi-
azepines produces the most severe withdrawal-
associated anxiety. Abrupt discontinuation of
benzodiazepines with shorter half-lives and no sig-
nificant active metabolite (e.g., alprazolam) is par-
ticularly anxiety-provoking.13 Anxiety can also be
problematic when therapy with anticonvulsants is
abruptly discontinued. Gabapentin withdrawal has
produced severe anxiety accompanied by
diaphoresis and palpitations.27
Kava-kava, a powder derived from a Fijian root,
was widely used for anxiety and insomnia until
2002, when reports of hepatotoxicity emerged. It is
still available in health food stores, vitamin shops,
and on the Internet.29,30 Valerian is another herbal
333
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334 SECTION IV • Drug-Induced Psychiatric Diseases

TABLE 19–1 Agents Implicated in Drug-Induced Anxiety*

Drug Incidence Level of Evidence
(see page xii for explanation)
4-8,a
Amphetamines 10–50% A
Anabolic steroids 7,9 10–50% B
Antipsychotics10,11 10–30% B
Aripiprazole 10,12 10–20% B
Benzodiazepines6,7,13,14,b 10–50% A
␤-blockers7,15,16,b 10–40% B
Bupropion4,7,a 10–20% B
Caffeine4,7,17,18 10–30% A
Cannabis19,b 30–70% B
Cycloserine20 30–60% B
Dopamine agonists7,21 10–30% B
Dopamine antagonists7,10,21,b 10–30% B
Dronabinol19 NK C
Efavirenz7,a NK B
7,22
Ephedrine NK A
Estrogen23-25,c NK A
Flumazenil7,20, a NK A
Fluoroquinolones7,26 NK C
Gabapentin27,b NK B
Gonadotropin-releasing hormone agonists28 NK C
Guarana7,22 NK B
Kava-kava29,30 NK C
Lidocaine7 NK C
Mefloquine31,32,a NK C
Methylphenidate, dexmethylphenidate4-8,33 10–30% A
Metoclopramide7,b NK C
Modafinil8,34 5 - 20% A
Nicotine4,7,35,b NK A
Nonsteroidal antiinflammatory drugs7,36,a NK C
Opioids20,23,b 30–70% B
Progesterone24,25 10–30% B
Pseudoephedrine4,7,37 NK A
Selective serotonin reuptake inhibitors4,7,38,39 10–40% A
Synephrine (bitter orange) 40 NK B
Testosterone23,41,42 NK B
Theophylline7,43,a 20–50% A
Thyroid4,50, a 10–50% B
Valerian44,45,b NK B
Varenicline46,47 NK A
Vinblastine48,49,a NK C
(Continued)
TisdaleC19_333-343 1/12/10 2:45 PM Page 335
TABLE 19–1 Agents Implicated in Drug-Induced Anxiety
Drug
4,7
Yohimbine
10,11
Ziprasidone
NK = not known.
*For all drugs listed, anxiety may occur during both treatment and withdrawal unless otherwise specified.
a
Anxiety may occur during treatment.
b
Anxiety may occur during withdrawal.
c
Anxiety may occur during fluctuations in plasma concentrations.
product that has been used as a sedative.
Symptoms of worsening anxiety and insomnia
have been reported after abrupt discontinuation of
valerian, suggesting that receptor dependence
occurs over time, an effect similar to that associat-
ed with benzodiazepines.44,45
Varenicline is a selective ␣4␤2-nicotinic acetyl-
choline partial receptor agonist that is indicated for
smoking cessation. During a controlled clinical
trial in 250 Asian patients taking varenicline, anxi-
ety developed in 5.6%, as compared with 2.4% in
the placebo group.46 Case reports of insomnia, anx-
iety, depression and psychosis associated with
varenicline therapy for smoking cessation prompt-
ed the Food and Drug Administration (FDA) to
issue a public health advisory in January 2008 (see
section entitled “Information for the Patient”).47
CNS-active agents are more obvious potential
causes of anxiety. However, new-onset symptoms
of anxiety have been associated with hormones
and other steroidal compounds, as well as with
antihypertensive drugs and even lipid-lowering
agents.7,15,16,36 Reports of drug-induced anxiety
associated with antiinfective agents, antiinflamma-
tory agents, antineoplastic agents, and herbal sup-
plements have been published.7,16,22,36,40 Drugs of
abuse or toxins are also known to cause anxiety
during intoxication or withdrawal.
Supplementation of the sex hormones estro-
gen, progesterone, and testosterone has been
linked with mood swings, including anxiety.23,24
The degree to which these hormones induce anxi-
ety is related to sex, individual susceptibility, and
dose or fluctuation in plasma concentration. For
example, estrogen withdrawal has been linked to
worsening anxiety, insomnia, and panic attacks in
women.7,23 A wide range in severity of anxiety
symptoms has been reported in premenstrual
women, postpartum, and during perimenopause,
as plasma estrogen concentrations decline before
stabilizing at menopausal concentrations.
CHAPTER 19 • Anxiety 335
(Continued)
Incidence Level of Evidence
NK B
10–20% B
Thyroid hormone supplementation does not
routinely lead to anxiety. However, excessive doses
may result in emotional symptoms, such as feeling
“on edge” or jittery, and physical symptoms,
including sweating or tachycardia.4,50 One study of
40 women with subclinical hypothyroidism ran-
domly assigned to receive either placebo or thyrox-
ine 50 to 100 mcg/day found no clinical benefit
from thyroxine supplementation over a period of 6
months. Significantly elevated anxiety scores, as
compared with baseline, were reported in 8 of 20
women treated with thyroxine, as compared with
only 1 of 14 women treated with placebo.50 Herbal
supplements for which thyroid-stimulating effects
are claimed can cause anxiety symptoms as well.
Gonadotropin-releasing hormone agonists such as
leuprolide and goserelin are used in women to treat
endometriosis and in men for the treatment for
prostate cancer, and have been associated with
mood swings, anxiety, and panic attacks.24,28
Symptoms typically resolve with cessation of treat-
ment.24 Danazol is an androgen that is sometimes
used for the treatment of endometriosis and fibro-
cystic breast disease. The risk of danazol-induced
anxiety and irritability is similar to that associated
with leuprolide and goserelin.7
Mood swings including anxiety are a well-
known adverse effect associated with the abuse of
anabolic steroids, including nandrolone,
oxymetholone, stanozolol, and oxandrolone.7,9
Anxiety is less common than rage, aggression, and
irritability, but panic attacks and worsening anxi-
ety have been reported.7,9
Antibiotics have been associated with neu-
ropsychiatric adverse effects, including anxiety,
although the occurrence is difficult to predict
because of multiple possible mechanisms and con-
founding variables.7,26,51 Fluoroquinolones are the
class of antiinfective agents associated with the
highest incidence of adverse central nervous sys-
tem effects, including anxiety and insomnia.7,26
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336 SECTION IV • Drug-Induced Psychiatric Diseases
Anxiogenic effects may be related to dose and indi-
vidual sensitivity.
Antimalarial agents, especially mefloquine,
may cause adverse neuropsychiatric effects, includ-
ing depression and anxiety in children and
adults.31,32,52 In one published case, a 10-year-old
child had feelings of impending doom, panic, a
specific spider phobia, separation anxiety, and
multiple physical symptoms of anxiety (hyperven-
tilation, restlessness, insomnia) after taking meflo-
quine for 2 weeks during a trip to Africa. Symptoms
slowly resolved over 1 to 3 months after the drug
was discontinued.31,32
Vinblastine is the cancer chemotherapeutic
agent that is most commonly associated with the
development of symptoms of depression and anxi-
ety, although worsening anxiety has been reported
in association with other cancer chemotherapy
drugs.7 Hormonal changes contribute to the devel-
opment of anxiety in patients with certain malig-
nancies, including cancer of the breast, ovaries, or
prostate.48,49 One study found no increase in the
incidence of anxiety attributed to cancer
chemotherapy in a group of premenopausal
women with breast cancer over a 3-year period.48
Angiotensin-converting enzyme inhibitors, ␤-
blockers, statins, and nonsteroidal antiinflamma-
tory drug may cause anxiety.7,16,36,53 The lack of
systematic reports and routine assessment for neu-
ropsychiatric adverse effects make it impossible to
determine an incidence of anxiety associated with
any of these agents.
EPIDEMIOLOGY
Estimates of the relative likelihood of anxiety
induced by specific agents based on available evi-
dence are provided in Table 19–1. The incidence of
primary anxiety disorders in the general popula-
tion is provided in Table 19–2.1,2,4
TABLE 19–2 Lifetime Prevalence of Primary
Anxiety Disorders in the General Population1-4
Anxiety Disorder Prevalence
Generalized anxiety disorder 4–7%
Social phobia 11–16%
Panic disorder 1.5–2%
Panic attacks (isolated) 7–10%
Post-traumatic stress disorder 8%
Obsessive–compulsive disorder 2–3%
MECHANISMS
For most agents, mechanisms of drug-induced anx-
iety are either poorly or incompletely understood.
Possible or probable mechanisms of drug-induced
anxiety, when known, are presented in Table
19–3.3-7,18,20,23,37,54 One of the best-understood
mechanisms for drug-induced anxiety involves
increasing noradrenergic outflow from the locus
ceruleus of the central nervous system. Stimulants,
yohimbine, and benzodiazepine withdrawal all
appear to increase noradrenergic outflow from the
central nervous system.6,7,23,54 Pseudoephedrine,
ephedrine, and bitter orange produce dose-related
symptoms of anxiety via ␣1-adrenergic stimulation
that increases nervousness centrally and causes
vasoconstriction and a “jittery” or restless feeling.
Caffeine and guarana (an herbal form of caf-
feine derived from the plant Paullinia cupana) exert
anxiogenic effects through antagonism of adeno-
sine and the phosphodiesterase enzyme, resulting
in excessive neurotransmitter activity.17,22,23
Anxiety associated with nicotine withdrawal is
believed to occur because of a lack of stimulation
of dopaminergic reward centers in the brain upon
abrupt discontinuation of nicotine.6,23 Yohimbine
is an herbal compound found in preparations used
to treat sexual dysfunction. It increases anxiety via
␣2-adrenergic antagonism, resulting in increased
outflow of norepinephrine from the CNS.4,20,23
Withdrawal from levodopa therapy may
induce anxiety as a result of declining levodopa
concentrations in the brain. A controlled trial
found that anxiety levels declined and motor per-
formance improved during a levodopa infusion.
Withdrawal of dopaminergic agonists or adminis-
tration of dopaminergic antagonists can cause sig-
nificant functionally-impairing anxiety in
individuals with dopaminergic deficits caused by
Parkinson’s disease.7,55
Antidepressant initiation or withdrawal anxi-
ety is likely related to acute changes in neurotrans-
mitter activity, as described in Table 19–3.23,38,39
Antipsychotic agents that antagonize dopamine
receptors but that exert no significant histamine
blockade, such as aripiprazole or ziprasidone, can
cause behavioral activation with associated anxi-
ety.11,12 Ziprasidone inhibits the reuptake of norep-
inephrine and dopamine. Aripiprazole results in
anxiety during initiation of therapy for some
patients because of dopaminergic agonist/antago-
nist effects.
Anxiety caused by fluctuating plasma concentra-
tions of hormones has been well described, although
the mechanism of anxiogenesis is poorly under-
TisdaleC19_333-343 1/12/10 2:45 PM Page 337
TABLE 19–3 Mechanisms of Drug-Induced Anxiety
Drug
Amphetamines, methylphenidate, stimulants,
bupropion, ziprasidone3-7,37,54
Benzodiazepines4,13,20,23
Caffeine, guarana, theophylline4,17,18,20,22,23
Dopamine agonists and antagonists 20,23
Opioids20,23
Selective serotonin reuptake inhibitors, venlafaxine,
tricyclic antidepressants4,20,23
GABA = Gamma-aminobutyric acid; CNS = Central nervous system.
stood. Estrogen exerts multiple complex effects on
neurotrophins, cortisol, and neurotransmitter sys-
tems.24 One theory linking estrogen dysregulation to
anxiety involves estrogen’s role in effective serotonin
use. When plasma estrogen concentrations decline
significantly, the associated serotonin dysregulation
causes anxiety.23 Progesterone deficiency and supple-
mentation has been linked with anxiety and irritabil-
ity in women.23,24 One potential mechanism
involves progesterone’s neuroactive steroid metabo-
lites (e.g., 5-tetrahydroprogesterone, allopreg-
nanolone). These metabolites are allosteric
modulators of GABA-A, causing anxiolytic effects in
some and anxiogenic effects in others, depending on
which metabolite is predominant. The development
of anxiety may be related to an individual’s genetic
susceptibility to forming these metabolites.56 In addi-
tion, progesterone possesses some antiestrogen activ-
ity that can precipitate anxiety in some individuals.23
Similarly, testosterone excess or deficiency in women
and men can result in anxiety, irritability, and aggres-
sion.41,56,57,59 Case studies in men with Parkinson’s
disease and low plasma testosterone concentrations
reported significant improvement in associated
symptoms of anxiety after testosterone supplementa-
tion.42 GnRH agonists are synthetic derivatives of the
native decapeptide produced by the hypothalamus,
and may cause anxiety via reversible suppression of
the synthesis and release of luteinizing hormone and
follicle-stimulating hormone.28
CLINICAL PRESENTATION AND
DIFFERENTIAL DIAGNOSIS
Signs and symptoms associated with drug-induced
anxiety are listed in Table 19–4. An individual with
significant anxiety suffers from physical, emotion-
CHAPTER 19 • Anxiety 337
Mechanism
Inhibition of norepinephrine and dopamine reuptake
Stimulation of dopamine receptors
Decreased GABA activity and increased noradrenergic
outflow from the CNS.
Antagonism of adenosine receptors, phosphodiesterase
inhibition
Fluctuating dopaminergic tone in central nervous system
Opioid-receptor withdrawal
Neurotransmitter reuptake inhibition (serotonin, dopamine)
al, and cognitive symptoms that may cause them
to lose the ability to interact with others, think
clearly, or participate in the activities of daily liv-
ing. Table 19–4 differentiates physical, emotional
and cognitive symptoms of anxiety that may be
rated as mild, moderate, or severe depending on
the impact on functioning. Emotional symptoms
include excessive fear, tension, nervousness, and
feeling jittery, irritable, or “on edge.” Cognitive
symptoms include difficulty concentrating,
“blanking out,” and excessive worries. Physical
symptoms include insomnia, restlessness, racing
heart, difficulty breathing, sweating, flushing,
weakness, and exhaustion.
Patient assessment should begin with docu-
menting the patient’s experience of anxiety subjec-
tively and objectively. Standardized anxiety rating
scales (e.g., Hamilton Anxiety Rating Scale, Covi
Anxiety Scale) are useful to establish objective
measures of anxiety and to monitor persistence or
remittance of symptoms over time.4,58 The time
course of the onset of anxiety in relation to initia-
tion or discontinuation of drug therapy is crucial
to determine whether the anxiety is likely drug-
induced.
Dopaminergic blockade associated with con-
ventional antipsychotics, such as haloperidol, or
with atypical agents including risperidone, ziprasi-
done, and aripiprazole can result in akathisia, the
subjective feeling of motor restlessness. Akathisia is
frequently accompanied by an intolerable feeling
of anxiety.10 An individual’s sensitivity to experi-
encing caffeine-induced anxiety can vary greatly,
but symptoms generally manifest within 15 to 30
minutes after ingesting between 200 and 500 mg of
caffeine or 3 to 5 cups of brewed coffee. Caffeine
and guarana produce emotional, cognitive, and
physical symptoms of anxiety during acute intoxi-
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338 SECTION IV • Drug-Induced Psychiatric Diseases

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
Diagnostic Interview
1. Record emotional, cognitive and physical symp-
toms of anxiety,
2. Rate each symptom as mild, moderate or severe
use standardized anxiety rating scales (eg. HAM-A)
3. Document functional impairment from anxiety
4. Conduct medication and substance abuse history
Key Questions
“Yes” responses increase likelihood of drug-induced
anxiety
1. Does individual have current psychiatric illness?
2. Does individual have a chronic medical illness?
3. Is situational anxiety considered unlikely?
4. Did the onset of anxiety happen within 1 week of
a b
the initiation of a substance or an or in dose
of a substance?
Physical Assessment
1. Physical examination
2. Record vital signs
3. Obtain toxicology screen
4. Obtain appropriate labs and tests, eg, TFTs if
hyperthyroidism, ECG if cardiac symptoms
reported
FIGURE 19–1 Clinical assessment and differential diag-
nosis for drug-induced anxiety.4,59
ECG = electrocardiogram; HAM-A = Hamilton Anxiety rating
scale; TFT = thyroid-function test.
that individuals with an existing anxiety disorder,
particularly panic disorder or post-traumatic stress
disorder, are especially sensitive to worsening
panic attacks, hypervigilance, and worsening anxi-
ety when taking even low doses of drugs known to
cause anxiety.23,40,61,62 Individuals with primary
anxiety disorders including social anxiety disorder,
generalized anxiety disorder, and obsessive–com-
pulsive disorder (OCD) are more susceptible to
worsening anxiety associated with well-known
anxiogenic substances such as caffeine or stimu-
lants. Other psychiatric illnesses, including schizo-
phrenia, schizoaffective disorder, bipolar disorder,
and attention deficit/hyperactivity disorder are
associated with higher rates of anxiety and anxiety
disorders as compared with the nonaffected popu-
lation. For this reason, drug-induced anxiety is also
more common in these patients.1,2,4
Approximately 40% to 50% of patients with
Parkinson’s disease experience symptoms of anxi-
CHAPTER 19 • Anxiety 339
TABLE 19–6 Risk Factors for Drug-Induced
Anxiety1-4,13,14,24,39,55,60
• Primary anxiety disorder(s)
• Presence of any chronic psychiatric illness (e.g., bipolar
disorder, major depression, schizoaffective disorder,
schizophrenia)
• Presence of chronic medical condition(s)
• Concomitant use of drug(s)/substance(s) known to
cause anxiety
• Currently withdrawing from sedative–hypnotic med-
ication
• Currently withdrawing from alcohol or another sub-
stance of abuse
• Elevated plasma concentrations of potentially anxiety-
provoking agents
ety that may be related to an overall dopaminergic
deficit from the disease state, or it may be an
adverse effect of drug treatment.55 A controlled
trial studying the anxiogenic effects of the
dopaminergic agonist bromocriptine and the
dopaminergic antagonist sulpiride found that stim-
ulation of dopaminergic function may cause anxi-
ety in high-anxiety individuals and may exert
anxiolytic effects in low-anxiety individuals.21
Nicotine-dependent individuals experience sig-
nificant anxiety upon withdrawal from nicotine.
The intensity of anxiety and other withdrawal
symptoms is related to the amount of daily nico-
tine use and individual sensitivity to withdrawal
discomfort. Nicotine withdrawal anxiety can occur
after abrupt cessation of cigarette smoking or after
abrupt discontinuation of nicotine gum, inhalers,
lozenges, or, less often, nicotine patches.35
Individuals who abuse stimulants or those with
narcolepsy taking high doses are the most likely to
experience intolerable symptoms of anxiety.5-7
Modafinil is a nonstimulant compound that may
cause anxiety at doses >400 mg daily.34 Individual
sensitivity to the anxiogenic effects of modafinil
has been documented, with some individuals expe-
riencing significant anxiogenic effects even at
lower doses, while others do not have anxiety.
Drug-induced anxiety is more pronounced at
high doses and in patients with impaired hepatic
or renal function who are taking potentially
causative agents for which the liver or kidney,
respectively, contribute substantially to drug clear-
ance. For example, it is uncommon for patients to
experience anxiety associated with pseu-
doephedrine at doses as low as 30 mg. However,
the 120 mg sustained-release dose is associated
with a greater risk of anxiety.37 Anxiety associated
TisdaleC19_333-343 1/12/10 2:45 PM Page 340
340 SECTION IV • Drug-Induced Psychiatric Diseases
with ephedrine, bitter orange (Cypraea aurantium,
synephrine), caffeine, guarana, and yohimbine is
dose-related.7,18,22,35,40
MORBIDITY AND MORTALITY
There is no direct link between drug-induced anxi-
ety and increased mortality. However, there is
increasing evidence linking anxiety to negative
health consequences, including heart disease,
impaired disease recovery, and increased propensi-
ty for poor health habits such as cigarette smoking
and alcohol and other substance use.63,64 Negative
emotions such as depression and anxiety have
been shown to increase plasma concentrations of
proinflammatory cytokines interleukin-6, tumor
necrosis factor ␣, and C-reactive protein, which is
recognized as an important risk factor for myocar-
dial infarction. Proinflammatory cytokines stimu-
late the hypothalamic–pituitary axis to release
cortisol, which can impair wound healing and
cause dysregulation of the autonomic nervous sys-
tem and reduced heart rate variability. The reduc-
tion in heart rate variability caused by anxiety and
depressive symptoms increases the risk of cardio-
vascular death associated with coronary heart dis-
ease and arrhythmias.65 One study showed that
patients with phobic, panic-like anxiety had three
times the risk of fatal congestive heart disease at a
7-year follow-up as compared with patients with
no anxiety.64 Anxiety symptoms were associated
with significantly increased risk of myocardial
infarction and coronary-related death over a 20-
year period in women who were homemakers.
Several studies link anxiety with increased cigarette
smoking and increased drug and alcohol use,2,3 all
of which have negative health consequences.
PREVENTION
Approaches to prevention of drug-induced anxiety
are listed in Table 19–7. Preventing drug-induced
anxiety starts with patient assessment to determine
whether risk factors are present. If one or more risk
factors exist, the clinician should carefully weigh
the risk versus the benefits of initiating therapy
with a drug known to cause anxiety. Alternative
treatments with a lower risk for inducing anxiety
should be considered. If the drug in question rep-
resents the most appropriate treatment option, ini-
tiation of therapy should be gradual, with careful
dose titration and monitoring to detect the emer-
gence of anxiety and determine the need for treat-
TABLE 19–7 Approaches to Help Prevent Drug-
Induced Anxiety1-4,32,48
• Assess patient for an underlying anxiety disorder to
determine drug-induced anxiety risk
• Counsel patient regarding the risk of anxiety when
initiating or discontinuing therapy with a potentially
causative drug
• Initiate therapy with potentially anxiety-provoking
medications slowly, with gradual dose titration. For
example, doses of selective serotonin reuptake
inhibitors can be reduced by half
• Consider potential for drug interactions; minimize
use of multiple medications with a risk for inducing
anxiety
ment with psychotherapeutic or pharmacologic
interventions.
If discontinuation of antidepressant therapy is
necessary, the dose should be reduced gradually
over 2 to 6 weeks to prevent a serotonin withdraw-
al syndrome that includes worsening anxiety or
insomnia.4,39 If discontinuation of therapy with a
benzodiazepine or anticonvulsant therapy is neces-
sary, tapering the dose gradually over weeks to
months can minimize the risk of drug-induced
anxiety.4,13 Doses of agents known to cause anxiety
that predominantly undergo renal or hepatic clear-
ance should be reduced in patients with kidney or
liver disease, respectively.
MANAGEMENT
Management of drug-induced anxiety is largely
supportive and typically involves discontinuation
of the causative agent. Supportive treatment may
include reassurance, instruction on relaxation
techniques, and avoidance of other substances
known to cause anxiety. Antidepressant-induced
anxiety is usually transient during initiation or dis-
continuation of therapy. Slower dose titration dur-
ing initiation of therapy and gradual dose tapering
during discontinuation can minimize or alleviate
anxiety symptoms. Antipsychotic-induced anxiety
can be managed by reducing the dose, modifying
the treatment plan to use an antipsychotic medica-
tion with lower dopaminergic antagonist activity,
or treating the anxiety with a ␤-blocker or benzodi-
azepine.10,11 In cases in which therapy with the
anxiety-provoking agent cannot be discontinued
(e.g., in patients who are undergoing cancer
chemotherapy), temporary management with a
benzodiazepine can be considered. Lorazepam 0.5
TisdaleC19_333-343 1/12/10 2:45 PM Page 341
to 1 mg administered two or three times daily
offers the advantage of rapid onset (30–45 min-
utes), intermediate duration of effect (~6–8 hours),
and no active metabolites that can accumulate.
Clonazepam 0.25 to 0.5 mg administered once or
twice daily can be considered if less frequent
administration is desired, but the onset of effect
may be longer (1–2 hours) and the drug can accu-
mulate over time, because of a long half-life of 20
to 50 hours. Appropriate duration of therapy
varies, based on the necessary duration of therapy
with the causative agent.4 Anxiety related to abrupt
benzodiazepine discontinuation may be attenuat-
ed through slower withdrawal of therapy (over
months instead of weeks). Alternatively, therapy
with an agent that increases ␥-aminobutyric acid
activity, such as valproic acid, can be initiated to
diminish withdrawal symptoms and associated
anxiety.13
Caffeine-induced anxiety and withdrawal
symptoms abate with time (typically 3–7 days) and
may be managed with mild analgesics to treat
headache symptoms.6,17,22 There is evidence that
exercise attenuates caffeine-induced anxiety.18
Nicotine supplementation with gradual tapering
can lessen anxiety associated with nicotine with-
drawal.23
The management of thyroid-induced anxiety is
simple and includes reducing the dose or discon-
tinuing the thyroid supplement and providing
patient counseling and reassurance as necessary.50
A clinician with expertise in hormone regulation
should be consulted when patients present with
anxiety related to hormonal imbalance.
Management strategies include hormonal supple-
mentation or discontinuation, treatment with
anti-anxiety medication (e.g., selective serotonin
reuptake inhibitors), or both.
INFORMATION FOR PATIENTS
Individuals prescribed medications known to
cause anxiety during treatment or withdrawal and
those who elect to take nonprescription agents
known to cause anxiety should be warned of the
risks. The FDA issued a health advisory asking cli-
nicians to advise patients and caregivers that
patients should discontinue therapy with vareni-
cline and contact a health care provider immedi-
ately if agitation, depressed mood, or changes in
behavior that are not typical for the patient are
observed, or if the patient has suicidal ideation or
suicidal behavior.47
Patient education regarding the risk of with-
drawal symptoms after discontinuation of a CNS-
CHAPTER 19 • Anxiety 341
active agent is essential. Individualized discontinu-
ation regimens should be developed based on
patient tolerance. For example, decreasing the dose
of a benzodiazepine by 25% per week is well toler-
ated by some patients, but others may require
more gradual tapering over weeks or even
months.4,13 Patients who have difficulty withdraw-
ing from benzodiazepine therapy because of exces-
sive anxiety should be offered the option of
therapy with anticonvulsant drugs, as these agents
have been used effectively to prevent anxiety and
other benzodiazepine withdrawal symptoms such
as insomnia and tremulousness.13,14
When drug-induced anxiety occurs, the care-
giver should reassure the patient that drug-induced
anxiety is usually of short duration (days to weeks)
and responds to a decreased dose or discontinua-
tion of the causative agent along with supportive
treatment. Patients at risk for anxiety should be
counseled regarding the type of anxiety symptoms
that may occur in association with the drug (e.g.,
panic attacks, jitteriness, fearful thoughts), the typ-
ical time of onset of symptoms, and available inter-
ventions should anxiety occur.
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CHAPTER 20
Psychosis
T he term psychosis was first introduced in the
19th century to describe the manner in which
mental illness, manifested as aberrant behavior,
related to both psychological and physical well-
being. Psychosis is currently defined as an impair-
ment of reality testing due to gross distortion or
disorganization of reality.1-5 Patients experiencing
psychosis demonstrate inaccuracy of perception,
even with evidence to the contrary. Visual, audito-
ry, and olfactory hallucinations, delusions or fixed
false beliefs, or illusions (distortion in perception)
often characterize the impaired reality testing asso-
ciated with psychosis. Related physical symptoms
can include agitation, anxiety, aggression, pacing,
unusual behaviors such as talking to someone not
visible to others, and withdrawal from society.
Although psychosis is a fairly common medical
disorder, it is not a specific diagnosis but rather a
feature of many disease states.1-8
CAUSATIVE AGENTS
Many medications are associated with drug-
induced psychosis and drug withdrawal psychosis
(Table 20–1).9-105 The agents most commonly
implicated include amphetamines, anticholiner-
gics, corticosteroids, anabolic steroids, dopaminer-
gic agents, ma huang, and tacrolimus.2,3,5-8 The
pharmacologic diversity of these agents clearly
indicates that no single mechanism of action can
be fully responsible for the occurrence of drug-
induced psychosis. In fact, the mechanisms seem
to be as complex and poorly understood as those
associated with idiopathic psychosis.
The causes of drug-induced psychosis extend
beyond Food and Drug Administration (FDA)–
344
Jessica L. Gören
approved medications to include herbals and
nutritional supplements. Numerous illicit drugs
such as lysergic acid diethylamide (LSD), psilocy-
bin, and phencyclidine (PCP) induce psychotic
states that are similar in presentation to psychosis
induced by legal medications.106-109 Drug-induced
psychosis may occur at normal doses, in excessive
doses (intoxication) or occasionally as part of a
withdrawal phenomenon.
EPIDEMIOLOGY
In the 19th century, Jacques-Joseph Moreau de
Tours was the first psychiatrist to describe drug-
induced psychosis.2 Despite such a long period of
awareness of the problem, the overall incidence
of drug-induced psychosis is still unknown.
Limited data exist regarding the incidence of psy-
chosis associated with specific medications or
conditions (Table 20–1). In addition, drug-
induced psychosis is often more common in
patients with certain disease states and when
drugs are abused chronically or used in high
doses. The incidence of psychosis in metham-
phetamine users was reported to be 11 times that
of the general population, with 23% of users
reporting at least one psychotic symptom in the
past year.109 In an FDA meta-analysis, therapeutic
doses of stimulants caused psychosis in 1 in 400
children. 15-17 Up to 21% of patients with
Parkinson’s disease receiving a dopamine agonist
experience psychotic symptoms, while less than
1% of patients with bipolar disorder exhibit simi-
lar symptoms.64 Predisposing factors such as age,
psychiatric and neurologic illnesses, and
polypharmacy are known to increase the inci-
TisdaleC20_344-356 1/12/10 2:46 PM Page 345

CHAPTER 20 • Psychosis 345

TABLE 20–1 Agents Implicated in Drug-Induced Psychosis

Drug Incidence Level of Evidence
(see page xii for explanation)
9,a
Alcohol 5% B
Albuterol10-12 NK C
Amantadine13-14 1–10% C
Amphetamines15-17 0.25% A
Anabolic steroids18 12% B
Angiotensin-converting–enzyme inhibitors19-21 NK C
Anticholinergics22-32 7% A
Anticonvulsants33-39 0.5–2.5% B
Benzodiazepines40,41, a NK B
Bupropion42-44 NK C
Celecoxib45 NK C
Chloroquine46 NK C
Corticosteroids47-51 1% B
Cyclobenzaprine52,53 <1% C
54
Cycloserine 15% B
Dapsone55 NK C
Dextromethorphan56,57 NK C
Digoxin21,58 NK C
Disulfuram59,60 NK C
Dopamine agonists61-64 >1% C
Doxazosin21 NK C
Dronabinol65 3–10% C
Efavirenz66 1% C
Ephedrine67,68 NK C
Ganciclovir69 <1% C
Histamine2-blockers70-73 NK C
Ifosfamide74 <12% B
Indomethacin75,76 <1% C
Isoniazide54 <1% C
Lidocaine77,78 NK C
Ketamine79 12% B
Levodopa–carbidopa80 NK A
Levothyroxine81,82 NK C
Mefloquine83,84 NK C
Meperidine85,86 NK C
Methylphenidate15-17 0.1% A
Modafinil87 NK C
Monoamine oxidase inhibitors88-90 NK C
Nitrous oxide91,92 NK C
Opiates93,94,a NK C
(Continued)
TisdaleC20_344-356 1/12/10 2:46 PM Page 346
346 SECTION IV • Drug-Induced Psychiatric Diseases
TABLE 20–1 Agents Implicated in Drug-Induced Psychosis
Drug
Pseudoephedrine57,95
Quinidine96,97
Sibutramine98,99
Statins100
Tacrolimus101,102
Trimethoprim–sulfamethoxazole103,104
Zolpidem105
NK = not known.
a
Psychosis onset associated with drug withdrawal.
dence of drug-induced psychosis. It is likely that
drug-induced psychosis is underdiagnosed.
MECHANISMS
Psychosis is not a single disorder, but rather a
symptom induced by multiple mechanisms. Table
20–2 lists the presumed mechanism of psychosis
induced by specific drugs. Overlap in clinical pres-
entation of idiopathic psychosis and psychosis
caused by both legal and illicit drugs suggests sim-
ilar mechanisms. Understanding of drug-induced
psychosis, therefore, may be enhanced by a discus-
sion of the mechanisms associated with idiopathic
psychosis and the psychosis associated with illicit
drug use.
Psychosis is often associated with alterations of
dopamine concentrations in various regions of the
brain.2,6 Enhanced dopaminergic function in the
mesolimbic pathway is associated with hallucina-
tions, delusions, and paranoia.2-3,5-7 Increased
release of dopamine, decreased metabolism or
uptake of dopamine, or both can cause psychotic
symptoms. This is supported by the observation
that the administration of mesolimbic dopamine
antagonists leads to clinical improvement of psy-
chotic symptoms.6
Other neurotransmitters may indirectly alter
synaptic concentrations of dopamine and cause
psychosis. Glutamate, serotonin, norepinepherine,
and acetylcholine are believed to produce second-
ary effects on dopamine neurotransmission and to
play a role in psychosis.2-3,5-7
The hyperdopaminergic state is an important
mechanism of psychosis.5-7 However, on the basis
of studies of both idiopathic and iatrogenic psy-
chotic states, it is clear that the hyperdopaminergic
(Continued)
Incidence Level of Evidence
NK C
<1% C
NK C
NK C
<15% C
NK C
1–10% C
hypothesis is only one mechanism involved in the
generation of psychotic symptoms.2-3,5-7
Altered serotonin (5-HT) receptor functioning
is also associated with psychosis. Patients with
schizophrenia are known to have abnormal 5-HT
receptor functioning, and many antipsychotic
agents induce significant effects on serotonergic
functioning.110-115 LSD, an agent known to induce
hallucinations, is structurally related to serotonin.
LSD and psilocybin induce psychosis through stim-
ulation of the 5-HT2A receptor.107,108
Glutamate is the major excitatory neurotrans-
mitter in the brain.5-7 Antagonism of the glutamate
N-methyl-D-aspartate receptor by PCP and keta-
mine induces states that may be the best model of
idiopathic psychosis.116 Biologic changes that sup-
port hypoglutamatergic function in schizophrenia
include decreased glutamate in the cerebrospinal
fluid, altered N-methyl-D-aspartic acid (NMDA)
receptor densities, and decreased glutamate
release.117-120
It has been hypothesized that altered intracel-
lular signal transduction may be involved in psy-
chosis.121 Antipsychotic agents induce genes to
increase expression of c-fos or its protein product.
This may alter expression of other genes, the prod-
ucts of which are involved directly in psychosis.
Another mechanism posited to play a role in psy-
chosis is episodic dysfunction of myelin sheaths
disrupting subcortical and cortical processes121,
which may lead to positive psychotic symptoms
and cognitive dysfunction.
The biologic mechanism of psychosis is com-
plex and probably involves multiple pathways. As
time progresses, it is likely that additional mecha-
nisms will be discovered. Therefore, the ability to
predict which drugs may induce psychosis based
on pharmacologic activity is limited, although the
TisdaleC20_344-356 1/12/10 2:46 PM Page 347

CHAPTER 20 • Psychosis 347

TABLE 20–2 Mechanisms of Drug-Induced Psychosis

Drug(s) Mechanism(s)
Dopamine agonists Increased dopamine concentrations
Levodopa
Amantadine
Albuterol Increased norepinephrine concentrations
Disulfiram
Dronabinol
Ephedrine
Ketamine
Nitrous oxide
Amphetamine Increased dopamine concentrations
Bupropion Increased norepinephrine concentrations
Cyclobenzaprine
Monoamine oxidase inhibitors
Methylphenidate
Pseudoephedrine
Sibutramine
Dextromethorphan Glutamate NMDA antagonist
Ketamine
Phencyclidine
Anabolic steroids Down regulation of serotonin 1B receptor density in the
hippocampus and globus pallidus
Up regulation of serotonin 2 receptor density in the nucleus
accumbens
Anticholinergics Decreased cholinergic function
Anticonvulsants Enhanced GABAergic effects
Zolpidem
Chloroquine NMDA agonist
Mefloquine GABA antagonist
Cycloserine NMDA partial agonist
Statins Decreased brain cell membrane cholesterol leading to
decreased serotonin receptors and serotonergic functioning
GABA = ␥-aminobutyric acid; NMDA = N-methyl-D-aspartic acid.

alteration of dopamine and serotonin pathways is
consistently associated with psychosis.
CLINICAL PRESENTATION AND
DIFFERENTIAL DIAGNOSIS
Many symptoms in patients with drug-induced
psychosis are similar to those of patients with idio-
pathic psychoses observed in conditions such as
schizophrenia.4,8 Schizophrenia is defined by a
triad of symptoms: positive, negative, and cogni-
tive. Positive symptoms include delusions, halluci-
nations, and disorganized speech and behavior.2-8
Negative symptoms include flat affect, avolition,
and social isolation.2-7 Cognitive symptoms can be
diverse but often present as difficulties with con-
centration and memory.7 Positive symptoms are
more typically associated with drug-induced psy-
chosis than negative symptoms (Table 20–3).
There is no individual test that is diagnostic for
drug-induced psychosis. Diagnosis depends on
identification of a temporal relationship between
the ingestion of the suspect substance and the
onset of psychotic symptoms, clinical presenta-
tion, and a thorough medical and medication his-
tory.4,8 Patients with acute psychosis may or may
not be able to provide an accurate history.
Consultation with family, friends and other health
care providers is useful in understanding any pre-
TisdaleC20_344-356 1/12/10 2:46 PM Page 348
348 SECTION IV • Drug-Induced Psychiatric Diseases
TABLE 20–3 Signs and Symptoms Associated
with Drug-Induced Psychosis2,4,122
• Hallucinations (visual, tactile, auditory)
• Paranoia
• Delusions
• Anxiety
• Agitation
• Grandiosity
• Disorganized speech and/or behavior
• Feelings that events have special meaning related to self
• Thought blocking/insertion/broadcasting
existing mental health issues and recent changes in
behavior or medical treatment.
A thorough medication history is crucial to the
differential diagnosis of drug-induced psychosis. A
clear understanding of a patient’s baseline psychi-
atric state and the medications being used to treat
the disorder may help clinicians distinguish
between an underlying disorder that is progressing
and a drug-induced psychosis.2-8 Table 20–4 lists
conditions that should be ruled out prior to the
diagnosis of drug-induced psychosis.
The medication history should include the
patients’ use of prescription, nonprescription, and
illicit drugs and should document any herbal prod-
ucts or nutritional supplements being ingested.
Recent discontinuation of medications should be
documented, because drug withdrawal can be
accompanied by psychotic symptoms.9,41,42,93-94 In
addition, recent changes in nonpsychotomimetic
medications can play a role in drug-induced psy-
chosis. For example, a nonpsychotomimetic drug
could antagonize the psychotomimetic effects of
another agent or induce its metabolism.2,6,8 When
TABLE 20–4 Conditions to Consider in the
Differential Diagnosis of Drug-Induced Psychosis2-8
• Infection, including human immunodeficiency virus
(HIV)
• Metabolic abnormalities
• Hepatic dysfunction
• Hyperthyroidism
• Substance abuse
• Seizure disorder
• Parkinson’s disease
• Huntington’s disease
• Tumor/lesions
• Stroke
• Autoimmune disorders
• Alzheimer’s disease
questions exist about the veracity of a patient’s
response to questions regarding substance abuse,
urine and blood toxicology screening should be
performed. Table 20–5 lists common drugs of abuse
and time of detection in the urine.
The psychotomimetic effects of many medica-
tions are dose-related.8,31,43,61 The dose at which a
medication can cause psychotic symptoms, howev-
er, varies from patient to patient. The recent initia-
tion of therapy with a new medication or a dose
increase of an existing psychotomimetic medica-
tion should always be considered as a possible
cause when a patient experiences a new onset of
psychotic symptoms.
Laboratory monitoring can be helpful to rule
out alternative causes of psychosis.2-8 Table 20–6
provides a list of laboratory tests useful in the dif-
ferential diagnosis of psychosis. In many cases, the
decision to perform laboratory monitoring will be
based on history and clinical presentation.
Diagnosis of drug-induced psychosis is a diag-
nosis of exclusion, rather than inclusion.2,4 The
integral components of diagnosis are accurate
medication, medical, psychiatric, and physical his-
tories, physical exam, and laboratory monitoring.2-
3,7-8
In many instances, obtaining a thorough
medical and medication history is sufficient to
diagnose drug-induced psychosis. The Diagnostic
and Statistical Manual of Mental Disorders, Text
Revision includes several diagnoses that encompass
drug-induced psychosis (termed “substance-
induced”), including “substance-induced psy-
chosis” and “substance-induced mania with
psychotic features.” A key criterion of substance-
induced psychosis is absence of delirium.4
Delirium is differentiated from psychosis by its
fluctuating course, disturbances of consciousness,
and changes in cognitive processes such as memo-
ry.4 Although these problems may occur in drug-
induced psychosis, they are more often indicative
of delirium.
TABLE 20–5 Time of Detection of Drugs in Urine
Following Last Ingestion2,3,5-7
Drug Limit
Alcohol 12 hr
Amphetamine Up to 2 days
Opioids Up to 3 days
Benzodiazepines 1–5 daysa
Barbiturates 1 day–3 wk
Marijuana 1 day–weeksa
a
Depends on quantity and frequency of usage.
TisdaleC20_344-356 1/12/10 2:46 PM Page 349
TABLE 20–6 Tests to Aid in the Diagnosis of
Drug-Induced Psychosis
Standard laboratory monitoring
• Complete blood count with differential count
• Electrolytes
• Liver function
• Thyroid function
• Toxicology screen
Monitoring if clinically indicated by patient history
• Human immunodeficiency virus
• Antinuclear antibodies
• Sedimentation rate
• Electroencephalogram
• Computed tomography/magnetic resonance
imaging scan
Prominent hallucinations or delusions are typ-
ically present in patients with drug-induced psy-
chosis.2,4,7 Often hallucinations are visual, tactile,
and gustatory in patients with drug-induced psy-
chosis, whereas auditory hallucinations predomi-
nate in those with idiopathic psychotic
disorders.2,4,7-8 Patients who have insight into psy-
chiatric symptoms being caused by a drug do not
meet the criteria for a substance-induced psy-
chosis.4 However, patient insight is a controversial
diagnostic exclusion, as many patients who have
insight into their symptoms still require treatment
for psychosis.122
Onset of illness must be assessed to accurately
diagnose drug-induced psychosis. Idiopathic psy-
chotic disorders tend to occur during specific peri-
ods in life and have a slow progressive and
degenerative course.2-8 Abrupt onset or atypical
presentations such as a late age at onset may indi-
cate drug-induced psychosis.2-8 Drug-induced psy-
chosis is usually related to the recent addition or
discontinuation of medication or changes in an
existing medication regimen. Typically, drug-
induced psychosis occurs within hours to days of
drug therapy initiation, discontinuation, or
change. In some rare cases, the onset may be more
protracted and, as is the case with corticosteroids,
may occur as late as 3 months after medication
changes.48-51
Duration of symptoms may also help clarify
the diagnosis. A review of the medication’s half-life
provides guidance about a time frame for resolu-
tion. When symptoms do not remit within 4 weeks
after discontinuation of the suspected agent, other
causes of psychosis must be considered.4 Protracted
psychosis is not common when the disorder is
drug-induced.
CHAPTER 20 • Psychosis 349
Physical symptoms may differ between drug-
induced psychosis, intoxication, and idiopathic
psychotic states. Typically, drug-induced psy-
chosis is not associated with gross physical abnor-
malities.4 Slurred speech or ataxia are more
commonly associated with intoxication and delir-
ium rather than with idiopathic or drug-induced
psychosis.2-3,5-7 Intoxication, drug withdrawal, or
delirium is often associated with physical charac-
teristics such as changes in pupil size, tachycar-
dia, sweating, pain and cramping, altered
gastrointestinal motility, and drug cravings, signs
and symptoms that are often not present in drug-
induced psychosis.4-5,7-8
Some drugs are associated with a pattern
of signs and symptoms that may help identify
them as causative agents. Stimulant-induced
psychosis is often associated with mydriasis, tachy-
cardia, arrhythmia, and brisk reflexes.2-3,5-7,15-17
Benzodiazepine withdrawal is associated with
tremors, fever, and seizures.2-3,5-7, 40-41,93-94
Mydriasis, tachycardia, urinary retention, and con-
stipation accompany anticholinergic-induced psy-
chosis.2-3,5-7,22-32 Although anticholinergic-induced
psychosis occurs more commonly in association
with oral or parenteral administration, it has also
been reported with transdermal use.28
RISK FACTORS
Specific risk factors for drug-induced psychosis are
listed in Table 20–7. Older age, compromised renal
or hepatic function, polypharmacy, concomitant
use of multiple psychoactive drugs, and metabolic
TABLE 20–7 Risk Factors for Drug-Induced
Psychosis
• Age >40 yr
• Infants and children
• Altered hepatic or renal function
• Substance abuse
• Concomitant medications
• Increased burden of medications with additive
effects, such as anticholinergic agents
• Drug interactions (including withdrawal of medica-
tions)
• Underlying disease states
• Lupus
• Parkinson’s disease
• Psychiatric illnesses
• Human immunodeficiency virus
• Head injury
TisdaleC20_344-356 1/12/10 2:46 PM Page 350
350 SECTION IV • Drug-Induced Psychiatric Diseases
abnormalities (e.g., electrolyte abnormalities) all
increase the risk of drug-induced psychosis.
Posttraumatic head injury can cause organic psy-
chosis as well as predispose a patient to drug-
induced psychosis.123-125 As the number of risk
factors increases, so does the likelihood of drug-
induced psychosis.
Patient populations in need of special atten-
tion are the elderly, infants and children, and
patients with concomitant illnesses. Weight- and
age-based dosing are important to decrease the risk
of drug-induced psychosis in the elderly and in
children. Individual drug-prescribing information
cites the dose adjustments, if any, that are neces-
sary because of concomitant illnesses such as
hepatic or renal failure.
In people of any age, concurrent administra-
tion of multiple medications may affect both the
pharmacokinetics and the pharmacodynamics of
drugs.5,7,126-130 Increased anticholinergic burden
from multiple medications or taking >9 medica-
tions daily substantially increases the risk of drug-
induced psychosis.2,5,7
Drug interactions that enhance the pharmaco-
logic effects, increase the serum concentration of
drugs, or both increase the incidence of drug-
induced psychosis. Pharmacodynamic interactions
occur when two medications with similar pharma-
cologic effects exert additive or synergistic effects.
The result is an exaggeration of expected adverse
effects. For example, stimulants and bupropion both
increase dopamine and norepinephrine concentra-
tions in the brain and thus can be anxiogenic. The
addition of a stimulant to bupropion treatment
could lead to significant anxiety that had been mild
or not present at all with bupropion monotherapy.
Another potential pharmacodynamic effect
could result from the combination of two drugs
that antagonize each other’s effects.131-133 For
example, use of a dopamine agonist in combina-
tion with a dopamine antagonist, which is some-
times prescribed when dopamine agonists induce
psychosis in patients with Parkinson’s disease,
could decrease dopaminergic antagonism and lead
to an increase in the dopamine antagonist dose.132-
136
Although one would not expect a particularly
robust change in the dopaminergic antagonism,
other pharmacologic effects, such as anticholiner-
gic transmission, could be increased, leading to a
higher incidence of adverse effects.
Medications commonly associated with phar-
macokinetic drug interactions include antibiotics
(e.g., ketoconazole, erythromycin), psychotropics
(e.g., fluvoxamine, fluoxetine, nefazodone), and
others (e.g., cimetidine, quinidine, protease
inhibitors).126,129-130 Addition of a cytochrome P-450
inhibitor may lead to decreased metabolism of spe-
cific drugs, increased plasma concentrations, and
potential for adverse effects.126,129 Alternatively, dis-
continuation of an agent that was inducing the
metabolism of a drug could lead to decreased drug
metabolism, increased blood concentrations, and
increased side effects, including psychosis.125,128-129
Some agents vulnerable to drug interactions and
drug-induced psychosis include stimulants, steroids,
opiates, anticholinergics, some antibiotics and
antiviral agents, angiotensin–converting–enzyme
inhibitors, dopaminergic agents, and anticonvul-
sant medications.2-3,5
Diligent assessment of medication profiles can
help clinicians identify and prevent or treat the
drug-induced psychosis attributable to drug inter-
actions. Familiarity with those drugs commonly
implicated in drug interactions could help reduce
the risk of drug-induced psychosis.
MORBIDITY AND MORTALITY
Drug-induced psychosis often requires medical
attention to protect the safety of the patient or
those around them, although harm due directly to
the psychotic state is relatively uncommon.
Typically, keeping the patient in a safe environ-
ment until the psychosis resolves is all that is nec-
essary. More severe cases may require the
short-term use of antipsychotic medications.
Death is rarely directly related to psychosis.2-3
Death as a direct outcome of the drug is most often
a result of a severe intoxication (as may occur with
stimulants) or drug withdrawal (as may occur with
benzodiazepines).2-5,93-94
There is limited information available on the
emergency room visits and hospitalizations related
to drug-induced psychosis. One study estimated
that 1% of all emergency room visits were related
to psychosis.137 However, the authors did not dif-
ferentiate between idiopathic and drug-induced
psychosis.
Psychosis impairs judgment and insight, which
can cause a person to make poor decisions and/or
engage in risky behaviors resulting in poor out-
comes such as motor vehicle accidents, suicide, or
assault.2-4 During the psychotic state, patients may
misinterpret surrounding events or participate in
illegal activities that could lead to incarceration.2-4
PREVENTION
Drug-induced psychosis may be prevented by min-
imizing risk factors (Table 20–8). A thorough histo-
TisdaleC20_344-356 1/12/10 2:46 PM Page 351
TABLE 20–8 Approaches to Help Prevent Drug-
Induced Psychosis
• Use lowest dosage possible
• Minimize total number of medications
• Limit medications with anticholinergic properties
• Adjust dosages for elderly
• Avoid use of multiple psychotomimetic medications
• Complete a thorough medication history, including
nonprescription drugs, herbal formulations, alcohol,
and illicit drugs
ry of past and current psychiatric and medical ill-
nesses should be completed. Patients with a histo-
ry of psychotic or bipolar disorders are at an
increased risk for drug-induced psychosis.
Awareness of all prescription, over-the-count-
er medications, herbal products, and nutritional
supplements is essential to accurately assess risk.
Direct inquiry about the use of herbal formula-
tions and nutritional supplements is necessary
because many patients will not volunteer this
information.137-139 Nonpejorative inquiry into
illicit drug use and alcohol consumption is impor-
tant.
Administration of minimal doses, age- and
weight-appropriate doses, avoidance of polyphar-
macy, and awareness of drug interactions can
decrease the incidence of drug-induced psychosis.
In addition, in populations with altered metabolic
function, aggressive therapeutic drug monitoring
may help prevent drug-induced psychosis.
No specific monitoring parameters exist for the
prevention of drug-induced psychosis. However,
educating the patient, his or her family and care-
givers regarding the signs and symptoms of drug-
induced psychosis may help with early
identification and treatment.
MANAGEMENT
Management of drug-induced psychosis depends
on the exclusion of alternative causes of psychosis
such as brain lesions, schizophrenia, or disorders
such as systemic lupus erythematosus.4-5,7 Some
patients may be held against their will for observa-
tion and medicated if the risk of harm to them-
selves or others is deemed unacceptable in a court
of law. Some states allow for administration of
medication without a court order in emergent situ-
ations. The duration of confinement is based on
presentation and state law, hence treatment
options differ from state to state.
CHAPTER 20 • Psychosis 351
Typically, drug-induced psychosis is self-limit-
ing and remits within several hours or, less com-
monly, several days after drug discontinuation.5,7
Treatment should include discontinuation of the
offending agent, except when it is determined to
be medically necessary and no alternative treat-
ments exist. In those situations, decreasing the
dose to below psychotomimetic levels, treatment
with antipsychotic medications, or both may be
appropriate. In some cases, the offending agent
may be temporarily discontinued and then reiniti-
ated at a lower dose after the resolution of psy-
chosis. The dose may then be carefully titrated
upward as appropriate.
Keeping the patient in a safe environment is an
important part of treatment during acute illness. A
safe environment is typically one in which the
patient can be observed and contained if necessary.
Several hours in an emergency room is often suffi-
cient for the resolution of symptoms. Drug treat-
ment is rarely necessary if the offending agent is
discontinued.
Medical management is needed if the patient is
clearly dangerous to herself or himself or to others.
In an acute psychotic state, dangerous behaviors
may include suicidal or homicidal ideation, vio-
lence, extreme paranoia, or unpredictable behav-
iors. Patients who may hurt themselves or others
or may put themselves in dangerous situations typ-
ically require hospitalization. The goal of short-
term treatment is to contain and calm the patient.
Short-term use of antipsychotics or benzodi-
azepines may be warranted, provided they are used
only during the period of psychosis. Long-term use
places patients at unnecessary risk for complica-
tions such as tardive dyskinesia or weight gain and
metabolic abnormalities. The oral route of admin-
istration is preferred; however, in some cases, par-
enteral administration may be necessary.
Hydration to decrease the risk of delirium is also
necessary. Indications of the need for medical
management include an inability to contain a
patient with nondrug measures such as a calm
environment, close observation, containment in a
limited area or room, or supportive contact with
medical professionals, family, or friends.
The choice of medication should be based on
efficacy, patient acceptability, and the adverse effect
profile of the drug. The anxiolytic and sedative
effects of benzodiazepines make them a useful
option for the treatment of acute agitation and anx-
iety. If a patient is disinhibited or becomes disinhib-
ited as a result of benzodiazepine use, antipsychotics
are the drugs of choice. An anticholinergic agent is
often administered concomitantly with any antipsy-
chotic agent likely to cause acute extrapyramidal
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352 SECTION IV • Drug-Induced Psychiatric Diseases
reactions. In patients who are overtly hostile, vio-
lent, or aggressive, a combination of benzodi-
azepines and antipsychotics may be useful.
In cases in which withdrawal from a medica-
tion is the cause of the psychosis, supportive care is
the treatment of choice.35-36 Monitoring of subjec-
tive symptoms and vital signs is useful for the iden-
tification of patients experiencing withdrawal
syndromes. If the discontinuation syndrome places
the patient at risk of death or injury, therapy with
the withdrawn medication may be reinstituted and
then the dose slowly tapered downward for the
patient’s safety. In the case of benzodiazepines,
replacing a shorter-acting drug with a longer-act-
ing agent before downward titration may improve
the tolerability of medication discontinuation.140
In instances in which discontinuing the offend-
ing agent is undesirable. When discontinuation of
the psychotomimetic drug would lead to intolera-
ble symptoms of the primary disorder, lowering the
dose may be sufficient to eradicate psychotic symp-
toms (i.e., antiparkinsonian agents, corticosteroids),
lowering the dose may be sufficient to eradicate
psychotic symptoms. In cases in which treatment
of the underlying illness is possible only with a drug
that is inducing psychosis, long-term antipsychotic
therapy is warranted. In patients with Parkinson’s
disease and drug-induced psychosis, low doses of
quetiapine or clozapine are the treatments of choice
to avoid exacerbation of the underlying movement
disorder.133-136 Because of adverse effects and associ-
ated monitoring procedures required for patients
receiving clozapine, quetiapine is typically viewed
as the first-line agent.133-135
In patients who have experienced drug-
induced psychosis, a retrial of the drug may be
clinically appropriate in certain situations. Ideal
candidates are patients in whom drug-induced psy-
chosis was the result of high drug doses or use of
medications in combination with other psy-
chotomimetic drugs. Patients who experience psy-
chotic symptoms at low drug doses should not
typically be rechallenged. If rechallenge is consid-
ered, discussion of the risks and benefits of therapy
with the patient is important. The agent should be
reintroduced at a low dose and with careful moni-
toring for early signs of psychosis (e.g., mild para-
noia, agitation, irritability, behavioral changes).
Dose increases should be done over extended time
intervals and in smaller increments than usual. In
any case, the dose of the agent reintroduced should
be kept below previous psychotomimetic doses.
Antidotes are available to several agents known
to cause drug-induced psychosis (Table 20–9).
These antidotes are usually necessary only in cases
of overdose.5,141-143 Discontinuation of the medica-
TABLE 20–9 Specific Antidotes for Drug-Induced
Psychosis142-144
Anticholinergics
Physostigmine 0.5–2 mg IM/IV/ SC to start repeating
every 20 min until response or adverse drug reaction
Opioids
Naloxone 0.1–0.2 mg IV every 2–3 min and repeat every
20–60 min
Benzodiazepines
Flumazenil 0.01 mg/kg over 15 sec (maximum, 0.2 mg);
repeat with 0.005–0.01 mg/kg as needed; do not
exceed 3 mg
tion and supportive care are often sufficient.5 In
cases in which an antidote is used, close monitor-
ing to avoid induction of a withdrawal psychosis is
necessary.37 Specific withdrawal psychosis proto-
cols are limited but are outlined in Table 20–10.
INFORMATION FOR PATIENTS
Patients and their caregivers should be alerted to the
potential risks and signs of psychosis whenever psy-
chotomimetic drugs are prescribed. The extent of
counseling will be dependent on several factors,
including the number of risk factors present, the
number and severity of comorbidities, polypharma-
cy, and the dose and number of psychotomimetic
medication to be used. Patients and/or caregivers
should be instructed to contact their clinician if feel-
ings of paranoia or agitation or hallucinations occur.
Patients should be instructed not to take non-
prescription medications without first consulting a
pharmacist or physician. Some nonprescription
agents associated with psychotomimetic properties
include pseudoephedrine, ma huang, diphenhy-
TABLE 20–10 Drug Withdrawal Protocols That
May Minimize the Occurrence of Withdrawal
Psychosis140,141
Substance Treatment
Alcohol/benzodiazepine Chlordiazepoxide 25–50 mg
PO every 2 hr as needed for
signs of withdrawal
Supportive care
Opioids Methadone 10–20 mg every
12 hr; taper over 5–10 days
Supportive care
TisdaleC20_344-356 1/12/10 2:46 PM Page 353
dramine, dextromethorphan, and caf-
feine.24,56,94,144-145 The combination of pseu-
doephedrine and dextromethorphan increases the
risk of psychosis.57 In addition, patients should be
instructed to avoid excessive consumption of caf-
feinated products.68-69 Education concerning which
foods and beverages are high in caffeine may be
necessary depending on the medical sophistication
of the patient.
In conclusion, drug-induced psychosis is often
a preventable disease. Careful inquiry regarding all
medications that a patient is taking, including
nonprescription drugs and complementary thera-
pies, should be completed before making recom-
mendations. Specific attention should be paid to
the combination of agents with a high propensity
for drug interactions.
Although the outcome of drug-induced psy-
chosis is often favorable, it is important to ade-
quately assess all patients for their risk of such
drug-induced diseases. Appropriate doses, disease
and drug monitoring, and minimization of risk fac-
tors can improve patient outcome.
Individualization of all patient assessments is
important because multiple risk factors may sub-
stantially increase the risk of adverse drug reac-
tions.
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SECTION V

DRUG-INDUCED
PULMONARY DISEASES

CHAPTER 21 Interstitial Lung Disease/Pulmonary Fibrosis

CHAPTER 22 Asthma and Bronchospasm

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TisdaleC21_357-377 1/20/10 11:13 PM Page 359
CHAPTER 21
Interstitial Lung Disease/
Pulmonary Fibrosis
P ulmonary toxicity has been associated with
many drugs, and pulmonary fibrosis is one of
the most serious drug toxicities. Pulmonary fibrosis
is a disease that is associated with an excessive
amount of connective tissue in the interstitial
spaces of the lungs. Simply stated, when normal air
spaces and blood vessels in the lungs are replaced
by fibrotic tissue, the lungs become small and
stiff.1 Proliferation and progressive accumulation
of connective tissue causes scarring of the lung
parenchyma. This may occur in the presence or
absence of preceding interstitial pneumonitis.2
Drug-induced pulmonary fibrosis is a diagnosis of
exclusion with the identification of a causative
agent. It is essential for clinicians to be attentive to
potential pulmonary toxicities of drugs in order to
recognize the condition and discontinue therapy
because of the severity of this toxicity and the high
rates of associated mortality. This chapter will pri-
marily discuss drug-induced pulmonary fibrosis,
but drug-induced interstitial pneumonitis will be
discussed where applicable.
CAUSATIVE AGENTS
A substantial number of drugs have been implicat-
ed in causing pulmonary fibrosis with or without
preceding interstitial pneumonitis.3-6 The list of
causative agents has grown to include close to 50
drugs (Table 21–1).7-304 No specific chemical com-
monality exists among these agents, but many of
the offending drugs are known to be cytotoxic. For
this reason, drugs that induce pulmonary fibrosis
are often classified as cytotoxic antineoplastic
drugs and noncytotoxic drugs.3 This is largely
because many of the drugs commonly known to
CoraLynn B. Trewet
provoke this adverse effect are used to treat malig-
nancies. Amiodarone is a noncytotoxic agent
that is well-known to cause pulmonary toxicity.
Other drug classes that have been associated
with pulmonary toxicity include antibiotics and
antirheumatic agents. In some situations, the use
of these drugs is substantially limited because of
the risk of pulmonary toxicity.4 An updated
Internet reference classifying pulmonary toxicity is
located at www.pneumotox.com. This site provides
clinicians with a current reference tool for all types
of drug-induced pulmonary toxicity linked to liter-
ature evidence, including studies and case reports.5
EPIDEMIOLOGY
Non-drug-related pulmonary fibrosis is a rare dis-
ease, and relatively little is known regarding its
incidence and prevalence. Although interstitial
lung disease is a broad classification of more than
200 different entities, idiopathic pulmonary fibro-
sis occurs most frequently. Minimal data are avail-
able regarding the prevalence and incidence of
drug-induced pulmonary fibrosis overall. However,
drug-induced pulmonary fibrosis comprises 2.5%
to 3% of all interstitial lung disease.305
Determination of the incidence and prevalence
of drug-induced pulmonary fibrosis is complicated
by a variety of factors. Many patients receiving
potentially causative agents are prone to infections
that may produce signs and symptoms that are
similar to those that are associated with drug-
induced pulmonary toxicity. Several of the drugs
known to cause pulmonary fibrosis are used in
combination in cancer chemotherapy regimens,
often in conjunction with radiation therapy,
359
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360 SECTION V • Drug-Induced Pulmonary Diseases

TABLE 21–1 Agents Implicated in Drug-Induced Interstitial Lung Disease/Pulmonary Fibrosis

Drug Incidence Level of Evidence
(see page xii for explanation)
7,8
Adalimumab NK C
Amiodarone9-45 1–15% A
Anagrelide46-47 NK C
Antithymocyte globulin48 NK C
Aurothiopropanosulfonate (gold salt)49-51 1% B
Azacitidine52-53 NK C
Bepridil54 NK C
Bleomycin55-63 3–40% A
Bromocriptine64-71 1–5.7% B
Busulfan72-88 3–29% B
Carmustine (BCNU)89-100 10–30% B
Chlorambucil101-106 NK C
Chlorozotocin (DCNU)107-109 1% B
Cyclophosphamide110-122 1–39% B
123-124
Danazol NK C
Dothiepin125 8.5% B
Etanercept126-129 NK C
Fluorouracil130 NK C
Flutamide131 NK C
Fotemustine132-133 NK C
Gemcitabine134-145 0.6–2.7% B
Hexamethonium146-149 NK C
Hydroxyurea150-154 NK C
Ifosfamide155 NK C
Imatinib156-161 NK C
Infliximab162-163 0.05% B
Labetalol164 NK C
Lomustine (CCNU)95,165-171 NK C
Medroxyprogesterone172 NK C
Melphalan173-177 NK C
Methotrexate178-221 1 –7% A
Methysergide222-227 NK C
Mitomycin C228-239 5–17.6% B
Mycophenolate mofetil240-241 NK C
Nabumetone242 NK C
Nitrofurantoin243-270 0.02% B
Nitrosoureas89-100,107-109,165-171 10–30% C
Penicillamine271-276 3% B
Pindolol277-278 NK C
Practolol279-281 NK C
(Continued)
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CHAPTER 21 • Interstitial Lung Disease/Pulmonary Fibrosis
TABLE 21–1 Agents Implicated in Drug-Induced Interstitial Lung Disease/Pulmonary Fibrosis
Drug
Procarbazine119, 282
Rituximab283-285
Sulfasalazine287-299
Tamoxifen300
Tocainide301-303
Zinostatin304
NK = not known.
a
In combination with radiation therapy. No incidence reported when used alone.
which may also contribute to pulmonary toxicity.6
Patients receiving therapy with potentially
causative agents are often immunocompromised
and more susceptible to adverse effects.306 In addi-
tion, drugs that may cause this disease are used pri-
marily by physicians who are not pulmonary
specialists, and who may not recognize and diag-
nose pulmonary fibrosis.6 It is believed that,
because of the lack of reporting mechanisms in the
United States and much of Europe, the incidence
of drug-induced pulmonary toxicity is underesti-
mated. A call for an international registry of
patients with idiopathic pulmonary fibrosis has
been recommended, and many believe that a reg-
istry is needed for drug-induced pulmonary fibrosis
as well.307
Information regarding the incidence of inter-
stitial lung disease associated with specific drugs is
somewhat scarce because of few cumulative data
and a reliance on reported cases. However, the inci-
dence of interstitial lung disease associated with
some agents has been reported. The estimated inci-
dence of pulmonary fibrosis associated with
bleomycin is 4%.55-63 The incidence of carmustine-
induced pulmonary toxicity is estimated to be
between 10% and 30%. One study found an inci-
dence of pulmonary toxicity of 10% in patients
receiving carmustine 1,000 mg/m2, but an inci-
dence of 100% in those who received 1,400 mg/m2,
suggesting a dose-dependent relationship.3 The
incidence of pulmonary fibrosis associated with
mitomycin monotherapy is approximately 5% to
10%. However, when used in combination with
vinca alkaloids, the incidence increases to
35%.3,228,229 Methotrexate induces pulmonary
fibrosis in 3% to 4% of patients when used for
rheumatoid arthritis and psoriasis, but the inci-
dence increases to 7% when used at higher and
more frequent doses for the treatment of malig-
nancies.4,178
361
(Continued)
Incidence Level of Evidence
NK C
2% B
NK C
35–53%a B
NK C
NK C
Amiodarone is the most widely reported non-
cytotoxic drug known to cause pulmonary fibro-
sis.4,6,9-23 The incidence of amiodarone-induced
lung toxicity has ranged from 0.1% to 50% in var-
ious reports.6,9-23 Amiodarone is an example of a
drug that may cause interstitial pneumonitis or
pulmonary fibrosis. In patients receiving intra-
venous amiodarone, such as patients who have
undergone cardio thoracic surgery, interstitial
pneumonitis may occur. In contrast, patients on
long-term oral amiodarone therapy are more like-
ly to develop pulmonary fibrosis. 9-11,13,14 In
patients receiving daily amiodarone doses of <200
mg, the incidence of pulmonary fibrosis is low
(0.1–1.6%), whereas the incidence in patients
receiving maintenance doses of >400 mg daily is
5% to 15%. The incidence may be even higher in
high-risk patients receiving larger doses. 9-11
Approximately 1% of patients receiving gold salts
experience pulmonary toxicity, which is similar
to expected incidences associated with other non-
cytotoxic agents.49-51,308
MECHANISMS
The exact mechanisms of pulmonary toxicity and
lung injury induced by drugs are not known.
Proposed mechanisms are based on theories of the
manner in which the lungs respond to injury
(Table 21–2). Although different drugs may cause
pulmonary fibrosis via different mechanisms, the
histopathologic changes that occur in the lungs of
patients with drug-induced pulmonary fibrosis are
generally similar to those in patients with idio-
pathic pulmonary fibrosis, with the persistence of
an inflammatory lesion resulting in alveolar, capil-
lary, or parenchymal-cell injury.2 Abnormal repair
disrupts the production of connective-tissue ele-
ments, and the normal lung is replaced by cystic
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362 SECTION V • Drug-Induced Pulmonary Diseases
TABLE 21–2 Mechanisms of Drug-Induced Interstitial Lung Disease/Pulmonary Fibrosis2
Drug
Bleomycin
Cyclophosphamide, nitrofurantoin
Carmustine, cyclophosphamide, nitrofurantoin
Amiodarone
spaces separated by thick fibrous tissue; this condi-
tion is known as “honeycomb lung.”309
Contributing mechanisms of injury include
cytokine imbalance, extracellular matrix remodel-
ing and fibrosis, apoptosis of epithelial cells and an
imbalance of oxidants or antioxidants.2 It is
thought that lung injury promotes recruitment of
circulating immune cells, which work together to
release cytokines. Animal and human studies have
shown an influx of inflammatory cells during
bleomycin-induced pulmonary fibrosis.4 Excess
oxygen produces highly reactive, partially reduced
oxygen metabolites, including a superoxide anion
(O2), hydrogen peroxide (H2O2), and the vitamin E
hydroxyl radical. The epithelial lining of the lungs
contains many oxidants and antioxidants. Drugs
such as bleomycin, cyclophosphamide, and nitro-
furantoin can produce toxicity through increasing
production of oxidants, while drugs such as car-
mustine, cyclophosphamide, nitrofurantoin may
induce toxicity by inhibiting the antioxidant sys-
tem.3,308 The imbalance of oxidants and antioxi-
dants in the lower respiratory tract causes an
accumulation of inflammatory cells such as alveo-
lar macrophages and neutrophils.2 For example,
bleomycin is known to be a powerful oxidizing
agent in the presence of iron and oxygen. The oxi-
dants generated in this reaction may lead to cellu-
lar apoptosis.310 Bleomycin may also generate
fibrin in the alveolar compartment.311 Bleomycin is
best known for its characteristic bronchiolitis oblit-
erans with organization pneumonitis, known as
BOOP, or may also present as an eosinophilic
hypersensitivity reaction.312 Both BOOP and the
hypersensitivity reaction are less prevalent in
patients with drug-induced pulmonary toxicity,
but are more likely to present as interstitial pneu-
monitis, which may progress to fibrosis.2
Nitrofurantoin has also been shown to exert
toxic effects through production of reactive oxy-
gen species.313 Most noncytotoxic agents, however,
Mechanism
Cytokine imbalance
Extracellular matrix remodeling and fibrosis
Apoptosis in epithelial cells
Oxidant imbalance
Oxidant imbalance
Antioxidant imbalance
Inhibition of lysosomal phospholipases, followed by break-
down spholipid-laden macrophages
produce an interstitial reaction that is histological-
ly different from the marked atypical cytotoxic
reactions. Unlike the effects of cytotoxic drugs, in
which the histology is uniform, noncytoxic drugs
exert more variable toxicity reactions, ranging
from eosinophilia to noncardiac pulmonary edema
to granulomatous interstitial lung disease.312 The
mechanism of amiodarone-induced pulmonary
toxicity is largely due to the drug’s unique pharma-
cokinetic properties. Amiodarone is an
amphiphilic molecule that contains a highly apo-
lar aromatic ring system and a polar side chain
with a positively charged nitrogen atom.4,314
Amphiphilic molecules are known to cause the
inhibition of lysosomal phospholipases, which
results in a phospholipid storage disorder in the
lungs.314 During long-term therapy with amio-
darone, both the drug and its metabolite accumu-
late in the lung and interfere with the normal
processing of endogenous phospholipids, which
also accumulate in the lung.6 The breakdown of
phospholipid-laden macrophages subsequently
results in pulmonary inflammation and fibro-
sis.4,314
Some mysteries still abound regarding the
mechanism of pulmonary toxicity associated with
other agents. For example, patients who experi-
ence pulmonary toxicity induced by methotrexate
rarely experience recurrence upon rechallenge. It is
thought that methotrexate may predispose the
patient to opportunistic infections, particularly
Pneumocystis jiroveci pneumonia, which may be an
underlying factor in the toxicity.308
CLINICAL PRESENTATION AND
DIFFERENTIAL DIAGNOSIS
The clinical presentation of pulmonary fibrosis is
diminished lung compliance, which presents in a
manner similar to that of restrictive airway disease.
TisdaleC21_357-377 1/20/10 11:13 PM Page 363
CHAPTER 21 • Interstitial Lung Disease/Pulmonary Fibrosis
Signs and symptoms of drug-induced pulmonary
fibrosis are listed in Table 21–3. The majority of
patients describe a gradual or insidious onset of
exertional dyspnea, and a nonproductive cough
rarely accompanied by a fever.2 The dry cough is
refractory to treatment with antitussive agents.315
The onset of illness may be abrupt or it may extend
over weeks to months.306 The duration of drug
therapy prior to the onset of pulmonary fibrosis is
highly variable, and complicated by the fact that
most patients report symptoms for more than 6
months prior to presentation. In most situations,
an abrupt onset represents interstitial pneumonitis
whereas a progressive pattern over time represents
pulmonary fibrosis. This often correlates with
duration of therapy, as short-term treatment is
more likely to result in interstitial pneumonitis
acutely whereas a longer treatment duration is
more likely to present as pulmonary fibrosis.
Physical examination findings show digital club-
bing in 25% to 50% of cases as well as end-expira-
tory crackles.2,3 The crackles are detected in more
than 80% of patients and are described as “dry”
and “Velcro” in quality, with a prevalence in the
TABLE 21–3 Signs and Symptoms of Drug-
Induced Interstitial Lung Disease/Pulmonary
Fibrosis
• Nonproductive cough
• Exertional dyspnea
• Lung crackles at the bases of the lung
• May experience:
• Fever
• Fatigue
• Digital clubbing
• Later stages:
• Cyanosis
• Cor pulmonale
• Right ventricular heave
• Peripheral edema
• Abnormal chest radiograph with diffuse opacity
(“ground-glass” appearance)
• Abnormal high-resolution computed tomography
with diffuse opacity (“ground-glass” appearance)
• Laboratory tests:
• Leukocytosis
• Increased erythrocyte sedimentation rate
• Pulmonary-function tests:
• Reduced total lung capacity and forced vital
capacity
• Reduced diffusing capacity for carbon monoxide
>15% from baseline
363
lung bases.315 In the late phases of the disease,
cyanosis, cor pulmonale, right ventricular heave,
and peripheral edema may be evident.315
Pulmonary-function tests (PFTs) should be per-
formed as a diagnostic tool. PFTs may be normal
initially, but may later reveal a restrictive impair-
ment and a reduced carbon monoxide diffusing
capacity (DLCO). PFTs indicating reduced total lung
capacity and forced vital capacity suggest restric-
tive lung disease rather than obstructive disease. In
the setting of restrictive disease, the measurement
of DLCO helps distinguish between intrinsic lung
disease, in which DLCO is usually reduced, from
other causes of restriction, in which DLCO is usual-
ly normal. Patients with reduced DLCO capacity by
>15% from baseline should be examined for addi-
tional signs and symptoms of pulmonary toxici-
ty.3,319 It is important to note, however, that
patients in whom pulmonary fibrosis did not
develop have also been shown to have reduced
DLCO.318 The patient may be too ill to undergo
extensive PFTs beyond measurement of arterial
blood gases, which often show hypoxemia, espe-
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-
tion of lung tissue via lung biopsy. However, this is
rarely a practical approach for patients in tradition-
al medical settings.316 Pulmonary fibrosis can also
be diagnosed using chest radiography, but it is
important to note that this test is nonspecific.2 The
disease usually begins asymmetrically and appears
to be very focal or unilateral upon imaging.312 In
patients with fully developed fibrosis, the typical
chest radiograph shows diffuse opacity, which has
been described as “ground glass” in appearance.
One-third of all cases of idiopathic interstitial
pneumonitis have been reported to be overlooked
by relying on chest radiography diagnosis alone.317
The patient may be symptomatic before the chest
radiograph appears abnormal, but high-resolution
computed tomography (HRCT) should reveal
abnormalities if this occurs.312,315 In patients with
idiopathic pulmonary fibrosis, HRCT diagnosis was
90% accurate, and combined with clinical findings
can lead to specific diagnosis in 60% to 80% of
cases of drug-induced pulmonary toxicity.2,315 This
has allowed for earlier diagnosis and helps to nar-
row the wide differential diagnosis that may
include heart failure, aspiration, infection, or acute
respiratory distress syndrome (Table 21–4).312,315,317
Because pulmonary fibrosis is isolated to the
lungs, little systemic evidence of the disease has
been found. Results of blood tests may be influ-
enced by concomitant illnesses, such as an ele-
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364 SECTION V • Drug-Induced Pulmonary Diseases
TABLE 21–4 Conditions to Consider in the
Differential Diagnosis of Drug-Induced Interstitial
Lung Disease/Pulmonary Fibrosis
• Idiopathic pulmonary fibrosis
• Viral infection
• Miliary tuberculosis
• Pneumocystis jiroveci pneumonia
• Systemic lupus erythematosus
• Wegener’s granulomatosis
• Idiopathic pneumonia syndrome after bone marrow
transplantation
• Radiation pneumonitis
• Bronchiolitis obliterans (viral)
• Hyperthyroidism
• Hypoxemia
• Heart failure
• Aspiration
• Acute respiratory distress syndrome
vated neutrophil count due to infection, and do
not generally help in the specific diagnosis.
Leukocytosis and an increase in circulating lac-
tate dehydrogenase concentrations are common
features that may or may not aid in the initial
diagnosis.6 An increase in erythrocyte sedimenta-
tion rate may also occur in patients with
pulmonary toxicity due to amiodarone. 319
Bronchoalveolar lavage has been studied but has
not been shown to aid in diagnosis of amio-
darone-induced pneumonitis.319,320
For these reasons, the diagnosis of drug-
induced pulmonary fibrosis is one of exclusion.
The differential diagnosis depends largely on expo-
sure to a causative agent. Few distinguishing symp-
toms, physical findings, laboratory tests, or
histopathologic findings are specific to drug-
induced pulmonary fibrosis as compared with var-
ious other interstitial lung diseases. Several other
conditions should be considered in the differential
diagnosis of drug-induced pulmonary fibrosis
including Pneumocystis jiroveci pneumonia and
radiation pneumonitis (Table 21–4). It is important
to note that many patients may have preexisting
conditions that predispose them to lung injury (see
the section on “Risk Factors” and Table 21–5). One
proposed set of criteria for diagnosis used in
patients receiving carmustine therapy includes the
following three requirements: (1) typical symp-
toms of nonproductive cough and dyspnea with or
without fever; (2) decrease of DLCO capacity by
>10% as compared with baseline; and (3) no clini-
cal evidence of active pulmonary infection.321
Figure 21–1 depicts a proposed clinical scoring sys-
Crackles on lung exam
2 points
Decrease in corrected carbon
monoxide diffusing capacity by
10%
from baseline
Decrease in O2 saturation
by  4% with 2-minute walk 3 points
Interstitial infiltrates on
chest radiography
Total points  6  Prednisone
Total points 6 = Weekly monitoring
FIGURE 21–1 Clinical scoring system for carmustine-
induced pulmonary fibrosis.
Adapted from Chap et al.322
tem used to determine the appropriateness of cor-
ticosteroid therapy for the management of pul-
monary fibrosis in patients on carmustine
therapy.322
The time to onset of the disease varies,
depending on the causative drug.3,4,308 Early diag-
nosis depends largely on close follow-up of
patients.316 Acute symptoms may appear after sin-
gle doses of an agent such as bleomycin, but
reports have demonstrated pulmonary toxicity in
pediatric patients up to 15 years after they
received carmustine.4 Pulmonary toxicity associat-
ed with alkylating agents such as busulfan and
chlorambucil usually develops 3 to 5 years after
initiating chemotherapy, but has been reported as
early as 6 months after initiation. Amiodarone-
induced pulmonary fibrosis has been reported
within 2 months of initiating therapy at oral doses
greater than 400 mg daily. In patients taking lower
maintenance doses of amiodarone, pulmonary
fibrosis may not appear for up to 2 years, with the
average onset at 18–24 months.6, 319 Dyspnea usu-
ally progresses over weeks to months and may be
exacerbated if the patient is in a hyperthyroid
state.319 Nitrofurantoin-induced pulmonary fibro-
sis may present acutely, within 1 month after the
initiation of therapy, or chronically, after 2
months to 5 years of continuous therapy. The
acute presentation occurs in 90% of cases, most
often within 2 weeks after starting therapy.
Patients in whom pulmonary toxicity develops
within the first 24 hours of therapy have usually
received nitrofurantoin therapy previously.308 This
hypersensitivity reaction is unique among drugs
that may cause interstitial lung disease. In general,
the dose and time frame are not consistent for the
development of drug-induced interstitial lung dis-
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CHAPTER 21 • Interstitial Lung Disease/Pulmonary Fibrosis 365

ease, making the diagnosis of this toxicity particu-

larly challenging. TABLE 21–5 Risk Factors for Drug-Induced
Interstitial Lung Disease/Pulmonary Fibrosis
All drugs
RISK FACTORS • Genetic factors involved with cytokine networks and
growth factors
Risk factors for drug-induced interstitial lung dis- • Environmental factors (exposure to asbestos or
ease are listed in Table 21–5. Few risk factors are cigarette smoke)
consistent among all potential causative agents. It • Concomitant use of other cytotoxic drugs
is thought that deposition and accumulation of the Amiodarone
drug in the tissue is the mechanism of disease and • Maintenance doses > 400 mg daily
thus increases risk. Although higher doses have • Long-term therapy
been implicated in the development of pulmonary • Cardiothoracic surgery (interstitial pneumonitis)
fibrosis induced by many agents, such as • Angiography
bleomycin and amiodarone, pulmonary fibrosis • Oxygen therapy
has also been reported at low doses of these drugs.
The risk of lung toxicity associated with amio- Bleomycin
darone is a combination of daily dose (>400 mg • Cumulative dose >400 mg
daily) and duration of treatment (cumulative • Age >70 yr
dose).319 Carmustine does not appear to be associ- • Radiotherapy
ated with a dose threshold for pulmonary toxicity, • Oxygen therapy
but does show a linear relationship of increased • Kidney disease
risk with increased dose.3,92-94 As discussed earlier, Busulfan
combination therapy may also increase the inci- • Cumulative dose >500 mg
dence, particularly with the concomitant use of • Radiotherapy
cyclophosphamide.3,56,57 For many drugs, no Carmustine
increased risk with higher doses or longer dura- • Increased dose
tions of treatment exists, and the development of • Age <7 yr
pulmonary toxicity remains largely unexpected • Radiotherapy
and idiosyncratic.6 • Oxygen therapy
For some drugs, such as bleomycin, older age • Preexisting pulmonary disease
increases the risk of pulmonary fibrosis, possibly as Cyclophosphamide
a result of diminished antioxidant defenses.3,55-57 • Radiotherapy
The incidence of bleomycin-induced pulmonary • Oxygen therapy
fibrosis increases with age, and is approximately
15% in patients older than 70 years of age.55-63 An Gold salts
inverse relationship exists between age and car- • Male sex
mustine-induced pulmonary toxicity, as patients Methotrexate
younger than 7 years of age appear to be at greater • Higher maintenance dose
risk.91,93 Evidence supports the concept that envi- • Higher frequency of use
ronmental factors, such as exposure to asbestos Mitomycin
and cigarette smoke, increase the risk.320,323,324 Few • Radiotherapy
data exist as to whether prior pulmonary adverse • Oxygen therapy
effects associated with a specific drug or related • Vinca alkaloid use
compounds increase the risk for lung toxicity. Nitrofurantoin
There is a possible genetic link between the acety- • Oxygen therapy
lator or human leukocyte antigen phenotype and • Age >40 yr
the activation and detoxication pathways of drugs,
which differ among individuals. More research is
needed in this area.6
Concomitant therapies and conditions that oxygen.2,3,6 The increased risk associated with radi-
may influence the cytochrome P-450 system or ation therapy is due to a synergistic production of
detoxification pathways or alter pharmacokinetics reactive oxygen metabolites.6 The mechanism of
of the offending agent may increase risk for toxici- risk associated with oxygen therapy is similar, as
ty.6 Two hazardous associations occur with radia- higher concentrations of oxygen generate reactive
tion and high inspired concentrations of metabolites that interact with the oxidant and
TisdaleC21_357-377 1/20/10 11:13 PM Page 366
366 SECTION V • Drug-Induced Pulmonary Diseases
antioxidant defense mechanism. Underlying dis-
ease is known to play a role, primarily in the pres-
ence of preexisting pulmonary disease.3,6 The risk
of bleomycin-induced pulmonary fibrosis may also
be increased in patients with kidney disease
because of prolonged excretion time.325
MORBIDITY AND MORTALITY
Few reports discuss the socioeconomic impact of
drug-induced pulmonary fibrosis. No published
reports pertain to cost, emergency room visits, or
length of stay. One retrospective study reviewed
hospitalizations due to pulmonary toxicity and
concurrent nitrofurantoin use.326 In this analysis,
very few hospital admissions were associated with
acute pulmonary toxicity. In the three cases of
nitrofurantoin-induced pulmonary toxicity, only
one prescription for nitrofurantoin was filled prior
to the hospitalization. The pulmonary symptoms
resolved after discontinuation of nitrofurantoin
therapy and initiation of supportive care. The
review did not report the length of hospital stay.326
The median duration of survival among per-
sons with any form of pulmonary fibrosis is
approximately 3 to 5 years. Respiratory failure is
the cause of death in over 80% of cases.327 Data col-
lected from the National Center for Health
Statistics estimated mortality from pulmonary
fibrosis, excluding connective-tissue disease,
asbestosis, and radiation fibrosis, to be 50.8 per 1
million people in the general population, adjusted
for age and sex.328 Age-adjusted mortality rates
have increased by 28.4% for men and 41.3% for
women since 1992. The incidence of pulmonary
fibrosis is higher in men, but the associated mortal-
ity rate is higher in women.328 The incidence of
mortality also increases with age.328 Mortality rates
associated with pulmonary fibrosis are higher than
those due to myeloid leukemia, multiple myeloma,
and bladder cancer.328 When the cause is not
known, as in idiopathic pulmonary fibrosis, the
prognosis is poor. The incidence of mortality in
patients with idiopathic pulmonary fibrosis who
are admitted to the intensive care unit is 86% to
97%.329
The incidence of mortality associated with
drug-induced pulmonary fibrosis is higher in asso-
ciation with cytotoxic drugs than that due to non-
cytotoxic agents. The incidence of mortality due to
bleomycin- or carmustine-induced pulmonary
fibrosis has been estimated to be as high as 70%,
although more recent data suggest that bleomycin-
induced pulmonary fibrosis carries a mortality rate
of 25%, as compared with 30% to 40% for carmus-
tine-induced pulmonary fibrosis.4 Mitomycin-
induced pulmonary fibrosis is associated with a
much lower incidence of mortality, approximately
5% to 10%.4 The incidence of mortality due to pul-
monary disease induced by methotrexate has been
estimated to be 10%, although the incidence may
be much lower in patients without cormorbid con-
ditions.3,213
Pulmonary fibrosis induced by gold salts is
associated with an estimated incidence of mortali-
ty of 10%. Nearly 50% of patients with gold-
induced pulmonary fibrosis show no residual
abnormalities after resolution of the disease.3,330
The incidence of mortality in patients with amio-
darone-induced pulmonary fibrosis is variable.
Amiodarone-induced pulmonary fibrosis has been
reported to be fatal in up to 64% of untreated cases,
in part because of the large number of comorbid ill-
nesses in patients taking this medication.10 The
mortality associated with amiodarone-induced pul-
monary fibrosis in patients admitted to the hospi-
tal is 21% to 33%.6,319 Early recognition of
amiodarone-induced pulmonary toxicity markedly
improves mortality rates.4
PREVENTION
Prevention of drug-induced lung disease requires
careful selection of potentially causative agents
and frequent follow-up of patients who are taking
drugs that may cause pulmonary fibrosis. Doses of
causative agents should be carefully chosen in
order to decrease the risk of drug-induced pul-
monary disease (Table 21–6). Beyond careful dose
selection, little agreement and minimal evidence
advocate for prevention or risk-reduction strate-
gies, but the importance of early diagnosis is
emphasized. In patients with pulmonary fibrosis,
PFTs are impaired and may be predictive of the
development of the toxicity, but this often does
not become evident until after the disease is
established. The measurement of DLCO through-
out drug therapy is recommended, although little
is known about whether this decreases the inci-
dence or aids in more prompt diagnosis.331 For
this reason, monitoring DLCO is recommended
only for patients taking drugs associated with a
high incidence of pulmonary fibrosis (Table
21–1). The frequency of monitoring of patients
taking drugs with a substantial risk of pulmonary
fibrosis should be patient-specific and drug-
dependent, with recommended monitoring of
DLCO every 2 weeks to every 2 to 4 months.4,312 If
a 15% to 20% reduction in DLCO is noted, further
pulmonary-function testing is warrant-
TisdaleC21_357-377 1/20/10 11:13 PM Page 367
CHAPTER 21 • Interstitial Lung Disease/Pulmonary Fibrosis
TABLE 21–6 Approaches to Help Prevent Drug-
Induced Interstitial Lung Disease/Pulmonary
Fibrosis
• Use lowest dose possible for desired effect
• Avoid combinations of drugs known to increase risk
• Frequent follow-up to monitor for symptoms of dys-
pnea on exertion and nonproductive cough2
• Monitor carbon monoxide diffusing capacity (DLCO)
every 2 wk to every 2–4 mo3,4,319,321,322
• Chest radiograph every 3–6 mo for patients receiving
high-risk drugs such as amiodarone and cytotoxic
agents6,319
• High-resolution computed tomography every 3–6
mo for patients receiving high-risk drugs, such as
amiodarone and cytotoxic agents6,312,315,317
• Prophylactic antibiotics (trimethoprim and sul-
famethoxazole) for patients receiving carmustine
therapy
• Inhaled corticosteroids (fluticasone 880 mcg every 12
hr) for patients receiving carmustine therapy
ed.3,4,319,321,322 If PFTs are normal and the clinical
presentation of the patient does not include
symptoms associated with pulmonary fibrosis,
drug therapy may proceed with continued moni-
toring.4 The predictive value of DLCO monitoring
and spirometry is 21% for amiodarone-induced
pulmonary fibrosis.332 Even with this low value, it
is recommended that patients undergo chest radi-
ography and PFT/DLCO monitoring every 3 to 6
months while taking maintenance amiodarone
therapy.6,319 The monitoring of DLCO and PFTs is
not as sensitive for patients taking drugs that are
less commonly associated with pulmonary fibro-
sis, such as methotrexate.4 Careful monitoring
should be conducted in patients who are at great-
est risk, including those with respiratory disease,
emphysema, and previous pneumonectomy.6 As
discussed previously, HRCT is a more sensitive
test, but the use of HRCT for prevention of amio-
darone-induced pneumonitis has not been exten-
sively studied.314
Carmustine, also known as BCNU, is often pre-
scribed in combination with cyclophosphamide,
cisplatin, and stem-cell transplantation for the
management of breast cancer. A clinical scoring
system has been developed to determine the neces-
sity for prophylaxis of pulmonary toxicity with
corticosteroids during carmustine therapy for
breast cancer (Figure 21–1). Patients with a score of
≥6 responded well to prednisone therapy, whereas
patients with a score of <6 continued to be moni-
tored weekly according to the clinical markers.322
367
The dose of prednisone was 60 mg twice daily for
10 days, followed by 30 mg daily for 1 week, then
20 mg daily for 1 week, with a gradual taper of 5
mg weekly until discontinuation. The regimen pro-
duced clinical improvement within 72 hours of the
initiation of therapy. Another recommended pred-
nisone dose during carmustine therapy is 1
mg/kg/day for 1 to 2 weeks followed by an 8-week
taper.321 Inhaled corticosteroids have been studied
as prophylaxis for pulmonary toxicity caused by
carmustine in patients with breast cancer. Inhaled
fluticasone 880 mcg every 12 hours has been
shown to significantly preserve pulmonary func-
tion and decrease the incidence of pulmonary tox-
icity.347 Due to the high incidence of Pneumocytis
jiroveci during carmustine therapy, some recom-
mend the prophylactic use of trimethoprim and
sulfamethoxazole.321
Other markers are under investigation for
monitoring higher-risk patients for the purpose of
early detection of interstitial lung disease, both
drug-induced and idiopathic. A great deal of
research in Japan has focused on circulating plas-
ma KL-6 concentrations.333-336 KL-6 is a glycopro-
tein classified as human MUC1 mucin that has
been studied in various interstitial lung diseases.
There have been documented case reports of
increased serum KL-6 concentrations in patients
with pulmonary toxicity induced by amiodarone,
misoprostol, and methotrexate.333,334 However,
the sensitivity of KL-6 for detection of drug-
induced pneumonitis was 53.3%, which was
lower than that for detection of non-drug-
induced interstitial lung diseases. Research has
indicated that the sensitivity of serum KL-6 con-
centrations was highest (88.9%) for detection of
specific drug-induced patterns, diffuse alveolar
damage and chronic interstitial pneumonia as
compared with less common types of drug-
induced interstitial lung disease.333
Some experimental evidence suggests that
pharmacologic inhibition of human epidermal
growth factor receptor 2 (HER2) with recombi-
nant monoclonal antibodies may reduce the risk
of bleomycin-induced pulmonary toxicity.
Experiments with mice have produced favorable
results, including increased survival, when used
to prevent pulmonary toxicity.337 Trastuzumab
and lapatinib are two recombinant monoclonal
antibodies therapies that target HER2, but have
not been extensively studied for this use.
Thalidomide, known to have an inhibitory effect
on interleukin-6–dependent cell growth, has
also been studied for the prevention of
bleomycin-induced pulmonary toxicity. 338 A
great deal of current research is being done
TisdaleC21_357-377 1/20/10 11:13 PM Page 368
368 SECTION V • Drug-Induced Pulmonary Diseases
regarding gene expression in patients with pul-
monary fibrosis, which may lead to preventive
treatments.339
MANAGEMENT
The cornerstone of therapy for drug-induced pul-
monary toxicity is discontinuation of therapy with
the causative agent. Corticosteroid therapy is
regarded as the standard treatment, despite the fact
that there has not been substantive evidence of
efficacy. More data exist regarding treatment
options for idiopathic pulmonary fibrosis than for
drug-induced pulmonary fibrosis. Noncortico-
steroid agents that have been studied for the treat-
ment of pulmonary fibrosis, both drug-induced
and idiopathic, are included in Table
21–7.311,315,316,338-349 Approximately 20% of patients
with idiopathic pulmonary fibrosis demonstrated
clinical improvement without corticosteroid thera-
py, but alternative treatment strategies have pro-
duced less favorable results.340 The American
Thoracic Society (ATS) guidelines for idiopathic
pulmonary fibrosis include the use of prednisone
40 to 100 mg daily for 2 to 4 months, followed by
tapering of therapy. The ATS guidelines also recom-
mend consideration of the addition of azathio-
prine or cyclophosphamide as well as colchicine
for treatment of idiopathic pulmonary fibro-
sis.315,349
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-
mide, curcumin, aerosolized heparin, and
aerosolized urokinase.311,338,345,346 Patients may
respond to treatment with corticosteroids, but pul-
monary disability often remains after resolution of
symptoms.4 Patients who experience drug-induced
pulmonary fibrosis associated with cytotoxic
agents may also experience repeated episodes of
pneumothorax because of poor reexpansion of the
fibrotic lung.6
Data are lacking with regard to the efficacy of
corticosteroids for the management of amio-
darone-induced pulmonary toxicity. However,
some evidence suggests that corticosteroid therapy
delays mortality and promotes clinical improve-
ment. Recurrence of amiodarone-induced pul-
monary fibrosis was linked to early
discontinuation of corticosteroid therapy.319 For
this reason, corticosteroids are the mainstay of
therapy, especially in situations in which discon-
tinuation of amiodarone therapy is undesirable.
Prednisone is recommended at a dose of 0.75 to 1
mg/kg daily for patients with amiodarone-induced
pulmonary fibrosis until clinical and radiographic
improvement occurs. If the patient does not
respond, the dose may be increased. Tapering of
prednisone therapy should occur gradually and
with caution. The total treatment duration should
be approximately 6 to 12 months. Providers should
carefully monitor patients’ pulmonary function
after corticosteroid therapy has been discontinued,
because of the long half-life of amiodarone and the
risk of recurrence.6,319
In most documented cases of drug-induced
pulmonary fibrosis, a positive clinical response
has been reported within the first 7 to 10 days
after discontinuing the causative agent and initiat-
ing therapy with corticosteroids. In some cases,
positive response has been reported even sooner.
According to guidelines, a favorable response is
depicted by a decrease in symptoms, specifically
an improvement in dyspnea on exertion or a
decline in the frequency or severity of cough, and
a reduction in parenchymal abnormalities on
HRCT. Furthermore, physiologic improvement is
defined by the presence of two or more of the fol-
lowing: >10% increase in total lung capacity or
vital capacity; >15% improvement in DLCO, or at
least 3 mL/min/mm Hg; and an improvement or
normalization of oxygen saturation (>4% increase)
or partial pressure of oxygen (>4 mm Hg from pre-
vious measurement) achieved during a formal car-
diopulmonary exercise test.315
TABLE 21–7 Therapeutic Approaches for
Interstitial Lung Disease/Pulmonary
Fibrosis311,315,316,338-349
Drug Dose (if known)
Drug-induced
Prednisone Variable start dose with extend-
ed taper 0.75–1 mg/kg common
Fluticasone 880 mcg inhaled twice daily
Idiopathic
Colchicine 0.6 mg 1–2 times daily
Azathioprine 2–3 mg/kg lean body weight
daily
Cyclophosphamide 2 mg/kg lean body weight daily
Pirfenidone
Interferon
N-acetylcysteine
Leukotriene B4
Prostaglandin E2
TisdaleC21_357-377 1/20/10 11:13 PM Page 369
CHAPTER 21 • Interstitial Lung Disease/Pulmonary Fibrosis
INFORMATION FOR PATIENTS
Providers have a responsibility to help patients
understand the risk of pulmonary fibrosis and
interstitial pneumonitis associated with pre-
scribed causative agents. Educating patients
regarding the benefits and the risks of treatment
should be the focus of the provider.348 Patients
should be strongly encouraged to stop smoking
prior to the initiation of potentially causative
agents.349 Patients should understand the risk
factors as well as common symptoms of nonpro-
ductive cough and progressive dyspnea, in order
to recognize early signs of toxicity. Patients
should be instructed to consult their health care
provider immediately if such symptoms occur. If
a patient is diagnosed with drug-induced inter-
stitial lung disease, it is important for him or her
to understand the disease process. Patients
should be counseled regarding rehabilitation
and body conditioning, including an exercise
program and nutritional instruction because of
the weight gain associated with corticosteroid
use. Communication between patients and
providers is essential when dealing with drug-
induced pulmonary fibrosis and interstitial
pneumonitis because of the minimal treatment
options and high incidence of mortality.
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288. Peters FP, Engels LG, Moers AM. Pneumonitis induced by
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290. Hamadeh M, Atkinson J, Smith LJ. Sulfasalazine-induced
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291. Yamakado S, Yoshida Y, Yamada T, et al. Pulmonary
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292. Jordan A, Cowan RE. Reversible pulmonary disease and
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293. Swinburn CR, Jackson GJ, Cobden I, et al. Bronchiolitis
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294. Averbuch M, Halpern Z, Hallak A, et al. Sulfasalazine
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295. Moseley RH, Barwick KW, Dobuler K, et al. Sulfasalazine-
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296. Wang KK, Bowyer BA, Fleming CR, et al. Pulmonary
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297. Sigvaldason A, Sorenson S. Interstitial pneumonia due to
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299. Parry SD, Barbatzas C, Peel ET, et al. Sulphasalazine and
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301. Perlow GM, Jain BP, Pauker SG, et al. Tocainide
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303. Feinberg L, Travis WD, Ferrans V, et al. Pulmonary
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304. Calvo DB, Legha SS, McKelvey EM, et al. Zinostatin-
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308. Cooper JAD Jr, White DA, Matthay RA. Drug-induced
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309. Kuwano K, Hagimoto N, Hara N. Molecular mechanisms
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311. Günther A, Lübke N, Ermert M, et al. Prevention of
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312. Limper AH, Rosenow EC. Drug-induced interstitial lung
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313. Martin WJ II. Nitrofurantoin: evidence for the oxidant
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314. Jessurun GAJ, Boersma WG, Rijns HJGM. Amiodarone-
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315. American Thoracic Society. Idiopathic pulmonary
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316. Batist G, Andrews JL Jr. State of the art: pulmonary
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317. Grenier P, Valeyre D, Cluzel P, et al. Chronic diffuse
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318. L’age-Stehr J, Diamanstein T. Induction of autoreactive T
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patients and review of the literature. Chest.
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321. Cao TM, Negrin RS, Stockerl-Goldstein KE, et al.
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322. Chap L, Shpiner R, Levine M, et al. Pulmonary toxicity
of high-dose chemotherapy for breast cancer: a non-
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323. Chouri N, Langin T, Lantuejoul S, et al. Pulmonary
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324. Bedrossian CW, Warren CJ, Ohar J, et al. Amiodarone
pulmonary toxicity: cytopatho logy, ultrastructure, and
immunocytochemistry. Ann Diagn Pathol. 1997;1:47-56.
325. Pfitzenmeyer P, Foucher P, Dennewald G, et al.
Pleuropulmonary changes induced by ergoline drugs. Eur
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326. Jick SS, Jick H, Walker AM, et al. Hospitalizations for
pulmonary reactions following nitrofurantoin use. Chest.
1989;96:512-515.
327. Raghu G, Weycker D, Edelsberg J, et al. Incidence of
prevalence of idiopathic pulmonary fibrosis. Am J Respir
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328. Olson AL, Swigris JJ, Lezotte DC, et al. Mortality from
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329. Saydain G, Islam A, Afessa B, et al. Outcome of patients
with idiopathic pulmonary fibrosis admitted to the
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CHAPTER 21 • Interstitial Lung Disease/Pulmonary Fibrosis
intensive care unit. Am J Respir Crit Care Med.
2002;166:839-342.
330. Zitnik RJ, Cooper JAD Jr. Pulmonary disease due to
antirheumatic agents. Clin Chest Med. 1990;11:139-150.
331. Chetta A, Marangio E, Olivieri D. Pulmonary function
testing in interstitial lung diseases. Respiration.
2004;71:209-213.
332. Gleadhill IC, Wise RA, Schonfeld SA, et al. Serial lung-
function testing in patients treated with amiodarone: a
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333. Ohnishi H, Yokoyama A, Yasuhara Y, et al. Circulating
KL-6 levels in patients with drug induced pneumonitis.
Thorax. 2003;58:872-875.
334. Miyata M, Sakuma F, Fukaya E, et al. Detection and
monitoring of methotrexate-associated lung injury using
serum markers KL-6 and SP-D in rheumatoid arthritis.
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335. Yokoyama A, Kondo K, Nakajima M, et al. Prognostic
value of circulating KL-6 in idiopathic pulmonary
fibrosis. Respirology. 2006;11:164-168.
336. Satoh H, Kurishima K, Ishikawa H, et al. Increased levels
of KL-6 and subsequent mortality in patients with
interstitial lung diseases. J Intern Med. 2006;260:429-434.
337. Faress JA, Nethery DE, FO Kern E, et al. Bleomycin-
induced pulmonary fibrosis is attenuated by a
monoclonal antibody targeting HER2. J Appl Physiol.
2007;103:2077-2083.
338. Tabata C, Tabata R, Kadokawa Y, et al. Thalidomide
prevents bleomycin-induced fibrosis in mice. J Immunol.
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339. Cutroneo KR, White SL, Phan SH, et al. Therapies for
bleomycin induced lung fibrosis through regulation of
377
TGF-_1 induced collagen gene expression. J Cell Physiol.
2007;211:585-589.
340. Green FHY. Overview of pulmonary fibrosis. Chest.
2002;122:334-339.
341. Lasky JA, Ortiz LA. Antifibrotic therapy for the treatment
of pulmonary fibrosis. Am J Med Sci. 2001;322:213-221.
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pulmonary fibrosis: an update. Q J Med. 2006;99:643-654.
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344. Antoniu SA. Pirfenidone for the treatment of idiopathic
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346. Punithavathi D, Venkatesan N, Babu M. Curcumin
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rats. Br J Pharmcol. 2003;139:1342-1350.
347. McGaughey DS, Nikcevich DA, Long GD, et al. Inhaled
steroids as prophylaxis for delayed pulmonary toxicity
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Biol Blood Marrow Transplant. 2001;7:272-278.
348. Michaelson JE, Aguayo SM, Roman J. Idiopathic
pulmonary fibrosis: a practical approach for diagnosis
and management. Chest. 2000;118:788-794.
349. Reynolds HY. Diagnostic and management of strategies for
diffuse interstitial lung disease. Chest. 1998;113:192-202.
TisdaleC22_379-398 1/12/10 2:49 PM Page 378
CHAPTER 22
Asthma and
Bronchospasm
A sthma is a common chronic disorder of the
airways characterized by airway inflamma-
tion, bronchial hyperresponsiveness, and airway
obstruction that is usually reversible spontaneous-
ly or with treatment. Most clinical signs and symp-
toms of asthma are caused by airway obstruction.1
The most common drug-induced respiratory prob-
lem is bronchospasm, and asthmatic signs and
symptoms or bronchospasm may be caused by a
plethora of drugs.2 Drug-induced bronchospasm
can be caused by a variety of mechanisms and may
present as an isolated event or as a symptom of
immunologic (anaphylaxis) or nonimmunologic
(anaphylactoid) anaphylactic reactions.3 Although
drug-induced bronchospasm occurs primarily in
patients with coexisting asthma, it may also occur
in patients with other forms of airway hyperre-
sponsiveness or drug allergies.2,4
CAUSATIVE AGENTS
Drugs that have been reported to cause bron-
chospasm or worsen asthma symptoms are listed
in Table 22–1.5-138 Although bronchospasm occurs
rarely in association with most of the listed
causative agents, aspirin, nonsteroidal antiinflam-
matory agents, ␤-adrenergic receptor antagonists
(␤-blockers), iodinated radiocontrast dyes, sulfites,
and N-acetylcysteine frequently cause bron-
chospasm.2,139 Bronchospasm associated with
angiotensin-converting–enzyme (ACE) inhibitors
is rare. However, cough, a symptom of asthma, is
one of the most common adverse effects of ACE
inhibitors.2,139 Therefore, ACE-inhibitor–induced
cough is covered in this chapter.
378
W. Greg Leader and Brice Labruzzo Mohundro
EPIDEMIOLOGY
The prevalence of asthma in the general popula-
tion is approximately 7.7%.140 The overall inci-
dence of drug-induced bronchospasm is unknown.
The incidence of bronchospasm associated with
individual drugs, when known, is listed in Table
22–1.
Aspirin and nonsteroidal antiinflammatory
drugs (NSAIDs) are associated with the highest
incidence of drug-induced bronchospasm.139,140
Reports of the prevalence of aspirin-induced asth-
ma (AIA) range from 0.6% to 44%.16-18 This broad
range is likely due to differences in the populations
studied or the diagnostic criteria used. Aspirin-
induced bronchospasm in patients without a diag-
nosis of asthma is rare, with a prevalence of
<1%.141,142 One meta-analysis identified the preva-
lence of AIA in adults, based on oral provocation
testing, as 9% in asthmatic patients with no histo-
ry of aspirin intolerance, 21.1% in all patients with
asthma (whether aspirin-intolerant or not) and
29.9% in patients with a previous history of AIA or
an increased risk or likelihood of AIA.17 The preva-
lence in children is lower, and was reported to be
5%.17 One study reported the prevalence of AIA in
children to be as high as 28%, but this study pop-
ulation consisted of patients with chronic sinusitis
and severe asthma.143 The prevalence of AIA in
patients with both asthma and nasal polyps is
higher, ranging from 30% to 64.5%.141,144
Because of their similar mechanisms of action,
patients with AIA also have symptoms of asthma
or bronchospasm due to NSAIDs that inhibit
cyclooxygenase-1 (COX-1).101,102 A meta-analysis
reported cross-sensitivity rates associated with rela-
TisdaleC22_379-398 1/12/10 2:49 PM Page 379

CHAPTER 22 • Asthma and Bronchospasm 379

TABLE 22–1 Agents Implicated in Drug-Induced Asthma and Bronchospasm

Drug Incidence Level of Evidence
(see page xii for explanation)
5,a b
Acetaminophen <6% A
24%c
32%d
N-acetylcysteine6-8 NK B
␣-Agonists9 NK C
Amiodarone10-12 NK C
Angiotensin-converting–enzyme inhibitors13-15 0 –44% (cough) A
NK (bronchospasm)
Aspirin16-19 4–44% A
Benzalkonium chloride20-24 NK A
␤-Blockers25-34 NK A
Betahistine35 NK C
Bromelin36 NK C
Carbamazepine37,38 NK C
Carboprost39,40 NK C
Cisapride1,41 NK C
Cocaine42,43 NK C
Colistin44 NK A
Cromolyn45,46 NK C
Cyclophosphamide47,48 NK C
D-Tubocurarine49-51 NK C
D-Penicillamine52 NK C
Desensitization extracts 53 NK C
Dipyridamole54-56 NK B
Estrogen57-59 NK B
Ethanol60-66 NK B
Ethylenediaminetetraacetic acid (EDTA)20,67-69 NK A
Etidronate70 NK C
Gallamine71 NK C
Glucosamine-chondroitin72 NK C
Heroin73-77 NK B
Hydrocortisone sodium succinate78-82,a 2% A
Interferon-alfa83 NK C
Interleukin-284-85 NK A
Iodinated radiocontrast media86 0.22–1% B
Isotretinoin87,88 NK C
Losartan89,90 NK C
Menthol91,92 NK C
Meperidine93 NK C
Methimazole94 NK C
Methotrexate95 NK C
(Continued)
TisdaleC22_379-398 1/12/10 2:49 PM Page 380

380 SECTION V • Drug-Induced Pulmonary Diseases

TABLE 22–1 Agents Implicated in Drug-Induced Asthma and Bronchospasm

Drug Incidence Level of Evidence
Methyldopa96 NK C
Methylprednisolone97 NK C
Mivacurium98 NK C
Neostigmine99,100 NK C
Nonsteroidal antiinflammatory drugs (COX-1 inhibitors)16-18,101,102 4–44% A
Oxytocin103 NK C
Pancuronium bromide104 NK C
Pentazocine105 NK C
Pentamidine106-108 NK A
Propafenone109 NK A
Propofol110-112 NK C
Propylthiouracil113 NK C
Psyllium114-118 5–12% B
Pyrethrin119-121 NK C
Sodium salicylate122 NK C
Sulfites123-128 5–11% A
Tamoxifen129 NK C
Tartrazine130,131 0–2.4% B
Tobramycin132-134 NK A
Venlafaxine135 NK C
Verapamil136 NK C
Yohimbine137 NK C
Zanamavir138 NK C
COX = cyclooxygenase; NK = Not known
a
In aspirin-sensitive patients.
b
Single doses of ≤ 650mg.
c
Single doses of 1000 mg.
d
Single doses of 1500 mg.

tively low doses of ibuprofen, naproxen, and
diclofenac of 98%, 100%, and 93%, respectively, in
aspirin-intolerant patients.17 Drugs that are poor
inhibitors of COX-1 (acetaminophen and salsalate)
or drugs that are partially selective inhibitors of
COX-2 (meloxicam) usually induce asthma only at
high doses. The prevalence of acetaminophen-
induced bronchospasm in aspirin-sensitive
patients with asthma is 0% to 6% at doses of 650
mg or less,5 and most patients can tolerate aceta-
minophen doses up to 500 mg.102 A case–control
study evaluating the cross reactivity of acetamino-
phen in aspirin-intolerant patients found that 24%
and 32% had bronchospasm after an oral challenge
with 1,000 mg or 1,500 mg of acetaminophen,
respectively. None of the patients with aspirin-tol-
erant asthma had bronchospasm related to aceta-
minophen ingestion.5 Furthermore, case–control
studies have found that increasing frequency of
acetaminophen use is associated with asthma in
adults.145,146 An ecologic study of aggregate aceta-
minophen consumption and asthma rates in
Europe demonstrated a 0.52% increase in the
prevalence of wheezing in 13- to 14-year-olds for
each gram increase in per capita acetaminophen
sales.147 Meloxicam loses its selectivity as the dose
increases, but may be tolerated in doses up to 22.5
mg in aspirin-intolerant patients. Bronchospasm
related to selective COX-2 inhibitors has been
found in two case reports.148,149 However, eight
clinical trials enrolling a total of 378 patients
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
COX-2 inhibitors and aspirin in aspirin-intolerant
patients.150 The incidence of cross reactivity may
be small enough that the combined sample size of
these trials may not be large enough to demon-
strate cross sensitivity.
Bronchospasm has been reported in associa-
tion with intravenous hydrocortisone succinate
when administered to patients with asthma,151 and
in particular, aspirin-intolerant asthmatic
patients.152 One study found that the prevalence of
bronchospasm associated with hydrocortisone suc-
cinate in aspirin-sensitive patients was 2%.78
Bronchospasm has also been reported in associa-
tion with methylprednisolone sodium succinate. It
is not clear as to whether the bronchospasm is
caused by the steroid moiety or the succinate.78
Even at high doses, ␤-blockers rarely cause
bronchospasm in patients without asthma.
However, they are a common trigger of bron-
chospasm in patients with asthma. The prevalence
of bronchospasm associated with non-selective ␤-
blockers is unknown, but it has been estimated
that 50% to 100% of patients with asthma exhibit
symptoms of bronchospasm after a single dose of a
nonselective ␤-blocker.139,153 In addition to prob-
lems caused by oral or intravenous administration
of these drugs, fatal asthma has also been reported
in association with topical ophthalmic use of tim-
olol.25 Because of the frequency and severity of the
reactions, nonselective ␤-blockers are contraindi-
cated in patients with asthma.26 Cardioselective ␤-
blockers decrease, but do not eliminate,
␤-blocker–induced bronchospasm. At higher doses,
these agents lose their selectivity, and the risk for
bronchospasm increases.26,154 Decreased forced
expiratory volume in 1 second (FEV1) and symp-
toms of bronchospasm have been demonstrated in
asthmatic patients receiving cardioselective ␤-
blockers.26,155 A 12-month comparative study of
topical timolol and betaxolol demonstrated no sig-
nificant differences between the groups in mean
spirometric values or number of dropouts due to
respiratory symptoms.27 A meta-analysis evaluat-
ing cardioselective ␤-blockers in patients with reac-
tive airway disease concluded that these agents do
not produce clinically significant adverse respirato-
ry effects in this population.28 However, the stud-
ied populations did not include patients with
severe disease, and therefore, the results may not
be extrapolated to this population. Four cases of
amiodarone-induced bronchospasm have been
reported.10-12 It is plausible that bronchospasm due
to amiodarone use may be related to its noncom-
petitive inhibition of ␤-adrenergic receptors.
Bronchospasm has also been reported in associa-
CHAPTER 22 • Asthma and Bronchospasm 381
tion with propafenone, which has weak ␤-blocking
activity in the majority of patients, but which has
more potent ␤-blocking activity in the 7% to 10%
of patients who are poor metabolizers of
cytochrome P-450 2D6.109
Angiotensin-converting–enzyme (ACE) inhi-
bitor–induced cough appears to be a class effect.
The prevalence of ACE inhibitor–induced cough in
the general population is approximately 10% to
20%, with reports in different populations ranging
from 0% to 44%.13-15 The frequency of cough
caused by ACE inhibitors appears greater in
patients with heart failure (26%) than in patients
with hypertension (14%).156 The prevalence of ACE
inhibitor–induced cough and bronchospasm in
patients with reactive airway disease appears simi-
lar to that in the general population.13,157,158
Although the incidence of cough and bron-
chospasm associated with angiotensin II receptor
antagonists is low, and they are often used in
patients with ACE inhibitor–induced cough, cases
of cough and bronchospasm have been reported in
patients taking losartan.89,90
Bronchospasm can occur as part of moderate
or severe anaphylaxis (anaphylactic or anaphylac-
toid reactions), with dyspnea and bronchospasm
occurring in 55% to 60% of cases.159,160 Any med-
ication can cause anaphylaxis.161 A thorough dis-
cussion of drug-induced anaphylaxis is provided
in Chapter 6.
Rarely, paradoxical bronchospasm associated
with bronchodilators delivered by metered-dose
inhaler or nebulization has been reported.162-166
Although the cause is unknown, it is postulated
that propellants, preservatives, or other additives
may play a role. Bronchospasm occurs in up to
6.9% of asthmatic patients after they inhaled from
a placebo metered-dose inhaler containing only
inert ingredients.167 The incidence of bron-
chospasm decreases to 1.55% to 4% when active
drug is added.67 Inactive ingredients in metered-
dose inhalers implicated include chlorofluorocar-
bons, sorbitan trioleate, oleic acid, and soya
lecithin.67 Some reports have implicated newer
metered-dose inhalers containing hydrofluoroalka-
ne delivery systems in causing paradoxical bron-
chospasm.162,164,168 However, many of these
inhalers contain similar inert ingredients.169 Other
preservatives and additives of concern include sul-
fites, benzalkonium chloride, and ethylenedi-
aminetetraacetic acid (EDTA). Sulfites and
metabisulfite have been commonly used in wine,
food and some pharmaceutical products to prevent
microbial spoilage and oxidative discoloration.
Sulfites are no longer used in inhaled asthma
drugs. However, sulfites are still used in injectable
TisdaleC22_379-398 1/12/10 2:49 PM Page 382
382 SECTION V • Drug-Induced Pulmonary Diseases
forms of isoproterenol and epinephrine. Sulfite-
induced bronchospasm rarely occurs in patients
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,
more recent reports have indicated that approxi-
mately 5% of steroid-dependent asthmatic patients
and 1% of asthmatic patients who do not require
steroids are sensitive to sulfites.125 Benzalkonium
chloride is a bacteriostatic agent that is still found
in some multidose vials of albuterol and metapro-
terenol. EDTA is a stabilizing agent that is also
found in some nebulizer preparations. Both com-
pounds have been implicated as a potential cause
of paradoxical bronchoconstriction induced by
nebulized medications.67,68,166 Inhalation of benza-
lkonium chloride causes dose-related cumulative
bronchoconstriction.67 In amounts similar to those
present in multiple-dose vials of albuterol (300 µg),
benzalkonium chloride caused marked bron-
choconstriction in 61% of patients and enhanced
lung response to inhaled histamine 1 hour later.68
However, when patients inhaled a single dose of
albuterol with or without benzalkonium chloride,
no difference was seen in pulmonary function.68,166
EDTA is added to some pharmaceutical prepara-
tions as a chelating agent to prevent solution dis-
coloration.68 Although EDTA has been shown to
cause bronchoconstriction when large doses are
inhaled,20 clinically important bronchospasm did
not occur when concentrations similar to those
found in commercial products were used.69
A number of case reports of bronchospasm
related to tartrazine, an azo dye used in food and
drugs (FD&C Yellow No. 5), have been reported,
primarily in aspirin-sensitive patients.2,123,130 The
prevalence of tartrazine-induced bronchospasm is
unknown, but it appears to occur almost exclusive-
ly in aspirin-sensitive patients.2,130 Cross sensitivity
of tartrazine with aspirin in aspirin-sensitive
patients with asthma was initially estimated to be
between 7% and 26%, although most of these stud-
ies were unblinded and poorly controlled.2,123,130
The incidence of cross reactivity to tartrazine in
aspirin-sensitive patients is more likely to be 0% to
2.4%.67,130,131 However, because of the perceived
potential for serious reactions, and the ubiquity of
tartrazine in food and nonprescription and pre-
scription medications, the Food and Drug
Administration requires all products containing
tartrazine to list this compound as an ingredient
on the package label.2,67,130 Rarely, patients with
AIA may demonstrate similar reactions to other
dyes, such as amaranth, brilliant blue (FD&C Blue
No. 1), erythrosine, indigo carmine (indigotin,
FD&C Blue No. 2), FD&C Red No. 40, methyl blue,
new coccine, ponceau, quinolone yellow, and sun-
set yellow.2,67,123
MECHANISMS
Drug-induced asthma or bronchospasm can be
caused by several mechanisms. Most reports of
bronchospasm are isolated cases, and the mecha-
nism is unknown. Mechanisms of bronchospasm
associated with individual drugs, when known, are
listed in Table 22–2. Bronchospasm can be caused
by a direct irritation of the airway such as that
caused by N-acetylcysteine or bisulfites, IgE-medi-
ated reactions in anaphylaxis, precipitation of IgG
antibodies such as that which may occur in associ-
ation with methyldopa, mast-cell degranulation in
anaphylactoid reactions, or as a result of an intend-
ed or unintended pharmacologic effect in patients
taking aspirin or ␤-blockers.2
Aspirin-induced asthma is a variant of
non–drug-induced asthma, characterized by pro-
gressive airway inflammation and hyperreactivity,
and is associated with exacerbations of asthma and
rhinitis after the ingestion of aspirin and most
other NSAIDs.170 Airway hyperreactivity and
inflammation are progressive and independent of
aspirin exposure, which serves as a trigger for an
acute reaction. Aspirin-induced asthma is charac-
terized by an association between aspirin intoler-
ance, asthma, and nasal polyposis, referred to as
the “aspirin triad” or “Samter’s syndrome.”171,172
The mechanism of AIA is not completely under-
stood.173 It is unlikely that the response to aspirin is
caused by an IgE-dependent mechanism, because of
the cross reactivity between aspirin and NSAIDs with
dissimilar chemical structures, because NSAIDs that
do not inhibit COX do not precipitate bron-
chospasm, and because cross desensitization occurs
with other NSAIDs with dissimilar chemical struc-
tures after aspirin desensitization. Currently pro-
posed mechanisms of AIA are presented in Figure
22–1. Aspirin-induced asthma is characterized by
increased production of cysteinyl leukotrienes (Cys-
LTs; leukotrienes C4, D4, and E4) and eosinophilic
infiltration.173 Cys-LTs are metabolic products of
phospholipid metabolism. Once phospholipid is lib-
erated from the nuclear membrane, it is converted by
phospholipase A2 to arachidonic acid, which is then
biotransformed into thromboxanes and
prostaglandins by COX-1 or COX-2, or lipoxins and
5-hydroperoxyeicosatetraenoic acid (5-HETE) by 5-
lipoxygenase (5-LO) and 5-lipoxygenase activating
protein (FLAP). 5-HETE is further metabolized by 5-
LO/FLAP to leukotriene A4 (LTA4), which is then con-
verted to leukotriene B4 by LTA4 hydrolase or
TisdaleC22_379-398 1/12/10 2:49 PM Page 383

CHAPTER 22 • Asthma and Bronchospasm 383

TABLE 22–2 Mechanisms of Drug-Induced Asthma and Bronchospasm

Drug Mechanism
Acetaminophen2,170-173,176,179,180,183 Not clearly understood. Probably an imbalance of proinflammatory
and antiinflammatory eicosanoids due to altered reaction to COX
inhibition.
N-acetylcysteine2,7,8 Airway irritation
␣-Adrenergic agonists9 Unknown. May be due to ␣-receptor activation during ␤-receptor
inhibition.
Amiodarone10,11 Unknown. Potentially due to ␤-receptor inhibition.
Angiotensin-converting–enzyme inhibitors187,189 Not clearly understood. May be related to increased concentrations
of bradykinin and substance P with related alterations in prostaglandin
homeostasis.
Aspirin3,139,170-173,176,178-180,183 Not clearly understood. Probably an imbalance of proinflammatory
and antiinflammatory eicosanoids due to altered reaction to COX
inhibition.
Benzalkonium chloride2,21,22,67 Anaphylactoid mast-cell degranulation
␤-Adrenergic antagonists5,31 ␤-receptor blockade
Bromelin2 Anaphylaxis (IgE-mediated)
Carbamazepine2 Precipitation of IgG antibodies
Cromolyn2 Airway irritation
Desensitization extracts2 Anaphylaxis (IgE-mediated)
Dipyridamole147 Unknown. May be related to increased plasma adenosine concentrations.
Estrogen59 Unknown. May sensitize mast cells.
Ethanol64,66 Unknown. May be due to increased acetaldehyde concentrations.
EDTA194 Unknown. May be related calcium chelation.
Iodine radiocontrast media242-244 Probable anaphylactoid mast-cell degranulation
Meperidine2 Anaphylactoid mast-cell degranulation
Methyldopa2 Precipitation of IgG antibodies
Neostigmine2 Increased concentrations of acetylcholine leading to cholinergic stim-
ulation
Nonsteroidal antiinflammatory drugs Not clearly understood. Probably an imbalance of pro-and anti-
(COX-1 inhibitors) 3,139,170-173,176,178-180,183 inflammatory eicosanoids due to altered reaction to COX inhibition.
Pancuronium bromide2 Anaphylactoid mast-cell degranulation
Propafenone109 Unknown. Probably due to ␤-blockade.
Psyllium2,117 Anaphylaxis (IgE-mediated)
Sulfites2,124 Three proposed mechanisms: (1) anaphylaxis; (2) sulfur dioxide–
induced cholinergic reflex, and (3) decreased sulfite oxidase
concentrations.
Tobramycin132-134 Unknown. Potentially due to direct airway irritation or anaphylaxis.
COX = cyclooxygenase; EDTA = ethylenediaminetetraacetic acid.

leukotriene C4 (LTC4) by LTC4 synthase. LTC4 is con-
verted to leukotriene D4 (LTD4) by ␥-glutamyl
transpeptidase, which is then metabolized by dipep-
tidase to leukotriene E4 (LTE4).173,174 Cys-LTs are
thought to be the primary mediators of AIA, as
biosynthesis of Cys-LTs appears to be up regulated in
AIA.175 Cys-LTs are potent inflammatory mediators
causing eosinophil chemotaxis, microvascular per-
meability, mucous-gland secretion, and bronchocon-
striction.176 Compared with eosinophils from aspirin
tolerant asthmatics, circulating blood eosinophils
from patients with AIA carry larger amounts of LTC4
TisdaleC22_379-398 1/12/10 2:49 PM Page 384

384 SECTION V • Drug-Induced Pulmonary Diseases

Phospholipid

Phospholipase A2

NSAID/ASA 15-LO 5-LO

Arachidonic Acid 15-HPETE 15-epoxytetraene
Acetylated COX-2
COX-1, COX-2 5-LO/FLAP
Thromboxane
Synthase 5-HPETE 15-EpiLXA4
TXA2 PGG2
LXA4
COX-1, COX-2 5-LO/FLAP
PGI PGE 5-HETE
5-LO/FLAP
Synthase PGH2 Synthase

PGD PGF LTA

Synthase Synthase PGE2
PGI2
LTC4 Synthase LTA4 Hydrolase
PGF2

LTC4 LTB4
PGD2
␥-Glutamyl transpetidase

LTD4
Pro-Inflammatory Anti-Inflammatory
Dipeptidase
LTC4 PGD2 PGE2
LTD4 PGF2 PGI2
LTE4 TXA2 LXA4 LTE4

LTB4

FIGURE 22–1 Mechanisms of Aspirin-Induced Asthma.

Aspirin/NSAID inhibition of cyclooxygenase (COX-1, COX-2) pathways forces the metabolism of arachi-
donic acid through the lipoxygenase pathway. Decreased prostaglandin E2 production and increased
leukotriene synthase activity results in increased production of the proinflammatory cysteinyl
leukotrienes. Production of lipoxin and lipoxin epimers also appears to be decreased. ASA = acetylsalicylic
acid (aspirin); COX = cyclooxygenase; 15-EpiLXA4 = 15-epilipoxin A4; HETE = hydroxyeicosatetraenoic acid;
HPETE = hydroperoxyeicosatetraenoic acid; LT = leukotriene; LXA4 = lipoxin A4; LO = lipoxygenase; FLAP =
5-lipoxygenase activating protein; NSAID = nonsteroidal antiinflammatory drug; PG = prostaglandin; TXA2
= thromboxane A2.

synthase, the rate-limiting enzyme for Cys-LT pro-
duction. Patients with AIA have a larger quantity of
eosinophils in bronchial tissue compared to patients
with aspirin tolerant asthma, and Cys-LT concentra-
tions in bronchial lavage fluids correlate with the
degree of eosinophilic infiltration of bronchial tissue
in patients with AIA.177 In addition, LTC4 synthase is
overexpressed in the bronchial mucosa of patients
with AIA.177 A single nucleotide polymorphism,
A(–444)C (rs730012) in the promoter gene for LTC4
synthase associated with severe AIA has been identi-
fied in Polish and Japanese patients and appears to
be a marker of severe AIA. This allele is not associat-
ed with AIA as a whole, nor has it been associated
with mild disease.178
It is postulated that aspirin and NSAID inhibi-
tion of COX forces arachidonic acid through the
leukotriene metabolic pathway.179 COX exists in
several isoforms, with COX-1 expressed constitu-
tively in most tissues and COX-2 induced by
inflammatory mediators.178 COX enzymes metabo-
lize arachidonic acid to the proinflammatory medi-
ators prostaglandins D2 (PGD2) and F2␣ (PGF2␣),
and the antiinflammatory mediator prostaglandin
E2 (PGE2).180 Exposure to aspirin and most NSAIDs
results in decreased production of COX metabolic
products such as prostaglandin E2, which normally
inhibits 5-lipooxygenase (LO).176 Inhaled PGE2 pro-
tects against aspirin-induced bronchospasm and
decreases the amount of LTE4 secreted in the urine
in patients with AIA.180 Plasma concentrations of
PGD2 and PGF2␣ are lower in aspirin-tolerant asth-
matic patients as compared with patients with AIA,
and concentrations of PGE2 and thromboxane B2
are decreased in patients with AIA.179,181 In patients
with AIA, lipoxin biosynthesis may be
reduced.178,182 Lipoxin A4 attenuates LTC4-induced
bronchoconstriction, and aspirin-derived lipoxins
may contribute to the antiinflammatory action of
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
acid, which is further converted by 5-LO to lipoxin
epimers.183 Altered COX-2 regulation and function
may be responsible for decreased production of
lipoxins and PGE2.183 Thus, decreased production
of PGE2 and lipoxins in conjunction with height-
ened biosynthesis of leukotrienes may precipitate
bronchoconstriction in patients with AIA.180
Therefore, AIA appears to be a complicated interac-
tion involving the imbalance of proinflammatory
and antiinflammatory eicosanoids.
␤-Blockers competitively inhibit stimulation of
␤-adrenergic receptors, resulting in unopposed
parasympathetic tone.26,139 Both ␤1- and ␤2-adrener-
gic receptors exist in the heart and the lungs, but ␤1-
receptors are found primarily in the heart, whereas
the density of ␤2-receptors is fourfold greater than
␤1-receptors in the lungs.139 In general, ␤-blockade
does not cause bronchospasm in healthy individuals.
However, in almost all asthmatic patients, nonselec-
tive ␤-receptor inhibition causes bronchospasm.184
In addition, nonselective ␤-blockade increases non-
specific bronchial hyperresponsiveness in asthmatic
patients.139 Bronchospasm induced by ␤-blockers
may also occur when the drug is administered via the
ocular route. ␤-Blockers administered topically into
the eye drain into the nasolacrimal duct and are
absorbed via the nasal mucosa, bypassing first-pass
metabolism.185,186 Thus, the plasma concentrations
resulting from two drops of timolol 0.5% given via
the ocular route can approximate those that are
achieved following a 10-mg oral dose.185
Nonselective ␤-blockade substantially shifts the
dose–response curve of inhaled ␤2-adrenergic agonist
(␤2-agonists), limiting their effectiveness in reversing
bronchospasm caused by nonselective ␤-blockers.
Cardioselective ␤-blockers preferentially bind to ␤1-
adrenergic receptors, but this selectivity is attenuated
at higher doses. Bronchospasm caused by cardiose-
lective ␤-blockers may be easier to reverse with
inhaled ␤2-agonists.26,155
The mechanism of ACE-inhibitor–induced
cough has not been clearly elucidated. In addition
to converting angiotensin I to angiotensin II, ACE
is a kinase responsible for metabolism of the proin-
flammatory kinins bradykinin, substance P, and
neurokinin A.139 It has been proposed that ACE-
inhibitor–induced cough may result from the accu-
mulation of these substances in the lungs.
Bradykinin and substance P activate mast cells,
releasing proinflammatory mediators.187 In addi-
tion, bradykinin is a vasodilator and increases vas-
cular permeability. Inhaled bradykinin causes
bronchospasm. These actions may be mediated
through bradykinin-induced increases in the pro-
duction of thromboxane A2, prostacyclin I2 (PGI2)
CHAPTER 22 • Asthma and Bronchospasm 385
and PGE2, which can activate rapidly acting recep-
tors of the afferent neuronal pathway, stimulating
the cough reflex.13,188 In addition, bradykinin,
PGI2, and PGE2 can directly activate unmyelinated
sensory C fibers, which are involved in the cough
reflex.187-189 The accumulation of substance P may
also play a role in ACE-inhibitor–induced cough, as
it serves as a neurotransmitter for the afferent neu-
rons, in particular sensory C fibers, and can cause
bronchoconstriction.187,189 Also, a genetic predis-
position for ACE-inhibitor–induced cough may
exist.190 Polymorphism in the genes for ACE191 and
the bradykinin B2 receptor192,193 have been associ-
ated with ACE-inhibitor–induced cough.
Paradoxical bronchospasm after medication
inhalation may be caused by several different mech-
anisms, including turbulent airflow due to inappro-
priate inhaler use, the deep inspiratory maneuver
used for drug inhalation, IgE-mediated reactions to
product excipients (e.g., soy lecithin), bronchial irri-
tation caused by propellants (e.g., chlorofluorocar-
bons), excipients in metered-dose inhalers (e.g.,
oleic acid), and hyperosmolar or acidic nebulizer
solutions. Bronchospasm may also be caused by
preservatives (e.g., sulfites, benzalkonium chloride,
EDTA) in nebulized solutions.162,165,194 Three differ-
ent mechanisms have been proposed to explain sul-
fite-induced bronchospasm.2 First, initial reports
indicated that sulfite-related bronchospasm was
caused by an IgE-mediated reaction, and there are
reports of anaphylactic reactions in patients with
positive sulfite skin tests.125 Second, sulfite may be
converted to sulfur dioxide in an acidic or warm
environment.2,125 Sulfur dioxide may cause bron-
choconstriction by a direct effect on tracheal
bronchial receptors causing a cholinergic reflex or
augmenting mast-cell mediator release.194,195 Sulfur
dioxide concentrations of 0.1 to 6 ppm have been
reported in commercially available nebulizer solu-
tions. When exercising, sensitive patients with asth-
ma may experience bronchospasm when inhaling as
little as 0.1 ppm, and 6 ppm may cause bron-
chospasm in patients without asthma.194 Finally, a
reduction in the concentration of sulfite oxidase,
the enzyme responsible for the final oxidation of
sulfite to inactive sulfate, has been demonstrated in
sulfite-sensitive asthmatic patients.124,195
It is thought that benzalkonium chloride caus-
es bronchospasm by causing nonspecific histamine
release from mast cells due to direct surface activa-
tion and the stimulation of central and neural
pathways in the lung.21,22 The response is dose-
related over a dose range of 0.13 to 2.0 mg/mL and
increases with subsequent doses.166,194 A decrease
in FEV1 of >20% has been demonstrated in associa-
tion with benzalkonium chloride doses ranging
TisdaleC22_379-398 1/12/10 2:49 PM Page 386
386 SECTION V • Drug-Induced Pulmonary Diseases
from 124 to 159 mcg.67 These doses can easily be
exceeded when using a multidose vial containing
0.1 mg/mL of benzalkonium chloride.25 EDTA-
related bronchoconstriction may be due to calcium
chelation. However, EDTA can also potentiate
bronchial responsiveness to histamine.194
CLINICAL PRESENTATION AND
DIFFERENTIAL DIAGNOSIS
The signs and symptoms of drug-induced bron-
chospasm are nonspecific and are the same as
those experienced by patients with other causes of
bronchospasm, such as asthma and chronic
obstructive pulmonary disease (COPD) (Table
22–3). Conditions that should be considered in the
differential diagnosis of drug-induced asthma or
bronchospasm are shown in Table 22–4. Recent
drug exposure and the presence of other risk fac-
tors as listed in Table 22–5 are usually required for
the diagnosis. When in doubt, the patient should
be challenged with the agent in a controlled envi-
ronment by specialists in clinics with the ability to
treat anaphylactic reactions.
Aspirin-induced asthma is an acquired condi-
tion that may develop as adult-onset asthma or be
superimposed on existing asthma. The typical pres-
entation is of the classic “aspirin triad” of rhinitis,
nasal polyps, and aspirin intolerance. Typically,
symptoms of chronic rhinitis present in the 20s or
TABLE 22–3 Signs and Symptoms Associated
with Drug-Induced Asthma and Bronchospasm
• Drug-induced asthma and bronchospasm245
• Tachypnea
• Tachycardia
• Wheezing
• Diaphoresis
• Cyanosis
• Dyspnea
• Cough
• Shortness of breath
• Chest tightness
• Anxiety
• Agitation
• ACE-inhibitor–induced cough15
• Tickling sensation in the back of the throat
• Dry, hacking, irritating nonproductive, paroxysmal
cough
• Hoarseness
ACE = angiotensin-converting enzyme.
TABLE 22–4 Conditions to Consider in the
Differential Diagnosis of Drug-Induced Asthma
and Bronchospasm
• Drug-induced asthma and bronchospasm1
• Underlying chronic asthma
• Underlying chronic obstructive pulmonary disease
• Allergic rhinitis and sinusitis
• Upper-respiratory-tract infection
• Foreign body in the trachea or bronchus
• Vocal-cord dysfunction
• Vascular rings or laryngeal webs
• Laryngotracheomalacia, tracheal stenosis, bron-
chostenosis
• Laryngeal edema
• Viral bronchitis or obliterative bronchiolitis
• Cystic fibrosis
• Bronchopulmonary dysplasia
• Aspiration
• Gastroesophageal reflux
• Heart failure
• Pulmonary embolism
• Tumor causing mechanical obstruction
• Acute bronchitis
• Pulmonary infiltration with eosinophilia
• Cough due to drugs
• ACE-inhibitor–induced cough189
• Upper-respiratory-tract infection
• Allergic rhinitis and sinusitis
• Asthma
• Chronic obstructive airway disease
• Gastroesophageal reflux
• Laryngitis
• Heart failure
• Mitral stenosis
• Pneumonia
• Pulmonary emboli
• Acute bronchitis
• Smoker’s cough
• Tuberculosis
• Lung carcinoma
30s and may follow a viral infection.196 Rhinitis
usually worsens, becomes refractory to treatment,
and progresses to chronic hyperplastic eosinophilic
sinusitis with nasal polyposis. Asthma may develop
3 months to 5 years after the development of rhini-
tis with polyposis.102 In most cases of AIA, patients
are not clinically distinguishable from aspirin-tol-
erant patients with asthma. However, chronic asth-
ma appears to be progressive, often requiring
therapy with systemic corticosteroids for symptom
control.172 Patients may have an acute asthma
attack with symptoms of rhinorrhea and conjunc-
TisdaleC22_379-398 1/12/10 2:49 PM Page 387
TABLE 22–5 Risk Factors for Drug-Induced
Asthma and Bronchospasm
• Aspirin-induced asthma102,170,172,196
• Asthma
• Nasal polyposis
• Age (20s or 30s)
• Female sex
• ß-Blockers3,139
• Preexisting airway hyperreactivity
• ACE-inhibitor–induced cough209, 214-219
• Female sex
• African-American or Asian race
• Elderly
• Heart failure
ACE = Angiotensin-converting enzyme
tival injection with minutes to 3 hours of ingestion
of aspirin or NSAIDs.2,170 Some patients experience
flushing of the head and neck, and occasionally
urticaria, periorbital edema, and abdominal pain
may develop.170 Often, reactions are severe and can
be life-threatening.
Diagnosis of AIA begins with a detailed medical
history. However, the history may not be complete
because the patient may have taken aspirin or
NSAIDs successfully in the past and may not be
aware of their reaction. AIA should be suspected
when there is a temporal relation of symptoms to
ingestion of aspirin or NSAIDs, persistent and
intractable rhinitis, particularly with negative aller-
gy skin tests, nasal polyposis and pansinusitis, and
the occurrence of frequent and severe asthma
attacks without apparent cause requiring hospital-
ization and intensive care.170,196 No in vitro test is
available for the diagnosis of AIA, and the defini-
tive diagnosis is made using aspirin provocation
tests,5 during which aspirin may be administered
by the oral, inhaled, nasal, or intravenous
route180,196 (only the oral route is available in the
United States). Patients should be challenged when
asthma is in remission with an FEV1 >70% of the
predicted value and >1,200 mL, and the provoca-
tion test should be carried out by specialists in clin-
ics with the ability to treat anaphylactic
reactions.139,180,196,197 Theophylline, oral ␤2-ago-
nists, and tiotropium should be discontinued 24 to
48 hours prior to testing, long-acting inhaled ␤2-
agonists should be discontinued 24 to 48 hours
prior to testing, and short-acting inhaled ␤2-ago-
nists should be withheld for 6 to 8 hours prior to
testing.197,198 In addition, ipratropium and cro-
molyn sodium should be discontinued 8 hours
CHAPTER 22 • Asthma and Bronchospasm 387
prior to testing and nedocromil therapy should be
withheld for 24 hours prior to testing.197 Therapy
with leukotriene-blocking agents should be discon-
tinued at least 1 week prior to the procedure.197
Previous maintenance treatment with an inhaled
corticosteroid may result in a false negative test.
During an oral provocation test, the patient
receives placebo capsules the day before the chal-
lenge to allow for estimation of bronchial stabili-
ty, and if the FEV1 varies by >15%, the test should
not be conducted.197,199 On day 2, increasing doses
of aspirin are administered until a decrease in FEV1
≥20% is documented, significant extrabronchial
symptoms occur, or a cumulative dose of 500 mg
is given.197 Pulmonary-function tests are per-
formed every 30 minutes, and the patient is mon-
itored for bronchospasm, chest tightness,
wheezing, rhinorrhea, nasal congestion, and con-
junctival injection. A positive reaction is the inter-
ruption of the test because of a decrease in FEV1 of
≥20% or because of significant extrabronchial
symptoms.199,200 In most patients, a cumulative
aspirin dose of 30 to 150 mg evokes a positive
reaction. A nasal provocation test involves the
administration of an 8-mg dose of lysine-aspirin
into each nostril (total dose, 16 mg) with rhino-
manometry performed every 10 minutes for 2 to 3
hours.197 A positive test is defined as a decrease in
nasal flow in at least one nostril of >40% as com-
pared with baseline that is sustained for at least
two rhinomanometry measurements and is
accompanied by clinical symptoms persisting for
30 minutes or more.200,201 During oral inhaled
provocation tests, an inhalation of normal saline
is administered, and if FEV1 does not decrease by
>10%, increasing oral inhaled doses of lysine-
aspirin are given every 30 minutes to a maximum
cumulative dose of 182 mg. Spirometry is per-
formed at 10, 20, and 30 minutes after each dose.
A decrease in FEV1 of >20% from saline baseline or
the occurrence of substantial extrabronchial
symptoms is considered positive for aspirin-
induced asthma. Bronchial provocation with
lysine-aspirin is as sensitive as, but less specific
than, oral provocation testing.199 Intravenous
provocation tests with antiinflammatory drugs
such as indomethacin and lysine-aspirin have also
been used.170,198
Bronchospasm due to ␤-blockade cannot be
distinguished clinically from an acute asthma
attack. Bronchospasm may occur minutes after
topical exposure to the drug,202 minutes to hours
after oral exposure,203-205or during chronic oral dos-
ing.206 Drug-induced bronchospasm should be sus-
pected in any asthmatic patient who wheezes
while taking a ␤-blocker.
TisdaleC22_379-398 1/12/10 2:49 PM Page 388
388 SECTION V • Drug-Induced Pulmonary Diseases
ACE-inhibitor–induced cough is typically char-
acterized as dry, irritating and nonproductive with
a persistent tickling sensation in the back of
the throat.14,15 The cough may present within
hours of the first dose, or it may be delayed up to
12 months after the initiation of therapy. ACE-
inhibitor–induced cough may cause hoarseness,
vomiting, and stress incontinence, and the cough
may worsen in the supine position or at
night.189,207 Although the cough may resolve with-
in a week after the discontinuation of ACE-
inhibitor therapy,189 it may linger for 1 to 3
months in some individuals.14 The differential
diagnosis of ACE-inhibitor–induced cough
includes asthma, chronic smoking, COPD, post-
nasal drip, heart failure, upper-respiratory-tract
infection, and gastroesophageal reflux.189,207,208
Diagnosis of ACE-inhibitor–induced cough
requires discontinuation of the drug and monitor-
ing of the cough. Diagnosis is confirmed by resolu-
tion of the cough within 1 to 4 weeks after
discontinuation. The cough usually recurs upon
rechallenge with the same or another ACE
inhibitor.209
Patients with paradoxical responses to inhaled
drugs demonstrate a lower-than-expected response
to the drug or worsening of their pulmonary symp-
toms. The response is usually rapid, and may occur
within minutes of inhaling the agent.210 Patients
with known severe asthma have reported severe
wheezing, chest tightness, and dyspnea after
ingesting sulfite-containing foods. The diagnosis of
sulfite sensitivity is made by taking a detailed his-
tory and may be confirmed by rechallenge.67
RISK FACTORS
Risk factors for drug-induced asthma and bron-
chospasm are listed in Table 22–5. The principal
risk factor for drug-induced bronchospasm is pre-
existing asthma. However, smoking, preexisting
airway disease, older age, and respiratory infection
may also increase the risk for drug-induced bron-
chospasm.3
Aspirin-induced asthma occurs primarily in
adults and generally does not manifest until the
20s or 30s.170 The frequency of AIA increases with
age, and the incidence is fourfold higher in
patients 40 years of age or older as compared with
those younger than 20.2 Women are affected 2 to
2.5 times more often than men.141,211,212 In a study
of 500 aspirin-intolerant asthmatic patients from
10 European countries, the prevalence of AIA was
2.3 times greater in women than in men. In
women, the onset of symptoms occurred earlier in
life, and the disease was more progressive and
severe.211 A study of 300 patients in the United
States found the prevalence to be only 1.3 times
greater in women than in men, and the severity of
the disease was similar in both sexes.213 There
appears to be no ethnic or familial distribution of
AIA, with only 6% of patients in the European
study and 1% in the U.S. study having a family his-
tory of AIA.211,213
Some patients with aspirin intolerance do not
have concomitant asthma. These patients experi-
ence urticaria and gastrointestinal effects but not
bronchospasm. In general, the more severe the
underlying, preexisting asthma, the greater the risk
of drug-induced bronchospasm.
ACE-inhibitor–induced cough occurs more
often in female patients,209,214,215 in patients of East
Asian descent,216-218 and in the elderly.217 One
study219 indicated a higher incidence of ACE-
inhibitor discontinuation because of cough in
African-Americans, but a meta-analysis218 did not
confirm these findings. Patients with chronic lung
disease such as COPD or asthma do not appear to
be at a greater risk for cough associated with ACE
inhibitors.13 Patients with heart failure have a
higher incidence of cough, but it is unclear
whether the cough is related to ACE inhibitors or
diminished left ventricular function.156
MORBIDITY AND MORTALITY
Any drug reaction that causes acute bronchospasm
or worsens asthma has the potential to negatively
impact patient morbidity and mortality. Patients
with AIA tend to have more severe asthma. In
these patients, aspirin therapy may be associated
with aggressive airway remodeling and, in some,
decreased diffusion capacity. A study evaluating
factors associated with the development of severe
asthma found that >30% of patients with severe
asthma experienced aspirin intolerance, and
aspirin was a significant risk factor for the develop-
ment of severe asthma (odds ratio 5.44; 95% confi-
dence interval [CI], 2.47–8.41)].220 Another study
evaluating 3307 adult patients with severe or diffi-
cult-to-treat asthma demonstrated that the mean
percent predicted postbronchodilator FEV1 was
decreased in those who were aspirin-intolerant as
compared with those who were aspirin-tolerant,
and patients with aspirin-intolerant asthma were
more likely to be assessed by physicians as having
severe asthma.221 A greater percentage of aspirin-
intolerant subjects had a history of intubation
(20% vs. 11%), and over a 3-month period, had
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
survey of 500 patients with AIA in 10 European
countries found that inhaled and oral corticos-
teroids were required in 80% and 50% of the
patients, respectively. The average corticosteroid
dose was equivalent to prednisone 8 mg daily.211 In
a 6-year follow-up of 145 patients with asthma,
25% of those who underwent mechanical ventila-
tion had aspirin intolerance.222 NSAID exposure
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-
tality if aspirin and NSAID avoidance is ensured.224
The risk of increased morbidity and mortality
due to ␤-blocker–induced bronchospasm is
unknown, but fatalities due to bronchospasm
caused by these agents have occurred.25
Furthermore, ␤-blockers shift the dose–response
curve for ␤2-agonists to the right, making bron-
chospasm caused by ␤-blockers more difficult to
treat.139 One retrospective analysis of emergency
room visits and hospitalizations found that, as
compared with controls, patients with asthma tak-
ing cardioselective ␤-blockers were at increased risk
of emergency room visits (relative risk [RR], 1.40;
95% CI, 1.20–1.60] and combined hospital and
emergency room visits (RR, 1.34; 95% CI, 1.16-
1.55). Patients with COPD taking cardioselective ␤-
blockers also had an increased risk for emergency
room visits (RR, 1.19; 95% CI, 1.02–1.39).225
Despite these risks, the morbidity and mortality
benefits of ␤-blockers in some populations—such
as patients who have had a myocardial infarction—
are significant, and the risks and benefits of the use
of a cardioselective ␤-blocker should be evaluat-
ed.154
Although rare, ACE inhibitors can contribute
to deteriorating lung function in patients with
asthma.187 The persistent cough associated with
ACE inhibitors may cause discontinuation of ther-
TABLE 22–6 Approaches to Help Prevent Drug-Induced Asthma and Bronchospasm
Drug Condition
Aspirin Asthma
␤-Blockers Bronchospasm
ACE inhibitors Cough
ACE = angiotensin-converting enzyme.
CHAPTER 22 • Asthma and Bronchospasm 389
apy, decreased quality of life, or greater use of
health care resources.189 Patients may seek nonpre-
scription or prescription medication to relieve the
cough.
The morbidity and mortality associated with
paradoxical bronchospasm is unknown. However,
an ineffective or worsening response from a bron-
chodilator during an active asthma attack could
lead to significant morbidity.
PREVENTION
The primary strategy for preventing drug-induced
asthma or bronchospasm is avoidance of causative
agents (Table 22–6). Alternative analgesic treat-
ments for patients with AIA include acetamino-
phen, salsalate, meloxicam, and celecoxib.139,150,226
Cases of successful use of COX-2 inhibitors have
been reported.227 However, there have also been
reports of bronchospasm induced by COX-2
inhibitors.228 Eight combined studies (n=206)
demonstrated that COX-2–selective NSAIDs may
be used safely in patients with AIA.150 All NSAIDs,
including those that are COX-2 selective, should be
used with caution because of the black-box warn-
ings associated with their use. These warnings
include increased risk of serious cardiovascular
thrombotic events, including myocardial infarc-
tion and stroke, as well as increased risk of serious
gastrointestinal adverse events such as bleeding,
ulceration, and perforation of the stomach or
intestines. These adverse effects may be fatal.229
According to a systematic review, fewer than 2% of
patients are sensitive to both aspirin and acetamin-
ophen, and reactions associated with acetamino-
phen have a tendency to be less severe.17
Acetaminophen and salsalate are poor COX-1
inhibitors and reactions typically emerge after
ingestion of high doses (acetaminophen
Prevention
Avoidance of aspirin
Aspirin desensitization
Acetaminophen, salsalate, meloxicam, or celecoxib may
be used instead of aspirin.
Use cardioselective ␤-blockers at lowest possible dose.
Avoidance of ACE inhibitors
Use angiotensin receptor blocker or antihypertensive
agent from a different class.
TisdaleC22_379-398 1/12/10 2:49 PM Page 390
390 SECTION V • Drug-Induced Pulmonary Diseases
1,000–1,500 mg or salsalate 2,000 mg). Even at
these high doses, adverse effects are milder than
those experienced with older NSAIDs and
aspirin.230 Aspirin desensitization is a possible
alternative if avoidance of aspirin, aspirin-contain-
ing products, or NSAIDs in patients with AIA is not
possible. Aspirin desensitization, a process involv-
ing repeated exposure to aspirin in increasing
doses in order to eliminate adverse effects related
to its use, allows patients to take aspirin or cross-
reacting NSAIDs.139,170,230 Numerous aspirin desen-
sitization protocols exist. One protocol involves
administering small doses of aspirin every 2 to 24
hours until 400 to 650 mg is tolerated by the
patient.150 Another protocol desensitizes patients
over several days, after which a maintenance dose
of 650 mg twice daily is prescribed.231 The effects of
aspirin desensitization last indefinitely after the
desensitized state is achieved, but long-term thera-
py is necessary to maintain desensitization.150,231 In
addition to benefiting from aspirin or NSAID use,
one long-term study demonstrated improvements
in clinical courses, decreased steroid doses, and
improved global assessment scores after 6 months
of aspirin 1,300 mg daily in patients with AIA.
These improvements did not diminish during the
remaining 1 to 5 years of the study.231
Because of the benefits demonstrated with ␤-
blockers, their use may be necessary in patients
with comorbid or preexisting conditions, such as
myocardial infarction, angina pectoris, hyperten-
sion, arrhythmias, or heart failure.155 Nonselective
␤-blockers are contraindicated in patients with
asthma. However, one meta-analysis concluded
that ␤-blockers that are selective for ␤1-receptors
should not be avoided in patients who may bene-
fit from their use.28 Reports of bronchospasm with
low doses and ␤2-receptor blockade associated with
high doses of cardioselective ␤-blockers have been
documented. Therefore, the chosen cardioselective
␤-blocker should have a short half-life and be initi-
ated at the lowest possible dose, upward titration
of which should occur slowly.155 Although cardios-
elective ␤-blockers are associated with a lower inci-
dence of respiratory adverse effects than
nonselective ␤-blockers, both types should be
avoided in patients with severe asthma. Patients
requiring therapy with a topical ophthalmic ␤-
blocker to decrease intraocular pressure should also
use a cardioselective agent such as betaxolol.155
MANAGEMENT
Based on one of the proposed mechanisms of AIA,
both 5-lipoxygenase inhibitors (zileuton) and cys-
LT1 receptor antagonists (zafirlukast and mon-
telukast) should play a role in the management of
AIA.150 In one small study (n = 7), patients after an
aspirin challenge demonstrated a mean maximal
decrease in FEV1 of 4.9% with placebo compared to
a 2.9% decrease with zileuton. Only two patients in
the study experienced complete inhibition of
aspirin-induced respiratory adverse effects.232
Another small study (n = 6) evaluated the effect of
zileuton and placebo before and during an aspirin
challenge. The mean aspirin dose provoking a res-
piratory reaction ranged from 57 mg (30–100 mg)
during initial challenge and increased to 122 mg
(45–325 mg) in patients taking zileuton 600 mg
four times daily. No participants were able to toler-
ate typical aspirin doses, and the authors conclud-
ed that the dose of zileuton was inadequate in
preventing aspirin-induced respiratory reac-
tions.233 A study of similar design (n = 8) demon-
strated much different results with zileuton,
showing decreased LTE4 excretion and a FEV1
decrease of 18.6% with placebo as compared with
4.4% after zileuton.234 Differences between the
studies may be due to differences in zileuton doses.
One study used escalating doses of zileuton, where-
as the other used a previously determined thresh-
old dose. Differences between the studies may also
be related to differences in disease severity of the
patients studied.235 Montelukast, a leukotriene-
receptor antagonist, has also been studied in
patients with AIA. In a small study of the effects of
montelukast in which patients with AIA took esca-
lating doses of aspirin, 9 of 10 patients experienced
respiratory effects and only 1 patient was protected
while taking therapeutic doses of aspirin.231
Although leukotriene modifiers may play a role in
AIA, insufficient evidence exists to determine the
exact role. Patients taking a 5-lipoxygenase
inhibitor or a Cys-LT1 receptor antagonist should
continue to exercise caution with aspirin, NSAIDs,
and other cross-reacting agents, because bron-
chospasm may occur.150
Older studies have demonstrated the effective-
ness of the inhaled anticholinergic bronchodila-
tors ipratropium and oxatropium in patients with
␤-blocker–induced bronchoconstriction. Ipratro-
pium is the preferred treatment for ␤-blocker–
induced bronchospasm (Table 22–7).1 Other med-
ications that have been documented to reverse ␤-
blocker–induced bronchospasm include ␤2-
agonists, atropine, aminophylline, isoproterenol,
steroids, halothane, and glucagon.155
Once ACE inhibitor-induced cough is suspect-
ed, the agent should be discontinued to determine
whether the cough is drug-induced.189 The cough
usually resolves within 7 days, but may take as
TisdaleC22_379-398 1/12/10 2:49 PM Page 391
TABLE 22–7 Management of Drug-Induced
Bronchospasm or Cough
Drug-Induced Management
Bronchospasm
or Cough
␤-Blocker–induced Ipratropium 17 mcg/
bronchospasm1 inhalation
2 to 3 puffs every 6 hr1
ACE-inhibitor–induced Cromolyn 800 mcg/
cough246 inhalation
2 puff four times daily1
ACE = angiotensin-converting enzyme.
long as 2 to 4 weeks, and, in some individuals, up
to 3 months.14,189 Substituting one ACE inhibitor
with another generally does not resolve the prob-
lem, as all ACE inhibitors may cause cough and
cross reactivity has been demonstrated.156,209,236
Alternatives to ACE-inhibitor therapy include
angiotensin-receptor blockers (ARBs) or antihyper-
tensive agents from a different class. ARBs exert
benefits similar to those of ACE inhibitors in
patients with hypertension or heart failure, but
these drugs do not directly inhibit ACE activity or
break down bradykinin. Randomized, controlled
studies of ARBs have demonstrated a lower inci-
dence of cough in patients with a history of ACE-
inhibitor–induced cough.237,238 Drug therapy,
including cromolyn (Table 22–7), baclofen, theo-
phylline, and NSAIDs has been reported to have
beneficial effects on ACE-inhibitor–induced cough.
However, the evidence supporting the use of these
therapies is derived from small studies or case
reports.14,189 Inhaled cromolyn, a mast-cell stabiliz-
er, is considered the most widely studied drug for
treating ACE-inhibitor–induced cough and is con-
sidered the drug of choice (Table 22–7).189 One
study investigating the effects of inhaled cromolyn
in 10 patients with ACE-inhibitor–induced cough
reported a 50% decrease in self-reported cough
score as compared with placebo.239
INFORMATION FOR PATIENTS
Patients with AIA should be instructed to avoid
potent COX-1 inhibitors such as aspirin, ibupro-
fen, ketoprofen, and others. Weak peripheral
inhibitors of COX-1 and COX-2 (e.g., acetamino-
phen, salsalate) may be used, but patients should
be informed that there is a chance of exacerbation
of asthma with these agents and to immediately
CHAPTER 22 • Asthma and Bronchospasm 391
discontinue therapy if this is suspected.139,150,240,241
Aspirin or NSAID allergy must be documented in
all medical records, including at the patient’s phar-
macy. Patients should be instructed to consult their
pharmacist in order to select nonprescription prod-
ucts that will not cross react with aspirin. Because
cross reactivity is dose-related for some medica-
tions, patients should be advised to take only doses
recommended by a health care provider.
Patients with a respiratory condition such as
asthma or COPD should inform providers of their
condition. If a patient is prescribed a ␤-blocker, he
or she should be instructed not to take more than
the prescribed dose. It is necessary for patients tak-
ing ␤-blockers to inform health care providers
about their use and be warned that they can exac-
erbate respiratory conditions.
If patients experience cough due to ACE
inhibitors, they should be instructed to contact
their health care provider and not to treat the
cough with nonprescription products.
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2005;115;S483-S523.
241. Levy S, Volans G. The use of analgesics in patients with
asthma. Drug Saf. 2001;24:829-841.
242. Gueant-Rodriguez R-M, Ramano A, Barbaud A, et al.
Hypersensitivity reactions to iodinated contrast media.
Curr Pharm Design. 2006;12:3359-3372.
243. Meth MJ, Maibach HI. Current understanding of contrast
media reactions and implications for clinical
management. Drug Saf. 2006;29:133-141.
244. Hash RB. Intravascular radiographic contrast media:
issues for family physicians. J Am Board Fam Pract.
1999;12:32-42.
245. Leader WG. Asthma. In: Chisholm-Burns MA, Wells BG,
Schwinghammer TL, et al., eds. Pharmacotherapy:
Principles and Practice. New York, McGraw Hill, Inc;
2006:209-230.
246. Allen TL, Gora-Harper ML. Cromolyn sodium for ACE
inhibitor-induced cough. Ann Pharmacother.
1997;31(6):773-775.
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TisdaleC23_399-427 1/20/10 11:24 PM Page 399

SECTION VI

DRUG-INDUCED
CARDIOVASCULAR DISEASES

CHAPTER 23 Myocardial Ischemia and Acute Coronary Syndromes

CHAPTER 24 Heart Failure

CHAPTER 25 Supraventricular Arrhythmias

CHAPTER 26 Ventricular Arrhythmias

CHAPTER 27 Hypertension

CHAPTER 28 Hypotension

CHAPTER 29 Valvular and Pericardial Heart Diseases

TisdaleC23_399-427 1/20/10 11:24 PM Page 400
TisdaleC23_399-427 1/20/10 11:24 PM Page 401
CHAPTER 23
Myocardial Ischemia and Acute
Coronary Syndromes
M yocardial ischemia occurs as a result of
increased myocardial demand, decreased
myocardial oxygen supply, or both, and most com-
monly occurs in patients with atherosclerotic coro-
nary artery disease. In this chapter, the specific
mechanisms by which drug therapy may cause
increased myocardial oxygen demand or decreased
supply will be discussed. Angina pectoris is a clini-
cal syndrome of chest discomfort caused by
reversible myocardial ischemia that produces dis-
turbances in myocardial function but no myocar-
dial necrosis. Myocardial ischemia can also occur
without any outward symptoms of angina and is
typically referred to as “silent myocardial
ischemia.” Acute myocardial infarction is a clinical
syndrome associated with the development of a
prolonged occlusion of a coronary artery leading to
decreased oxygen supply, myocardial ischemia, and
irreversible damage to myocardial tissue.
Myocardial infarction in patients with coronary
artery disease is usually associated with a coronary
artery thrombosis superimposed on a damaged ath-
erosclerotic plaque. The specific mechanisms by
which drugs may facilitate or cause myocardial
infarctions will be discussed. An acute coronary
syndrome is defined as one of three syndromes: ST-
segment elevation myocardial infarction, non–ST-
segment elevation myocardial infarction, and
unstable angina.1,2 For the purposes of this chapter,
it is difficult to separate the acute coronary syn-
dromes, because, for the most part, the individual
case data in the literature do not provide sufficient
detail to allow this. Therefore, in most cases, the
specific acute coronary syndromes will not be dis-
cussed separately. Furthermore, based on the avail-
able literature, it is difficult to distinguish drugs
based on whether they cause ischemia or infarction.
Kevin M. Sowinski
CAUSATIVE AGENTS
Drugs that have been reported to cause angina
pectoris, myocardial ischemia, an acute coronary
syndrome, or all three are listed in Table 23–1.3-410
Drug-induced myocardial ischemia or acute coro-
nary syndrome can occur in association with
short-term drug administration or during long-
term therapy. Because of the temporal nature of
case reporting of these drug-induced diseases, in
most cases the chapter will review drugs that
cause myocardial ischemia or infarction acutely,
although the tables do not differentiate between
these causation patterns. In some cases, larger and
longer-term clinical trials or epidemiologic evi-
dence support a relationship between the devel-
opment of myocardial ischemia or infarction and
long-term administration of a drug. Chronic use
of drugs, such as cocaine, oral contraceptives,
nicotine, rosiglitazone, selective cyclooxygenase-
2 (COX-2) inhibitors and nonselective nons-
teroidal antiinflammatory drugs (NSAIDs) and
others may facilitate or increase the risk of ather-
osclerotic coronary artery disease and ensuing
myocardial ischemia and infarction. This phe-
nomenon may be thought of as analogous to
other factors that increase the risk of coronary
artery disease (such as diabetes mellitus, obesity,
and others). This subject area has received consid-
erable attention from the media, patients, and
regulatory agencies because of studies suggesting
an increased risk of cardiovascular disease associ-
ated with selective COX-2 inhibitors and nonse-
lective NSAIDs.7,18-22,27,411 Finally, drugs may cause
myocardial ischemia or acute coronary syndrome
if abruptly discontinued.
401
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402 SECTION VI • Drug-Induced Cardiovascular Diseases

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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CHAPTER 23 • Myocardial Ischemia and Acute Coronary Syndromes 403

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)
TisdaleC23_399-427 1/20/10 11:24 PM Page 404
404 SECTION VI • Drug-Induced Cardiovascular Diseases
TABLE 23–1 Agents Implicated in Drug-Induced Myocardial Ischemia and/or Acute Coronary Syndromes (Continued)
Drug
Iloprost
Immune modulators319-323
Ioversol
Nicotine
Ondansetron
Rosiglitazone
Sildenafil
Sympathomimetics17, 104, 283, 295, 324-349
Terfenadine
Theophylline
Tegaserod
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-
dial ischemia or infarction were provided in a paper
summarizing 20 years of reports (1975–1994) to a
Netherlands national center for adverse drug
reporting.17 During this period, 19,141 adverse drug
reactions were reported, of which 220 described
likely cases of drug-induced chest pain or myocar-
dial infarction. The article describes 183 cases for
which sufficient data were provided to evaluate the
cases and adjudicate the findings. Data obtained
from spontaneous reporting systems such as that in
this article or from reports to the Food and Drug
Administration (FDA) must be interpreted cautious-
ly, as they typically suffer from both underreporting
and selective reporting. Of particular note in this
article is the absence of several classes of drugs or
drug classes that are well known to cause myocar-
dial ischemia or infarction, specifically cocaine and
cytotoxic drugs. In addition, the underlying dis-
eases of those patients for which adverse drug reac-
tions were reported are not described.
EPIDEMIOLOGY
The incidence of drug-induced ischemia and acute
coronary syndromes in the general population is
unknown and, with the exception of a small num-
ber of drugs, nearly impossible to determine.
Nonetheless, drug-induced acute coronary syn-
drome and ischemia are not trivial. Both chest pain
and myocardial infarction were among the most
common adverse events with serious outcomes
reported to the FDA’s voluntary reporting system
between 1969 and 2002.412 While these reporting
systems are flawed for the reasons discussed previ-
Incidence Level of Evidence
NK C
NK C
NK C
NK C
NK C
Odds ratio 1.43 B
NK C
NK C
NK C
NK C
NK C
ously, they nevertheless suggest that drug-induced
ischemia and acute coronary syndromes are a com-
mon and important problem. Because of the
nature of these reports, the underlying conditions
of the patients cannot be determined.
With the exception of certain groups (e.g.,
cocaine users, patients with chronic coronary artery
disease, or those at high risk for coronary events)
the incidence of these drug-induced diseases is like-
ly to be low. However, several drugs/drug classes,
including cocaine, oral contraceptives/hormone-
replacement therapy, cytotoxic agents, ergot alka-
loids, and triptans may cause myocardial ischemia
or acute coronary syndromes in individuals who do
not have clinically evident cardiovascular dis-
ease.290 To put into perspective the difficulty of
determining the incidence of drug-induced
ischemia and acute coronary syndromes, it is help-
ful to review the epidemiology of myocardial
ischemia and acute coronary syndromes associated
with cocaine and oral contraceptives, the drugs for
which the most data are available. The risk of
cocaine-induced myocardial infarction is estimated
to be 24 to 31 times the baseline risk during the first
hour after cocaine exposure.286,287,291 The reported
lifetime risk of acute myocardial infarction in
chronic cocaine users is 6 to 7 times greater than
that in nonusers. In view of the fact that 25 million
Americans have used cocaine at least once in their
lifetime, cocaine-induced myocardial ischemia/
infarction has the potential to be a major public
health problem. In the year 2000, 175,000 emer-
gency room visits were cocaine-related, 40% of
which included patients with chest discomfort.
Cocaine or cocaine metabolites are detectable in the
urine of 14% to 25% and 7% of patients presenting
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CHAPTER 23 • Myocardial Ischemia and Acute Coronary Syndromes
to the emergency room with nontraumatic chest
pain in urban and suburban hospitals, respectively.
Although these data do not provide the actual inci-
dence of chest pain or acute coronary syndrome
associated with cocaine, they do provide some
alarming information regarding the epidemiology
and potential impact of this drug-induced dis-
ease.286,287,290,291 The actual incidence of cocaine-
induced myocardial infarction among patients who
present to the emergency department with cocaine-
induced chest pain is highly variable, but it is
thought to range between 0.7% and 6.0 %.413-416
Soon after oral contraceptives became available
in the early 1960s, the first case report of myocardial
infarction associated with these drugs was pub-
lished.417 Since then, controversy regarding the
potential for myocardial ischemia/infarction
induced by oral contraceptives and other female hor-
mones has lingered. Because exogenous female hor-
mones (i.e., oral contraceptives and
hormone-replacement therapy) are used by millions
of women worldwide, the importance of the poten-
tial for myocardial ischemia or acute coronary syn-
dromes associated with these agents is clear. Usually,
oral contraceptives are taken by otherwise healthy
young women with a low background risk of coro-
nary artery disease and resulting myocardial
ischemia or acute coronary syndromes. Numerous
studies have been conducted to determine the risk of
an acute coronary syndrome or other coronary event
associated with oral contraceptive drugs, but the risk
remains poorly defined. Depending on the study
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
risk to a fivefold higher risk.417 The hazard increases
in women who smoke, have hypertension, or are
over the age of 35 years.417 The effect of hormone-
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
of hormone-replacement therapy for reducing the
risk of primary or secondary coronary events.418,419 In
January 2003, the FDA approved new labeling for all
estrogen and estrogen/progesterone products, high-
lighting “the increased risk for heart disease, heart
attacks” and that “these products are not approved
for heart disease prevention.”420
Selective COX-2 inhibitors were introduced into
the U.S. market in the late 1990s, with the potential
to revolutionize the manner in which pain and
inflammatory disorders were managed. However,
several randomized active and placebo-controlled
trials, observational studies, and meta-analyses have
raised concerns that the selective COX-2 inhibitors
and nonselective NSAIDs may increase the risk of
405
myocardial infarction.7,18,411 Prospective well-
designed studies comparing the effects of COX-2
inhibitors to those of other NSAIDs are not avail-
able, although until recently it was thought that
nonselective NSAIDs did not increase cardiovascular
risk. While these trials have limitations, it seems
clear that there is an increase in risk associated with
both selective and nonselective NSAIDs and that the
risk is variable within each group of agents. The data
suggest that the cardiovascular risk is highest with
rofecoxib, followed by celecoxib and diclofenac, fol-
lowed by naproxen and ibuprofen. Whether this is
due to decreasing COX-2 selectivity from rofecoxib
to ibuprofen is a topic of considerable debate.22
Two of the selective COX-2 inhibitors, rofecoxib
and valdecoxib, were withdrawn voluntarily from
the worldwide market in September 2004 and April
2005, respectively. “Black box” warnings for the
remaining selective COX-2 inhibitor, celecoxib, and
all other NSAIDs except aspirin were added to pack-
age inserts in 2006, stating: “NSAIDs may cause an
increased risk of serious cardiovascular thrombotic
events, myocardial infarction, and stroke, which can
be fatal. This risk may increase with duration of use.
Patients with cardiovascular disease or risk factors
for cardiovascular disease may be at greater risk.” At
the very least, these new warnings should cause
health care professionals to question the routine use
of these agents in patients with cardiovascular dis-
ease. The concerns have led to a scientific statement
from the American Heart Association with recom-
mendations for the clinical use of these agents.421
MECHANISMS
Mechanisms of drug-induced myocardial ischemia
and/or acute coronary syndromes are listed in
Table 23–2.
Drug-Induced Myocardial Ischemia
Myocardial ischemia results from an imbalance in
coronary blood flow, myocardial oxygen supply, and
the metabolic needs of the myocardium (myocardial
oxygen demand). Myocardial ischemia occurs when
myocardial oxygen demand exceeds myocardial oxy-
gen supply. Figure 23–1 illustrates the determinants
of myocardial oxygen supply and demand and pro-
vides potential mechanisms by which drugs may
cause myocardial ischemia. The three major determi-
nants of myocardial oxygen demand are heart rate,
contractility, and left ventricular systolic wall ten-
sion.422 Heart rate is the easiest of these factors to
assess clinically; an increase in heart rate leads to
increased myocardial oxygen demand. Myocardial
contractility is reflected by the rate of rise in the
TisdaleC23_399-427 1/20/10 11:24 PM Page 406
406 SECTION VI • Drug-Induced Cardiovascular Diseases
TABLE 23–2 Mechanisms of Drug-Induced Myocardial Ischemia and Acute Coronary Syndrome
Drug-Induced Disease and Mechanism
Drug-Induced Myocardial Ischemia
• Increased Myocardial Oxygen Demand
• Increased heart rate
• Increased myocardial contractility
• Increased left ventricular systolic wall tension
• Increased preload
• Increased afterload
• Deceased Myocardial Oxygen Supply (temporary,
nontotal occlusion)
• Increased coronary vascular resistance (vasospasm,
thrombosis)
• Decreased coronary diastolic perfusion pressure
• Decreased oxygen-carrying capacity
Drug-Induced Acute Coronary Syndromes
• Acute coronary syndrome associated with acute
drug therapy
• Coronary artery thrombosis, superimposed on a
damaged atherosclerotic plaque
• Coronary artery vasospasm (with or without a
superimposed coronary artery thrombosis)
• Acute coronary syndrome associated with chronic
drug therapy
• Increased cardiovascular risk
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-
traction and is influenced by a number of variables,
including the autonomic nervous system, heart rate,
blood calcium concentration, and body temperature.
The third determinant, systolic wall tension, is
directly related to ventricular systolic pressure and
ventricular wall radius and is inversely related to wall
thickness. Preload and afterload are important deter-
minants of these components. Reducing systolic
blood pressure reduces afterload, which ultimately
decreases myocardial oxygen demand. A drug may
cause myocardial ischemia simply by modifying any
one of these factors. For example, drugs that increase
heart rate, either directly (e.g., cocaine, ␤-adrenergic
receptor agonists, abrupt discontinuation of ␤-block-
Examplesa
Directly: Cocaine, adrenergic adrenergic ␤-agonists,
sympathomimetics, withdrawal of ␤-antagonists
Indirectly: potent vasodilators (Nifedipine,
minoxidil, hydralazine)
Directly: Cocaine, adrenergic ␤-agonists, sympathomimetics,
withdrawal of ␤-antagonists
Indirectly: potent vasodilators (Nifedipine, minoxidil,
hydralazine)
Cocaine, phenylephrine
Cocaine, anti-migraine agents (ergot alkaloids, triptans)
Enalapril, nifedipine, minoxidil, hydralazine, nitroprusside,
adenosine, dipyridamole
Cocaine, oral contraceptives, estrogens, COX-2 inhibitors,
NSAIDs
Cocaine, anti-migraine agents (ergot alkaloids, triptans)
Cocaine, estrogens, COX-2 inhibitors, NSAIDs, HIV
agents/protease inhibitors, oral contraceptives,
rosiglitazone
ers) or indirectly by reflex mechanisms (e.g., potent
vasodilators such as nifedipine, minoxidil, and
hydralazine) may induce myocardial ischemia.
Similarly, drugs that increase systolic blood pressure
(e.g., cocaine, phenylephrine) may also induce
myocardial ischemia. Clinicians should be alert to
drugs that modify any of these factors, as they may
cause ischemia.
Myocardial oxygen supply is determined by coro-
nary blood flow and the oxygen-carrying capacity of
blood.422 The most important of these determinants
clinically is coronary blood flow. Normally, the arteri-
olar resistance vessels are the most important regula-
tors of coronary blood flow, whereas large epicardial
vessels are low-resistance vessels. Complex factors
TisdaleC23_399-427 1/20/10 11:24 PM Page 407
Humoral Factors
Neural Factors Metabolic Control
Autoregulation
Vascular Resistance
Coronary Blood Flow
Myocardial
Oxygen Supply
Oxygen carrying capacity
FIGURE 23–1 Factors affecting myocardial oxygen supply and demand. Adapted from Ardehali and Ports.422
that determine coronary blood flow include duration
of diastole and coronary vascular resistance.
Coronary vascular resistance is determined by meta-
bolic control, autoregulation, extravascular compres-
sive forces, and humoral and neural factors. Drug
therapy may reduce myocardial oxygen supply by
influencing any of these determinants. Most com-
monly, when considering drug-induced reductions in
myocardial oxygen supply, agents that cause throm-
bosis or vasospasm of large coronary epicardial vessels
are thought of as typical culprits. However, drugs that
cause microvascular changes should also be consid-
ered. Unfortunately, these changes are more difficult
to assess clinically. Finally, oxygen-carrying capacity
can be affected by conditions such as anemia.
There are several examples of drugs that may pre-
cipitate ischemia by decreasing myocardial oxygen
supply. Cocaine causes ischemia not only via increas-
es in heart rate and blood pressure, but also via coro-
nary vasoconstriction, which is mediated by
cocaine-induced blockade of norepinephrine reup-
take, leading to increased plasma norepinephrine
concentrations and enhanced ␣1-adrenoceptor-medi-
ated vasoconstriction.286,290,294,296 Some data also sug-
gest that cocaine increases plasma concentrations of
endothelin-1, a powerful vasoconstrictor that con-
tributes to coronary vasospasm.290 Each of these
mechanisms contributes to cocaine-induced coro-
nary artery vasospasm. The ergot alkaloids and asso-
ciated derivatives are widely known to cause coronary
vasoconstriction. The mechanism of ergot-induced
coronary artery vasoconstriction is simply an exten-
sion of the drug’s therapeutic effects, which is cerebral
vasoconstriction. Another group of drugs used in the
CHAPTER 23 • Myocardial Ischemia and Acute Coronary Syndromes 407
Compressive Forces
Diastolic Phase Systolic Left Ventricular
Duration Pressure Volume
Wall Tension
Myocardial
Contractility
Oxygen Demand
Heart Rate
treatment migraines, triptans, are contraindicated in
patients with coronary artery disease. Like ergot alka-
loids, the purported mechanism of increased
ischemia is coronary artery vasoconstriction or
vasospasm or both, in the case of triptans, mediated
by agonism of 5-hydroxytriptophan (5-HT) receptors.
One often-unrecognized mechanism by which a
drug may reduce myocardial oxygen supply is reduc-
tion of blood pressure too aggressively, leading to
reductions in diastolic perfusion pressure and coro-
nary blood flow. Patients with existing coronary ath-
erosclerosis are particularly at risk for drug-induced
ischemia via this mechanism. Any drug that reduces
blood pressure, especially potent vasodilators, may
cause ischemia or an acute coronary syndrome via
this mechanism. An observational study suggested
that the short-acting dihydropyridine calcium-chan-
nel blocker nifedipine may increase the risk of
ischemic events and myocardial infarction in
patients with coronary artery disease, likely through
this mechanism.159,177 This study was highly contro-
versial and led to debate for many years. While the
debate was contentious in many ways, there was
general agreement that short-acting dihydropyridine
calcium-channel blocking agents such as the imme-
diate-release formulations of nifedipine or nicardip-
ine should be avoided in patients with coronary
artery disease.160 Whether or not these restrictions
should be applied to all calcium-channel blockers is
still being debated. Another drug thought to increase
the risk of acute myocardial infarction by reducing
coronary perfusion pressure is enalapril. In a land-
mark clinical trial, the Cooperative North
Scandinavian Enalapril Survival Study-II (CONSEN-
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408 SECTION VI • Drug-Induced Cardiovascular Diseases
TABLE 23–3 Signs and Symptoms Associated
with Drug-Induced Myocardial Ischemia
Quality of symptoms
• Sensation of pressure or heavy weight on the chest
• Burning sensation
• Feeling of tightness
• Shortness of breath with feeling of constriction
about the larynx or upper trachea
• Visceral quality (deep, heavy, squeezing, aching)
• Gradual increase in intensity followed by gradual
fading away
Location of symptoms
• Over or very near the sternum
• Anywhere between the epigastrium and pharynx
• Occasionally limited to left shoulder and left arm;
rarely limited to right arm
• Limited to lower jaw
• Lower cervical or upper thoracic spine
• Left interscapular or suprascapular area
Precipitating factors
• Relationship to exercise
• Effort that involves use of arms above the head
• Weather factors (cold, warm, humid)
• Walking against wind
• Large meal
• Emotional factors involved with exercise, fright, or
anger
• Coitus
• Drugs
Relief of pain
• Nitroglycerin relief
Radiation
• Left arm and shoulder
• Jaw
• Right arm (occasionally)
Duration of symptoms
• 0.5–30 min
SUS II), early intravenous administration of enalapri-
lat followed by oral enalapril therapy was not associ-
ated with a reduction in the incidence of
mortality.423 One postulated mechanism for this lack
of benefit was early hypotension resulting in reduced
coronary perfusion pressure. Reduction in coronary
perfusion pressures during the acute phase of a
myocardial infarction may lead to larger areas of
subendocardial tissue damage. An additional exam-
ple of this phenomenon is the concomitant use of
phosphodiesterase-5 inhibitors, such as sildenafil,
with nitrates, the combination of which may cause
marked hypotension leading to reduced myocardial
oxygen supply and consequent myocardial ischemia
or infarction.424 The combined use of these drug
classes is discouraged by the manufacturers, national
organizations and government regulators, although
clinically the combination is still used frequently.
An alternative to exercise stress testing as a
means to functionally evaluate the clinical and car-
diovascular responses is pharmacologic stress testing.
These tests provide some prognostic and diagnostic
information about the underlying coronary artery
disease. Two types of drugs are used: coronary artery
vasodilators (adenosine and dipyridamole) and
agents that increase cardiac work (dobutamine and
arbutamine). Unlike agents that increase cardiac
work, adenosine and dipyridamole do not cause
ischemia by increasing myocardial oxygen demand.
Rather, these coronary artery vasodilators may cause
myocardial ischemia by preferentially dilating nor-
mal coronary arteries versus diseased vessels. This
“steals” blood flow away from diseased segments
(frequently referred to as “coronary steal”). These
drugs are used in a controlled setting and frequently
cause myocardial ischemia, but myocardial infarc-
tion induced by these drugs is uncommon.
Drug-Induced Acute Coronary Syndromes
The mechanism by which a drug can induce an acute
coronary syndrome may be thought of in two differ-
ent, yet complementary pathways, related to the
temporal nature of the event. First, acute drug thera-
py may cause an acute coronary syndrome. Second,
drugs may increase the risk of an acute coronary syn-
drome with continued, long-term exposure, as a
result of the drug increasing the underlying degree of
cardiovascular risk. Certain drugs may increase both
the acute and chronic risk. The following discussion
addresses each of these situations.
Acute Coronary Syndrome Associated with
Short-Term Drug Therapy
Classically, the pathogenesis of an acute coronary
syndrome is an occlusion of an epicardial coronary
artery caused by a coronary artery thrombosis super-
imposed on a ruptured atherosclerotic plaque.425 Less
commonly, an acute coronary syndrome may occur
despite an absence of clinically significant coronary
atherosclerosis, and is caused by coronary artery
vasospasm with or without a superimposed coronary
artery thrombosis.425 Even though this mechanism is
thought to be less common, in one study, 31 prescrip-
tion, nonprescription, and illicit drugs and approxi-
mately 100 cases were associated with drug-induced
acute coronary syndrome caused by coronary artery
spasm in teenagers and young adults.122 The acute
causation of drug-induced acute coronary syndrome
may occur in association with either of the above-
described situations. In either case, for drug-induced
myocardial infarction to occur, coronary blood flow
must be occluded for a sufficient amount of time to
TisdaleC23_399-427 1/20/10 11:24 PM Page 409
CHAPTER 23 • Myocardial Ischemia and Acute Coronary Syndromes
result in necrosis of myocardial tissue. Thus, a drug-
induced acute coronary syndrome could result from
drug-induced coronary vasospasm (e.g., cocaine) or
drug-induced coronary artery thrombosis (e.g., estro-
gens, cocaine, COX-2 inhibitors). For example, in the-
ory, selective COX-2 inhibitors, which do not inhibit
COX-1 and therefore do not decrease plasma concen-
trations of platelet-derived thromboxane, may exert
different influences on the occurrence of cardiovascu-
lar events than other nonselective NSAIDs such as
aspirin or naproxen. Inhibition of COX-2 is believed
to suppress the endothelial production of prostacy-
clin, while leaving the production of thromboxane
A2, mediated by COX-1, relatively unaffected. This
may potentially lead to vasoconstriction, platelet
aggregation, thrombosis, and ultimately an acute
coronary syndrome.20,22
Acute Coronary Syndrome Associated
with Long-Term Drug Therapy/Increased
Cardiovascular Risk
Drugs may also increase the risk for the development
of coronary artery disease by accelerating the natural
course of pathogenesis of atherosclerosis. The follow-
ing have been identified as modifiable risk factors by
the American Heart Association: cigarette smoking,
elevated plasma low-density lipoprotein cholesterol
concentrations, reduced plasma high-density
lipoprotein cholesterol concentrations, hyperten-
sion, obesity, and diabetes.426 Thus, any drug that
alters these risk factors in a negative way has the
potential to increase the risk of a coronary event.
Examples of drugs that have been shown to acceler-
ate the development of coronary atherosclerosis
include protease inhibitors (via induction of dyslipi-
demia) and cocaine. Postmortem studies of cocaine
abusers have shown that cocaine accelerates the
development of atherosclerosis by causing structural
changes in the endothelial membrane, resulting in
increased permeability to low-density lipoproteins.
In addition, cocaine has been shown to enhance
white-cell migration and increase the expression of
adhesion molecules in the endothelium.290 Other
examples, among many others, may include oral
contraceptives, COX-2 inhibitors, and rosiglitazone.6
Drug Discontinuation
Several drugs are known to cause myocardial
ischemia or acute coronary syndromes when abrupt-
ly discontinued, in most cases in patients who have
underlying coronary artery disease (see Table 23–1).
There are several mechanisms by which this may
occur. For example, abrupt discontinuation of ␤-
blockers may lead to increased myocardial oxygen
demand secondary to ␤-adrenoceptor upregulation
and hypersensitivity to catecholamine stimulation.
409
It should be emphasized that these cases of drug-
induced ischemia or acute coronary syndrome occur
primarily in patients with a history of coronary
artery disease. Following the short-term treatment of
an acute coronary syndrome, discontinuation of
heparin and aspirin leads to an increase in adverse
cardiovascular events.14 These events seem to “clus-
ter” early (~10 hours) after discontinuation and have
been attributed to rethrombosis in coronary arteries.
Maintenance of aspirin therapy has been proposed as
a means of reducing the risk of this phenomenon.
Additional data have suggested that discontinuation
of clopidogrel may result in an increased risk of
death or recurrent acute coronary syndrome.6 In that
study, the incidence of death and recurrent myocar-
dial infarction was higher in the first 90 days follow-
ing clopidogrel discontinuation, in patients with
acute coronary syndromes who were treated both
medically and with intervention. The mean duration
of clopidogrel therapy prior to discontinuation was
approximately 300 days, and more than 80 percent
of patients had received clopidogrel for more than 3
months. The theoretical mechanism of this
increased risk is platelet activation and increased
thrombotic risk immediately upon discontinuation
of therapy. This has led to some questions about the
appropriate duration of clopidogrel therapy.6 Finally,
there is some evidence, though conflicting, that
abrupt discontinuation of statins may increase the
risk of cardiovascular events.16 Further research in
this area is required.
In summary, there are numerous ways in
which drugs may cause myocardial ischemia or
acute coronary syndromes. Cocaine is an example
of a drug that may cause this drug-induced disease
by many of these mechanisms, including increased
myocardial oxygen demand (increased heart rate,
contractility, blood pressure, and development of
left ventricular hypertrophy), decreased myocar-
dial oxygen supply (platelet aggregation and
thrombus formation, coronary artery vasoconstric-
tion), and enhanced development of coronary
artery disease (premature atherosclerosis).
CLINICAL PRESENTATION AND
DIFFERENTIAL DIAGNOSIS
Drug-Induced Myocardial Ischemia
The clinical presentation of a patient with drug-
induced ischemia is similar to that of any patient
with angina or ischemia associated with atheroscle-
rotic coronary artery disease. The most apparent dif-
ference is that drug-induced ischemia may occur in
individuals who do not have, or who are not at risk
for, coronary artery disease. For example, it is unusu-
TisdaleC23_399-427 1/20/10 11:24 PM Page 410
410 SECTION VI • Drug-Induced Cardiovascular Diseases
al for a young individual to present with symptoms
consistent with myocardial ischemia. Pharmacists
and other health care professionals must be aware of
drugs, both licit and illicit, that may precipitate
angina or an acute coronary syndrome and evaluate
the causality in appropriate patients.
Typical signs and symptoms that are associated
with angina pectoris are summarized in Table 23–3.
Briefly, angina typically presents as substernal, ret-
rosternal, or transsternal discomfort that radiates,
usually, to the neck and left arm. The discomfort is
usually characterized by a dull sensation, rather
than a sharp or stabbing pain, and patients may
describe it as a strangling or constricting sensation.
Patients often use the following descriptors to
describe the discomfort: pressure, heaviness, full-
ness, squeezing, burning, aching, gas, “vise-like,” or
anxiety. Anginal discomfort usually has a gradual
onset and lasts only a few minutes if the precipitat-
ing factor is removed. In addition, relief is usually
afforded by rest, sublingual nitroglycerin, or both.
Longer durations of angina may imply severe
ischemia, coronary vasospasm, unstable angina, or
impending or ongoing myocardial infarction.
Drug-Induced Acute Coronary Syndrome
In most situations, the clinical presentation of a
patient with drug-induced acute coronary syndrome is
similar to that of any patient with non–drug-induced
acute coronary syndrome. However, there are several
exceptions to this generalization. Like myocardial
ischemia, acute coronary syndromes are relatively
unusual in young populations (<45 years of age).
Approximately 25% of all acute myocardial infarc-
tions in individuals 18 to 45 years of age have been
associated with frequent cocaine use.296 The typical
patient who presents with cocaine-induced acute
coronary syndromes is a relatively young man who
smokes cigarettes and does not have any other obvi-
ous cardiovascular risk factors. Thus, in younger
patients without any obvious risk for acute coronary
syndromes, the use of cocaine or other drugs that are
known to be associated with drug-induced acute coro-
nary syndromes should be considered. However, clini-
cians must consider the possibility of cocaine use in
any patient who presents with an acute coronary syn-
drome. Since cocaine accelerates cardiovascular risk, it
is certainly possible that its use is associated with acute
coronary syndromes in older patients. Current recom-
mendations suggest that urine screening for cocaine
metabolites should be used only in patients who are
unable to communicate or when other sources of a
reliable patient history are unavailable.291
Like cocaine-associated acute coronary syn-
dromes, acute coronary syndromes associated with
oral contraceptives usually occur in younger
patients. The typical woman who presents with an
acute coronary syndrome secondary to oral-contra-
ceptive therapy is usually over the age of 35 years,
smokes cigarettes, and may not have any other obvi-
ous cardiovascular risk factors. This presentation
contrasts with that of the typical women presenting
with a non–drug-induced acute coronary syndrome.
Acute coronary syndromes classically present as
prolonged chest discomfort described as oppressive
pain, choking, squeezing, or burning that may radiate
to the neck, throat, jaw, shoulders, or both arms. The
discomfort associated with an acute coronary syn-
drome is generally similar in quality and location as
anginal pain, except that the duration is longer (>30
minutes), it occurs at rest, and is not relieved by sub-
lingual nitroglycerin or rest. Patients may present
with other symptoms, such as nausea, vomiting,
diaphoresis, shortness of breath, weakness, light-
headedness, or a sense of impending doom. Not all
patients present with classic symptoms; some present
with atypical signs or symptoms, are asymptomatic,
or are unable to provide a history. The physical exam-
ination is not necessarily helpful in establishing the
diagnosis of an acute coronary syndrome. However,
the findings are important as a guide to immediate
management and as a baseline for future comparison.
Signs or symptoms of left or right ventricular dysfunc-
tion may be detected. Patients may present with
bradycardia or tachycardia, low-grade fever, elevated
respiratory rate, and leukocytosis. Most of these find-
ings are nonspecific and do not confirm the diagno-
sis of an acute coronary syndrome.425 We assume that
the presentation of a drug-induced acute coronary
syndrome is similar to that of other causes of acute
coronary syndromes. For many drugs this may be
true, although data are not available, except for
cocaine. Like other acute coronary syndromes,
patients with cocaine-induced acute coronary syn-
dromes experience pressure-like chest discomfort,
anxiety, palpitations, dizziness, and nausea. Dyspnea
and diaphoresis occur in 60% and 40% of patients,
respectively. However, it has been suggested that
fewer than 50% of patients actually experience chest
pain with cocaine-associated acute coronary syn-
dromes, making the identification of cocaine-induced
acute coronary syndromes more difficult.291
The classification and diagnosis of an acute
coronary syndrome is based on three important
features: chest pain, electrocardiographic changes,
and serum biomarker (troponin) concentra-
tions.1,427 The diagnostic features of an acute
myocardial infarction are provided in Table 23–4.
The classification and diagnosis of drug-induced
acute coronary syndromes is generally performed
in the same manner as with non–drug-induced
acute coronary syndromes. Interested readers are
directed to these guidelines for more in-depth dis-
TisdaleC23_399-427 1/20/10 11:24 PM Page 411
CHAPTER 23 • Myocardial Ischemia and Acute Coronary Syndromes
TABLE 23–4 Definition of Myocardial Infarction
Based on the ESC/ACCF/AHA/WHF427 and WHO
Criteria
ESC/ACCF/AHA/WHF Definition of Myocardial
Infarction
• The term myocardial infarction should be used when
there is evidence of myocardial necrosis in a clinical
setting consistent with myocardial ischemia. Under
these conditions any one of the following criteria
meets the diagnosis for myocardial infarction:
• Detection of rise or fall, or both, of cardiac bio-
markers (preferably troponin I or T) with at least
one value above the 99th percentile of the
upper reference limit together with evidence of
myocardial ischemia with at least one of the
following:
• Symptoms of ischemia
• ECG changes indicative of new ischemia (new
ST–T changes or new left bundle-branch block):
• ST elevation: New ST elevation in two con-
tiguous leads with the following cutoff points:
ⱖ0.2 mV in men or ⱖ0.15 mV in women in
leads V2–V3, ⱖ0.1 mV in other leads, or both
• ST depression and T-wave changes: New hori-
zontal or down-sloping ST depression ⱖ0.05
mV in two contiguous leads, T inversion ⱖ0.1
mV in two contiguous leads with prominent
R-wave or R/ S ratio ⱖ1, or both
• Development of pathologic Q waves in the ECG
• Imaging evidence of new loss of viable myocardi-
um or new regional wall-motion abnormality
• Sudden, unexpected cardiac death, involving car-
diac arrest, often with symptoms suggestive of
myocardial ischemia, and accompanied by pre-
sumably new ST elevation, or new LBBB, with or
without evidence of fresh thrombus by coronary
angiography or at autopsy, but death occurring
before blood samples could be obtained, or at a
time before the appearance of cardiac biomarkers
in the blood
• Pathologic findings of an acute myocardial infarc-
tion
WHO Definition of Myocardial Infarction
• Clinical history of chest pain/discomfort consistent
with myocardial infarction. Greater than 20–30 min-
utes and unrelieved by sublingual nitroglycerin
• Serially obtained ECG changes (described above)
• Typical rise and fall of biomarkers consistent with
myocardial necrosis (described above)
ACCF = American College of Cardiology Foundation; AHA =
American Heart Association; ECG = electrocardiogram; ESC =
European Society of Cardiology; LBBB = left bundle-branch
block; WHO = World Health Organization; WHF = World Heart
Foundation.
411
cussion of the classification and diagnosis of an
acute coronary syndrome.1,427,428 These diagnostic
features are likely to be of use in differentiating
drug-induced ischemia from drug-induced acute
coronary syndromes. Conditions to consider in the
differential diagnosis of drug-induced acute coro-
nary syndromes are presented in Table 23–5.
RISK FACTORS
Specific risk factors for drug-induced myocardial
ischemia or acute coronary syndromes are likely to
be similar to those for non–drug-induced myocar-
dial ischemia or acute coronary syndromes (Table
23–6). Although it may be difficult to predict which
specific risk factors are necessary for increasing the
risk of this disease associated with many of the
causative agents, certain risk factors are well known
to increase the risk of myocardial ischemia or acute
coronary syndromes associated with cocaine, oral
contraceptives, and estrogen-replacement therapy.
Most patients with cocaine-related chest pain or
acute coronary syndromes are young, nonwhite,
male tobacco smokers with no history of coronary
TABLE 23–5 Conditions to Consider in the
Differential Diagnosis of Drug-Induced Myocardial
Ischemia and Acute Coronary Syndromes
All Drugs
• Non–drug-induced acute coronary syndrome and
ischemia
Cocaine
• Aortic dissection
• Pulmonary hypertension
• Acute pulmonary syndrome (“crack lung”)
TABLE 23–6 Risk Factors for Drug-Induced
Myocardial Ischemia and Acute Coronary
Syndromes
All drug-induced acute coronary syndromes/myocar-
dial ischemia
• Preexisting coronary artery disease
Cocaine-induced acute coronary syndromes/myocar-
dial ischemia
• Smoking/tobacco use
• Ethanol use
Oral-contraceptive–induced acute coronary syn-
dromes
• Age >35 years
• High-dose estrogen
• Smoking/tobacco use
• Hypertension
TisdaleC23_399-427 1/20/10 11:24 PM Page 412
412 SECTION VI • Drug-Induced Cardiovascular Diseases
atherosclerosis. In fact, nearly 50% of patients with
cocaine-related chest pain or myocardial infarction
do not have evidence of coronary atherosclerosis.290
Tobacco smoking also increases the risk of a coro-
nary event while taking oral contraceptives or hor-
mone-replacement therapy.417 This increase in the
risk of a coronary event associated with smoking is
consistent with the increased risk associated with
smoking in patients with coronary artery disease or
in those at high risk for a coronary event.
MORBIDITY AND MORTALITY
The majority of individuals without a history of
coronary artery disease in whom drug-induced
ischemia and angina develop seek medical atten-
tion. In contrast, patients with a history of coronary
artery disease and ischemic heart disease who expe-
rience drug-induced chest pain and angina often
attribute symptoms to those associated with their
underlying disease process and may not seek addi-
tional medical care. However, depending on the
severity of the drug-induced ischemia, these individ-
uals may suffer recurrent disease exacerbations
requiring additional care or alterations in drug regi-
mens. It is likely that this situation occurs very com-
monly, but the cause is attributed to disease-induced
ischemia rather than to drug-induced ischemia.
On the other hand, most patients in whom
persistent chest pain develops with no history of
coronary artery disease and those in whom a drug-
induced acute coronary syndrome develops seek
medical attention, whether or not they have
underlying coronary artery disease. Many of these
patients require hospitalization and urgent treat-
ment. Drug-induced acute coronary syndromes,
like non–drug-induced acute coronary syndromes,
may increase the risk of sudden death or death
related to associated complications, including the
development of left ventricular dysfunction or
ventricular arrhythmias or both.
There are considerable data describing the mor-
tality associated with non–drug-induced acute
coronary syndromes, and the statistics are alarm-
ing. It is estimated that approximately 37% of
patients who experience a coronary event and 16%
who experience a myocardial infarction in a given
year will die.429 Unfortunately, data regarding mor-
tality associated with drug-induced chest pain and
acute coronary syndromes are sparse, with the
exception of that related to cocaine-induced coro-
nary syndromes. The risk of mortality and recur-
rent myocardial infarction associated with
cocaine-induced chest pain is low (1-year risk
approximately 2% and 1% respectively).430 With
continued cocaine use, the risk of recurrent chest
pain is very high. In patients who suffer a cocaine-
induced myocardial infarction, the risk of compli-
cations is substantially higher. In a study of
patients with cocaine-induced myocardial infarc-
tion, the risk of cardiac complications, most com-
monly heart failure and arrhythmias, was 38%.288
The majority of complications occurred within the
first 12 hours of hospitalization. Interestingly, no
patients died during the hospitalization period. In
another series, the risk of death associated with
continued cocaine use was approximately 5%.431
PREVENTION
Approaches to help prevent drug-induced myocar-
dial ischemia or acute coronary syndromes are listed
in Table 23–7. Because patients with underlying
coronary artery disease and those at high risk for the
development of coronary artery disease are also like-
ly to be at higher risk for the development of drug-
induced ischemia or infarction, it is prudent to
avoid drugs that may cause myocardial ischemia or
infarction (see Table 23–1) in this population unless
treatment is absolutely necessary. If a potentially
causative agent must be used, extra caution and
monitoring should be used with these agents in
patients at high risk for a coronary event (i.e., those
with multiple risk factors, such as smoking, dyslipi-
demia, hypertension, diabetes mellitus, or others).
In addition, the use of illicit drugs known to cause
myocardial ischemia or infarction should be dis-
couraged both in individuals and as a public health
strategy. In patients with a history of coronary artery
disease, particular attention to increased frequency
TABLE 23–7 Approaches to Help Prevent Drug-
Induced Myocardial Ischemia/Infarction
• Instruct patients who have a history of coronary artery
disease to avoid drugs that may cause myocardial
ischemia or infarction whenever possible.
• For patients who have underlying coronary artery
disease and a history of anginal symptoms, self-care
of angina symptoms should be the same as if the
pain was associated with exertion or some other
precipitant of an ischemic event.
• Individuals who do not have a history of coronary
artery disease, acute coronary syndrome, or myocardial
ischemia should be made aware that specific drugs that
they are receiving may, in unusual circumstances, pre-
cipitate a coronary event, and patients should be coun-
seled regarding the symptoms that could result.
• Drug toxicities could be avoided through public
health initiatives that warn about the dangers of illic-
it-drug use.
TisdaleC23_399-427 1/20/10 11:24 PM Page 413
CHAPTER 23 • Myocardial Ischemia and Acute Coronary Syndromes
of angina symptoms and/or use of sublingual nitro-
glycerin is warranted. More aggressive monitoring of
chronic antianginal medications may be necessary.
There are no strong recommendations for con-
sidering drugs to be absolutely contraindicated in
patients with known coronary artery disease for
the avoidance of drug-induced myocardial
ischemia and myocardial infarction, with a few
exceptions. The use of sildenafil in patients receiv-
ing long-term nitrate therapy for exertional angina
(i.e., patients with chronic coronary artery disease
and angina) has been strongly discouraged by the
American Heart Association.355 This strong state-
ment is necessary because of the increased risk of
coronary events and death when sildenafil is used
in combination with short- or long-term nitrate
therapy. Ergot alkaloids should also be avoided in
patients with underlying coronary artery disease.
In patients without a history of coronary artery
disease, strategies for avoidance of drug-induced
ischemia or infarction may be less clear. The approach
in these patients should be increased awareness of
drugs that have been associated with drug-induced
ischemia or infarction. Unfortunately, no routine
monitoring or prevention strategies can prevent the
occurrence of drug-induced myocardial ischemia or
infarction in all individuals. However, individuals
who smoke should be strongly advised against using
oral contraceptives or hormone-replacement therapy.
In response to the clinical data suggesting an
increase in cardiovascular events, NSAIDs have
come under intense scrutiny. A discussion of the use
of NSAIDs in patients with cardiovascular disease is
provided in the next section.
MANAGEMENT
With the exception of the management of cocaine-
induced chest pain and myocardial infarction,
there are very few specific data regarding the
appropriate therapy for patients with drug-induced
myocardial ischemia or acute coronary syndromes.
Because the risk of the development of either dis-
ease in an otherwise normal population is very
low, the consensus guidelines for the treatment of
stable angina, unstable angina, or acute myocardial
infarction provide limited guidance about drug-
induced diseases. More recent focused updates and
scientific statements1,291 have addressed cocaine-
induced disease. However, limited information is
available regarding other drugs known to cause
ischemia or acute coronary syndromes.
With that introduction, it is most appropriate to
consider treatment of three general groups of
patients: (1) patients with a history of chronic coro-
nary artery disease who experience drug-induced
413
ischemia; (2) patients with no history of coronary
artery disease who experience drug-induced ischemia;
and (3) patients with drug-induced acute coronary
syndromes. In all three cases, it should be obvious
that illicit drugs that are the cause of any of these
drug-induced or drug-exacerbated diseases should be
immediately and permanently discontinued.
Drug-Induced Ischemia in Patients
with Coronary Artery Disease
Standard therapy for non–drug-induced ischemia
secondary to coronary artery disease typically
includes short-term management, long-term (pro-
phylactic) therapy, and risk-factor modification.432,433
Acute therapy typically involves the administration
of sublingual nitrates when an anginal attack occurs
or just before exertion in an effort to prevent or treat
ischemia. In addition, most patients also require
long-term prophylactic therapy with a ␤-blocker, cal-
cium-channel blocker, a long-acting nitrate, or all
three. The treatment of drug-induced ischemia is no
different from that of classic non–drug-induced
ischemia. Unless patients have been warned that a
particular drug they are receiving has the propensity
to increase the risk of ischemia and subsequent angi-
na, most patients will not associate an increase in the
incidence of chest pain with specific drug therapy.
Patients should be made aware that specific drugs
they are receiving may cause angina and potentially
exacerbate their disease. When possible, the most
effective treatment is to discontinue therapy with
the offending agent. In some cases, this is not possi-
ble, and maximization of the patient’s medical ther-
apy of the underlying ischemia is necessary.
Drug-Induced Ischemia in Patients with No
History of Coronary Artery Disease
In most cases, the most effective and logical thera-
py is to treat the anginal episode with standard
therapy as necessary and immediately discontinue
therapy with the offending agent. Inasmuch as
there is no apparent underlying disease (i.e., no ath-
erosclerotic coronary artery disease), discontinua-
tion of the offending drug removes the sole cause of
the symptoms.432,433 In certain situations, discon-
tinuation of a culprit agent is impractical or even
life-threatening. For example, withholding therapy
with a cancer chemotherapeutic agent may not be
possible, because it may be the only effective treat-
ment. In these cases, although no specific data are
available to support this in all occasions, use of
short-term or prophylactic therapies, such as sub-
lingual nitrates, maybe necessary to minimize the
ischemia. In most other cases, however, discontinu-
ation of the offending agent is the most effective
treatment approach. Finally, as discussed in the sec-
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414 SECTION VI • Drug-Induced Cardiovascular Diseases

tion above, it is prudent to treat these individuals
with risk-factor–reduction therapies.
Drug-Induced Acute Coronary Syndromes
The therapies for acute coronary syndromes are out-
lined in consensus guidelines and reviews and are
summarized in Table 23–8.1,424,428 The consensus
guidelines outlined in the table illustrate standard
treatment of acute coronary syndromes (ST-segment
elevation [STSE] acute coronary syndromes [ACS]
and non–ST-segment elevation [NSTSE] ACS) and
management of cocaine-induced acute coronary syn-
drome from two distinct guidelines. Management of
cocaine-induced acute coronary syndromes is the
only drug-induced treatment illustrated since this is
the only specific drug for which guidance exists and
a specific section is devoted to its treatment.
The management of conventional (non–drug-
induced) acute coronary syndromes typically

TABLE 23–8 Therapy of Drug-Induced Acute Coronary Syndromes

Acute Coronary Syndromes Cocaine-Induced Acute Coronary Syndrome
STEMI ACC/AHA NSTEMI/UA–ACC/AHA NSTEMI/UA–ACC/AHA AHA-Cocaine Specific For
2007 Focused Update1 2007 Guidelines2 Cocaine-Specific 2007 Chest Pain and MI 2007
Guidelines2 Scientific Statement291
Oxygen Oxygen Not discussed in cocaine Oxygen
section
Aspirin Aspirin Not discussed in cocaine Aspirin
section
Benzodiazepine Benzodiazepine Not discussed in cocaine Benzodiazepine
anxiolytics anxiolytics section anxiolytics
Analgesics (morphine) Analgesics (morphine) Not discussed in cocaine Not discussed
section
Intravenous nitroglycerin Intravenous nitroglycerin Intravenous nitroglycerin Intravenous nitroglycerin
(nitroprusside or
phentolamine may be
considered for persistent
hypertension)
␤-Blockers ␤-Blockers ␤-Blocker use is controversial, ␤-Blocker use should be
including labetalol avoided in the acute phase.
Labetalol does not offer any
advantage, carvedilol has
not been studied.
Reperfusion Reperfusion If ST-segment elevation If ST-segment elevation
Thrombolytics Primary PCI present and patient is present, percutaneous
Primary PCI unresponsive to initial coronary intervention is
therapy, immediate coronary preferred over thrombolytic
angiography is preferred therapy.
over thrombolytic therapy. If NSTSE, evaluate with
cardiac catheterization.
Unfractionated heparin, Unfractionated heparin, Not discussed in cocaine Unfractionated heparin,
enoxaparin, enoxaparin, fondaparinux, section enoxaparin
fondaparinux bivalirudin
CCBs only when patients CCBs only when patients CCBs CCBs may be considered for
are unresponsive to NTG are unresponsive to NTG patients who do not
and ␤-blockers and ␤ -blockers respond to benzodiazepines
and nitroglycerin.
ACC = American College of Cardiology; AHA = American Heart Association; CCB = calcium-channel blocker; MI = myocardial infarction;
NSTSE = non–ST-segment elevation; NSTEMI = non–ST-segment elevation myocardial infarction; NTG = nitroglycerin; PCI = percuta-
neous coronary intervention; STEMI = ST-segment myocardial infarction; UA = unstable angina; WHF = World Heart Foundation; WHO
= World Health Organization.
TisdaleC23_399-427 1/20/10 11:24 PM Page 415
CHAPTER 23 • Myocardial Ischemia and Acute Coronary Syndromes
includes antiplatelet agents (i.e., aspirin), unfrac-
tionated heparin or low-molecular-weight heparin,
nitrates, ␤-blockers, anxiolytic drugs, and anal-
gesics. In patients with STSE ACS, the addition of
revascularization therapy with percutaneous coro-
nary intervention (PCI) or thrombolytic therapy is
generally indicated, and glycoprotein IIb/IIIa recep-
tor antagonists are used in select patients. In
patients with NSTSE ACS, thrombolytic agents are
not indicated, but PCI and glycoprotein IIb/IIIa
receptor antagonists may be used. In general, ther-
apy for a drug-induced acute coronary syndrome is
the same as that for a non–drug-induced acute coro-
nary syndrome. The therapies are similar mainly
because there are few data to suggest that they
should be different. Following in-hospital care,
patients with evidence of drug-induced myocardial
infarction or atherosclerosis should be treated in a
manner similar to that of patients with a non–drug-
induced acute coronary syndrome. Aggressive car-
diovascular risk-factor reduction with smoking
cessation therapy and control of hypertension, dia-
betes, and plasma lipids is necessary. Treatment
with traditional secondary prevention therapies,
including aspirin, clopidogrel, ␤-blockers, statins,
and angiotensin-converting enzyme inhibitors
should also be used in these patients.
Treatment of Cocaine-Induced
Acute Coronary Syndromes
As illustrated in Table 23–8, treatment guidelines
for cocaine-induced ACS have been published. In
addition, new sections regarding cocaine have been
added to consensus guidelines for the management
of acute coronary syndromes.1,2,291 The mechanism
of cocaine-induced acute coronary syndrome is
multifactorial (increased myocardial oxygen
demand, decreased myocardial oxygen supply due
to vasoconstriction, and thrombus formation), but,
unlike non–drug-induced acute coronary syn-
dromes, a major component of cocaine’s effect is
secondary to coronary vasoconstriction (in contrast
to that of a classic acute coronary syndrome).
Therefore, treatment approaches target the vaso-
constrictive component as well as the classic thera-
peutic targets. In addition, cocaine toxicity affects
other organ systems, particularly the central nerv-
ous system, increasing the risk of seizures, hyper-
thermia, and subarachnoid hemorrhage. These
factors must be considered when treating cocaine-
induced acute coronary syndromes. American
Heart Association recommendations for treatment
of cocaine-induced chest pain are provided in
Figure 23–2, and are based on risk profile. All
patients should be evaluated in a chest-pain unit
and receive aspirin and benzodiazepines initially. If
415
pain is not responsive, nitroglycerin, nitroprusside
(for persistent hypertension not controlled with
nitroglycerin) or phentolamine (alternative) are rec-
ommended. Patients should then be managed
based on whether they are classified as high or low-
risk as outlined in Figure 23–2.291
Considerable controversy exists regarding
whether ␤-blockers, thrombolytic therapy, and calci-
um-channel blockers should be used for the manage-
ment of cocaine-induced acute coronary syndromes.
In theory, ␤-receptor-blocking drugs have the poten-
tial to exacerbate coronary artery and systemic vaso-
constriction. As described above, cocaine inhibits
peripheral norepinephrine reuptake, leading to
increased plasma norepinephrine concentrations and
enhanced ␣1-adrenoceptor-mediated vasoconstric-
tion. When administered to patients who have
ingested cocaine, ␤-blockers, especially nonselective
agents, may further enhance coronary vasoconstric-
tion through enhancement of unopposed ␣1-adreno-
ceptor agonism, potentially further increasing blood
pressure and heart rate and possibly increasing the
risk of seizures and mortality.286 Available data suggest
that labetalol (a ␤-adrenergic and ␣1-receptor
inhibitor) may convey benefit in patients with
cocaine-induced acute coronary syndromes, but
labetalol administration has also been associated with
increased seizure activity and mortality in animal
models and little effect on coronary vasoconstriction
in humans.1,284 Carvedilol, which is also a ␤-adrener-
gic and ␣1-receptor inhibitor, may theoretically ben-
efit patients with cocaine-induced acute coronary
syndromes as well, although data supporting
carvedilol use in this situation are not available.
Several treatment guidelines and expert reviews sug-
gest that ␤-blockers of any kind should not be admin-
istered during the acute phase of an acute coronary
syndrome.1,286,290,428 However, these recommenda-
tions have been questioned. Results of a retrospective
study indicated that ␤-blockers are associated with a
substantially lower risk of cocaine-induced myocar-
dial infarction.434 The authors of this study suggested
that warnings against ␤-blocker use may apply only
to patients with acute cocaine intoxication. In view of
the retrospective nature of the study, prospective ani-
mal and human studies are needed to further define
this issue. The current recommendations against ␤-
blocker administration provide the most prudent
approach to treating patients with cocaine-induced
acute coronary syndrome.
Thrombolytic administration to individuals
with cocaine-induced acute coronary syndrome is
also very controversial. There have been several
reports of intracranial hemorrhage or death sec-
ondary to thrombolytic use in this popula-
tion.284,435,436 Therefore, an alternative approach to
thrombolytics as a first-line therapy is to adminis-
TisdaleC23_399-427 1/20/10 11:24 PM Page 416

416 SECTION VI • Drug-Induced Cardiovascular Diseases

Cocaine-associated Chest Pain

Oxygen

ASA, Benzodiazepine Anxiolytics

Persistent hypertension; IV NTG, Nitroprusside or alternative: Phentolamine

High Risk Low Risk

STEMI NSTE ACS Observe in Chest Pain Unit

Primary Cardiac Drug Abuse Counseling

PCI Catheterization Stress Test Optional
Inpatient or Outpatient

Avoid ␤-blockers acutely

Use antithrombotic and antiplatelet therapy
per existing guidelines

Discharge Therapy: Drug abuse counseling plus:

ASA, clopidogrel, statin and ACE inhibitor per existing guidelines
Consider ␤-blockers especially if high-risk features (LVSD, arrhythmia) present

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
by calcium-channel blockers or phentolamine.286 If
this initial medical therapy fails, reperfusion thera-
py with thrombolytics or revascularization with
PCI should be the next option. These issues related
to cocaine-induced acute coronary syndromes sug-
gests that the standard treatment of drug-induced
acute coronary syndromes is less than clear, and is
sometimes dependent on the specific drug causing
the acute coronary syndrome.
The use of calcium-channel blockers for the
treatment of cocaine-induced chest pain and acute
coronary syndromes is also controversial. In theo-
ry, calcium-channel blockers should reverse the
vasoconstriction frequently associated with
cocaine ingestion. In cardiac catheterization stud-
ies, verapamil has been shown to reverse cocaine-
associated vasospasm. However, results of animal
studies regarding the effects of calcium-channel
blockers on survival, seizure frequency, and
arrhythmias associated with cocaine-induced
ischemia have been variable. Current recommen-
dations suggest that the short-acting dihydropyri-
dine calcium-channel blockers should never be
used in patients with cocaine-induced acute coro-
nary syndromes. This recommendation is consis-
tent with that of standard treatment of chronic
and acute coronary syndromes. Verapamil or dilti-
azem should not be used in the presence of left-
ventricular systolic dysfunction. Therapy with
calcium-channel blockers should be reserved for
patients with cocaine-induced acute coronary syn-
dromes who do not respond to therapy with nitro-
glycerin and benzodiazepines.291
Finally, after hospitalization, outpatient treat-
ment of patients with evidence of cocaine-induced
myocardial infarction or atherosclerosis should be
similar to that used for patients with a non–drug-
induced acute coronary syndrome. Aggressive car-
diovascular risk-factor reduction with smoking
cessation therapy and control of blood pressure,
diabetes, and plasma lipids is necessary. Traditional
secondary prevention methods including aspirin,
clopidogrel, statins, and angiotensin-converting
enzyme inhibitors should be used in these patients.
Therapy with ␤-blockers should be used if required
based on risk and in consideration of the potential
for continued cocaine use.
TisdaleC23_399-427 1/20/10 11:24 PM Page 417
CHAPTER 23 • Myocardial Ischemia and Acute Coronary Syndromes
Alternatives to the Use of NSAIDs
Current guidelines recommend against the routine
use of nonselective NSAIDs and selective COX-2
NSAIDs.1,2 Although these recommendations are
focused on the treatment of acute coronary syn-
dromes, they should likely be applied to all patients
with cardiovascular disease. During the acute peri-
od, narcotic analgesics such as morphine should be
administered for pain management. Following dis-
charge from the hospital and during the postinfarc-
tion period, a stepped-care approach for managing
musculoskeletal pain is recommended by the
American Heart Association.421 These recommenda-
tions strongly advise clinicians to closely evaluate
symptoms and to use nonpharmacologic approach-
es initially. If these techniques are ineffective for
pain control, first-line agents may include aceta-
minophen, aspirin, tramadol, short-term narcotic
analgesics or nonacetylated salicylates. The next
tier of therapy involves a progression from non-
COX-2 selective NSAIDs (e.g., naproxen, ibuprofen)
to NSAIDs with some selectivity (e.g., diclofenac,
celecoxib) to COX-2 selective NSAIDs (e.g. rofecox-
ib, etoricoxib). The recommendations also suggest
that once the second tier of agents is chosen, the
lowest dose of NSAID should be used, and addition-
al therapy should include aspirin 81 mg daily and a
proton pump inhibitor.421 These recommendations
have been met with some disagreement in the liter-
ature, as they are based mainly on cardiovascular
risk, rather than the need for pain management.
INFORMATION FOR PATIENTS
Information for patients regarding prevention of
these drug-induced conditions is provided in Table
23–8. Patients who are taking drugs that may cause
myocardial ischemia or acute coronary syndromes
should be instructed that the specific drug may, in
some cases, cause chest pain. For patients who have
underlying coronary artery disease and a history of
anginal symptoms, self-care of angina symptoms
should be the same as if the pain was associated with
exertion or some other precipitant of an ischemic
event. Individuals who do not have a history of
coronary artery disease, acute coronary syndrome,
or myocardial ischemia should be made aware that
specific drugs that they are receiving may, in unusu-
al circumstances, precipitate a coronary event, and
patients should be counseled regarding the symp-
toms that could result. Patients should be instructed
to consult their pharmacist or physician or go to an
emergency department if chest pain, palpitations,
light-headedness, dizziness, or shortness of breath
occur. Finally, and most unfortunately, many cases
of drug-induced ischemia and infarction are associ-
417
ated with illicit-drug use (e.g., cocaine, ampheta-
mines). The best method to avoid these toxicities is
through public health initiatives that warn about
the dangers of illicit-drug use.
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430. Hollander JE, Todd KH, Green G, et al. Chest pain
associated with cocaine: an assessment of prevalence in
suburban and urban emergency departments. Ann Emerg
Med. 1995;26:671-676.
431. Hollander JE, Hoffman RS, Gennis P, et al. Cocaine-
associated chest pain: one-year follow-up. Acad Emerg
Med. 1995;2:179-184.
432. Gibbons RJ, Abrams J, Chatterjee K, et al. ACC/AHA 2002
guideline update for the management of patients with
chronic stable angina—summary article: a report of the
American College of Cardiology/American Heart
Association Task Force on practice guidelines (Committee
on the Management of Patients With Chronic Stable
Angina). J Am Coll Cardiol. 2003;41:159-168.
433. Fraker TD Jr, Fihn SD, Gibbons RJ, et al. 2007 chronic
angina focused update of the ACC/AHA 2002 Guidelines
for the management of patients with chronic stable
angina: a report of the American College of
Cardiology/American Heart Association Task Force on
Practice Guidelines Writing Group to develop the
focused update of the 2002 Guidelines for the
management of patients with chronic stable angina.
Circulation. 2007;116:2762-2772.
434. Dattilo PB, Hailpern SM, Fearon K, et al. Beta-blockers are
associated with reduced risk of myocardial infarction
after cocaine use. Ann Emerg Med. 2008;51:117-125.
435. Hollander JE, Wilson LD, Leo PJ, et al. Complications from
the use of thrombolytic agents in patients with cocaine
associated chest pain. J Emerg Med. 1996;14:731-736.
436. LoVecchio F, Nelson L. Intraventricular bleeding after the
use of thrombolytics in a cocaine user. Am J Emerg Med.
1996;14:663-664.
TisdaleC24_428-444 1/12/10 2:51 PM Page 428
CHAPTER 24
Heart Failure
H eart failure is a major cause of morbidity and
mortality in Western society.1-4 Patients with
heart failure experience frequent exacerbation of
symptoms, often leading to hospitalization. Heart
failure remains one of the most common reasons
for hospitalization, with over 5 million hospitaliza-
tions per year in the United States5 and 106,000 per
year in Canada.4 The duration of stay for patients
hospitalized with heart failure is long, averaging
about 13 days, and in-hospital mortality is high,
between 3.2 and 15%.4,6
Coronary artery disease is by far the most com-
mon cause of heart failure, accounting for approx-
imately three-fourths of cases. Drug-induced heart
failure in patients without preexisting left ventric-
ular dysfunction is quite rare; however, drug-
induced exacerbation of symptoms of heart failure
occur more frequently in those with established
heart failure.
CAUSATIVE AGENTS
The agents that are implicated in drug-induced
heart failure are listed in Table 24–1.7-104 In evalua-
tion of these agents, causality is often difficult to
ascertain because of the multiplicity of factors that
can exacerbate symptoms of heart failure. Most cal-
cium-channel blockers (except felodipine and
amlodipine), thiazolidinediones (“glitazones”:
rosiglitazone and pioglitazone), antiarrhythmic
agents, anthracyclines (doxorubicin), trastuzumab,
nonsteroidal antiinflammatory agents (NSAIDs),
selective cyclooxygenase-2 (COX-2) inhibitors, and
adrenergic ␤-receptor antagonists (␤-blockers) have
all been implicated in drug-induced heart failure
and therefore will be the focus of this chapter.
428
Ross T. Tsuyuki and Mark J. Makowsky
Isolated case reports have identified other
agents as possible causes of drug-induced heart fail-
ure (see Table 24–1). Since causality for these
agents is much less certain, these will not be dis-
cussed in detail in this chapter. The reader is
referred to a comprehensive review by Amabile and
Spencer105 that outlines medications to avoid in
patients with heart failure and review papers by
Feenstra et al.106 and Slordal and Spigset107 for fur-
ther discussion of heart failure associated with
these agents.
Although drug-induced heart failure in
patients without preexisting left ventricular dys-
function is relatively rare, drug-induced exacerba-
tions of symptoms in those with preexisting left
ventricular dysfunction is more common. Drug-
induced causes, expressed as a proportion of all
heart-failure exacerbations, are shown in Table
24–2. In a prospective study of factors associated
with acute exacerbation of heart failure, Tsuyuki
et al.108 reported on 323 episodes of worsening
heart failure in 180 patients during the 43 weeks
of the Randomized Evaluation of Strategies for
Left Ventricular Dysfunction (RESOLVD) pilot
study. Although the most commonly identified
precipitant of exacerbations of acute heart failure
was excessive salt intake (22%), antiarrhythmic
agents, study medications (which could have
been a ␤-blocker or placebo and candesartan
and/or enalapril administered in a blinded fash-
ion), and calcium-channel blockers were all impli-
cated. Interestingly, however, medications were
not thought to be the primary cause of any of
these exacerbations.108 In a review of 401 patients
over the age of 70 years and hospitalized with
heart failure, Rich et al.109 determined that 28
patients (7%) had iatrogenic causes of heart fail-
TisdaleC24_428-444 1/12/10 2:51 PM Page 429

CHAPTER 24 • Heart Failure 429

TABLE 24–1 Agents Implicated in Drug-Induced Heart Failure

Drug Incidence Level of Evidence
(see page xii for explanation)

␣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)
TisdaleC24_428-444 1/12/10 2:51 PM Page 430

430 SECTION VI • Drug-Induced Cardiovascular Diseases

TABLE 24–1 Agents Implicated in Drug-Induced Heart Failure (Continued)

Drug Incidence Level of Evidence

Pioglitazone60, 61 HR, 1.8 (95% CI, 1.4–2.2) 59
A
0.1–14.1%
HR, 2.15–7.03
RR, 2.09 (95% CI, 1.52–2.88)
11%
HR, 1.41 (95% CI, 1.14–1.76)
Hydralazine29 NK C
Ifosfamide13, 62 NK C
Imatinib63 NK C
Infliximab46,64 14/101 (14%) vs. 5/49 (10%) control B
Interferon ␣65-67 NK C
Itraconazole68 NK C
Licorice69 NK C
Mannitol70 NK C
Megestrol71 NK C
Minoxidil72 NK C
Mitoxantrone73 1.5% C
NSAIDs74-81 RR, 1.8–9.9 (95% CI, 1.4–2.4) B
COX-2 inhibitors
Celecoxib82-84 0.4–1.9% A
Rofecoxib80-84 0–1.9% A
RR, 1.17–1.80
Paclitaxel85,86 NK C
PEG lavage solution87 NK C
Penicillins88,89 NK C
Ampicillin89 NK C
Pergolide90,91 NK C
Pregabalin92 NK C
Sodium-containing antacids29 NK C
Trastuzumab93 Monotherapy: 3–7%94, 95, 97, 98 A
NYHA class III or IV: 0–3.9%96
LVEF decrease >10%: 3–34%96
Tricyclic antidepressants99-102 NK C
Imipramine NK C
Amitriptyline NK C
Protriptyline NK C
Nortriptyline NK C
Clomipramine NK C
Venlafaxine103 NK C
Zidovudine104 NK C
CI = confidence interval; HR = hazard ratio; LVEF= left ventricular ejection faction; NK = not known; NYHA = New York Heart
Association; OR = odds ratio; PEG = polyethylene glycol; RR = relative risk.
TisdaleC24_428-444 1/12/10 2:51 PM Page 431

CHAPTER 24 • Heart Failure 431

TABLE 24–2 Proportion of Heart Failure Exacerbations That Are Drug-Induceda

Study Precipitating Agent(s) Incidence
Tsuyuki et al.108,b Antiarrhythmic agents 15%
“Study medications” (␤-blockers or placebo) 15%
Calcium-channel blockers 13%
Nonstudy open-label ␤-blockers 9%
NSAIDS 5%
Rich et al.109 Fluids (Excessive intravascular volume expansion) 5.5%
␤-Blockers 0.25%
Verapamil 0.25%
Garcia Robles et al.26 ␤-Blockers 2%
NSAIDs = nonsteroidal antiinflammatory drugs.
a
Does not include underuse of drugs (i.e., withdrawal of diuretics).
b
Categories not mutually exclusive.

ure. The agents implicated were mostly related to
excessive intravascular volume expansion (mostly
due to overhydration), as well as ␤-blockers and
verapamil, each in one patient.109 In a review of
100 hospitalizations due to heart failure in
patients over 65 years of age, Garcia Robles et al.
identified 2 cases (2%) caused by ␤-blockers.26
Other studies revealed coronary ischemia, respira-
tory infection, uncontrolled hypertension,
arrhythmias, and poor adherence to medication
as common precipitants of exacerbations of heart
failure.108-112
highlighting the significant hazard of the use of
diltiazem in patients with left ventricular dysfunc-
tion after myocardial infarction.33 In a random-
ized, double-blind crossover study of 8 weeks of
treatment with isosorbide dinitrate alone, isosor-
bide dinitrate in combination with nifedipine, or
nifedipine alone in 28 patients with mild to mod-
erate heart failure, Elkayam et al.34 observed inci-
dences of hospitalization for heart failure of 26%
and 24% in the isosorbide dinitrate plus nifedipine
and nifedipine alone groups, respectively (as com-
pared with none in the isosorbide dinitrate alone
group).

EPIDEMIOLOGY
The incidence of drug-induced heart failure is out-
lined in Table 24–1. The exact incidence of drug-
induced heart failure is difficult to determine,
because it is often difficult to differentiate drug-
induced heart failure from the many other precipi-
tants of this syndrome.108
Calcium-Channel Blockers
In a post hoc analysis of the Multicentre Diltiazem
Postinfarction Trial (MDPIT), Goldstein et al.33
reported new or worsened heart failure in 12.0%
and 20.5% of 623 patients receiving placebo or dil-
tiazem, respectively, with left ventricular ejection
fraction (LVEF) <0.40 at baseline. There was no dif-
ference in the incidence of new or worsened heart
failure in patients with LVEF >0.40 at baseline,
Glitazones
The glitazones are now well known to cause fluid
retention.49,50,52,53 Tang et al.50 reviewed the records
of 111 consecutive patients with heart failure and
diabetes who were prescribed a glitazone and
reported that the incidence of fluid retention was
17%. In the randomized A Diabetes Outcome
Progression Trial (ADOPT), an incidence of edema
of 14.1% was reported in the rosiglitazone group as
compared with 7.2% in patients receiving met-
formin and 8.5% in those receiving glyburide dur-
ing the 4-year period of follow-up.113
More recently, several clinical trials and meta-
analyses have investigated the impact of glitazone
therapy on cardiovascular outcomes, including the
incidence of heart failure. In the Diabetes
Reduction Assessment with Ramipril and
Rosiglitazone Medication (DREAM) study, 5,269
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432 SECTION VI • Drug-Induced Cardiovascular Diseases
adults with impaired fasting glucose or impaired
glucose tolerance or both and no previous cardio-
vascular disease were randomly assigned to receive
rosiglitazone or placebo.55 Heart failure developed
in 14 (0.5%) participants in the rosiglitazone group
and in 2 (0.1%) in the placebo group (P = 0.01). An
increased incidence of heart failure was also docu-
mented in an interim analysis of the Rosiglitazone
Evaluated for Cardiac Outcomes and Regulation of
Glycemia (RECORD) study, in which 4,447 patients
with inadequate glycemic control were randomly
assigned to receive add-on rosiglitazone therapy or
metformin plus sulfonylurea (control group). The
hazard ratio for the development of heart failure
associated with rosiglitazone was 2.15 (95% confi-
dence interval [CI],: 1.3–3.57].56 Pioglitazone has
also been associated with an increased risk of heart
failure. In the Prospective Pioglitazone Clinical
Trial In Macrovascular Events (PROactive) study, in
which 5,238 patients with type 2 diabetes and evi-
dence of macrovascular disease were randomly
assigned to receive pioglitazone or placebo, piogli-
tazone was associated with an increase in the inci-
dence of heart failure (11% vs. 8%; P<0.0001).60
Several meta-analyses have also documented an
increased incidence of heart failure in patients
receiving glitazones (Table 24–1).54,57,58,61
Notably, although both rosiglitazone and
pioglitazone have been associated with an
increased incidence of heart failure, to date only
rosiglitazone has been shown to be associated with
an increased risk of myocardial infarction (odds
ratio [OR] 1.43; 95% CI, 1.03–1.98).114 Neither
rosiglitazone nor pioglitazone has been found to
increase the risk of cardiovascular mortality.54,57,61
A joint consensus statement by the American Heart
Association and the American Diabetes Association
recommended cautious use of lower doses of glita-
zones in patients with New York Heart Association
(NYHA) functional class I–II symptoms and avoid-
ance of these agents in those with NYHA class
III–IV symptoms.51
Antiarrhythmic Agents
Ravid et al.23 reviewed the incidence of drug-
induced heart failure in 407 patients during 1,133
serial electrophysiologic drug tests with encainide,
moricizine, lorcainide, mexiletine, propafenone, or
tocainide. Using a strict definition of heart failure,
they reported an overall incidence of drug-induced
heart failure of 1.8%. The incidence was 3.8% in
patients with a history of heart failure. In this
study, lorcainide was associated with the lowest
rate of heart failure (0.7%), while propafenone was
associated with the highest (4.7%). In a random-
ized, controlled trial investigating the impact of
antiarrhythmic therapy postmyocardial infarction,
Greene et al. documented an incidence of heart
failure requiring hospitalization in 26% of patients
receiving encainide, flecainide, moricizine, or
imipramine as compared with 18% of those receiv-
ing placebo.22 Pfisterer estimated that the inci-
dence of drug-induced heart failure associated with
older antiarrhythmic agents (excluding ibutilide
and dofetilide) is about 5% overall and approxi-
mately 10% in those with a history of heart fail-
ure.24
Amiodarone, ibutilide, and dofetilide appear
to exert minimal negative inotropic effects, and
amiodarone and dofetilide have been shown to
not adversely affect survival in patients with
heart failure.1 Therefore, although not part of the
routine treatment of patients with heart failure,
amiodarone is the agent most likely to be safe
and effective if antiarrhythmic therapy is neces-
sary to prevent recurrent atrial fibrillation or
symptomatic ventricular arrhythmias. 1,2
However, the Antiarrhythmic Trial with
Dronedarone in Moderate to Severe CHF
Evaluating Morbidity Decrease (ANDROMEDA)
trial found that dronedarone, a novel antiar-
rhythmic drug with properties similar to amio-
darone, was associated with increased early
mortality related to the worsening of heart fail-
ure in patients who were hospitalized with symp-
tomatic heart failure and severe left ventricular
systolic dysfunction.25 During a median follow-
up of 2 months, 8.1% of patients receiving
dronedarone died, as compared with 3.8% receiv-
ing placebo (hazard ratio [HR], 2.13; 95% CI,
1.07–4.25), and this excess mortality was
predominantly related to worsening of heart
failure (3.2% vs. 0.6%). This increase in mortal-
ity was not observed in another trial in
which patients with decompensated heart fail-
ure or NYHA class IV heart failure were excluded
(no difference in all-cause mortality, and a reduc-
tion in death from cardiovascular causes—
dronedarone, 2.7%, vs. placebo, 3.9%; HR, 0.71;
95% CI, 0.51–0.98).115
Anthracyclines
The incidence of drug-induced heart failure is
best characterized for doxorubicin. Von Hoff et
al.15 reviewed eight National Cancer Institute tri-
als involving over 3,900 patients and reported an
overall incidence of doxorubicin-induced heart
failure of 2.2%. However, a more recent retro-
TisdaleC24_428-444 1/12/10 2:51 PM Page 433
spective analysis of three clinical trials, including
630 patients receiving doxorubicin, reported a
higher overall incidence of doxorubicin-related
heart failure (5.1%).16 Kremer et al.17 performed a
systematic review of the frequency of anthracy-
cline-induced heart failure in children and
reported a frequency between 0% and 16% across
30 studies. More recently, van Dalen et al report-
ed an incidence of anthracycline-induced heart
failure of 2.5% in a cohort of 830 children treat-
ed with a mean cumulative anthracycline dose of
288 mg/m2 during a mean follow-up of 8.5
years.18
Trastuzumab
Although trastuzumab has clearly been associated
with cardiac dysfunction, determination of the
incidence is complicated by the coadministration
of other cardiotoxic medications such as anthra-
cyclines and cyclophosphamide. In the first large
phase 3 trial of trastuzumab in patients with
metastatic breast cancer that overexpressed
human epidermal growth factor receptor 2 (HER-
2), patients were randomly assigned to standard
chemotherapy plus trastuzumab (doxorubicin,
epirubicin, or cyclophosphamide for those who
had not previously received adjuvant anthracy-
cline therapy or paclitaxel for those who had
received previous adjuvant anthracycline thera-
py) or standard chemotherapy alone. Cardiac dys-
function occurred in 27% of the patients
receiving anthracycline, cyclophosphamide, and
trastuzumab, 8% in those who received only
anthracycline and cyclophosphamide, 13% in
those receiving trastuzumab plus paclitaxel, and
1% of patients receiving paclitaxel alone.93 In
addition, five major trials 116-120 investigating
trastuzumab as adjuvant therapy for patients with
HER-2-positive breast cancer have reported an
incidence of severe heart failure (NYHA class III or
IV) of 0% to 3.9% in trastuzumab-treated patients
as compared with 0% to 1.3% in control groups.96
In these trials, 3% to 34% of trastuzumab-treated
patients experienced a decrease in LVEF of >10%,
as compared with 2% to 17% of patients in con-
trol groups.96 In addition, trastuzumab has been
used as a single agent in several trials in which the
incidence of cardiac dysfunction associated with
the drug has been 3% to 7%.97 Finally, in a retro-
spective review of 173 women with metastatic
breast cancer who received trastuzumab for at
least 1 year at a single institution, 10.9% experi-
enced symptomatic heart failure or had a LVEF
between 20 and 40%.121
CHAPTER 24 • Heart Failure 433
NSAIDs
In a study of more than 10,000 patients over 55
years of age, Heerdink et al.74 reported an adjust-
ed relative risk of hospitalization for heart failure
of 1.8 in patients receiving diuretics and NSAIDs
versus those taking diuretics only. Bleumink et
al.75 reviewed five studies (including the afore-
mentioned trial) regarding the development of
heart failure in patients taking NSAIDs, and
reported an odds ratio of approximately 2.0. In a
review of employers’ drug insurance databases,
Zhao et al.84 reported 102 new outpatient visits
for heart failure among 20,838 new recipients
(adjusted rate per 1,000 patient-days, 0.124) of
new prescriptions for traditional NSAIDs in
patients with stable hypertension and no heart
failure.
COX-2 Inhibitors
Although the COX-2 inhibitors were originally
thought to be free of renal and hemodynamic
effects, this has ultimately not proven to be the
case. In a randomized, double-blind trial in 1,092
patients ≥65 years of age with hypertension and
osteoarthritis, Whelton et al.82 reported inci-
dences of heart failure of 0.4% and 0.6% associat-
ed with celecoxib and rofecoxib, respectively. In
the aforementioned review of hypertensive
patients in an administrative database, Zhao et
al.84 reported 377 outpatient billings for heart fail-
ure among 19,663 users of celecoxib (adjusted
rate per 1,000 patient-days, 0.110) and 228
among 12,218 users of rofecoxib (adjusted rate,
0.139). In a population-based cohort study in eld-
erly patients, there was an increased risk of hospi-
tal admission in those taking rofecoxib (adjusted
rate ratio, 1.8; 95% CI, 1.5–2.2) and nonselective
NSAIDS (adjusted rate ratio, 1.4; 95% CI,
1.0–1.9).80 NSAID and COX-2 inhibitor-induced
heart failure is a particularly vexing clinical prob-
lem, as many patients with heart failure have
comorbidities such as osteoarthritis and gout,
which negatively impact quality of life, and these
patients could otherwise benefit from these ther-
apies. In these situations, alternative nonpharma-
cologic and pharmacologic therapies (e.g.,
acetaminophen) may be preferable.
␤-Blockers
Although it has been known for some time that ␤-
blockers can precipitate heart failure in susceptible
individuals, use of these drugs is now standard
TisdaleC24_428-444 1/12/10 2:51 PM Page 434
434 SECTION VI • Drug-Induced Cardiovascular Diseases
care in the management of heart failure, based on
morbidity and mortality benefits demonstrated in
numerous randomized trials.1,2,122-124 In 1974,
Greenblatt and Koch-Weser27 reported an inci-
dence of heart failure of 1% in 319 consecutive
hospitalized patients who were prescribed propra-
nolol. These investigators also reviewed 23 studies
of 797 outpatients receiving propranolol, and
reported an incidence of heart failure of 5.4%.
These early results should be balanced against the
now incontrovertible evidence supporting the
benefit of ␤-blockers on mortality and morbidity
in patients with heart failure.1,2,122-124 Indeed, in
systematic reviews and clinical trials, the use of ␤-
blockers has been consistently shown to reduce
the incidence of mortality from heart failure by
34% and hospitalizations by 40% to 50% as com-
pared with placebo.122,123 In a systematic review of
13 randomized trials of ␤-blockers, heart failure
was reported as an adverse event in 16.7% of
patients receiving ␤-blockers, as compared with
25.1% in those receiving placebo.122 More recent-
ly, in an overview of randomized, controlled trials
of patients with heart failure comparing ␤-block-
ers to placebo, Ko et al. reported that, although ␤-
blocker therapy was associated with significant
increases in the risk of bradycardia, hypotension,
and dizziness, ␤-blocker therapy is associated with
reductions in the incidence of all-cause mortality,
hospitalizations for heart failure, worsening heart
failure, and all-cause withdrawal of medica-
tions.125
MECHANISMS
The mechanisms by which drugs can induce
heart failure can be categorized in general as
those reducing myocardial contractility (calci-
um-channel blockers, antiarrhythmic agents,
anthracyclines, ␤-blockers), those increasing pre-
load (glitazones, NSAIDs, COX-2 inhibitors, cor-
ticosteroids), and those increasing afterload
(sympathomimetic agents). Virtually all drug-
induced failure is reversible. Mechanisms of
drug-induced heart failure are listed in Table
24–3. There are several drugs for which the
mechanism is unknown, including amantadine,
aminocaproic acid, amphotericin B, ampicillin,
anti-digoxin antibody fragments, bromocriptine,
clozapine, cytarabine, dapsone, doxazosin, etan-
ercept, foscarnet, hydralazine, ifosfamide, inflix-
imab, mannitol, pregabalin, venlafaxine, and
zidovudine.
Calcium-Channel Blockers
The common mechanism of action of the heteroge-
neous group of calcium-channel blockers is antago-
nism of L-type calcium channels. All
calcium-channel blockers are negative inotropes to
varying degrees,126 but their net effect on cardiac out-
put and symptoms of heart failure depends on other
hemodynamic effects in association with the under-
lying cardiac dysfunction of the patient. Verapamil
and diltiazem have strong negative inotropic effects
and should be avoided in all patients with heart fail-
ure.127 Nifedipine has strong negative inotropic
effects in vivo128 and also causes neurohormonal
activation via the renin–angiotensin–aldosterone
system. Indeed, nifedipine has been associated with
serious exacerbations of heart failure requiring hospi-
talization and should be avoided in all patients with
left ventricular dysfunction.34 Second-generation
dihydropyridine calcium-channel blockers appear to
be more vascular-selective, with low potential for
worsening of heart failure.129,130 In fact, felodipine
and amlodipine have both been evaluated as poten-
tial therapeutic agents for heart failure. Neither agent
was found to have beneficial effects on patient out-
comes. However, neither showed an excess of exacer-
bations of heart failure as compared with placebo,
suggesting that these agents may be used safely for
other purposes (e.g., hypertension, ischemia) in
patients with heart failure, though other alternatives
are available.129,130
Glitazones
Although the glitazones appear to have mostly
favorable hemodynamic effects in heart failure,
their use has been associated with fluid retention
and heart failure.49-53 Glitazones increase plasma
volume by 6% to 7%.50 The mechanism of fluid
retention is not known, but it may relate to
increased endothelial-cell permeability or effects on
renal hemodynamics.49 Fluid retention associated
with glitazones appears to be refractory to diuretics,
but is reversible on discontinuation of therapy.49,52
However, more recent reports and mechanistic
studies suggest that diuretics active in the distal col-
lecting duct, (i.e., hydrochlorothiazide and spirono-
lactone) may be effective for reducing the degree of
fluid retention associated with glitazones.131,132
Antiarrhythmic Agents
Virtually all antiarrhythmic drugs reduce myocar-
dial contractility; the net clinical effects reflect the
balance of other hemodynamic effects.24,133
Disopyramide, flecainide, propafenone, and calci-
TisdaleC24_428-444 1/12/10 2:51 PM Page 435
TABLE 24–3 Mechanisms of Drug-Induced Heart Failure
Drug
Anagrelide
Doxorubicin, epirubicin, mitoxantrone
Amitriptyline, carbamazepine, clomipramine, diltiazem,
disopyramide, encainide, ethmozine, fluorouracil,
imipramine, itraconazole, lidocaine, lorcainide,
mexiletine, nifedipine, nortriptyline, propranolol,
propafenone, protriptyline, tocainide, verapamil
Cabergoline, pergolide
Aspirin (non–low-dose), celecoxib, diclofenac, diflunisal,
etodolac, fenoprofen, flurbiprofen, ibuprofen,
indomethacin, ketoprofen, licorice, mefenamic acid,
megestrol, meloxicam, minoxidil, nabumetone, naproxen,
PEG lavage solution, pioglitazone, piroxicam,
prednisolone, rofecoxib, rosiglitazone, sodium-containing
antacids, sulindac, tenoxicam, tiaprofenic acid
Cyclophosphamide
Interferon alfa
Blue cohosh, imatinib
Paclitaxel
PEG = Polyethylene glycol.
um-channel blockers appear to have the strongest
negative inotropic effects,22,23,133 whereas amio-
darone, ibutilide, and dofetilide appear to have no
adverse negative inotropic effects. Although the
mechanism by which dronedarone causes worsen-
ing heart failure is unclear, the ANDROMEDA
investigators postulated that it may be related to
partial inhibition of a specific tubular organic
cation transporter in the kidney.25
Anthracyclines
Although the mechanisms of anthracycline-
induced heart failure have not been entirely eluci-
dated, they are thought to involve oxidative
damage.134 Formation of a toxic metabolite, gener-
CHAPTER 24 • Heart Failure 435
Mechanism
Positive inotropic activity, tachycardia
Thought to be related to reduced myocardial contractility.
Potential mechanisms:
Formation of a toxic metabolite
Generation of oxygen free radicals
Interference with ␤-adrenergic stimulation of the heart
Disturbances in intracellular calcium transport
Reduced adenosine diphosphate-stimulated respiration
Release of excessive vasoactive compounds such as his-
tamine and catecholamines
Reduced myocardial contractility (i.e., negative inotropic
effect)
Valvular fibrosis
Increased preload (i.e., fluid retention)
Endothelial damage, toxic metabolite
Impairment of myocyte metabolism
Increased oxygen demand
Toxic cardiomyopathy
Potential exacerbation of anthracycline-induced
cardiotoxicity
ation of oxygen free radicals, interference with ␤-
adrenergic stimulation of the heart, disturbances in
intracellular calcium transport, reduced adenosine
diphosphate–stimulated respiration, or release of
excessive vasoactive compounds such as histamine
and catecholamines have all been suggested as pos-
sible mechanisms.134,135 Although anthracycline-
induced heart failure is generally considered
irreversible, case reports of complete recovery after
doxorubicin-induced cardiac dysfunction have
been published.106,134,136
Trastuzumab
The mechanism of trastuzumab-induced cardiac
dysfunction is unknown, but it is different from
TisdaleC24_428-444 1/12/10 2:51 PM Page 436
436 SECTION VI • Drug-Induced Cardiovascular Diseases
that induced by the anthracyclines.96 In contrast to
the effect of anthracyclines, trastuzumab car-
diotoxicity is associated with a loss of contractility,
rather than myocyte death.137 This is supported by
myocardial biopsies from patients with trastuzum-
ab cardiac dysfunction, which do not show typical
ultrastructural changes on electron microscopy.138
Data from in vivo and in vitro studies suggest that
the mechanism of toxicity may be at least partly
directly related to HER-2 blockade and may be
associated with disruption of the epidermal growth
factor signaling system that is present within the
heart.96,139 Trastuzumab-induced cardiac dysfunc-
tion does not appear to be related to cumulative
trastuzumab dose, it is largely reversible (although
this has been questioned140), and rechallenge is
generally well tolerated.96
NSAIDs and COX-2 Inhibitors
The NSAIDs are a chemically diverse group of com-
pounds associated with a common mechanism of
action which is inhibition of the cyclooxygenase
enzyme. In patients with heart failure, renal home-
ostasis is maintained mostly by renal prostaglandin
E2 (PGE2). Inhibition of cyclooxygenase by
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
and diuretics.141 There appears to be little clinical-
ly important difference between these agents in
terms of their potential to exacerbate symptoms of
heart failure.141,142 The mechanism for sodium and
fluid retention associated with COX-2 inhibitors is
similar to that of NSAIDs.84,142
␤-Blockers
␤-Blockers likely cause their acute effect in patients
with heart failure by reducing contractility
through competitive antagonism of ␤1-receptors.
Longer-term treatment has been shown to improve
contractility and LVEF and to exert major benefi-
cial effects on the incidence of hospitalization and
mortality.122,124 Several mechanisms have been pos-
tulated to explain the beneficial effect of ␤-blockers
in heart failure, including reduction in long-term
exposure to catecholamines; restoration of myocar-
dial inotropic and chronotropic responsiveness;
reduction in circulating plasma concentrations of
vasoconstrictors such as norepinephrine, renin,
and endothelin; reduction in myocardial gene pro-
duction of inflammatory cytokines; attenuation of
left ventricular remodeling; and reduction in the
frequency of ventricular premature beats and inci-
dence of sudden cardiac death.143
CLINICAL PRESENTATION AND
DIFFERENTIAL DIAGNOSIS
The clinical presentation of patients with drug-
induced heart failure is not different from that
from other causes. Symptoms may occur gradually
following initiation of a culprit drug. Signs and
symptoms associated with drug-induced heart fail-
ure are presented in Table 24–4.
The differential diagnosis of drug-induced ver-
sus other causes of exacerbation of symptoms of
heart failure may be difficult to distinguish from
other common precipitants, such as sodium and
fluid excesses, ischemia, poor adherence to medical
therapy, uncontrolled hypertension, arrhythmias
(especially atrial fibrillation), systemic infections,
impairment in kidney function, anemia, thyrotox-
icosis, ethanol ingestion, pulmonary embolism,
and respiratory insufficiency (Table 24–5).26,108-112
In general, a temporal sequence of administration
of a new potentially offending agent (or dose
increase) with gradually increasing symptoms of
TABLE 24–4 Signs and Symptoms Associated
with Drug-Induced Heart Failure
• Ascites
• Jugular venous distention
• Hepatojugular reflux
• Hepatomegaly
• Peripheral edema
• Rales
• Pleural effusion
• Pulmonary edema
• Third heart sound (S3)
• Gallop rhythm
• Abdominal pain
• Nausea
• Bloating
• Cough
• Dyspnea
• Hemoptysis
• Orthopnea
• Paroxysmal nocturnal dyspnea
• Nocturia
• Weakness
• Fatigue
• Decreasing cognitive function (especially in older
patients)
TisdaleC24_428-444 1/12/10 2:51 PM Page 437

CHAPTER 24 • Heart Failure 437

heart failure heightens the suspicion of a drug-

induced cause. TABLE 24–6 Risk Factors for Drug-Induced
For most drugs that induce heart failure, wors- Heart Failure
ening symptoms of heart failure begin shortly Antiarrhythmic Agents
(within days) after initiation of therapy with the • Preexisting left ventricular dysfunction
drug or increasing the dose. For those drugs caus- Glitazones
ing fluid retention, plasma volume expansion may • Preexisting left ventricular dysfunction
take several days to manifest in symptoms of dysp- • History of myocardial infarction
nea. The onset of anthracycline-induced heart fail- • History of symptomatic coronary artery disease
ure has been well characterized. Von Hoff et al.15 • Hypertension
reported an average time of onset of symptoms of • Left ventricular hypertrophy
heart failure of 33 days, with a range of 0 to 231 • Significant aortic or mitral valve disease
days after the last drug administration. • Advanced age (>70 yr)
• Long-standing diabetes (>10 yr)
• Preexisting edema
RISK FACTORS • Current treatment with loop diuretics
• Development of edema or weight gain
Risk factors for drug-induced heart failure are pre- • Insulin coadministration
sented in Table 24–6. The most important risk fac- • Chronic kidney disease
tor for the development of drug-induced heart
Anthracyclines
failure is preexisting symptomatic or asympto-
• Cumulative doxorubicin dose (550 mg/m2)
matic left ventricular dysfunction.106 In general,
• Three-week schedule of administration
older patients are more susceptible to drug-induced
• Advancing age (adults)
diseases; whether this factor is independent of left
• Concomitant cardiac irradiation
ventricular function is not known.
• Concomitant use of cyclophosphamide, amsacrine,
fluorouracil, dactinomycin, mithramycin, mitomycin,
Glitazones or vincristine
• Children:
In their review of 111 consecutive patients with
• Higher cumulative dose
diabetes and systolic heart failure treated with a gli-
• Cardiac irradiation
tazone, Tang et al.50 noted upon univariate analy-
• Age at treatment (<4 yr)
ses that females and insulin users appeared to have
• Maximal dose within 1 week (> 45 mg/m2)
a higher risk of fluid retention. Interestingly, these
• Time since treatment (within 1 wk of treatment)
authors found no association between the baseline
• Use of daunorubicin (as opposed to doxorubicin)
severity of heart failure and the occurrence of fluid
• Amsacrine
retention. Risk factors for glitazone-induced heart
• Black race
failure, including those described by the American
• Female sex
• Trisomy 21
Trastuzumab
TABLE 24–5 Conditions to Consider in the • Older age
Differential Diagnosis of Drug-Induced Heart • Higher body-mass index
Failure • Antihypertensive therapy
• Lower pre-trastuzumab left ventricular ejection
• Sodium and fluid excesses fraction
• Myocardial ischemia • Concurrent anthracycline use
• Poor adherence to medical therapy • Cumulative anthracycline dose
• Uncontrolled hypertension
• Arrhythmias (especially atrial fibrillation)
• Systemic infections
Heart Association/American Diabetes Association
• Impairment in kidney function
consensus statement,51 are presented in Table 24–6.
• Anemia
• Thyrotoxicosis
• Ethanol ingestion Antiarrhythmic Agents
• Pulmonary embolism
As with most other heart failure–inducing agents,
• Respiratory insufficiency
the predominant risk factor for the development of
TisdaleC24_428-444 1/12/10 2:51 PM Page 438
438 SECTION VI • Drug-Induced Cardiovascular Diseases
this complication is preexisting left ventricular
dysfunction.24 Unfortunately, this is usually the
subgroup of patients at highest risk for sudden car-
diac death.
Anthracyclines
Risk factors for anthracycline-induced heart failure
have been well described (Table 24–6).15,17,134,135
Von Hoff et al.15 reported a continuum of increas-
ing risk of heart failure with increasing cumulative
dose of doxorubicin. The schedule of administra-
tion also appears to influence the risk of doxoru-
bicin-induced heart failure; weekly doses were
associated with a significantly lower incidence of
heart failure as compared with larger doses on a 3-
week schedule. There is a general increase in the
risk of development of doxorubicin-induced heart
failure with increasing age, although in children,
defined in this study as younger than 15 years of
age, the incidence appears somewhat higher as
compared with the adult population. All three of
these risk factors remained as independent predic-
tors of the development of heart failure after mul-
tivariate analysis.15 The use of other antitumor
therapies such as cardiac irradiation and specific
antineoplastic agents may also increase the risk.135
Risk factors for drug-induced heart failure in chil-
dren receiving anthracycline therapy are also pre-
sented in Table 24–6. Kremer et al.17 determined
that the multivariate risk factors were a maximal
dose >45 mg/m2 within 1 week and the use of
daunorubicin.
Trastuzumab
Risk factors for trastuzumab-induced cardiac dys-
function include old age,93 higher body-mass
index,117 antihypertensive therapy,144 lower pre-
trastuzumab LVEF,117 concurrent anthracycline
use,93 and cumulative anthracycline dose.117
MORBIDITY AND MORTALITY
In general, the mortality associated with heart fail-
ure is very high, with an annual mortality risk of
5% to 10% in patients with mild disease and up to
30% to 40% in those with more advanced disease.3
The incidence of in-hospital mortality associated
with heart failure is 3.5% to 15%.4,6 Moreover,
about 20% to 50% of patients discharged alive
from the hospital with heart failure will be read-
mitted within the next 6 to 12 months.4,145
Specific data regarding the incidence of mor-
bidity and mortality associated with drug-induced
TABLE 24–7 Approaches to Help Prevent Drug-
Induced Heart Failure
• Avoid potentially causative agents
• Prevent anthracycline-induced cardiomyopathy with
coenzyme Q10, carnitine, pretreatment with antihist-
amines, anti-adrenergics, cromolyn sodium, probucol,
or dexrazoxane
• Prevent ␤-blocker–induced heart failure by starting at
low doses with slow careful titration of doses over
6–8 wk.
heart failure are scarce. Doxorubicin-induced heart
failure has been reported to have a mortality rate
between 30% and 60%.15,135 Clearly, there is a need
for more epidemiologic data to address the magni-
tude of this problem.
PREVENTION
Obviously, the best preventive measure is to avoid
the offending agents (Table 24-7). Although this is
not always possible, particular caution should be
exercised in patients with preexisting left ventricu-
lar dysfunction.
Because of the high incidence of drug-induced
heart failure, diltiazem, verapamil, disopyramide,
flecainide, and propafenone should be considered
as contraindicated in patients with heart failure or
asymptomatic left ventricular dysfunction (LVEF
<0.40). As mentioned previously, felodipine and
amlodipine are safer alternatives in patients with
heart failure, as compared with nondihydropyri-
dine calcium-channel blockers or nifedipine. As
defined by current heart failure guidelines,
implantable cardioverter–defibrillators (ICDs) and
biventricular devices may be preferable over antiar-
rhythmic agents in certain situations.1,146 In gener-
al, patients with diabetes and heart failure should
be treated in a similar manner to those without
heart failure, with the exception that diabetes-
related comorbidities may influence drug doses
and monitoring of therapy. Alternatives to glita-
zones for blood-glucose control include insulin
secretagogues (e.g., sulfonylureas, meglitinides),
metformin (in those with an estimated glomerular
filtration rate >30 mL/min), ␣-glucosidase
inhibitors, incretin agents, and insulin.147,148
A number of agents have been suggested for
reducing the incidence of anthracycline-induced
cardiomyopathy,134 including coenzyme Q10, car-
nitine, pretreatment with antihistamines, anti-
adrenergics, cromolyn sodium, probucol,149
TisdaleC24_428-444 1/12/10 2:51 PM Page 439
dexrazoxane, N-acetylcysteine, vitamin E, amifos-
tine, carvedilol, ACE inhibitors, vitamin A, vitamin
C, selenium and glutathione.150 Dexrazoxane
(60–900 mg/m2 with 60 mg/m2 of doxorubicin or
500 mg/m2 with 50 mg/m2 of doxorubicin) is indi-
cated for reduction of the incidence and severity of
cardiomyopathy associated with doxorubicin in
women with breast cancer who received a cumula-
tive dose of 300 mg/m2 and who would benefit
from further doxorubicin administration.134
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-
cline, replacing bolus administration with slow
infusion, and using liposomal anthracyclines in
place of traditional formulations.
Depending on the indication, several alterna-
tives to NSAIDs or COX-2 inhibitors exist. For
example, for the treatment of osteoarthritis in the
presence of heart failure, nonpharmacologic (e.g.,
physical therapy) and traditional pharmacologic
(e.g., acetaminophen, intraarticular injections) and
nontraditional pharmacologic (e.g., glucosamine)
therapies may be preferable. In patients initiated
on ␤-blockers for heart failure, starting at low doses
with slow and careful of titration of doses over 6 to
8 weeks or more will help to minimize adverse
effects on ventricular function.1,2,124
MANAGEMENT
The management of acute exacerbations of heart fail-
ure symptoms includes aggressive diuresis and gener-
al supportive care.1,151 Following the discontinuation
of therapy with the offending agent, management of
drug-induced heart failure exacerbations is the same
as the usual management of heart failure. Generally,
recovery of the myocardium is related to the elimina-
tion half-life of the offending agent (the exception is
doxorubicin, with an average onset of recovery of 30
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
therapies (and at target doses), including ACE
inhibitors, ␤-blockers, and, in selected patients,
spironolactone or digoxin or both. 1,2
The high prevalence of heart failure and the
clinical fragility of such patients suggest that close
monitoring by pharmacists can have a great
impact. In a systematic review by Koshman et al. of
12 randomized trials including 2,060 patients, the
addition of a pharmacist to the heart failure team
resulted in a 31% reduction in heart failure hospi-
talizations.152 Pharmacists can identify patients at
CHAPTER 24 • Heart Failure 439
risk for drug-induced heart failure, identify drug-
induced causes of exacerbations of symptoms of
heart failure, guide treatment choices to avoid
agents that could exacerbate heart failure, institute
appropriate preventive measures when necessary,
counsel patients with heart failure on the use of
nonprescription medications, and ensure that
patients are receiving all proven efficacious thera-
pies for heart failure (ACE inhibitors, ␤-blockers,
spironolactone, digoxin) at target doses.
INFORMATION FOR PATIENTS
When the use of a potentially offending agent is
unavoidable in patients with left ventricular dys-
function, patients should be alerted to the signs and
symptoms of heart failure. Early detection and treat-
ment of drug-induced heart failure may prevent
hospitalization or death. This is particularly impor-
tant in light of studies that have shown that, even in
patients with long-standing heart failure, knowledge
of the signs and symptoms of heart failure is very
poor.153,154 All patients with heart failure should be
alerted to the dangers of nonprescription therapies
such as nonprescription NSAIDs, licorice-containing
herbal remedies, and sympathomimetics such as
those in cough and cold preparations. Patients with
heart failure should consult their physician or phar-
macist prior to initiating therapy with any new
medications, including nonprescription and herbal
remedies. Education of patients and their families
and friends is very important to improve patients’
recognition of early warning symptoms and signs,
ensure early intervention before acute heart failure
deterioration, and avoidance of exacerbations of
drug-induced heart failure. In addition, patients
should weigh themselves daily to track changes in
body weight that might be indicative of fluid reten-
tion (>1 kg/day). In certain situations, patients may
be taught how to adjust their diuretic dose based on
these changes in body weight and symptoms.
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 CHAPTER 25
Supraventricular
Arrhythmias
D rugs may induce a variety of supraventricular
arrhythmias that may be associated with symp-
toms, hemodynamic instability, stroke, and, in some
cases, an increased risk of death. Supraventricular
arrhythmias that may be induced by drugs include
sinus bradycardia, atrioventricular (AV) nodal block-
ade, atrial fibrillation or flutter, atrial tachycardia,
and AV nodal reciprocating tachycardia.
SINUS BRADYCARDIA/
ATRIOVENTRICULAR (AV)
NODAL BLOCKADE
Sinus bradycardia is defined as a sinus rate <60
bpm.1 Drugs that inhibit sinus node function
resulting in sinus pauses or sinus arrest will also be
included in this section. Sinus pauses occur when
function of the sinus node is impaired transiently,
leading to “pauses” without p waves on the electro-
cardiogram (Figure 25–1).1,2 Sinus pauses are also
known as periods of sinus arrest.
22 minutes
23 minutes
28 minutes
30 minutes
TisdaleC25_445-484-corrected, marks.pdf 1
James E. Tisdale
AV nodal blockade occurs when conduction of
impulses from the atria to the ventricles through the
AV node is inhibited.3 AV nodal blockade is classified
as first, second, or third degree. First degree AV nodal
blockade is defined as prolongation of the PR inter-
val to >0.2 seconds on an electrocardiogram (ECG).
Second degree AV block is a progression of AV nodal
dysfunction to the point at which some impulses are
not conducted from the atria to the ventricles. Third
degree AV nodal blockade, often referred to as “com-
plete heart block” or “AV dissociation,” is defined by
the absence of a relationship between atrial and ven-
tricular depolarization. During third degree AV nodal
blockade, atrial depolarization occurs independently
of ventricular depolarization, as a result of the com-
plete inability of the AV node to conduct impulses.3
CAUSATIVE AGENTS
Sinus bradycardia with or without sinus pauses
may be associated with a wide variety of drugs
(Table 25–1).4-330 In addition to occurring as a result
FIGURE 25–1. Sinus pauses/sinus
arrest at several time points follow-
ing ibutilide 1.0 mg/kg in a patient
subsequently determined to have
underlying sinus node dysfunction.
Reproduced with permission from Amin
et al.136
445
12/13/2010 11:45:13 AM
 446 SECTION VI • Drug-Induced Cardiovascular Diseases

TABLE 25–1 Agents Implicated in Drug-Induced Sinus Bradycardia

Drug Incidence Level of Evidence
(see page xii for explanation)
4-6
Adenosine 1–8% A
Adrenergic b-receptor blockers7,8 0.6–3.8% A
Amiodarone9-11 0–3%a A
Baclofen12-14,b NK C
Bupivicaine15,16 NK C
Carbamazepine17,18 NK C
Cimetidine19-25 NK C
Cisplatin26-28 NK B
Citalopram29-31 0.1–1.0% C
Clonidine32-58 0–17.5% A
Clozapine59,60 NK C
Cocaine61 NK B
Dexmedetomidine62-79 4.4–55% A
Diazepam21,b NK C
80-83
Digoxin 0 –7% B
Diltiazem84-96 5–16% A
Dipyridamole97-103,c 0.5–6.7% B
Disopyramide104-107 0 –4% B
Donepezil108-111 0.6% B
Dronedarone112,113 0.7–2.3% A
Escitalopram114 NK C
Etidocaine15 NK C
Flecainide115-121 2.0–13.2% B
Fluoxetine122-128 NK B
g-Hydroxybutyric acid129-131 NKd B
Halothane132-135 11–24% A
Ibutilide136-139 0 –4.5% B
Isradipine140,b NK C
Ketamine141-145 0–5.5%e B
Lidocaine146-151 NK C
Methadone152-154 NK C
Methylprednisolone155-161 NK B
Milrinone162 0–13% A
Neostigmine163-174 OR 2.7 (95% CI, 1.4–5.4) B
Nicardipine175,176 0–10% B
Nitroglycerin177-185 0–0.7% B
Olanzapine186-189 0.7% B
Paclitaxel190-198 3–29% A
Pentazocine199 5%f B
(Continued)

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 CHAPTER 25 • Supraventricular Arrhythmias 447

TABLE 25–1 Agents Implicated in Drug-Induced Sinus Bradycardia (Continued)

Drug Incidence Level of Evidence

Propafenone200-203 0.7%g B
10%h B
Propofol204-216 0–50% (14.7% in analysis B
of combined studies)
Physostigmine166,217,218 NK B
Pyridostigmine166 NK C
Ranitidine219-227 NK C
Remifentanil228-240 0–39% A
Risperidone241,242 NK C
Sevoflurane133,243-252 0–53% A
Sotalol253-274 2.5–17.2% A
Succinylcholine275-287 0–50% A
Tacrolimus288,289 NK C
Thalidomide290-301 3.2–53% A
Verapamil132,302-330 0–11% A
CI = confidence interval; NK = not known; OR = odds ratio.
a
May be as high as 10% in patients receiving high doses (3 g over 24 hr) of intravenous amiodarone.
b
In overdose.
c
Reported with intravenous use
d
Incidence in g-hydroxybutyric acid intoxication: 38%.130
e
Incidence as high as 21.1% in infants.143
f
Intramuscular administration in children.
g
Oral propafenone.
h
Intravenous propafenone.

of drugs administered orally or intravenously, sinus
bradycardia and sinus pauses may be induced by
drugs administered as eye drops. Numerous cases
of sinus bradycardia associated with topical adren-
ergic b-receptor antagonists (b-blockers) have been
reported.331,332 The incidence of sinus bradycardia
associated with topical timolol is significantly
higher (18.4%) than that associated with topical
carteolol (4.5%).331 The lower incidence of sinus
bradycardia associated with carteolol may be a
result of the intrinsic sympathomimetic activity of
the drug.
Drugs that have been reported to cause AV
nodal blockade are listed in Table 25–2.4,5,17,83,86,
90,105,107,111,115,190-192,333-447
EPIDEMIOLOGY
The overall incidence of drug-induced sinus brady-
cardia or AV nodal blockade is unknown. The inci-
dence of sinus bradycardia and sinus pauses associ-
ated with specific agents, where known, is present-
ed in Table 25–1, and the incidence of
drug-induced AV nodal blockade associated with
specific drugs, where known, is presented in Table
25–2.
Amiodarone has been reported to cause sinus-
node and AV nodal bradyarrhythmias requiring
pacemaker insertion.11 In a study of 15,824
patients with atrial fibrillation and a history of
myocardial infarction who were receiving amio-
darone, the incidence of pacemaker implantation
was 2.2% per person-year (mean duration [±SD] of
follow-up, 1.8±1.5 years), and was 5.2% per per-
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
2.14 (95% confidence interval [CI] 1.30 to 3.54).448
Although the incidence of sinus bradycardia asso-
ciated with conventional doses of intravenous
amiodarone (1 to 2 g/24 hr) is similar to that asso-

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 448 SECTION VI • Drug-Induced Cardiovascular Diseases

TABLE 25–2 Agents Implicated in Drug-Induced Atrioventricular Nodal Blockade

Drug Incidence Level of Evidence
(see page xii for explanation)
333,334
Aconite NK C
Adenosine4,5,335-351 3–11% A
Adrenergic b-receptor blockers352-361 NK A
Amiodarone357,362-366 0–14.8% A
Amitriptyline367,368 NK C
Bupivacaine369,370 3.5% B
Carbamazepine17,371-376 NK C
Chloroquine377-379 NK C
Cimetidine380 NK C
Citalopram381 NK C
Clonidine382-385 NK C
Cocaine386 NK C
Digoxin83,387-402 NK B
Diltiazem86,90,359,403-405 0–2% A
406-408
Dipyridamole NK C
Disopyramide105,107,409-411 0–2% B
Donepezil111,412 NK C
Etomidate413 NK C
Flecainide115,414 NK C
Guanabenz415 NK C
Hydroxychloroquine416 NK C
Imipramine417,418 NK C
Nicardipine419 NK C
Paclitaxel190-192,420 0 –4.4% B
Pentamidine421 NK C
Phenylpropanolamine422,423 NK C
Propafenone424-426 0.3% A
Propofol427-429 NK C
Pyridostigmine430 NK C
Sotalol431 0 –4.2% B
Thioridazine432,433 NK C
Verapamil359,385,405,434-447 0–8% A
NK = not known.

ciated with oral amiodarone,449 the incidence may
be as high as 10% when doses of 3 g per 24 hours
are administered.450
Sinus bradycardia or arrest or AV nodal blockade
may be caused by digoxin, primarily in overdose or
other situations in which serum digoxin concentra-
tions become elevated.83 The overall incidence of
sinus bradycardia or AV nodal blockade associated
with digoxin is unknown. In an analysis of patients
with a discharge diagnosis of digoxin intoxication,
“definite” sinus bradycardia and sinus pauses <2 sec-
onds were documented in 26% and 19%, respective-
ly, of those with digoxin intoxication.83 In addition,
“definite” second or third degree AV nodal blockade
was documented in 33% of patients with digoxin
intoxication.83 Sotalol has been reported to cause

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clinically important sinus bradycardia and sinus
pauses in up to 17.2% of patients being treated for
atrial fibrillation, with 2.5% requiring permanent
pacemaker implantation.269
Zelster et al.359 reviewed a series of 169 consec-
utive patients admitted or discharged with the
diagnosis of second or third degree AV nodal block-
ade that was not caused by acute myocardial
infarction, vasovagal syncope, radiofrequency
ablation, or digitalis toxicity. Of these, 54% were
receiving therapy with b-blockers with or without
diltiazem, diltiazem alone, or verapamil. The inves-
tigators reported that drug discontinuation was fol-
lowed by resolution of AV nodal blockade in 41%
of patients, but that 56% of these patients subse-
quently had recurrence of AV nodal blockade in
the absence of causative drugs. Based on their cri-
teria for causation, the investigators concluded
that drugs were the specific cause of AV nodal
blockade in only 15% of the patients who were
receiving therapy with b-blockers with or without
diltiazem, diltiazem alone, or verapamil.359
MECHANISMS
Drug-induced sinus bradycardia may be caused by
inhibition of automaticity of the node, slowing of
sinus node conduction, or prolongation of sinus
node repolarization (Table 25–3). AV nodal block-
ade may be caused by agents that inhibit AV node
conduction or prolong AV node repolarization
(Table 25–4). Both the sinus node and the AV node
are heavily influenced by sympathetic and
parasympathetic nervous system activity. Drugs
that inhibit activity of the sympathetic nervous
TABLE 25–3 Mechanisms of Drug-Induced Sinus Bradycardia
Drug
All drugs that may cause sinus bradycardia (except nitrates)
Adrenergic b-receptor blockers
Clonidine
Neostigmine, physostigmine, pyridostigmine
Nitroglycerin
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CHAPTER 25 • Supraventricular Arrhythmias 449
system (e.g., b-blockers) and drugs that stimulate
the parasympathetic nervous system (e.g., neostig-
mine, physostigmine, pyridostigmine) may cause
sinus bradycardia or AV nodal blockade. The action
potentials of both the sinus node and the AV node
depend primarily on calcium and sodium flux, and
calcium or sodium channel inhibitors may cause
sinus bradycardia, AV nodal blockade, or both.
Nitrates may cause a syndrome associated with
sinus bradycardia and hypotension.177-185 Sinus
bradycardia induced by nitrates is an idiosyncratic
reaction. This syndrome resembles neurocardio-
genic syncope, but may occur when patients are in
the supine position. The mechanism of nitrate-
induced sinus bradycardia remains unclear, but
evidence suggests that nitrates may stimulate
peripheral sensory receptors with vagal afferents to
the medulla, resulting in sympathetic nervous sys-
tem inhibition via stimulation of central a2-recep-
tors (Table 25–3).451
CLINICAL PRESENTATION AND
DIFFERENTIAL DIAGNOSIS
Normal heart rate is usually defined somewhat
arbitrarily as ranging between 60 and 100 bpm.
However, many individuals routinely have heart
rates <60 bpm and even <50 bpm without evidence
of symptoms. Patients with symptomatic sinus
bradycardia resulting in the need for medical atten-
tion typically have heart rates between 30 and 50
bpm, resulting in hemodynamic compromise.
Signs and symptoms associated with clinically
important sinus bradycardia and sinus pauses are
listed in Table 25–5.1
Mechanism
Inhibition of automaticity of the sinus node and/or slowing
of sinus node conduction and/or prolongation of
sinus node repolarization
Inhibit activity of sympathetic nervous system, leading to
inhibition of automaticity of sinus node
Stimulates central a2-receptors, reducing release of
norepinephrine
Stimulate activity of the parasympathetic nervous system,
leading to inhibition of automaticity of sinus node
Stimulates peripheral sensory receptors with vagal afferents
to the medulla, resulting in sympathetic nervous system
inhibition via stimulation of central a2-receptors
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 450 SECTION VI • Drug-Induced Cardiovascular Diseases
TABLE 25–4 Mechanisms of Drug-Induced Atrioventricular (AV) Nodal Blockade
Drug
All drugs that may cause AV nodal blockade
Adrenergic b-receptor blockers
Clonidine
Neostigmine, physostigmine, pyridostigmine
First degree AV nodal block is a common elec-
trocardiographic phenomenon that is almost
always asymptomatic3, and is therefore not a drug-
induced disease as defined in this text. However,
second and third degree AV blockade can result in
bradycardia, leading to symptoms that result in the
need for medical attention or even requiring hospi-
talization.
Second degree AV block occurs most common-
ly in two distinct patterns. Mobitz type I second-
degree AV block (also known as Wenckebach) is
characterized by progressive prolongation of the
PR interval on ECG until a P wave is not followed
by a QRS complex (Figure 25–2).3 Mobitz type I is
usually caused by impulse conduction delay in the
AV node (as opposed to further down in the bun-
dle of His).1 Mobitz type II second degree AV block
is typified by constant PR intervals with abrupt,
intermittent absence of QRS complexes (Figure
25–3). Mobitz type II second degree AV block often
occurs in specific patterns with P wave to QRS com-
plex ratios such as 2:1, 3:1, or 4:1. This type of sec-
ond degree AV block is likely caused by
impulse-conduction delay in the bundle of His.
During third degree AV nodal blockade, the AV
node is completely unable to conduct impulses,
and atrial depolarization occurs independently of
ventricular depolarization. Therefore, P waves and
TABLE 25–5 Signs and Symptoms Associated
with Drug-Induced Sinus Bradycardia and
Atrioventricular Nodal Blockade
• Dizziness
• Light-headedness
• Fatigue
• Weakness
• Syncope
• Chest pain
• Symptoms of heart failure
TisdaleC25_445-484-corrected, marks.pdf 6
Mechanism
Inhibition of conduction through the AV node
Inhibit activity of sympathetic nervous system, leading to
inhibition of conduction through the AV node
Stimulates central a2-receptors, reducing release of norepi-
nephrine
Stimulate activity of the parasympathetic nervous system,
leading to inhibition of conduction through the AV node
QRS complexes are present on ECG but bear no
relationship to one another (Figure 25–4). Third
degree AV nodal blockade can occur either in the
AV node itself or further down in the bundle of
His.3
Second or third degree AV nodal blockade may
result in bradycardia, with heart rates in the range
of 40-60 bpm. Symptoms of second or third degree
AV nodal blockade are the same as those associated
with sinus bradycardia (Table 25–5).
Drug-induced sinus bradycardia or AV nodal
blockade must be distinguished from other causes
of sinus or AV node impairment. Dysfunction of
the sinus node unrelated to drug therapy is com-
mon, with a prevalence as high as 1 in 600 patients
over the age of 65 years.452 Intrinsic AV nodal
abnormalities also may occur during the aging
process. Transient sinus node dysfunction may
occur in the setting of acute myocardial ischemia
or infarction when the infarct/ischemia-related
vessel is the right coronary artery or the left cir-
cumflex artery, but permanent sinus-node damage
in this setting is uncommon. Myocardial infarction
may result in some degree of permanent AV nodal
dysfunction in some patients. Conditions to con-
sider in the differential diagnosis of drug-induced
sinus bradycardia or AV nodal blockade are listed
in Table 25–6.1
FIGURE 25–2. Mobitz type I second degree AV nodal
blockade associated with phenylpropanolamine.
Reproduced with permission from Woo et al.423
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1
2 after myocardial infarction. Rather, therapy with
3
FIGURE 25–3. Mobitz type II second degree AV nodal
blockade associated with amiodarone.
Reproduced with permission from Mangiardi et al.363
Drug-induced sinus or AV node dysfunction
can often be distinguished from non–drug-related
sinus bradycardia or AV nodal blockade. When a
patient with symptoms that appear to be related to
sinus bradycardia/sinus pauses/sinus arrest or AV
nodal inhibition seeks medical attention, therapy
with drugs known to induce sinus or AV node dys-
function should typically be discontinued. If the
sinus or AV node dysfunction persists after five
half-lives of the respective drug(s) have passed, a
drug-induced cause may be ruled out. While await-
ing drug washout, evaluation and diagnostic test-
ing for nonpharmacologic causes can be
performed, including determination of serum
potassium and magnesium concentrations, thyroid
function tests, and assessment for myocardial
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CHAPTER 25 • Supraventricular Arrhythmias 451
ischemia or infarction. However, it may not be pos-
sible or desirable in every case to discontinue ther-
apy with drugs suspected of causing sinus
bradycardia or AV nodal blockade. For example, b-
blocker therapy should not generally be discontin-
ued in a patient being treated for heart failure or
the b-blocker should be continued and implanta-
tion of a permanent pacemaker considered as a
means to protect against possible drug-induced
sinus or AV node dysfunction.
RISK FACTORS
Risk factors for drug-induced sinus bradycardia are
listed in Table 25–7.41,136,453 Conditions that may
result in elevated plasma concentrations of drugs
known to cause sinus bradycardia increase the risk.
Patients with kidney disease who are receiving renal-
ly eliminated drugs that may cause sinus bradycar-
dia (atenolol, clonidine, digoxin) are also at
increased risk. Kidney disease has been identified as
a risk factor for sinus bradycardia associated with
clonidine.41 Drugs that have been reported to cause
sinus bradycardia that require dose adjustment in
patients with kidney disease are listed in Table 25–8.
In addition, concomitant use of drugs that inhibit
the hepatic metabolism of drugs known to induce
sinus bradycardia should be avoided (Table 25–9).454
Other interactions may result in sinus brady-
cardia. Dipyridamole inhibits the cellular uptake of
adenosine455; therefore, patients receiving adeno-
sine concomitantly with dipyridamole are at
increased risk of adenosine-associated sinus brady-
FIGURE 25–4. Third degree
AV nodal blockade associated
with carbamazepine.
Reproduced with permission
from Ide and Kamijo.376
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 452 SECTION VI • Drug-Induced Cardiovascular Diseases
TABLE 25–6 Conditions to Consider in the
Differential Diagnosis of Drug-Induced Sinus
Bradycardia or Atrioventricular Nodal Blockade1
Intrinsic causes
• Idiopathic degeneration due to aging
• Myocardial ischemia/infarction (transient)
• Infiltrative diseases (sarcoidosis, amyloidosis,
hemochromatosis)
• Collagen vascular diseases (systemic lupus erythe-
matosus, scleroderma, rheumatoid arthritis)
• Myotonic muscular dystrophy
• Surgical trauma (valve replacement, heart transplanta-
tion, correction of congenital heart disease)
• Infectious diseases (Chagas’ disease, endocarditis)
Extrinsic causes
• Autonomically mediated syndromes
• Neurocardiac syncope
• Carotid sinus hypersensitivity
• Situational disturbances (coughing, micturition,
defecation, vomiting)
• Hypothyroidism
• Hypothermia
• Electrolyte abnormalities
• Hyperkalemia
• Hypokalemia
• Hypermagnesemia
cardia/sinus pauses.6 A number of drugs inhibit the
elimination of digoxin, particularly amiodarone,456
verapamil,457 and quinidine,458 and concomitant
use of these drugs with digoxin increases the risk of
digoxin-induced sinus bradycardia, unless appro-
priate digoxin dose reduction is implemented. In
addition, patients receiving therapy with more
than one drug known to reduce heart rate are at
increased risk.41,459
Women are at greater risk for amiodarone-
induced bradycardia requiring implantation of a
permanent pacemaker.460 In a study of 1,005
patients with new-onset atrial fibrillation, the haz-
ard ratio for amiodarone use requiring a perma-
nent pacemaker was 4.69 (95% CI, 1.99 to 11.05)
in women, as compared with 1.05 (95% CI, 0.42 to
2.58) in men.460 Mechanisms for the increased risk
of bradycardia requiring pacemaker implantation
in women are unknown.
Specific risk factors for the majority of drug-
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
no significant differences in age, male sex, or pres-
ence of hypertension or ischemic heart disease
between patients receiving therapy with b-blockers
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TABLE 25–7 Risk Factors for Drug-Induced Sinus
Bradycardia or Atrioventricular (AV) Nodal
Blockade
Sinus bradycardia41,136,453
• Pretreatment heart rate <60 bpm
• Underlying sinus-node dysfunction (may occur with
advancing age)
• Impaired baroreflex control (risk factor for nitro-
glycerin-induced sinus bradycardia)
• Concomitant use of >1 sinus-node inhibiting drug
• Elevated plasma drug concentrations due to organ
dysfunction or drug interactions
Atrioventricular nodal blockade
• Concomitant use of >1 AV nodal blocking drug
• Pretreatment PR interval >0.2 sec
• Underlying AV nodal disease (may occur with
advancing age)
• Elevated plasma drug concentrations due to organ
dysfunction or drug interactions
• Hypothyroidism (may be a risk factor for amio-
darone-induced AV block)363
with or without diltiazem or verapamil and those
not receiving therapy with drugs that could induce
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-
ade induced by digoxin, and include the drug inter-
actions listed above, inadequate dose reduction in
patients with kidney disease, hypokalemia, hypo-
magnesemia, hypoxia, and hypothyroidism.461
MORBIDITY AND MORTALITY
The incidence of morbidity, hospitalization, or
death associated with drug-induced sinus bradycar-
dia or AV nodal blockade is unknown. Drug-
induced sinus bradycardia or AV nodal blockade
may result in the need for temporary or permanent
pacemaker implantation.11,30,448 In a population of
patients with new-onset atrial fibrillation, the
adjusted hazard ratio for amiodarone use leading
to a requirement for a permanent pacemaker was
2.01 (95% CI, 1.08 to 3.76).460 Death due to drug-
induced sinus bradycardia or AV block is likely very
uncommon.
PREVENTION
Drug-induced sinus or AV node dysfunction (or
both) is often preventable (Table 25–10). When
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 CHAPTER 25 • Supraventricular Arrhythmias 453

agents. Patients who are taking drugs with the

TABLE 25–8 Drugs Known to Cause Sinus potential to cause sinus bradycardia, sinus pauses,
Bradycardia or Atrioventricular Nodal Blockade or AV nodal blockade should be taught to monitor
That May Require Dose Adjustment in Patients their heart rate daily, and to consult their pharma-
with Kidney Disease cist or physician if heart rate falls below 50 bpm or
• Acebutolol if they experience symptoms of bradycardia (Table
• Atenolol 25–5). Combinations of drugs that may inhibit
• Baclofen sinus or AV node function should be minimized,
• Betaxolol but are not contraindicated if the benefits of such
• Bisoprolol therapy outweigh the risks.
• Carteolol Drug-induced sinus or AV node dysfunction
• Cimetidine may be prevented by not exceeding maximum
• Cisplatin (recommended to be avoided in cases of daily doses of drugs known to cause these drug-
preexisting renal dysfunction) induced diseases and by appropriate dose adjust-
• Clonidine ment of specific drugs to account for organ
• Dexmedetomidine dysfunction, drug interactions, or both.
• Digoxin Maintaining serum digoxin concentrations <2.0
• Disopyramide ng/mL may prevent digoxin-associated sinus or AV
• Flecainide node dysfunction. In certain circumstances, substi-
• Guanabenz tuting medications within a class may prevent
• Isradipine drug-induced sinus or AV node dysfunction. For
• Nadolol example, a patient with kidney disease who is
• Nicardipine receiving atenolol is at higher risk for atenolol-
• Ranitidine induced sinus bradycardia or AV nodal blockade as
• Sotalol a result of diminished atenolol clearance. In this
situation, replacing atenolol with a non–renally
cleared b-blocker such as metoprolol or propanolol
possible, drugs with the potential to inhibit sinus may reduce the likelihood of drug-induced sinus
or AV node function should be avoided in patients bradycardia or AV nodal blockade.
with known sinus or AV node dysfunction in the Patients receiving drugs known to inhibit AV
absence of a functioning pacemaker. Once a pace- nodal conduction should undergo a 12-lead ECG
maker has been implanted, however, patients with periodically and at least every 6 months. First
sinus node dysfunction may receive sinus degree AV block is not an absolute contraindication
node–inhibiting drugs, and patients with AV node to receiving AV nodal blocking drugs, but the PR
dysfunction may receive AV node–inhibiting interval should be monitored every 3 to 6 months

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

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 454 SECTION VI • Drug-Induced Cardiovascular Diseases
TABLE 25–10 Approaches to Help Prevent Drug-
Induced Sinus Bradycardia and Atrioventricular
(AV) Nodal Blockade
For all drugs that may cause sinus bradycardia, AV
block, or both
• Patient should take pulse daily, report if <50 bpm.
• Do not exceed maximum daily doses.
• Use combinations of drugs that may cause sinus
bradycardia or AV block only when necessary and
when the benefits likely outweigh the risks.
• Avoid sinus or AV node–inhibiting drugs in patients
with underlying sinus node dysfunction, unless a
functioning pacemaker is present (in the case of AV
node inhibiting drugs, there must be a functioning
ventricular pacemaker).
For digoxin
• Measure serum digoxin concentrations:
• If kidney function is changing.
• If a drug that interacts with digoxin is added to
therapy.
• Every 6 mo if there is no organ dysfunction or con-
comitant use of interacting drugs.
to ensure that AV nodal blockade is not progressing.
In addition, combinations of AV nodal blocking
drugs are best avoided in patients with pretreat-
ment PR intervals >0.2 seconds. If the PR interval
progresses to >0.2 seconds while on AV nodal block-
ing therapy, it is not necessary to discontinue ther-
apy, but more frequent ECG monitoring is
recommended and administration of additional AV
nodal blocking agents should be avoided.
MANAGEMENT
Management options for patients with drug-
induced sinus bradycardia or AV nodal blockade are
presented in Table 25–11. In some cases, a reduction
in dose of the offending medication may be suffi-
cient, but in most cases in which drug-induced sinus
or AV node dysfunction has resulted in a hospital-
ization, discontinuation of therapy is necessary. In
the case of sinus bradycardia or AV block induced by
adenosine, treatment is not usually required because
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.
Percutaneous insertion of a temporary pacemak-
er may be necessary. If the patient is subsequently
diagnosed with underlying intrinsic sinus or AV node
dysfunction, therapy with the offending medication
may be reinitiated after the implantation of a perma-
nent pacemaker. In severe cases, intravenous atropine
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TABLE 25–11 Management of Drug-Induced
Sinus Bradycardia or Atrioventricular (AV) Nodal
Blockade
• Discontinue the causative agent
• Temporary pacemaker
• If underlying sinus or AV node dysfunction—perma-
nent pacemaker may be necessary (if AV node dys-
function, must be a ventricular pacemaker)
• In severe cases: atropine 0.5–1.0 mg every 3–5 min-
utes until heart rate increases or total dose of 0.04
mg/kg is administered
• If due to calcium-channel blocker or b-blocker over-
dose:
• Gastric lavage
• Activated charcoal 25–50 g in an aqueous slurry of
120–240 mL water
• Glucagon 2.0–5.0 mg intravenously
• Temporary pacemaker, if necessary
may be administered in doses of 0.5 to 1.0 mg every
3 to 5 minutes to a total dose of 0.04 mg/kg, the dose
at which full blockade of the parasympathetic nerv-
ous system occurs in humans.462
If the drug-induced bradycardia or AV block is
a result of an overdose of verapamil, diltiazem or a
b-blocker, gastric lavage may be performed if the
patient presents within 1 hour of ingestion.
Activated charcoal may be administered and may
be particularly useful if the drug was ingested in
the form of a sustained-release preparation.
Although administration of calcium salts has been
shown to be effective for reversing the hemody-
namic effects of calcium-channel blockers, calcium
salts have not been particularly effective for revers-
ing the electrophysiologic effects of these drugs.463
Glucagon 2 to 5 mg intravenously may be effective
for reversing the bradycardic effects of calcium-
channel blockers or a b-blocker.463,464 Insertion of a
temporary pacemaker may be necessary.
For patients with a history of myocardial infarc-
tion or heart failure in whom sinus bradycardia or
AV nodal blockade induced by b-blockers develops,
implantation of a permanent pacemaker may be
necessary to allow the patient to continue therapy
with these agents,465 which have been shown to
prolong survival in these specific conditions.466,467
INFORMATION FOR PATIENTS
Patients should be instructed that specific drug(s)
may cause the heart rate (pulse) to become slower.
Patients should be taught to take their pulse and
to monitor their heart rate daily. Patients should
be instructed to consult their pharmacist or physi-
12/13/2010 11:45:14 AM

cian if their heart rate falls below 50 beats per
minute, or if they feel lightheaded, dizzy, tired,
weak, short of breath, or experience chest pain.
ATRIAL FIBRILLATION/
ATRIAL FLUTTER
Atrial fibrillation is a supraventricular arrhyth-
mia that is characterized on ECG by an irregular-
ly irregular pattern of narrow QRS complexes, an
absence of discernible P waves, and an undulat-
ing baseline (Figure 25–5). Atrial flutter is a
supraventricular arrhythmia that is characterized
on ECG by a regular pattern of narrow QRS com-
plexes, with discernible P waves that exhibit a
“sawtooth” appearance (Figure 25–6). Atrial flut-
ter is often associated with a ratio of P waves to
QRS complexes of 4:1, 3:1 or, in some cases, 2:1.
CAUSATIVE AGENTS
Drugs that have been associated with atrial fibrilla-
tion or atrial flutter are listed in Table
25–12.123,162,196,218,349,468-545 The majority of drugs
that have been associated with induction of atrial
fibrillation or flutter are cardiovascular agents, but
drugs from other classes have been implicated as
well, including the bisphosphonate drugs alen-
dronate496,497 and zoledronic acid.545
EPIDEMIOLOGY
The overall incidence of drug-induced atrial fibrilla-
tion or flutter is not known, but it is likely very low.
Adenosine has been reported to cause a substantial
incidence of atrial fibrillation in patients undergo-
ing treatment for AV nodal reentrant tachycardia.475
Although the incidence of alcohol-induced atrial
fibrillation (often referred to as the “holiday heart”
syndrome) is unknown, in a case–control study of
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CHAPTER 25 • Supraventricular Arrhythmias 455
patients with acute idiopathic atrial fibrillation, 62%
of cases were associated with heavy alcohol use.489
In a prospective cohort study of the association
between self-reported alcohol use and incident atri-
al fibrillation, moderate alcohol intake was not asso-
ciated with new-onset atrial fibrillation. However,
consumption of 35 or more drinks per week was
associated with a hazard ratio for atrial fibrillation of
1.45 (95% CI, 1.02 to 2.04) in men.546 About 5% of
cases of atrial fibrillation in men were estimated to
be attributable to heavy alcohol intake.
In a randomized study of the prevention of frac-
tures in postmenopausal women, the bisphospho-
nate drug alendronate was found to increase the risk
of “serious” atrial fibrillation (1.5% vs. 1.0% in the
placebo group; relative hazard, 1.51; 95% CI, 0.97 to
2.40; P = 0.07).496 However, alendronate did not
increase the risk of “all atrial fibrillation adverse
events.” In addition, in a case–control study in
women, a higher proportion of patients with atrial
fibrillation had ever used alendronate as compared
with those who had never used any bisphosphonate
(odds ratio of atrial fibrillation, 1.86; 95% CI, 1.09 to
3.15).497 Furthermore, another bisphosphonate drug,
zoledronic acid, was reported to increase the risk of
“serious” atrial fibrillation as compared with placebo
(1.3% vs. 0.5%, P<0.001).545 However, zoledronic acid
did not increase the risk of all atrial fibrillation events.
In a cohort study of 15,795 patients with fractures
treated with oral bisphosphonates, the adjusted risk
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
1.29).547 A database analysis of over 40,000 women
conducted in the United Kingdom showed no evi-
dence of an overall risk of bisphosphonate-associated
atrial fibrillation, but a potential increased risk of atri-
al fibrillation associated with alendronate during the
first few months of therapy.548 However, other studies
have not reported an increased risk of atrial fibrilla-
tion associated with bisphosphonates.549,550
Determining whether bisphosphonate drugs are asso-
ciated with atrial fibrillation requires further study.
FIGURE 25–5. Atrial
fibrillation induced by
albuterol.
Reproduced with permis-
sion from Breeden and
Safirstein.485
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 456 SECTION VI • Drug-Induced Cardiovascular Diseases
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
also uncommon, but has been reported to occur in
patients with atrial fibrillation who are receiving
Vaughan Williams class IC antiarrhythmic agents (fle-
cainide or propafenone) or amiodarone (Table 25–12).
MECHANISMS
Mechanisms by which some drugs induce atrial fib-
rillation or flutter are presented in Table 25–13. Atrial
fibrillation is believed to be induced by ectopic
impulses originating from pulmonary veins, atria, or
both, and it has been proposed that adenosine may
induce increased atrial ectopic activity, which may
then trigger the development of atrial fibrillation.475
In addition, atrial fibrillation is maintained by multi-
ple reentrant wavelets, and evidence indicates that
the shorter the wavelength, the more likely that atri-
al fibrillation develops and is sustained.551,552
Wavelength is the product of the atrial conduction
velocity and the atrial effective refractory peri-
od.551,552 Adenosine has been shown to shorten the
atrial effective refractory period, and therefore may
promote reduction in atrial wavelength and the
development of multiple reentrant atrial
wavelets.553,554 The mechanism of alcohol-induced
atrial fibrillation is believed to be related to increased
sympathetic nervous system stimulation.494
Mechanisms by which the bisphosphonate
drugs alendronate and zoledronic acid may cause
atrial fibrillation are unclear. It has been suggested
that bisphosphonate drugs may cause atrial fibrilla-
tion through the release of inflammatory
TisdaleC25_445-484-corrected, marks.pdf 12
cytokines,496,555 which have been associated with
the development of atrial fibrillation.556 Further
study is necessary to determine the mechanism of
bisphosphonate-induced atrial fibrillation and to
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
cause atrial fibrillation or atrial flutter have common-
ly been used for the management of these arrhyth-
mias. Despite the fact that flecainide has been shown
to be effective for the prevention and management of
atrial fibrillation, data from studies in animals indi-
cate that flecainide may shorten atrial conduction
velocity558 and wavelength,559 effects which may pro-
mote the development of atrial fibrillation.
Amiodarone-induced atrial fibrillation may, at least in
some cases, be due to amiodarone-induced thyrotox-
icosis.560.561 Dobutamine has been shown to shorten
atrial effective refractory periods,562 while theo-
phylline has been shown to increase atrial automatic-
ity.563 Mechanisms by which other drugs may induce
atrial fibrillation or flutter require further study.
CLINICAL PRESENTATION AND
DIFFERENTIAL DIAGNOSIS
The symptoms of drug-induced atrial fibrillation
and atrial flutter are related to the degree of tachy-
cardia and the resultant effect on blood pressure
and cardiac output (Table 25–14). The symptoms of
atrial fibrillation may be indistinguishable from
those of atrial flutter, and therefore atrial fibrilla-
tion and atrial flutter must be distinguished from
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 CHAPTER 25 • Supraventricular Arrhythmias 457

TABLE 25–12 Agents Implicated in Drug-Induced Atrial Fibrillation or Atrial Flutter

Drug Incidence Level of Evidence
(see page xii for explanation)
349,468-482 a
Adenosine 1–12% B
Albuterol483-485 NK C
Alcohol486-495 NK B
Alendronate496,497 0.5% A
OR, 1.86 (95% CI, 1.09–3.15)
Amiodarone498, 499 NK B
Caffeine500 NKb B
Diltiazem501 NK C
Dobutamine162,502-516 0–18% A
Enoximone513 8.3% A
Flecainide517,518 NK C
Fluoxetine123,519 NK C
Ipratropium bromide520 NK C
Levosimendan515 0–9.1% A
Loxapine519 NK C
Metaproterenol521 2.5% A
Methylprednisolone522-526 NK C
Milrinone162,527-530 2.9–5% A
Mitoxantrone531 1.4% B
Ondansetron532,533 NK C
Paclitaxel196,534 2% (atrial flutter) B
1–1.7% (atrial fibrillation)
Physostigmine218,535 NK C
Propafenone498,518,536 9%c C
Theophylline483,537-542 NK B
Verapamil543,544 5% C
Zoledronic acid545 0.8% A
CI = confidence interval; NK = not known; OR = odds ratio.
a
Atrial fibrillation, 1–11%, atrial flutter, 1%.
b
Espresso only.
c
Percent of patients with atrial fibrillation who develop new atrial flutter during propafenone therapy.536

one another (and from other tachyarrhythmias) by
ECG (Figures 25–5 and 25–6).
The onset of drug-induced atrial fibrillation or
flutter is variable, depending on the inducing drug.
Adenosine-induced atrial fibrillation or flutter occurs
within 1 minute of administration of this extremely
short-acting agent.349 In a study of amiodarone- or
propafenone-induced atrial flutter, the mean (±SD)
time of onset was 5.0+5.5 months after the initiation
of treatment,498 whereas atrial flutter has been
reported in association with flecainide therapy of 2
months’ duration.517 The duration of episodes of
drug-induced atrial fibrillation or flutter is also some-
what variable; a case of albuterol-induced atrial fibril-
lation lasted several hours,484 whereas atrial flutter
associated with amiodarone or propafenone may
require intervention to terminate the arrhythmia.498
Sinus rhythm was the preceding rhythm in 88%
of patients in whom atrial fibrillation associated with
adenosine developed, whereas the remaining 12% of
patients had atrial ectopic activity prior to the devel-
opment of atrial fibrillation.475 The mean ventricular
rate associated with adenosine-induced atrial fibrilla-
tion was 107+43 bpm.475 Adenosine-induced

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 458 SECTION VI • Drug-Induced Cardiovascular Diseases
TABLE 25–13 Mechanisms of Drug-Induced Atrial Fibrillation/Flutter
Drug
Adenosine, dobutamine, flecainide
Alcohol
Theophylline
Other drugs
TABLE 25–14 Signs and Symptoms Associated
with Drug-Induced Atrial Fibrillation/Flutter
• Palpitations
• Dizziness
• Light-headedness
• Shortness of breath
• Chest pain (if underlying coronary artery disease is
present)
• Near-syncope
• Syncope
episodes of atrial fibrillation tend to be of short dura-
tion. The mean duration of episodes of atrial fibrilla-
tion associated with adenosine was 5.6+6.7 minutes
(range, 8 seconds to 20.7 minutes).475
Conditions to consider in the differential diag-
nosis of drug-induced atrial fibrillation/flutter are
presented in Table 25–15. Non–drug-induced atrial
fibrillation/flutter must be considered; drug-induced
atrial fibrillation/flutter is more likely in patients
who are receiving drugs that have been reported to
cause atrial fibrillation or flutter, particularly in
patients with no known risk factors or causes for
non–drug-induced atrial fibrillation/flutter, such as
hypertension, ischemic heart disease, heart failure,
valvular heart disease, rheumatic fever, or hyperthy-
roidism, or in those who have undergone thoracic
surgery within the previous 2 to 5 days.
RISK FACTORS
Although all risk factors for drug-induced atrial fib-
rillation or flutter have not yet been fully charac-
terized, known risk factors are presented in Table
25–16. Atrial fibrillation associated with adenosine
does not appear to be related to sex or age and may
occur in patients with no history of atrial fibrilla-
tion.475 Atrial fibrillation induced by adenosine is
not related to the type of arrhythmia being treat-
ed.475 Premature atrial contractions occur signifi-
cantly more frequently in patients who have
experienced adenosine-induced atrial fibrillation
(100%) as compared with those who did not
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Mechanism
Shorten atrial effective refractory period/atrial wavelength
Sympathetic nervous system stimulation
Increases atrial automaticity
Unknown
TABLE 25–15 Conditions to Consider in the
Differential Diagnosis of Drug-Induced Atrial
Fibrillation/Flutter
• Atrial fibrillation or flutter not induced by drugs
• Sinus tachycardia
• Atrial tachycardia
• Atrioventricular nodal reentrant tachycardia
• Ventricular tachycardia
(58%), and therefore may be somewhat predictive
of impending drug-induced atrial fibrillation.475
Alcohol dose is a risk factor for alcohol-induced
atrial fibrillation. In one study, the mean dose of
alcohol consumed during the week prior to the
atrial fibrillation episode was 186g, as compared
with 86g in a control population in whom alcohol-
induced atrial fibrillation did not develop.493
Another study found that the risk of alcohol-
induced atrial fibrillation was increased in patients
who consumed more than an average of 30g alco-
hol daily.492 Alcohol withdrawal may increase the
risk of alcohol-induced atrial fibrillation.490
In patients receiving amiodarone for treatment
of atrial fibrillation, amiodarone-induced atrial flut-
ter does not appear to be related to age, sex, presence
of structural heart disease, left ventricular function,
or duration of atrial fibrillation; however, left atrial
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.
MORBIDITY & MORTALITY
Symptoms associated with drug-induced atrial fib-
rillation or flutter could potentially result in hospi-
talization or prolonged duration of stay in a
hospital or critical care unit, although prolonged
duration of hospital stay as a result of drug-
induced atrial fibrillation or flutter has not been
reported. Hypothetically, drug-induced atrial fibril-
lation could result in stroke, but this has not yet
been described. Death due to drug-induced atrial
fibrillation or flutter has not been reported.
12/13/2010 11:45:14 AM

TABLE 25–16 Risk Factors for Drug-Induced
Atrial Fibrillation/Flutter
Adenosine
• Premature atrial contractions
Alcohol
• Dose > 30g daily
• Withdrawal
Amiodarone
• Left atrial hypertrophy
Other drugs
• Unknown
PREVENTION
For the most part, specific methods of prevention
have not been determined. However, the risk of
alcohol-induced atrial fibrillation can be mini-
mized by avoiding binge drinking and excessive
doses of alcohol, and by consuming <30g alcohol
daily (Table 25–17).492,493 Moretti et al.524 reported
the case of a patient treated with intermittent
courses of high doses of intravenous methylpred-
nisolone for multiple sclerosis in whom recurrent
atrial fibrillation attributed to the corticosteroid
developed. Pretreatment prophylaxis with sotalol
was ineffective, but pretreatment prophylaxis with
oral propafenone 300 mg three times daily was
effective at preventing methylprednisolone-
induced atrial fibrillation.
MANAGEMENT
The causative agent should be discontinued. In a
series of cases of adenosine-induced atrial fibrilla-
tion, 67% of patients converted to sinus rhythm
spontaneously, whereas 33% required cardiover-
sion.475 Therefore, hemodynamically stable drug-
induced atrial fibrillation or atrial flutter is
associated with a high incidence of spontaneous
conversion, and treatment may not be necessary. In
patients who do not convert spontaneously to sinus
rhythm, intravenous drugs for ventricular rate con-
trol should be administered (Table 25–18).564 For
patients with normal left ventricular function, an
intravenous b-blocker or calcium-channel blocker
should be administered. Diltiazem may be preferred
over verapamil as a result of a lower risk of sympto-
matic hypotension.565 For patients with heart fail-
ure due to left ventricular dysfunction, intravenous
calcium-channel blockers and b-blockers should be
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CHAPTER 25 • Supraventricular Arrhythmias 459
TABLE 25–17 Approaches to Help Prevent Drug-
Induced Atrial Fibrillation/Flutter
Alcohol492,493
• Avoid binge drinking/excessive doses
• Consume <30g daily
Methylprednisolone524
• Propafenone 300 mg three times daily
Other drugs
• Administer lowest effective dose
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
therapy for ventricular rate control, or in patients
with atrial fibrillation/flutter in whom symptoms
are unacceptable, direct-current cardioversion
should be administered. However, if atrial fibrilla-
tion has been present for >48 hours, or if the dura-
tion of the episode of atrial fibrillation is unknown,
patients should undergo transesophageal echocar-
diography to rule out an atrial thrombus before
electrical or pharmacologic cardioversion is per-
formed.
After the administration of agents to control
the ventricular rate, drug-induced atrial fibrillation
or flutter should be converted to sinus rhythm,
using either elective direct-current cardioversion or
pharmacologic cardioversion. Acceptable agents
for pharmacologic cardioversion include amio-
darone, dofetilide, flecainide, ibutilide, or
propafenone (Table 25–18). If the atrial fibrillation
was induced by a sodium channel blocking agent,
conversion to sinus rhythm should be achieved
using direct-current cardioversion or ibutilide. It
should be noted, however, that the effectiveness of
antiarrhythmic drug therapy for drug-induced atri-
al fibrillation or atrial flutter has not been studied.
In patients with atrial fibrillation in whom new
atrial flutter induced by amiodarone or
propafenone develops, radiofrequency catheter
ablation of the isthmus between the tricuspid
annulus and the inferior vena cava has been used
to terminate the atrial flutter while allowing
patients to remain on antiarrhythmic drug therapy
for the management of the atrial fibrillation.498,499
Radiofrequency catheter ablation of drug-induced
atrial flutter is successful in 90% to 100% of
patients, and drug-induced atrial flutter did not
recur in 14 of 15 patients during a 1-year follow-up
period.498
If the drug-induced atrial fibrillation is a result
of a theophylline overdose, activated charcoal may
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 460 SECTION VI • Drug-Induced Cardiovascular Diseases

TABLE 25–18 Treatment Options for Drug-Induced Atrial Fibrillation564

Discontinue the offending agent.
Drug/Treatment Recommended Doses
Ventricular rate control in patients with normal left ventricular function
Esmolol Loading dose: 500 mcg/kg IV over 1 min
Maintenance infusion: 60–200 mcg/kg/min IV
Metoprolol 2.5–5 mg IV bolus over 2 min; up to 3 doses
Propranolol 0.15 mg/kg IV
Diltiazem Loading dose: 0.25 mg/kg IV over 2 min
Maintenance infusion: 5–15 mg/hour IV
Verapamil 0.075–0.15 mg/kg IV over 2 min
Ventricular rate control in patients with heart failure due to left ventricular systolic dysfunction
Digoxin 0.25 mg IV every 2 hr, up to total dose of 1.5 mg
Amiodarone Loading dose: 150 mg IV over 10 min
Maintenance infusion: 0.5–1 mg/min IV
Conversion to sinus rhythm
Direct-current cardioversion 200 J initially, followed by 360 J, if necessarya
Amiodaroneb Loading dose: 5–7 mg/kg IV over 30–60 min
Maintenance dose: 1.2–1.8 g daily by continuous IV infusion
Dofetilide CrCL >60 mL/min: 500 mcg orally twice daily
CrCL 40–60 mL/min: 250 mcg orally twice daily
CrCL 20–40 mL/min: 125 mcg orally twice daily
CrCL <20 mL/min: contraindicated
Flecainideb 200–300 mg single oral dose
Ibutilide 1 mg IV over 10 min. Repeat with a second 1 mg dose 10 min after the first dose if
atrial fibrillation persists.
Propafenoneb 600 mg single oral dose
CrCL = creatinine clearance; IV = intravenously.
a
Applies to both monophasic and biphasic shocks.
b
If the cause of the atrial fibrillation is a sodium channel blocking drug (amiodarone, flecainide, propafenone), avoid the use of addi-
tional sodium channel blocking agents and administer direct-current cardioversion or ibutilide. If the atrial fibrillation is caused by
theophylline toxicity: administer activated charcoal 50–100 g, followed by 50 g every 4 hr. Alternatively, continuous hemodialysis with
filtration may be performed.

be administered.566 Alternatively, continuous he-

modialysis with filtration may be performed.542
INFORMATION FOR PATIENTS
Patients who are taking drugs known to cause atri-
al fibrillation or flutter should be instructed that
the medication, in rare instances, may cause the
heart rate (pulse) to become faster. Patients should
take their pulse daily, and should be instructed to
consult their pharmacist or physician if the heart
rate increases to above 100-120 bpm, or if they feel
palpitations, light-headed, dizzy, tired, weak, or
short of breath or experience chest pain.
ATRIAL TACHYCARDIA
Atrial tachycardia is a supraventricular arrhythmia
that is characterized on ECG by narrow QRS com-
plexes, at a rate usually between 100 and 250
bpm.567 There are two primary types of atrial tachy-
cardia: focal atrial tachycardia (which will be
referred to simply as “atrial tachycardia”), in which
the arrhythmia is initiated at a single atrial focus,
and multifocal atrial tachycardia, in which there
are multiple atrial foci. Focal atrial tachycardia is
characterized by regular intervals between QRS
complexes on ECG, while multifocal atrial tachy-
cardia is associated with irregular QRS intervals and
three or more P wave morphologies.567 Atrial

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 CHAPTER 25 • Supraventricular Arrhythmias 461

TABLE 25–19 Agents Implicated in Drug-Induced Atrial Tachycardia

Drug Incidence Level of Evidence
(see page xii for explanation)
483
Albuterol NK C
Caffeine568,569 NK C
Digoxin83,388,570-580 0 –4% B
Phenylpropanolamine569 NK C
Terbutaline581 NK C
Theophylline537,581-586 0–16%a B
a
Incidence increases with increasing serum theophylline concentration

tachycardia may occur intermittently, which is
commonly referred to as “paroxysmal atrial tachy-
cardia.”
CAUSATIVE AGENTS
Drugs that have been reported to cause atrial
tachycardia are listed in Table 25–19.83,388,483,537,568-
586
EPIDEMIOLOGY
Paroxysmal atrial tachycardia is often described as
a characteristic arrhythmia associated with digoxin
toxicity.578 However, at one large urban medical
center, “definite” paroxysmal atrial tachycardia
was documented in only 2% of 219 patients with a
discharge diagnosis of digoxin intoxication.83 In
this analysis, paroxysmal atrial tachycardia
occurred less frequently than any other arrhythmia
associated with digoxin intoxication. Therefore,
despite the commonly held belief that paroxysmal
atrial tachycardia is commonly associated with
digoxin toxicity, it appears to occur relatively
rarely.
The incidence of multifocal atrial tachycardia
associated with theophylline is dependent on
serum theophylline concentrations.586 In an analy-
sis of 100 patients receiving theophylline, atrial
tachycardia did not occur in the patients with
serum theophylline concentrations <10 mcg/mL.
However, in patients with serum theophylline con-
centrations between 10 and 20 mcg/mL, the inci-
dence of atrial tachycardia was 8%, and the
incidence rose to 16% in patients with serum theo-
phylline concentrations >20 mcg/mL.586
MECHANISMS
Mechanisms of drug-induced atrial tachycardia are
not entirely clear, but are likely related to increas-
ing the automaticity of atrial tissue (Table
25–20).567 This may occur because of b-receptor

TABLE 25–20 Mechanisms of Drug-Induced Atrial Tachycardia

Drug Mechanism
Albuterol, terbutaline Stimulation of b-receptors, leading to enhanced atrial
automaticity
Caffeine, theophylline Phosphodiesterase inhibition, leading to increased plasma
concentrations of cyclic adenosine monophosphate, result-
ing in enhanced atrial automaticity
Digitalis glycoside toxicity Extreme inhibition of the sodium–potassium–adenosine
triphosphatase pump, leading to markedly increased
myocyte concentrations of sodium, which is exchanged
with calcium, ultimately resulting in markedly increased
myocyte calcium concentrations, promoting enhanced
atrial automaticity

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 462 SECTION VI • Drug-Induced Cardiovascular Diseases
stimulation associated with drugs such as albuterol
or terbutaline or through phosphodiesterase inhi-
bition and the resulting elevated concentrations of
cyclic adenosine monophosphate associated with
caffeine or theophylline.
The mechanism of paroxysmal atrial tachy-
cardia with AV nodal blockade associated with
digitalis glycoside toxicity is likely related to
extreme inhibition of the sodium–potassium–
adenosine triphosphatase pump. This leads to
markedly increased myocyte sodium concentra-
tions, which in turn is exchanged with calcium,
ultimately resulting in markedly increased
myocyte concentrations of calcium. This pro-
motes enhanced atrial automaticity due to
delayed phase-4 repolarization in the atrial action
potential.587
CLINICAL PRESENTATION AND
DIFFERENTIAL DIAGNOSIS
The symptoms of drug-induced atrial tachycardia
are related to heart rate and the resultant effect on
blood pressure and cardiac output (Table 25–21).
The diagnosis of drug-induced atrial tachycardia
must be made primarily on the basis of the appear-
ance on ECG (Figure 25–7). Conditions to consider
in the differential diagnosis of drug-induced atrial
tachycardia are presented in Table 25–22.
RISK FACTORS
Risk factors for drug-induced atrial tachycardia are
presented in Table 25–23. Paroxysmal atrial tachy-
cardia with AV nodal blockade is extremely rare at
therapeutic serum digoxin concentrations, but
occurs primarily when serum digoxin concentra-
tions increase to >2.0 ng/mL. Therefore, risk factors
for digoxin-induced paroxysmal atrial tachycardia
TABLE 25–21 Signs and Symptoms Associated
with Drug-Induced Atrial Tachycardia
• Palpitations
• Dizziness
• Light-headedness
• Shortness of breath
• Chest pain (if underlying coronary artery disease is
present)
• Near-syncope
• Syncope
TisdaleC25_445-484-corrected, marks.pdf 18
V1
V2
V3
FIGURE 25–7. Paroxysmal atrial tachycardia with varying
AV nodal blockade induced by digitalis toxicity. Arrows are
pointing to p waves, which are occurring at regular intervals.
Reproduced with permission from Storstein and Rasmussen.571
with AV block are the same as those for digoxin
toxicity. Since digoxin is cleared primarily by the
kidneys, renal dysfunction is a primary risk factor
for digoxin toxicity and digoxin-induced atrial
tachycardia with AV nodal blockade. In addition,
drug interactions that result in increased serum
digoxin concentrations enhance the risk of digox-
in-related arrhythmias. Amiodarone,456 vera-
pamil,457 and quinidine458 are known to
significantly increase serum digoxin concentra-
tions.
Paroxysmal atrial tachycardia with AV block asso-
ciated with digitalis toxicity may occur in patients
across a wide range of ages. In one series, in which 31
cases of paroxysmal atrial tachycardia with AV block
were reported in association with digitoxin, the age
range of patients varied from 20 to 73 years (average,
52).571 There were 15 women and 16 men, with a vari-
ety of underlying cardiovascular disorders, including
valvular heart disease (n = 14), congenital heart dis-
eases (n = 6), and ischemic heart disease (n = 1).571 As
mentioned previously, elevated serum theophylline
concentration is a risk factor for theophylline-
TABLE 25–22 Conditions to Consider in the
Differential Diagnosis of Drug-Induced Atrial
Tachycardia
• Atrial fibrillation
• Atrial flutter
• Atrial tachycardia not induced by drugs
• Sinus tachycardia
• AV nodal reentrant tachycardia
• Ventricular tachycardia
12/13/2010 11:45:14 AM

TABLE 25–23 Risk Factors for Drug-Induced
Atrial Tachycardia
Digoxin
• Serum digoxin concentrations >2.0 ng /mL
• Kidney disease
• Drug interactions leading to elevated serum digoxin
concentrations
Theophylline
• Serum theophylline concentrations >20 mcg /mL
induced atrial tachycardia. New supraventricular
arrhythmias including multifocal atrial tachycardia
were reported in 7 patients with serum theophylline
concentrations between 21 and 40 mcg/mL.585
MORBIDITY AND MORTALITY
Patients with paroxysmal atrial tachycardia with AV
nodal blockade may present to the emergency
department and require hospitalization for manage-
ment of digoxin toxicity. The incidence of mortality
associated with digitalis-induced paroxysmal atrial
fibrillation and AV nodal blockade has not been
reported, but is likely extremely low. In the series of
31 patients with digitoxin-induced paroxysmal atri-
al tachycardia, two patients died, but neither death
appears to have been related to the arrhythmia or
the digitoxin toxicity.571 Patients with atrial tachy-
cardia associated with other drugs may also present
to the emergency department for treatment, partic-
ularly in the event of theophylline toxicity.
PREVENTION
Digoxin-associated paroxysmal atrial tachycardia
with AV nodal blockade is usually preventable by
maintaining serum digoxin concentrations <2.0
ng/mL (Table 25–24). Measurement of serum digoxin
concentrations is therefore recommended in patients
who may be at risk for elevated concentrations,
including patients with kidney disease or changing
kidney function and those receiving concomitant
therapy with drugs known to increase serum digoxin
concentrations (particularly amiodarone, verapamil,
or quinidine). In patients with kidney disease, appro-
priate dose adjustment should be made. In general,
patients with calculated creatinine clearance588 ≤20
mL/min should received an initial reduced digoxin
dose of 0.125 mg daily.589 In patients with calculated
creatinine clearance <20 mL/min who are receiving
concomitant therapy with drugs known to inhibit
TisdaleC25_445-484-corrected, marks.pdf 19
CHAPTER 25 • Supraventricular Arrhythmias 463
TABLE 25–24 Approaches to Help Prevent Drug-
Induced Atrial Tachycardia
Digoxin
• Maintain serum digoxin concentrations <2.0 ng /mL
• Appropriate dose adjustment for kidney disease
• Appropriate dose adjustment in the presence of inter-
acting drugs, particularly amiodarone, verapamil, or
quinidine
Theophylline
• Maintain serum theophylline concentrations <20
mcg /mL
the elimination of digoxin, the initial digoxin dose
should be 0.125 mg every other day.
Atrial tachycardia associated with theophylline
may be prevented by maintaining serum theo-
phylline concentrations <20 mcg/mL.
MANAGEMENT
Treatment options for drug-induced atrial tachy-
cardia are presented in Table 25–25. Digoxin-asso-
ciated paroxysmal atrial tachycardia with AV nodal
blockade should be managed by withholding
digoxin therapy until serum digoxin concentra-
tions decline to <2.0 ng/mL. Because paroxysmal
atrial tachycardia with AV block is rarely life-
threatening, it is usually not necessary to adminis-
ter digoxin immune antibody fragments. In the
very rare event that the arrhythmia is hemody-
namically unstable, synchronized direct current
cardioversion should be used to terminate the
arrhythmia. Attempts to sedate the patient should
be made, unless the urgency of the situation does
not permit them. Initial cardioversion energy
should be 50 J. Subsequent cardioversion attempts
should be performed with 100, 200, 300, and 360
J. Following the conversion of hemodynamically
unstable paroxysmal atrial tachycardia with AV
block, digoxin immune antibody fragments should
be administered to prevent recurrence of the
hemodynamically unstable arrhythmia.
Drug-induced atrial tachycardia may be
responsive to treatment with adenosine.590 In addi-
tion, drug-induced atrial tachycardia may be treat-
ed with verapamil583 or metoprolol.591 In one
study, intravenous metoprolol was more effective
than verapamil for termination of atrial tachycar-
dia.592 Intravenous magnesium has also been effec-
tive for managing multifocal atrial tachy-
cardia,593,594 although in one study it was not more
effective than placebo.595 If the drug-induced atrial
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 464 SECTION VI • Drug-Induced Cardiovascular Diseases

TABLE 25–25 Management of Drug-Induced Atrial Tachycardia

Discontinue the offending agent.
Drug
Hemodynamically unstable
Hemodynamically stable
DC = direct current; IV = intravenously; J = Joules.
Recommended Doses
Synchronized DC cardioversion (initial energy 50 J, followed by 100 J, 200 J, 300 J,
360 J, if necessary)
If due to digoxin toxicity:
Administer digoxin immune antibody fragments. The dose is based on the serum
digoxin concentration:
Number of 38-mg vials = serum digoxin concentration x weight (kg) 4 100.
If the arrhythmia is a result of an acute digoxin overdose and the amount of digoxin
ingested is known, the dose of digoxin immune antibody fragments should be calcu-
lated as follows:
Number of 38-mg vials = mg digoxin ingested acutely x 0.8 4 0.5.
If due to theophylline toxicity:
Administer activated charcoal: 50–100 g, followed by 50 g every 4 hr
Metoprolol 25–50 mg single oral dose
or
5 mg IV x two doses, each administered over 5 min, doses separated by 20 min
Verapamil 5 mg IV administered over 2–5 min; second 5-mg IV dose may be adminis-
tered 20 min later
Magnesium 2 g IV administered over 10 min

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).

INFORMATION FOR PATIENTS CAUSATIVE AGENTS

Patients who are taking drugs that are known to Drugs that have been associated with AVNRT are
cause atrial tachycardia should be instructed that listed in Table 25–26.483,506,509,539,585,596-632
the drug may in rare cases cause the heart rate
(pulse) to become faster. Patients should be taught
to take their pulse and to monitor their heart rate
daily. Patients should be instructed to consult their EPIDEMIOLOGY
pharmacist or physician if the heart rate increases
The incidence of drug-induced AVNRT is largely
above 100 to 120 bpm, or if they feel light-headed,
unknown. The incidence of AVNRT associated with
dizzy, tired, weak, or short of breath or experience
albuterol and dobutamine is presented in Table
chest pain.
25–26.

AV NODAL RECIPROCATING MECHANISMS

TACHYCARDIA
AV nodal reciprocating tachycardia (AVNRT) is the
most common form of the group of arrhythmias
commonly referred to as “paroxysmal supraven-
tricular tachycardia.” AVNRT is characterized on
Mechanisms of drug-induced AVNRT are some-
what unclear. Non–drug-related AVNRT was previ-
ously thought to be caused by a reentrant circuit
involving the AV node, in which there is ante-
grade conduction over the slow-conducting por-

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 CHAPTER 25 • Supraventricular Arrhythmias 465

provoke AV nodal reentry. In cases of AVNRT that

FIGURE 25–8. AV nodal reciprocating tachycardia at a
rate of 200 bpm associated with fluoxetine.
Reproduced with permission from Gardner et al.624
occurred in association with continuous
furosemide infusions in infants or children after
cardiac surgery, the authors speculated that a
rapid change in intravascular volume may have
contributed to the development of the arrhyth-
mias, possibly as a result of intercompartmental
electrolyte shifts.626 Overall, the mechanisms by
which drug-induced AVNRT occurs have not been
determined, but are likely related to stimulation
of premature atrial depolarizations, alterations in
AV nodal conduction velocity or repolarization,
or both.

CLINICAL PRESENTATION AND

tion of the circuit and retrograde conduction over
the faster-conducting portion.633,634 However, it is
now recognized that the reentrant circuit often is
not confined to the AV node, but involves perin-
odal tissue.567 AV nodal or perinodal reentry is
usually initiated by a premature atrial impulse
that “uncovers” the latent reentrant circuit by
creating the circumstances required for reentry,
namely creating unidirectional block in the fast
pathway and further slowing of impulse conduc-
tion down the slow pathway. Therefore, it is pos-
sible that drugs that cause AVNRT do so by
stimulating premature atrial depolarizations that
DIFFERENTIAL DIAGNOSIS
The symptoms of drug-induced AVNRT are similar
to those of other tachyarrhythmias (Table 25–27),
and are related to heart rate and the resultant effect
on blood pressure and cardiac output. Ventricular
rates associated with drug-induced AVNRT can be
quite fast, ranging from 150 to 300 bpm.625,626,631
Conditions to consider in the differential diagnosis
of drug-induced AVNRT are presented in Table
25–28. The diagnosis of AVNRT must be made pri-
marily on the basis of the appearance on ECG
(Figure 25–8).

TABLE 25–26 Agents Implicated in Drug-Induced Atrioventricular Nodal Reciprocating Tachycardia

Drug Incidence Level of Evidence
(see page xii for explanation)
483,596-604 a
Albuterol 0–21% A
Caffeine605-607,b NK C
Carbamazepine608 NK C
Clozapine609 NK C
Dobutamine506,509,610-623 0–12% A
Enoximone610 NK A
Fluoxetine624, 625 NK C
Furosemide626 NK C
Ipratropium627,628 0.5% A
Methylprednisolone629,630 NK C
Phenylpropanolamine631 NK C
Theophylline483,539,583,585,596,632 NKa C
NK = not known.
a
Incidence reported to be up to 76% in patients receiving concomitant therapy with albuterol and theophylline.
b
Suicide attempt or overdose, 2.7–35 g caffeine ingested; 1 case with intravenous caffeine administration.

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 466 SECTION VI • Drug-Induced Cardiovascular Diseases
TABLE 25–27 Signs and Symptoms Associated
with Drug-Induced Atrioventricular Nodal
Reciprocating Tachycardia
• Palpitations
• Dizziness
• Light-headedness
• Shortness of breath
• Chest pain (if underlying coronary artery disease is
present)
• Near-syncope
• Syncope
TABLE 25–28 Conditions to Consider in the
Differential Diagnosis of Drug-Induced
Atrioventricular (AV) Nodal Reciprocating
Tachycardia
• Atrial fibrillation
• Atrial flutter
• Atrial tachycardia
• Sinus tachycardia
• AV nodal reentrant tachycardia not induced by drugs
• Ventricular tachycardia
RISK FACTORS
Known or potential risk factors for drug-induced
AVNRT are presented in Table 25–29. Albuterol-
induced AVNRT appears to be more likely in
patients receiving the drug intravenously, particu-
larly at infusion rates >60 mcg/min.597,603 AVNRT
associated with dobutamine occurs more common-
ly in men than in women,615 and in elderly
patients.509,616 In addition, severity of myocardial
ischemia has been shown to be an independent
predictor of dobutamine-induced AVNRT; in a
study of 1,076 patients undergoing dobutamine
stress myocardial perfusion imaging, the mean
myocardial infarction score (calculated based on
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
those without it, and the infarction score was an
independent predictor of AVNRT.616
All of the reported cases of AVNRT associated
with continuous furosemide infusions (n = 3
patients) have occurred in infants or children
after cardiac surgery. In these patients, the
arrhythmia occurred within 3 to 7 hours after the
initiation of a furosemide infusion of 1.0
TisdaleC25_445-484-corrected, marks.pdf 22
TABLE 25–29 Risk Factors for Drug-Induced
Atrioventricular Nodal Reciprocating Tachycardia
Albuterol
• Continuous intravenous infusion
• Intravenous infusion rate >60 mcg/min
• Concomitant therapy with theophylline
Dobutamine
• Male sex
• Elderly
• Myocardial infarction score on dobutamine stress test
Furosemide
• Reported only in infants or children following cardiac
surgery
• Continuous infusion resulting in profound diuresis
(8–10 mL/kg /hr)
Theophylline
• Serum theophylline concentrations >20 mcg /mL
• Concomitant therapy with albuterol
mg/kg/hr. A common factor in these three
patients was substantial diuresis resulting from
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
potassium concentration was below normal lim-
its in one of the three patients in whom the
arrhythmia developed, but remained normal in
the other two cases. Therefore, it is possible that
a large amount of fluid loss may be a risk factor
or predictor of drug-induced AVNRT in infants or
children receiving a continuous infusion of
furosemide after cardiac surgery. Serum theo-
phylline concentration is a risk factor for theo-
phylline-induced supraventricular arrhythmias;
new supraventricular arrhythmias were reported
in 7 patients with serum theophylline concentra-
tions between 21 and 40 mcg/mL.585 Risk factors
for AVNRT associated with other drugs have not
been identified.
MORBIDITY AND MORTALITY
Drug-induced AVNRT may result in symptoms suf-
ficient to result in presentation to the emergency
department and hospitalization.605,606,624,628 In
addition, drug-induced AVNRT may result in pro-
longation of stays in the intensive care unit and
the hospital.625,626 Mortality associated with drug-
induced AVNRT is likely quite rare.
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TABLE 25–30 Approaches to Help Prevent Drug-
Induced Atrioventricular Nodal Reciprocating
Tachycardia
Albuterol
• Avoid continuous intravenous infusions at rate >60
mcg/min
• Avoid concomitant therapy with theophylline
Furosemide
• Avoid diuresis of volumes >2.5 mL /kg /hr over periods
of 3–7 hr in infants/children after cardiac surgery
Theophylline
• Maintain serum theophylline concentrations <20
mcg /mL
• Avoid concomitant therapy with albuterol
PREVENTION
The likelihood of albuterol-induced AVNRT may be
reduced by avoiding continuous intravenous infu-
sions at doses >60 mcg/min (Table 25–30).
Combinations of drugs that may induce AVNRT
should be avoided, particularly the concomitant
administration of albuterol and theophylline. In
the cases of furosemide-induced AVNRT in infants
and children after cardiac surgery, substantial fluid
elimination appears to have been a risk factor, and
in that population, avoidance of diuresis of vol-
TABLE 25–31 Management Options for Drug-Induced AV Nodal Reciprocating Tachycardia
In hemodynamically unstable patients:
Discontinue the offending agent
Synchronized DC cardioversion (initial energy 50 J,
followed by 100 J, 200 J, 300 J, 360 J if necessary).
DC = Direct current; IV = intravenously; J = Joules; LVEF = Left ventricular ejection fraction
TisdaleC25_445-484-corrected, marks.pdf 23
CHAPTER 25 • Supraventricular Arrhythmias 467
umes >2.5 mL/kg/hr over periods of 3 to 7 hours
may minimize the risk.626 Maintaining serum theo-
phylline concentrations <20 mcg/mL reduces the
risk of theophylline-induced supraventricular
arrhythmias.
MANAGEMENT
Management options for drug-induced AVNRT are
presented in Table 25–31. As with other drug-
induced arrhythmias, initial management of drug-
induced AVNRT is discontinuation of therapy with
the offending agent. If the patient is hemodynam-
ically unstable, synchronized direct-current car-
dioversion should be administered, using an initial
energy of 50 J.567 Sedation of the patient is always
preferred unless hemodynamic instability is so
severe that there is no time for sedation. If the ini-
tial conversion attempt is unsuccessful, subsequent
attempts at conversion should be made with
increasing amounts of energy (100 J, 200 J, 300 J,
360 J).567
In patients who are hemodynamically stable,
drug-induced AVNRT may respond to agents typi-
cally used to treat non–drug-induced AVNRT.
Adenosine has been found to be effective for
AVNRT associated with albuterol600,604 and may be
used as a drug of first choice for hemodynamically
In hemodynamically stable patients:
Discontinue the offending agent
Vagal maneuvers (cough, carotid sinus massage, Valsalva)
Adenosine 6 mg IV rapid bolus, followed by saline flush
If no response within 2 minutes, adenosine 12 mg IV rapid
bolus, followed by saline flush
If no response within 2 minutes, adenosine 12 mg IV rapid
bolus, followed by saline flush
If no response to adenosine, and patient has LVEF > 40%
and/or no history of heart failure: Diltiazem 0.25 mg/kg IV
bolus, followed if necessary by 0.35 mg/kg IV bolus, fol-
lowed by continuous infusion of 5-15 mg/hr; or verapamil
0.075-0.15 mg/kg IV over 2 minutes
If no response to adenosine, and patient has LVEF < 40%
and/or a documented history of heart failure: Digoxin 0.25
mg IV every 2 hours, up to total dose of 1.5 mg
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 468 SECTION VI • Drug-Induced Cardiovascular Diseases
stable AVNRT.567 Intravenous verapamil 2.5 mg has
been effective for terminating AVNRT associated
with fluoxetine.625 Intravenous verapamil should
be avoided in patients with left ventricular dys-
function567; in this population, intravenous digox-
in should be administered.
INFORMATION FOR PATIENTS
Patients who are taking drugs that may cause
AVNRT should be instructed that the medication
may, in rare instances, cause the heart rate (pulse)
to become faster. Patients should be instructed to
take their pulse daily and to consult their pharma-
cist or physician if the heart rate increases to above
100 to 120 bpm, or if they feel palpitations, light-
headed, dizzy, tired, weak, or short of breath or
experience chest pain.
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TisdaleC26_485-515 1/12/10 2:54 PM Page 485
CHAPTER 26
Ventricular
Arrhythmias
D rugs may induce potentially life-threatening
ventricular arrhythmias. Drug-induced ven-
tricular arrhythmias can be divided into two cate-
gories: monomorphic ventricular tachycardia, and
the polymorphic ventricular tachycardia known as
torsades de pointes.
MONOMORPHIC VENTRICULAR
TACHYCARDIA
CAUSATIVE AGENTS
Drugs that have been reported to cause or exacer-
bate monomorphic ventricular tachycardia are list-
ed in Table 26–1.1-95 New monomorphic
ventricular tachycardia may be caused by any of
the drugs listed. Incessant, sinusoidal-appearing
ventricular tachycardia is particularly associated
with the potent sodium channel blocking agents
belonging to the Vaughan Williams antiarrhyth-
mic class IC (e.g., flecainide, propafenone).
EPIDEMIOLOGY
Although the overall incidence of drug-induced
ventricular tachycardia is not known, the inci-
dences associated with some specific drugs have
been reported (Table 26–1). Ventricular tachycardia
is recognized as a consequence of digoxin toxici-
ty.17-20 The incidence of ventricular tachycardia in
patients taking digoxin is unknown. However, in
an analysis of patients discharged from a major
urban medical center with the diagnosis of digoxin
intoxication, 7% had “definite” ventricular tachy-
cardia.18
James E. Tisdale
MECHANISMS
Mechanisms of drug-induced monomorphic ven-
tricular tachycardia vary depending on the
causative agent(s) (Table 26–2). Many of the drugs
that cause monomorphic ventricular tachycardia
(e.g., amiodarone, chlorpromazine, disopyramide,
flecainide, imipramine, procainamide, propafen-
one), do so as a result of potent inhibition of
myocardial sodium channels, leading to a reduc-
tion in ventricular conduction velocity.96 This
changes the relationship between ventricular con-
duction velocity and ventricular refractoriness,
which may promote the manifestation of reentrant
circuits in ventricular tissue. These drugs may par-
ticularly perturb the relationship between ventric-
ular conduction velocity and refractoriness in
patients with a history of myocardial infarction in
whom alteration of electrophysiologic characteris-
tics has already occurred in the border zone of the
infarcted tissue. This is also an important proar-
rhythmic effect in patients with left ventricular
dysfunction, in whom ventricular electrophysiolo-
gy is also altered as a result of left ventricular
hypertrophy and accumulation of connective tis-
sue in the left ventricle. In particular, potent sodi-
um-channel inhibition caused by Vaughan
Williams class IC antiarrhythmic agents (e.g., fle-
cainide, propafenone) can lead to incessant, sinu-
soidal ventricular tachycardia.96,97
Adenosine may cause monomorphic ventricu-
lar tachycardia as a result of enhancement of arte-
rial chemoreceptor and baroreceptor activity,
leading to increased activity of the sympathetic
nervous system98 or due to inducing myocardial
ischemia as a result of “coronary steal,”7 or both.
Digoxin-induced ventricular tachycardia, which is
485
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486 SECTION VI • Drug-Induced Cardiovascular Diseases

TABLE 26–1 Agents Implicated in Drug-Induced Monomorphic Ventricular Tachycardia

Drug Incidence Level of Evidence
(see page xii for explanation)
1-6
Aconites NK C
Adenosine7-11 Up to 5% B
Amiodarone12 NK C
Chlorpromazine13 NK C
Desipramine14-16,a NK C
Digoxin17-20 NK B
Disopyramide21 NK C
Ephedrine22 NK C
Flecainide23-53 0–13% A
Gingko biloba54 NK C
Ibutilide55-62 0–9.8% A
Imipramine63 NK C
Procainamide64 NK C
Propafenone65-78 0–10% B
79
Sotalol NK C
Terbutaline80-84 0–15%b A
Theophylline82,84-91 NK B
Thioridazine15 NK C
Trazodone92,93 NK C
Venlafaxine94,95,a NK C
NK = not known.
a
Primarily in overdose.
b
15% incidence reported in patients with a history of ventricular arrhythmias

usually a manifestation of serum concentrations
that are markedly elevated above the therapeutic
range, occurs as a result of profound inhibition of
the sodium–potassium–adenosine triphosphatase
pump, leading to marked increases in intramy-
ocyte concentrations of calcium, provoking after-
depolarizations and ventricular ectopic activity.99
CLINICAL PRESENTATION AND
DIFFERENTIAL DIAGNOSIS
Whether drug-induced or due to other causes,
monomorphic ventricular tachycardia is a series of
consecutive ventricular premature depolarizations
and is characterized by wide, misshapen QRS com-
plexes on an electrocardiogram (ECG), with a
heart rate >100 bpm, and sometimes as high as
150 to 250 bpm (Figure 26–1). Heart rates are often
faster and may be as high as 150 to 250 bpm. As
indicated by the term “monomorphic”, QRS com-
plexes possess similar beat-to-beat morphologic
characteristics. Potent sodium channel blocking
drugs may also cause a specific, often incessant
ventricular tachycardia characterized by wide QRS
complexes with a sinusoidal appearance (Figure
26–2). This incessant, sinusoidal ventricular tachy-
cardia is often slower than typical spontaneous
ventricular tachycardia, but occasionally can be
quite rapid.28
Drug-induced monomorphic ventricular
tachycardia may be nonsustained or sustained.
Nonsustained ventricular tachycardia is defined as
at least three consecutive beats of ventricular
tachycardia, lasting ≤30 seconds and terminating
spontaneously. Sustained ventricular tachycardia
lasts >30 seconds and requires intervention for ter-
mination. Sinusoidal-appearing ventricular tachy-
cardia is often sustained and is more likely to be
incessant and refractory to overdrive pacing or
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CHAPTER 26 • Ventricular Arrhythmias 487

TABLE 26–2 Mechanisms of Drug-Induced Monomorphic Ventricular Tachycardia

Drug Mechanism
Adenosine Enhanced activity of the sympathetic nervous system,
via increased arterial chemoreceptor and baroreceptor
activity
Myocardial ischemia due to coronary steal
Amiodarone Inhibition of sodium-channel conductance
Chlorpromazine
Desipramine
Disopyramide
Flecainide
Imipramine
Procainamide
Propafenone
Digoxin Inhibition of the sodium–potassium–adenosine
triphosphatase pump, leading to increased intracellular
calcium concentrations, resulting in afterdepolarizations
and ventricular ectopic activity
Terbutaline Stimulation of ß2-receptors, leading to ventricular ectopic
activity
Theophylline Phosphodiesterase inhibition, leading to elevated
concentrations of cyclic adenosine monophosphate,
causing increased intracellular calcium concentrations,
resulting in afterdepolarizations and ventricular ectopic
activity
Ibutilide Unknown
Sotalol
Trazodone
Venlafaxine

direct current cardioversion than other monomor-
phic ventricular tachycardias. Occasionally, sinu-
soidal-appearing ventricular tachycardia is
characterized by frequent nonsustained episodes
that terminate spontaneously but quickly recur.28
Drugs may cause new ventricular tachycardia
in patients who did not previously have this
arrhythmia or may aggravate or worsen an under-
lying ventricular tachycardia. For example, specific
drugs may increase the rate of a patient’s preexist-
ing ventricular tachycardia, make it more sympto-
matic, more difficult to terminate, or both.97 The
symptoms of drug-induced ventricular tachycardia
are related to heart rate and the resultant effect on
blood pressure and cardiac output (Table 26–3).
However, in some patients, the initial symptom of
drug-induced ventricular tachycardia may be sud-
den cardiac death as a result of rapid degeneration

FIGURE 26–1. Nonsustained

V4
monomorphic ventricular
tachycardia associated with
trazodone during an exercise
treadmill test.
Reproduced with permission from
Vitullo et al.93
TisdaleC26_485-515 1/12/10 2:54 PM Page 488
488 SECTION VI • Drug-Induced Cardiovascular Diseases
FIGURE 26–2. Sinusoidal
ventricular tachycardia, with
two distinct morphologies and
rates, induced by flecainide.
Reproduced with permission from
Sagie et al.43
of ventricular tachycardia to ventricular fibrilla-
tion.
The time from drug therapy initiation to the
development of drug-induced monomorphic ven-
tricular tachycardia is somewhat variable. In cases
of drug overdose or elevated plasma drug concen-
trations during therapy, the arrhythmia may devel-
op within a few minutes to several hours after the
ingestion or the plasma concentration elevation.
The majority of cases of drug-induced monomor-
phic ventricular tachycardia occur within hours to
days after the initiation of therapy.
Drug-induced monomorphic ventricular
tachycardia must be differentiated from other
tachycardias (Table 26–4). Further, drug-induced
monomorphic ventricular tachycardia must be dis-
tinguished from spontaneously occurring
non–drug-induced ventricular tachycardia (Table
26–5). Diagnosis of drug-induced ventricular
tachycardia is usually based on the occurrence of a
new ventricular tachycardia in a patient with no
history of ventricular tachycardia before the initia-
tion of drug therapy. In addition, drug-induced
ventricular tachycardia may be diagnosed in a
TABLE 26–3 Signs and Symptoms Associated
with Drug-Induced Monomorphic Ventricular
Tachycardia
• Palpitations
• Dizziness
• Light-headedness
• Shortness of breath
• Chest pain (in patients with underlying coronary
artery disease)
• Near-syncope
• Syncope
• Tachycardia
• Hypotension
• Seizure (due to cerebral hypoxia)
• Sudden cardiac death (if ventricular tachycardia is
pulseless)
• Monomorphic ventricular tachycardia on electrocar-
diogram
• Sinusoidal ventricular tachycardia on electrocardio-
gram
patient with a history of non–drug-induced ven-
tricular tachycardia if the morphology of the ven-
tricular tachycardia that develops after the
initiation of drug therapy differs from that of the
ventricular tachycardia that occurred in the
absence of drug therapy. The occurrence of inces-
sant sinusoidal ventricular tachycardia may be
considered a drug-induced arrhythmia, as this
form of ventricular tachycardia has not been
described in the absence of drug therapy and is not
typical of ventricular tachycardia occurring as a
result of myocardial infarction, acute coronary
ischemia, left ventricular dysfunction, or other
common causes of ventricular tachycardia. Drug-
induced ventricular tachycardia may also be diag-
nosed if a patient’s underlying ventricular
tachycardia becomes more rapid, more sympto-
matic, more difficult to terminate after the initia-
tion of therapy with a new drug, or some
combination of these factors.
RISK FACTORS
Structural heart disease, particularly a history of
myocardial infarction or coronary artery disease
even without a history of myocardial infarction, is
a major risk factor for ventricular tachycardia
induced by potent sodium channel blocking
agents such as flecainide or propafenone (Table
26–6).100 The Cardiac Arrhythmia Suppression Trial
(CAST)101 was designed to test the hypothesis that
suppression of asymptomatic ventricular ectopic
TABLE 26–4 Conditions to Consider in the
Differential Diagnosis of Drug-Induced
Monomorphic Ventricular Tachycardia
• Sinus tachycardia
• Atrial fibrillation
• Atrial flutter
• Atrial tachycardia
• Atrioventricular nodal reentrant tachycardia
• Torsades de pointes
• Non-Torsades de pointes polymorphic ventricular
tachycardia
TisdaleC26_485-515 1/12/10 2:54 PM Page 489
TABLE 26–5 Differentiation of Drug-Induced
Monomorphic Ventricular Tachycardia from
Non–Drug-Induced Ventricular Tachycardia
In patient with no history of VT
• New VT on drug therapy (VT not present before drug
therapy)
• No obvious underlying cause for new VT, such as:
• Ischemic heart disease
• Heart failure
• Hypokalemia
• Hypomagnesemia
In patient with history of VT
• VT on drug therapy has a different morphology than
patient’s previous clinical VT
• VT on drug therapy is substantially faster than
patient’s previous clinical VT
• VT on drug therapy is sustained, whereas patient pre-
viously had only nonsustained VT
• VT on drug therapy is sinusoidal
• VT on drug therapy is more difficult to terminate than
patient’s previous clinical VT
VT = ventricular tachycardia.
activity after a myocardial infarction reduces the
incidence of postinfarction mortality. In CAST,
patients who had experienced a myocardial infarc-
tion within the previous 1 week to 6 months were
recruited to enter a run-in study phase in which
the efficacy of flecainide, encainide, and mori-
cizine (encainide and moricizine are no longer
available in the United States [U.S.]), were tested to
determine the efficacy of each agent for the sup-
pression of ventricular ectopic activity. Patients in
whom one of these drugs was effective for the sup-
pression of ventricular ectopic activity were then
randomly assigned to the most effective (in that
specific patient) of the three agents or placebo. The
TABLE 26–6 Risk Factors for Drug-Induced
Monomorphic Ventricular Tachycardia
• Coronary artery disease
• Heart failure due to left ventricular dysfunction (left
ventricular ejection fraction <40%)
• Serum digoxin concentrations >2.0 ng/mL
• Serum theophylline concentrations >20 mcg/mL
• Hypokalemia, hypomagnesemia, and hypercalcemia
are risk factors for ventricular tachycardia associated
with digoxin.
• History of ventricular arrhythmias may be a risk factor
for terbutaline-induced ventricular tachycardia.
CHAPTER 26 • Ventricular Arrhythmias 489
flecainide and encainide arms of the study were
discontinued prematurely as a result of excess mor-
tality in the treatment group. The arrhythmic mor-
tality incidence in the patients who received
flecainide or encainide was more than three times
higher than in the placebo group.102 The mori-
cizine arm of the study was continued but, like the
flecainide and encainide arms of the original CAST
trial, was subsequently discontinued because of an
increased incidence of mortality in moricizine-
treated patients during the first two weeks of treat-
ment.102 Subsequent analysis indicated that active
treatment with encainide or flecainide was associ-
ated with greater mortality than placebo in the
majority of subgroups, but that patients with
non–Q-wave myocardial infarction and frequent
premature ventricular depolarizations were at
highest risk.101 As a result of the findings of CAST,
flecainide and moricizine are contraindicated in
patients with a documented history of coronary
artery disease. In addition, although propafenone
was not included in CAST, as a Vaughan Williams
class IC antiarrhythmic drug with potent sodium
channel blocking properties, it is also considered to
be contraindicated in patients with a documented
history of coronary artery disease, even though
there are so studies specifically associating
propafenone therapy with increasing mortality
incidence.
A subsequent meta-analysis of 138 random-
ized, controlled trials of antiarrhythmic agents
that enrolled a total of approximately 98,000
patients with a history of myocardial infarction
receiving the drugs for arrhythmia prophylaxis
also reported an increased risk of mortality associ-
ated with the sodium channel blocking antiar-
rhythmic agents from Vaughan Williams class
IA (quinidine, procainamide, disopyramide).
Although the cause of death in these studies was
not documented, proarrhythmia was believed to
be the major cause.103
Left ventricular dysfunction with a left ven-
tricular ejection fraction <40% is also likely a risk
factor for ventricular tachycardia induced by
drugs.104 Some risk factors are drug-specific. For
example, serum digoxin concentrations >2.0
ng/mL—particularly in patients with
hypokalemia, hypomagnesemia, or hypercal-
cemia—is a risk factor for monomorphic ventricu-
lar tachycardia caused by digoxin. Serum
theophylline concentrations >20 mcg/mL increase
the risk of theophylline-induced monomorphic
ventricular tachycardia.89 Patients with a history
of ventricular arrhythmias may be at higher risk
for monomorphic ventricular tachycardia induced
by terbutaline.81
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490 SECTION VI • Drug-Induced Cardiovascular Diseases
MORBIDITY AND MORTALITY
There is little published information regarding the
impact of drug-induced monomorphic ventricular
tachycardia on hospitalization or emergency room
visits, but based on the symptoms associated with
this disease, it seems likely that these could be con-
sequences. Drug-induced monomorphic ventricu-
lar tachycardia may degenerate into ventricular
fibrillation and cause sudden cardiac death. Potent
sodium channel blocking drugs in Vaughan
Williams antiarrhythmic classes IA and IC have
been shown to increase death due to arrhythmias
in patients with a history of myocardial infarc-
tion.101-103 Death has been reported as a result of
drug-induced incessant, sinusoidal ventricular
tachycardia.105 The incidence of mortality among
patients who experience drug-induced ventricular
tachycardia is unknown.
PREVENTION
The risk of drug-induced ventricular tachycardia
may be minimized by avoiding the use of specific
causative drugs in high-risk populations and by
maintaining serum potassium and magnesium
concentrations at >4.0 and >2.0 mEq/L, respective-
ly (Table 26–7). Flecainide and propafenone are
TABLE 26–7 Prevention of Drug-Induced
Monomorphic Ventricular Tachycardia
• Avoid use of Vaughan Williams class IA (quinidine,
procainamide, disopyramide) or class IC (flecainide,
propafenone) agents in patients with coronary artery
disease.
• Avoid use of disopyramide, flecainide, procainamide,
and propafenone in patients with heart failure due
to left ventricular systolic dysfunction (left ventricu-
lar ejection fraction <40%).
• Appropriately adjust doses of digoxin, procainamide,
and sotalol in patients with kidney disease.
• Avoid concomitant use of hepatically metabolized
drugs that may cause monomorphic ventricular
tachycardia and drugs that inhibit the cytochrome P-
450 enzyme system.
• Maintain serum digoxin concentrations <2.0 ng/mL.
• Maintain serum theophylline concentrations <20 mcg/mL.
• Maintain serum potassium concentrations within
normal range.
• Maintain serum magnesium concentrations within
normal range.
contraindicated in patients with documented coro-
nary artery disease. In addition, long-term use of
oral quinidine, procainamide, and disopyramide
should be avoided in patients with coronary artery
disease. Drugs with substantial potential to impair
myocardial contractility, including flecainide,
disopyramide, procainamide, propafenone, and
sotalol, should be avoided in patients with left ven-
tricular dysfunction. In patients receiving digoxin,
serum digoxin concentrations maintained at <2.0
ng/mL, and appropriate dose adjustment is neces-
sary in patients with kidney disease. Similarly,
patients receiving procainamide and, in particular,
sotalol should undergo appropriate dose adjust-
ment for kidney disease. Serum theophylline con-
centrations should be maintained at <20 mcg/mL.
MANAGEMENT
In patients with drug-induced monomorphic ventric-
ular tachycardia, the causative agent should be dis-
continued (Figure 26–3). Hemodynamically unstable
drug-induced ventricular tachycardia should be ter-
minated using synchronized direct current cardiover-
sion, starting at 100 J, and increasing to 200, 300 and
360 J if necessary.106-108 Ventricular tachycardia is usu-
ally considered hemodynamically unstable if it results
in altered mental status, ongoing chest pain,
hypotension or other signs of shock, or some combi-
nation of these.107 Hemodynamic instability is
uncommon at heart rates <150 bpm.107 In the event
that hemodynamically unstable drug-induced
monomorphic ventricular tachycardia is refractory to
direct current cardioversion, intravenous amiodarone
may be administered, unless amiodarone is believed
to be the causative agent.108 Hemodynamically stable
drug-induced monomorphic ventricular tachycardia
may be also be treated with synchronized direct cur-
rent cardioversion, at the energy levels described
above, with appropriate sedation prior to shock
administration.108 Alternatively, hemodynamically
stable drug-induced monomorphic ventricular tachy-
cardia may be treated initially with intravenous pro-
cainamide (Figure 26–3), unless procainamide is
believed to be the causative agent.108 Intravenous
amiodarone may be administered if hemodynamical-
ly stable monomorphic ventricular tachycardia is
refractory to direct current cardioversion, or pro-
cainamide is not effective.108
Incessant sinusoidal ventricular tachycardia is
sometimes resistant to direct current cardioversion
or overdrive pacing, and is often resistant to antiar-
rhythmic drugs such as procainamide.43 However,
flecainide-induced incessant sinusoidal ventricular
tachycardia has been successfully treated with
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CHAPTER 26 • Ventricular Arrhythmias 491

Discontinue causative agent(s)

Correct hypokalemia and/or hypomagnesemia
If caused by digoxin, administer digoxin immune antibody fragments

Hemodynamically Hemodynamically stable Hemodynamically stable

unstable monomorphic VT sinusoidal VT

Sedate Procainamidea Lidocainec

(where possible)

Amiodaroned
Synchronized direct Amiodaroneb
current cardioversion

FIGURE 26–3. Management of Drug-Induced Monomorphic Ventricular Tachycardia

a
20 mg/min continuous intravenous infusion until arrhythmia is suppressed, hypotension occurs, QRS complex prolongs 50% from pre-
treatment value, or a total of 17 mg/kg has been administered. Continuous infusion of 1–4 mg/min may be administered if necessary.107
b
150 mg intravenously over 10 minutes, followed by continuous intravenous infusion of 1 mg/min for 6 hr, followed by continuous intra-
venous infusion of 0.5 mg/min for 18 hr.107
c
75 mg intravenous bolus, followed 10 min later by 50 mg intravenous bolus, followed by continuous intravenous infusion of 2 mg/min.42
d
600 mg intravenously over 20 min, followed by 2 g by continuous intravenous infusion over 24 hr, with a concomitant oral regimen of 2
g /24 hr.43

intravenous lidocaine, administered as a loading
dose of 75 mg, followed in 10 minutes by another
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
amiodarone, administered as a loading dose of 600
mg over 20 minutes, followed by 2 g over 24 hours,
with a concomitant oral regimen of 2 g/24 hours.43
INFORMATION FOR PATIENTS
feel palpitations, light-headed, dizzy, tired, weak,
or short of breath or experience chest pain.
TORSADES DE POINTES
Torsades de pointes is a potentially life-threatening
ventricular tachyarrhythmia associated with pro-
longation of the QT interval.109,110 QT interval pro-
longation and torsades de pointes may be
congenital or acquired. Acquired torsades de
pointes is most often caused by drugs.110

Patients who are taking drugs that may cause ven-

tricular tachycardia should be told that the medica-
tion may, in rare cases, cause the heart rate (pulse)
to become faster. Patients should be instructed to
consult their pharmacist or physician if their heart
rate increases to above 100 to 120 bpm or if they
CAUSATIVE AGENTS
Drugs that have been reported to cause torsades de
pointes are presented in Table 26–8.13,111-461 Drugs
that have been reported to cause prolongation of
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492 SECTION VI • Drug-Induced Cardiovascular Diseases

TABLE 26–8 Agents Implicated in Drug-Induced Torsades de Pointes

Drug Incidence Level of Evidence
(see page xii for explanation)
112-114
Amantadine NK C
Amiodarone115-158 0.7% B
Amitriptyline159,160 NK C
Arsenic161-165 NK C
Atazanavir166 NK C
Azimilide167-172 1.0% A
Azithromycin173,174 NK C
Bepridil175-181 0.9% B
Chloral hydrate182,a NK C
Chloroquine183 NK C
Chlorpromazine13,184 NK C
Ciprofloxacin172,185-189 NK C
Cisapride190-199 0.1–5.7% B
Citalopram200-204 NK C
191,195,205-211
Clarithromycin NK C
Clozapine212,213 NK C
Cocaine214-217 NK C
Disopyramide115,206,208,218-227 NK C
Dobutamine228-230 NK C
Dofetilide231-242 0–10%b A
Dolasetron243 NK C
Domperidone244,245 NK C
Doxepin246,247 NK C
Droperidol248-252 <0.1% B
Epinephrine253 NK C
Erythromycin198,254-275 0.4% B
Famotidine276 NK C
Flecainide130,277-280 NK C
Fluconazole160,281-289 NK C
Fluoxetine290-292 NK C
Halofantrine293,294 NK C
Haloperidol295-308 3.6%c C
Ibutilide55-57,59,135,309-317 1.4–11.5% A
Imipramine116,a NK C
Indapamide318,319 NK C
Ketoconazole320 NK C
Levofloxacin153,185,284,321-324 NK C
Levomethadyl325 NK C
Loratadine142 NK C
Methadone326-347 NK C
(Continued)
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CHAPTER 26 • Ventricular Arrhythmias 493

TABLE 26–8 Agents Implicated in Drug-Induced Torsades de Pointes (Continued)

Drug Incidence Level of Evidence

Metoclopramide348,349 NK C
Metronidazole148 NK C
Moxifl¡oxacin350-352 NK C
Ofloxacin185 NK C
Pentamidine353-368 Up to 21% B
Pimozide209,369 NK C
Procainamide116,370-375 0–3.6%b A
Propafenone376,377 NK C
Quetiapine378 NK C
Quinidine116,126,132,220,273,379-392 2–12% A
Risperidone202,393,394 NK C
Roxithromycin395-397 NK C
Sertraline212 NK C
Sibutramine398,399 NK C
Solifenacin400 NK C
Sotalol239,374,390,401-437 0.4–5%b A
Sparfloxacin438,439 NK C
Tacrolimus440,441 NK C
Thioridazine442-456 NK C
Trazodone129 NK C
Trimethoprim–sulfamethoxazole457,458 NK C
Voriconazole459,460 NK C
Ziprasidone113,461 NK C
Zoldipem149 NK C
NK = not known.
a
In overdose.
b
Incidence varies depending on the presence or absence of left ventricular dysfunction and whether or not drug dosage is properly
adjusted in patients with kidney disease. The incidence may be as high as 10% when proper dosage adjustments are not made.
c
Intravenous haloperidol in critically ill patients.

the corrected QT (QTc) interval on ECG but have
not been reported to induce torsades de pointes are
not included, as drug-induced QTc interval prolon-
gation in the absence of torsades de pointes is not
a drug-induced disease. Up-to-date lists of drugs
with the potential to cause torsades de pointes may
be found at http://www.azcert.org/medical-
pros/drug-lists/drug-lists.cfm, a Web site main-
tained by the University of Arizona Center for
Education and Research on Therapeutics.111
EPIDEMIOLOGY
The incidence of drug-induced torsades de pointes
in the general population is unknown. An attempt
was made to determine the overall incidence of
drug-induced ventricular proarrhythmia in a study
conducted by the Swedish Medical Products
Agency.462 This study was conducted over a period
of 28 days in 32 hospitals, with a reference popula-
tion of approximately 4.2 million people. All
episodes of ventricular arrhythmias that were
encountered during admission to the hospital or
that were tracked by ambulatory ECG recordings in
the hospitals and that were considered to be asso-
ciated with drugs were recorded. Fourteen cases of
“medium or high confidence torsades de pointes”
were recorded. This corresponded to an incidence
of 3.3 cases per million during the 28-day period of
the study, which was annualized to an incidence of
4 cases per 100,000 people annually.462 This study
TisdaleC26_485-515 1/12/10 2:54 PM Page 494
494 SECTION VI • Drug-Induced Cardiovascular Diseases
was very small and of very short duration.
Nonetheless, if this incidence could be extrapolat-
ed to the population of the U.S., it would corre-
spond to approximately 12,000 cases of
drug-induced torsades de pointes annually.
In another study conducted in Sweden,
adverse drug reactions reported to the Swedish
adverse drug reaction reporting system between
1991 and 2006 were analyzed.463 Of 61,788 report-
ed adverse drug reactions, 101 were drug-induced
torsades de pointes. Drug-induced torsades de
pointes was estimated to comprise 5% to 7% of all
cases of ventricular tachycardia, ventricular fibril-
lation, or sudden cardiac death in a population-
based study conducted in southwest France.464
These studies did not attempt to determine the
overall incidence of drug-induced torsades de
pointes in the population. Further research is nec-
essary to determine the overall incidence of drug-
induced torsades de pointes.
The incidence of torsades de pointes associated
with specific agents is presented in Table 26–8.
MECHANISMS
Torsades de pointes occurs in the setting of prolon-
gation of ventricular repolarization resulting in
lengthening of ventricular action potential dura-
tion, which is manifested as prolongation of the
QTc interval on the ECG.109,110,465 As a result of acti-
vation of inward depolarizing currents, action
potential prolongation leads to increased suscepti-
bility to early afterdepolarizations, which are man-
ifested as depolarizing oscillations in membrane
voltage during phase 2 or 3 of the action poten-
tial.109 These early afterdepolarizations may result
in triggered upstrokes, which, when occurring dur-
ing the latter portion of phase 3 of the action
potential, may initiate torsades de pointes via reen-
try.109,465
Prolongation of ventricular repolarization and
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
potential (or both). Drugs induce torsades de
pointes through inhibition of outward current
through specific potassium channels, primarily the
rapid component of the delayed rectifier potassium
channel (IKr), resulting in action potential prolon-
gation.109,110,465 Some drugs, such as ibutilide, also
appear to prolong ventricular action potential, in
part through activation of slow sodium current
during phase 2 of the action potential. It is
believed that early afterdepolarizations that trigger
torsades de pointes may be caused by increased
inward calcium current through calcium channels
that become reactivated as a result of prolongation
in action potential duration.110,465,466
Although inhibition of IKr current and prolon-
gation of ventricular repolarization and the corre-
sponding QTc interval are requisite for the
development of torsades de pointes, those factors
alone are not sufficient for the arrhythmia to
occur. Many patients taking drugs that inhibit IKr
current have QTc interval prolongation but do not
experience torsades de pointes. A major factor that
is believed to increase the likelihood of torsades de
pointes, and which may in part explain the lack of
a direct correlation between QTc interval and the
occurrence of torsades de pointes, is heterogeneity
of repolarization (also referred to as dispersion of
repolarization or refractoriness).110 Action poten-
tial duration varies throughout the three primary
ventricular cell types (epicardial, mid-myocardial
[M cells], endocardial), as a result of variations in
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
dispersion of ventricular refractoriness. In addi-
tion, evidence exists to suggest that the risk of tor-
sades de pointes may be dependent on instability
of the action potential and by the degree of trian-
gulation of the action potential. Instability of the
action potential indicates rapid fluctuations in
action potential duration. Triangulation of the
action potential refers to the ratio of the action
potential duration at 30% repolarization to that of
action potential duration at 90% repolarization; as
this ratio increases, the action potential takes on a
more triangular shape. In vitro and ex vivo studies
have suggested that the risk of torsades de pointes
is enhanced when action potential instability and
triangulation are present.467 Further study is
required to better understand the conditions
required for torsades de pointes to develop in
patients with QTc interval prolongation.
CLINICAL PRESENTATION AND
DIFFERENTIAL DIAGNOSIS
Symptoms associated with torsades de pointes are
similar to those of other tachyarrhythmias and are
related to heart rate and resulting effects on blood
pressure and cardiac output (Table 26–9). Although
torsades de pointes is sometimes transient, self-lim-
iting, and spontaneously terminating, it can
degenerate into ventricular fibrillation and cause
sudden cardiac death.
TisdaleC26_485-515 1/12/10 2:54 PM Page 495
TABLE 26–9 Signs and Symptoms Associated
with Drug-Induced Torsades de Pointes
• Torsades de pointes on electrocardiogram—polymor-
phic ventricular tachycardia in setting of prolonged
QTc interval
• Often a “long–short” initiating sequence on electro-
cardiogram
• Tachycardia
• Hypotension
• Palpitations
• Dizziness
• Light-headedness
• Shortness of breath
• Chest pain (in patients with underlying coronary artery
disease)
• Near-syncope
• Syncope
• Seizure (due to cerebral hypoxia)
• Syndrome of sudden cardiac death
The diagnosis of torsades de pointes is depend-
ent on the ECG. Torsades de pointes is a specific
polymorphic ventricular tachycardia associated
with prolongation of the QTc interval in the sinus
beats that precede the arrhythmia. QT interval cor-
rection is necessary because the QT interval varies
depending on the heart rate; as heart rate increas-
es, the QT interval shortens, and vice versa. There
are numerous published formulas for correcting
the QT interval, but that which is most commonly
used in practice, and which is programmed into
ECG machines, is the Bazett’s correction468:
QTc = QT interval
√冪 RR interval
Torsades de pointes, or “twisting of the points,”
is characterized by the apparent twisting of the
wide QRS complexes around the isoelectric base-
line (Figure 26–4) and occurs at rates of 150 to 300
bpm. A characteristic feature of torsades de pointes
is a “long–short” initiating sequence (Figure 26–4),
which occurs as a result of a ventricular premature
beat followed by a compensatory pause, which is
I FIGURE 26–4 Torsades de
CHAPTER 26 • Ventricular Arrhythmias 495
followed by the first beat of the torsades de
pointes.
The onset of drug-induced torsades de pointes
is variable, particularly when it is associated with
oral drug therapy. Torsades de pointes associated
with intravenous drug therapy usually coincides
with the expected time of peak concentration of
the causative agent. For example, many of the
cases of torsades de pointes induced by intra-
venous erythromycin occurred during the infusion
or within 30 minutes of completion of the infu-
sion.254,256,259,264,266,274 Torsades de pointes induced
by intravenous haloperidol occurs within 15 to 220
minutes after the infusion.304 Ibutilide-induced tor-
sades de pointes occurs within 2 to 60 minutes
after drug administration, but most often occurs
within 15 minutes.55-57,59,309-317
Torsades de pointes induced by oral drugs may
be delayed. In an analysis of 144 published articles
describing 249 patients who experienced torsades
de pointes associated with noncardiac drugs, only
18% of the cases occurred within 72 hours of the
initiation of oral therapy; 42% occurred between 3
and 30 days after the initiation of therapy, and
40% occurred more than 30 days after the initia-
tion of therapy.469
Conditions to consider in the differential diag-
nosis of drug-induced torsades de pointes are listed
in Table 26–10. Other tachyarrhythmias must be
excluded, through review of the ECG. If the patient
has polymorphic ventricular tachycardia, torsades
de pointes must be distinguished from non–tor-
sades de pointes polymorphic ventricular tachycar-
dia; this can be done by determining whether
prolongation of the QTc interval is present prior to
or shortly after the episode of polymorphic ventric-
ular tachycardia. The patient’s list of current med-
ications should be reviewed to determine whether
he or she is receiving a drug that has been report-
ed to cause torsades de pointes, or at least to cause
QTc interval prolongation. In addition, the patient
should be evaluated for the presence of concomi-
tant risk factors for torsades de pointes, which sub-
stantially increase the likelihood of the occurrence
of the tachyarrhythmia.
pointes associated with intra-
venous haloperidol. Strip
shows prolonged QT interval
and long-short initiating
sequence prior to arrhythmia.
Reprinted with permission from
Sharma et al.304
TisdaleC26_485-515 1/12/10 2:54 PM Page 496
496 SECTION VI • Drug-Induced Cardiovascular Diseases
TABLE 26–10 Conditions to Consider in the
Differential Diagnosis of Drug-Induced Torsades de
Pointes
• Sinus tachycardia
• Atrial fibrillation
• Atrial flutter
• Atrial tachycardia
• Atrioventricular nodal reentrant tachycardia
• Monomorphic ventricular tachycardia
• Non–torsades de pointes polymorphic ventricular
tachycardia
RISK FACTORS
Specific risk factors for drug-induced torsades de
pointes have been identified (Table 26–11).
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-
magnesemia, left ventricular systolic dysfunction,
and conditions leading to elevated plasma concen-
trations of causative drugs, such as kidney disease,
liver disease, drug interactions, or some combina-
tion of these.109,110,170
Drug-induced torsades de pointes appears to
occur exceedingly rarely in patients without con-
comitant risk factors. An analysis of 144 published
articles describing 249 patients who experienced tor-
sades de pointes associated with noncardiac drugs
revealed that nearly 100% of the patients had at least
one risk factor, and 71% of the patients had at least
two risk factors.469 More than two thirds of the
patients were female; 41% had heart disease (defined
as myocardial infarction, heart failure, valvulopathy,
or cardiomyopathy); 28% had hypokalemia; 19%
had “drug toxicity” (defined as administration of
higher-than-recommended doses or lack of dose
adjustment for organ dysfunction); 18% had a famil-
ial history of long-QT syndrome, a history of previ-
ous drug-induced torsades de pointes, or a history of
drug-induced QT interval prolongation.469 Drug
interactions leading to increased plasma concentra-
tions of the causative agent were present in 35% of
the patients. These data indicate that the vast major-
ity of patients in whom torsades de pointes induced
by noncardiac drugs develops have risk factors that
are easily identifiable.
Explanations for an increased risk of drug-
induced torsades de pointes in specific patient pop-
ulations are under investigation. Reasons that
women are at increased risk for drug-induced tor-
sades de pointes are unclear, but may involve
TABLE 26–11 Risk Factors for Drug-Induced
Torsades de Pointes
• QTc interval >500 msec
• Increase in QTc interval by >60 msec compared with
the pretreatment value
• Female sex
• Advanced age
• Left ventricular systolic dysfunction
• Hypokalemia
• Hypomagnesemia
• 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
cause QTc interval prolongation or torsades de
pointes
• Possible genetic predisposition
• History of drug-induced torsades de pointes
arrhythmogenic effects of estrogen in women or
protective effects of testosterone in men.470
Baseline QTc interval is longer in women than in
men.471 In one series of 332 cases of torsades de
pointes associated with antiarrhythmic agents,
70% of the cases occurred in women.472 Other stud-
ies have documented a female predisposition to
torsades de pointes associated with azimilide,170
dofetilide,473 erythromycin,474 ibutilide,475 quini-
dine,476 sotalol,416 and terfenadine.477 The influ-
ence of sex hormones on ventricular repolarization
and risk for torsades de pointes has been investigat-
ed and is a subject of ongoing study. One group of
investigators administered a small dose of intra-
venous ibutilide to healthy women during three
phases of the menstrual cycle and attempted to
correlate plasma concentrations of estradiol and
progesterone with ibutilide-induced prolongations
in the QTc interval. QTc interval prolongation was
not correlated with plasma estradiol concentra-
tion, but was inversely correlated with the plasma
progesterone concentration and the plasma prog-
esterone-to-estradiol ratio, suggesting that estrogen
may not be proarrhythmic, but that progesterone,
an androgenic compound, may be protective.478 In
vitro studies have shown that dihydrotestosterone
shortens basal action potential duration and
diminishes the effects of potassium channel block-
ing drugs on action potential duration.479
Therefore, androgens may protect against the elec-
trophysiologic effects of drugs with the potential to
induced torsades de pointes.
Bradycardia has also been shown to be a risk
factor for drug-induced torsades de pointes.
TisdaleC26_485-515 1/12/10 2:54 PM Page 497
Ventricular repolarization is dependent on heart
rate; the slower the heart rate, the longer the peri-
od of ventricular repolarization.466 The majority of
drugs with the potential to cause torsades de
pointes bind to potassium channels in a manner
that is known as “reverse-use-dependent,” which
means that the slower the heart rate, the more
tightly the drug binds to the potassium channel,
which likely explains the higher risk of torsades de
pointes at slower heart rates.480
Left ventricular systolic dysfunction is a major
risk factor for drug-induced torsades de pointes.
The incidence of torsades de pointes associated
with drugs such as ibutilide310,311 and dofetilide233-
239
has been shown to be more than twice as high
in patients with left ventricular systolic dysfunc-
tion than in patients with normal left ventricular
function. Mechanisms behind the increased risk of
drug-induced torsades de pointes in this popula-
tion are unclear, although it has been shown that
downregulation of potassium channels occurs in
patients with left ventricular systolic dysfunc-
tion,481 promoting prolongation in ventricular
repolarization. In a study of ibutilide pretreatment
for facilitation of direct current cardioversion of
atrial fibrillation, two of 64 ibutilide-treated
patients (3.1%) had torsades de pointes; both
patients had a left ventricular ejection fraction
<20%.314 On the basis of this study, many recom-
mend that QTc interval–prolonging drugs should
not be administered to patients with a left ventric-
ular ejection fraction <20%.
Some patients in whom drug-induced torsades
de pointes develops may have a genetic predisposi-
tion. Eight specific genetic defects have been iden-
tified that underlie the congenital long-QT interval
syndromes.482 Clinically “silent” gene mutations
have been identified in some patients who have
experienced drug-induced torsades de pointes and
their family members.466 Mutations or polymor-
phisms of genes that are known to predispose to
the congenital long-QT interval syndromes may be
present in 10% to 15% of patients who experience
drug-induced torsades de pointes.483
Prolongations in QTc interval have been
repeatedly shown to be a risk factor for drug-
induced torsades de pointes. Evidence indicates
that the risk of torsades de pointes increases
markedly when QTc interval becomes prolonged to
>500 msec, or, alternatively, when the QTc interval
increases by more than >60 msec as compared with
pretreatment values.170,304,484 Some investigators
have also suggested that dispersion of the QT inter-
val may also indicate increased risk of torsades de
pointes. QT interval dispersion is calculated by
subtracting the minimum QT interval from the
maximum QT interval on the 12-lead electrocar-
CHAPTER 26 • Ventricular Arrhythmias 497
diogram, and represents dispersion of ventricular
repolarization. QT interval dispersion was signifi-
cantly increased in 9 patients who experienced tor-
sades de pointes associated with Vaughan Williams
class IA antiarrhythmic agents as compared with
29 patients who did not have torsades de
pointes.485 Similarly, QT interval dispersion was
increased significantly in 6 patients with torsades
de pointes induced by the investigational Vaughan
Williams class III antiarrhythmic agent
almokalant, as compared with 94 patients who did
not have torsades de pointes while receiving the
drug.486 However, evidence indicates that measure-
ment of QTc interval prolongation is a better pre-
dictor of the development of drug-induced
torsades de pointes than measurement of QT inter-
val dispersion.487 Further, some evidence suggests
that uncorrected QT interval may be at least as
good as corrected QT interval for prediction of
drug-induced torsades de pointes.488
Elevated plasma concentrations of drugs
known to cause torsades de pointes is an important
risk factor. The majority of cases of torsades de
pointes associated with erythromycin254,256,259,263-
266,269,270,274
or haloperidol299-302,304-307 occurred after
intravenous administration of the drug, possibly as
a result of higher peak plasma concentrations. In
addition, failure to adjust specific drug doses for
kidney disease has resulted in torsades de pointes
associated with dofetilide,489 levofloxacin,324 pro-
cainamide,371 and sotalol.411,413,417,418 Drugs that
have been reported to cause torsades de pointes
that require dosage adjustment in patients with
kidney disease are listed in Table 26–12. Drug inter-
TABLE 26–12 Drugs Known to Cause Torsades de
Pointes That May Require Dose Adjustment in
Patients with Kidney Disease
• Amantadine
• Bepridil
• Ciprofloxacin
• Disopyramide
• Dofetilide
• Famotidine
• Flecainide
• Fluconazole
• Gatifloxacin
• Levofloxacin
• Loratadine
• Metoclopramide
• Ofloxacin
• Pentamidine
• Procainamide
• Sotalol
• Trimethoprim–sulfamethoxazole
TisdaleC26_485-515 1/12/10 2:54 PM Page 498

498 SECTION VI • Drug-Induced Cardiovascular Diseases

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
drug-induced torsades de pointes. Of 25 cases of
torsades de pointes associated with terfenadine
that were reported to the Food and Drug
Administration (FDA), 9 patients were receiving
concomitant therapy with ketoconazole or itra-
conazole, which inhibit the metabolism of terfena-
dine.477 Numerous reported cases of drug-induced
torsades de pointes occurred as a result of drug
interactions leading to elevate plasma concentra-
tions of the offending agent.129,191,195,198,
206,209,250,262,267,273,275
QT interval–prolonging drugs
that are substrates for the cytochrome P-450 sys-
tem, and therefore subject to drug interactions
when used in combination with inhibitors of
enzymes of the cytochrome P-450 system, are list-
ed in Table 26–13.490
Use of combinations of QT interval–prolong-
ing drugs increases the risk for drug-induced tor-
sades de pointes. A retrospective cohort study of an
outpatient prescription claims database revealed
that 9.4% of approximately 1.1 million patients
who filled a prescription for a QT interval–prolong-
ing drug also filled an overlapping prescription for
a second QT interval–prolonging drug or for a drug
known to inhibit the clearance of the QT inter-
val–prolonging agent.491 In a similar study, auto-
mated drug-dispensing data from 2 million health
plan members from a total of 10 health mainte-
nance organizations were reviewed to determine
the proportion of these patients who had been pre-
scribed QT interval–prolonging drugs, and the pro-
portion of those patients for whom a second QT
interval–prolonging drug or a drug known to alter
the clearance of the QT interval–prolonging med-
ication was prescribed.492 Of the patients from
whom data were obtained, 11.4% had received pre-
scriptions for a potentially QT interval–prolonging
drug. Of the patients who received prescrip-
tions for a QT interval–prolonging drug, 4.6% also
received a prescription for a potentially interacting
drug that could increase the risk of torsades de
pointes.492
A history of drug-induced torsades de pointes
increases the risk for torsades de pointes associated
with other QT interval–prolonging drugs.115, 132,377
MORBIDITY AND MORTALITY
Torsades de pointes may result in clinical symptoms
requiring medical attention. More importantly, tor-
TisdaleC26_485-515 1/12/10 2:54 PM Page 499

CHAPTER 26 • Ventricular Arrhythmias 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
TisdaleC26_485-515 1/12/10 2:54 PM Page 500
500 SECTION VI • Drug-Induced Cardiovascular Diseases
induced torsades de pointes may be prevented by
minimizing risk factors associated with torsades de
pointes (Table 26–11). Intravenous erythromycin
doses of 1g every 6 hours should be avoided, unless
Legionella pneumophila infection is documented.
The maximum daily dose of intravenous haloperi-
dol should not exceed 35 mg.304
In patients receiving drugs known to promote
the development of torsades de pointes, the QTc
interval should be monitored and maintained at
<500 msec. In hospitalized patients receiving drugs
known to cause torsades de pointes, QTc intervals
should be monitored daily, preferably using a 12-
lead ECG, but at least using a lead II ECG strip.
Patients receiving long-term oral therapy with
drugs known to promote the development of tor-
sades de pointes should undergo a 12-lead ECG for
the measurement of QTc intervals every 3 to 6
months depending on the presence or absence of
other risk factors. As mentioned previously, QTc-
interval monitoring has been shown to be more
predictive of the development of torsades de
pointes than measurement of QT interval disper-
sion, which is not necessary.487 In addition, there is
some evidence to suggest that the uncorrected QT
interval is at least as accurate as the corrected QT
interval for the prediction of drug-induced torsades
de pointes.488
Although drugs with the potential to cause tor-
sades de pointes should not necessarily be avoided
in female patients, other risk factors associated
with drug-induced torsades de pointes are easily
identifiable prior to the initiation of therapy with
QTc interval–prolonging drugs,469 and use of QT
interval–prolonging drugs in patients with these
other risk factors should be avoided whenever pos-
sible. In particular, concomitant administration of
more than one QT interval–prolonging drugs
should be avoided, concomitant administration of
susceptible QT interval–prolonging drugs with
drugs that inhibit their metabolism should be
avoided, and doses of renally eliminated QT inter-
val–prolonging drugs should be adequately adjust-
ed in patients with kidney disease. Ideally, doses of
drugs that are predominantly hepatically metabo-
lized should be adjusted in patients with liver dis-
ease. However, there are few guidelines with
respect to dose adjustment in hepatic disease, and
it is best to avoid hepatically metabolized QTc
interval–prolonging drugs in patients with
advanced liver disease.
Prophylactic administration of magnesium has
been shown to attenuate the effects of drugs on QT
interval prolongation. Administration of magne-
sium sulfate 2 g intravenously prior to administra-
tion of ibutilide 1 mg significantly diminished the
effect of ibutilide on QT interval prolongation in
patients with normal serum magnesium concen-
trations as compared with that in a group of nor-
momagnesemic patients who received placebo
prior to ibutilide. In addition, pretreatment with
magnesium significantly reduced the risk of ibu-
tilide-induced QT interval prolongation >30 msec
as compared with pre-ibutilide values.497 However,
there are no published data to demonstrate that
pretreatment with magnesium reduces the risk of
drug-induced torsades de pointes. In view of a lack
of data regarding the effects of magnesium pre-
treatment on the incidence of drug-induced tor-
sades de pointes, it cannot be routinely
recommended. Nonetheless, magnesium pretreat-
ment may be a reasonable strategy in high-risk
patients with multiple risk factors for torsades de
pointes for whom acute intravenous administra-
tion of a potentially QT interval–prolonging drug
cannot be avoided.
Specific guidelines have been published regard-
ing monitoring of patients for prevention of
methadone-induced torsades de pointes.498 These
guidelines recommend that all patients on
methadone therapy should undergo a pretreat-
ment ECG for determination of the QTc interval, a
follow-up 12-lead ECG for determination of the
QTc interval within 30 days of the initiation of
methadone treatment, and a 12-lead ECG for QTc
interval determination annually. More intensive
QTc interval monitoring is recommended for
patients who require daily methadone doses
greater than 100 mg, and for those that experience
unexplained syncope or seizures. Although these
recommendations have not met with universal
approval,499 QTc interval monitoring seems pru-
dent and reasonable in patients initiating and tak-
ing long-term methadone therapy.
MANAGEMENT
A treatment strategy for drug-induced torsades
de pointes is presented in Figure 26–5.107,108,500
Management of drug-induced torsades de
pointes is dependent on recognition of the
arrhythmia and distinguishing it from
monomorphic ventricular tachycardia or
non–torsades polymorphic ventricular tachycar-
dia. Therapy with drugs with the potential to
cause torsades de pointes should be discontin-
ued. Hypokalemia or hypomagnesemia should
be corrected with intravenous potassium or
intravenous magnesium, respectively. Patients
with torsades de pointes who are hemodynami-
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CHAPTER 26 • Ventricular Arrhythmias 501

Discontinue causative agent(s)

Correct hypokalemia and/or hypomagnesemia

Hemodynamically Hemodynamically
unstable stable

Administer sedation Intravenous

when possible magnesium
sulfate 1–2 g, diluted in
50–100 mL D5W,
administered over 5–60 mina

Defibrillation (asynchronous shocks)

Biphasic shock: 120–200 J
Monophasic shock: 360 J

Temporary transvenous
overdrive pacing

Intravenous isoproterenol FIGURE 26–5 Management of Drug-

2–10 ␮g/min infusionb
Sedation, followed by:
Defibrillation (asynchronous shocks)
Biphasic shock: 120–200 J
Monophasic shock: 360 J
Induced Torsades de Pointes
D5W = 5% dextrose in water.
a
Doses may be repeated to a total of 12 g.
Alternatively, a continuous infusion may be ini-
tiated after the first bolus, at a rate of 0.5–1.0
mg per hour
b
Titrate to heart rate (aim for heart rate > than
current torsades de pointes rate) and decreas-
ing QT interval.

cally unstable should be treated with asynchro- centration.116,203,346,375,387,413,426,501-508 The mecha-

nous shocks (i.e., defibrillation).107 While syn-
chronized direct current cardioversion is
preferred for organized rhythms, synchroniza-
tion of shocks is often not possible in patients
with polymorphic ventricular tachycardias such
as torsades de pointes, because the multiple QRS
complex configurations and fluctuating heart
rates render it very difficult, and sometimes
impossible, to synchronize the delivery of the
shock to a QRS complex.107
Several treatment options are available for
patients with hemodynamically stable torsades de
pointes (Figure 26–5). Intravenous magnesium has
been reported to terminate torsades de pointes,
irrespective of the patient’s serum magnesium con-
nism by which intravenous magnesium terminates
torsades de pointes is not clear, but termination
may occur via inhibition of early afterdepolariza-
tions as a result of calcium-channel blockade.
Overdrive pacing via the percutaneous inser-
tion of a temporary pacemaker is also effective
for termination of torsades de pointes, as over-
drive pacing leads to shortening of the QT inter-
val.108,221,368,401,458 Intravenous isoproterenol may
also terminate torsades de pointes, by increasing
heart rate and shortening the QT inter-
val.108,373,509 In addition, refractory torsades de
pointes associated with sotalol has been success-
fully managed using hemodialysis412,419 or peri-
toneal dialysis.420
TisdaleC26_485-515 1/12/10 2:54 PM Page 502
502 SECTION VI • Drug-Induced Cardiovascular Diseases
INFORMATION FOR PATIENTS
Patients who are taking drugs that may cause tor-
sades de pointes should be instructed that the drug
may in rare cases cause the heart rate (pulse) to
become faster. Patients should be instructed to
consult their pharmacist or physician if the heart
rate increases to above 100 to 120 bpm, or if they
feel palpitations, light-headed, dizzy, tired, weak,
short of breath, or chest pain. Patients who are tak-
ing drugs that may cause torsades de pointes
should be instructed not to take any nonprescrip-
tion medication without first consulting their
pharmacist or physician because of the possibility
of interactions of potentially proarrhythmic med-
ications with nonprescription drugs such as cime-
tidine. In addition, patients should make sure that
their pharmacist and physician are fully aware of
all medications that they are taking, to avoid
receiving new medications that may potentially
interact with drugs that may cause torsades de
pointes.
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3. Dickens P, Tai YT, But PP, et al. Fatal accidental aconitine
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421. Gottlieb SS, Cines M, Marshall J. Torsades de pointes
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CHAPTER 26 • Ventricular Arrhythmias 513
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440. Johnson MC, So S, Marsh JW, et al. QT prolongation and
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442. Kemper AJ, Dunlap R, Pietro DA. Thioridazine-induced
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443. Liberatore MA, Robinson DS. Torsade de pointes: a
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445. Toivonen LK, Leinonen H. Limited effect of magnesium
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447. Bastecký J, Kvasnicka J, Vortel J, et al. Suicidal ingestion
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450. Donatini B, Le Blaye I, Krupp P. Transient cardiac pacing
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452. Le Blaye I, Donatini B, Hall M, et al. Acute overdosage
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453. Hulisz DT, Dasa SL, Black LD, et al. Complete heart block
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454. Buckley NA, Whyte IM, Dawson AH. Cardiotoxicity more
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456. Denvir MA, Sood A, Dow R, et al. Thioridazine, diarrhoea
and torsades de pointe. J R Soc Med. 1998;91:145-147.
457. Wiener I, Rubin DA, Martinez E, et al. QT prolongation
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458. Lopez JA, Harold JG, Rosenthal MC, et al. QT
prolongation and torsades de pointes after
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459. Alkan Y, Haefeli WE, Burhenne J, et al. Voriconazole-
induced QT interval prolongation and ventricular
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460. Philips JA, Marty FM, Stone RM, et al. Torsades de
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461. Heinrich TW, Biblo LA, Schneider J. Torsades de pointes
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462. Darpö B. Spectrum of drugs prolonging QT interval and
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463. Aström-Lilja C, Odeberg JM, Ekman E, et al. Drug-
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464. Molokhia M, Pathak A, Lapeyre-Mestre M, et al. Case
ascertainment and estimated incidence of drug-induced
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465. Roden DM. Drug-induced prolongation of the QT
interval. N Engl J Med. 2004;350:1013-1022.
466. Viskin S. Long QT syndromes and torsade de pointes.
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467. Hondeghem LM, Carlsson L, Duker G. Instability and
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468. Bazett HC. An analysis of time relationships of the
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469. Zeltser D, Justo D, Halkin A, et al. Torsade de pointes due
to noncardiac drugs: most patients have easily
identifiable risk factors. Medicine. 2003;82:282-290
470. Pham TV, Rosen MR. Sex, hormones, and repolarization.
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472. Makkar RR, Fromm BS, Steinman RT, et al. Female gender
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473. Pedersen HS, Elming H, Siebæk M, et al. Risk factors and
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in patients with left ventricular systolic dysfunction
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474. Drici MD, Knollman BC, Wang W-X, et al. Cardiac
actions of erythromycin. Influence of female sex. JAMA.
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475. Gowda RM, Khan IA, Punukollu G, et al. Female
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476. Roden D, Woosley R, Primm R. Incidence and clinical
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477. Woosley RL, Chen Y, Freiman JP, et al. Mechanisms of
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478. Rodriguez I, Kilborn MJ, Liu XK, et al. Drug-induced QT
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JAMA. 2001;285:1322-1326.
479. Pham TV, Sosunov EA, Anyukhovsky EP, et al.
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480. Nattel S. The molecular and ionic specificity of
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1999;10:272-282.
481. Nabauer M, Kaab S. Potassium channel down-regulation
in heart failure. Cardiovasc Res. 1998;37:324-334.
482. Modell SM, Lehmann MH. The long QT syndrome family
of cardiac ion channelopathies: a HuGE review. Genet
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483. Yang P, Kanki H, Drolet B, et al. Allelic variants in long-
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484. Committee on Proprietary Medicinal Products. The
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485. Hii J, Wyse D, Gillis A, et al. Precordial QT interval
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Circulation. 1992;86:1376-1382.
486. Houltz B, Darpö B, Edvardsson N, et al.
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487. Tisdale JE, Rasty S, Padhi ID, et al. The effect of
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CHAPTER 26 • Ventricular Arrhythmias 515
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TisdaleC27_516-528 1/12/10 2:56 PM Page 516
CHAPTER 27
Hypertension
O ver 70 million Americans have hypertension,
or approximately one out of three adults.1
Moreover, over 50 million adult Americans have
prehypertension. Hypertension is a chronic med-
ical condition that is characterized by persistent
increases in systolic or diastolic blood pressure, or
both. Prehypertension is a term used to identify
patients with elevated blood pressures that are not
high enough to be classified as hypertension, but
are higher than normal.2 Patients with prehyper-
tension are at high risk for progressing to hyperten-
sion in the future. Hypertension and pre-
hypertension are both nearly always asympto-
matic. Target organ damage (e.g., coronary artery
disease, chronic kidney disease/failure, ischemic
stroke), commonly presenting as a cardiovascular
event, is the primary cause of associated morbidity
and mortality in patients with hypertension.2 Most
patients (90–95%) with hypertension have primary
(also called “essential”) hypertension. The remain-
der have secondary hypertension, which includes
patients with drug-induced causes.
CAUSATIVE AGENTS
Drug-induced hypertension is defined as high
blood pressure caused by using or discontinuing
the use of a chemical substance, drug, or medica-
tion.3 Expert reviews of drug-induced hypertension
are available, but do not thoroughly evaluate
recent published literature to support the associa-
tion between cited drugs and drug-induced hyper-
tension.4,5 Drugs that have been reported to cause
hypertension are listed in Table 27–1.6-107 Drugs on
this list are also identified as potential causes of
resistant hypertension.108 There are some limita-
516
Joseph J. Saseen
tions to this list. Adverse drug effect reporting
often identifies increases in blood pressure, not
always drug-induced hypertension per se.
Therefore, for many drugs that have been reported
to increase blood pressure, the incidence of drug-
induced hypertension may be unknown. This list
also represents agents that are used primarily for
chronic conditions or that are used for a prolonged
period of time. These medications may cause
hypertension, exacerbate previously well-con-
trolled hypertension, or antagonize the effects of
antihypertensive pharmacotherapy.
EPIDEMIOLOGY
Hypertension is one of the most common chronic
medical conditions. Despite increased public
awareness, the prevalence of hypertension is not
declining. Almost 30% of the American population
has hypertension.109 There are several public
health challenges related to hypertension.1
Although most patients who truly have hyperten-
sion are aware of their condition (nearly 80%),
only two thirds of these patients are being treated
for hypertension, and less than half have con-
trolled blood pressure values.1 When considering
these statistics, the potential impact of drug-
induced hypertension is significant, as many
patients in whom drug-induced hypertension
develops may not be identified or appropriately
treated. Although the exact incidence of drug-
induced hypertension in the general population is
unknown, it is reasonable to assume that some
undiagnosed cases of hypertension may have drug-
induced causes. The prevalence of drug-induced
hypertension is possibly very low, but drug-
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CHAPTER 27 • Hypertension 517

TABLE 27–1 Agents Implicated in Drug-Induced Hypertension

Drug Incidencea Level of Evidence
(see page xii for explanation)
6,7
Amphetamines NK A
Antihypertensive agentsb,8-27 NK B
Bevacizumab28-32 8–18% A
Buproprion33-35 2–6.1% B
Caffeine36 NK B
Celecoxib37-42 2.4–12.5% A
Cocaine43 NK C
Corticosteroids44-49 NK A
Cyclosporine50-56 11.2–50% A
Darbepoetin-alfa57 23% A
Desvenlafaxine58 1.3–2.3% A
Ephedra alkaloids59-61 NK B
Ergot alkaloids62 NK C
Erythropoetin-alfa63,64 24% A
65-71
Estrogen-containing oral contraceptives 5% A
Licorice72-74 NK C
Monoamine oxidase inhibitorsc,75,76 NK C
NSAIDs77-82 NK A
Phenylephrine83,84 NK C
Pseudoephedrine 85-89 NK A
Sibutramine90-95 NK A
Sorafenib96,97 17% A
Sunitinib98-100 15–30% A
Tacrolimus101-103 47–50% A
Testosterone104,105 3% A
Venlafaxine106,107 3–13% A
NK = not known; NSAID = nonsteroidal antiinflammatory drug.
a
Based on reported incidence of hypertension or persistent blood pressure elevation, not just increase in blood pressure, from prod-
uct information or literature (not placebo-corrected).
b
When abruptly discontinued.
c
Result of a drug–food interaction with tyramine-containing foods or a drug–drug interaction.

induced exacerbations of hypertension are likely
more common.
The seventh report of the Joint National
Committee on Prevention, Detection, Evaluation,
and Treatment of High Blood Pressure (JNC-7) has
identified several drugs that can cause hyperten-
sion.2 These agents may either cause hypertension
or be a reason for resistant hypertension.108 This
chapter expands on the list provided by the JNC-7
to include additional agents. Estimated incidences
of drug-induced hypertension associated with spe-
cific agents are also presented in Table 27–1. The
exact incidence of drug-induced hypertension
associated with several agents is unknown; howev-
er, these agents have been shown to increase blood
pressure.
MECHANISMS
Arterial blood pressure is regulated by several fac-
tors: the adrenergic nervous system, the
TisdaleC27_516-528 1/12/10 2:56 PM Page 518
518 SECTION VI • Drug-Induced Cardiovascular Diseases
renin–angiotensin–aldosterone system, kidney func-
tion and blood flow, hormonal regulatory systems
(adrenal cortical hormones, vasopressin, thyroid,
insulin), and the vascular endothelium (nitric oxide,
bradykinin, prostacyclin, endothelin).5,110 Drug-
induced alterations of these systems may explain
persistent increases in blood pressure associated
with certain agents. The various mechanisms by
which drugs may induce hypertension (Table 27–2)
are broadly categorized as: fluid-volume expansion,
stimulation of sympathetic nervous system activity,
interference with the action of antihypertensive
drugs, paradoxical responses to antihypertensive
agents, and unknown mechanisms.5
Certain drugs (e.g., cocaine, amphetamines,
ephedra, some antidepressants) can activate the
sympathetic nervous system through norepineph-
rine or norepinephrine-like stimulation. Stimu-
lation of peripheral adrenergic ␣-receptors causes
vasoconstriction, while stimulation of myocardial
adrenergic ␤-receptors increases heart rate and con-
tractility, both of which can increase blood pres-
sure. Under normal circumstances, compensatory
mechanisms are triggered that decrease total
peripheral resistance, which usually maintains nor-
mal blood pressure. However, drugs that cause
hypertension may blunt or impair this compensa-
tory response.
The renin–angiotensin–aldosterone system
functions with the kidneys to regulate arterial
blood pressure. Decreases in blood pressure or kid-
ney blood flow, volume depletion, or sodium
depletion all increase secretion of renin from the
kidney. Renin mediates the transformation of
angiotensinogen to angiotensin I, which is con-
verted by angiotensin-converting enzyme to
angiotensin II. Angiotensin II is a potent direct
vasoconstrictor that stimulates production of
aldosterone, which causes sodium and water reten-
tion. Several drugs (e.g., nonsteroidal antiinflam-
matory drugs [NSAIDs], including the cyclo-
oxygenase-2 [COX-2] selective inhibitor celecoxib,
certain immunosuppressants) can indirectly trigger
renin release, primarily by decreasing kidney perfu-
sion.111,112 In premenopausal women, estrogens
have been shown to stimulate the renin-
angiotensin-aldosterone system by increasing
hepatic production of angiotensinogen.113,114
These effects are normally overcome by negative-
feedback mechanisms that prevent excessive renin
release. However, this may not occur in patients
taking drugs known to induce hypertension or in
patients with chronic kidney disease or cardiovas-
cular risk factors. Generalized vasoconstriction,
especially in the kidney, is the hypothesized cause
of cyclosporine-induced hypertension.50,115
Certain drugs that alter hormonal regulation
(e.g., oral contraceptives, corticosteroids) can cause
hypertension. The estrogen component of oral
contraceptives is primarily responsible for blood-
pressure elevation, but the mechanism is unclear.
In premenopausal women, oral contraceptive use
achieves serum estrogen and progestin concentra-
tions that are higher than those that result from
endogenous hormone production. This is in sharp
contrast to the use of estrogen-replacement thera-
py (ERT) or hormone-replacement therapy (HRT)
in postmenopausal women, during which serum
estrogen and progestin concentrations are lower
than those associated with premenopausal endoge-
nous hormone production. Clinical trials have
shown that the use of either ERT or HRT in both
premenopausal and postmenopausal women
increases the risk of cardiovascular events.116-119
However, ERT or HRT does not cause drug-induced
hypertension in postmenopausal women.120
Hormonal dysregulation can cause hyperten-
sion by inducing insulin resistance (the metabolic
syndrome), sodium and water retention, or myriad
other effects. Other miscellaneous agents cause
hypertension via unique mechanisms outside of
these neurohumoral effects. Both erythropoietin-
alfa and darbepoetin-alfa can cause dose-depend-
ent increases in blood pressure.121 Possible
mechanisms include increased hematocrit and ery-
throcyte mass, changes in the production or sensi-
tivity of endogenous vasopressor and vasodilatory
factors, alterations in vascular smooth muscle,
direct vasoconstriction, and arterial remodeling by
stimulation of vascular cell growth.122 However,
the exact mechanism is unknown.
The adrenergic antihypertensive agents ␤-
blockers and centrally acting ␣-receptor agonists
can cause rebound hypertension when therapy is
abruptly discontinued.8-27 Long-term exposure to ␤-
blocking agents causes upregulation and increased
expression of ␤-receptors. When ␤-blocker therapy
is abruptly discontinued, excessive stimulation of
these additional ␤-receptors occurs, potentially
resulting in increases in blood pressure and heart
rate, leading to rebound hypertension. Cardio-
selective ␤-blockers or those with intrinsic sympa-
thomimetic activity have been touted as not being
associated with rebound hypertension, but this has
not been proved. The mechanism by which
rebound hypertension occurs with central ␣-ago-
nists has not been fully established, but is believed
to be similar to that of ␤-blockers. When exposed to
long-term central ␣-agonist therapy, ␣-receptor
density, sensitivity, or both can increase.5 Abrupt
discontinuation of therapy with the central ␣-ago-
nist leads to elevated plasma norepinephrine con-
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CHAPTER 27 • Hypertension 519

TABLE 27–2 Mechanisms of Drug-Induced Hypertension

Drug Mechanism
Calcineurin inhibitors Increased prostaglandin production that decreases sodium,
water, and potassium excretion, causing increased fluid-
volume expansion
Co oids Stimulation of the mineralocorticoid receptor, causing
Licorice increased fluid-volume expansion

Erythropoiesis-stimulating agents Supratherapeutic effects of increasing blood cell

production, causing increased fluid volume
Estrogen-containing oral contraceptives Increased hepatic production of angiotensinogen, causing
stimulation of the renin–angiotensin–aldosterone system
NSAIDs and COX-2 inhibitors Inhibition of prostaglandins, causing stimulation of the
renin–angiotensin–aldosterone system, causing increased
fluid-volume expansion
Testosterone Increased fluid-volume expansion; stimulation of
sympathetic nervous system activity
Amphetamines Increased stimulation of sympathetic nervous system
Caffeine activity
Cocaine
Desvenlafaxine
Ergot alkaloids (ergonovine, methysergide)
Phenylephrine—ocular
Pseudoephedrine
Sibutramine
Venlafaxine
Anti–vascular endothelin growth factor agents Possible mechanism: endothelin damage secondary to
decreased nitric oxide release and release of growth
factors that stimulate the renin–angiotensin–aldosterone
system
Monoamine oxidase inhibitors Overall stimulation of sympathetic nervous system activity
by increased production of adrenergic substances second-
ary to ingesting tyramine-containing foods or a drug
interaction
␤-blockers and centrally acting ␣-agonists Abrupt discontinuation, causing overstimulation of
␣- and/or ␤-receptors
COX = cyclooxygenase; NSAID = nonsteroidal antiinflammatory drug.

centrations, peripheral ␣-receptor stimulation, and pressure, prehypertension, stage 1 hypertension,

increased blood pressure. This occurs in association
with both oral and transdermal administration.
CLINICAL PRESENTATION AND
DIFFERENTIAL DIAGNOSIS
The classification of blood pressure is based on sys-
tolic and diastolic blood pressure values (Table
27–3).2 This classification includes normal blood
and stage 2 hypertension. Elevated blood pressure
and the development of hypertension are nearly
always asymptomatic. Therefore, assessing patients
for the presence signs and symptoms of drug-
induced hypertension (Table 27–4) is not very
helpful. When blood pressure elevations are
extreme (usually much higher than 200/110 mm
Hg) symptoms consistent with hypertensive emer-
gency (e.g., anxiety, chest pain, confusion, exces-
sive perspiration, nausea/vomiting, pale or red
TisdaleC27_516-528 1/12/10 2:56 PM Page 520
520 SECTION VI • Drug-Induced Cardiovascular Diseases
skin, visual changes) are more likely to be present,
but are still not common.
The clinical significance of elevated blood pres-
sure associated with the use of a drug is variable,
depending on an individual’s baseline blood pres-
sure. Moreover, the exact time of onset for drug-
induced hypertension is unknown and is likely
highly variable and dependent on the particular
mechanism of drug-induced hypertension. For the
purposes of this chapter, drug-induced hyperten-
sion will be defined as blood pressure increases
from baseline that confer stage 1 hypertension or
higher, just as it is reported in product inserts. It is
important to note that the threshold blood pres-
sure for the diagnosis of hypertension varies. In
most patients, the threshold is at 140/90 mm Hg.
However, several patient populations with
increased cardiovascular risk have lower threshold
values of 130/80 mm Hg, and even as low as
120/80 mm Hg in patients with left ventricular
dysfunction (see Table 27–3).
Drug-induced blood pressure elevations, if
persistent, may be clinically significant even if
the blood pressure is not increased to above an
individual’s goal value. Many drugs have been
reported to induce statistically significant blood
pressure increases, some as small as 2 to 4 mm
Hg.6-107 The clinical significance of these small
increases is debatable. However, data from obser-
vational studies and randomized trials suggest
that a 2 mm-Hg reduction in diastolic blood pres-
sure correlates with a 17% decrease in the preva-
lence of hypertension, a 6% reduction in the risk
of coronary heart disease, and a 15% reduction in
the risk of stroke and transient ischemic
attacks.123-125 It has also been documented that
patients with prehypertension have a higher risk
of cardiovascular disease and events than patients
TABLE 27–3 Blood Pressure Classification According to the JNC-72 to Detect Drug-Induced Hypertensiona
Systolic Blood
Classification Pressure (mm Hg)
Normala <120
Prehypertensionb 120–139
Stage 1 hypertension 140–159
Stage 2 hypertension ⱖ160
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
TABLE 27–4 Signs and Symptoms Associated
with Drug-Induced Hypertension
• Patient usually reports no symptoms.
• Increase in blood pressure
• In patients with a history of treated hypertension,
requirement for increased doses of antihypertensive
medications
• In patients with a history of treated hypertension,
need for additional antihypertensive agents to main-
tain blood pressure goal
with normal blood pressure (see “Morbidity and
Mortality” section, below).126 Therefore, depend-
ing on a patient’s baseline blood pressure, small
but persistent blood pressure increases may be
clinically significant.
Several other conditions should be considered
in patients with suspected drug-induced hyperten-
sion (Table 27–5). The possibility of new-onset pri-
mary hypertension must always be considered. The
patient’s blood pressure history and a comprehen-
sive medical examination are necessary compo-
nents for this evaluation. Secondary hypertension,
although uncommon, should also be ruled out.
Additional diagnostic tests may be required for a
comprehensive evaluation.
RISK FACTORS
Patient-specific risk factors for drug-induced hyper-
tension are listed in Table 27–6. Perhaps the most
relevant is a history of elevated blood pressure,
either significant enough to fulfill the diagnostic
criteria for hypertension or high enough to be clas-
sified as prehypertension. A history of drug-
Diastolic Blood
Pressure (mm Hg)
and <80
or 80–89
or 90–99
or ⱖ100
TisdaleC27_516-528 1/12/10 2:56 PM Page 521
induced hypertension or drug-induced increases in
blood pressure is also noteworthy. There are many
major cardiovascular risk factors that increase the
risk of target organ damage associated with hyper-
tension. One prospective cohort study evaluating
oral contraceptive–induced hypertension showed
that the relative risk for hypertension increased
from 1.5 to 1.8 when other hypertension risk fac-
tors were considered.66 Therefore, major cardiovas-
cular risk factors should be considered when
evaluating a patient’s overall risk of drug-induced
hypertension.
Age has been identified as a risk factor for sev-
eral forms of cardiovascular disease.5 NSAID-
induced elevations in blood pressure are especially
prominent in the elderly population.77 Data from a
case–control study of 9,411 elderly patients in
whom antihypertensive therapy was initiated
revealed that chronic NSAID users had a higher risk
of initiating antihypertensive therapy than
nonusers (odds ratio, 1.66; 95% confidence inter-
val, 1.54–180).79 A dose-dependent relationship
with regard to risk was also found in this database.
These findings suggest that age and dose, at least
with persistent NSAID therapy, are both risk factors
for drug-induced hypertension.
MORBIDITY AND MORTALITY
Morbidity and mortality, manifesting as cardiovas-
cular disease, are clearly increased in patients with
primary hypertension. However, the exact associa-
TABLE 27–5 Conditions to Consider in the
Differential Diagnosis of Drug-Induced
Hypertension
Primary hypertension
• New onset
• Undiagnosed
• Previously diagnosed, but not at goal blood pressure
Secondary hypertension
• Alcohol abuse
• Chronic kidney disease
• Coarctation of the aorta
• Cushing’s syndrome
• Parathyroid disease
• Pheochromocytoma
• Primary aldosteronism
• Renovascular disease
• Sleep apnea
• Thyroid disease
CHAPTER 27 • Hypertension 521
TABLE 27–6 Risk Factors for Drug-Induced
Hypertension
• Elevated blood pressure in the past
• Either a history of hypertension or prehypertension
blood pressure values
• Previous history of drug-induced hypertension
• Decreased glomerular filtration rate (especially <60
m l /min/ 1 .73 m2)
• Metabolic syndrome
• Advanced age
• Persistent use of high-dose NSAID therapy
NSAID = nonsteroidal antiinflammatory drug.
tion between drug-induced hypertension and mor-
bidity and mortality is unknown. A reasonable
assumption is that prolonged drug-induced hyper-
tension would result in a similar increase in risk of
cardiovascular disease as compared with primary
hypertension. Approximately 80 million
Americans have some form of cardiovascular dis-
ease.1 Coronary heart disease (CHD) is a long-term
complication of hypertension that is the largest
contributor to hypertension-related morbidity and
mortality. It is often the fatal event related to car-
diovascular mortality. Estimates have identified
CHD as the most costly physical health condition
in the United States (U.S.).127 Moreover, cardiovas-
cular disease is the primary cause of death in the
U.S.1
Hypertension-related complications manifest
as target organ damage. The various forms of target
organ damage include: heart disease (left ventricu-
lar hypertrophy, CHD [angina, myocardial infarc-
tion, acute coronary syndrome], heart failure),
cerebrovascular disease (ischemic stroke, transient
ischemic attacks), chronic kidney disease, peripher-
al arterial disease, and retinopathy. Observational
data have established a direct correlation between
blood pressure elevation and risk of target organ
damage in patients of all ages with hyperten-
sion.125,128 Randomized, double-blind, placebo-
controlled clinical trials have also clearly
demonstrated reduced morbidity and mortality
associated with blood pressure reduction in
patients with hypertension, even in the very elder-
ly.2,129-135 Therefore, persistent drug-induced hyper-
tension may be associated with long-term
increased risk of target organ damage.
A consistent, continuous, and independent
relationship between blood pressure and risk of
cardiovascular disease and other target organ
damage is present in patients with elevated blood
pressure that is not high enough to be classified
TisdaleC27_516-528 1/12/10 2:56 PM Page 522
522 SECTION VI • Drug-Induced Cardiovascular Diseases
as hypertension.2,126 Starting at a blood pressure
of 115/75 mm Hg, the risk of future cardiovascu-
lar disease doubles with every 20 mm Hg increase
in systolic blood pressure and 10 mm Hg increase
in diastolic blood pressure.128 Analyses of the
Framingham population who had blood-pressure
values in the higher half of the prehypertension
classification (systolic blood pressure of 130–139
mm Hg, diastolic blood pressure of 85–89 mm
Hg, or both) demonstrate an incremental
increase in cardiovascular risk.126 The 10-year
cumulative incidence of cardiovascular disease in
women aged 35–64 years who had prehyperten-
sion was 4%, versus 8% in men of the same age
and 18% in older individuals between the ages of
65 and 90 years. Therefore, drug-induced increas-
es in blood pressure, even within the prehyper-
tension blood pressure range, may be associated
with a long-term increased risk of morbidity and
mortality.
PREVENTION
Prevention strategies for drug-induced hyperten-
sion are listed in Table 27–7. Drug-induced hyper-
tension is ideally detected by closely monitoring
blood pressure. Clinic-based blood pressure meas-
urements should be obtained 2 to 4 weeks after
starting a drug known to increase blood pressure.
Home or ambulatory blood pressure monitoring
may be helpful, but are not essential.136-138
Moreover, both home and ambulatory blood pres-
sure values are lower than those measured in the
clinic. Average home blood pressure measure-
ments are typically 5 mm Hg lower than clinic val-
ues, and 24-hour ambulatory blood pressure
measurements in individuals with hypertension
are typically 10 mm Hg lower.138 Patients with self-
measured blood pressure values of 135/85 mm Hg
are generally considered to have hypertension.2
However, clinic-based blood pressure measure-
ments are sufficient for detecting drug-induced
hypertension.
The most effective prevention strategy is avoid-
ing the use of agents known to cause drug-induced
hypertension. This is especially important in
patients with either established cardiovascular dis-
ease or multiple risk factors for drug-induced
hypertension or cardiovascular disease (see Table
27–6). For women requiring oral contraceptive
therapy, preparations with low estrogen (ⱕ30 mcg
ethinyl estradiol) and progestin (ⱕ1 mg norethin-
drone) content appear to be associated with the
lowest risk of hypertension.
Lifestyle modifications that lower cardiovascu-
lar risk and blood pressure should be recommend-
ed for all patients, especially those using drugs
known to increase blood pressure.139,140 These
modifications include diet and exercise recommen-
dations. The Dietary Approaches to Stop Hyper-
tension (DASH) diet is rich in vegetables, fruits,
and low-fat dairy products and has been proven to
lower blood pressure.140 Other methods, such as
weight reduction, dietary sodium restriction, mod-
erate and regular aerobic activity, and moderation
of alcohol consumption are also effective in lower-
ing blood pressure.
MANAGEMENT
Management of drug-induced hypertension
depends on differentiating drug-induced from
either primary or other secondary causes of hyper-
tension. When drug-induced hypertension is
TABLE 27–7 Approaches to Help Prevent Drug-
Induced Hypertension.
• Avoid use of agents reported to cause drug-induced
hypertension in high-risk patients.
• For patients taking agents known to cause drug-
induced hypertension:
• Avoid tyramine-containing foods in patients taking
monoamine oxidase inhibitors.
• Use minimum effective dose of NSAIDs, including
celecoxib.
• Measure blood pressure at least every 2–4 wk.
• Evaluate for symptoms of hypertension-related tar-
get organ damage periodically.
• Engage in lifestyle modifications:
• Weight reduction: Maintain normal body weight
body-mass index, 18.5–24.9 kg/ma
• Adopt the DASH eating plan: consume a diet
rich in fruits, vegetables and low-fat dairy prod-
ucts with a reduced content of saturated and
total fat.
• Reduce dietary sodium intake to 1.5 g sodium
• Engage in regular aerobic physical activity (at
least 30 min/day, most days of the week).
• Moderate alcohol consumption: limit consump-
tion to ⱕ2 drinks/day in most men and ⱕ1
drink/day in women and lighter-weight persons.
DASH = Dietary Approaches to Stop Hypertension; NSAID =
nonsteroidal antiinflammatory drug.
a
Body-mass index is calculated as the weight in kilograms
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
discontinued when possible (Table 27–8). Blood
pressure should then return to baseline values
within 2 to 4 weeks under most circumstances. If
the blood pressure remains consistently elevated
after discontinuing therapy with the offending
agent, further investigation to evaluate primary
hypertension or other secondary causes is needed.
The offending agent should not be reintroduced.
However, if no reasonable treatment alternative
can be identified, a reintroduction of therapy with
a reduced dose and blood pressure monitoring may
be attempted. Lifestyle modifications to lower
blood pressure, as previously discussed, should be
implemented in these patients.
When certain offending agents must be con-
tinued, specific management approaches may be
considered (see Table 27–8). Cyclosporine and
tacrolimus, which are calcineurin inhibitors, are
immunosuppressant agents that are used in
patients after solid organ transplantation and to
treat a variety of other conditions.51-53,101 Patients
with calcineurin inhibitor–induced hypertension
usually cannot discontinue therapy with the
drug. Therefore, managing the drug-induced
TABLE 27–8 Management of Drug-Induced Hypertension
Drug Condition
Most agents Various
Cyclosporine Solid organ transplant,
other immunologic diseases
Oral contraceptives Prevention of pregnancy
Erythropoietin- Anemia
and darbepoetin
Rebound hypertension Hypertension
from discontinuation
of therapy with
␤-blockers or central
␣-agonists
CHAPTER 27 • Hypertension 523
hypertension is the primary goal in these
patients.
A consensus guideline based on reports from
clinical trials and from clinical experience using
cyclosporine in patients with rheumatoid arthritis
was published in 1999.141 When patients taking
cyclosporine have stage 1 hypertension on at least
two consecutive visits, the cyclosporine dose
should be reduced by 25%. The dose should be
reduced by 50% in those in whom stage 2 hyper-
tension develops, and initiation of antihyperten-
sive pharmacotherapy may be necessary. If blood
pressure remains elevated despite initial dose
reductions, additional reductions and initiation of
antihypertensive pharmacotherapy should be con-
sidered. Persistent blood pressure elevation may
require cyclosporine discontinuation if an accept-
able alternative drug can be used.
Dihydropyridine calcium-channel blockers
(e.g., amlodipine, felodipine) are preferred agents
for the treatment of cyclosporine-induced hyper-
tension.115,141 These agents do not interact with
cyclosporine and promote vasodilation of the
afferent and efferent renal arterioles. Pharma-
cologically, this mechanism of action is ideal for
Management
Discontinue offending agent when possible.
• If stage 1 hypertension, decrease dose by 25%.
• If stage 2 hypertension, decrease dose by 50%, and con-
sider antihypertensive therapy.
• Dihydropyridine calcium-channel blockers are preferred
antihypertensive agents.
• Monitor blood pressure for up to 3 mo after
discontinuation
• When no other form of contraception is feasible, use
the lowest estrogen/ progestin-content product and
treat with antihypertensive therapy.
• Use the lowest effective dose: decrease dose if
hemoglobin concentration approaches 12 g/dL or if
hemoglobin increase is greater than 1 g/dL in a 2-week
period; hold dose if hemoglobin concentration exceeds
13 g/dL.
• Subcutaneous administration is preferred over intra-
venous to minimize abrupt increases in blood pressure.
• Reinitiate therapy with agent at previous long-term
dose.
• Gradually taper if therapy is to be discontinued.
TisdaleC27_516-528 1/12/10 2:56 PM Page 524
524 SECTION VI • Drug-Induced Cardiovascular Diseases
managing cyclosporine-induced hypertension.
Nondihydropyridine calcium-channel blockers
(i.e., diltiazem, verapamil) increase serum
cyclosporine concentrations and are less desirable
pharmacotherapy options for cyclosporine-
induced hypertension. Patients with preexisting
hypertension that is treated with a ␤-blocker can
remain on this therapy. However, diuretics,
angiotensin-converting–enzyme inhibitors, or
angiotensin-II receptor blockers are not highly
effective for managing this type of hypertension,
and their use as first-line agents for cyclosporine-
induced hypertension is discouraged.115,141
Guidelines for management of tacrolimus-
induced hypertension do not exist. An approach
similar to that recommended for cyclosporine-
induced hypertension is reasonable. However,
manufacturers’ recommendations are to control
blood pressure “with any of the common” antihy-
pertensive agents.101 These recommendations state
that because tacrolimus may cause hyperkalemia,
potassium-sparing diuretics should be avoided. As
with cyclosporine, certain calcium-channel block-
ers (diltiazem, verapamil) can increase serum
tacrolimus serum concentrations and should be
avoided or used with extreme caution.
Women who are treated with oral contracep-
tive agents should have their blood pressure meas-
ured within the first month of treatment, then
after 3, 6, and 12 months. If oral contraceptive–
induced hypertension occurs, the drug should be
discontinued and replaced with an alternative
form of contraception. Blood pressure should
return to pretreatment values within 3 months
after discontinuation of therapy. If it does not,
additional evaluation for primary hypertension or
other secondary forms of hypertension is neces-
sary. If an alternative form of contraception cannot
be used and after other secondary forms of hyper-
tension have been ruled out, a oral contraceptive
agent with a low estrogen (ⱕ30 mcg ethinyl estra-
diol) and progestin (ⱕ1 mg norethindrone) con-
tent may be used. Lifestyle modifications should be
implemented, with the addition of antihyperten-
sive drug therapy when necessary.
Erythropoietin-␣ and darbepoetin-␣ are ery-
thropoiesis-stimulating agents that are indicated
for the treatment of anemia associated with chron-
ic kidney disease, human immunodeficiency virus
infection and chemotherapy, and for reduction of
allogeneic blood transfusion in surgery.57,63,64 These
drugs can enhance quality of life and improve car-
diac function. Discontinuing therapy is not always
a feasible option to manage hypertension induced
by these drugs. Although lifestyle modifications
might minimize blood pressure increases, close
monitoring of serum hemoglobin concentration
during therapy is essential to avoid excessive ther-
apeutic effects that can result in blood pressure ele-
vations. The dose of either of these agents should
be reduced if serum hemoglobin concentrations
approach 12 g/dL or if increases in serum hemoglo-
bin concentration exceed 1 g/dL in a 2-week peri-
od. Therapy should be withheld if serum hemo-
globin concentrations exceed 13 g/dL.57,63,64
Use of erythropoiesis-stimulating agents in
patients with chronic kidney disease undergoing
dialysis treatment requires close monitoring for the
development of drug-induced hypertension. The
need for dialysis alone increases the risk of hyper-
tension or worsening of hypertension. Optimizing
dialysis treatments in patients with kidney disease,
closely monitoring and managing volume status
when needed, and using subcutaneous administra-
tion to ensure gradual red blood cell increases are
additional strategies that may minimize the risk of
blood pressure elevations.142
Rebound Hypertension
When rebound hypertension occurs after abrupt
discontinuation of a ␤-blocker or a centrally acting
␣-receptor agonist, therapy with the drug should
be reinitiated at the previous long-term dose. If the
offending agent is intended to be discontinued,
therapy can be restarted, with the dose subsequent-
ly gradually decreased and then discontinued.
There are no guidelines regarding the optimal
manner in which to gradually discontinue such
medications. However, the dosing schedule should
be individualized based on the dose of the drug
that caused the rebound hypertension. A 50% dose
decrease for 3 to 7 days is considered a tapering
step. If a patient experiences rebound hypertension
on a low-to-moderate dose of a drug, one tapering
step may be sufficient to treat rebound hyperten-
sion, whereas two or more tapering steps may be
needed for patients receiving higher doses.
INFORMATION FOR PATIENTS
Patients taking drugs that are known to cause drug-
induced hypertension should be made aware of this
potential risks. Patients should be counseled that
their blood pressure may increase to the point of a
diagnosis of hypertension. They should be instruct-
ed to comply with medical visits to detect elevations
in blood pressure. Patients should also be encour-
aged to periodically monitor and document their
blood pressure values outside of their prescribing
practitioner’s office (e.g., at home, in a community
TisdaleC27_516-528 1/12/10 2:56 PM Page 525
pharmacy). If persistent increases in systolic or dias-
tolic blood pressure values are detected (even if
small) or blood pressure increases to above their goal
value (see Table 27–3), patients should consult a
health care professional (e.g., pharmacist, physi-
cian). If symptoms consistent with hypertensive
emergency develop (e.g., chest pain, unilateral
weakness, severe headache, shortness of breath),
patients should be instructed to seek emergency
care.
Lifestyle modifications (see Table 27–7) should
be encouraged in all patients at risk for hyperten-
sion, especially those receiving drugs that may
cause hypertension. Patients using ␤-blockers or
centrally acting ␣-receptor agonists should be edu-
cated regarding potential rebound hypertension
and instructed not to abruptly discontinue therapy
with these agents. Use of any nonprescription
medication without first consulting a pharmacist
or medical practitioner to treat elevated blood pres-
sure should be discouraged. Lastly, patients should
be encouraged to ensure that all health care profes-
sionals involved with providing their care are fully
aware of all current medications and risk factors for
hypertension so that new medications that may
potentially interact with drugs or further increase
the risk of hypertension can be avoided.
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118. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and
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CHAPTER 28
Hypotension
D rug-induced hypotension is a clinically impor-
tant and potentially disabling problem that
may lead to syncope, falls and injury, or sustained
lack of organ perfusion resulting in ischemia,
infarction, or both. The majority of episodes of
drug-induced hypotension involve a drop in blood
pressure after a patient assumes an upright posi-
tion. This is known as orthostatic hypotension and
has also been referred to as postural hypotension.
Orthostatic hypotension is defined as a reduction
in systolic blood pressure of at least 20 mm Hg or
diastolic pressure of at least 10 mm Hg within 3
minutes of standing.1
Orthostatic hypotension may result from two
different disorders in autonomic cardiovascular
control: autonomic failure and neurally mediated
syncope.2-4 Autonomic failure involves chronic
debilitation of sympathetic efferent activity such
that vasoconstriction is impeded. Upon standing,
blood pressure precipitously falls and presyncope
or syncope develops. In neurally mediated ortho-
static hypotension, the typical pattern of auto-
nomic outflow that preserves blood pressure in the
standing position is acutely reversed in response to
a trigger. Drug-induced orthostatic hypotension is
primarily due to autonomic failure in which the
causative agent affects central or peripheral auto-
nomic pathways.2-4
CAUSATIVE AGENTS
Drugs that cause hypotension can be separated
into two groups: those having a desired and
intended hypotensive effect and those for which
hypotension is an unintended adverse effect.
Phenothiazines, tricyclic antidepressants, antianxi-
Robert Lee Page II and Jean M. Nappi
ety agents, levodopa, diuretics, and central and
peripheral acting antihypertensive agents are only
a few of the medications known to cause orthosta-
tic hypotension. Table 28–1 lists drugs that have
been reported to cause hypotension and their
respective incidences.5-345
EPIDEMIOLOGY
Orthostatic hypotension from all causes has been
estimated to occur in 0.5% of individuals in the
general population; however, in the acute care set-
ting, the incidence may be as high as 17%.5 The
prevalence of orthostatic hypotension among
patients presenting to the emergency department
with syncope ranged from 21% to 64%.6,7 The
most susceptible and vulnerable population is the
elderly. In community-dwelling adults 65 years of
age or older, the prevalence of orthostatic hypoten-
sion is approximately 20%, and it may be as high
as 30% in those 75 years of age or older. In frail,
elderly nursing home residents, the prevalence is as
high as 50%.8 Drug-induced orthostatic reactions
occur at a frequency of 5% to 33% in geriatric
patients.9
MECHANISMS
Mean arterial pressure is determined by heart rate,
stroke volume, and total peripheral resistance.
When a person changes from a supine to an
upright position, orthostatic hypotension results
from a profound and immediate shift of blood vol-
ume primarily to the lower extremities. Within 10
to 15 minutes of a posture change, stroke volume
529
TisdaleC28_529-553 1/12/10 2:57 PM Page 530

530 SECTION VI • Drug-Induced Cardiovascular Diseases

TABLE 28–1 Agents Implicated in Drug-Induced Hypotension

Drug Incidence Level of Evidence
(see page xii for explanation)
ANTIHYPERTENSIVES
ACE Inhibitorsa,b,c
Benazepril84 0.3–0.4% A
Captopril85-87 3% A
Enalapril (particularly with IV)27,84 1.2–28% A
Fosinopril84 1.2–4.4% A
Lisinopril84 0.3–9.7% A
Moexipril84 0.5–1% A
Perindopril84 0.3–1% A
Ramipril84 <1% A
Quinapril84 0.5–11% A
Trandolapril84 0.3–11% A
Angiotensin-Receptor Blockersa,b,c
Candesartan84 18.8% A
Eprosartan84 <1% A
Irbesartan88 0.1–5.4% A
Losartan84,89-92 0.5–2.2% A
Olmesartan93,94 0.1% A
Telmisartan96 0–23 % A
Valsartan85,96 6.9% A
Peripheral ␣-blockersb,c
Alfuzosin97 0.4–2% A
Doxazosin98 0.3–1.7% A
Prazosin99-105 1 –4% A
Tamulosin97 0.2–0.4% A
Terazosin97 0.6–3.9 A
␤-Adrenergic Blockers (particularly with IV)
Acebutolol106 10% B
Atenolol97,b 4% A
Betaxolol97, b <2% A
Bisoprolol107 4% A
Carvedilol (particularly with immediate-release)97,a 2–20% A
Esmolol97 20–50% A
Propranolol108-110 NK A
Labetalol97,111 5% A
Metoprolol (particularly with immediate-release)112,113,a 1 –4.2% A
Nadolol114 1% A
Pindolol97,115 2% A
Nebivolol116 0.5% A
(Continued)
TisdaleC28_529-553 1/12/10 2:57 PM Page 531

CHAPTER 28 • Hypotension 531

TABLE 28–1 Agents Implicated in Drug-Induced Hypotension (Continued)

Drug Incidence Level of Evidence

Calcium-Channel Blockers
Amlodipine117-119,b <1% A
Diltiazem (particularly with IV)120-124 6–11% A
Felodipine89,125 0.5–1.5% A
Isradipine125 < 1% A
Nicardipine (particularly with IV) 125 0.9–5.6% A
Nifedipine (particularly with immediate-release)125 0.5–5% A
Nimodipine125 < 8.0 A
Nisoldipine125 < 1% A
Verapamil (particularly with IV)126-128 1–3% B
Centrally Acting ␣-Adrenergic Agonistsb
Clonidine (lowest with patch, highest with IV)97 0.5–33% A
Guanfacine97 15% A
Guanabenz129-131 <1% A
97
Methyldopa NK A
Reserpine97,132,133 16% A
Peripheral-acting arterial vasodilators®
Diazoxide134-139 NK B
Hydralazine (particularly with IV)134-139 NK B
Minoxidil140-142 NK B
Nitroprusside114,143 NK B
Diureticsa,b
Amiloride144,145 <1% B
Bumetanide146 0.8% A
Chlorothiazide147,148 NK B
Chlorthalidone149 2.2% A
Ethacrynic acid150 NK B
Furosemide151-153 20% A
Hydrochlorothiazide153,154 12.5–60% A
Indapamide155 < 5% A
Metolazone156,157 NK B
Torsemide158-161 0 –7% A
Dopamine Agonists
Fenoldopam162-165,b,d 2% A
Renin Inhibitors
Aliskerin166 0.1% A
NON-ANTIHYPERTENSIVES
Alzheimer’s Agents
Galantamine167,168,b,c 1–3.6% A
Donepezil169,171,b,c 1–3% A
(Continued)
TisdaleC28_529-553 1/12/10 2:57 PM Page 532

532 SECTION VI • Drug-Induced Cardiovascular Diseases

TABLE 28–1 Agents Implicated in Drug-Induced Hypotension (Continued)

Drug Incidence Level of Evidence

Anesthetic Agents/Adjunct
Bupivacaine172,173,b NK B
Halothane174,175,b NK B
Isoflurane176-178,b NK B
Propofol179-183,b 3–10% A
Antianginal Agents
Amyl nitrate184,185 NK C
Isosorbide dinitrate186,191 16% A
Isosorbide mononitrate192 < 5% A
Nitroglycerin193-198,b,c 1 –48% A
Antiarrhythmic Agents
Amiodarone (IV only)199-201 10–20% A
Bretylium202-207,d 50% A
Ibutilide208-212 2% A
213,e
Mexiletine <1% C
Procainamide (IV only)214-216 NK C
Quinidine127,217-221,c-e NK C
Sotalol222,223 5–9% A
Tocainide224 3% A
Vernakalant225,226,d 5–6% A
Antidepressant Agents
Amitriptyline227-231,b,e 5–20% A
Clomipramine232,b,e 27% B
Doxepin233,b 3–4% B
Desipramine228,231,234,b,e 12% A
Imipramine228,231,235-239,b,e 20–37% A
Trazodone152,b 58% B
Antiemetic Agents
Droperidol240,c NK B
Prochlorperazine241,242,c 1.2% B
Promethazine243,d NK B
Antiepileptic Agents
Phenytoin (IV only)244-247,c-e 4.9% A
Fosphenytoin (IV only)248,c,d 7.7% A
Gabapentin249 <1 % C
Pregabalin250 NK C
Antihistaminic Agents
Diphenhydramine251,e NK C
(Continued)
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CHAPTER 28 • Hypotension 533

TABLE 28–1 Agents Implicated in Drug-Induced Hypotension (Continued)

Drug Incidence Level of Evidence

Antimicrobial Agents
Pentamidine (IV and IM only)252,253 1.7–5% B
Levofloxacin (IV only)254,d NK C
Vancomycin (IV only)255-259,d 0–63% A
Antiparkinsonian Agents
Bromocriptine260-263,b,c 0.2–0.7% A
Carbidopa plus levodopa264,265,b,c 1% A
Pergolide260,266-268,b 10% A
Pramipexole269,270,b <5% A
Ropinirole271,b 8–25% A
Selegiline272,b 9.8% A
Rasagiline273,b 6–9% A
Entacapone274-276,b 2.7% A
Tolcapone277,b 3% A
Antipsychotic Agents
Aripiprazole278,b 0.6–1.5% A
Chlorpromazine (particularly IV)279,b 0–10% A
Clozapine280,281,b,c 4.8–16.7% A
Haloperidol282,283,b 0–2% A
Loxapine284,b,c 25% A
Olanzapine282,285,b 4.2% A
Quetiapine286,287,b 7–14% A
Pimozide227,288,289,b NK C
Risperidone290,291,b 3% A
Thioridazine292,293,b 16% A
Thiothixene284,294 4% A
Trifluoperazine282 NK C
Ziprasidone282,295,296,b,c 1.3–18% A
␤-Adrenergic Agonists
High-dose dobutamine297-299,c 20% A
Biologic Agents
Interleukin-2300,301,c 2–36% A
Muromonab-CD3302,303 25% A
Chemoprotectant Agents
Amifostine19-21,304,305,c,d 3–62% A
Chemotherapy Agents
Carmustine306,307,c NK B
Dacarbazine308,c NK B
Etoposide309,310,d 1–2% A
Fludarabine311,312 1–2% A
Vinblastine313,b NK B
Vincristine314,315,b,c 4% A
(Continued)
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534 SECTION VI • Drug-Induced Cardiovascular Diseases

TABLE 28–1 Agents Implicated in Drug-Induced Hypotension (Continued)

Drug Incidence Level of Evidence

Endothelin-Receptor Antagonists
Bosentan316 7% A
Treprostinil317 4–11% A
Magnesium318,319,c 4% A
Natriuretic Peptide Agents
Nesiritide22,194,c,d 4–35% A
Neuromuscular Blocking Agents
Atracurium320,c NK A
Mivacurium320,321,c,d NK A
Succinylcholine322 NK A
d-Tubocurare323 NK C
Opiates
Codeine (particularly with IV)324-326,c NK C
Fentanyl (particularly with IV)327,328,d 2.8–4% A
329,d
Hydromorphone (particularly with IV) 20% A
Morphine (particularly with IV)330-332,d NK A
Osmotic Diuretics
Mannitol333,334,b,c NK C
Phosphodiesterase Inhibitors
Milrinone335,336 2.9–10% A
Vardenafil337,338 <2% A
Sildenafil339,340 <2% A
Prostaglandin Agents
Epoprostenol341,342,c,d 13–16% A
Iloprost343-345 11–76% A
ACE = angiotension-converting enzyme; IM = intramuscular; IV = intravenous; NK = not known.
a
Higher incidence in patients with heart failure.
b
May also cause orthostatic hypotension.
c
Dose-related.
d
Rate-related.
e
In overdose.

may decline by 15%, and roughly 1 L of blood may
pool in capacitance vessels below the
diaphragm.10,11 The resultant reduction in venous
return and decreases in cardiac output and blood
pressure stimulate arterial baroreceptors, which
trigger intricate compensatory mechanisms.
Centrally mediated activation of the sympathetic
efferent neurons increases vascular tone, myocar-
dial contractility, and heart rate. Cardiopulmonary
volume receptors cause vasopressin release, which
also leads to arteriolar vasoconstriction and water
conservation by the kidney. All of these reflex
mechanisms limit the potentially adverse hemody-
namic effects of an upright posture; however,
should any one or a combination of these mecha-
nisms fail, orthostatic hypotension may result.5
Diseases such as diabetes mellitus and
Parkinson’s disease, which may impair mobility or
lead to extended inactivity, have been associated
with orthostatic hypotension. Conditions that
TisdaleC28_529-553 1/12/10 2:57 PM Page 535
impair diastolic filling such as blood loss, dehydra-
tion, and excessive diuresis may also lead to this
condition. A decrease in blood pressure may occur
after eating, as a result of splanchnic blood pool-
ing.12
In healthy patients of any age, orthostatic
hypotension occurs infrequently. However, as
patients age, changes in cardiovascular physiology
as well as concomitant diseases or exposure to
medications that may reduce blood pressure
increase the risk of orthostatic hypotension.
Physiologic changes that may contribute to ortho-
static hypotension include alterations in barore-
ceptor activity, parasympathetic activity, arterial
and cardiac compliance, renal sodium conserva-
tion, vasopressin response, plasma renin activity,
plasma angiotensin and aldosterone concentra-
tions, and plasma volume.13
Genomic factors can also play a role in the
development of orthostatic hypotension. A single-
nucleotide polymorphism with a glycine to argi-
nine switch at position 389 of the ␤1-adrenergic
receptor has been found to significantly lower con-
tractile responsiveness to catecholamines, thus
increasing susceptibility to orthostatic hypoten-
sion.14
Even in healthy elderly patients, orthostatic
hypotension can be unmasked or exacerbated by
the administration of drugs that interfere with the
cardiovascular reflex response. For example, anti-
hypertensive agents may produce hypotension by
decreasing sympathetic outflow, through central
and peripheral vasodilatory actions, or by deplet-
ing intravascular volume. Drugs can induce
hypotension through many different mechanisms
(Table 28–2).5,11,51,75-80,83,98,111,126-132,133,137,150,200,201,
216,217,206,236-253
CLINICAL PRESENTATION AND
DIFFERENTIAL DIAGNOSIS
Orthostatic hypotension may manifest with symp-
toms as mild as light-headedness or as severe as
presyncope or syncope (Table 28–3).5,15,16 Syncope
is defined as a sudden, transient loss of conscious-
ness with a loss of postural tone usually lasting no
more than 15 seconds.15 Presyncope can be charac-
terized as near fainting, light-headedness, or
extreme dizziness; it may be a part of a continuum
that leads to syncope or may occur as an isolated
event. The “common faint,” or neurocardiogenic
syncope (also called “vasovagal syncope”), is the
most common type of syncope.5 Neurocardiogenic
syncope is a syndrome in which the triggering of a
neural reflex results in a usually self-limited
CHAPTER 28 • Hypotension 535
episode of systemic hypotension characterized by
both bradycardia and peripheral vasodilation.16
Overall, patients experiencing orthostatic
hypotension may report blurred vision, neck pain,
weakness, buckling of the legs, cognitive slowing,
headache, seizures (usually clonic jerks), or post-
prandial angina pectoris. Focal neurologic find-
ings, if present, may suggest concomitant
cerebrovascular disease.17 If syncope occurs,
patients typically respond immediately after being
placed in a horizontal position. Once the patient is
horizontal, hypoperfusion-related symptoms typi-
cally resolve.16 The syncope associated with ortho-
static hypotension is generally differentiated from
other causes by a lack of postictal confusion or
drowsiness. Common findings associated with
orthostatic hypotension include mild anemia,
hypohidrosis, a parkinsonian-like syndrome, recur-
rent urinary tract infections or bladder dysfunction
or both, sleep apnea, hoarseness, nasal stuffiness,
impotence, and constipation or diarrhea or both.5
Symptoms of syncope are most commonly docu-
mented in the morning, after medication adminis-
tration or following meals.
A diagnosis of drug-induced orthostatic
hypotension requires documentation of hypoten-
sion accompanied by one or more of the previous-
ly discussed symptoms.18 A detailed medication
history, which includes a review of prescription
and nonprescription medications and herbal sup-
plements, a medical history, a thorough physical
exam, and in some cases, specific diagnostic tests
should be used to rule out other possible causes of
hypotension. Conditions to consider in the differ-
ential diagnosis of drug-induced hypotension are
presented in Table 28–4.12-16 To evaluate a patient
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
supine position for 5 minutes, immediately after
the patient stands, and 1 to 2 minutes after stand-
ing. If the heart rate does not increase in the pres-
ence of orthostatic hypotension, then baroreceptor
reflex dysfunction may be implicated. Early-morn-
ing measurements, especially after a high-carbohy-
drate meal, are helpful to identify postprandial
hypotension. Heart-rate responses to deep breath-
ing and to the Valsalva maneuver may also aid in
differentiating between autonomic impairment
and other causes of orthostatic hypotension.
Detection may require multiple blood pressure
measurements on different days, which may neces-
sitate use of an ambulatory blood pressure moni-
tor. Patients should be instructed to measure their
blood pressure before breakfast, after taking their
medications, after meals, and before bedtime.13
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536 SECTION VI • Drug-Induced Cardiovascular Diseases

TABLE 28–2 Mechanisms of Drug-Induced Hypotension

Drug Mechanism
Benazepril27 Inhibition of angiotensin II with increase in bradykinin
Captopril27 concentrations
Enalapril27
Fosinopril27
Lisinopril27
Moexipril27
Perindopril27
Ramipril27
Quinapril27
Trandolapril27
Aliskerin27 Inhibition of renin
Candesartan346 Inhibition of angiotensin II at the receptor level
Eprosartan346
Irbesartan346
Losartan346
Olmesartan346
Telmisartan346
Valsartan346
Acebutolol97 Blockade of ␤-adrenoreceptors
Atenolol97
Betaxolol97
Bisoprolol97
Esmolol97
Propranolol97
Metoprolol97
Nadolol97
Pindolol97
Nebivolol97
Carvedilol97 Blockade of ␤- and ␣l-adrenoreceptors
Labetalol97
Amiloride347,348 Inhibition of renal sodium reabsorption thereby leading to
Bumetanide349 intravascular volume depletion
Chlorothiazide349
Chlorthalidone349
Ethacrynante349
Furosemide349
Hydrochlorothiazide349
Indapamide349
Metolazone349
Torsemide349
Mannitol333,334 Intravascular volume depletion
Atracurium41,320 Release of histamine
Codeine330,331,350
d-Tubocurare41
Hydromorphone330,331,350
Fentanyl350
Mivacurium41,320
Morphine330,331,350
Succinylcholine351
Vancomycin257
(Continued)
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CHAPTER 28 • Hypotension 537

TABLE 28–2 Mechanisms of Drug-Induced Hypotension (Continued)

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)
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538 SECTION VI • Drug-Induced Cardiovascular Diseases

TABLE 28–2 Mechanisms of Drug-Induced Hypotension (Continued)

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)
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CHAPTER 28 • Hypotension 539

TABLE 28–2 Mechanisms of Drug-Induced Hypotension (Continued)

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

Hg.23 The frequency of orthostatic hypotension

RISK FACTORS
Risk factors for drug-induced hypotension are pre-
sented in Table 28–5.12-16 As mentioned previous-
ly, elderly patients are at increased risk. Patients at
highest risk of amifostine-induced hypotension
are those who receive doses in excess of 910
mg/m2; have infusion times of 15 minutes or
longer; have head and neck, esophageal, or lung
cancer; have undergone neck irradiation; have
carotid artery disease, or have hypercalcemia.19-22
Hypotension associated with intravenous opiates
occurs primarily in patients with hypovolemia;
therefore, these agents should be avoided in
patients with shock or reduced blood volumes.
The incidence of symptomatic hypotension
induced by nesiritide is higher in patients with a
pretreatment systolic blood pressure <100 mm
caused by tricyclic antidepressants and antipsy-
chotic agents increases in patients with overt heart
disease, particularly in those with left ventricular
dysfunction, autonomic disease, and advancing
age.24-26 Patients receiving angiotensin-converting
enzyme (ACE) inhibitors are at risk for hypoten-
sion if they are receiving high doses of diuretics,
have a low serum sodium concentration (<130
mEq/L), or have a serum creatinine concentration
>1.7 mg/dL.27 Hypotension associated with ␤-
adrenergic-receptor blocking agents is more likely
in patients with a pretreatment systolic blood
pressure <90 mm Hg, a heart rate <60 beats/min, a
depressed left ventricular ejection fraction, or
changes in fluid status.28,29 The risk of hypoten-
sion associated with diuretics is increased in
patients with generalized disability, dehydration,
intravascular volume depletion, or concomitant
use of vasodilating agents such as nitrates, alco-
hol, barbiturates, or narcotics.30

TABLE 28–3 Signs and Symptoms Associated

with Drug-Induced Hypotension5,15,16 MORBIDITY AND MORTALITY
• Drop in systolic blood pressure ⱖ20 mm Hg or dias-
Drug-induced orthostatic hypotension may lead
tolic blood pressure ⱖ10 mm Hg within 1–3 minutes
to syncope and falls, and may be particularly
of standing
hazardous in the elderly population. In commu-
• Light-headedness
nity-dwelling elderly who sustain a fall, 5% to
• Presyncope
10% suffer a serious injury such as a fracture,
• Syncope
head trauma, or serious laceration. These
• Blurry vision
injuries can lead to considerable long-term mor-
• Weakness
tality. In the older population, 1% of falls result
• Buckling of legs
in a hip fracture. Within 1 year, these fractures
• Cognitive slowing
are associated with a mortality rate of 20% to
• Headache
30%.31-34 Fifty percent of admissions due to an
• Chest pain (in patients with underlying coronary artery
injury from a fall result in a discharge to a nurs-
disease)
ing home.33 The most severe consequences of
• Seizure (due to cerebral hypoxia)
drug-induced orthostatic hypotension are cere-
• Dizziness
brovascular accident, myocardial infarction, and
• Tachycardia
death.35-38
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540 SECTION VI • Drug-Induced Cardiovascular Diseases

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
TABLE 28-6 Approaches to Help Prevent Drug-
Induced Hypotension12,13,16
• Obtain an extensive medical and medication history.
• Administer a low dose of the antihypertensive agent,
closely monitoring for hypotension during the appro-
priate time interval before providing maintenance
therapy.
• Initiate therapy with the lowest possible dose, admin-
istering the first dose at bedtime, and increasing the
dosage slowly.
• Administer prophylactic doses of oral or intravenous
histamine blockers for histamine-related hypoten-
sion.
• Elevate the head of the bed to a 5- to 20-degree
angle.
• Instruct the patient to arise slowly upon waking,
allowing the feet to dangle over the side of the bed
for a few seconds to minutes, before rising to a com-
pletely elevated stance.
• Instruct the patient to avoid situations that may
potentially induce orthostatic hypotension (see Table
28–5).
• Instruct the patient to minimize alcohol intake.
• Instruct the patient to eat low-carbohydrate foods.
• Instruct the patient to avoid consuming large meals.
• Instruct the patient to consume 200–250 mg of caf-
feine (two cups of coffee) with a meal.
• Encourage mild-to-moderate exercise.
• Use Jobst stockings, waist high custom-fitted elastic
stockings, and knee-length elastic stockings with an
abdominal binder.
• Instruct the patient to eat sodium-containing foods
and increase water intake.
fluid in the extremities.42 Patients should arise
slowly upon waking, allowing their feet to dangle
over the side of the bed for a few seconds to min-
utes before rising to a completely elevated position.
Situations that may potentially induce orthostatic
hypotension should be avoided (see Table 28–5).13
Postprandial hypotension can be minimized by
reducing alcohol intake, eating low-carbohydrate
foods, and avoiding large meals. Consumption of
two cups of coffee (200 to 250 mg of caffeine) with
breakfast and lunch can increase systolic pressure
by about 12 mm Hg and diastolic pressure by about
6 mm Hg by blocking adenosine receptors.43,44
Exercise may be helpful in patients with poor
orthostatic tolerance. Mild exercise may improve
symptoms with minimal effects on resting blood
pressure. Postural maneuvers may also be used to
increase blood pressure. Leg crossing and squatting
may allow patients to increase their blood pressure
by as much as 13 to 44 mm Hg.12-16
CHAPTER 28 • Hypotension 541
Compression stockings, waist-high custom-fit-
ted elastic stockings, and knee-length elastic stock-
ings with an abdominal binder may help decrease
venous pooling of blood. In patients with no con-
traindications, water and foods containing sodium
can be taken liberally.12,13,16 As little as 240 mL of
water may exert a pressor effect.45,46 Seated blood
pressure may increase within 5 minutes and peak
within 35 minutes of consumption and may be
sustained for 60 minutes or longer.47
MANAGEMENT
When possible, the offending medication should be
identified, discontinued, and replaced with another
medication with a lower risk of causing hypotension.
Because drug-induced hypotension may be directly
related to a high therapeutic dose, overdose, or
administration rate, management will vary depend-
ing on the medication. Table 28–7 provides specific
recommendations for managing hypotension caused
by particular medications.5,51,81,82,98,111,126-130,133-
142,165,171,187,205,219,220,225,226,243,263,279,280,281
If the pre-
ventive and initial management measures listed in
Tables 28–5 and 28–6 do not sufficiently correct
hypotension, then drug treatment may be consid-
ered (Table 28–8).282-313
Fludrocortisone, a potent mineralocorticoid
with minimal glucocorticoid effects, may increase
blood volume by stimulating renal sodium reten-
tion and vascular sensitivity to norepinephrine
and by raising peripheral vascular resistance by
enhancing catecholamine release. Doses begin at
0.1 mg once daily and should be titrated upward
every 1 to 2 weeks to a maximum dose of 1
mg/day. The full therapeutic effect may take up to
1 to 2 weeks. Adverse effects include hypokalemia
and hypomagnesemia, which may occur within
the first 2 weeks of therapy. Headache, edema, and
supine hypertension may also occur. Despite the
fact that fludrocotisone is commonly used for
orthostatic hypotension, limited data exist regard-
ing its efficacy, and some studies have questioned
its value as compared with placebo.48-51
Midodrine, a prodrug of desglymidorine, is a
peripherally acting ␣-adrenergic agonist that con-
stricts both the arterial and the venous vasculature.
This agent is approved by the Food and Drug
Administration for the treatment of orthostatic
hypotension and has demonstrated impressive
results in small randomized, controlled trials.52-54
The initial dose is typically 2.5 mg two to three
times daily and may be titrated upward by 2.5 mg
daily at weekly intervals to a maximum daily dose
of 30 mg. The drug should be administered three
times daily, with the last dose given 4 hours before
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542 SECTION VI • Drug-Induced Cardiovascular Diseases

TABLE 28–7 Medication-Specific Management for Drug-Induced Hypotension

Medication Recommendation
ACE inhibitors27 Reduce or briefly discontinue diuretic and/or ACE inhibitor. Restart at 50% of the
dose.
Amiodarone199,200 Reduce rate of IV infusion. May consider use of fluids or vasopressor or inotrope.
Amifostine304 Place patient in the Trendelenburg position, discontinue amifostine, and initiate fluid
infusion (saline). Infusion duration greater than 15 min is associated with a higher
incidence of adverse effects.
Antipsychotic agents230,368,369 Discontinue agent. Restart at 25–50% of initial dose. In severe cases, begin fluid resus-
citation or vasopressors (i.e., dopamine, epinephrine, norepinephrine).
Centrally acting ␣-adrenergic Slowly decrease dose and discontinue agent. In severe cases, begin fluid
agonists29,369 resuscitation, vasopressors (i.e., epinephrine), or naloxone, or all of these.
Direct-acting arterial If severe, consider fluid resuscitation and/or vasopressors (i.e., dopamine).
vasodilators30,369
Dopamine agonists282,288 Use lowest dose possible.
␤-Blockers30,369 Reduce dose of ␤-blocker, adjust dose of ACE inhibitor and diuretic, or both. If severe,
consider fluid resuscitation and/or vasopressors (epinephrine or
norepinephrine).
Epoprostenol341,342 Stop infusion and hypotension should resolve within 5 min. Begin again at a
slower rate.
Etoposide355 If hypotension occurs, stop the infusion and, if necessary, administer fluids. Infuse
etoposide over at least 30–60 min.
Fenoldopam162 Stop IV infusion and restart at slower rate and lower dose.
Interleukin-2355 Use IV fluids judiciously. Vasopressors such as dopamine or phenylephrine may be required.
Levofloxacin254 Stop IV infusion and restart at slow rate (over 60 to 90 min)
Milrinone335,336 Consider fluid resuscitation, vasopressors (i.e., dopamine, norepinephrine, phenyle-
phrine), or vasopressin (0.03–0.07 units/min)
Nesiritide23 Discontinue nesiritide and observe patient. Once stabilized, restart dose with no
bolus at 30% of initial dose.
Nitrates30,369 For IV, stop infusion and restart at a lower dose
Opiates30,369 Stop IV infusion and begin at a slower rate. Pretreat with histamine antagonists. For
severe hypotension, administer naloxone. Avoid use of IV codeine.
Pentamidine252-253 Patients should be lying down and blood pressure monitored closely during and fol-
lowing administration until the blood pressure is stable.
Phenytoin244-247 Slow rate of IV infusion or discontinue the agent.
Fosphenytoin248
Procainamide216 Slow rate of IV infusion, lower the dose, or both.
Tricyclic antidepressants229,370 Slowly decrease dose, then discontinue. Consider alternative agent such as SSRI or
nortryptiline. If severe, begin fluid resuscitation or vasopressors (i.e., dopamine,
epinephrine).
Vancomycin255-259 Stop IV infusion and restart at slower rate. Infuse over more than 1 hr. Fluids, antihista-
mines, or corticosteroids may also be considered.
ACE = angiotensin-converting enzyme; IV = intravenous; SSRI = selective serotonin reuptake inhibitor.

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
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CHAPTER 28 • Hypotension 543

TABLE 28–8 Drug Therapy Regimens Used to Treat Hypotension

Medication Dose Proved Effective Level of Evidence
(see page xii for explanation)
63,65
Atenolol 50 mg po daily No A
Clonidine77,79 0.4 mg po twice daily Yes B
Dihydroergotamine72,73 0.5–1.0 mg IM twice daily Yes A
Ergotamine tartrate74 1–3 mg po daily or twice daily Yes C
Ergotamine75,76 0.36–0.72 mg by inhalation twice or three times daily Yes A
Epoetin alpha71 25–75 units/kg SQ three times weekly Yes B
Fludrocortisone49,50 0.1–1.0 mg po daily Conflicting A
Flurbiprofen56,57 50–200 mg po twice to three times daily Yes B
Indomethacin54,55 25–50 mg po three times daily
Metoprolol64 50–100 mg twice daily No A
Midodrine51,53 2.5–10 mg po three times daily Yes A
Octreotide69,70 1.2–2.4 mcg/kg/day SQ in 1–3 divided doses; Yes B
can be combined with midodrine
Paroxetine68 20 mg po daily Yes A
Pindolol58,60 5 mg po three times daily Yes B
Propranolol61,62 40–240 mg po daily in three to four divided doses Yes C
Yohimbine80,82 5 mg po twice to three times daily Yes B
IM = intramuscular; IV = intravenous; po = oral; SQ = subcutaneous.

increasing peripheral vascular resistance. In addi-
tion, these agents cause sodium retention, thus
increasing intravascular volume. Indomethacin 50
mg orally three times daily and flurbiprofen
50–200 mg orally two to three times daily, either
alone or in combination with fludrocortisone,
have each been shown to relieve symptoms of
orthostatic hypotension and increase blood pres-
sure.55-58 However, indomethacin should be avoid-
ed, when possible, because of the increased risk of
confusion, and all NSAIDS should be used with
caution because of the risk of gastrointestinal and
renal adverse effects.
In patients with low plasma catecholamine
concentrations and impaired baroreceptor func-
tion, therapy with oral propranolol or pindolol
may re-establish sympathetic homeostasis.59-63
Blocking ␣-adrenergic receptors allows plasma cat-
echolamines to exhibit predominant effects on the
vasoconstrictive ␤-adrenergic receptors. Use of ␤1
selective ␤-blockers remains controversial.64-68 It
has also been reported that 5-hydroxytriptamine
(serotonin) may play an important role in the
modulation of central nervous blood pressure and
heart rate regulation; thus, fluctuations in central
serotonin concentrations could play a role in the
pathogenesis of neurocardiogenic vasovagal syn-
cope. Currently, only the serotonin reuptake
inhibitor paroxetine has robust data suggesting
that it improves symptoms of patients with vasova-
gal syncope who are unresponsive to or intolerant
of traditional medications. In these studies, parox-
etine was well tolerated.69
Subcutaneous octreotide, a somatostatin ana-
logue, can be used to treat postprandial hypoten-
sion owing to its ability to decrease splanchnic
blood flow and the release of insulin and
glucagon. Effects are observed within 4 hours of
injection, with only mild gastrointestinal side
effects. Midodrine in combination with octreotide
can also cause a synergistic pressor effect that may
be useful in patients with orthostatic hypotension
associated with autonomic neuropathy.70,71 For
patients with concomitant anemia, erythropoietin
25 to 75 units/kg administered subcutaneously
three times per week with oral iron therapy may
be effective in raising blood pressure by 10 mm
Hg.5,72 The ergot alkaloids ergotamine and dihy-
droergotamine administered intravenously or
orally have shown some promise in improving
blood pressure or venous pooling defects.73-77 In
patients with refractory or severe orthostatic
hypotension, therapy with the central ␣2-adrener-
gic receptor agonist clonidine or the peripheral ␣2-
adrenergic receptor antagonist yohimbine may be
considered.78-83
TisdaleC28_529-553 1/12/10 2:57 PM Page 544
544 SECTION VI • Drug-Induced Cardiovascular Diseases
INFORMATION FOR PATIENTS
Patients prone to hypotension and their care
providers should be educated regarding the proper
measurement of blood pressure in both the supine
and upright positions, acceptable blood-pressure
ranges, and medications that may cause hypoten-
sion. Patients should be instructed that simply sit-
ting or lying down quickly may alleviate
symptoms of orthostatic hypotension. However,
patients should be warned not to lie down for sev-
eral hours after taking short-acting pressor agents.
Patients taking antihypertensive medications
should be instructed to always change their pos-
ture gradually, pausing for 10 to 30 seconds before
arising from a seated position. If orthostatic
hypotension develops in a seated position, patients
should place their feet on a footrest. Several small-
er meals rather than larger meals should be ingest-
ed to decrease the risk of postprandial
hypotension. Patients should avoid excessive alco-
hol consumption, avoid exposure to extended peri-
ods of heat, and stay well hydrated at all times.
Because physical deconditioning may worsen
orthostatic hypotension, health care providers may
wish to encourage mild-to-moderate physical
activity.
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TisdaleC29_554-568 1/12/10 2:59 PM Page 554
CHAPTER 29
Valvular and Pericardial
Heart Disease
A lthough cardiovascular disease is the leading
cause of death in the United States (U.S.), valvu-
lar and pericardial disease remain relatively uncom-
mon as compared with other cardiovascular
diseases, including hypertension and ischemic heart
disease. Valvular heart disease accounts for approxi-
mately 2.4% of all cardiovascular deaths in the U.S.,1
and pericardial disease accounts for approximately
0.1% of hospital admissions.2 Drug therapy may
result in a wide variety of cardiovascular complica-
tions, including valvular heart disease and pericar-
dial disease. Although more commonly a result of
degenerative or rheumatic processes, valvular heart
disease (which includes aortic, mitral, and tricuspid
regurgitation) has been reported to occur in associa-
tion with or as a result of drug therapy. Pericardial
disease associated with drug therapy includes peri-
carditis due to drug-induced systemic lupus erythe-
matosus (SLE)–like syndrome (with or without
cardiac tamponade), acute pericarditis, constrictive
pericarditis, and hemopericardium. This chapter
will review the manifestations of drug-induced
valvular and pericardial heart disease.
CAUSATIVE AGENTS
Drugs that have been reported to induce valvular or
pericardial heart disease are listed in Table 29–1.3-123
The earliest reports of drug-induced valvular heart
disease appeared in the 1960s, in association with
the ergot alkaloids ergotamine16,17,23 and methy-
sergide.62,63 The anorectic agents fenfluramine and
its D-isomer dexfenfluramine, as well as fenflu-
ramine in combination with phentermine, a com-
bination commonly referred to as “fen-phen,” have
been reported to be associated with left-sided regur-
554
Sarah A. Spinler and Frank E. Silvestry
gitant valvular lesions.4-15,18-21 Both fenfluramine
and dexfenfluramine were withdrawn from the U.S.
market in 1997, after reports of valvular heart dis-
ease associated with these agents began to
appear.8,19 The ergot-derived dopamine agonists
bromocriptine,3,105 cabergoline,77,79,80,86-91,97 and
pergolide,22,76,77,78,80-88,90-97 used to treat Parkinson’s
disease, have also been reported to result in both
left- and right-sided valvular disease. In 2006, the
U.S. Food and Drug Administration (FDA) ordered
the inclusion of a black-box warning in pergolide's
labeling regarding the potential for valvular heart
disease. The drug was withdrawn from the U.S. mar-
ket in 2007 amid continuing reports of this drug-
induced disease. Cabergoline, when used in lower
doses for the treatment of prolactinoma, has not
been associated with valvulopathy.124-127
Acute pericarditis has been reported to be asso-
ciated with a wide variety of drugs, including those
that may induce the syndrome resembling SLE
(hydralazine,35-37 isoniazid,38,39 methyldopa,40
phenytoin,35 procainamide48-53), cancer chemother-
apeutic agents24 (busulfan,25 cyclophosphamide,27,28
cytarabine,29-31 methotrexate,110,111 doxorubicin,34
daunorubicin,34 tretinoin54), and other drugs,
including mesalamine,75 sulfasalazine,99,109 minoxi-
dil,41-44 dantrolene sodium,32,33 phenylbutazone,45-47
and cromolyn sodium.26 Clozapine has been associ-
ated with pericarditis, often in conjunction with
myocarditis.107-117 Constrictive pericarditis has been
noted in association with ergotamine,57 methy-
sergide,58-63 cyclophosphamide,55 cytarabine,56 and
procainamide.48 Finally, hemopericardium, with or
without pericarditis, has been described after fibri-
nolytic therapy for acute myocardial infarction65-71
or stroke,68 during busulfan therapy in conjunction
with severe thrombocytopenia,64 and during thera-
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CHAPTER 29 • Valvular and Pericardial Heart Disease 555

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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556 SECTION VI • Drug-Induced Cardiovascular Diseases

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
warfarin.72-74
EPIDEMIOLOGY
There are no available estimates of the overall inci-
dence or frequency of drug-induced valvular and
pericardial diseases. However, incidences of pericar-
dial effusion due to minoxidil, pericarditis in
patients with drug-induced SLE, valvular disease
with long-term ergot alkaloid therapy, hemoperi-
cardium after fibrinolysis for myocardial infarction,
and regurgitant valvular disease induced by anorec-
tic agents have all been relatively well described.
The incidence of pericardial effusion occurring
during minoxidil therapy ranges from 3.8% (73 of
1,919 patients)41 to 20% (1 of 5)43 depending on
the population studied, with a higher frequency
noted in patients with kidney disease. The preve-
lence of acute pericarditis in those with idiopathic
SLE ranges from 30% to 45%.48 Reported rates of
acute pericarditis complicating drug-induced SLE
are similar to those associated with idiopathic SLE;
the incidences of acute pericarditis associated with
isoniazid and procainamide are approximately
30% and 18–57%, respectively.48 Pericarditis in
patients with SLE secondary to hydralazine37 and
methyldopa40 is relatively uncommon. Cardiac
tamponade occurring in patients with idiopathic
or drug-induced SLE is rare.36,37
Although the vascular complications associat-
ed with ergot alkaloid treatment have been known
for well over a century, the frequency of valvular
disease is less well characterized. Early reports
relied on auscultatory findings, which are less sen-
sitive than echocardiography in the detection of
valvular disease. Graham and colleagues62,63 esti-
mated that the incidence of methysergide-associat-
ed valvular disease is 1 in 5,000 patients treated.
The incidence of echocardiographically detected
pericardial effusion and hemopericardium after fib-
rinolysis is highly variable, ranging from 8.75% in
80 consecutive patients treated with streptokinase69
to 24% in 112 patients treated with alteplase.71 In a
study of 192 patients who underwent serial echocar-
diography on days 1, 5, 10, and 21 of the study and
then annually for 3 years, pericardial effusion was
detected at least once in 43% of patients, and the
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
frequency of pericardial effusion varies depending
on the duration of echocardiographic follow-up,
with an increasing frequency occurring during the
first 5 days after myocardial infarction, regardless of
whether fibrinolytic drugs were administered.70
The best-studied example of drug-induced
valvular heart disease is that of mitral and aortic
regurgitation caused by the anorexiant agents fen-
fluramine and dexfenfluramine. In 1997, the FDA
defined anorexiant drug–related cardiac valvulopa-
thy as moderate or greater mitral regurgitation,
mild or greater aortic regurgitation, or both detect-
ed on a standard echocardiogram, in the absence of
other known causes of valvular disease. Patients
with these drug-related findings are defined as
“FDA-positive.”8 Using that definition, the report-
ed prevalence of fenfluramine-associated and
dexfenfluramine-associated valvular disease ranged
from <0.1% to 38%, depending on the population
studied and method used.8,9 If the reports of FDA-
positive valvular heart disease due to anorexiant
drugs are limited to controlled studies, the inci-
dence varies from 1% to 15%, which is still signifi-
cantly higher than the incidence reported in
controls (3–6%).5,6,128,129 Aortic regurgitation
occurs more frequently than mitral regurgita-
tion.6,77,78 A prospective study did not find an asso-
ciation between phentermine (when taken without
fenfluramine or dexfenfluramine) and valvulopa-
thy, and as a result, phentermine remains current-
ly used as monotherapy.5,10 Moderate to severe
cardiac valvular regurgitation disease associated
with ergot alkaloids in patients with Parkinson’s
disease has also been well studied. Case–control
studies comparing the frequency of cardiac valvu-
lar disease with ergot drugs (pergolide, cabergoline)
TABLE 29–2 Mechanisms of Drug-Induced Valvular and Pericardial Heart Disease
Drug
Fenfluramine, dexfenfluramine (valvulopathy)
Ergotamine (valvulopathy)
Pergolide (valvulopathy)
Cabergoline (valvulopathy)
MDMA
Alteplase, reteplase, streptokinase, tenecteplase
(hemopericardium)
HT = hydroxytryptamine; MDMA = methylenedioxymethamphetamine.
CHAPTER 29 • Valvular and Pericardial Heart Disease 557
to either nonergot drugs (such as ropinirole or
pramipexole) or controls report a frequency of 18%
to 37% in ergot-treated patients, 0% to 25% in
non-ergot-treated patients and 4% to 18% in con-
trols, with ergot-treated patients at increased risk of
valvular heart disease.79,80,81,83,84,87,93,94
MECHANISMS
Although there are a number of proposed mecha-
nisms for drug-induced valvular and pericardial heart
disease (Table 29–2), a common link between valve
regurgitation after ergotamine, methysergide, fenflu-
ramine, and dexfenfluramine is that these agents are
structurally similar to serotonin and are potent ago-
nists of the 5-hydroxytryptamine (HT)2B subtype of
serotonin receptor, which promotes serotonin
release.5,7,130-132 The type of valvular lesions observed
in association with these agents is similar to that
observed in patients with carcinoid heart syndrome,
which is also associated with high concentrations of
circulating serotonin.5 Human cardiac valves express
large numbers of 5-HT2B receptors and no apprecia-
ble 5-HT2C receptors.80 Examination of the affected
native valves excised after valve-replacement surgery
reveals glistening white leaflets and chordae covered
with a thick coating; however, underlying structures
in the valves are preserved. On histologic examina-
tion, there is a proliferation of myofibroblasts with
deposition of abundant extracellular matrix.
Echocardiography has defined diastolic doming and
anterior leaflet thickening with affected mitral
valves. Leaflet mobility is preserved in the anterior
leaflets, but is impaired in the posterior leaflets.6,16
Animal models suggest that activation of the 5-HT2B
receptor and decreased 5-HT transporter gene activi-
Mechanism
Activation of the 5-HT2B subtype of serotonin receptor,
which promotes serotonin release
Activation of the 5-HT2B subtype of serotonin receptor,
which promotes serotonin release
Activation of the 5-HT2B subtype of serotonin receptor,
which promotes serotonin release
Activation of the 5-HT2B subtype of serotonin receptor,
which promotes serotonin release
Activation of the 5-HT2B subtype of serotonin receptor,
which promotes serotonin release
Fibrinolytic effect coupled with pericarditis caused by
myocardial infarction
TisdaleC29_554-568 1/12/10 2:59 PM Page 558
558 SECTION VI • Drug-Induced Cardiovascular Diseases
ty (resulting in reduced 5-HT clearance and process-
ing at the receptor) are associated with valvulopathy
due to 5-HT administration. Pergolide, cabergoline,
and bromocriptine are derivatives of ergotamine and
are believed to share the same mechanism of cardiac
valvulopathy. These agents activate 5-HT2B recep-
tors.132,133 Bromocriptine has a lower receptor-bind-
ing affinity and is a partial agonist of the 5-HT2B
receptor, which may be the reason that there are
fewer and inconsistent reports of valvulopa-
thy.77,79,97,134 Interestingly, 3,4-methylenedioxymeth-
amphetamine (MDMA, or “ecstasy”) also binds to
and stimulates serotonin 5-HT2B receptors, produc-
ing an in vitro mitogenic response in cardiac valvu-
lar interstitial cells that is identical to that induced by
fenfluramine.132 One case–control echocardiograph-
ic study comparing the frequency of valvular heart
disease using the FDA criteria for appetite suppres-
sant–induced valvular heart disease in users of
MDMA (mean duration of use, 6.1 years) found an
alarming incidence of 28% (8 of 29) in these young
adults, as compared with 0% (0 of 28) among non-
user controls.98
Acute pericarditis and pericardial effusion occur-
ring in patients with drug-induced SLE syndrome is
pathologically indistinguishable from that occur-
ring in association with idiopathic SLE. A more
detailed discussion of the proposed mechanisms of
drug-induced SLE may be found in Chapter 7.
Pericarditis associated with mesalamine therapy has
been postulated to be a type IV hypersensitivity
reaction; there is an amnestic response to reexpo-
sure, with recurrence on subsequent exposure to sul-
fasalazine.75 The association of dantrolene with
development of concomitant pleural and pericardial
effusion and eosinophilia suggests an allergic-type
reaction as well.32 Pericarditis and pericardial effu-
sion associated with cancer chemotherapy in the
absence of pericardial metastases are thought to be
caused by an inflammatory reaction secondary to
direct cytotoxicity, an immune-mediated hypersen-
sitivity process, or both.24,29,34
Hemopericardium in patients with acute
myocardial infarction who are treated with fibri-
nolytics is believed to be secondary to the anti-
thrombotic effect of the fibrinolytic agent coupled
with pericarditis caused by the acute infarction.
However, at least one case of fibrinolytic-associated
hemopericardium with cardiac tamponade has
been reported after treatment of acute ischemic
stroke with alteplase in the absence of myocardial
infarction.68 Hemopericardium associated with
administration of the oral vitamin K antagonist
warfarin occurs most often, but not exclusively, in
the setting of underlying pericarditis72 or after car-
diac surgery74 and is thought to be secondary to
the anticoagulant effect of the drug.
CLINICAL PRESENTATION AND
DIFFERENTIAL DIAGNOSIS
Symptoms associated with drug-induced valvular and
pericardial heart disease are similar to those of non-
drug-induced disease and may occur at any time after
initiation of therapy (Table 29–3). Patients with drug-
induced valvular disease may present with a murmur
on auscultation, signs of atrial or ventricular enlarge-
ment or dysfunction, fatigue, exercise intolerance,
dyspnea on exertion, peripheral or pulmonary
edema, as well as other signs of acute or chronic heart
failure.134-136 Many patients have no symptoms or
obvious physical findings. Those with tricuspid regur-
gitation present with right-sided heart failure, symp-
toms of peripheral edema, ascites, hepatomegaly,
jugular venous distention, or any combination of
TABLE 29–3 Signs and Symptoms Associated
with Valvular and Pericardial Heart Disease
VALVULAR HEART DISEASE
• Murmur characteristic of the involved valve(s) detect-
ed on auscultation
• Atrial and ventricular enlargement on physical exami-
nation, echocardiogram, or both
• Dyspnea at rest or on exertion
• Signs and symptoms of heart failure, including peripheral
edema, ascites, hepatomegaly, venous distention, rales
• Signs and symptoms of endocarditis
ACUTE AND CONSTRICTIVE PERICARDITIS
• Pericardial friction rub on auscultation
• Pulsus paradoxus
• PR-interval depression and diffuse ST-segment eleva-
tion on 12-lead electrocardiogram
• Concomitant pleural effusion
• Dyspnea
• Cough
• Abdominal distention
• Chest pain
• Signs and symptoms of systemic lupus erythematosus
syndrome
• Retroperitoneal fibrosis (ergotamine, methysergide,
pergolide, cabergoline)
PERICARDIAL TAMPONADE
• Pulsus paradoxus
• Diffuse low voltage on 12-lead electrocardiogram
• Pericardial effusion
• Tachycardia
• Tachypnea
• Feeling of apprehension
• Signs of hemodynamic compromise such as hypoten-
sion or cardiogenic shock
• Pulseless cardiac arrest
TisdaleC29_554-568 1/12/10 2:59 PM Page 559

CHAPTER 29 • Valvular and Pericardial Heart Disease 559

these.136 Patients with drug-induced valvular disease

may also present with endocarditis.135,136 Individuals
with drug-induced pericarditis may present with an
enlarged cardiac silhouette, suggesting pericardial
effusion on chest radiography, a characteristic pericar-
dial friction rub on auscultation, dyspnea, pulsus
paradoxus, cough, abdominal distention secondary
to hepatic congestion, and chest pain.135 A 12-lead
electrocardiogram (ECG) may reveal PR-interval
depression and diffuse concave upward ST-segment
elevation, as is observed in patients with other causes
of acute pericarditis. Pleural effusion may also accom-
pany pericardial effusion. Other causes of pericarditis,
such as infection or malignancy, may be excluded
using pericardiocentesis and cell cytology. FIGURE 29–2 Transthoracic echocardiogram with color
Percutaneous pericardial biopsy is often performed in Doppler map from the parasternal window in the long axis
conjunction with pericardiocentesis and reveals fibro- of the same patient as in Figure 29–1, demonstrating a jet
sis and nonspecific inflammation. Patients with peri- of moderate mitral regurgitation (arrow) directed slightly
carditis and pericardial effusion secondary to posteriorly, due to mild restriction of the posterior leaflet,
SLE syndrome may also present with signs and symp- as is characteristic of anorexiant-induced valvulopathy.
toms of SLE, which are described in more detail in (See color section.) LV = left ventricle; RV = right ventricle.
Chapter 7. Those with ergot-induced valvular or peri-
cardial heart disease may also present with concomi- study is nondiagnostic because of technical limita-
tant retroperitoneal fibrosis.58,89,137 Patients with tions. Calcification, stenosis, and rheumatic thick-
cardiac tamponade typically present with tachycar- ening of the valves are generally absent. Examples
dia, tachypnea, pericardial effusion, pulsus para- of echocardiographic findings in patients with
doxus, diffuse low voltage on 12-lead ECG, and anorexiant-associated valvulopathy are shown in
clinical signs of hemodynamic compromise, such as Figures 29–1 through 29–3, and cardiac tamponade
hypotension. In addition, they may present with car- associated with drug-induced SLE-like syndrome is
diogenic shock or pulseless cardiac arrest.135 shown in Figures 29–4 and 29–5.
All patients with suspected drug-induced Conditions to consider in the differential diag-
valvular or pericardial disease should undergo full nosis of drug-induced valvular or pericardial dis-
transthoracic echocardiography with Doppler ease are presented in Table 29–4. All patients
interrogation of the valves. Transesophageal
echocardiography may be used if the transthoracic

FIGURE 29–3 Apical 4-chamber view from a transthoracic

FIGURE 29–1 Transthoracic echocardiogram from the
parasternal window in the long axis demonstrating a nor-
mal left atrium (LA), left ventricle (LV), and right ventricle
(RV), with mild thickening and restriction of the posterior
mitral-valve leaflet (arrow), a finding that is typical of
anorexiant induced valvulopathy.
echocardiogram from the same patient as in Figures 29-1 and
29-2, demonstrating a jet of moderate mitral regurgitation
(arrow) directed slightly posteriorly and laterally, due to mild
restriction of the posterior leaflet, characteristic of anorexi-
ant induced valvulopathy. (See color section.) LA = Left atri-
um; LV = Left ventricle; RA = Right atrium; RV = Right ventricle.
TisdaleC29_554-568 1/12/10 3:00 PM Page 560
560 SECTION VI • Drug-Induced Cardiovascular Diseases
FIGURE 29–4 Transthoracic echocardiogram from the
parasternal window demonstrating a large circumferential
pericardial effusion (PE) surrounding the heart in a patient
with a drug-induced syndrome resembling systemic lupus
erythematosus and subsequent massive pericardial effu-
sion with tamponade. Note the small and underfilled left
atrium (LA), left ventricle (LV), and right ventricle (RV).
Ao = aorta.
presenting with suspected drug-induced valvular
disease should undergo evaluation to exclude the
diagnosis of carcinoid tumor using a 24-hour urine
collection for determination of 5-hydroxy-
indolacetic acid excretion, serum analysis of chro-
mogranin A, as well as radiologic imaging to
exclude the presence of a primary tumor or liver
metastases.3,138 Alternative causes of mitral regurgi-
tation should be excluded, including myxomatous
degeneration of the mitral valve, infective endo-
carditis, rheumatic heart disease, SLE, amyloidosis,
congenital heart disease, papillary muscle rupture,
Marfan’s syndrome, and hypertrophic cardiomy-
opathy.135,136 Other causes of aortic regurgitation
should be excluded, including congenital abnor-
mality of the aortic valve, calcific degeneration,
rheumatic disease, myxomatous proliferation,
infective endocarditis, aortic dissection, Marfan’s
syndrome, and traumatic injury.135,136 Other dis-
eases causing tricuspid regurgitation that should be
considered include left ventricular dysfunction and
heart failure, cardiac tumors, pulmonary hyperten-
sion, mitral stenosis, congenital heart disease such
as Ebstein’s anomaly, rheumatic heart disease, col-
lagen vascular diseases, and intrinsic pulmonary
diseases such as chronic obstructive pulmonary
disease.135,136 Patients with mitral stenosis should
be evaluated for rheumatic heart disease and other
degenerative valvular diseases in addition to carci-
noid syndrome, including Fabry’s disease,
mucopolysaccharidosis, Whipple’s disease, gout,
FIGURE 29–5 Transthoracic echocardiogram from the
parasternal window of the heart in short axis demonstrat-
ing a large circumferential pericardial effusion (PE) sur-
rounding the right ventricle (RV) and left ventricle (LV) in a
patient with a drug-induced syndrome resembling sys-
temic lupus erythematusos and subsequent massive peri-
cardial effusion with tamponade. Note the thickened
visceral pericardium (arrow), which is typical of patients
with inflammatory PE.
and rheumatoid arthritis.135 The diagnoses of
malignancy, trauma, and uremia should be consid-
ered in patients presenting with cardiac tampon-
ade.135 Viral, bacterial, and fungal infection, as well
as tuberculosis, uremia, myocardial infarction, neo-
plasm, trauma, and collagen vascular disease
should be considered in patients presenting with
acute or constrictive pericarditis.135
RISK FACTORS
Risk factors for certain types of drug-induced
valvular and pericardial heart disease have been
identified (Table 29–5). Risk factors for the develop-
ment of mitral or aortic regurgitation associated
with fenfluramine and dexfenfluramine include
duration of therapy, dose, older age, and female
sex.6 Exposure to fenfluramine or dexfenfluramine
for <3 months is associated with a lower incidence
of valvulopathy than that associated with treat-
ment durations >6 months.13,21,129 Doses >60
mg/day have also been associated with the devel-
opment of valvular regurgitation.21 Continuous
use of methysergide or ergotamine for >9 months,
rather than episodic use, has been associated with
the development of valvulopathy.23,58 Larger doses
of ergotamine (>6 mg/day) and methysergide (>8
mg/day) have also been associated with the devel-
opment of valvular heart disease.23,57,58 In a
transthoracic echocardiographic study of 78
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CHAPTER 29 • Valvular and Pericardial Heart Disease 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-
TisdaleC29_554-568 1/12/10 3:00 PM Page 562
562 SECTION VI • Drug-Induced Cardiovascular Diseases
ment. Higher doses of cancer chemotherapy are
associated with a greater risk of cardiotoxici-
ty.11,24,25,28,31,55 Mean total cyclophosphamide doses
of 174 mg/kg were associated with a higher rate of
pericarditis as compared with that associated with
a regimen of 87 mg/kg.28 High-doses of cytarabine
(≥3 g/m2) have been associated with pericarditis
and heart failure symptoms occurring as early as
after the first dose.24 Minoxidil-associated pericar-
dial effusion has been noted more frequently in
patients with chronic kidney disease than in
patients with normal kidney function.41
Risk factors for the development of hemoperi-
cardium after fibrinolytic therapy include con-
comitant underlying pericarditis and pericardial
effusion.65 Pericarditis, excessive anticoagulation,
and recent cardiac surgery are risk factors for the
development of hemopericardium associated with
oral vitamin K antagonist therapy.72,74
MORBIDITY AND MORTALITY
After cessation of therapy with fenfluramine and
dexfenfluramine, approximately 50% of valve
lesions stabilize, approximately 30% improve, and
<10% worsen over a subsequent 6-month to 1-year
period.4,5,6,14,18 Outcomes after the discontinuation
of therapy with ergot derivatives in patients with
Parkinson’s disease are not well studied, and no
conclusions can be made.76
Most cases of drug-induced pericarditis are self-
limited and resolve within 2 to 4 weeks after with-
drawal of the offending agent. Although extremely
rare, death may occur secondary to cardiogenic
shock in patients with drug-induced cardiac tam-
ponade24,43 as well as after valve-replacement sur-
gery in patients with drug-induced valvular
disease.8
PREVENTION
There are no specific recommendations to prevent
drug-induced valvular or pericardial heart disease.
Some general suggestions for the prevention of
valvular or pericardial heart disease are listed in
Table 29–6. Fenfluramine and dexfenfluramine
have been removed from the market, and ergot
therapy for migraine has been supplanted by selec-
tive 5-HT1 receptor agonist therapy. When possi-
ble, these other agents should be selected for
treatment. Pergolide has been removed from the
U.S. market. Nonergot dopamine agonists, either
ropinirole or pramipexole, should be selected to
treat Parkinson’s disease, as those agents do not
TABLE 29–6 Approaches to Help Prevent Drug-
Induced Valvular and Pericardial Heart Disease
• Ergotamine (valvulopathy): Administer episodically
and limit treatment duration to <9 mo
• Minoxidil (pericarditis/pericardial effusion): Monitor
closely for signs and symptoms of pericarditis in
patients with kidney disease
• Fibrinolytic therapy (hemopericardium): Exclude the
diagnosis of pericarditis before administering to
patients with acute myocardial infarction
bind substantially to the 5-HT2B receptor.134
Patients receiving cabergoline for prolactinoma
should have a baseline echocardiogram performed.
Patients with kidney disease taking minoxidil
should be monitored more closely for clinical signs
of pericarditis. The diagnosis of pericarditis should
be excluded clinically before the administration of
fibrinolytics, and the dose of anticoagulants
should be carefully monitored, especially in
patients undergoing cardiothoracic surgery, to pre-
vent hemopericardium.
MANAGEMENT
Management of drug-induced valvular or pericar-
dial heart diseases should be individualized based
on the specific type and severity of cardiac disease.
Treatment options for the management of drug-
induced valvular and pericardial diseases are pre-
sented in Table 29–7.
Whether all patients who are exposed to an agent
with the potential to induce valvular heart disease
require an initial screening echocardiogram is not
known. It is prudent for clinicians to maintain a high
index of suspicion and to screen patients carefully for
potential cardiac symptoms, cardiac murmurs on aus-
cultation, or electrocardiographic abnormalities. If
drug-associated valvulopathy is suspected, therapy
with the suspected culprit agent should be discontin-
ued. Serial echocardiography should be performed
every 6 to 12 months to monitor for progression of
valvular disease if significant valvular disease is iden-
tified at the time of the baseline exam.9 The most
recent valvular heart disease guidelines from the
American College of Cardiology/American Heart
Association are not specific regarding diagnosis or
monitoring of suspected drug-associated valvular
heart disease.135 It seems prudent to perform echocar-
diography in all patients who have received therapy
with fenfluramine, dexfenfluramine, pergolide, or
cabergoline. Routine follow-up echocardiography is
not recommended for patients classified as having
TisdaleC29_554-568 1/12/10 3:00 PM Page 563
TABLE 29–7 Treatment Options for Management
of Drug-Induced Valvular and Pericardial Heart
Disease
Management of valvular heart disease
• Discontinue the offending agent
• Obtain baseline and serial echocardiograms
• Valve replacement or repair for severe symptomatic
disease
• Treat heart failure symptoms with diuretics and
vasodilators
• Administer antimicrobial prophylaxis against endo-
carditis before invasive procedures
Management of pericarditis
• Discontinue the offending agent
• Bed rest
• NSAID with supplemental narcotic analgesia if needed
• Corticosteroids for patients with drug-induced SLE-
like syndrome
• Surgical pericardectomy for severe constrictive peri-
carditis
• Management of large pericardial effusion or hemo-
pericardium and cardiac tamponade
• Pericardiocentesis
• Surgical pericardiotomy
Management of large pericardial effusion or hemoperi-
cardium and cardiac tamponade
• Discontinue the offending agent
• Pericardiocentesis
• Surgical pericardiotomy
NSAID = nonsteroidal antiinflammatory drug; SLE = systemic
lupus erythematosus.
trivial disease or in those without valvular abnormal-
ities on the initial echocardiogram.139 Either transtho-
racic or transesophageal echocardiography may be
used for initial diagnosis and serial evaluations for
patients with suspected drug-induced valvulopa-
thy.140 Symptomatic severe valvular regurgitation
may necessitate valve replacement or repair based on
standard criteria.139 Heart failure symptoms should be
treated with diuretics and vasodilators. Patients with
valvular heart disease due to drug therapy should
receive antimicrobial prophylaxis against endocardi-
tis before undergoing invasive procedures that are
likely to result in bacteremia.139
Patients with pericarditis should be placed on
bed rest, receive nonsteroidal antiinflammatory
drugs, and, in severe cases of SLE-associated peri-
cardial disease, should receive therapy with sys-
temic corticosteroids.135 Surgical pericardectomy
may be required for constrictive pericarditis.135
Patients with cardiac tamponade and some
patients with large pericardial effusion or hemo-
CHAPTER 29 • Valvular and Pericardial Heart Disease 563
pericardium require pericardiocentesis or surgical
pericardiotomy.135
INFORMATION FOR PATIENTS
Patients who take drugs known to cause valvular or
pericardial heart disease should be instructed to
report symptoms of heart failure to their health
care provider. Patients taking drugs associated with
pericarditis should be told to immediately report
symptoms of dyspnea, chest pain, or peripheral
edema. Those taking agents associated with drug-
induced SLE-like syndrome should be advised of
the symptoms of this condition. All patients
exposed to drugs associated with valvular or peri-
cardial disease should be carefully screened, and
appropriate diagnostic testing should be initiated if
any abnormalities are detected by history, physical
exam, or ECG.
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SECTION VII

DRUG-INDUCED
ENDOCRINE DISEASES
CHAPTER 30 Glucose and Insulin Dysregulation

CHAPTER 31 Thyroid Disorders

CHAPTER 32 Hypothalamic, Pituitary and Adrenal Diseases

CHAPTER 33 Weight Gain

CHAPTER 34 Temperature Dysregulation

CHAPTER 35 Sexual Dysfunction in Males

CHAPTER 36 Gynecologic Diseases and Infertility in Women

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TisdaleC30_569-585 1/20/10 11:30 PM Page 571
CHAPTER 30
Glucose and Insulin
Dysregulation
Devra K. Dang, Frank Pucino, Jr., Charles D. Ponte, and Karim Anton Calis
G lucose homeostasis is regulated by the complex
interplay of insulin, hepatic glucose production,
peripheral glucose utilization, and counterregulatory
mechanisms. Insulin is secreted by pancreatic
cells
in response to an increase in plasma glucose concen-
tration and promotes glucose uptake by the liver,
muscle, and adipose tissue. Insulin stimulates glyco-
gen synthesis, lipogenesis, and protein synthesis and
inhibits lipolysis and hepatic gluconeogenesis. In
healthy individuals, a normal plasma glucose level
concentration is needed to maintain physiologic
function and meet the energy needs of the brain and
various tissues. Insulin secretion is reduced as plasma
glucose concentrations decline. When plasma glu-
cose concentrations decrease below the physiologic
range, counterregulatory hormones are secreted,
including glucagon, adrenaline (epinephrine),
growth hormone, and cortisol. These hormones nor-
mally restore plasma glucose concentrations to the
physiologic range through various effects, including
stimulating gluconeogenesis and glycogenolysis,
inhibition of insulin secretion and peripheral glucose
utilization, and stimulation of lipolysis.
Hypoglycemia and hyperglycemia both result from
an imbalance between plasma glucose and insulin
concentrations. Drugs may induce hyperglycemia or
hypoglycemia through a variety of mechanisms,
including alterations of insulin secretion and sensi-
tivity, changes in gluconeogenesis, and direct cyto-
toxic effects on pancreatic
cells. Drug-induced
hyperglycemia or hypoglycemia can lead to signifi-
cant consequences, including diabetes mellitus,
severe hypoglycemia, coma, and death. However,
these events can be prevented or minimized with
awareness of the problem, close monitoring, and
judicious use of drugs associated with hypo- or
hyperglycemia.
CAUSATIVE AGENTS
Tables 30–1 and 30–2 list the medications that
have been associated with alterations in the regula-
tion of glucose or insulin or both.1-191 Although
sporadic reports of glucose and insulin dysregula-
tion associated with many drugs appear in the lit-
erature, only drugs with data adequate to establish
a clear relationship between the specific agent and
drug-induced hyperglycemia or hypoglycemia will
be discussed in this chapter. Glucocorticoids, pro-
tease inhibitors, atypical antipsychotics, niacin,
pentamidine, and diazoxide are among the agents
that have been consistently associated with hyper-
glycemia and diabetes mellitus. For drug-induced
hypoglycemia, commonly implicated agents
include insulin, sulfonylureas, and ethanol alone
or taken concomitantly. In a review of 1,418 cases
of severe hypoglycemia between 1940 and 1989,
these agents accounted for more than 70% of the
reports.123 In children 2 years of age or younger,
salicylate poisoning was reported to cause the
majority of cases of drug-induced hypoglycemia.123
EPIDEMIOLOGY
The true incidence of glucose and insulin dysregu-
lation associated with most drugs is unknown. This
is due, in large part, to a lack of data from con-
trolled clinical trials, under-reporting of postmar-
keting events, and failure to establish causality. For
some drugs, the incidence of drug-induced hyper-
glycemia or hypoglycemia may also vary depend-
ing on the dose, frequency, or duration (or any
combination of these) of drug administration as
571
TisdaleC30_569-585 1/20/10 11:30 PM Page 572

572 SECTION VII • Drug-Induced Endocrine Diseases

TABLE 30–1 Agents Implicated in Drug-Induced Hyperglycemia

Drug Incidencea Level of Evidence
(see page xii for explanation)
1-9 b
Atypical antipsychotics NK B

-Adrenergic receptor blockers10-12 NKc B
Calcium-channel blockers13-16 Rare C
Cyclosporine17-20 New-onset PTDM: 4–11% in kidney
transplant patients B
21-24
Diazoxide NK B
Diuretics25-32 NKd A
Fish oil33-37 NKe B
Glucocorticoids25,38-46 Less than 1–46% for new-onset diabetesf A
Growth hormone18,47,48 NK C
Interferons49-51 NK C
L-asparaginase18,52-57 NK B
Megesterol acetate18,58-64 NK B
Niacin (nicotinic acid)18,65-67 NK A
Nucleoside reverse-transcriptase inhibitors18,68-76 NKg B
Oral contraceptives77-81 NKh B
Pentamidine82-89 NK B
Phenothiazines90,91 NKi B
Phenytoin92-95 Rare B
Protease inhibitors96-104 5% for new-onset diabetes mellitus; up to B
40% for impaired glucose tolerance
Rifampin105 NK B
Ritodrine106-108 NK C
Tacrolimus20,109-113 Variesj A
Terbutaline114-116 NK A
Thalidomide117,118 NK B
NK = not known; PTDM = post-transplant diabetes mellitus.
a
Incidence may be related to drug dose.
b
Highest incidence with olanzapine and clozapine.
c
Incidence higher with nonselective
-blockers.
d
Most commonly reported with thiazides. Incidence is lower with doses <25 mg of hydrochlorothiazide equivalent.
e
Usually occurs only in patients with impaired glucose tolerance or diabetes mellitus. Risk is usually associated with doses >3 g/day. A
2008 Cochrane meta-analysis concluded that there were no significant changes in fasting glucose or glycated hemoglobin in random-
ized, placebo-controlled trials conducted in patients with type 2 diabetes.
f
Incidence varies depending on dose, duration, and route of administration. Lower incidence with inhaled formulations.
g
More commonly associated with stavudine, zidovudine, and didanosine.
h
More common with formulations containing high-dose estrogen (>35 mcg ethinyl estradiol or equivalent) or second-generation progestin.
i
Most case reports are for chlorpromazine.
j
New-onset insulin-dependent PTDM: 20% (kidney transplant patients), 11–18% (liver transplant patients). Hyperglycemia: 22% (kidney
transplant patients), 33–47% (liver transplant patients). Patients received concomitant steroid therapy. Lower incidence 1 year after
transplantation. Higher incidence with tacrolimus than with cyclosporine.
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CHAPTER 30 • Glucose and Insulin Dysregulation 573

TABLE 30–2 Agents Implicated in Drug-Induced Hypoglycemia

Drug Incidencea Level of Evidence
(see page xii for explanation)
119-122
Angiotensin-converting enzyme inhibitors NK A

-Adrenergic receptor blockers 11,123-129
NKb C
Bitter melon (Momordica charantia—also commonly known as karela)130-136 NK B
Disopyramide137-141 NK B
119,123,124,142
Ethanol NK C
Exenatide 143
4.5–35.7%c A
Fenugreek (Trigonella foenum graecum)135,144-146 NK Bd
Fluoroquinolones147-153 NK B
Ginseng 135,154-157
NK Bd
Insulin158-160
Variese A
Ivy gourd (Coccinia indica)135,161 NK Bd
L-Carnitine135,162-164 NK B
165-167
Non-sulfonylurea secretagogues NK; lower incidence as compared A
to with sulfonylureas
85,86,88,168-171
Pentamidine 6–40% with intravenous or B
intramuscular formulations, 1% or
less with nebulized formulation
Pramlintide 172-174
0.6–16.8%f A
Quinine124,175-180 NK B
124,175,181
Quinidine NK B
Salicylates 123,124,182,183
NKg B
Sitagliptin184 Up to 12.2%; not all studies reported A
hypoglycemia with sitagliptin, increased
risk when combined with sulfonylurea
Sulfamethoxazole185-189 NKh C
Sulfonylureas 123,160,190,191
Variesi A
NK = not known.
a
Incidence may be related to drug dose.
b
Effects more commonly associated with nonselective
-blockers.
c
Increased risk when combined with sulfonylurea.
d
Even though there are one or more randomized, controlled clinical trials demonstrating the glucose-lowering effect of this herbal
agent, a B rating for level of evidence is given because the overall effect is inconclusive.
e
2.76 to 62 episodes per 100 patient-years for severe hypoglycemia requiring assistance. Higher incidence in patients with type 1 ver-
sus type 2 diabetes.
f
Does not cause hypoglycemia when used alone but increases risk of insulin-induced hypoglycemia when combined with insulin.
Higher incidence in patients with type 1 (0.9–16.8%) versus type 2 (0.4–8.2%) diabetes. Incidence is lowered (0.9–5.7%) when the dose
of preprandial insulin is decreased by 50% when initiating pramlintide.
g
More common in children as compared to adults. Most common cause of severe hypoglycemia in children ≤2 years.
h
Rare reaction with renal failure and/or high doses.
i
1.4-20% per year for recorded hypoglycemia. Higher incidence reported with chlorpropamide and glyburide.
TisdaleC30_569-585 1/20/10 11:30 PM Page 574
574 SECTION VII • Drug-Induced Endocrine Diseases
well as a patient’s underlying disease state(s). For
example, in the Diabetes Control and
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-
tions) as compared with the conventionally treated
group (1 to 2 daily insulin injections).158 Within a
specific drug class, the incidence of drug-induced
hyperglycemia or hypoglycemia also may vary. For
example, hyperglycemia and diabetes mellitus
occur more commonly with olanzapine and cloza-
pine as compared to the other atypical antipsy-
chotic drugs.1,192 However, an increased
background risk for diabetes mellitus with schizo-
phrenia, in addition to the rising incidence of dia-
betes in the general population, complicate
determination of precise risk estimates. The inci-
dence of treatment-related hyperglycemia also may
be higher if the patient has predisposing risk fac-
tors for diabetes mellitus, such as obesity or a fam-
ily history. Hypoglycemia is more common with
long-acting (e.g., chlorpropamide and glyburide)
than shorter-acting (e.g., tolbutamide) sulfony-
lureas.190,193 The reported incidence of drug-
induced hypoglycemia may also vary depending
on the definition of hypoglycemia used. In addi-
tion, factors such as the presence of active drug
metabolites, the route of elimination, and the pres-
ence of other risk factors for hypoglycemia also
account for the difference in reported incidences of
hypoglycemia among the drugs. Finally, the route
of administration and systemic availability of a
drug may also influence the incidence of drug-
induced hyperglycemia or hypoglycemia. For
example, inhalation of corticosteroids or pentami-
dine infrequently causes alterations in glucose
homeostasis as compared with administration via
the oral or parenteral route.38, 168
MECHANISMS
Drugs induce hyperglycemia or hypoglycemia
through multiple mechanisms, including alter-
ation of insulin secretion or clearance, changes in
insulin sensitivity (either directly at the receptor
level or by indirect effects on weight or adiposity),
changes in gluconeogenesis or glucose metabolism,
and direct cytotoxic effects on pancreatic
-cells.
(Drug-induced pancreatitis is addressed in Chapter
41.) The mechanisms by which specific agents are
thought to alter glucose or insulin regulation are
listed in Tables 30–3 and 30–4. With some drugs, it
is not clear whether hyperglycemia is a direct effect
of the drug itself or if the drug is simply a con-
tributing factor, as occurs in cases when a drug
unmasks a patient’s preexisting diabetes.25
CLINICAL PRESENTATION AND
DIFFERENTIAL DIAGNOSIS
The signs and symptoms of drug-induced hyper-
glycemia and diabetes mellitus are listed in Table
30–5. The diagnosis of diabetes mellitus can be
made if, on two separate occasions, a patient’s gly-
cosylated hemoglobin (A1C) is  6.5%, fasting
plasma glucose is  126 mg/dl, or the patient is
found to have a plasma glucose of  200 mg/dl two
hours after a 75 gram oral glucose load; or if the
patient has classic symptoms of diabetes and a ran-
dom plasma glucose of  200 mg/dl.194 Depending
on the causative agent, drug-induced hyper-
glycemia can appear within hours or weeks to
months after administration of the offending
agent. Hyperglycemia may be severe in some cases,
manifesting as diabetic ketoacidosis and hyper-
glycemic coma.
Although there is considerable interindividual
variation, the typical signs and symptoms associat-
ed with drug-induced hypoglycemia are presented
in Table 30–6. The glycemic threshold at which
patients experience hypoglycemic symptoms
varies. Symptoms commonly manifest when plas-
ma glucose falls below 60 mg/dl. However, factors
such as prolonged hyperglycemia, caffeine use, or
frequent episodes of hypoglycemia may shift this
threshold in either direction. Patients who experi-
ence repeated episodes of hypoglycemia over a
short period of time may become unaware of these
events. They do not experience typical hypo-
glycemic symptoms and may fail to take corrective
action because of central nervous system impair-
ment.195 Severe hypoglycemia can lead to cognitive
dysfunction, mental status changes, seizures,
coma, or even death.
Before implicating a drug as the cause of glu-
cose or insulin dysregulation, other possible caus-
es must be ruled out (Table 30–7). Hyperglycemia
may occur during periods of physiologic stress,
such as surgery, infection, or trauma. Elevations
in serum glucose associated with Cushing syn-
drome may result either from exogenous adminis-
tration or endogenous overproduction of
glucocorticoids. When assessing possible causes
of hypoglycemia, intentional self-administration
of hypoglycemic drugs, usually insulin or a sul-
fonylurea (i.e., factitious hypoglycemia), and
iatrogenic causes (including medication-dispens-
ing errors) should be considered.196 Hypoglycemia
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CHAPTER 30 • Glucose and Insulin Dysregulation 575

TABLE 30–3 Mechanisms of Drug-Induced Hyperglycemia

Drug Mechanisma
Atypical antipsychotics b b
peripheral insulin sensitivity, insulin secretion (inhibition of
-cell
responsiveness via antagonism of the 5-HT1A receptor), promote weight gain; may
also cause hyperglycemia through drug-induced pancreatitis

-Adrenergic receptor b b
insulin secretion, insulin sensitivity; effects attenuated but not abolished with
blockers cardioselective
-blockers
Calcium-channel antagonists b insulin secretion
Cyclosporine b b
insulin production, inhibits insulin secretion,
-cell volume and function, a
insulin resistance
Diazoxide b insulin secretion, may also a b
glucose production and insulin sensitivity
Didanosine Causes pancreatitis leading to
-cell injury; inhibits insulin release secondary to
hypokalemia. See also nucleoside reverse-transcriptase inhibitors.
Diuretics b insulin release secondary to hypokalemia (hyperglycemia may be preventable
through correction/prevention of hypokalemia); other mechanisms, including a
b a
direct inhibition of insulin release, insulin sensitivity, hepatic gluconeogenesis,
a direct toxic effect on pancreatic
-cells from increased free fatty acids, and
increased sympathetic nervous system activity (contributing to hypokalemia) have
also been proposed
Fish oil Unknown
Glucocorticoids a gluconeogenesis, a b
insulin resistance, pancreatic insulin secretion
Growth hormone Causes insulin resistance
Interferons Formation of islet cell antibodies
l-Asparaginase b insulin synthesis
Megesterol acetate b insulin sensitivity and promotes weight gain. Binds to glucocorticoid receptor
Niacin (nicotinic acid) b a
insulin sensitivity, hepatic gluconeogenesis
Nucleoside reverse-transcriptase a insulin resistance, promote lipodystrophy; can also cause pancreatitis
inhibitors (excluding didanosine)
Oral contraceptives bperipheral insulin sensitivity
Pentamidine Direct cytolytic effects on pancreatic
cells; causes hypoglycemia initially;
effect may be irreversible; can also cause pancreatitis
Phenothiazines b insulin secretion, promote weight gain, may cause insulin aggregation and
inactivation
Phenytoin b insulin secretion, may also b insulin sensitivity
Protease inhibitors a insulin resistance directly or indirectly, promote lipodystrophy, b insulin
secretion
Rifampin Unknown, may a intestinal absorption of glucose
Ritodrine a hepatic gluconeogenesis
Tacrolimus b insulin secretion,b insulin sensitivity; may cause pancreatic islet-cell toxicity;
hyperglycemia and diabetes mellitus reported without use of concomitant
corticosteroids
Terbutaline a gluconeogenesis and glycogenolysis, b peripheral insulin sensitivity
Thalidomide b insulin-stimulated glucose uptake and glycogen synthesis
a = increase(s); b= decrease(s); HT = hydroxytryptamine.
a
Listed mechanisms include both those that are known and those that have been proposed.
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576 SECTION VII • Drug-Induced Endocrine Diseases

TABLE 30–4 Mechanisms of Drug-Induced Hypoglycemia

Drug Mechanisma
Angiotensin-converting enzyme a peripheral insulin sensitivity
inhibitors

-Adrenergic receptor blockers Mask many autonomic hypoglycemic symptoms, can delay recovery from hypo-
a b
glycemia; may peripheral glucose uptake and indirectly gluconeogenesis
Bitter melon (Momordica a
Components of extracts structurally similar to animal insulin, insulin
charantia) (also commonly a a a
secretion, tissue glucose uptake, hepatic glycogen synthesis, peripheral
known as karela) b
glucose oxidation in erythrocytes and adipocytes, hepatic gluconeogenesis
Disopyramide a insulin secretion
Ethanol Inhibits hepatic gluconeogenesis, impairs activation of the hypothalamic–
pituitary–adrenal axis’ hormonal response to hypoglycemia; can potentiate
hypoglycemic effects of other drugs. More problematic when glycogen stores
are low.
Exenatide Stimulates glucose-dependent insulin release; suppresses glucagon secretion
Fenugreek (Trigonella Slows carbohydrate absorption, inhibits glucose transport
foenum graecum)
Fluoroquinolones Unknown, may be due to stimulation of pancreatic insulin secretion, interaction
with antidiabetes agents. or both; most reports with gatifloxacin; resistant hypo-
glycemia (resolves with discontinuation only) may occur.
Ginseng brate of carbohydrate absorption into portal hepatic circulation,
a glucose transport and uptake mediated by nitric oxide, a glycogen storage,
modulation of insulin secretion; most clinical trials done using American ginseng
(Panax quiquefoliu)
Insulin a glucose utilization
Ivy gourd (Coccinia indica) Insulin-mimetic
L-Carnitine a a
insulin sensitivity, glucose uptake and storage
Non-sulfonylurea secretagogues a pancreatic insulin secretion
Pentamidine a insulin release through direct cytotoxic effects to pancreatic
-cells (see Table
30–1)
Pramlintide Suppresses postprandial glucagon secretion, slows gastric emptying
Quinine a pancreatic insulin secretion, usually high doses or rapid intravenous infusion
needed; Plasmodium falciparum infection itself associated with hypoglycemia
Quinidine a pancreatic insulin secretion; see Quinine
Salicylates a a b
pancreatic insulin secretion, peripheral glucose utilization, g oneogenesis;
usually occurs only with antiinflammatory doses
Sitagliptin Inhibits degradation of the incretin hormones glucose-dependent insulinotropic
polypeptide (GIP) and glucagon-like peptide-1 (GLP-1); GLP-1 and GIP increase
b
glucose-dependent insulin synthesis and release; GLP-1 also glucagon secretion
from -cells in the pancreas
Sulfamethoxazole a pancreatic insulin secretion
Sulfonylureas a pancreatic insulin secretion
a= increase(s); b= decrease(s).

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
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CHAPTER 30 • Glucose and Insulin Dysregulation 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
578 SECTION VII • Drug-Induced Endocrine Diseases
TABLE 30–8 Risk Factors for Drug-Induced
Hyperglycemia
Patients with underlying risk factors for type 2 dia-
betes mellitus198
• Age  45 yr
• Family history of diabetes
• High-density lipoprotein cholesterol  35 mg/dl
(0.9 mmol/L), a triglyceride level  250 mg/dl
(2.82 mmol/L), or both
• History of gestational diabetes mellitus or delivery
of a baby weighing  9 lb
• History of vascular disease
• Hypertension ( 140/ 90 mm Hg in adults)
• Overweight or obese (body-mass indexa  25)
• Polycystic ovary syndrome
• Poor dietary habits
• Previously identified impaired fasting glucose or
impaired glucose tolerance
• Race /ethnicity (e.g., African-Americans, Hispanic-
Americans, Native Americans, Asian-Americans,
and Pacific Islanders)
• Sedentary lifestyle
• Higher doses (e.g., thiazide diuretics or corticos-
teroids) or misuse of suspected drug
• Use of more than one drug that can induce hyper-
glycemia
• Drug interactions—use of drugs that may increase
the concentration or hyperglycemic effect (or both)
of offending drug
a
Body-mass index is the weight in kilograms divided by the
square of the height in meters.
tus or those predisposed to this condition (e.g.,
individuals with metabolic syndrome) may be at
particular risk for drug-induced hyperglycemia
because of worsening of preexisting insulin
resistance and
-cell dysfunction. Those with
other underlying disease states also may be at
increased risk. For example, hypertension and
schizophrenia are associated with a higher inci-
dence of diabetes mellitus and therefore may
confound the diagnosis of drug-induced hyper-
glycemia.2,198 Polypharmacy is another impor-
tant risk factor, since the use of multiple
medications associated with glucose or insulin
dysregulation may lead to additive pharmacoki-
netic and/or pharmacodynamic effects. For
example, the combined use of sulfonylureas and
nonsteroidal antiinflammatory drugs, including
ibuprofen and aspirin, may lead to an increased
risk of hypoglycemia due in part to decreased
sulfonylurea metabolism or increased insulin
release.183,199,200
TABLE 30–9 Risk Factors for Drug-Induced
Hypoglycemia
• Advanced age
• Decreased carbohydrate intake (e.g., overnight fast,
missed meals)
• Hepatic dysfunction (decreased gluconeogenesis)
• Higher doses or misuse of offending drug
• History of hypoglycemia
• Hospitalization within past 30 days
• Increased carbohydrate utilization (e.g., exercise) or
reduced stores (e.g., malnutrition)
• Pharmacodynamic or pharmacokinetic interactions
(e.g., increased response or concentration [or both]
of suspected drug)
• Recent or excessive alcohol intake
• Renal dysfunction (decreased insulin clearance)
• Tight glycemic control in patients with diabetes
• Use of more than one drug that can induce hypo-
glycemia
MORBIDITY AND MORTALITY
Drug-induced hyperglycemia may be transient or
may result in permanent changes in glucose regu-
lation. Similar to other causes of diabetes mellitus,
drug-induced hyperglycemia is believed to increase
the risk of microvascular (retinopathy, neuropathy,
nephropathy) and macrovascular (atherosclerotic
cardiovascular disease, cerebrovascular disease, and
peripheral vascular disease) complications, delayed
wound healing and resolution of infections, hyper-
osmolar coma, and death. Cases of diabetic
ketoacidosis and death have been reported in asso-
ciation with many of the agents listed in Table
30–1. Diabetic nephropathy, sensorimotor periph-
eral neuropathy, ketoacidosis, hyperosmolar coma
or precoma, myocardial infarction, and stroke were
reported in a cohort of renal transplant recipients
(followed on average for 9.3 years) in whom post-
transplantation diabetes mellitus developed. The
immunosuppressive regimen prescribed for these
patients consisted of cyclosporine and corticos-
teroids.201 Drug-induced hyperglycemia may not
always lead to the development of macrovascular
complications. This was evident in the
Antihypertensive and Lipid-Lowering Treatment to
Prevent Heart Attack Trial (ALLHAT), a large, ran-
domized, controlled study of older patients with
hypertension, some with and others without meta-
bolic syndrome.26 Although the incidence of newly
diagnosed diabetes was greater in chlorthalidone-
treated patients as compared with those treated
TisdaleC30_569-585 1/20/10 11:30 PM Page 579
with either lisinopril or amlodipine, the risk of
coronary heart disease, stroke, end-stage renal dis-
ease, and all-cause mortality did not differ signifi-
cantly among groups.
Although drug-induced hypoglycemia typical-
ly produces transient, mild-to-moderate symp-
toms, some patients may experience discomfort
and reduced quality of life and discontinue treat-
ment because of fear of recurrent episodes.
Hypoglycemic episodes, if severe, can lead to
changes in mental status, seizures, loss of con-
sciousness, permanent neurologic damage, and
death. Sulfonylurea-induced hypoglycemia has
resulted in permanent neurologic deficits in 5% of
survivors and has a reported mortality rate of 10%.
Furthermore, hypoglycemia associated with
insulin may be responsible for approximately 2%
to 4% of deaths reported in patients with type 1
diabetes.119,159
Drug-induced glucose and insulin dysregula-
tion carries a significant economic burden.
Hospitalizations and urgent care visits related to
drug-induced hyperglycemia or hypoglycemia can
substantially increase health care costs.202,203
Health care expenditures include not only direct
treatment costs, but also costs associated with the
investigations required to rule out non-drug-relat-
ed causes.
PREVENTION
Approaches for preventing drug-induced glycemic
changes are listed in Table 30–10. Although not
always possible, avoiding suspect drugs in high-
risk patients is the best preventive strategy. The
relative risks and benefits of drug therapy must be
considered on a case-by-case basis. Close monitor-
ing for signs and symptoms of abnormalities in
blood glucose concentrations is essential in
patients receiving drugs that may alter glucose or
insulin regulation. Health care providers should
always inquire about their patients’ use of non-
prescription medications and dietary supple-
ments, as some of these have been linked to
changes in glycemic control (see Tables 30–1 and
30–2). Depending on risk assessment, blood glu-
cose concentrations should be obtained before
initiating therapy with drugs known to cause glu-
cose or insulin dysregulation and periodically
thereafter. The frequency of blood glucose moni-
toring will depend on several factors, including
the patient’s risk for, or overt manifestations of,
hypoglycemia or hyperglycemia, provider assess-
ment, and the availability of published guidelines
CHAPTER 30 • Glucose and Insulin Dysregulation 579
TABLE 30–10 Approaches to Help Prevent Drug-
Induced Glucose and Insulin Dysregulation
• Avoid or minimize administration of drugs that may
have pharmacokinetic or pharmacodynamic drug inter-
actions with suspected drug.
• Avoid or minimize administration of more than one
drug that can induce glucose or insulin dysregulation.
• Inquire about symptoms of hyperglycemia and hypo-
glycemia at each office visit.
• Monitor fasting plasma glucose within the first few
weeks after initiating high-risk drugs and regularly
thereafter, especially in the presence of weight
changes or preexisting disorders of glucose metabo-
lism.
• Monitor weight at each office visit.
• Obtain baseline fasting plasma glucose level concen-
tration prior to initiation of suspected drugs, particu-
larly in patients with risk factors.
• Use lowest effective dose for the shortest duration
of administration possible.
or recommendations. Monitoring for changes in
blood glucose concentrations and for the clinical
manifestations of hypoglycemia or hyper-
glycemia also is recommended following discon-
tinuation of medications known to induce
glucose or insulin dysregulation.
MANAGEMENT
Strategies for managing drug-induced glucose and
insulin dysregulation are listed in Table 30–11.
Although withdrawal of the offending agent will
usually reverse the drug-induced hypoglycemia or
hyperglycemia, this strategy may not always be
possible. It may not be feasible to discontinue
therapy with protease inhibitors, atypical antipsy-
chotics, or tacrolimus, for example. In some of
these cases, changing therapy to a drug less likely
to affect blood glucose concentrations can be con-
sidered. For example, Spivak et al. reported a case
of olanzapine-induced diabetes mellitus that
resolved after therapeutic substitution with
ziprasidone.204 Also, short-term improvements in
insulin resistance have been reported when a non-
nucleoside reverse-transcriptase inhibitor or aba-
cavir was substituted for a protease inhibitor in
patients infected with human immunodeficiency
virus type 1.96
The time to improvement of signs and symp-
toms or return to baseline glycemic status after dis-
TisdaleC30_569-585 1/20/10 11:30 PM Page 580
580 SECTION VII • Drug-Induced Endocrine Diseases
TABLE 30–11 Management of Drug-Induced
Glucose and Insulin Dysregulation
Hyperglycemia
• Administer antidiabetes medications if diabetes melli-
tus develops.
• Assess glycemic control (e.g., home blood-glucose
monitoring, hemoglobin A1c) as appropriate.
• Discontinue or reduce dose of suspected drug, if pos-
sible.
• Implement appropriate dietary and lifestyle changes,
including increased physical activity.
• Use suspected drug for shortest duration possible at
the lowest effective dose.
Hypoglycemia
• Administer treatment to reverse hypoglycemia as
appropriate (e.g., glucose, dextrose, glucagon, diazox-
ide).
• Assess glycemic control (e.g., fasting plasma glucose)
as appropriate.
• Discontinue or reduce dose of suspected drug, if pos-
sible.
• Implement dietary changes (e.g., frequent,
small meals)
• Use suspected drug for shortest duration possible at
the lowest effective dose.
continuation of the culprit drug depends on its
pharmacokinetic and pharmacodynamic proper-
ties. In most cases, drug-induced hyperglycemia is
reversible within days, but recovery may take
longer with drugs such as atypical antipsychotics,
protease inhibitors, or corticosteroids that cause
hyperglycemia via weight gain or peripheral
insulin resistance. In some cases, the effects may be
irreversible (e.g. pentamidine-induced destruction
of pancreatic
-cells). For agents that exhibit a
dose-dependent effect on plasma glucose concen-
trations (e.g., corticosteroids), reducing the dose
may ameliorate or reverse the drug-induced dis-
ease.
Approaches specific to the management of
drug-induced glucose abnormalities have not been
studied systematically, and typically, patients with
drug-induced hyperglycemia or hypoglycemia are
treated similarly to patients with diabetes or hypo-
glycemia following accepted clinical practice
guidelines and recommendations for these condi-
tions.159,194,205 Patients with preexisting diabetes
may require an adjustment to their antidiabetes
medications to compensate for drug-induced
changes in glycemic control. Initiation or discon-
tinuation of antidiabetic agents also may be
required.
INFORMATION FOR PATIENTS
Patients receiving medications known to cause
hypoglycemia or hyperglycemia should be educat-
ed regarding the associated signs and symptoms,
the importance of follow-up testing, and the need
for careful management and close medical supervi-
sion. Those who already have a diagnosis of dia-
betes should be informed that they may need to
monitor their blood glucose concentrations more
frequently and may require adjustments to their
antidiabetes regimen. Patients should be educated
about the risks and benefits of using medications
known to induce glucose or insulin dysregulation
and should be counseled to discontinue a suspect-
ed medication only under medical supervision.
They should be further advised to inform each of
their health care providers about all drug use,
including nonprescription medications and dietary
supplements.
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TisdaleC31_586-604 1/12/10 3:32 PM Page 586
CHAPTER 31
Thyroid
Disorders
Judy T. Chen, Betty J. Dong, Frank Pucino, Jr., and Karim Anton Calis
T he thyroid gland affects virtually every organ
system. Thyroid hormones regulate the meta-
bolic rate and affect the growth and function of
systems throughout the body. Medications may
affect thyroid hormone synthesis, release, func-
tion, or regulation.1-3 The clinical significance of
drug-induced thyroid abnormalities ranges from
negligible to potentially life-threatening.
Medications that have the potential to induce clin-
ically significant thyroid disorders are the focus of
this chapter.
Thyroid hormone synthesis is dependent on
dietary iodine, which is transported into thyroid
follicular cells and is incorporated into thyroglobu-
lin via thyroid peroxidases. The process of organi-
fication produces mono-iodotyrosines and
di-iodotyrosines, which are bound to thyroglobu-
lin. Thyroglobulin is secreted by the follicular cells
and serves as a storage form for thyroid hormone
precursors. Thyroid-stimulating hormone (TSH;
thyrotropin) stimulates iodotyrosines to combine
to form thyroxine (T4) and triiodothyronine (T3)
through a process known as “coupling.” Once
released into the circulation, both T4 and T3 are
highly bound to thyroid-binding globulin and
other plasma proteins. Intrinsically, T3 is more
potent than T4, with approximately 80% of T3
derived from the peripheral conversion of T4 by 5’-
monodeiodinase.
CAUSATIVE AGENTS
Medications have the potential to induce
hypothyroidism, hyperthyroidism, and goiter.
Agents implicated in drug-induced thyroid disor-
586
ders are listed in Table 31–1.4-79 Causality has been
assessed for drugs included in this table.80 Each
has been implicated as the cause of drug-induced
thyroid disease in at least one published case
report in which a patient exhibited signs or symp-
toms of disease in addition to any laboratory
abnormalities that may have been present. Agents
that affect thyroid-function tests without causing
substantial clinical effects (i.e., subclinical
hypothyroidism or hyperthyroidism) are included
in Table 31–2.81-95 Drugs known to cause analytical
interference with thyroid laboratory tests are not
included.
Patients infected with human immunodefi-
ciency virus (HIV) and those with advanced
acquired immunodeficiency syndrome are com-
monly affected with thyroid abnormalities.96
Controversy exists regarding the association of
highly active antiretroviral therapy (HAART)
with the development of thyroid abnormalities
in HIV-infected patients. Antiretroviral therapy
has been associated with subclinical hypothy-
roidism, particularly after stavudine therapy.96-98
Subclinical hypothyroidism is defined as an ele-
vated serum TSH level, while free T3 (FT3) and
free T4 (FT4) levels remain within their reference
ranges in a patient with no symptoms or with
mild, nonspecific symptoms. In a cohort study of
350 HIV-infected patients, the use of stavudine
was associated with subclinical hypothyroidism
in one subgroup of patients and with low serum
FT 4 concentrations in another subgroup. 98
Graves’ disease also has been reported after
immune restoration with HAART.96 However,
HIV-infected persons usually are clinically
asymptomatic, and recommendations for routine
TisdaleC31_586-604 1/12/10 3:32 PM Page 587

CHAPTER 31 • Thyroid Disorders 587

TABLE 31–1 Agents Implicated in Drug-Induced Thyroid Disorders

Drug Incidence Level of Evidence
(see page xii for explanation)

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

588 SECTION VII • Drug-Induced Endocrine Diseases

TABLE 31–2 Mechanisms of Drug-Induced Thyroid Disorders

Drug Mechanism
Acetylsalicylic acid (aspirin) Decreases TSH release and/or response to TRH
Activated charcoal Decreases TH bioavailability
Aluminum hydroxide Decreases TH bioavailability
Amiodarone Inhibits iodide binding/transport; inhibits iodination; inhibits
endocytosis, inhibits proteolysis; inhibits intrathyroidal deio-
dination of T4; inhibits TH secretion; inhibits peripheral deio-
dination; inhibits TH receptor binding/uptake /action;
increases TSH release and/or response to TRH; decreases
thyrotropin receptor response; increases autoimmunity,
Amphetamines Increases TSH release and/or response to TRH
Androgens Decreases TBG
Antipyrine Inhibits iodination, inhibits coupling
Bexarotene Inhibits TH receptor binding/uptake /action
Bromine Inhibits iodide binding/transport
Bromocriptine Decreases TSH release and/or response to TRH
Calcium carbonate85 Decreases TH bioavailability
Carbamazepine Increases hepatic metabolism
Chlorpromazine Increases TSH release and/or response to TRH
Cholestyramine Decreases TH bioavailability
Chromium Decreases TH bioavailability
Cimetidine Increases TSH release and/or response to TRH
Clofibrate Increases TBG
Clomiphene Increases TSH release and/or response to TRH
Clomipramine Inhibits intrathyroidal deiodination of T4; inhibits peripheral
deiodination
Colchicine Inhibits endocytosis
Colestipol Decreases TH bioavailability
Cytokines Inhibits iodination; inhibits TH secretion; increases autoimmunity
Diazepam Displacement from protein-binding sites
Dietary/environmental goitrogens Goitrogens
Dopamine/dopaminergics Decreases TSH release and/or response to TRH
Estrogens Increases TBG
Ethionamide Inhibits iodide binding/transport
Ferrous sulfate Decreases TH bioavailability
Fluorouracil Increases TBG
Fluorine Inhibits iodide binding/transport
Free fatty acids (lipid emulsions in TPN) Displacement from protein-binding sites
Furosemide (>80 mg) Displacement from protein-binding sites; inhibits TH
receptor binding/uptake /action
Glucocorticoids Inhibits intrathyroidal deiodination of T4; decreases TBG;
inhibits peripheral deiodination; decreases TSH release
and/or response to TRH
(Continued)
TisdaleC31_586-604 1/12/10 3:32 PM Page 589

CHAPTER 31 • Thyroid Disorders 589

TABLE 31–2 Mechanisms of Drug-Induced Thyroid Disorders (Continued)

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
590 SECTION VII • Drug-Induced Endocrine Diseases
TABLE 31–2 Mechanisms of Drug-Induced Thyroid Disorders
Drug
Rifampin
Salicylamides
Serotonin antagonists
Sertraline
Sevelamer
Sodium polystyrene sulfonate
Spironolactone
Sucralfate
Sulfonamides
Sulfonylureas
Tamoxifen
Thioamides
Thioridazine
Thyroid hormones
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-
versial because of the absence of supporting evi-
dence.96
EPIDEMIOLOGY
In the general population, the prevalence of
hypothyroidism is estimated to be 1.5% to 2%
in women and 0.2% in men. 99 This condition is
more common than hyperthyroidism, and its
incidence increases with advancing age. A 20-
year follow-up study of 2,779 adults in
Whickham, England, reported an annual inci-
dence of overt hypothyroidism of 3.5 and 0.6
cases per 1,000 women and men, respective-
ly. 100 In women 75 to 80 years of age, the annu-
al incidence increased to 14 cases per 1,000.
With increased use of sensitive TSH assays, the
diagnosis of subclinical thyroid disease has
become more prevalent. In the United States
(U.S.), subclinical hypothyroidism affects up to
20% of patients over 60 years of age. 101 In the
Whickham study, the annual incidence of
hyperthyroidism was 0.8 case per 1,000
women. 100 The prevalence of subclinical hyper-
(Continued)
Mechanism
Increases hepatic metabolism
Inhibits iodide binding/transport; inhibits iodination; inhibits
coupling; displacement from protein-binding sites; goitrogens
Decreases TSH release and/or response to TRH
Increases hepatic metabolism of TH
Decreases TH bioavailability
Decreases TH bioavailability
Increases TSH release and/or response to TRH
Decreases TH bioavailability
Inhibits iodide binding/transport; inhibits iodination; inhibits
coupling
Inhibits iodide binding/transport; inhibits iodination; inhibits
coupling; displacement from protein-binding sites
Increases TBG
Inhibits coupling
Decreases TSH release and/or response to TRH
Decreases TSH release and/or response to TRH
thyroidism in the general population is 2% to
16%. 102 In women with underlying multinodu-
lar goiter, the prevalence of subclinical hyper-
thyroidism is 20%. 103
The overall incidence of drug-induced thy-
roid disorders has not been clearly elucidated.
The incidence associated with specific agents,
where known, is listed in Table 31–1.4-79 Thyroid
disorders associated with amiodarone and lithi-
um are the most extensively documented.
Amiodarone contains 37.3% iodine by weight,
and global variations in iodine intake influence
the epidemiology of amiodarone-induced thy-
roid dysfunction.104 In countries such as the U.S.
and the United Kingdom, where iodine intake is
adequate, the incidence of amiodarone-induced
hyperthyroidism and hypothyroidism is 1.7% to
3% and 13% to 22%, respectively.102,105 However,
in areas with inadequate iodine intake, hyper-
thyroidism occurs in 10% to 12% of amio-
darone-treated patients, whereas only 6.4% have
hypothyroidism.102,105,106 The epidemiology of
lithium-induced thyroid dysfunction has also
been well described, with hypothyroidism and
goiter observed in 4% to 34% of patients
exposed to this drug.45,46,49,107,108 Exposure to
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CHAPTER 31 • Thyroid Disorders 591

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

lithium has also been implicated in the develop-

ment of thyroid carcinoma, but the exact inci-
dence remains unknown.109-111 Published data
concerning thyroid abnormalities associated
with lithium therapy consist mostly of case
reports, prevalence studies, retrospective studies,
and small or short-term prospective studies. A
15-year evaluation of thyroid function in 150
patients using lithium showed a relative risk of
clinical hypothyroidism of 8.4 in patients with
antithyroid antibodies.45
MECHANISMS
Drug-induced thyroid disorders occur as a result of
changes in thyroid hormone synthesis, transport,
metabolism, secretion, or function. Thyroid dys-
function may also result from alterations in the
synthesis or release of TSH from the pituitary gland
or dysregulation of thyroid-releasing hormone
(TRH) at the level of the hypothalamus. Specific
mechanisms include changes in autoregulation,
TisdaleC31_586-604 1/12/10 3:32 PM Page 592
592 SECTION VII • Drug-Induced Endocrine Diseases
inflammatory and autoimmune thyroiditis, and de
novo development or increased levels of thyroid
antibodies. Many mechanisms have not been fully
elucidated, and some medications may have multi-
ple thyroid-related effects. Most notable among the
medications with relatively well-described mecha-
nisms are iodides, amiodarone, lithium, interferon-
␣, and tyrosine kinase inhibitors (e.g., sunitinib).
Possible mechanisms by which drugs affect the
thyroid gland are presented in Figure 31–1112 and
Table 31–2.81-95
Drug-Induced Hyperthyroidism
Iodine is a required substrate for thyroid-hormone
synthesis. Iodide enters the thyroid and becomes
oxidized via thyroid peroxidase. The oxidized
iodine atom is then added to selected tyrosyl
residues within thyroglobulin. This process is
referred to as “organification.” The optimal iodine
intake is 150 to 250 mcg/day113; consumption of
1,000 mcg or more per day is considered toxic. In
the presence of excess iodine, the thyroid normal-
ly inhibits organification, which is referred to as
Wolff–Chaikoff block.37,114 This is a method of
autoregulation that prevents excessive hormone
production in response to an increase in the
intrathyroidal iodine content. In individuals with
a normal thyroid, the gland eventually escapes
from this inhibitory effect and iodide organifica-
tion resumes; nonetheless, the suppressive action
of high intrathyroidal iodide content may persist
in patients with underlying autoimmune thyroid
disease. Patients residing in iodine-deficient areas
often have multinodular goiter as a result of the
loss of the Wolff–Chaikoff block and autoregula-
tion. Thus, iodine-induced hyperthyroidism, or
Jod–Basedow phenomenon, occurs when patients,
particularly those with multinodular goiters,
increase their iodine intake or exposure.38,115,116
Medications with high iodine content include
amiodarone, radiographic contrast media (e.g., dia-
trizoate), iodinated glycerol, and certain nonpre-
scription preparations (e.g., kelp tablets). A list of
iodine-containing medications and dietary supple-
ments is presented in Table 31–3.38,117-119
Amiodarone contains 37.3% iodine by
weight.104 Each 200-mg tablet contains 75 mg of
iodine and releases approximately 6 mg of free
iodine, thus exceeding the recommended daily
intake, optimal daily allowance, and the toxic
dosage range. In addition to its iodine content, the
effects of amiodarone on the thyroid may be relat-
ed to its structural homology with thyroid hor-
mones. There are two ways in which amiodarone
has been proposed to induce hyperthyroidism.
Type 1 amiodarone-induced hyperthyroidism is
related to the drug’s high iodine content, and most
often occurs in patients with preexisting or under-
lying risk factors for thyroid disorders (e.g., autoim-
mune thyroid disease, multinodular goiter). Type 2
amiodarone-induced hyperthyroidism results from
a destructive inflammatory type of thyroiditis, caus-
ing excessive release of stored thyroid hormone
into the systemic circulation. This typically occurs
in patients with ostensibly normal thyroid
glands.120-123 The inflammatory process is postulat-
ed to be caused by the large iodine burden, or more
likely, by a direct toxic effect of the drug.124
Interferon-␣ also has been associated with two
types of drug-induced hyperthyroidism, a Graves’-
like immune disorder and an inflammatory
destructive thyroiditis similar to that associated
with amiodarone. Typically, the pattern of thyroid
dysfunction with interferon-␣ is biphasic, present-
ing as initial hyperthyroidism followed by
hypothyroidism. In some cases, thyroid abnormal-
ities may persist even after discontinuation of
interferon-␣.
Long-term lithium therapy has been associated
with silent thyroiditis resulting in hyperthy-
roidism.125,126 Silent thyroiditis, an inflammation
of the thyroid gland, is often a self-limiting disor-
der characterized by transient thyrotoxicosis with
subsequent hypothyroidism. A retrospective
review of 400 patients with thyroid disease identi-
fied a 4.7-fold increase in the likelihood of lithium
exposure in patients with silent thyroiditis as com-
pared to those with Graves’ disease.125 Lithium
may also cause hyperthyroidism by acting as an
immunomodulator.
Drug-Induced Hypothyroidism
Excess iodine ingestion can also cause hypothy-
roidism. Iodide administration inhibits thyroid-
hormone synthesis and release and decreases
iodide trapping.127,128 Iodide-induced hypothy-
roidism ensues when the gland is unable to escape
from the Wolff–Chaikoff block. Iodine excess may
also result in impaired TSH response, inhibition of
proteolytic enzymes responsible for cleaving T3
and T4 from thyroglobulin before release, and inhi-
bition of peripheral 5’-monodeiodinase conversion
of T4 to T3.2 Patients who are most susceptible to
iodide-induced hypothyroidism include those with
undiagnosed Hashimoto’s thyroiditis and those
with a history of autoimmune thyroiditis not
receiving thyroxine replacement. Consumption of
an iodine-rich seaweed (kelp) diet has been associ-
ated with hypothyroidism and goiter in regions of
Japan.40,41 However, a short-term prospective clini-
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CHAPTER 31 • Thyroid Disorders 593

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)
TisdaleC31_586-604 1/12/10 3:32 PM Page 594
594 SECTION VII • Drug-Induced Endocrine Diseases
TABLE 31–3 Iodine Content of Selected Medications and Dietary Supplements38, 117-119
Medication Route
Metrizamide Parenteral (subarachnoid)
Potassium iodide Oral
(losat, Thyro-Block) Oral
Pima
SSKI
Potassium iodide and nicotinamide Oral
Povidone–iodine 0.5–10% (various) Topical
Sodium iodide Parenteral
Thyroid, desiccated Oral
Tyropanoate sodium Oral
Modified from Roti and Uberti.38
cal trial of euthyroid patients supplemented with
kelp for 4 weeks found no signs or symptoms of
thyroid abnormality despite evidence of chemical
hypothyroidism.129 With amiodarone, the
Wolff–Chaikoff effect persists, resulting in a con-
tinuous decline in T4 production. In addition,
amiodarone may inhibit thyroid hormone cellular
uptake, pituitary and peripheral deiodination, and
binding to thyroid receptor sites.3
Lithium impairs thyroid hormone synthesis
by inhibiting iodide release from the thyroid tis-
sue.51,108,130-132 The resulting decrease in hormone
production induces sustained TSH release, which
can lead to development of a simple nontoxic
goiter. The reported annual incidence of lithium-
induced goiter is 2.1%.133 However, regression of
goiter was observed during a 15-year follow-up
study in patients who continued to receive lithi-
um treatment. In this population, the incidence
of palpable goiter decreased from 53% to 29%.45
Lithium also may reduce iodine-concentrating
capacity and inhibit synthesis of iodotyrosine
and iodothyronines. 2 Interferon-␣–induced
hypothyroidism is more common than hyperthy-
roidism and typically follows episodes of hyper-
thyroidism.
The mechanism of sunitinib-induced hypothy-
roidism is postulated to be secondary to impaired
iodine uptake or partial inhibition of thyroid per-
oxidase.70,71 The risk of hypothyroidism is positive-
ly correlated with the duration of sunitinib
treatment. On average, the onset of symptoms
begins after 50 weeks of therapy.69 Progressive
worsening of preexisting hypothyroidism is
observed in most cases, but sudden development
Iodine Content (mcg)
170,000-300,000/mL
99,385/tablet
99,385/tablet
764,500/mL
115,000/tablet
500–10,000/mL
85,000/mL
29/65 mg
430,000/capsule
of severe hypothyroidism also has been
described.70 Clinically significant thyroid dysfunc-
tion has also been reported with sorafenib,
although not as frequently as with sunitinib.134
Imatinib has been associated with increased dosage
requirements in patients who have undergone thy-
roidectomy and receiving thyroid hormone
replacement therapy.135
Antibody Formation
Thyroid autoantibodies, antithyroid peroxidase
antibodies, and antithyroglobulin autoantibodies
have been detected in patients with both autoim-
mune hypothyroidism and hyperthyroidism.101
TSH-receptor antibodies and thyroid-stimulating
immunoglobulins that stimulate the TSH receptor
are present only in patients with hyperthyroidism.
Antithyroid peroxidase antibodies are often pres-
ent in patients experiencing hypothyroidism sec-
ondary to lithium or interferon-␣.25,108 However, a
15-year follow-up study of 150 patients reported a
1.7% annual rate of new-onset autoimmunity asso-
ciated with lithium therapy, a rate similar to that
found in the general population.45,100 Antithyroid
peroxidase antibodies develop in 15% of patients
receiving interferon-␣ and have been reported in
up to 53.3% of patients.20,136-142 The link between
interferon-␤1b and antithyroid antibodies is less
well defined. In a cohort of 156 patients using
interferon-␤1b, de novo antithyroid antibodies
developed in 6 patients but persisted in only 2.31
Interpretation is confounded by the patients’
underlying conditions (e.g., chronic hepatitis C,
multiple sclerosis) which also have been associated
TisdaleC31_586-604 1/12/10 3:32 PM Page 595
with autoimmune complications and make it diffi-
cult to establish causality.31,143,144
Other Mechanisms
The exact mechanism of HAART-induced hypothy-
roidism is not known. HIV infection has been asso-
ciated with autoimmunity, and it is difficult to
determine whether thyroid abnormalities found in
HIV-infected patients are related to progression of
the underlying disease or exposure to HAART.96
Nevertheless, case reports suggest that protease
inhibitors may accelerate glucuronidation of
levothyroxine, thereby necessitating an increased
dosage of thyroid hormone for replacement thera-
py.145
Sertraline may increase serum T3 concentra-
tions in the presence of normal TSH and T4 concen-
trations.146 One report noted that sertraline
increased serum TSH concentrations in patients
with hypothyroidism who were receiving levothy-
roxine therapy, although the mechanism was not
well established.68
The precise mechanism of central hypothy-
roidism induced by bexarotene is not clearly
understood. Central hypothyroidism is a rare cause
of hypothyroidism characterized by insufficient
thyroid-hormone production resulting from
impaired hypothalamic or pituitary function.
Patients with central hypothyroidism often present
with low FT4 serum concentrations, while TSH lev-
els may be low, normal, or mildly elevated. A study
that evaluated healthy individuals who received a
single dose of bexarotene 400 mg/m2 found that
there was rapid suppression of TSH without signif-
icant effects on serum prolactin, cortisol, glucose,
insulin, triglycerides, or free fatty acids.147
Bexarotene has been postulated to increase clear-
ance of TSH independently of the effects of thyroid
hormones.147,148 Thyroid hormone replacement
has been required in approximately 37% of
patients receiving bexarotene, and higher replace-
ment doses are required in those receiving higher
bexarotene doses.16 Bexarotene-induced central
hypothyroidism is often associated with a sup-
pressed TSH and subsequent reduction in FT4
serum concentrations. Clinical symptoms of
hypothyroidism reverse within weeks of stopping
therapy.15,149
Ethionamide also has been reported to induce
hypothyroidism. Ethionamide can inhibit thyroid-
hormone synthesis, most likely because of its struc-
tural similarity to methimazole. This drug-induced
hypothyroidism appears to be reversible with dis-
continuation of therapy.18
CHAPTER 31 • Thyroid Disorders 595
CLINICAL PRESENTATION AND
DIFFERENTIAL DIAGNOSIS
The clinical features associated with drug-induced
hyperthyroidism and drug-induced hypothy-
roidism are often related to accelerated or impaired
metabolism, respectively, or to an underlying
autoimmune process. Specific signs and symptoms
are presented in Table 31–4.101 The severity, dura-
tion, and extent of illness may vary greatly from
patient to patient.
Unfortunately, the extent of exposure (dose
and duration) and dose-response are not well
established for many of the agents implicated in
drug-induced thyroid disease. Possible risk factors
that should be evaluated include the patient’s age,
sex, thyroid status, iodine status, overall nutrition-
al status, and the presence of coexisting medical
conditions (e.g., previous thyroid disease, diabetes,
rheumatoid arthritis, pernicious anemia). In coun-
tries where the population receives adequate
iodine supplementation, such as the U.S., it is gen-
erally reasonable to assume that iodine deficiency
was not a factor.
In patients presenting with symptoms of
hyperthyroidism, primary causes of the disease
should be excluded. These include Graves’ disease,
toxic multinodular goiter, subacute thyroiditis,
toxic adenoma, and thyrotoxicosis factitia.
Common causes that should be considered in the
differential diagnosis of hyperthyroidism are
included in Table 31–5. Some patients may present
with new-onset or worsening heart failure, atrial
fibrillation, or angina. In elderly patients with
unexplained weight loss, an evaluation for possible
malignancies is indicated.
Individuals with symptoms of hypothyroidism
should be evaluated for primary causes such as
Hashimoto’s thyroiditis, dyshormonogenesis,
iodine deficiency, infiltrative diseases (e.g., amyloi-
dosis, sarcoidosis), and transient subacute thyroidi-
tis. Central hypothyroidism associated with
secondary (i.e., hypopituitarism) and tertiary (i.e.,
hypothalamic disease) causes also should be
excluded. Early symptoms such as constipation,
fatigue, weight gain, and dry skin may be incor-
rectly attributed to aging. Common causes that
should be considered in the differential diagnosis
of hypothyroidism are included in Table 31–5.
Laboratory evaluation of thyroid function is
also required for patients with suspected drug-
induced thyroid disease. A serum TSH concentra-
tion is the single most important diagnostic test.101
A suppressed or undetectable serum TSH concen-
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596 SECTION VII • Drug-Induced Endocrine Diseases

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
free T3 (FT3) concentrations may be helpful.
Medications that modify TSH secretion, alter thy-
roid-binding globulin (TBG), displace thyroid hor-
mone from protein-binding sites, increase hepatic
metabolism, decrease T4-to-T3 conversion, or
impair T4 absorption (Table 31-2) may confound
interpretation of laboratory findings. In addition
to medications, certain disease states can alter
serum TBG concentrations. For example, patients
with nephrotic syndrome may present with low
total serum T4 concentrations due to lowered
serum TBG concentrations, but serum FT4 and TSH
concentrations often remain normal.150
Subclinical disease should always be consid-
ered in the differential diagnosis of drug-induced
thyroid dysfunction. Management of subclinical
hypothyroidism is controversial because the risks
and benefits of treatment are not well under-
stood. Nonetheless, progression to overt hypothy-
roidism can lead to significant health risks, such
as hyperlipidemia and associated atherosclerotic
complications.151 Moreover, patients with sub-
clinical hyperthyroidism, especially the elderly,
may have an increased risk for cardiovascular
complications (e.g., atrial fibrillation) and osteo-
porosis.101
It can be difficult to differentiate between the
two types of amiodarone-induced hyperthy-
roidism. In both, serum TSH concentrations are
suppressed and serum FT4 concentrations are ele-
vated. In type 1 amiodarone-induced thyrotoxico-
sis, increased thyroidal blood flow and
hypervascularity are present on color-flow
Doppler sonography. In contrast, type 2 amio-
darone-induced thyrotoxicosis is characterized by
decreased or normal thyroidal blood flow on
sonography.152 Elevations in serum interleukin-6
concentrations also have been reported in type 2
disease, but changes are negligible in type 1.153
The time to onset of amiodarone-induced
hypothyroidism is quite variable and may range
from 1 to 24 months after the initiation of thera-
py.154,155
Lithium-induced thyroid changes may occur
within a few weeks of therapy initiation but are
most often observed after prolonged treat-
ment.45,51,108
RISK FACTORS
Risk factors for drug-induced thyroid dysfunction
are listed in Table 31–6.156 A personal or family his-
tory of thyroid disease or presence of thyroid anti-
bodies is associated with an increased risk of
drug-induced thyroid illness. Without normal thy-
CHAPTER 31 • Thyroid Disorders 597
TABLE 31–6 Risk Factors for Drug-Induced
Thyroid Disorders156
• Current thyroid abnormality
• Hashimoto’s thyroiditis
• Thyroid autoimmunity
• Partial thyroidectomy
• Previous thyroid abnormality
• Previous thyroid disease
• History of radioactive iodine administration
• History of postpartum thyroid disease
• Family history of thyroid disease
• Female sex
roid adaptive mechanisms, excess iodine intake
may result in hyperthyroidism, hypothyroidism,
or goiter. The clinical presentation of drug-induced
thyroid dysfunction is generally more severe in
patients who already have an underlying thyroid
disease. Autoimmune thyroiditis, such as
Hashimoto’s disease, has been implicated as a risk
factor.157 Women are considered to be at greater
risk for thyroid disease and drug-induced thyroid
dysfunction. Partial thyroidectomy, preexisting or
new thyroid autoimmunity, a history of radioac-
tive iodine administration, postpartum thyroid dis-
ease, and previous thyroid damage also have been
identified as risk factors for the development of
drug-induced thyroid disease.
Nutritional deficiencies, malnutrition, and
dietary goitrogens are other potential risk factors
for the development of thyroid abnormalities.
Foods that may be goitrogenic include
choumoellier, cassava, sorghum, corn, millet,
cabbage, kale, brussels sprouts, cauliflower,
kohlrabi, turnip, rutabaga, mustard, and horse-
radish. Iodine deficiency is the leading cause of
goiter. National iodine supplementation pro-
grams are designed to protect populations
against chronic iodine deficiency. Most industri-
alized countries provide dietary iodine supple-
ments, and the World Health Organization has
been active in promoting universal supplementa-
tion programs. Because of the possible effects of
selenoenzymes on control of thyroid hormone
metabolism, a diet low in selenium may be asso-
ciated with increased serum T3, resulting in sub-
clinical hyperthyroidism. 158 In addition to
thyroid disease associated with nutritional defi-
ciencies, endemic goiter may result from con-
sumption of foods rich in antithyroid substances
such as cyanogenic glucosides, thioglucosides,
thiocyanate, or goitrin. Goiter has occurred as a
result of excessive direct or indirect (typically
TisdaleC31_586-604 1/12/10 3:32 PM Page 598
598 SECTION VII • Drug-Induced Endocrine Diseases
transferred through cow’s milk) exposure to these
compounds.
MORBIDITY AND MORTALITY
Drug-induced thyroid disease may result in clinical
manifestations of hypothyroidism, hyperthy-
roidism, or goiter. Left untreated, overt hyperthy-
roidism may result in serious medical
complications, including structural thyroid gland
changes, osteoporosis, exaggerated hyperthy-
roidism symptoms, and cardiac complications such
as dysrhythmias and heart failure, which may be
associated with substantial morbidity and mortali-
ty. Severe, uncontrolled hypothyroidism can result
in a decompensated thyroid state leading to
hypothermia, biochemical abnormalities, respira-
tory failure, cardiovascular collapse, and myxede-
ma coma, which can be fatal. A goiter, when
substantially enlarged, may be cosmetically unac-
ceptable and lead to respiratory distress and swal-
lowing difficulties that, in some cases, can be
relieved only by surgical intervention.
PREVENTION
Baseline laboratory tests and physical examination,
including evaluation of the thyroid gland, should
be performed in all patients receiving a drug with
the potential to cause thyroid dysfunction (Table
31–1).4-79 Except in patients who have an abnormal
hypothalamic–pituitary–adrenal axis (e.g., those
with Cushing’s syndrome or Addison’s disease), a
baseline serum TSH concentration (and possibly a
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
with any drug known to cause thyroid disease.
During therapy, laboratory evaluation should be
performed periodically, with the frequency based
on the patient’s risk factors for thyroid disease and
the likely seriousness of drug-induced thyroid dis-
ease should it occur. Patients receiving bexarotene
may benefit from monitoring of FT4 for manage-
ment of central hypothyroidism, since serum TSH
alone cannot reliably be used as an indicator of
thyroid status.15 In patients receiving amiodarone,
interferon-alfa, sunitinib, or lithium, laboratory
tests (e.g., TSH, FT4, thyroid antibodies) should be
monitored at baseline and at 3- to 6-month inter-
vals, and if symptoms occur or dosages are modi-
fied.92,159,160 Although serum interleukin-6
concentrations may be elevated with destructive
thyroid disease (e.g., type 2 amiodarone-induced
hyperthyroidism), this test is not readily available
or consistently helpful. A conservative approach to
minimize the risk of potential complications is to
use the lowest effective dose of drugs that may
cause thyroid disorders for the shortest time possi-
ble. Because the onset of drug-induced thyroid dis-
ease is highly variable, routine laboratory
monitoring, patient education, and vigilance for
symptom onset are important components of dis-
ease surveillance. Specific strategies for prevention
are summarized in Table 31–7.
MANAGEMENT
In a patient with new-onset thyroid dysfunction,
drugs with the potential to cause thyroid irregular-
ities should be discontinued, if feasible. Resolution
of the thyroid abnormality may require several
months and, in some cases, the condition may be
irreversible. Rechallenge with the offending agent
should not be attempted unless medically neces-
sary. If the drug cannot be discontinued or if the
condition does not resolve after discontinuation,
appropriate antithyroid therapy or thyroid hor-
mone replacement may be required (Table 31–8).
Drug-induced hypothyroidism is best treated
with levothyroxine. The initial dose should be
1.6 –1.7 mcg/kg/day, and the dose should be titrated
upward, as necessary, every 4 to 6 weeks until the
patient is clinically and chemically euthyroid. Lower
initial doses (e.g., 25 mcg) and a more gradual dosage
escalation (12.5–25 mcg every 6–8 weeks) may be
necessary in the elderly and in those with clinically
significant cardiovascular disease (e.g., angina, palpi-
TABLE 31–7 Approaches to Help Prevent Drug-
Induced Thyroid Disorders
• Avoid drugs known to cause thyroid disorders.
• Avoid goitrogens.
• Consume a sufficient amount of iodine to prevent a
iodine deficiency.
• Consume an adequate amount of selenium.
• Correct underlying thyroid abnormalities.
• Educate patients and families about the possible
symptoms associated with drug-induced thyroid dis-
ease and the need to promptly inform their health
care providers about symptoms.
• Screen for thyroid abnormalities before initiating
therapy and periodically thereafter.
• Use alternative agents that are not associated with
thyroid disease in high-risk patients, when possible.
TisdaleC31_586-604 1/12/10 3:32 PM Page 599
TABLE 31–8 Management of Drug-Induced
Thyroid Disorders
Hypothyroidism
• Thyroid replacement (e.g., levothyroxine)
Hyperthyroidism
• Adrenergic (␤-receptor blockers
• Calcium-channel blockers
• Glucocorticoids
• Iodides
• Iodinated contrast media
• Thioamide (e.g., methimazole, propylthiouracil)
• Thyroidectomy
tations). Serum TSH and FT4 concentrations should
be determined after levothyroxine has reached a
steady state (approximately 4 to 6 weeks after the ini-
tiation of therapy). For patients with amiodarone-
induced hypothyroidism, levothyroxine require-
ments may be higher because of inhibition of pitu-
itary and peripheral conversion of T4 to T3.123
Managing amiodarone-induced hyperthy-
roidism is more complex because it is often diffi-
cult to distinguish between the two types of
thyrotoxicoses. Antithyroid medications, such as
methimazole or propylthiouracil, combined with
potassium perchlorate often are used for the treat-
ment of type 1 amiodarone-induced hyperthy-
roidism as its underlying pathogenesis is related to
the drug’s high iodine content, which results in
excessive thyroid-hormone synthesis. In contrast,
type 2 amiodarone-induced hyperthyroidism is
often unresponsive to thioamide, and treatment
with corticosteroids is most effective because of the
underlying inflammatory process.122 The dose of
prednisone (or equivalent doses of other corticos-
teroids) can range from 30 mg daily for 2 weeks fol-
lowed by gradual tapering and discontinuation
after 3 months of therapy122 to doses of 0.5
mg/kg/day until euthyroidism is restored.161
Baseline FT4 and thyroid volume (measured by
ultrasonography) appear to be independently use-
ful in identifying patients at risk for delayed treat-
ment response with corticosteroids.161 Because of
the potential for additive cardiac effects with amio-
darone, adrenergic ␤-receptor blockers or calcium-
channel blockers are typically not recommended
for control of hyperthyroid symptoms.
Results from a study of 13 patients with type 2
amiodarone-induced hyperthyroidism suggest that
there is no difference in the duration of thyrotoxi-
cosis between patients who continued or tem-
porarily discontinued amiodarone therapy. This
suggests that amiodarone may be continued in
cases in which withdrawal could result in detri-
CHAPTER 31 • Thyroid Disorders 599
mental cardiac consequences and the use of alter-
native antiarrhythmic agents is contraindicated.162
Discontinuation of amiodarone does not result in
complete resolution of thyroid abnormalities, and
cases of amiodarone-induced hyperthyroidism
have been reported several months after the cessa-
tion of therapy.163,164 In patients who require con-
tinued amiodarone therapy, thyroidectomy can be
considered for cosmetic or medical reasons, partic-
ularly dysphagia, respiratory difficulty, or voice
alterations.165 Radioactive iodine is not recom-
mended because the gland is already iodine-
loaded, thereby interfering with uptake and
retention of radioactive iodine.
␤-Blockers can be administered if needed for
symptomatic relief in patients with interferon-
␣–induced hyperthyroidism, although the disorder
typically resolves spontaneously within weeks to
several months after drug discontinuation. In
patients with interferon-␣–induced hypothy-
roidism who are asymptomatic, T4 therapy is often
not necessary. If levothyroxine treatment is initiat-
ed, it should be discontinued 6 months after the
cessation of interferon-␣ therapy and thyroid sta-
tus reevaluated to determine the need for contin-
ued replacement.
INFORMATION FOR PATIENTS
Individuals with a history of thyroid disease appear
to be at increased risk for drug-induced thyroid
complications. Patients who receive medications
known to be associated with thyroid abnormalities
should be taught to recognize and instructed to
report symptoms of hypothyroidism, hyperthy-
roidism, or gland enlargement. Specifically, they
should be advised to consult their primary health
care providers if they experience fatigue, constipa-
tion, palpitations, nervousness, heat or cold intol-
erance, or any other new or unusual symptoms
(Table 31–4).101 Certain weight-loss preparations
may contain thyroid hormones or excessive
amounts of iodine.166 Given that these prepara-
tions and some herbal and other alternative thera-
pies have the potential to induce thyroid
dysfunction or interfere with thyroid-related med-
ications, their use without medical supervision
should be discouraged.
ACKNOWLEDGMENT
The authors are grateful to Dr. Nayahmka McGriff-
Lee for her significant contributions to this chapter
in the first edition of the book.
TisdaleC31_586-604 1/12/10 3:32 PM Page 600
600 SECTION VII • Drug-Induced Endocrine Diseases
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604 SECTION VII • Drug-Induced Endocrine Diseases
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2005;165:831-834.
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C H A P T E R 32
Hypothalamic, Pituitary,
Pituitary
and Adrenal Diseases
D rug-induced disorders of the hypothalamus,
pituitary, and adrenal are difficult to classify
because of the complex interrelationship of the
various endocrine glands. Nonetheless, the most
commonly reported are those caused by adrenocor-
tical dysfunction and those caused by excess pro-
lactin secretion by the anterior pituitary. Adrenal
glands are responsible for the secretion of cate-
cholamines and three hormones responsible for
the regulation of some of the most basic and vital
processes in the body. Aldosterone, the main end
product of mineralocorticoid production, is secret-
ed by the zona glomerulosa and is responsible for
electrolyte and volume homeostasis. The zona fas-
ciculata is responsible for glucocorticoid produc-
tion, mainly cortisol, and controls fat, protein, and
glucose metabolism. The zona reticularis is respon-
sible for production of the sex steroids (estrogen
and testosterone) that control the development of
primary and secondary sex characteristics.
The pituitary gland, also known as the
hypophysis, is essential for maintaining the body’s
homeostasis. It is under the control of the hypo-
thalamus through direct nerve stimulation (poste-
rior lobe) and by the action of inhibitory and
releasing hormones (anterior lobe) such as thy-
rotropin-releasing hormone and corticotropin-
releasing hormone (CRH). The anterior lobe of the
pituitary gland is responsible for the synthesis of
growth hormone, prolactin, luteinizing hormone,
follicle-stimulating hormone, thyroid-stimulating
hormone, and adrenocorticotropin (ACTH). In
addition, vasopressin, also known as antidiuretic
hormone, and oxytocin, are synthesized in neu-
rons of the hypothalamus, stored in the posterior
lobe of the pituitary, and released upon direct
nerve stimulation. The complex interplay between
John G. Gums and Shawn D. Anderson
the hypothalamus, pituitary, and adrenal glands is
commonly referred to as the hypothalamic–pitu-
itary–adrenal (HPA) axis (Figure 32–1).
GLUCOCORTICOID EXCESS
(CUSHING’S SYNDROME)
In 1932, Cushing first described a syndrome of pitu-
itary basophilism that attracted national attention.
It was not until this time that patients with unex-
plained central obesity, striae, osteoporosis, weak-
ness, hypertension, and diabetes mellitus had a
definitive diagnosis. Daughaday discovered elevated
steroids in the urine of patients with Cushing’s dis-
ease, and the syndrome was at last correctly
explained as an excess of cortisol in the plasma.
There are two general types of Cushing’s syn-
drome: exogenous and endogenous. Exogenous
Cushing’s syndrome is most commonly caused by
the administration of supraphysiologic doses of
glucocorticoids, while the endogenous form of the
syndrome is due to oversecretion of glucocorti-
coids by the adrenal glands. Endogenous
Cushing’s syndrome is often subdivided into
ACTH-dependent and ACTH-independent forms.
ACTH-dependent Cushing’s syndrome is most
commonly caused by a pituitary tumor and is
referred to as “Cushing’s disease.” The majority of
drug-induced causes of Cushing’s syndrome are
exogenous.
CAUSATIVE AGENTS
Specific drugs that have been reported to induce
Cushing’s syndrome are listed in Table 32–1.1-37
605
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606 SECTION VII • Drug-Induced Endocrine Diseases

syndrome occurs as a result of supraphysiologic

concentrations of circulating glucocorticoids from
an exogenous source. In vivo, glucocorticoids
resemble the naturally occurring glucocorticoid,
Hypothalamus cortisol, and bind with high affinity to specific
(Median Eminence)
cytoplasmic glucocorticoid receptors (GRs) found
(⫺) in virtually all tissues of the body. This binding
CRH Release induces a response by modifying transcription and
ultimately by causing changes in protein synthesis
GH that can produce adverse physiologic effects similar
FSH to those seen in classic Cushing’s disease. Cushing’s
PRL syndrome has been demonstrated to occur with
TSH
LH
oral, inhaled, intranasal, topical, ocular, intraarticu-
Anterior Pituitary lar, intradermal, intramuscular, intralesional, and
paraspinal administration of glucocorticoids.1-24,40
CORTISOL

(⫺) It has been suggested that increased sensitivity to

ACTH Release
glucocorticoids is the underlying mechanism
responsible for drug-induced Cushing’s syndrome,
especially when the route of administration is
expected to result in minimal systemic exposure.41
Drugs that inhibit the metabolism of glucocorti-
coids may precipitate Cushing’s syndrome when
used in combination with glucocorticoids with
high first-pass metabolism such as fluticasone,
(⫺) budesonide, and mometasone.5-11 Medroxy-
Adrenal Cortex
progesterone acetate (MPA) and megestrol acetate
possess glucocorticoid-like activity and appear to
Cortisol Release induce Cushing’s syndrome through their ability to
bind to the GRs.26-31,38,39 ACTH or drugs that stimu-
late ACTH release from the pituitary (e.g. ␥ -hydrox-
Periphery
ybutyric acid) may also contribute.25,38

FIGURE 32–1 CRH = Corticotropin-releasing hormone;

ACTH = Adrenocorticotropin; GH = Growth hormone; FSH
= Follicle-stimulating hormone; PRL = Prolactin; TSH =
Thyroid-stimulating hormone; LH = Luteinizing hormone.
EPIDEMIOLOGY
The incidence of drug-induced Cushing’s syndrome
in the general population is unknown; however,
the syndrome has been recognized with increased
frequency as the use of glucocorticoids for a wide
range of nonendocrine diseases has expanded.
Cushing’s syndrome results from excessive concen-
tration of circulating glucocorticoids and any gluco-
corticoid is a potential causative agent regardless of
the route of administration.1-24,38-40
MECHANISMS
Mechanisms for drug-induced Cushing’s syndrome
are listed in Table 32–2. Drug-induced Cushing’s
CLINICAL PRESENTATION AND
DIFFERENTIAL DIAGNOSIS
Signs and symptoms of drug-induced Cushing’s syn-
drome are a result of high concentrations of circulat-
ing glucocorticoids and often are indistinguishable
from those of other forms of Cushing’s syndrome or
Cushing’s disease. They include progressive adiposi-
ty, dermopathies, myopathy, hypertension, insulin
resistance, hyperlipidemia, psychiatric changes,
osteoporosis, gonadal and thyroid dysfunction, and
growth deceleration in children.38,40,42 Signs and
symptoms associated with Cushing’s syndrome are
presented in Table 32–3.38,40,42
The biochemical diagnosis of Cushing’s syn-
drome relies on the demonstration of hypercorti-
solism. Hypercortisolism can be established using
the 24-hour urinary free cortisol test, the midnight
serum cortisol test, the late-night salivary cortisol
test, or the low-dose dexamethasone-suppression
test.32-37 No test is perfect, and all have differing
sensitivities and specificities, especially when mul-
tiple cutoffs are used to determine elevated con-
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CHAPTER 32 • Hypothalamic, Pituitary and Adrenal Diseases 607

TABLE 32–1 Agents Implicated in Drug-Induced Cushing’s Syndrome

Drug Incidencea Level of Evidence
(see page xii for explanation)

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.

centrations.36 It may be necessary to evaluate mul- es secondary to the stress of hospitalization. An

tiple samples and to compare the results of multi-
ple tests in order to confirm the diagnosis of
hypercortisolism in some cases. Elevated urinary
free cortisol values four times the upper limit of
normal, late-night salivary cortisol >250 ng/dL,
midnight serum cortisol >7.5 mcg/dL, and morn-
ing serum cortisol after low-dose dexamethasone-
suppression test >1.8 mcg/dL strongly suggest
Cushing’s syndrome.32-37 Midnight serum cortisol
is often considered to be a second-line test, since
admission to the hospital for 48 hours prior to test-
ing is advised to help avoid false positive respons-
additional confirmatory test is the determination
of the plasma ACTH concentration, where values
<5 pg/mL confirm drug-induced Cushing’s syn-
drome.32-37
Because of its similar clinical picture, drug-
induced Cushing’s syndrome may be easily mistak-
en for another, more common cause of
hypercortisolism, Cushing’s disease. Drugs, stress,
renal insufficiency, alcohol ingestion, obesity, preg-
nancy, sleep disorders and psychiatric illness can
interfere with the diagnostic tests, making it chal-
lenging to differentiate between the causes (Table
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608 SECTION VII • Drug-Induced Endocrine Diseases

TABLE 32–2 Mechanisms of Drug-Induced Cushing’s Syndrome

Drug Mechanism
Glucocorticoids41 Glucocorticoids resemble the naturally occurring
glucocorticoid, cortisol, and bind with high affinity to
specific cytoplasmic glucocorticoid receptors. Binding
modifies transcription and causes changes in protein
synthesis that can produce adverse physiologic effects.
Progestins29 Possess glucocorticoid-like activity and have the ability to
bind to the glucocorticoid receptors
Adrenocorticotropin (corticotropin, ACTH)38 Stimulates cortisol release from the zona fasciculata of the
adrenal cortex
␥ -Hydroxybutyric acid25 Stimulates ACTH release from the pituitary

32–4).32,36 A careful history in combination with
dynamic testing of the integrity of the HPA axis are
essential to making a correct diagnosis. Other signif-
icant laboratory findings in these patients include
high concentrations of offending medication in the
urine, elevation of total cholesterol, high concentra-
tions of very-low-density lipoprotein and triglyc-
erides, hypokalemia, and low bone density as
measured by dual-X-ray absorptiometry.33
RISK FACTORS
Risk factors associated with Cushing’s syndrome
are presented in Table 32–5.40 Prolonged use of
high doses of drugs that can cause Cushing’s syn-
drome is a known risk factor. Although inhaled,
TABLE 32–3 Signs and Symptoms Associated
with Drug-Induced Cushing’s Syndrome
• Moon-shaped face
• Buffalo hump
• Central obesity
• Hirsutism
• Kyphosis
• Easy bruising
• Hypertension
• Proximal muscle weakness
• Psychiatric mood changes
• Glucose intolerance
• Diabetes
• Oligomenorrhea or amenorrhea
• Osteopenia or osteoporosis
• Thin skin
• Acne
• Striae
nasal, and topical glucocorticoids are intended to
circumvent systemic absorption, absorption may
occur when they are administered in high doses
and may be sufficient to cause Cushing’s syn-
drome.1-18,40 High doses of drugs that possess gluco-
corticoid-like activity may enhance GR binding, as
seen with oral progestins (e.g., 200–400 mg of MPA
or 160 mg of megestrol acetate).26–31 An additional
risk factor for absorption of topical glucocorticoids
is their use on diseased or atrophic skin.17,40
Administration of high-potency glucocorti-
coids or drugs with a high affinity for GRs is anoth-
er known risk factor for drug-induced Cushing’s
syndrome. Of the available inhaled glucocorticoids
(IGCs), fluticasone is considered the most
potent.2,5 This agent’s unique pharmacologic and
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
high doses and for prolonged periods, has been
reported to induce Cushing’s syndrome.43
TABLE 32–4 Conditions to Consider in the
Differential Diagnosis of Drug-Induced Cushing’s
Syndrome
• Cushing’s disease
• Renal insufficiency
• Alcohol abuse
• Obesity
• Pregnancy
• Sleep disorders
• Psychiatric illness
• Stress
• Diabetes mellitus (Type 2)
• Metabolic syndrome
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CHAPTER 32 • Hypothalamic, Pituitary and Adrenal Diseases
TABLE 32–5 Risk Factors for Drug-Induced
Cushing’s Syndrome
• Administration of high doses of offending agent
• Prolonged duration of therapy
• Use of high-potency glucocorticoids
• Administration of drugs that inhibit the metabolism
of endogenous glucocorticoids
• Use of topical glucocorticoids in patients with broken
or atrophic skin and in infants
Inhibition of the metabolism of drugs known to
cause Cushing’s syndrome is also a risk factor.
Potent inhibitors of the Cytochrome P450
(CYP450) isoenzyme family can lead to elevated
plasma concentrations of glucocorticoids metabo-
lized by these isoenzymes resulting in increased
binding to the GRs. Cases of drug-induced
Cushing’s syndrome have been reported when nor-
mal doses of inhaled fluticasone are co-adminis-
tered with ritonavir and itraconazole, known
inhibitors of fluticasone’s metabolism.5,6,8-11 Also,
some individuals may be poor metabolizers of
IGCs, and cushingoid features may develop even
when the patient is treated with normal doses.41
MORBIDITY AND MORTALITY
The incidence of death due to drug-induced
Cushing’s syndrome is unknown. Cardiovascular
complications have traditionally been regarded as
the major contributor to morbidity and mortality
in these patients.32,42 However, osteoporosis, frac-
tures, thromboembolic events, and psychiatric ill-
nesses are also common if hypercortisolism is not
corrected.32,42
PREVENTION
Approaches to help prevent drug-induced
Cushing’s syndrome are presented in Table 32–6.
Drug-induced Cushing’s syndrome may be pre-
vented by minimizing the risk factors presented in
Table 32–5.40 When administering agents with the
potential to induce Cushing’s syndrome, practi-
tioners should make every effort to use the lowest
effective dose for the shortest period of time. In
addition, concurrent administration of agents that
may cause pharmacokinetic drug interactions such
as inhibition of metabolism should be avoided.
Inhaled and intranasal glucocorticoid adminis-
tration can minimize systemic absorption and may
609
TABLE 32–6 Approaches to Help Prevent Drug-
Induced Cushing’s Syndrome
• Use lowest effective dose of offending agent.
• Avoid prolonged use.
• Avoid drug combinations that will interact to increase
plasma concentrations of the offending agent.
• Use alternative route of administration to minimize
systemic absorption.
help prevent Cushing’s syndrome. Topical glucocor-
ticoids can produce desired pharmacologic effects
without associated systemic adverse effects,
although caution is advised in patients with broken
skin or when occlusive dressings are required. The
administration of glucocorticoids in the form of
enemas may obviate the need for systemic glucocor-
ticoids in patients with inflammatory bowel disease.
Practitioners should be aware of these and other
alternatives to systemic glucocorticoid therapy.
MANAGEMENT
Once a drug has been identified as the cause of
Cushing’s syndrome, the first step in management is
to discontinue that drug, if possible, and to initiate
therapy with an appropriate alternative. If the patient
has been receiving a supraphysiologic dose of gluco-
corticoids, that dose must be tapered to a physiologic
dose over months before discontinuation to avoid
precipitating adrenal insufficiency. A physiologic
dose is equal to 5 to 7.5 mg daily of prednisone or its
equivalent. After a physiologic dose has been
achieved, the patient should either be switched to
morning, alternate-day therapy, or continue to have
the dose slowly tapered for up to 1 year until the HPA
axis has returned to normal function. Morning serum
cortisol may be used to test for HPA axis integrity.
Glucocorticoid replacement may be discontinued
when cortisol plasma concentrations are >20 mcg/dL,
as this suggests normal functioning. In cases in which
alternative therapy is not an option and it is essential
to continue steroid treatment, strategies to reduce
inhibition of the HPA axis should be considered,
including the use of alternate dosing schedules, the
use of a less potent glucocorticoid, and non-systemic
routes of administration (Table 32–7).30,32
INFORMATION FOR PATIENTS
Patients receiving long-term glucocorticoid thera-
py by any route of administration should be taught
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610 SECTION VII • Drug-Induced Endocrine Diseases
TABLE 32–7 Management of Drug-Induced
Cushing’s Syndrome
• Discontinue offending agent
• Initiate appropriate therapeutic alternative
• Consider alternate dosing schedule (e.g., every other
day)
• Switch to a less potent glucocorticoid
• Consider a different route of administration to mini-
mize systemic absorption
to recognize the signs and symptoms of Cushing’s
syndrome and advised to contact their pharmacist
or physician if any of these develop. Patients
should also be instructed not to abruptly discon-
tinue glucocorticoid therapy in order to avoid the
adrenal crisis that may occur in patients with sup-
pression of the HPA axis.
SECONDARY ADRENAL
INSUFFICIENCY
Hypoproduction of cortisol is the hallmark of
adrenal insufficiency, which can be separated
into two categories: primary and secondary.
Primary adrenal insufficiency, more commonly
known as Addison’s disease, is caused by the
inability of the adrenal cortex to produce corti-
sol, aldosterone, and androgens while the preced-
ing components of the HPA axis remain
functional. Because of the reduced negative feed-
back on the hypothalamus and pituitary, CRH
and ACTH plasma concentrations are elevated.
Secondary adrenal insufficiency most commonly
results from exogenous glucocorticoid use, which
leads to suppression of the HPA axis, decreased
release of ACTH, and impaired cortisol and
androgen production. In secondary adrenal
insufficiency, CRH and ACTH concentrations are
usually low and aldosterone production is essen-
tially normal.
Primary and secondary adrenal insufficiency
share many clinical features related to hypocorti-
solism. There are differences, however, due primari-
ly to the elevated CRH and ACTH levels and
aldosterone deficiency characteristic of Addison’s
disease. Increased CRH stimulates release of
melanocyte-stimulating hormone. Melanocyte-
stimulating hormone and ACTH cause melanocytes
to form melanin in the epidermis of the skin, lead-
ing to hyperpigmentation. In addition, patients
with Addison's disease more commonly experience
electrolyte abnormalities, especially hyperkalemia.
CAUSATIVE AGENTS
Drugs that have been reported to suppress the HPA
axis and cause secondary adrenal insufficiency
(SAI) on discontinuation are listed in Table
32–8.5,15-17,21,22,27-30,38,40,44-71
EPIDEMIOLOGY
SAI has an estimated prevalence of 150 to 280 per-
sons per 1 million population.72 Excessive gluco-
corticoid therapy induces atrophy of pituitary
corticotroph cells and is thought to be the primary
cause of this disorder. The prevalence may be as
high as 50% in patients taking exogenous gluco-
corticoids for long periods.73 Drug-induced SAI is
usually only clinically relevant during or after glu-
cocorticoid withdrawal, although a few cases have
occurred as a result of other mechanisms described
below. Although higher glucocorticoid doses of
longer duration (>7.5 mg of prednisone or equiva-
lent for >3 weeks) are often implicated in SAI,
patient response is highly variable and HPA axis
suppression may occur with any dose or duration
of therapy.40 As with Cushing’s syndrome, many
routes of glucocorticoid administration may sup-
press the HPA axis.5,15-17,21,22,38,40,44-52 In most
patients, adrenal function returns to normal with-
in 14 days after glucocorticoid withdrawal.74 In a
minority of patients, normalization of the adrenal
gland may take up to 1 year.40,75
MECHANISMS
Mechanisms of drug-induced SAI are listed in Table
32–9. Drug-induced SAI is characterized by a reduc-
tion in ACTH secretion from the pituitary gland,
resulting in atrophy of the adrenal cortex. Low
endogenous cortisol concentrations are not clinical-
ly relevant if glucocorticoid activity is supplemented
through exogenous glucocorticoid administration.
However, when exogenous glucocorticoid therapy is
abruptly stopped or when the patient is exposed to
stressful stimuli (e.g., surgery, trauma, infection),
adrenal suppression becomes clinically apparent
because of the inability of the adrenal cortex to
mount an appropriate cortisol response.
Sustained stimulation of the negative feedback
effect on glucocorticoid receptors in the anterior
pituitary gland and hypothalamus, such as with
exogenous glucocorticoid administration, may
lead to prolonged suppression of CRH. This in turn
suppresses ACTH release from the anterior pitu-
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CHAPTER 32 • Hypothalamic, Pituitary and Adrenal Diseases 611

TABLE 32–8 Agents Implicated in Drug-Induced Adrenal Insufficiency

Drug Incidencea Level of Evidence
(see page xii for explanation)

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.
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612 SECTION VII • Drug-Induced Endocrine Diseases

TABLE 32–9 Mechanisms of Drug-Induced Secondary Adrenal Insufficiency

Drug Mechanism
Glucocorticoids72,76 Sustained stimulation of the negative feedback effect on
glucocorticoid receptors in the anterior pituitary gland
and hypothalamus leads to prolonged suppression of CRH,
which in turn suppresses ACTH release from the anterior
pituitary and results in a lack of adrenal secretion of corti-
sol. This process is also referred to as suppression of the
HPA axis.
Progestins53,55 Suppress HPA through their ability to bind to the GR
Ketoconazole57,58 Inhibits cholesterol side-chain cleavage and cytochrome
P-450 enzymes, 17␣-hydroxylase and 17,20-lyase, resulting
in reduced cortisol synthesis.
Etomidate60 Inhibits 17␣-hydroxylase and 11␣-hydroxylase, resulting in
reduced cortisol synthesis.
Mitotane62 Inhibits 11␣-hydroxylase, 18-hydroxylase, 3␣-hydroxylase,
and cholesterol side-chain cleavage, resulting in reduced
cortisol synthesis.
Aminoglutethimide63 Inhibits the conversion of cholesterol to pregnenolone,
resulting in reduced cortisol synthesis
Rifampin64,65 Induces Cytochrome P450 isoenzymes responsible for
cortisol metabolism.
Mirtazapine66 Antagonizes central 5-hydroxytryptamine2 and/or
histamine1 receptors, resulting in decreased CRH release,
ACTH secretion, and cortisol release.
Hydromorphone67 Inhibits CRH release through binding to hypothalamic ␦- and
␬-opiate receptors.
Fentanyl68 Inhibit pituitary response to CRH.
Flunitrazepam69

itary and results in a lack of adrenal secretion of
cortisol.38,72,76
Numerous studies have documented the abil-
ity of inhaled and nasal glucocorticoids to sup-
press the HPA axis, especially when administered
in high doses or when combined with inhibitors
of CYP450 3A4.5,44-51 At recommended doses,
however, inhaled and nasal glucocorticoids rarely
suppress adrenal function. Topical, intra-articu-
lar, intradermal, intramuscular, intralesional, and
paraspinal administration of glucocorticoids
have also been implicated in SAI. 15-17,21,22,52
Patients with compromised skin integrity who
use high-potency topical glucocorticoids (e.g.,
clobetasol propionate) may be at higher risk for
SAI .15-17,43,52
When administered at high doses, progestins
or progestin analogs appear to have the capacity
to suppress the HPA axis. These agents, MPA and
megestrol acetate, possess glucocorticoid-like
activity thought to be due to existing cross-reac-
tivity within this family of steroid receptors.27-
30,53-56
Ketoconazole. etomidate, and other agents
used to treat Cushing’s disease have also been
shown to cause SAI by interfering with cortisol
synthesis.38,57-63 Rifampin, phenytoin, and phe-
nobarbital may suppress the axis by inducing
CYP450 isozymes that are responsible for corti-
sol metabolism.38,64,65 Mirtazapine appears to
cause adrenal suppression by antagonizing cen-
tral 5-hydroxytryptamine2 receptors responsible
for the stimulation of cortisol secretion. 66
Opioids inhibit CRH release by binding to hypo-
thalamic ␦- and ␬-opiate receptors.67,68 Certain
benzodiazepines may inhibit pituitary response
to CRH.69
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CHAPTER 32 • Hypothalamic, Pituitary and Adrenal Diseases
CLINICAL PRESENTATION AND
DIFFERENTIAL DIAGNOSIS
Signs and symptoms associated with drug-induced
SAI are presented in Table 32–10.71,72,75-77 Patients
may present with abnormal laboratory values such
as hyponatremia, hypoglycemia, mild normocytic
anemia, lymphocytosis, and mild eosinophilia.
Table 32–11 lists conditions that must be consid-
ered in the differential diagnosis of drug-induced
SAI.72 Rarely, acute adrenal insufficiency may be
life-threatening. Patients with this disorder may
exhibit severe hypotension or hypovolemic shock,
hypoglycemia, acute abdominal pain, vomiting,
and fever.75,77
The laboratory diagnosis of adrenal insufficien-
cy involves measurement of early morning plasma
cortisol concentration as well as dynamic testing.71-
73,75-77
Adrenal insufficiency can be ruled out by
measuring a plasma cortisol concentration between
7 and 9 a.m. A concentration of <3 mcg/dL (100
nmol/L) is indicative of adrenal insufficiency, and a
concentration of >18 mcg/dL (500 nmol/L) rules out
the disorder.71,72 Dynamic testing is required for
patients with cortisol concentrations between 3 and
18 mcg/dL and can also be useful in determining the
cause of the disease. Dynamic tests include the
insulin-tolerance test, metyrapone test, ACTH stim-
ulation test, and CRH stimulation test.71-73,75-77
The insulin-tolerance test is considered the
standard for the evaluation of SAI because hypo-
glycemia in normal subjects results in rapid activa-
tion of the HPA axis.71,72,76 This test is
labor-intensive, however, with patients requiring
constant supervision by a medical professional
TABLE 32–10 Signs and Symptoms Associated
with Drug-Induced Secondary Adrenal
Insufficiency
• Weakness
• Fatigue
• Weight loss
• Anorexia
• Myalgia
• Arthralgia
• Hypotension
• Gastrointestinal symptoms (abdominal cramps, nau-
sea, diarrhea, vomiting)
• Postural hypotension
• Vitiligo
• Anemia, lymphocytosis, eosinophilia
• Hypoglycemia
• Hyponatremia
613
TABLE 32–11 Conditions to Consider in the
Differential Diagnosis of Drug-Induced Secondary
Adrenal Insufficiency
• Addison’s disease
• Chronic fatigue syndrome
• Neuropsychiatric weakness
• Myopathies
• Chronic heart failure
• Liver disease
• Syndrome of inappropriate antidiuretic hormone
• Anemia
• Pigmentation disorders
since a serum glucose of <40 mg/dL and symptoms
of hypoglycemia are required elements of the test.
The insulin-tolerance test is contraindicated in
patients >60 years of age, those with cardiovascular
disease, and those who have a history of
seizures.71,72 An ACTH stimulation test is often pre-
ferred because of its ease of use and relatively high
correlation with the insulin-tolerance test. Patients
are given 250 mcg of synthetic ACTH (cosyntropin)
intravenously or intramuscularly, and serum corti-
sol concentrations are measured at baseline and 60
to 90 minutes after the injection. An increase in the
cortisol concentration to >18 mcg/dL at 60 to 90
minutes rules out adrenal insufficiency. In several
studies, doses of 0.5 mcg or 1 mcg instead of the
customary 250 mcg dose of synthetic ACTH have
been shown to be effective in stimulating a cortisol
response and have been associated with higher sen-
sitivity in identifying patients with subtle SAI.
Recent studies also suggest that cortisol concentra-
tions should be obtained at 30 to 60 minutes for the
low-dose test.71-73,75,76 The CRH stimulation test also
correlates well in patients with SAI, but it is less well
standardized and is costly. 71-73,75,76
RISK FACTORS
Specific risk factors associated with drug-induced
SAI are presented in Table 32–12.3,38,40,43,75,78
Because this disorder is, in part, a result of the
exogenous administration of glucocorticoids, risk
factors for SAI and Cushing’s syndrome are very
similar and, in some instances, may be identical.
In contrast to the use of standard doses, admin-
istration of high doses of inhaled and intranasal
glucocorticoids have been associated with a higher
incidence of adrenal suppression.4,45,46,49,49-51 A
meta-analysis of 27 studies completed from 1995
through 1998 concluded that IGCs such as
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614 SECTION VII • Drug-Induced Endocrine Diseases

one, mometasone) may be increased with drugs

TABLE 32–12 Risk Factors for Drug-Induced
Secondary Adrenal Insufficiency
• Administration of high doses of offending agent
• Prolonged duration of therapy
• Use of high-potency glucocorticoids
• Administration of drugs that inhibit the metabolism
of endogenous glucocorticoids
• Physical stress (stressful situation, surgery, infection,
trauma)
beclomethasone dipropionate, budesonide, and
triamcinolone acetonide at doses >1.5 mg/day and
fluticasone propionate at a dose >0.75 mg/day
caused marked adrenal suppression.3 Likewise, top-
ical glucocorticoids administered at high doses are
associated with a higher risk of adrenal suppres-
sion.43
Systemic absorption is a known risk factor for
adrenal suppression with glucocorticoids, and the
degree of CRH suppression is proportional to the
amount of circulating cortisol or cortisol-like com-
pound. Because of rapid and extensive systemic
absorption, the long-term (>3 week) use of oral glu-
cocorticoids may induce significant adrenal sup-
pression regardless of the dose administered.40,43,75
IGCs are intended to limit systemic absorption
through local deposition in the lung and high first-
pass metabolism of any swallowed drug. However,
60% to 90% of the IGC dose may be swallowed and
available for gastrointestinal absorption and sys-
temic absorption of small IGC particles may occur
via lung alveoli.79 Therefore, the risk of SAI from
IGCs with high first-pass metabolism (e.g. fluticas-
(e.g., ketoconazole, ritonavir) that inhibit the
metabolism of glucocorticoids, when a spacer is
used to increase lung deposition, and when step-
down therapy is not practiced following the rever-
sal of airflow obstruction and inflammation.
Use of high-potency glucocorticoids increases
the risk of drug-induced SAI. A list of commonly
used glucocorticoids can be found in Table 32–13.
In a meta-analysis of 21 studies, inhaled fluticas-
one exhibited significantly greater dose-related
adrenal suppression as compared with inhaled
beclomethasone, budesonide, or triamcinolone.3
In another study, mometasone showed similar
adrenal suppression at medium and high doses as
compared with fluticasone.80 Levin and Maibach
identified the use of high-potency topical gluco-
corticoids such as clobetasol propionate as a risk
factor for mild or reversible adrenal suppression.52
Other risk factors for SAI associated with topical
administration of glucocorticoids include pro-
longed duration of treatment, use on thin or dam-
aged skin, and use in children and infants.52
Most cases of adrenal crisis in those with
chronic SAI occur because of reduction of the glu-
cocorticoid dose or as a result of failure to adjust
glucocorticoid-replacement doses properly in the
presence of stressors.72 Concomitant diseases
(e.g., hypothyroidism, acquired immunodeficien-
cy syndrome) may impair the central response to
stress and cortisol secretion and are also risk fac-
tors for the development of adrenal insufficien-
cy.77 The estimated overall risk of adrenal crisis
serious enough to require hospitalization in
patients with chronic adrenal insufficiency is 3.3

TABLE 32–13 Pharmacologic Characteristics of Glucocorticoids

Relative Antiinflammatory Dosage Approximate
Glucocorticoid Potency Equivalent (mg) Half-Life (min)
LOW POTENCY
Cortisone 0.8 25 30
Hydrocortisone 1 20 90
MEDIUM POTENCY
Prednisone 3.5 5 60
Prednisolone 4 5 200
Triamcinolone 5 4 300
Methylprednisolone 5 4 180
HIGH POTENCY
Betamethasone 25 0.6 100-300
Dexamethasone 30 0.75 100-300
TisdaleC32_605-628 1/12/10 3:33 PM Page 615
CHAPTER 32 • Hypothalamic, Pituitary and Adrenal Diseases
per 100 years.72 However, the risk of crisis is much
higher in patients with primary adrenal insuffi-
ciency (3.8 per 100 years) and in women (4.4 per
100 years).72
MORBIDITY AND MORTALITY
As discussed above, drug-induced SAI is accompa-
nied by a constellation of nonspecific and non-life-
threatening symptoms such as fatigue, anorexia,
asthenia, weight loss, abdominal pain, nausea,
vomiting, and weakness. However if unrecognized
and untreated, it may be a potentially fatal disease
because of the risk of circulatory collapse.77
PREVENTION
Methods to prevent drug-induced secondary adre-
nal insufficiency are presented in Table 32–14.
Drug-induced SAI may be prevented by minimiz-
ing the risk factors associated with drug-induced
adrenal insufficiency (Table 32–12). Practitioners
should make an effort to use the lowest possible
dose of agents that are known to suppress the HPA
axis. This can be accomplished by using a step-
down approach when symptoms resolve and by
not exceeding the dose limits for the selected
agent.
The inhalational, intranasal, and topical routes
of administration may help reduce the amount of
systemically absorbed glucocorticoid and hence
the likelihood of adrenal suppression.40 The use of
a spacer attached to a metered-dose inhaler may
reduce the amount of drug that is swallowed and
therefore decrease gastrointestinal absorption. This
mode of prevention is more important for IGCs
with lower first-pass metabolism. For higher-poten-
cy IGCs (e.g. fluticasone), appropriate administra-
tion, use of a spacer, and using the lowest possible
maintenance dose may help reduce the risk of
SAI.79 To reduce the risk of adrenal suppression
TABLE 32–14 Approaches to Help Prevent Drug-
Induced Adrenal Insufficiency
• Use lowest effective dose of offending agent.
• Minimize systemic absorption by using topical gluco-
corticoids.
• Minimize swallowed glucocorticoid after use a
metered-dose inhaler by using a spacer.
• Use step-down therapy with inhaled glucocorticoid
after pulmonary obstruction and inflammation subside.
615
with topical glucocorticoids, use low-potency
agents at lower concentrations, limit treatment
duration, apply to smaller surface areas, and do not
use on damaged, broken, or thin skin.43
MANAGEMENT
The first step in treating patients with drug-
induced SAI is identification and discontinuation
of the offending medication and substitution of an
appropriate therapeutic alternative. Other avail-
able options include changing the route of admin-
istration of the offending agent to limit systemic
absorption, attempting to use a lower potency glu-
cocorticoid to minimize effects on the HPA axis, or
both. In patients with chronic SAI or in those in
whom discontinuation of the offending medica-
tion is not possible, glucocorticoid replacement is
the treatment of choice (Table 32–15).
Glucocorticoid replacement usually involves
the administration of two or three daily doses. On
average, the healthy adult produces approximately
10 to 30 mg of cortisol per day, with the peak con-
centration occurring around 8:00 a.m. This is
equivalent to 15 to 20 mg of hydrocortisone or
about 5 to 7.5 mg of prednisone every day. One-
half to two-thirds of the dose may be given in the
morning to mimic the normal diurnal variation of
cortisol.72,81 Hydrocortisone and prednisone are
preferred over agents with longer half-lives, such as
prednisolone, triamcinolone, dexamethasone, and
betamethasone, because they may allow the HPA
axis more opportunity to recover and appropriate-
ly release CRH and ACTH based on the body’s need
for cortisol.40,72,75,77 Patients should be instructed to
double or triple their oral glucocorticoid dose dur-
ing febrile illness or injury, and may be supplied
with and instructed regarding the proper use of
hydrocortisone intramuscular injections for emer-
gency use. In some non-severe cases (e.g., patients
experiencing nausea or vomiting), the glucocorti-
TABLE 32–15 Management of Drug-Induced
Secondary Adrenal Insufficiency
• Discontinue offending agent
• Initiate appropriate therapeutic alternative
• Taper, if necessary, depending on agent being discon-
tinued
• If glucocorticoid replacement is needed, the usual
dose of hydrocortisone is 15–20 mg/day and that of
prednisone 5–7.5 mg/day. (One-half to two-thirds of
the dose may be given in the morning.)
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616 SECTION VII • Drug-Induced Endocrine Diseases
coid can be given in the form of rectal supposito-
ries.72,81
Minor abnormalities discovered upon dynamic
testing should be treated only in the presence of
symptomatic adrenal insufficiency. Testing should
be performed on any patient who reports suggestive
symptoms or on any child whose growth velocity is
slowed. The lowest effective dose of glucocorticoid
should be used, and dosing should be guided by
symptomatic management of fatigue and other
symptoms as described in Table 32–10.71,72,81
Because suppression of the HPA axis is a major
concern only when exogenous glucocorticoids are
withdrawn, practitioners should never abruptly
stop oral glucocorticoids taken for longer than 14
days. A variety of recommendations for steroid
tapering are available; however, no consensus
exists regarding the best approach.38,40 In general,
in patients who have been on long-term steroid
therapy, the steroid should be gradually withdrawn
toward physiologic doses over months. As the
steroid dose approaches physiologic levels, the
taper should be slowed and the patient checked for
HPA axis function. The primary modes to test HPA
axis integrity are the ACTH test, either high- or
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
not needed. If the morning serum cortisol concen-
tration is between 3 and 20 mcg/dL, an ACTH test
or an CRH stimulation test may be useful in the
assessment of pituitary–adrenal function.40 A
morning cortisol concentration <3 mcg/dL indi-
cates axis suppression and the need for continued
replacement therapy. Caution should be used to
prevent disease exacerbation during the steroid
taper and the resultant need to treat the patient
with another course of high-dose steroids.38
Adrenal crisis has been reported after the dis-
continuation of MPA and megestrol acetate; there-
fore, tapering is also recommended for patients
receiving these agents. Although there is clear evi-
dence that adrenal suppression can occur in
patients receiving inhaled, intranasal, and topical
glucocorticoids, supplementation during periods
of stress and/or tapering of doses prior to complete
discontinuation is usually not needed.52
INFORMATION FOR PATIENTS
Patients receiving long-term inhaled, topical, and
oral glucocorticoids should be educated regarding
the signs and symptoms associated with SAI and
instructed to contact their health care provider if
these develop. Patients should carry an information
card with details about their current treatment and
instructions for emergency treatment, including
instructions on doubling or tripling the glucocorti-
coid dose during febrile illness or injury and using
alternative routes of administration during vomit-
ing.71,72,81 Patients should be instructed to rinse
their mouth after administration of an inhaled glu-
cocorticoid to minimize side effects (e.g., thrush,
hoarseness) as well as to decrease systemic absorp-
tion from oropharyngeal deposition. Lastly,
patients should be educated to not use topical glu-
cocorticoids on thin skin areas (e.g., eyelid, scro-
tum), on broken skin, or over large surface areas.
DRUG-INDUCED
HYPERPROLACTINEMIA
The regulation of prolactin is unique among other
anterior pituitary hormones. Prolactin is regulated
through hypothalamic inhibition, and dopamine
is the main inhibitory factor. As a result, drug-
induced hyperprolactinemia may occur with any
drug that inhibits the action of dopamine in the
central nervous system.
CAUSATIVE AGENTS
Specific drugs that have been reported to induce
hyperprolactinemia are listed in Table 32–16.82-132
EPIDEMIOLOGY
Hyperprolactinemia is the most common
endocrine disorder of the HPA axis, with an esti-
mated prevalence of 0.4% in the normal adult pop-
ulation and as high as 9% among women with
amenorrhea.133 The prevalence is approximately
5% among men presenting with impotence. The
highest prevalence is among women with amenor-
rhea and galactorrhea, at 70%.133 The incidence of
drug-induced hyperprolactinemia (DIH) is
unknown. Antipsychotics are the drug class most
often implicated in drug-induced hyperprolactine-
mia, and women are known to have a pronounced
prolactin-releasing response to these agents.82
MECHANISMS
Mechanisms of drug-induced hyperprolactinemia
are listed in Table 32–17. Prolactin secretion by the
lactotroph cells of the anterior pituitary is con-
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CHAPTER 32 • Hypothalamic, Pituitary and Adrenal Diseases 617

TABLE 32–16 Agents Implicated in Drug-Induced Hyperprolactinemia

Drug Incidence Level of Evidence
(see page xii for explanation)

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)
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618 SECTION VII • Drug-Induced Endocrine Diseases

TABLE 32–16 Agents Implicated in Drug-Induced Hyperprolactinemia (Continued)

Drug Incidence Level of Evidence

ANTIRETROVIRALS
Protease inhibitors122-124 NK C
Nevirapine125 NK C
MISCELLANEOUS
Alcohol126 NK C
Cyproterone acetate127 NK C
Azathioprine128 NK C
Cisplatin129 NK C
Cocaine130 NK B
Cyclosporin131 NK C
Tetrahydrocannabinol132 NK C
NK = not known.
a
Not approved for use in the United States.
b
Incidence depends on dose.

TABLE 32–17 Mechanisms of Drug-Induced Hyperprolactinemia

Drug Mechanism
Anti-emetics (D2-antagonist)82,85,95 Prolactin’s secretion is controlled by the inhibitory effect of
Antipsychotics (D2-antagonist)82,85,104 the hypothalamus through one or more prolactin inhibitory
Methyldopa82,85,98 factors. Dopamine is the main physiologic prolactin
Reserpine82,85,100 inhibitory factor. Any drug that is associated with inhibition
of dopamine production (e.g. methyldopa), release
(e.g. reserpine) or action (e.g. D2-antagonsists) can induce
hyperprolactinemia.
Antidepressants88,89 Serotonin is a strong stimulator of prolactin secretion.
Antidepressants inhibit the reuptake or breakdown of
serotonin.
Verapamil82,85,101 Decreases dopaminergic activity by blocking N-type
calcium channels
Estrogens82,85,114 Increase the number of prolactin-secreting cells in the
pituitary
Tetrahydrocannabinol132 Stimulates the release of prolactin possibly through a
decreased inhibitory effect of dopamine
Gonadotropin-releasing hormone analogs115,116 Decrease in the release of hypothalamic prolactin
inhibitory factors
H2-receptor antagonists118,119 Unknown centrally mediated prolactin release
Opioids120,121 Bind to mu receptors that may inhibit hypothalamic
dopamine secretion
Antiretrovirals122,123 Most likely due to concomitant antiemetics or concurrent
infection
Alcohol126 Stimulates the release of prolactin possibly through a
decreased inhibitory effect of dopamine
TisdaleC32_605-628 1/12/10 3:33 PM Page 619

CHAPTER 32 • Hypothalamic, Pituitary and Adrenal Diseases 619

trolled by the inhibitory effect of the hypothala-

mus through one or more prolactin inhibitory TABLE 32–18 Signs and Symptoms Associated
factors (PIFs). Dopamine is the main physiologic with Drug-Induced Hyperprolactinemia
PIF; therefore, any drug that is associated with • Women
inhibition of dopamine release or action can • Oligomenorrhea
induce hyperprolactinemia. Antipsychotics82 and • Amenorrhea
antiemetics82 with strong dopamine-receptor (D2) • Hirsutism
blockade such as the phenothiazine derivatives, • Men
haloperidol, and metoclopramide work through • Erectile dysfunction
this mechanism and have traditionally been • Gynecomastia
reported to cause hyperprolactinemia.82-85,95-97,104- • Decreased body hair
113,124,134
Serotonin is a strong stimulator of pro- • Men and women
lactin secretion; therefore, antidepressants that • Infertility
inhibit the reuptake or breakdown of serotonin82 • Decreased libido
can increase prolactin concentrations.82-94 • Weight gain
Antihypertensives82 such as methyldopa and reser- • Galactorrhea
pine stimulate prolactin secretion by negating • Osteoporosis
dopaminergic inhibition, whereas hormones such
as estrogen82 appear to promote prolactin secretion
by stimulating lactotroph growth. 82-85,98,99,114 It is TABLE 32–19 Conditions to Consider in the
unknown how verapamil causes hyperprolactine- Differential Diagnosis of Drug-Induced
mia, but it is believed to decrease dopaminergic Hyperprolactinemia
activity by blocking N-type calcium channels in
the cell membranes of neurons in the tuberoin- • Pregnancy or postpartum prolactin elevation
fundibular dopaminergic tract.82,85,101 While pro- • Breast stimulation
tease inhibitors have been identified as a possible • Sexual activity
direct cause of hyperprolactinemia, the condition • Renal failure
is most likely due to concomitant use of antiemet- • Cirrhosis
ics or the presence of infection in patients receiv- • Hypothyroidism
ing protease inhibitors.122-125 • Prolactin-secreting adenomas
• Macroprolactinemia
• Acromegaly
CLINICAL PRESENTATION AND • Polycystic ovarian syndrome
DIFFERENTIAL DIAGNOSIS • Postictal (1–2 hr after seizure prolactin elevation)
• Chest wall trauma and surgery
The most common symptoms of hyperprolactine- • Excessive exercise
mia are amenorrhea, galactorrhea, or both in • Nonfasting blood sample used for determination of
women and decreased libido, impotence, or both prolactin concentration
in men.85,133-135 Sustained hyperprolactinemia can
also be associated with pituitary tumors, breast
cancer, decreased bone mineral density, venous cause. In drug-related hyperprolactinemia, serum pro-
thromboembolism, and depression.85,134 Signs and lactin concentrations rarely exceed 100 mcg/L,
symptoms associated with hyperprolactinemia are whereas prolactin concentrations exceeding 200
presented in Table 32–18.82,85,133-135 mcg/L are almost always associated with pituitary
The diagnosis of hyperprolactinemia requires two macroadenomas.84,85,133,135 Macroprolactinemia, or
or more serum prolactin concentrations above 20 to big, big prolactin, must be ruled out, as this abnor-
25 mcg/L (400–500 mU/L) in combination with mality is found in 10% of patients with hyperpro-
symptoms. However, as in drug-induced Cushing’s lactinemia.84 Macropro-lactinemia is often
syndrome, determining the cause can prove challeng- asymptomatic, and initiating treatment for asympto-
ing. A thorough and careful medication history will matic patients is controversial.136
help identify possible drug-related causes of hyper-
prolactinemia, and an evaluation of thyroid, kidney,
and liver function is essential to rule out elevated pro- RISK FACTORS
lactin concentrations secondary to organ dysfunction
(Table 32–19).84,85,133,135 The severity of hyperpro- Risk factors associated with DIH are presented in
lactinemia can also be useful in determining the Table 32–20.82,84,85,133-135 The highest risk for devel-
TisdaleC32_605-628 1/12/10 3:33 PM Page 620
620 SECTION VII • Drug-Induced Endocrine Diseases
TABLE 32–20 Risk Factors Drug-Induced
Hyperprolactinemia and Growth Hormone
Deficiency
• Hyperprolactinemia
• Administration of high doses of offending agent
• Use of potent D2-receptor antagonists
• Female sex
• Growth hormone deficiency
• Development of Cushing’s syndrome (see Table
32–5)
• Family history
oping hyperprolactinemia is associated with the
use of potent D2 receptor antagonists such as con-
ventional antipsychotics, risperidone, and the
antiemetics, metoclopramide, and domperi-
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
Higher doses of drugs with alternative mechanisms
to potentiate prolactin (e.g. estrogen, antidepres-
sants) are probably needed to induce hyperpro-
lactinemia.85,135 It should be noted that mental
illness itself is not a risk factor for DIH; however,
women generally have a more pronounced pro-
lactin elevation than men when taking conven-
tional antipsychotics.85
MORBIDITY AND MORTALITY
The incidence of death due to DIH is unknown.
Spontaneous galactorrhea, amenorrhea, gyneco-
mastia in men, and sexual dysfunction may lead to
embarrassment and reduced quality of life.85
Osteoporosis is a long-term consequence that may
lead to fracture, and certain fractures (e.g. hip) may
increase the risk of death. Other potential long-
term consequences of DIH include pituitary
tumors, breast cancer, venous thromboembolism,
and depression.85,134 Most, if not all, symptoms
resolve when prolactin levels return to normal.85
PREVENTION
Methods to prevent DIH are presented in Table
32–21. DIH may be prevented by minimizing the
risk factors associated with hyperfunction of the
hypothalamus, adrenal, or pituitary glands. When it
is necessary to use agents that have the potential to
induce hyperprolactinemia, practitioners should
TABLE 32–21 Approaches to Help Prevent Drug-
Induced Hyperprolactinemia
• Use lowest effective dose of offending agent.
• Avoid drug interactions that increase plasma concen-
trations of the offending agent.
• Avoid drugs that exert potent D2-receptor antagonism.
make an effort to use the lowest effective dose of less
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-
ing the dose if and when adverse effects occur. In
addition, agents that interact pharmacokinetically
(e.g., inhibit metabolism) with drugs known to
cause hyperprolactinemia should be avoided.
MANAGEMENT
Management of DIH requires recognition that a
drug is the causative agent. Once a drug has been
identified as the cause, the logical first step is to
attempt to discontinue the offending medication
and replace it with an appropriate alternative. This
can be problematic when a patient is well con-
trolled with the offending agent and/or alterna-
tives are not available. This is often the situation
practitioners face with conventional or first-gener-
ation antipsychotics. In these cases, changing to an
antipsychotic with less potential to cause DIH
(e.g.,. quetiapine, aripiprazole, clozapine) is per-
haps the most appropriate option, as administra-
tion of a dopamine agonist may worsen psychiatric
symptoms.85,134 If maintaining the offending agent
is the only option, initiating a dopamine agonist
and, in those who require it (e.g., patient with
estrogen deficiency), sex-steroid replacement are
pharmacologic options.82,85,133-136 Sex steroid
monotherapy may be the safest option for patients
treated with antipsychotics.
The greatest evidence for the effectiveness of
dopamine agonist use in patients with hyperpro-
lactinemia exists for the ergot derivatives, such as
bromocriptine and cabergoline.136 However, some
studies of the treatment of Parkinson’s disease
show that ergot derivatives (cabergoline and per-
golide) increase the risk of cardiac valvulopathy.137
It is unknown whether this adverse effect occurs
when ergot derivatives are used for the treatment
of hyperprolactinemia, since much lower doses are
required. Pramipexole and ropinirole are non-ergot
derivatives that may possess a safer cardiac profile;
TisdaleC32_605-628 1/12/10 3:33 PM Page 621
CHAPTER 32 • Hypothalamic, Pituitary and Adrenal Diseases
however, very limited data exist for their use in the
treatment of hyperprolactinemia.136 Treatment
options available for patients with hyperpro-
lactinemia are presented in Table 32–22.
INFORMATION FOR PATIENTS
It is important to inform patients who are receiv-
ing dopamine agonists for the treatment of DIH
that treatment may restore fertility and they
should take appropriate contraceptive precautions
if pregnancy is not desired.85,135 Common adverse
effects associated with dopamine agonists are nau-
sea, insomnia, somnolence, peripheral edema, and
orthostatic hypotension and patients should be
properly warned about these.136
GROWTH HORMONE DEFICIENCY
Growth hormone (GH) deficiency in adults is usu-
ally characterized by alterations in body composi-
tion, lipid and carbohydrate metabolism, bone
mineral density, and quality of life. Long-standing
GH deficiency may also increase the risk of cardio-
vascular morbidity and mortality. The secretion of
growth hormone is different from that of most
other hormones in that it is released in a pulsatile
fashion. This timing of release often complicates
the diagnosis of GH deficiency, and provocative
testing is required for accurate diagnosis.
TABLE 32–22 Management of Drug-Induced
Hyperprolactinemia
• Discontinue offending agent
• Initiate appropriate therapeutic alternative
• Consider initiation of dopamine agonist
• Bromocriptine (2.5–10 mg/day)a
• Cabergoline (0.25–1 mg/wk)a
• Pramipexoleb
• Ropiniroleb
• Pergolidec
• Consider sex-steroid replacement in patients who
require it
• Testosterone
• Estrogen
• Consider a bisphosphonate if low bone mineral den-
sity is found
a
United States Food and Drug Administration–approved indi-
cation for hyperprolactinemia.
b
Limited evidence of effectiveness.
c some even reporting stimulation of GH secre-
Not approved for use in the Unites States.
621
CAUSATIVE AGENTS
Specific drugs that have been reported to cause
growth hormone deficiency are listed in Table
32–23.38,138-149
EPIDEMIOLOGY
The frequency of drug-induced GH deficiency in
the general population is unknown, but it is
assumed to be rare. The incidence of growth hor-
mone deficiency from any cause is approximately
1.76 per 100,000 persons as reported in a nation-
wide study from Denmark.150 The most common
cause of growth hormone deficiency is a pituitary
adenoma.150,151
MECHANISMS
Mechanisms for drug-induced growth hormone
deficiency are listed in Table 32–24. GH secretion is
under the control of two hypothalamic peptides:
GH-releasing hormone (GHRH) and somatostatin
or somatotropin-release–inhibiting factor (SRIF),
which are responsible for inhibiting pituitary GH
release.142,144 Inhibition of GH secretion by ␣- and
␤-adrenergic agonists may be mediated by an
increase in SRIF secretion; however, ␤-adrenergic
agonists may also reduce the GH response to
GHRH.138,142 Glucocorticoid excess increases hypo-
thalamic secretion of somatostatin by enhancing
␤-adrenergic responsiveness, thus inhibiting GH
release from the pituitary.149 In addition, glucocor-
ticoids reduce the number of growth hormone
receptors.143 Therefore, any glucocorticoid has the
potential to induce GH deficiency and reduce tis-
sue response to GH. Gonadotropin-releasing hor-
mone agonists used to treat precocious puberty
and hormone-responsive cancers decrease hor-
mone release from the pituitary.141,147
Gonadotropin-releasing hormone is normally
released in a pulsatile fashion; however, continu-
ous administration down regulates pituitary recep-
tors, ultimately decreasing sex- and growth-
hormone release.38 Methylphenidate has a potent
effect on dopaminergic systems involved in the
regulation of GH secretion. Nevertheless, the effect
of methylphenidate and amphetamines on the GH
axis has been a matter of controversy, with some
studies reporting inhibition, some no change, and
tion.144
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622 SECTION VII • Drug-Induced Endocrine Diseases

TABLE 32–23 Agents Implicated in Drug-Induced Growth Hormone Deficiency

Drug Incidencea Level of Evidence(s)
(see page xii for explanation)

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 32–24 Mechanisms of Drug-Induced Growth Hormone Deficiency

Drug Mechanism
Alpha-adrenergic antagonists138,142 May increase secretion o opin-release–inhibiting
factor
Beta-adrenergic agonists138,142 May increase secretion o opin-release–inhibiting
factor.
May also reduce the GH response to growth
hormone–releasing hormone.
Glucocorticoids143,148,149 Increase hypothalamic secretion of somatostatin by
enhancing ␤-adrenergic responsiveness, thus inhibiting
GH release from the pituitary. Reduce the number of
growth hormone receptors in tissue.
Somatostatin analogs142,144 Directly inhibit GH release from the pituitary.
GnRH agonists141,147 Continuous administration down-regulates pituitary recep-
tors ultimately decreasing growth hormone release.
Amphetamine derivatives144 Possibly decreases GH release through dopaminergic effects.
May decrease sleep-related GH release.
GH = growth hormone.

when compared with the general population, adults

CLINICAL PRESENTATION AND
DIFFERENTIAL DIAGNOSIS
Signs and symptoms associated with GH deficiency
are presented in Table 32–25.38,152,153 The character-
istic patient is a short, plump child with a round
immature-looking face. There is also evidence that
GH deficiency in patients with hypopituitarism
increases the risk of cardiovascular disease possibly
due to dyslipidemia, and insulin resistance and,
with GH deficiency have an increased fat mass,
reduced muscle mass and strength, lower bone den-
sity, and reduced well-being and quality of life.153,154
The diagnosis of drug-induced GH deficiency is
made when there are signs and symptoms of disease
and documented low GH under provocative testing
and the patient is taking an agent known to cause the
disease. Low serum GH concentrations alone are not
conclusive because GH secretion is pulsatile.155
Diagnosis can be made if the serum GH concentration
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CHAPTER 32 • Hypothalamic, Pituitary and Adrenal Diseases
TABLE 32–25 Signs and Symptoms Associated
with Drug-Induced Growth Hormone Deficiency
• Children
• Short stature
• Reduced growth velocity
• Adults
• Central obesity
• Decreased lean muscle mass
• Reduced muscle strength
• Low bone mineral density
• Dyslipidemia
• Increased homeostasis model assessment
• Difficulty forming relationships
• Decreased well-being
• Reduced energy
• Emotional lability
• Social isolation
• Impaired socioeconomic performance
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
made if the serum GH concentration after provocative
testing is <10 mcg/L.152 The standard for the diagnosis
of GH deficiency is the insulin-induced hypoglycemia
stimulation test, but the GHRH–arginine stimulation
test provides a safer alternative in children and in
patients with a history of seizure disorder and cardio-
vascular disease.155 Alternative causes, such as pitu-
itary adenoma, genetic GH deficiency, abuse/neglect,
and diabetes, must still be ruled out (Table 32–26).
RISK FACTORS
The main risk factor associated with GH deficiency is
the presence of Cushing’s syndrome. This is usually
manifested as weight gain and is frequently associat-
ed with growth failure and GH deficiency. The sever-
ity of growth impairment is directly related to the age
at onset and the duration of hypercortisolemia.156 It
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
administration of glucocorticoids) should be consid-
ered a risk factor (Table 32–20).
MORBIDITY AND MORTALITY
The risk of death from drug-induced GH deficiency
is unknown, but data suggest that adults with GH
623
TABLE 32–26 Conditions to Consider in the
Differential Diagnosis of Drug-Induced Growth
Hormone Deficiency
• Prepubertal
• Idiopathic growth hormone deficiency
• Genetic growth hormone deficiency
• Brain tumor (craniopharyngioma)
• Central nervous system surgery or radiation
• Noonan Syndrome, Turner Syndrome
• Hypothyroidism
• Cushing’s disease /syndrome
• Metabolic disturbances (e.g., uncontrolled diabetes)
• Short stature associated with abuse or neglect
deficiency from other causes have reduced life
expectancy.154 Increased mortality is mostly attrib-
uted to premature cardiovascular disease and may
be more pronounced in childhood-onset GH defi-
ciency and in females.158
PREVENTION
Prevention of drug-induced GH deficiency
includes avoidance of known risk factors, primari-
ly Cushing’s syndrome. If glucocorticoid excess is
the culprit, changing the route of administration
to limit systemic absorption or using a lower-
potency steroid may prove to be effective (Table
32–27).
MANAGEMENT
Management of drug-induced GH deficiency is
dependent on recognition of the offending drug as
the cause. It is imperative to discontinue the
offending medication and start an appropriate
therapeutic alternative. In children whose growth
has been impaired by persistent hypercortisolism,
GH therapy should be initiated as soon as cortisol
TABLE 32–27 Approaches to Help Prevent Drug-
Induced Growth Hormone Deficiency
• Use lowest effective dose of offending agent.
• Avoid prolonged use.
• Avoid drug interactions that will increase plasma con-
centrations of the offending agent.
• Use alternative route of administration to minimize
systemic absorption.
TisdaleC32_605-628 1/12/10 3:33 PM Page 624
624 SECTION VII • Drug-Induced Endocrine Diseases
has normalized because a limited window of
opportunity to promote increases in linear growth
exists. On the other hand, the role of GH replace-
ment in adults has been a matter of controversy.
GH replacement may be considered for sympto-
matic relief as well as to increase muscle mass,
decrease fat mass, and increase bone mineral den-
sity.32,153,159
The first growth hormone preparation was a
pituitary extract from cadavers.160 This preparation
was known to cause Creutzfeldt–Jakob disease and
lead to the production of recombinant growth hor-
mone preparations. There are many available
recombinant growth hormone preparations (soma-
totropin) available today. Dosing is individualized
to patient need and, in general, premenopausal
women and women taking estrogen therapy
require higher doses than men because of reduced
growth hormone response in the periphery due to
estrogen.155 Children typically require much high-
er doses than adults. Somatropin should be started
at low doses (e.g., 300 mcg/day) and slowly titrat-
ed upward by 100 to 200 mcg/day every 1 to 2
months in adults. Somatropin is routinely started
at 20 mcg/kg/wk for children.152,155 Subcutaneous
injections may be given nightly or once per week
at night. Clinical response, adverse effects, and
possibly the measurement of insulin-like growth
factor I concentrations guide therapy in adults.155
In children, height and height velocity are the
main therapeutic outcomes, with normalization of
growth the goal of therapy.152 Somatropin may be
discontinued in children when growth normalizes
and full somatic development (i.e., maximal bone
and muscle mass) is achieved.152 Normalization of
growth hormone sensitivity in adults may take up
to 2 years.32 Therapy for an indefinite period of
time may be considered if the offending agent
must be continued. Table 32–28 summarizes man-
agement strategies.
INFORMATION FOR PATIENTS
It is important to inform patients who are receiv-
ing growth hormone that slow titration over
months is necessary to reduce adverse effects asso-
ciated with treatment. Common adverse effects
that are dose-dependent include fluid retention,
arthralgia, myalgia, headache, nausea, and vomit-
ing. Injection site reactions are also common and
are dose dependent. Growth hormone require-
ments change with age and also with the addition
of sex hormones. Testosterone sensitizes tissues,
whereas oral estrogen causes a reduced response to
growth hormone. If transdermal estrogen is used to
TABLE 32–28 Management of Drug-Induced
Growth Hormone Deficiency
• Discontinue offending agent
• Children
• Initiate growth hormone (somatropin) at 20
mcg/kg/wk. Height and height velocity guide
therapy. Goal: growth normalization
• Adults
• Initiate growth hormone (300 mcg/day) for symp-
tomatic relief and to increase muscle mass, de-
crease fat mass, and increase bone mineral density
• Titrate dose by 100–200 mcg every 1–2 months.
Clinical response, adverse effects, and insulin-like
growth factor I concentrations guide therapy. Goal:
normalization of growth-hormone sensitivity
replace oral estrogen, GH requirements are less and
a lower dose is needed.155
HYPOALDOSTERONISM AND
HYPERALDOSTERONISM
Hypoaldosteronism is rare and usually not related to
medications. Nevertheless, generalized secondary
adrenal insufficiency may be responsible for a subset
of patients with nonselective hypoaldosteronism.38
Likewise, most cases of hyperaldosteronism are pri-
mary, that is, due to physiologic abnormalities that
arise in the adrenal cortex.38,161 A small number of
patients may present with secondary hyperaldos-
teronism that occurs as a result of overstimulation of
the zona glomerulosa by the renin–angiotensin–
aldosterone system. Excess potassium and use
of oral contraceptives may also contribute. Signs
and symptoms include hypokalemia, hypertension,
and possibly evidence of end-organ damage.
Normalizing serum potassium and considering alter-
native forms of contraception are the first treatment
steps that should be taken. If oral contraceptives
must be continued, using an estrogen/progestin
combination that contains drospirenone, a spirono-
lactone derivative, or adding an aldosterone antago-
nist may be considered.
ADRENAL VIRILISM
Virilism is the excessive secretion of androgens
from the adrenal gland, and, in most cases, it is a
result of congenital enzyme defects. Virilism is usu-
ally seen in females, with hirsutism being the dom-
inant feature.83,162
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CHAPTER 32 • Hypothalamic, Pituitary and Adrenal Diseases
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CHAPTER 33
Weight
Gain
W eight gain is a complex process involving
environmental and genetic factors that ulti-
mately contribute to a metabolic imbalance
between caloric intake and energy expenditure.
Although weight gain is most commonly associat-
ed with lifestyle factors, it also may occur as an
unintended response to drug therapy. Drug-
induced weight gain increases obesity-related
health risks and may compromise patient adher-
ence to drug therapy. Observational studies have
reported that a modest weight gain of ≥5 kg in
healthy adults is associated with a significant
increase in the risk for hypertension, type 2 dia-
betes, and coronary heart disease.1-4
CAUSATIVE AGENTS
Drugs that have been reported to cause clinically
relevant weight gain—defined as weight gain of ≥5
kg—are listed in Table 33–1.5-146 Drugs listed in this
table include only those associated with unintend-
ed weight gain. Drugs that are used to promote
weight gain are not included.
EPIDEMIOLOGY
According to current guidelines from the
National Institutes of Health, a body-mass index
(BMI; the weight in kilograms divided by the
square of the height in meters) ≥25 defines over-
weight, and obesity is defined as a BMI ≥30.4 The
number of overweight and obese individuals in
the United States (U.S.) has increased significant-
ly over the past two decades, and the latest epi-
Amy Heck Sheehan
demiologic data estimate that approximately
66% of the U.S. adult population is overweight or
obese.147 The exact incidence of clinically rele-
vant drug-induced weight gain is unknown.
Estimating the incidence of clinically relevant
drug-induced weight gain is complicated because
body weight fluctuations are multifactorial and
can depend on variables such as lifestyle, habits,
genetic predisposition, and concomitant disease
states. Because the majority of drugs associated
with relevant weight gain are used in the man-
agement of psychiatric disorders, most data
regarding the incidence of drug-induced weight
gain have been generated from this patient pop-
ulation. Weight loss is a common symptom of
many untreated psychiatric disorders, including
depression and schizophrenia. Therefore, suc-
cessful treatment of these disorders with appro-
priate drug therapy may be associated with
weight gain that returns the patient’s body
weight to baseline. Unfortunately, baseline body
weight measurements prior to the development
of psychiatric illness are typically not available,
making it difficult to assess true drug-induced
weight gain. Differences in study design and
methods also complicate the assessment of drug-
induced weight gain. Most studies that have
reported data regarding drug-induced weight
gain were not specifically designed to assess this
outcome. The majority of available information
has been generated from adverse event data col-
lected during prospective clinical trials or from
retrospective observational studies. These studies
include differing patient populations, inconsis-
tent definitions of significant weight gain (e.g.,
>5%, >7%, >10%), variable periods of follow-up,
and different methods of reporting weight gain
629
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630 SECTION VII • Drug-Induced Endocrine Diseases

TABLE 33–1 Agents Implicated in Drug-Induced Weight Gain

Drug Incidencea Level of Evidence
(see page xii for explanation)

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

(4 wk)86,f; 65% (long-term)86,f A

Paliperidone87 6-9% (6 wk)87 A
Quetiapine80,88-91 16% (18 mo)80; 8-23% (3–6 wk) 91 A
Risperidone77,80,84,85,92-98 18% (6–8 wk)98; 14% (18 mo)80 A
Ziprasidone80,99 10% (4–6 wk)99; 7% (18 mo)80 A
CONVENTIONAL ANTIPSYCHOTICS
Chlorpromazine68,100-104 NK A
Fluphenazine102,105-107 NK A
Haloperidol83,84,85,97,102,103,106,108,109 10–22% (4–6 wk)108,109; 39–87.5% (1–2 yr)83,85 A
Lithium24,82,110-113 9.8% (1 yr)82 A
Perphenazine80,100,102,103,114-116 12% (18 mo)80 A
Thioridazine102,103,117-119 NK A
Thiothixene102,103,120 NK A
Trifluoperazine102,120,121 NK A
(Continued)
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CHAPTER 33 • Weight Gain 631

TABLE 33–1 Agents Implicated in Drug-Induced Weight Gain (Continued)

Drug Incidencea Level of Evidence

ADJUVANT CHEMOTHERAPY
Adjuvant chemotherapy for early-stage NK B
breast cancer122-128
HORMONES
Glucocorticoids129-131 NK A
Insulin132-138 NK A
Medroxyprogesterone139-146 NK A
NK = not known.
a
Weight % of baseline weight as reported in prospective, randomized clinical trials with length of therapy listed in paren-
thesis.
b
Incidence of weight gain >7.5% of baseline weight over 16 weeks of therapy.
c
Time period of treatment not specified.
d
Children.
e
8%, 19%, and 30% based on a baseline body-mass index (weight in kilograms divided by the square of the height in meters) of >27,
23–27, and <23, respectively.
f
Adolescents.

(e.g., kilograms, body mass index) and the extent

of weight gain (e.g., mean, median, range, pro-
portion of patients gaining significant weight).
Because of these limitations, it is often difficult
to compare the incidence and extent of weight
gain caused by different medications. For the
purpose of clinical trials, the Food and Drug
Administration (FDA) defines clinically relevant
weight gain as an increase ≥7% of baseline
weight. This corresponds to an approximate
weight gain of 5 kg in a 70 kg individual.
Unfortunately, statistics regarding weight gain
are not collected in all clinical trials and there-
fore data are not available for all drugs. In some
cases, clinical trials are not long enough to ade-
quately evaluate a drug’s potential to cause
weight gain. When available, the incidence of
weight gain ≥7% of baseline as reported during
prospective, randomized clinical trials is present-
ed in Table 33–1.
MECHANISMS
The proposed mechanisms for drug-induced
weight gain are specific to each particular class of
medication, and for many drugs, the exact cause
of weight gain is unknown. Table 33–2 summa-
rizes the mechanisms of drug-induced weight
gain proposed for various drug classes.
CLINICAL PRESENTATION AND
DIFFERENTIAL DIAGNOSIS
The clinical presentation and extent of weight gain
caused by drugs may vary depending on the drug
class. The extent of weight gain associated with
specific drugs and drug classes is presented in Table
33–3. Several endocrine and psychiatric disorders
as well as environmental and behavioral factors
should be assessed in the process of differentiating
drug-induced weight gain from weight gain due to
other causes. Table 33–4 lists conditions to consid-
er in the differential diagnosis of drug-induced
weight gain.
Anticonvulsants
Anticonvulsant agents, including carbamazepine,
gabapentin, pregabalin, and valproic acid are com-
monly associated with weight gain in children and
adults. Anticonvulsant-induced weight gain is gen-
erally characterized by an increased appetite and
increased calorie consumption.16 A case series of
four patients with epilepsy who were receiving car-
bamazepine therapy describes weight gain ranging
from 7 to 15 kg after 2 months of therapy.5 A more
recent double-blind, randomized study designed to
assess efficacy of carbamazepine add-on therapy in
patients receiving phenytoin for partial seizures
TisdaleC33_629-643 1/12/10 3:34 PM Page 632
632 SECTION VII • Drug-Induced Endocrine Diseases
TABLE 33–2 Mechanisms of Drug-Induced Weight Gain
Drug
Anticonvulsants16
Antidepressants148,149
Antipsychotics148-150
Lithium151
Adjuvant chemotherapy for early-stage breast
Insulin138,152
Steroid hormones139,153,154
cAMP = cyclic adenosine monophosphate; GABA – ␥ = aminobutyric acid; HT = hydroxytryptamine; NK = Not known.
reported weight gain of >7.5% of baseline weight
in 4.7% of patients after 16 weeks.7 Gabapentin has
been reported to cause dose-dependent increases in
weight.8-10 In a randomized, dose-controlled trial of
275 patients (doses ranging from 600 to 2,400
mg/day), 16 patients (6%) experienced weight gain
as an adverse event; 7 (2.6% of the total sample) of
these patients experienced a weight gain >7% of
baseline weight after 26 weeks of therapy.8 In a
review of 44 patients treated with high-dose
gabapentin (mean dose 3,520 mg/day) for
intractable seizures, 34% gained 5% to 10% of
baseline weight and 23% gained >10% of baseline
weight over a period of at least 12 months.10 One
patient who was receiving 6,000 mg of gabapentin
per day discontinued treatment after gaining 27 kg
during 1 year of treatment. Pregabalin has also
been reported to cause dose-dependent weight
gain.11-15 During clinical trials assessing the efficacy
of pregabalin for treatment of partial seizures,
Proposed Mechanism
Enhancement of GABA: 1appetite and 2basal metabolic
rate
Decreased blood glucose concentrations: 1appetite
Blockade of noradrenergic (␣2) receptors:1appetite
Blockade of serotonin (5-HT2C) receptors: 1appetite
Blockade of histamine (H1) receptors: 1sedation and
2physical activity
Blockade of serotonin (5-HT2C ) receptors: 1appetite
Blockade of dopamine (D2) receptors: 1appetite
Blockade of histamine (H1) receptors: 1sedation and
2physical activity
Blockade of noradrenergic (␣1) receptors: 1appetite
Blockade of muscarinic (M1) receptors: 1appetite
Blockade of cAMP in renal tubules: 1thirst (1consumption
of high-calorie drinks)
Blockade of dopamine (D2) receptors: 1appetite
Inhibition of thyroid hormone synthesis: 2basal metabolic
rate
Enhancement of GABA: 1appetite and 2basal metabolic
rate
NK
Promotes glucose uptake into cells: 1glycemic control and
1energy storage
Hypercortisolemia and hyperinsulinemia: 1appetite and
1energy storage
weight gain was reported in 9% to 20% of
patients.11,12 In a retrospective analysis of 101
patients with epilepsy who were treated with pre-
gabalin add-on therapy for at least 1 year, 26
(25.7%) experienced weight gain of >10% of base-
line weight.12 In a 6-month, randomized, con-
trolled trial specifically designed to assess weight
gain associated with pregabalin therapy for epilep-
sy, 41% (25 of 61) of patients experienced a weight
gain >5 kg.13 Valproic acid and valproate are well
recognized as causes of weight gain, with numer-
ous reports in the literature describing significant
weight gain in adults and children.16-21 In their
review of 16 clinical trials, Jallon and Piccard noted
that the incidence of weight gain with valproic
acid varied from 4% to 71%.16 The magnitude of
weight gain reported in the literature has ranged
from 2 to 49 kg during long-term valproate thera-
py.17-21 In a prospective, randomized clinical trial
specifically designed to assess weight changes asso-
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CHAPTER 33 • Weight Gain 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

634 SECTION VII • Drug-Induced Endocrine Diseases

TABLE 33–3 Extent of Weight Gaina Reported with Selected Drugs and Drug Classes (Continued)

Drug Extent of Weight Gain Reported in the Literature

HORMONES
Prednisone 2.6–13 kg over 1 yr129-131
Insulin 2.6–8 kg over 2 mo to 1 yr132,134,135,138
Depot medroxyprogesterone 4.3–9.4 kg over 1–5 yr139-146
a
Reported as mean weight gain unless otherwise noted.

weight increases ranging from 2.4 kg over 4 weeks

TABLE 33–4 Conditions to Consider in the of treatment to 16 kg over 5 months of therapy.43-
Differential Diagnosis of Drug-Induced Weight 45
During short-term clinical trials, 7.5% of adult
Gain4 patients and 49% of children receiving mirtazapine
Endocrine disorders experienced a weight gain ≥7% of baseline
• Cushing’s syndrome weight.22 Serotonin reuptake inhibitors and mixed
• Growth hormone deficiency serotonergic and noradrenergic antidepressants
• Hypothyroidism have been reported to induce small amounts of
• Insulinoma weight loss during short-term clinical trials.148
• Leptin deficiency However, the weight loss observed during the early
Environmental and behavioral factors weeks of therapy may be followed by weight gain
• Overconsumption of calories with long-term treatment.28,29,33,34,36,39 Based on
• Sedentary lifestyle available literature, paroxetine appears to be the
• Smoking cessation most likely to induce significant weight gain.28,29,36
Although the monoamine oxidase inhibitor
Psychiatric disorders (MAOI) phenelzine has been reported to cause clin-
• Binge eating disorder ically significant weight gain, other drugs within
• Depression the MAOI class of antidepressants have not been
• Schizophrenia associated with this effect.47,48

ciated with valproate as compared with lamotrig-

ine, the average weight gain in patients randomly
assigned to the valproate group was 5.8 kg over 32
weeks of treatment.20
Antidepressants
Weight gain induced by tricyclic antidepressant
(TCA) medications has been reported to be dose-
dependent, treatment-duration dependent, and
typically associated with increased appetite and
cravings for sweets and other carbohydrates.24,156 A
review of studies evaluating weight gain associated
with amitriptyline, nortriptyline, and imipramine
reported the average weight increase to be 0.57 to
1.37 kg per month of therapy.24 In comparison to
other TCAs, amitriptyline has been associated with
the largest degree of weight gain.24-26 The tetra-
cyclic antidepressants maprotiline and mirtazapine
have also been reported to cause significant weight
gain in psychiatric patients.40-45 Mirtazapine
increases appetite and has been associated with
Antipsychotics
The drug class with the strongest association with
significant weight gain is the antipsychotics. A
landmark meta-analysis evaluated data regarding
weight gain associated with antipsychotics from
over 80 clinical trials.155 Clozapine was associated
with the greatest extent of weight gain, with an
average gain of 4.45 kg over 10 weeks of treatment
in patients receiving standard doses. Olanzapine,
risperidone, and ziprasidone were associated with
average weight gains of 4.15 kg, 2.10 kg, and 0.04
kg, respectively. Weight gain associated with
ziprasidone was not statistically different from that
associated with placebo. Significant mean weight
increases of 0.48 kg, 2.58 kg, and 3.19 kg were
reported in association with the conventional
antipsychotics haloperidol, chlorpromazine, and
thioridazine, respectively. In this analysis, placebo
treatment was associated with an average weight
loss of 0.74 kg over 10 weeks. The investigators
used a 10-week treatment period for comparisons
because weight measurement data were available at
TisdaleC33_629-643 1/12/10 3:34 PM Page 635
this time point for most patients. However, avail-
able data suggest that weight gain induced by
clozapine and olanzapine continues with treat-
ment duration.
Average weight gains ranging from 7.5 to 10.9
kg over 6 months to 1 year of therapy have been
reported in patients receiving clozap-
ine.55,60,63,64,68,69 In one study, 21% of outpatients
with schizophrenia experienced a weight gain of
≥20% of baseline weight, and 58% of outpatients
experienced weight gains of ≥10% of baseline
weight during 1 year of clozapine therapy.60
Additional case reports have documented marked
weight gains ranging from 30 to 50 kg associated
with clozapine therapy.54,67,70 In patients receiving
olanzapine, average weight gains of 4.1 to 12 kg
have been reported following 6 months to 1 year of
treatment.71,73,74,78,80,81,83-85 Of patients receiving
long-term therapy with olanzapine during clinical
trials (median treatment period, 238 days), 56%
experienced a weight gain of ≥7% of baseline
weight.86
Although conflicting data exist, antipsychotic-
induced weight gain does not appear to be dose-
related.157 Weight gain induced by clozapine and
olanzapine is associated with increased appetite,
carbohydrate craving, and binge eating in some
patients.56,67,158 Based on available information
regarding atypical antipsychotic agents, it appears
that clozapine and olanzapine are associated with
the greatest degree of weight gain.159 Weight gain
with olanzapine and clozapine can progress over 6
months to 1 year of therapy before reaching a
plateau, with most weight gain occurring during
the first 12 weeks.57,58,74 However, some reports
have suggested that clozapine-induced weight gain
may persist for up to 3 to 4 years.57,66 As compared
with other atypical antipsychotics, ziprasidone and
aripiprazole appear to be associated with the small-
est degree of weight gain.158,159
Lithium
Weight gain is a common adverse effect of lithium
therapy, occurring in up to 65% of patients during
long-term treatment.110-113,151 The average weight
gain induced by lithium has been reported to range
from 4.5 to 11.5 kg over 1 to 6 years.110-112
However, weight increases of up to 28 kg have been
described.110 Women and patients with elevated
baseline BMI may be more likely to gain weight
with lithium therapy than other patients. Weight
gain induced by lithium occurs primarily within
the first 2 years of therapy before stabilizing, and is
characterized by an increase in appetite and thirst,
CHAPTER 33 • Weight Gain 635
resulting in overconsumption of high-calorie bev-
erages.110,111,160
Adjuvant Chemotherapy in
Early Stage Breast Cancer
Observational studies conducted in women with
early-stage breast cancer have reported significant
weight increases in the majority of patients receiv-
ing adjuvant chemotherapy.122-128 Weight gain
associated with adjuvant chemotherapy in this
patient population has been reported to range
from 2.5 to 6.2 kg during the treatment phase, and
from 2.3 to 12.3 kg for 1 to 2 years after treat-
ment.127,128 Specific drugs reported to be associated
with weight gain in this patient population include
tamoxifen, prednisone, cyclophosphamide,
methotrexate, and fluorouracil.125,126 In contrast,
some studies have reported no significant increas-
es in weight in women who have received adjuvant
chemotherapy regimens consisting of cyclophos-
phamide alone or in combination with paclitax-
el.161,162 The exact cause of weight gain in patients
with early-stage breast cancer is poorly understood,
but may be related to the underlying disease state,
increased calorie consumption, and decreased
physical activity.163
Hormones
Weight gain is well documented as a consequence
of therapy with exogenously administered hor-
mones, including glucocorticoids, insulin, and sex-
steroid analogs. In fact, some steroid hormones are
specifically used to promote weight gain in certain
patient populations.164-167 Daily oral prednisone
therapy has been associated with dose-dependent
increases in weight ranging from 2.6 to 13 kg over
1 year of treatment.129,131 Glucocorticoid-induced
weight gain is characterized by central adiposi-
ty,153,154 which is associated with increased health
risks as compared with peripheral obesity.4
Insulin therapy is associated with an increase
in body weight in patients diagnosed with both
type 1 and type 2 diabetes.132-138 Weight gain is
more common in patients receiving intensive
insulin therapy than in those receiving conven-
tional therapy.132-134,137 Weight gain has been
reported to range from 2.6 to 8 kg over 2 months
to 1 year of insulin therapy.132,134,135,138 Although
sulfonylurea and thiazolidinedione drugs have
been reported to cause increases in weight, partic-
ularly when used in combination with insulin, the
weight gain associated with these agents alone
does not typically exceed 5 kg.152,168,169
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636 SECTION VII • Drug-Induced Endocrine Diseases

Conflicting literature exists regarding the sig-

nificance of weight gain associated with oral con-
traceptives.170 Depot medroxyprogesterone has
been reported to induce weight gain ranging from
4.3 to 9.4 kg over treatment periods varying in
length from 1 to 5 years.139-146 Adolescents and
women with elevated baseline BMI appear to be at
increased risk for weight gain associated with hor-
monal contraceptives.143,144
RISK FACTORS
The incidence and extent of drug-induced weight
gain differ significantly between patients and
across drug classes. Potential risk factors for drug-
induced weight gain are listed in Table 33–5.
TABLE 33–5 Risk Factors for Drug-Induced
Weight Gain
Anticonvulsants16
• Dose-dependent (valproic acid, gabapentin)
• Female sex (valproic acid)
Antidepressants148,171
• Dose-dependent
• Increased treatment duration
• Weight increases during first week of therapy
Antipsychotics109,148,155,172
• Low baseline BMI
• Children and adolescents
• Positive treatment responsea
• Increased treatment duration (clozapine)
• Genetic 5-hydroxytryptamine2c-receptor polymor-
phism
• Treatment with clozapine or olanzapine
Lithium148,151
• Female sex
• Elevated baseline BMI
Adjuvant chemotherapy for early-stage breast
cancer173
• Premenopausal status
• Multi-agent chemotherapy regimens of long duration
Glucocorticoids129,131
• Dose-dependent
• Increased treatment duration
Insulin152
• Intensive insulin therapy
Depot medroxyprogesterone140
• Adolescents with elevated baseline BMI
a
Indicates inconsistent reports in the literature.
BMI = Body-mass index
MORBIDITY AND MORTALITY
Obesity is a chronic disease that contributes signif-
icantly to overall morbidity and mortality.4,174,175
Epidemiologic data suggest that morbidity and
mortality begin to increase with a BMI ≥25.176
Increased morbidity has also been reported with
modest weight increases, even when weight
remains within the healthy weight range (BMI,
18–24).1-3 Obesity is directly linked to the develop-
ment of hypertension, hyperlipidemia, and type 2
diabetes, and is considered an independent risk
factor for the development of coronary heart dis-
ease.4 Importantly, obesity may be the second most
common factor contributing to preventable death
in the U.S., making it second only to cigarette
smoking.175 Obesity and overweight play signifi-
cant roles in the development of gallbladder dis-
ease, degenerative joint disease, sleep apnea, and
certain types of cancers. In addition to these health
risks, overweight and obesity are associated with a
significant psychological burden, potentially lead-
ing to depression and other psychological condi-
tions. Therefore, drug-induced weight gain,
particularly to the extent that it contributes to
overweight or obesity, may be associated with an
increased risk of morbidity and mortality. Patients
experiencing antipsychotic-induced weight gain
have been shown to be at increased risk for type 2
diabetes and dyslipidema.159
PREVENTION
Prevention of drug-induced weight gain is
achieved primarily through the implementation of
counseling strategies that instruct patients and
caregivers about behavioral modification, a proper
weight-maintenance diet, and routine exercise
prior to initiation of the potentially causative
agent.159,177-179 Few studies have evaluated the clin-
ical effectiveness of behavioral and dietary inter-
ventions to minimize or prevent drug-induced
weight gain. However, small differences in weight
changes between patients receiving behavioral and
dietary interventions and those receiving standard
care have been reported after 6 months of treat-
ment when the interventions were implemented at
the time of initiation of antipsychotic thera-
py.180,181 Small studies have also evaluated the effi-
cacy of drug treatment for the prevention of
antipsychotic-induced weight gain.182-185 In gener-
al, these studies have not reported positive results.
No significant differences in degree of weight gain
were reported in association with the concomitant
TisdaleC33_629-643 1/12/10 3:34 PM Page 637
use of drugs such as fluoxetine, nizatidine, famoti-
dine, and metformin in patients receiving olanzap-
ine therapy.182-185 However, two small uncontrolled
trials evaluating topiramate combination treat-
ment with olanzapine or risperidone, in patients
diagnosed with bipolar disorder, reported an aver-
age weight loss of 0.5 kg and 1.1 kg, respectively,
after 1 year of therapy.186,187 Additional studies are
needed to define the role of pharmacotherapy for
the prevention of drug-induced weight gain. At
present, behavioral and dietary interventions are
the mainstay for prevention.
For antipsychotic medications, a joint consen-
sus statement issued by the American Diabetes
Association, the American Psychiatric Association,
the American Association of Clinical
Endocrinologists, and the North American
Association for the Study of Obesity, provides spe-
cific recommendations for patient monitoring
with regard to weight.159 The panel recommends
collection of baseline personal and family history
regarding obesity, and measurement of height,
weight, and waist circumference to determine
whether the patient is currently overweight or
obese or at risk to become overweight or obese in
the future. Selection of an antipsychotic agent with
less likelihood to cause significant weight gain may
be preferable for at-risk patients. The patient, fam-
ily members and caregivers should also be
informed of the potential for significant weight
gain and the subsequent increased risk of diabetes
and dyslipidemia. Body weight should then be
reassessed at 4, 8, and 12 weeks after the initiation
of therapy and quarterly thereafter. The panel rec-
ommends switching the antipsychotic agent to
another medication with less propensity to cause
weight gain if the patient gains >5% of baseline
weight during any time in therapy. Approaches to
help prevent drug-induced weight gain are
reviewed in Table 33–6.
MANAGEMENT
The first step in managing clinically relevant drug-
induced weight gain is to consider discontinuation
of the causative drug and substituting another
agent within the same drug class that is associated
with less weight gain. Unfortunately, this option
may not always be practical or possible. If discon-
tinuing the offending drug is not feasible, behav-
ioral modification in combination with a
low-calorie diet and increased physical activity has
proven effective for some obese patients taking
antipsychotic agents.180,188-194 A 1-year study of
standard nutrition, exercise, and behavioral inter-
CHAPTER 33 • Weight Gain 637
TABLE 33–6 Approaches to Help Prevent Drug-
Induced Weight Gain159,160,177-179
• Consider patients’ baseline height, weight, waist cir-
cumference, and risk factors for weight gain when
selecting drug therapy.
• Educate the patient, family, and caregivers regarding
diet, physical activity, and behavior medication.
• Monitor weight regularly and frequently.
• Refer patients to weight-management programs or
nutritional counseling.
• If patient gains >5% of baseline weight, switch to
another agent that is less likely to cause weight gain.
ventions in patients with schizophrenia who had
gained weight while receiving antipsychotic agents
reported an average weight loss of 3 kg, while a
comparison group of similar schizophrenic
patients receiving usual care experienced an aver-
age weight increase of 3.2 kg.194 Current guidelines
recommend a low-calorie diet that reduces daily
caloric intake by 500 to 1,000 kcal and mimics the
diet outlined by the Third Report of the Expert
Panel on the Detection, Evaluation, and Treatment
of High Blood Cholesterol in Adults.195 With
respect to recommendations regarding physical
activity, an appropriate initial plan consists of 30
to 45 minutes of moderate exercise 3 to 5 days each
week, with an ultimate goal of 30 minutes of mod-
erate exercise every day. A realistic treatment goal
for the above recommendations is a 10% reduction
in body weight over 6 months of therapy, which
correlates to a loss of approximately 1 to 2 lb per
week.4
Drug therapy is generally recommended as an
adjunct to behavioral modification, a low-calorie
diet, and increased physical activity when the com-
bination of these three interventions has failed to
produce sufficient weight loss in patients with BMI
measurements ≥30 or those with BMI ≥27 who
have comorbid conditions.4 Few data exist regard-
ing the efficacy of pharmacotherapy for the treat-
ment of drug-induced weight gain. However, case
reports and small studies have reported some suc-
cess associated with use of amantadine, bupropion,
metformin, nizatidine, sibutramine, topiramate,
and orlistat in psychiatric patients with drug-
induced weight gain.196-212 Of the drugs that have
been used to treat patients with drug-induced
weight gain, orlistat and sibutramine are the only
agents currently approved by the U.S. FDA for the
long-term management of obesity. Finally, it is
important to note that a small number of case
reports have documented psychotic episodes asso-
ciated with sibutramine therapy in obese patients
TisdaleC33_629-643 1/12/10 3:34 PM Page 638
638 SECTION VII • Drug-Induced Endocrine Diseases
with psychiatric illness as well as in patients who
had no previous history of psychiatric illness.213-215
Therefore, careful assessment of mental status
before and during therapy is recommended.
Although it appears that some patients may bene-
fit from pharmacotherapy when the combination
of behavioral modification, low-calorie diet, and
increased physical activity has failed to produce
sufficient weight loss, further studies are needed to
better define the role of pharmacotherapy in the
management of drug-induced weight gain.
INFORMATION FOR PATIENTS
Patients who are to receive medications that may
cause clinically relevant weight gain should be
informed of the potential for this drug-induced dis-
ease prior to initiation of therapy. Moreover,
patients should be encouraged to begin a weight-
maintenance diet plan and exercise routine prior
to the initiation of therapy to help minimize
potential weight gain. Appropriate education is a
critical component in successful weight manage-
ment. Therefore, patients should be provided with
behavior modification information and education
related to appropriate dietary choices and lifestyle
modification. In addition, patients should be
instructed to monitor their weight to detect any
changes during drug therapy.
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TisdaleC34_644-685 1/12/10 3:35 PM Page 644
CHAPTER 34
Temperature
Dysregulation
N ormal human body temperature is 36.7 to
37°C orally; when measured rectally, tempera-
ture is 1° higher, and axillary temperature is 1°
lower. Intraindividual body temperature varies
throughout the day and over time, and slight vari-
ations may also be noted between individuals. The
anterior hypothalamus maintains body tempera-
ture within a relatively narrow range by sensing
core body temperature and adjusting (homeostatic)
mechanisms in the autonomic nervous system.
Central dopaminergic and serotonergic pathways
are also involved in temperature regulation via the
autonomic nervous system. Disruptions of function
of the hypothalamus, a relative decrease in serum
dopamine concentrations, or alterations in sero-
tonin balance may lead to autonomic impairment
and dysregulation in body temperature. Drugs may
act as antigens to induce an immune-mediated
response, causing the release of endogenous pyro-
gens such as interleukin-1 and tumor necrosis fac-
tor from leukocytes, resulting in a febrile response.
Uncommonly, drugs may cause an idiosyncratic
temperature dysregulation. Peripheral factors that
help maintain normal body temperature include
cutaneous and regional blood flow, hormonal
responses, shivering, and sweating. Drugs such as
anticholinergics and sympathomimetics that affect
these peripheral factors directly or indirectly will
not be discussed in detail in this chapter.
Drug-induced hyperthermia may be divided
into five general categories: altered thermoregula-
tory mechanisms, drug administration–related
fever, fevers relating to the pharmacologic action
of the drug, idiosyncratic reactions, and hypersen-
sitivity reactions.1
A drug may alter thermoregulation by disrupt-
ing central dopamine or serotonin homeostasis, or
644
Susan M. Wilson
via peripheral alteration of normal hypothalamic
temperature balance. Two such drug-induced dys-
regulation diseases, neuroleptic malignant syn-
drome (NMS) and serotonin syndrome, will be
discussed in subsequent sections.
Drug administration–related fever is caused by
pyrogens or endotoxins and is often encountered in
association with agents that are derived from micro-
bial products. These pyrogens induce an immune-
mediated response causing the release of cytokines
such as interleukin-1 and tumor necrosis factor from
leukocytes, leading to fever. Examples of this
include fever during amphotericin B and bleomycin
infusion. Further, an administration-related
response associated with fever may occur in associa-
tion with drugs given intravenously (phlebitis) or
intramuscularly (sterile abscess). Pentazocine and
paraldehyde are known to induce such a response
when administered intramuscularly.
Fevers relating to the pharmacologic action of
drugs are most commonly observed in the treat-
ment of infections or cancer as pyrogen is released
from damaged or dying cells. The classic example
of this is the Jarisch–Herxheimer reaction that
occurs during the treatment of syphilis. Patients
taking clozapine may experience fever potentially
due to the immunomodulating effects of increased
concentrations of interleukin-6 and tumor necrosis
factor.2,3
Malignant hyperthermia is a specific idiosyn-
cratic reaction that results in the development of
severe fever and muscle damage in susceptible
individuals receiving causative drugs. Malignant
hyperthermia will be discussed in detail later in
this chapter.
Finally, the most common cause of drug-
induced hyperthermia is a hypersensitivity reac-
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CHAPTER 34 • Temperature Dysregulation 645

tion. The reaction is mediated through immuno-
logic mechanisms caused by drugs, most common-
ly antibiotics.1
Conditions to consider in the differential diag-
nosis of the drug-induced hyperthermia include
primary central nervous system disorders (infec-
tion, tumors, ischemic or hemorrhagic stroke, trau-
ma, seizures), systemic diseases (infections, cancer,
metabolic conditions, endocrinopathies, autoim-
mune disorders), and toxins (carbon monoxide,
phenols, strychnine, tetanus). Drug rash with
eosinophilia and systemic symptoms, discussed in
Chapter 6, “Allergy, Pseudoallergy, and Cutaneous
Diseases,” is another condition in which hyper-
thermia is often observed. A comparison of the
signs and symptoms of the drug-induced hyper-
thermic conditions to aid in diagnosis is presented
in Table 34–1.
In general, antipyretics have no role in the
treatment of drug-induced hyperthermia.
Although they are effective in the treatment of
hyperthermia due to drug fever and serum sick-
ness–like reaction, careful temperature monitoring
is very important. The mechanism of fever in these
cases is a hypothalamus-mediated increase in the
body’s core temperature. Antipyretics are not effec-
tive for the treatment of hyperthermia secondary
to NMS, serotonin syndrome, or malignant hyper-
thermia because the hyperthermia represents an
alteration in thermoregulatory balance and hyper-
metabolism and not a fever.
Drug-induced hypothermia is much less com-
mon than hyperthermia. Drug-induced hypother-
mia is not normally observed in association with
prescription or nonprescription drugs, but rather
typically occurs in association with illicit drugs.
Agents with agonist activity at the gamma-
aminobutyric acid (GABA) receptor are often asso-
ciated with hypothermic effects. GABA is a primary
inhibitory central neurotransmitter. GABA,
dopamine, serotonin, and opioid peptides are
mediators in temperature regulation; the primary
effect of GABA is to decrease temperature.
HYPERTHERMIA DUE
TO DRUG FEVER
Drug fever is generally recognized as a febrile
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
646 SECTION VII • Drug-Induced Endocrine Diseases
may be elucidated.1 Drug fever tends to be a diag-
nosis of exclusion following a review of a patient’s
drug therapy, clinical presentation characteristics,
and laboratory values. An early presumptive diag-
nosis of drug fever and initiation of treatment may
reduce unnecessary further evaluation and patient
discomfort.
CAUSATIVE AGENTS
Although any drug has the potential to cause drug
fever, certain medications should be considered
with a higher level of suspicion. Drugs that have
been reported to cause drug fever are listed in Table
34–2.4-113 Anticonvulsants, certain antihyperten-
sive drugs, antiarrhythmic agents, and antibiotics
are the drugs that have been most commonly asso-
ciated with drug fever. Of the antibiotics, peni-
cillins and cephalosporins are most often
implicated. Antibiotics that are rarely or have
never been reported to cause drug fever include
chloramphenicol, erythromycin, clindamycin, and
aminoglycosides.1,10 It is important for clinicians to
be aware of the clinical presentation of patients
with drug fever and to suspect this condition in
patients with hyperthermia in whom other causes
are unlikely or have been ruled out.
EPIDEMIOLOGY
The true incidence of drug fever is unknown
because of underreporting and misdiagnosis. It
has been estimated that a drug is the cause of fever
in approximately 5% to 15% of hospitalized
patients.114-116 The incidence is even higher in
patients receiving antimicrobials other than
antibiotics, such as antiviral agents, and in
patients receiving other classes of medications,
particularly cardiovascular drugs.7 It has been pos-
tulated that the incidence of drug fever is higher
in older patients and in female patients; however,
this has not been substantiated.7,114 It has been
demonstrated that drug fever due to antibiotics is
more likely to occur in younger patients.10
Determination of the true incidence is difficult
because the total number of patients treated is not
known.
MECHANISMS
Drug fever has been hypothesized to be a type III
hypersensitivity immune response reaction, based
upon the time course of the onset of symptoms,
the clinical presentation, which may include
eosinophilia, and its usual recurrence with rechal-
lenge.1,10,115,117,118 Drugs or their metabolites may
be directly antigenic or act as haptens and combine
with endogenous proteins, which become anti-
gens. The immune response may include release of
immune mediators and cause the release of pyro-
gens, thereby inducing fever.
CLINICAL PRESENTATION AND
DIFFERENTIAL DIAGNOSIS
Signs, symptoms, and characteristics of drug fever
are presented in Table 34–3. The onset of fever is
generally 7 to 10 days from the time of initiation of
therapy with the culprit drug. The time of onset
may vary by drug class, with the shortest time
interval observed with antineoplastic agents
(mean, 6 days) and antimicrobials (mean, 7.8
days), and a much longer time interval observed
with central nervous system agents (mean, 18.5
days) and cardiac drugs (mean, 44.7 days).7 Because
of this variability, assessment of the temporal rela-
tionship between drug initiation and fever onset
does not generally aid in the diagnosis. Patients
who have been previously sensitized have symp-
toms much more quickly, usually within hours of
reintroduction of the offending drug.
The pattern of fever varies as well and may
present as continuous, remittent, intermittent, or
hectic.1,7,8,10,114 Hectic fever is variable or fluctuat-
ing; the use of antipyretics or other cooling meas-
ures may contribute to this pattern. Chills and
rigors may occasionally accompany fever, mimick-
ing the symptoms of sepsis, thereby complicating
the diagnosis. Patients may experience a low max-
imum temperature (Tmax), or it may be as high as
43°C.7 No strong association has been made
between Tmax and any patient characteristics,
except an inverse relationship between Tmax and
age.7 Higher temperatures have been observed in
patients taking antineoplastic agents; however, this
may have been due to the underlying disease.
Cutaneous manifestations are observed in 18%
to 29% of patients.1,7,10 After discontinuation of
the offending agent, a maculopapular rash may
occur that may have an urticarial component with
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
some patients. This relative bradycardia in patients
without another explanation (e.g., those taking ␤-
blockers, second- or third-degree heart block) has
been used as evidence favoring the diagnosis of
drug fever, particularly in patients in whom infec-
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CHAPTER 34 • Temperature Dysregulation 647

TABLE 34–2 Agents Implicated in Drug Fever4

Drug Incidence Level of Evidence
(see page xii for explanation)

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

648 SECTION VII • Drug-Induced Endocrine Diseases

TABLE 34–2 Agents Implicated in Drug Fever4 (Continued)

Drug Incidence Level of Evidence

Isoniazid58-62 NK C
Levamisole63 NK C
Lysergic acid diethylamide (LSD)64,65 NK C
Maprotiline8 NK C
Mebendazole66 NK C
Methicillin7 NK C
Methotrexate17 NK C
Methyldopa7,67-73 NK C
Metoclopramide74 NK C
Mezlocillin27,28 NK C
Minocycline75 NK C
Mycophenolate76 NK C
Nafcillin28 NK C
Nifedipine77 NK C
7,78
Nitrofurantoin NK C
Penicillin1,7,28 NK C
Phenytoin1,7 NK C
Piperacillin10,27,28 NK C
Potassium iodide1,79,80 NK C
Procainamide7,81-83 NK C
Procarbazine84 NK C
Propafenone85 NK C
Propylthiouracil7,86-90 NK C
Quinidine7,83,91-97 NK C
Quinine93 NK C
Ranitidine98 NK C
Rifampin62,99 NK C
Stavudine100 NK C
Streptomycin101 NK C
Streptozocin102,103 NK C
Sulfonamides1,7,91,104,105 NK C
Teicoplanin106 NK C
Tetracycline7 NK C
Thioridazine107 NK C
Tolmetin108 NK C
Trazodone8 NK C
Triameterene109,110 NK C
Trifluoperazine111 NK C
Vancomycin7,112 NK C
Zoledronic acid113 NK C
NK = Not known.
TisdaleC34_644-685 1/12/10 3:35 PM Page 649
TABLE 34–3 Signs and Symptoms of Drug
Fever
• Relative sense of well-being
• Headache
• Myalgias
• More common
• Fever
• Leukocytosis
• Less common
• Maculopapular rash
• Relative bradycardia
• Thrombocytopenia
• Eosinophilia
• Elevated erythrocyte sedimentation rate
• Elevated serum aspartate concentration
tion or sepsis is suspected.114,115 Another common
observation in patients with drug fever is the
appearance of well-being relative to the degree of
hyperthermia; often patients are not aware of the
fever.
Laboratory abnormalities that may occur
include leukocytosis, thrombocytopenia, eosin-
ophilia, and markedly elevated erythrocyte sedi-
mentation rate and serum aspartate amin-
otransferase, alanine aminotransferase, and alka-
line phosphatase concentrations.7,10,27,44,74,85,110,120
Patients may also experience headache and myal-
gias.7
Differential diagnosis of drug fever is difficult
because of the inconsistent and nonspecific signs
and symptoms described above. Patients often
undergo an extensive evaluation and treatment for
infection, including blood cultures, radiologic
studies, antibiotics, and antipyretic therapy. A rea-
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
fever-inducing medications may be considered.
RISK FACTORS
Risk factors for the development of drug fever have
not been fully elucidated. Patients with a prior
drug allergy and those with a history of atopic dis-
ease have not been shown to be more susceptible
to drug fever.7 Patients with glucose-6-phosphate
dehydrogenase deficiency may be at higher risk for
drug fever associated with methyldopa, because of
drug accumulation and higher serum concentra-
tions.73 Younger patients may be at higher risk for
drug fever due to antibiotics; female and older
CHAPTER 34 • Temperature Dysregulation 649
TABLE 34–4 Conditions to Consider in the
Differential Diagnosis of Drug Fever
• Infection
• Sepsis
• Heat stroke
• Endocrine disorders
• Hematologic or solid organ malignancy
• Drug withdrawal (alcohol, benzodiazepines, levodopa)
patients may be at higher risk with other
drugs.10,114
MORBIDITY AND MORTALITY
The outcome for patients with drug fever may
range from full recovery from very mild illness to
significant morbidity and mortality, although
death due to drug fever is relatively rare. In one
evaluation of 290 cases of drug fever, 10 patients
died.7 Those who died were more likely to have
higher temperatures and an underlying diagnosis
of cancer.7 Most other reviews and cases in the lit-
erature have not reported death as a common
event associated with drug fever. Continuing the
offending agent may put a patient at risk for more
serious sequelae, including organ dysfunction, as
the syndrome may be expected to worsen.
Progression of disease and organ dysfunction is the
most probable cause of death due to drug fever.
Admission to the hospital is common for the eval-
uation of fever, and the extensive laboratory and
radiologic testing required for hospitalized patients
may increase the length of stay and cost of treat-
ment in these patients.1,7
PREVENTION
The recurrence of drug fever may be prevented by
avoiding the offending agent and using an alterna-
tive drug if possible. Cross-sensitivity is a potential
concern but has not been reported after the reac-
tion has completely resolved. After discontinua-
tion of the offending agent, a secondary immune
reaction may be observed if the patient is taking
another sensitizing drug.1 The mechanism by
which this occurs is not well understood but is not
thought to be mediated via cross-allergenicity, as
these drugs are often pharmacologically unrelat-
ed.116 Desensitization protocols should be imple-
mented in patients for whom no other treatment
options are possible. Desensitization is usually
TisdaleC34_644-685 1/12/10 3:35 PM Page 650
650 SECTION VII • Drug-Induced Endocrine Diseases
accomplished by administering very small doses of
the drug via the intravenous or oral route. The dose
is gradually increased over hours or days until the
full therapeutic dose may be safely administered.
In addition to general desensitization guidelines,
specific desensitization protocols have been pub-
lished for many drugs that cause drug fever, includ-
ing acyclovir, allopurinol, aspirin, imipenem–
cilastatin, isoniazid, penicillin, rifampin, ticar-
cillin–clavulanate, trimethoprim–sulfamethoxa-
zole, chlorambucil, and vancomycin.121,122
MANAGEMENT
Immediate discontinuation of the suspected
causative agent is imperative, as drug-induced fever
is unlikely to remit otherwise (Table 34–5). The fever
generally resolves within 72 hours of discontinua-
tion of the offending drug, and no other treatment
may be necessary. Rarely, 4 to 5 days may be
required for resolution of fever if drug or metabolite
elimination is prolonged. For patients receiving
therapy with multiple medications and for whom
the fever-inducing drug is not known, it is advisable
to discontinue all non-life-sustaining medications,
particularly those of higher suspicion, including all
antimicrobial drugs, if possible. Medications may be
reintroduced cautiously, one at a time, if necessary
after fever abatement. Corticosteroids may be used
to help prevent or treat fever and other manifesta-
tions of drug fever if continuation or reintroduction
of a particular potential culprit drug is necessary.
Corticosteroids are also indicated in patients with
severe systemic manifestations of drug fever, includ-
ing vital organ involvement. Corticosteroids should
be used judiciously, particularly in patients with
concomitant infection or increased risk of infection
or in those with preexisting immunosuppression
from disease or other drug therapy. Antipyretics
should be avoided in order to facilitate monitoring
of the patient’s response to discontinuation of sus-
pected sensitizing medications, and should be
reserved for use as a comfort measure, if necessary.
TABLE 34–5 Management of Drug Fever and
Serum Sickness–Like Reaction
• Discontinue suspected agent
• Discontinue all non-life-sustaining therapies
• Corticosteroids for treatment of severe systemic signs
and symptoms
• Antihistamines may be considered for rash-associated
pruritus
Rechallenge is controversial. Numerous pa-
tients have been rechallenged with relatively few
serious sequelae; however, there is the potential for
the occurrence of a faster onset, more severe drug
fever reaction after rechallenge.7 The risks and ben-
efits of rechallenge should be weighed prior to
reintroduction of the suspected agent.
Appropriate monitoring for patients with sus-
pected drug fever includes resolution of signs and
symptoms after discontinuation of the suspected
drug or drugs, most importantly fever, within 72
hours (Table 34–6). Patients should also be moni-
tored for signs and symptoms of infection in the
event that drug fever was misdiagnosed or in cases
of concomitant infection.
INFORMATION FOR PATIENTS
General education of patients receiving a new pre-
scription for a medication that may cause drug
fever is imperative. This is particularly important
for those receiving prescriptions for antibiotics or
other drugs with which drug fever occurs more fre-
quently, including anticonvulsants. Patients
should be counseled regarding the approximate
time of onset and signs and symptoms to monitor,
and should be instructed about when to seek med-
ical attention. Sudden onset of fever within hours
of initiating drug therapy, particularly with a drug
to which the patient has been previously exposed,
requires medical evaluation. A fever that is not
associated with other symptoms of infection, and
one that is temporally related to the initiation of
drug therapy, should prompt the patient to contact
a health care professional. Clinicians should
instruct patients to be aware of a fever and the cor-
TABLE 34–6 Monitoring Parameters for Patients
in Whom Drug Fever or Serum Sickness–Like
Reaction Develops
• Temperature
• Heart rate
• Respiratory rate
• Pulse oximetry
• White cell count with differential
• Platelets
• Coagulation profile
• Serum electrolyte concentrations
• Blood urea nitrogen and serum creatinine concentra-
tions
• Liver function tests (aspartate aminotransferase, ala-
nine aminotransferase) and alkaline phosphatase
TisdaleC34_644-685 1/12/10 3:35 PM Page 651
responding time interval expected for each drug
class. Patients receiving antibiotics, central nervous
system agents, or cardiac drugs should report a
fever that presents within 7 to 10 days, 3 weeks, or
4 to 6 weeks, respectively, after initiation of thera-
py. Finally, patients with a history of safe antibiot-
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.
HYPERTHERMIA DUE TO SERUM
SICKNESS–LIKE REACTION
Serum sickness occurs after the administration of
heterologous antitoxin serum. When the syn-
drome is associated with any other antigenic
source, it is known as a serum sickness–like reac-
tion (SSLR).123,124 SSLR occurs most commonly
because of drug administration. Although antibi-
otics are commonly implicated, SSLR has been
reported in association with a wide variety of med-
ications. SSLR may be a form of drug fever, may
accompany drug fever, or may be an extension of
drug fever.
CAUSATIVE AGENTS
As first described, the primary drugs reported to
cause SSLR were those that contain antigenic (for-
eign) material, such as antitoxins, vaccines and
antivenom.125-128 Since the advent of recombinant
human-derived biologic agents, most reports of
SSRL have been described in association with
antibiotics, classically cefaclor. Drugs that have
been reported to induce SSRL are listed in Table
34–7.129-192
EPIDEMIOLOGY
It is difficult to determine the incidence of SSLR.
Most available information is related to antibiotic-
associated SSLR. It has been estimated that SSLR
occurs in approximately 0.2% of drug courses and
in 0.5% of pediatric patients receiving multiple
courses of antibiotics.133 Serum sickness accounts
for up to 68% of drug-induced reactions reported
in association with cefaclor.152 One review of
antibiotic use found 5 cases of SSLR in 3,553 cours-
es of cefaclor; 5 cases in 5,597 courses of amoxi-
cillin; 1 case in 13,487 courses of trimethoprim–
CHAPTER 34 • Temperature Dysregulation 651
sulfamethoxazole; and 1 case in 2,325 courses of
penicillin.134 The relative risk of SSLR associated
with antibiotic therapy was 65.1. The risk of SSLR
associated with cefaclor was 14.8 relative to amox-
icillin. Multiple courses of antibiotics have been
found to increase the risk of the syndrome.134,169
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
endogenous proteins may form soluble immune
complexes or antigens. These circulating soluble
immune complexes deposit in tissues and activate
an inflammatory response, causing the release of
mediators such as histamine, serotonin, comple-
ment, and platelet-activating factor. This leads to
tissue injury and the clinical manifestations of
serum sickness.
CLINICAL PRESENTATION AND
DIFFERENTIAL DIAGNOSIS
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-
ing secondary exposure is much shorter, usually 1
to 4 days.163,164 The reaction may occur even after
discontinuation of a causative agent, and diagno-
sis can be considerably more difficult in this situa-
tion.136,161 Fever, malaise, and lymphadenopathy
are the cardinal symptoms of SSLR (Table 34–8).
Patients may also experience arthralgias, particu-
larly in the major joints, and myalgias, commonly
in the hands and feet. Urticaria and various types
of skin eruptions are common, including a morbil-
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
leukocytosis with or without a left shift, increased
aspartate aminotransferase, alanine aminotrans-
ferase, lactate dehydrogenase, and alkaline phos-
phatase concentrations, although these are
inconsistent findings. Proper diagnosis requires
careful questioning in patients with the suggestive
signs and symptoms. Other conditions to consider
in the differential diagnosis include febrile illness
and other drug-induced hyperthermic conditions
(Table 34–9). In general, the presence of fever,
arthralgias, and lymphadenopathy, although not
always present, are useful clues to the diagnosis of
drug-induced SSLR.
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652 SECTION VII • Drug-Induced Endocrine Diseases

TABLE 34–7 Agents Implicated in Drug-Induced Serum Sickness–Like Reaction

Drug Incidence Level of Evidence
(see page xii for explanation)
129
6-Mercaptropurine NK C
Amoxicillin130-135 0.089% B
Bupropion136-140 NK C
Carbamazepine141 NK C
Cefaclor132,142-152 0.141% B
Cefazolin153 NK C
Cefprozil154 NK C
Ceftriaxone155 NK C
Cefuroxime155,156 NK C
Cephalexin132 NK C
Ciprofloxacin157,158 NK C
Clopidogrel159,160 NK C
Fluoxetine161-164 NK C
Griseofulvin165 NK C
166
Infliximab NK C
Iron dextran167 NK C
Itraconazole168 NK C
Meropenem169 NK C
Metronidazole170 NK C
Minocycline171-175 NK C
N-acetylcysteine176 NK C
Natalizumab177 NK C
Penicillin133,134,178 0.043% B
Propranolol179 NK C
Rifampin180 NK C
Rituximab181-187 NK C
Streptokinase188-191 NK C
Sulfonamides with trimethoprim132,134 0.007% B
Ticlopidine192 NK C
NK = Not Known

for patients with significant arthralgic involvement

RISK FACTORS due to disability and for supportive therapy.

Risk factors for the development of SSLR in chil-

dren prescribed amoxicillin or cefaclor include
younger age (<5 years), longer course of antibiotic
therapy, and multiple courses of antibiotics.134 Risk
factors in adults and for SSLR due to drugs other
than antibiotics have not been identified.
MORBIDITY AND MORTALITY
In general, the course and outcome of drug-induced
SSLR are benign. Hospitalization may be required
PREVENTION
An initial event of drug-induced SSLR is unlikely to
be effectively prevented. Judicious antibiotic use,
particularly in children, is recommended. The use
of cefaclor is associated with a higher incidence of
occurrence as compared with that due to other
antibiotics; however, this is not reason enough to
avoid the use of this agent.
For secondary prevention of SSLR, the offend-
ing agent should not be administered again.
TisdaleC34_644-685 1/12/10 3:35 PM Page 653
TABLE 34–8 Signs and Symptoms Associated
with Drug-Induced Serum Sickness–Like Reaction
• Malaise
• Arthralgias
• Myalgias
• Urticaria
• Fever
• Lymphadenopathy
• Morbilliform or purpuric rash
• Edema
• Leukocytosis
• Increased liver transaminases (aspartate aminotrans-
ferase, alanine aminotransferase), lactate dehydroge-
nase, and alkaline phosphatase
Another drug from the same pharmacologic class
may be initiated, with close monitoring and
thorough patient education. There are no data
demonstrating a risk of cross reactivity, and there
are cases reported in which another drug from
the same class was used without sequelae.142,195
Fluoxetine desensitization has been implement-
ed successfully in patients with a previous SSLR
reaction.164
MANAGEMENT
Discontinuation of the causative drug is the pri-
mary treatment (see Table 34–5), and typically
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
completely resolve.175 Medical management may
include antihistamines for urticaria and pruritus,
and in more severe or worsening cases, corticos-
teroids.137 Steroids have proven very successful in
rapidly reversing symptoms, including rash, joint
pain, and facial swelling or edema. Corticoste-roids
may be administered intravenously or orally in a
fixed or tapering regimen over 5 to 14
days.137,139,142,150,151,157-159,161,167,168,172,180,181,188
Monitoring parameters in patients with SSLR
include those listed in Table 34–6, in addition to
resolution of rash, pruritus, and arthralgias.
INFORMATION FOR PATIENTS
Patient education is similar for drug fever and
drug-induced SSLR. Patients should be aware of the
CHAPTER 34 • Temperature Dysregulation 653
TABLE 34–9 Conditions to Consider in the
Differential Diagnosis of Drug-Induced Serum
Sickness–Like Reaction
• Infection
• Heat stroke
• Endocrine disorders
• Hematologic or solid organ malignancy
• Drug withdrawal (alcohol, benzodiazepines, levodopa)
potential for drug-induced SSLR, the approximate
onset, signs and symptoms, and when to seek addi-
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.
HYPERTHERMIA DUE TO
NEUROLEPTIC MALIGNANT
SYNDROME
First described in 1960, neuroleptic malignant syn-
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-
ity, and altered mental status.196 Although NMS is
an uncommon disorder, the sequelae may be seri-
ous, particularly if the condition is unrecognized
and left untreated.
CAUSATIVE AGENTS
Hundreds of cases of NMS have been reported in
the literature, most secondary to neuroleptic
agents, particularly haloperidol. 197-200 Other
agents that inhibit dopamine have been impli-
cated, including prochlorperazine, metoclo-
pramide, lithium, and anticonvulsants. 200-219
Drugs that have been associated with NMS are
listed in Table 34–10.197-280 The older, higher-
potency antipsychotic agents such as haloperidol
and fluphenazine are more likely to induce NMS
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
been described in patients who abruptly discon-
tinue therapy with baclofen.281-285 In the majori-
ty of these cases, patients were receiving baclofen
intrathecally.281-283
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654 SECTION VII • Drug-Induced Endocrine Diseases

TABLE 34–10 Agents Implicated in Drug-Induced Neuroleptic Malignant Syndrome197

Drug Incidence Level of Evidence
(see page xii for explanation)

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

ing psychomotor agitation and mental retardation

EPIDEMIOLOGY are significantly more likely to develop NMS.295,296

NMS is relatively rare, with a reported incidence

ranging from 0.02% to 3.23% in patients treated
with neuroleptics.286-293 The true incidence may be
higher because of a lack of recognition and underre-
porting. The reported number of NMS cases is
decreasing, perhaps because of the availability of
newer, lower-potency antipsychotics.294 NMS occurs
approximately twice as commonly in men than in
women and has been reported to occur more fre-
quently in young and middle-aged adults, with an
average age at occurrence of 40 years, although con-
flicting evidence exists.291,293 Patients with pre-exist-
MECHANISMS
NMS is a dose-related idiosyncratic reaction that is
a result of a relative depletion of dopamine in the
central nervous system. NMS may also involve the
serotonergic and cholinergic systems. Inhibition of
dopaminergic systems in the central nervous sys-
tem and metabolic changes in peripheral skeletal
muscle lead to a sustained muscle contraction,
resultant heat production, and inappropriate vaso-
constriction decreasing heat dissipation, leading to
TisdaleC34_644-685 1/12/10 3:35 PM Page 655
hyperthermia. This occurs as a result of drug-
induced antagonism of dopamine receptors but
has also been reported after discontinuation of
antiparkinsonian agents and amantadine, which
are dopamine agonists. In these cases, NMS
resolves after reinitiation of therapy with these
drugs.209,297-300
CLINICAL PRESENTATION AND
DIFFERENTIAL DIAGNOSIS
NMS usually occurs within hours to months after
the initiation of neuroleptic therapy or following
a dose increase, but may take up to a year or longer
to manifest. In most cases, NMS develops within
the first 4 weeks of therapy with the offending
agent. Classic signs and symptoms of NMS (Table
34–11) develop progressively over 1 to 3 days and
include hyperthermia, severe muscle rigidity
(described as “lead-pipe rigidity”), autonomic dys-
function (tachycardia, tachypnea, hypertension or
fluctuating blood pressure, diaphoresis), and men-
tal status changes (delirium, stupor, obtundation,
coma). Other signs that may be observed include
increased serum creatine kinase (CK) concentra-
TABLE 34–11 Signs and Symptoms Associated
with Drug-Induced Neuroleptic Malignant
Syndrome
• Diaphoresis
• Mental status changes
• Altered consciousness
• Muscle rigiditya (“lead-pipe rigidity”)
• Increased serum creatine kinase
• Autonomic dysfunction
• Hyperthermia
• Tachycardia
• Tachypnea
• Hypertension or fluctuating blood pressure
• Mental status changes
• Delirium
• Stupor
• Obtundation
• Coma
• Leukocytosis with or without a left shift
• Electrolyte abnormalities
• Hypocalcemia
• Hypokalemia
• Hypomagnesemia
• Rhabdomyolysis and myoglobinuria
a
This classic sign may not always be observed in patients with neu-
roleptic malignant syndrome caused by atypical antipsychotics,
CHAPTER 34 • Temperature Dysregulation 655
tions, leukocytosis with or without a left shift, and
electrolyte abnormalities (hypocalcemia, hypo-
kalemia, hypomagnesemia). Increased CK concen-
trations have been found in over 95% of reported
cases and may be demonstrated in patients with-
out the classic muscle rigidity.276,286,301
Rhabdomyolysis and resultant myoglobinuria may
develop and, without intervention, may progress
to renal failure and metabolic acidosis.
Temperature elevation may follow other signs and
symptoms, and the absence of hyperthermia
should not preclude the consideration of NMS.
Temperatures in excess of 41.1°C may occur. NMS
is often confused with heat stroke, since both may
cause mental status changes and because neu-
roleptics are a risk factor for both conditions. In
contrast to those with NMS, patients with heat
stroke present with hot, dry skin, hypotension,
and limb flaccidity.
Temperature elevation may not be as pro-
nounced in association with the atypical antipsy-
chotics, particularly risperidone and
paliperidone.263,273,302,303 In addition, NMS induced
by atypical antipsychotics may be associated with
a longer time to onset and the absence of muscle
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
in early diagnosis and recognition. In more than
80% of cases, mental status changes and rigidity
(or CK elevations) can be expected to precede auto-
nomic dysfunction and hyperthermia.298
Because NMS has various manifestations, dif-
ferential diagnosis must include many neurologic,
psychiatric, systemic, and drug-induced disorders.
Catatonia may be an early sign of NMS and may be
confused with the underlying illness, leading the
clinician to increase the dose of the neuroleptic,
which may worsen the condition. Patients with
preexisting catatonia may be at increased risk for
NMS, but there is some speculation that NMS and
catatonia are part of the same neurochemical syn-
drome or that NMS is an exacerbation of catato-
nia.306-310 Catatonia is usually treated with
neuroleptics, and therefore NMS may be more like-
ly to develop because of continued treatment or
dose escalation. The initial presentation may be
helpful for differentiating catatonia from NMS:
lethal catatonia often begins with extreme psy-
chotic excitement, while NMS usually begins with
muscle rigidity, although there are exceptions. It
should be recognized that there is a relationship
between the two syndromes, and in patients with
catatonia or NMS with catatonic signs or symp-
toms, consideration should be given to alternative
TisdaleC34_644-685 1/12/10 3:35 PM Page 656
656 SECTION VII • Drug-Induced Endocrine Diseases
therapy, such as benzodiazepines or electroconvul-
sive therapy.
Serotonin syndrome, anticholinergic delirium,
and lithium toxicity are other disorders with signs
and symptoms that overlap with NMS (Table
34–12). In one review of 28 patients who met crite-
ria for NMS, 22 also met diagnostic criteria for sero-
tonin syndrome.311 Another review compared signs
and symptoms of NMS induced by olanzapine with
the 10 “classical” signs and symptoms of serotonin
syndrome.312 Three or more signs and symptoms of
serotonin syndrome were identified in 11 of the 17
patients, indicating considerable overlap between
these drug-induced diseases.312 Identification of
the causative agent aids in the differential diagno-
sis. Correct diagnosis is essential, as chlorpro-
mazine, a common treatment option for serotonin
syndrome, may worsen signs and symptoms in a
patient with NMS. Serum lithium concentrations
should be obtained to rule out toxicity as a poten-
tial cause. The clinical presentation in children dif-
fers slightly from that in adults; children may
exhibit more dystonia and less tremor.313
RISK FACTORS
In a case–control study, higher neuroleptic dose,
faster dose escalation, more intramuscular neu-
roleptic injections, and a greater degree of psy-
chomotor agitation were found to be risk factors
for NMS (Table 34–13).314 Other reported risk fac-
tors for the development of NMS include dehydra-
tion, exhaustion, preexisting brain disorder
(bipolar disease, delirium tremens, postoperative
delirium, Alzheimer’s dementia, and mental retar-
dation), and catatonia, although many patients
treated with neuroleptics may possess some of
these factors.288-290,295-297,306-308,315-319 In addition,
there has been one report of NMS in a patient with
TABLE 34–12 Conditions to Consider in the
Differential Diagnosis of Drug-Induced Neuro-
leptic Malignant Syndrome
• Infection
• Sepsis
• Heat stroke
• Endocrine disorders
• Hematologic or solid organ malignancy
• Drug withdrawal (alcohol, benzodiazepines, levodopa)
• Serotonin syndrome
• Anticholinergic delirium
• Lithium toxicity
TABLE 34–13 Risk Factors for Drug-Induced
Neuroleptic Malignant Syndrome
Drug-related
• Higher dose
• Faster dose escalation
• Intramuscular route
Patient-related
• Psychomotor agitation
• Mental retardation
• Dehydration
• Exhaustion
• Bipolar disease
• Alzheimer’s dementia
• Catatonia
bilateral subdural hematoma who had been stable
on a neuroleptic agent for 10 years.216 It is clear
that the use of drugs with higher potency, at high-
er doses, administration via the parenteral route,
and history of a prior episode increase the risk for
the development of NMS.203,286,287,291,294,306,314,320,321
There have been reports of NMS cases within fam-
ilies; however, a genetic link has not been estab-
lished conclusively.322-324
MORBIDITY AND MORTALITY
If left untreated or mistreated because of misdiag-
nosis, NMS can result in very serious sequelae,
including permanent disability, coma, and
death.325,326 Mortality has been reported to occur in
4% to 25% of patients as a consequence of NMS
and results from progression of the clinical syn-
drome.202,286-288 The resultant acute renal failure
due to ischemia and rhabdomyolysis, respiratory
failure, metabolic acidosis, and electrolyte imbal-
ances may be irreversible and fatal. The rate of
mortality has declined over time because of
prompt recognition, discontinuation of the offend-
ing agent, supportive care, and drug therapy man-
agement, and is now estimated to be about
10%.209,289,318 The risk of significant morbidity and
mortality do not seem to be diminished in patients
with atypical antipsychotic-induced NMS.304
PREVENTION
Because NMS is an idiosyncratic reaction, avoid-
ance is difficult. Recommendations for prevention
are listed in Table 34–14. The lowest possible dose
of neuroleptic should be used to control patient
TisdaleC34_644-685 1/12/10 3:35 PM Page 657
TABLE 34–14 Approaches to Help Prevent Drug-
Induced Neuroleptic Malignant Syndrome
• Use lowest dose of neuroleptic possible.
• Titrate dose slowly.
• Ensure adequate hydration for patients undergoing
active dose escalation.
• Rechallenge at least 2 wk after signs and symptoms
have resolved.
behavior. Patients who are receiving high doses of
parenteral neuroleptics or who are having the dose
adjusted upward should be well hydrated and
monitored for signs and symptoms. Patients with a
history of NMS should be optimally treated with
an alternative agent, such as a newer atypical
antipsychotic, a drug with lower potency, or a
lower dose of the same agent, and treatment
should not be initiated or reinitiated until at least
2 weeks after signs and symptoms have
resolved.327-329
One study reported the experience with rechal-
lenge in 15 patients with a prior episode of NMS.327
Ten patients were successfully rechallenged initial-
ly; 4 of 5 patients who were unsuccessfully rechal-
lenged underwent a second rechallenge, which was
successful in 2. One of the patients who had a fail-
ure was rechallenged a third time, and on that
occasion therapy with the neuroleptic drug was
successfully initiated and maintained. Overall,
neuroleptic agents were tolerated in 13 of the 15
patients with a prior history of NMS. The time
from the resolution of signs and symptoms to the
rechallenge attempt correlated significantly with
success. Twelve of 13 rechallenges were successful
if the rechallenge was attempted more than 2
weeks after the signs and symptoms of NMS had
resolved, whereas 6 of 7 that were attempted in less
than 2 weeks were unsuccessful.327 Similar results
have been reported in other cases of attempted
rechallenge.328,329 Neither the specific neuroleptic
agent used nor the dose was found to be a signifi-
cant factor related to successful rechallenge; how-
ever, most rechallenges were attempted with
lower-potency agents or lower doses of the same
drug.327 Others have noted that the use of lower-
potency agents improves the success of rechallenge
as well: 47% and 83% of patients had a relapse
when given a drug of equal potency, but only 15%
and 10% had a relapse when a lower-potency agent
was used.290,330 Administration of an atypical neu-
roleptic (clozapine) was reported to be used suc-
cessfully in a patient with three prior episodes of
NMS associated with haloperidol, lithium, and
molindone.201 There are other reports of successful
CHAPTER 34 • Temperature Dysregulation 657
atypical antipsychotic rechallenge in 15 of 19
patients who had NMS with atypical antipsy-
chotics.304 Eleven of the patients were successfully
rechallenged with the same agent without recur-
rence of symptoms.
In a patient with a history of NMS, the lowest
possible dose of neuroleptic should be used, and
the dose should be titrated upward slowly. The use
of the parenteral route, particularly depot intra-
muscular injections, should be avoided. Electro-
convulsive therapy, as opposed to drugs, should be
considered in patients requiring management of
an acute psychotic episode and a recent diagnosis
(especially of less than 2 weeks) of NMS.
MANAGEMENT
Strategies for management of NMS are presented in
Table 34–15. In some cases, NMS is a self-limiting
disease with signs and symptoms resolving as soon
as 7 to 10 days after the causative drug is discontin-
ued. Therapy should be initiated when rigidity,
mental status, and autonomic changes are appar-
ent and the temperature is ≥38°C. However, treat-
ment may be initiated if a presumptive diagnosis of
NMS is made prior to the onset of hyperthermia in
the presence of other progressing signs and symp-
toms. One review of published cases reported a
TABLE 34–15 Management of Drug-Induced
Neuroleptic Malignant Syndrome
• Discontinue suspected agent
• Cooling measures and other supportive care
• Surface cooling
• Cooled intravenous fluids
• Ice water nasogastric lavage
• Fluid and electrolyte replacement as needed
• Bromocriptine 2.5–5 mg orally 3–4 times daily up to
80 mg daily for up to 10 days after symptoms abate;
then taper
• Amantadine 100–200 mg orally 2–3 times daily for
up to 10 days after symptoms abate; then taper
• Benzodiazepines
• Lorazepam 2–4 mg intravenously or orally as need-
ed for control of symptoms
• Diazepam 5 mg intravenously or orally as needed
for control of symptoms
• Dantrolene 2–3 mg/kg (up to 5 mg/kg) intravenously
divided 3–4 times daily until symptoms abate, then 1
mg/kg orally every 6 hr for up to another 10 days;
then taper
• Electroconvulsive therapy
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658 SECTION VII • Drug-Induced Endocrine Diseases
mortality rate of 9.7% in patients who received
drug therapy (dantrolene, bromocriptine, lev-
odopa, amantadine) as compared with 21% in
patients who did not receive any specific drug ther-
apy intervention.331
All medications that cause dopamine-depleting
or antagonistic effects should be discontinued, par-
ticularly any antipsychotic agents that have been
initiated recently, or for which the dose has recent-
ly been increased. Supportive measures include
fluid, electrolyte, and acid–base management.
Rapid cooling measures, including cooled intra-
venous solutions, surface cooling, and ice water
gastric lavage should be used for management of
significant temperature elevation.
Bromocriptine, amantadine, other dopamine
agonists and dantrolene have been used successful-
ly in the management of NMS. Bromocriptine is
considered the drug of initial choice. Doses of 2.5
to 5 mg (range, 2.5–20 mg) should be administered
orally three to four times daily for 10 days,
although a longer duration of treatment may be
required.220,250,292,330-335 Treatment with bromocrip-
tine should be continued until signs and symp-
toms resolve, after which the dose should be
tapered gradually. Improvement in signs and
symptoms is usually observed within 24 to 72
hours.
Amantadine is a treatment alternative for NMS.
The recommended dose is 100 to 200 mg orally
two to three times per day and should be contin-
ued for 10 days after signs and symptoms are con-
trolled, after which the dose should be tapered to
avoid rebound NMS.206,336-339
Dantrolene has been used successfully to treat
NMS by relieving muscle rigidity and heat genera-
tion, via inhibition of calcium release from the
endoplasmic reticulum.215,340-346 Often patients are
unable to take oral medications during NMS,
necessitating use of the intravenous route.
Dantrolene therapy is recommended if the temper-
ature exceeds 40°C, rhabdomyolysis is suspected,
cardiorespiratory or renal failure is imminent, and
administration of dopamine agonists has not been
successful.289 These patients have severe NMS and
are at high risk of serious morbidity or death and
require the most rigorous intervention.315,347
Dantrolene should be administered at a dose of 2
to 3 mg/kg intravenously (up to 5 mg/kg) divided
three to four times daily until signs and symptoms
have been adequately controlled.348 When the
patient is able to take oral medications, dantrolene
may be administered at a dose of 1 mg/kg every 6
hours orally for another 10 days, and then the dose
may be tapered. Although combination therapy of
a dopamine agonist (bromocriptine or amanta-
dine) plus dantrolene has no proven advantage, it
may be considered in refractory or extremely
severe cases, as this approach offers treatment with
drugs with different mechanisms of action.344-
346,349,350
Although they successfully control some of the
signs and symptoms of NMS, anticholinergic
agents are not recommended because they inhibit
heat dissipation and may worsen hyperther-
mia.288,319,349,350 Pancuronium with concomitant
diazepam administration was reported to be effec-
tive for cessation of muscle rigidity in a patient
with NMS in whom treatment with anticholiner-
gics failed but who was not treated with dantro-
lene.351 Carbidopa–levodopa may also be effective
because of its dopamine agonist properties.345,346,352
Intravenous diazepam may be used to manage
involuntary movements, fever, tachycardia, hyper-
tension, muscle rigidity, tremor, and diaphoresis
associated with NMS.353,354 Benzodiazepines may
be useful as adjunct therapy for suspected catato-
nia and for treatment of agitation.355-357
Electroconvulsive therapy (ECT) may be consid-
ered for the treatment of NMS refractory to other
therapies, although there are no prospective com-
parative studies.358-364 One retrospective review of
NMS cases demonstrated a mortality rate of 10.3%
in patients who underwent ECT, as compared with
21% in patients who received no specific interven-
tion, a difference that did not reach statistical sig-
nificance.331 ECT should be considered the therapy
of choice in patients with suspected catatonia.
Resolution of mental status changes, muscle
rigidity, serum creatine kinase concentrations,
acid–base abnormalities and myoglobinuria should
be closely monitored. Progression of these signs
and symptoms requires more aggressive manage-
ment. Monitoring parameters for patients with
NMS are listed in Table 34–16.
With appropriate care, patients with NMS gen-
erally fully recover within several days to weeks.
Signs and symptoms may persist longer and may
be more difficult to manage in patients who have
received intramuscular (depot) antipsychotic
agents.315 A residual catatonic state has been
described in several patients for 1 to 6 months after
resolution of hyperthermic signs and symptoms.326
Rigidity and mental status changes persisted in
these patients for unknown reasons.
INFORMATION FOR PATIENTS
Patient education may be uniquely difficult in the
patient population treated with neuroleptic agents.
Despite the potential obstacles, patients and care-
TisdaleC34_644-685 1/12/10 3:35 PM Page 659
TABLE 34–16 Monitoring Parameters for Patients
with Drug-Induced Neuroleptic Malignant
Syndrome or Drug-Induced Serotonin Syndrome
• Temperature
• Heart rate
• Respiratory rate
• Pulse oximetry
• White cell count with differential
• Coagulation profile
• Serum electrolyte concentrations
• Serum blood urea nitrogen and serum creatinine con-
centrations
• Serum creatine kinase concentrations (NMS)
• Urine myoglobin concentrations
• Mental status
• Muscle rigidity (NMS)
• Myoclonus (SS)
NMS = neuroleptic malignant syndrome; SS = serotonin syn-
drome.
givers should be alerted to the signs and symptoms
of NMS and instructed when to seek medical atten-
tion. Patients and care givers should be instructed
to call a health care professional or visit a health
care facility in the event of sudden onset of muscle
rigidity, tachycardia, tachypnea, diaphoresis, or
mental status changes. It is particularly important
to stress to patients that medications should not be
discontinued if signs and symptoms develop, and
to seek medical attention to ensure that a proper
diagnosis is achieved.
HYPERTHERMIA DUE TO
SEROTONIN SYNDROME
Serotonin syndrome is a potentially serious and
occasionally fatal complication of therapy associat-
ed with drugs that cause an increase in serotoner-
gic activity. Fever is one common component of
the syndrome. With the significant increase in the
number of patients treated with selective serotonin
(5-hydroxytryptamine [5-HT]) reuptake inhibitors
(SSRIs), it may be expected that the prevalence of
this drug-induced disease will continue to increase.
CAUSATIVE AGENTS
Any drug that causes a direct or indirect increase in
the effective serotonin concentration in the central
nervous system has the potential to induce sero-
tonin syndrome. Drugs that have been reported to
CHAPTER 34 • Temperature Dysregulation 659
cause serotonin syndrome are listed in Table
34–17.365-455 Included are cases in which drugs were
used in combination and the specific causative
agent could not be conclusively determined. In
addition, paroxetine and fluoxetine are inhibitors
of the cytochrome P-450 2D6 enzyme and may
increase serum concentrations of serotonergic
metabolites when used in combination with
trazadone and nefazadone; the combination
should be used cautiously. Selective and nonselec-
tive SSRIs have been implicated in numerous case
reports of serotonin syndrome, as have selective
and nonselective monoamine oxidase inhibitors
(MAOIs) alone and in combination with opioids.
Linezolid has nonselective MAOI properties and
has been reported to precipitate serotonin syn-
drome when combined with a serotonergic agent
but also when used with a synthetic opioid anal-
gesic without the presence of an SSRI.403
EPIDEMIOLOGY
The incidence of serotonin syndrome is not
known. However, the incidence may be relatively
low, considering the widespread use of medica-
tions, alone and in combination, known to disrupt
serotonin balance. One retrospective review exam-
ined the use of SSRIs and linezolid, a weak
inhibitor of MAO, and found that 3% of patients
had a high probability of serotonin syndrome.400
In another retrospective review of the records of
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
small, and the SSRI doses were not discussed.
Although there is an increased awareness of the
triggering factors for serotonin syndrome, the dis-
ease is still not commonly considered in patients
presenting with suspicious signs and symptoms.
SSRIs are being prescribed with increased frequen-
cy, however there is declining use of MAOIs, result-
ing in an unknown net effect on the true incidence
of this drug-induced disease.
MECHANISMS
Mechanisms by which drugs cause serotonin syn-
drome are presented in Table 34–18. Excessive sero-
tonergic activity is responsible for serotonin
syndrome. Seven 5-HT receptor subtypes have
been identified, and it is believed that 5-HT1A and
5-HT2A are involved specifically with the adverse
TisdaleC34_644-685 1/12/10 3:35 PM Page 660

660 SECTION VII • Drug-Induced Endocrine Diseases

TABLE 34–17 Agents Implicated in Drug-Induced Serotonin Syndrome

Drug Incidence Level of Evidence
(see page xii for explanation)
365
L-Tryptophan NK C
Dexamphetamine366 NK C
3,4-Methylenedioxymethamphetamine; MDMA (ecstasy)367-375 NK C
Levodopa376 NK C
MAO INHIBITORS NK C
Isocarbazid377,378 NK C
Selegiline379 NK C
Tranylcypromine380-383 NK C
Moclobemide (reversible MAO inhibitor)369,384-390 NK C
Linezolid391-403 NK C
SSRIS NK C
Citalopram366,390,391,404-406 NK C
Duloxetine402,412 NK C
Escitalopram413 NK C
395,399,404,405,414-417
Fluoxetine NK C
Fluvoxamine412,418-421 NK C
Paroxetine386,392,421-425 NK C
Sertraline377,393,394,411,427-433 NK C
Trazodone378,396,428,434 NK C
Nefazadone406,417,422 NK C
Venlafaxine366,380,381,384,396,401,429,434-444 NK C
TCAs NK C
Amitriptyline438,439 NK C
Clomipramine382,445 NK C
Imipramine379 NK C
Nortriptyline383 NK C
Amantadine433,446 NK C
Buspirone447 NK C
Dextromethorphan406,423,448 NK C
Buprenorphine449 NK C
Fentanyl411,450 NK C
Meperidine408,415,438,450 NK C
Oxycodone412 NK C
Sibutramine450,451 NK C
Tramadol409,416,424,452,453 NK C
Hypericum perforatum (St. John’s Wort)447,454,455 NK C
Lithium436,443 NK C
Metoclopramide + venlafaxine429 NK C
HT = hydroxytryptamine; MAO = monoamine oxidase ; NK = not known; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic
antidepressant.
TisdaleC34_644-685 1/12/10 3:35 PM Page 661

CHAPTER 34 • Temperature Dysregulation 661

TABLE 34–18 Mechanisms of Drug-Induced Serotonin Syndrome

Drug Mechanism
L-Tryptophan Increase 5-HT synthesis or release
Dexamphetamine Increase 5-HT synthesis or release
Inhibit 5-HT reuptake
3,4-Methylenedioxymethamphetamine; MDMA (ecstasy) Increase 5-HT synthesis or release
Inhibit 5-HT reuptake
Levodopa Increase 5-HT synthesis or release
MAO INHIBITORS
Isocarbazid Increase 5-HT synthesis or release
Inhibit 5-HT metabolism
Tranylcypromine Increase 5-HT synthesis or release
Inhibit 5-HT metabolism
Selegiline Increase 5-HT synthesis or release
Inhibit 5-HT metabolism
Moclobemide (reversible MAO inhibitor) Increase 5-HT synthesis or release
Inhibit 5-HT metabolism
Linezolid Increase 5-HT synthesis or release
SSRIS
Citalopram Inhibit 5-HT reuptake
Duloxetine Inhibit 5-HT reuptake
Escitalopram Inhibit 5-HT reuptake
Fluoxetine Inhibit 5-HT reuptake
Fluvoxamine Inhibit 5-HT reuptake
Paroxetine Inhibit 5-HT reuptake
Sertraline Inhibit 5-HT reuptake
Trazadone Inhibit 5-HT reuptake
Nefazadone Inhibit 5-HT reuptake
Venlafaxine Inhibit 5-HT reuptake
TCAS
Amitriptyline Inhibit 5-HT reuptake
Clomipramine Inhibit 5-HT reuptake
Imipramine Inhibit 5-HT reuptake
Nortriptyline Inhibit 5-HT reuptake
Amantadine Increase 5-HT synthesis or release
Buspirone Postsynaptic receptor stimulation
Dextromethorphan Inhibit 5-HT reuptake
Buprenorphine Mechanism unknown
Fentanyl Inhibit 5-HT reuptake and/or other unknown
Meperidine Inhibit 5-HT reuptake and/or other unknown
Oxycodone Mechanism unknown
Sibutramine Inhibit 5-HT reuptake and/or other unknown
Tramadol Inhibit 5-HT reuptake and/or other unknown
(Continued)
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662 SECTION VII • Drug-Induced Endocrine Diseases
TABLE 34–18 Mechanisms of Drug-Induced Serotonin Syndrome
Drug
Hypericum perforatum (St. John’s Wort)
Lithium
Metoclopramide + venlafaxine
HT = hydroxytryptamine; MAO = monoamine oxidase; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant.
sequelae encountered with serotonin syn-
drome.457,458 Controversy exists regarding which of
these two receptors is most responsible for the syn-
drome. It is likely that both of these receptor sub-
types, and possibly others, are involved in the
clinical manifestations of serotonin syndrome. The
syndrome generally occurs after initiating therapy
with, or increasing the dose of, a drug with one or
more of the following actions: (1) inhibition of
serotonin metabolism; (2) potentiation of sero-
tonin activity; (3) direct activation of serotonin
receptors; (4) inhibition of serotonin uptake; and
(5) increase of substrate supply. Serotonin syn-
drome has been associated with single-drug thera-
py; however, because it is a dose-dependent
phenomenon, combinations of drugs in particular
are associated with the development of the syn-
drome. Pharmacodynamic (combinations of drugs
that have a similar effect on serotonin) and phar-
macokinetic drug interactions result in an increase
in effect at the serotonin receptor, leading to exces-
sive serotonergic effects.406,425 Some drugs inhibit
the metabolism of SSRIs while some SSRIs inhibit
cytochrome P-450 2D6, which metabolizes other
drugs with serotonergic effects, such as dex-
tromethorphan. In general, opioid analgesics are
thought to inhibit the reuptake of serotonin, there-
by increasing the risk of serotonin syndrome when
combined with agents that have serotonergic activ-
ity. There may be other mechanisms involved,
however, as serotonin syndrome has been reported
with oxycodone and buprenorphine, which do not
inhibit the reuptake of serotonin.411,449
CLINICAL PRESENTATION AND
DIFFERENTIAL DIAGNOSIS
The onset of the signs and symptoms of serotonin
syndrome may be almost immediate, with approx-
imately 60% of cases presenting within 6 hours
after the offending agent has been initiated, the
dose increased, or the serum concentration
increased by a drug–drug interaction. Serotonin
(Continued)
Mechanism
Inhibit 5-HT reuptake
Inhibit 5-HT metabolism
Postsynaptic receptor stimulation
Inhibit 5-HT reuptake
syndrome manifests as a succession of signs and
symptoms that progress rapidly, over the course of
hours, and may be highly variable, making identi-
fication and diagnosis difficult. Serotonin syn-
drome is most appropriately thought of as a
spectrum of diseases and has been classified into
severity categories to aid in earlier or more accurate
diagnosis.457,459,460 Some of the signs and symp-
toms associated with milder forms of serotonin
syndrome (tremor, confusion, incoordination)
may be difficult to distinguish from the underlying
illness.457 The more severe symptoms of serotonin
toxicity (temperature of (38.5°C, myoclonus, diar-
rhea) are generally observed in overdose situations
or when an MAOI or a serotonin-releasing agent is
used in combination with an SSRI.457,461
Signs and symptoms of serotonin syndrome may
be divided into three categories for patient assess-
ment: autonomic dysfunction (fever, shivering,
diaphoresis, diarrhea, tachycardia, labile blood pres-
sure); neuromuscular hyperactivity (clonus,
myoclonus, hyperreflexia, incoordination, tremor);
and mental status changes (confusion, agitation,
mania possibly progressing to hallucinations, obtun-
dation, coma). The original criteria for diagnosis of
serotonin syndrome as proposed by Sternbach are
the presence of at least three symptoms temporally
related to a suspect medication; other causes have
been ruled out; and a neuroleptic agent has not been
started or dose increased prior to the onset of signs
and symptoms (indicating possible NMS).457
Problems with the Sternbach criteria may exist and
include the weight of mental status changes in the
criteria, causing patients with abnormal mental
states to be misdiagnosed and a diagnosis of sero-
tonin syndrome to be missed in patients with mild
serotonin toxicity. Others have determined that sero-
tonin syndrome may be misdiagnosed in patients
with infection using Sternbach’s criteria.400 Because
of this lack of sensitivity, diagnostic decision rules
have been developed based on the evaluation of
2,222 cases of serotonin overdose which were report-
ed to the Hunter Area Toxicology Service.461 These
criteria are simpler and include primarily clonus, agi-
TisdaleC34_644-685 1/12/10 3:35 PM Page 663
tation, diaphoresis, tremor, hyperreflexia, hyperto-
nia, and hyperthermia. The most important sign in
the Hunter criteria is clonus and, if spontaneously
present in a patient taking a serotonergic agent, is by
itself adequate to make the diagnosis. Important to
note is that the diagnostics decision rules were devel-
oped from data in patients with overdoses and have
not yet been validated to be sensitive and specific for
patients with serotonin syndrome at therapeutic
doses of serotonergic agents. Fulminant cases of sero-
tonin syndrome may progress to seizures, rhabdomy-
olysis, renal failure, and death. Other conditions to
consider in the differential diagnosis of serotonin
syndrome include infection, sepsis, heat stroke, and
NMS (Table 34–19) Although both NMS and sero-
tonin syndrome may present with some common
symptoms—including catatonia, tremors, rigidity,
and hyperthermia—differences may aid in the diag-
nosis. Proper diagnosis is essential, as bromocriptine
is a treatment considered for NMS but should be
strictly avoided in patients with serotonin syndrome
because it may worsen the condition. The rigidity
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
which the rigidity is described as “lead pipe” and is
not usually limited to the lower extremities. With
NMS, the progression of signs and symptoms occurs
over the course of days and there may be a lower
incidence of tremors, clonus, and myoclonus. There
are usually no gastrointestinal symptoms; however,
hyperthermia may be more common. The most reli-
able method for appropriate diagnosis is an accurate
medication history, including starting dates and
doses of medications that increase serotonergic activ-
ity and specific information regarding dose escala-
tion, if available.
RISK FACTORS
No patient-specific risk factors for the development
of serotonin syndrome have been definitively iden-
TABLE 34–19 Conditions to Consider in the
Differential Diagnosis of Drug-Induced Serotonin
Syndrome
• Infection
• Sepsis
• Heat stroke
• Endocrine disorders
• Hematologic or solid organ malignancy
• Drug withdrawal (alcohol, benzodiazepines, levodopa)
• Neuroleptic malignant syndrome
CHAPTER 34 • Temperature Dysregulation 663
tified, although increased age and female sex may
be predisposing factors (Table 34–20). In addition,
risk factors may include endogenous or acquired
defects in MAO activity that lead to impairment in
SSRI metabolism, such as those occurring in
patients with cardiovascular diseases—including
hypertension and hyperlipidemia—liver disease,
and pulmonary disease and in those who smoke
cigarettes. Genetic variation in the ability to
metabolize serotonergic drugs and activities of
MAO isoenzymes may predispose patients to sero-
tonin syndrome. Approximately 7% of individuals
are poor metabolizers of SSRIs.462 This genetic pre-
disposition may enhance a patient’s sensitivity to
serotonergic agents and increase the propensity for
the development of serotonin syndrome.
Other potential risk factors for serotonin syn-
drome are drug-specific features, including drug
potency, total daily dose, rapid dose escalation,
and use of concomitant agents that may increase
serotonin activity or interact with serotonergic
agents.
MORBIDITY AND MORTALITY
Most patients fully recover following discontinua-
tion of the causative agent and implementation of
supportive care; however, deaths have been report-
ed due to serotonin syndrome.368,369,376,379,385,391,445
Deaths are reported more often in association with
intentional overdose of SSRIs alone or in combina-
tion with an MAOI. Death from serotonin syn-
drome generally occurs secondary to multiple
organ dysfunction, including rhabdomyolysis lead-
ing to renal failure, disseminated intravascular
coagulation, adult respiratory distress syndrome,
TABLE 34–20 Risk Factors for Drug-Induced
Serotonin Syndrome
DRUG-RELATED
• Higher-potency agents
• Higher total daily dose
• Rapid dose escalation
• Use of concomitant drugs that increase serotonin
activity
PATIENT-RELATED
• Older age
• Female sex
• Endogenous or acquired defects in MAO activity
• Poor metabolizers of SSRIs
MAO = monoamine oxidase; SSRI = selective serotonin reup-
take inhibitor.
TisdaleC34_644-685 1/12/10 3:35 PM Page 664
664 SECTION VII • Drug-Induced Endocrine Diseases
and cardiovascular collapse from muscular hyper-
activity and hyperthermia. With prompt interven-
tion, however, patients usually recover without
long-term sequelae.
PREVENTION
Keys to the prevention of serotonin syndrome are
careful initiation and dose escalation of SSRIs, in
addition to appropriate patient education regard-
ing drug-induced diseases, drug interactions, and
recognition of signs and symptoms of toxicity
(Table 34–21). SSRI therapy should be initiated at a
low dosage and titrated upward slowly, particularly
in elderly patients or those with impairment of
liver or renal function.
Following discontinuation of the culprit drug,
a washout period of at least 5 to 7 days prior to ini-
tiating therapy with an MAOI or another SSRI is
important; the duration should be determined
based on the half-life of the active compound. A
washout period of 5 weeks or longer may be neces-
sary for SSRIs with very long half-lives or those
with active metabolites such as fluoxetine, sertra-
line, and clomipramine. In addition, if delayed
elimination is suspected in selected patients, a
longer drug-free period is warranted. MAOIs inhib-
it the metabolism of SSRIs, and therefore directly
increase serotonin concentrations at the site of
activity. MAOIs should be discontinued at least 4
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-
centrations should be avoided. Appropriate dose
adjustments should be made in older patients and
TABLE 34–21 Approaches to Help Prevent
Drug-Induced Serotonin Syndrome
• Carefully initiate and titrate serotonergic agents
• Adjust dose appropriately for elderly patients and
those with hepatic dysfunction or chronic kidney
disease.
• Ensure adequate washout period when switching
from MAOI to serotonergic agents or serotonergic
agents to MAOI.
• Carefully switch from one serotonergic agent to
another.
• Be aware of drug interactions and avoid if possible.
MAOI = monoamine oxidase inhibitor.
in those with renal or hepatic impairment, in addi-
tion to closer monitoring of these patients for signs
or symptoms of toxicity.
MANAGEMENT
Discontinuation of the offending agent is impera-
tive, as is supportive care, which often results in
resolution of signs and symptoms within 24
hours without specific pharmacotherapeutic
intervention (Table 34–22). Fluid therapy should
be implemented in patients in whom diaphoresis
has been a significant clinical symptom, in addi-
tion to those requiring cooling augmentation.
Although there are no clinical trials that have
specifically evaluated the efficacy of any thera-
peutic intervention for serotonin syndrome, sev-
eral drugs have anecdotally been reported to be
successful.
Cyproheptadine, a histamine1 (H1) antagonist
with nonselective anti–5-HT and anticholinergic
properties, has been a successful treatment for sero-
tonin syndrome. In some reports, cyproheptadine
has not been found to alter the time course of sero-
tonin syndrome but may relieve signs and symp-
toms.463 Others have indicated that
cyproheptadine can shorten the duration of some
symptoms of serotonin syndrome, including
tachycardia, tremor, neuromuscular features, and
anxiety.366 The recommended dose of cyprohepta-
TABLE 34–22 Management of Drug-Induced
Serotonin Syndrome
• Discontinue suspected agent
• Supportive care
• Surface cooling
• Cooled fluids
• Fluid replacement for patients with severe
diaphoresis
• Cyproheptadine 4–12 mg orally every 8 hr up to 48
hr; 30 mg may be given as a single dose; single, small-
er doses may also be effective
• Chlorpromazine 12.5 mg as a single dose, up to 1
mg/kg, orally or intramuscularly; repeat dose if
symptoms return
• Lorazepam, diazepam, or propranolol may be added
to the above therapy in refractory cases as needed
to control signs and symptoms
• Neuromuscular blocking agents may be considered
for patients with sustained myoclonus or severe
hyperthermia
TisdaleC34_644-685 1/12/10 3:35 PM Page 665
dine for the management of serotonin syndrome is
12 mg initially followed by 4 to 8 mg orally (or via
nasogastric tube) every 6 to 8 hours. In children,
0.25 mg/kg/day has been administered. It has been
suggested that these doses are lower than those
required to adequately block the 5-HT2A receptors,
and that 30 mg is a more optimal dose in an adult,
potentially explaining some reported treatment
failures.464,465 In most cases, the duration of thera-
py has been no longer than 48 hours, with many
patients receiving only a single dose. Cyprohepta-
dine should be avoided in patients in whom anti-
cholinergic toxicity has not been ruled out. The
drug may cause hypotension, and fluid therapy
may be used, if necessary, for management.
Chlorpromazine has been used in the man-
agement of serotonin syndrome, although far
less commonly than cyproheptadine and benzo-
diazepines.464 In addition to having antimus-
carinic effects, chlorpromazine inhibits
dopamine, ␣-adrenergic, and 5-HT2 receptors.
Chlorpromazine is available as an injectable
agent and therefore may be considered in more
severe cases and in cases in which more prompt
onset of the effect is desired. Chlorpromazine
should not be used in patients with suspected
NMS, because dopamine receptor inhibition
could worsen the condition. Chlorpromazine
should be considered in cases of cyproheptadine
failure or in cases with a significant hyperpyrexi-
al or behavioral manifestation. The suggested
dose of chlorpromazine is 12.5 to 25 mg (up to 1
mg/kg) initially and then every 6 hours. The drug
may be administered orally, intramuscularly, or
intravenously.383 Single-dose therapy has general-
ly been effective, but the dose may be repeated if
signs or symptoms return. Patients receiving
chlorpromazine should be adequately hydrated,
as it may cause hypotension due to ␣2-adrenergic
receptor antagonism.464
Benzodiazepines have also been used in the
treatment of serotonin syndrome and should be
strongly considered in patients with anxiety or
agitation. Single-dose therapy has been used, but
multiple doses may be administered as needed for
management of symptoms. Lorazepam and
diazepam have been used alone and in combina-
tion with prochlorperazine and propranolol to
control the symptoms of serotonin syn-
drome.382,423,429,450,454,466 Propranolol has also been
used as monotherapy and is thought to possess
some 5-HT1a-receptor blocking activity.442,466,467
Propofol has been used for serotonin syndrome as
well. One case describes rapid resolution of tachy-
cardia and neuromuscular tone and normaliza-
tion of reflexes with the use of propofol starting
CHAPTER 34 • Temperature Dysregulation 665
at 10 mcg/kg/min and titrated up to 30
mcg/kg/min in a patient with serotonin syn-
drome due to intentional dextromethorphan
ingestion.448 Signs and symptoms returned when
the propofol was discontinued 2 hours after pres-
entation but again resolved after propofol was
restarted. The propofol infusion was continued
for an additional 8 hours. Neuromuscular block-
ade may be considered for patients with severe
serotonin syndrome who experience sustained
myoclonus and hyperthermia.386,423 Serotonin
syndrome should be treated aggressively if symp-
toms are worsening and in overdose situations, as
the disease may be fatal. Signs and symptoms
must be monitored closely; Table 34–16 lists
important monitoring parameters for patients
with serotonin syndrome.
INFORMATION FOR PATIENTS
Patients should be instructed to notify health
care professionals of all prescription and nonpre-
scription medications and herbal products that
they are taking. Health care providers should
ensure that patients are aware of potential drug
interactions, specific medications that should be
avoided (such as nonprescription cough medica-
tions that contain dextromethorphan) and
should instruct patients to ask a pharmacist if
they have any questions regarding safe combina-
tions of medications. Clinicians should encour-
age patients to follow the dosage regimen
prescribed closely and accurately, and not to dou-
ble any doses unless specifically instructed to by
the prescriber. Patients should be aware of the
signs and symptoms of serotonin syndrome and
should be instructed about when to seek medical
attention. Development of fever, shivering or
diaphoresis, or myoclonus or any mental status
changes should prompt patients or caregivers to
contact a health care facility for further evalua-
tion and treatment.
MALIGNANT HYPERTHERMIA
Malignant hyperthermia is a rare but serious idio-
syncratic reaction observed primarily in associa-
tion with inhaled anesthetics. Hyperthermia
occurs quickly, is often severe, and may be associ-
ated with muscle weakness, increased muscular
tone, and damage including rhabdomyolysis and
metabolic acidosis. Early recognition and interven-
tion are crucial in the management of this drug-
induced disease.
TisdaleC34_644-685 1/12/10 3:35 PM Page 666
666 SECTION VII • Drug-Induced Endocrine Diseases
CAUSATIVE AGENTS
Drugs that have been reported to cause malig-
nant hyperthermia are listed in Table 34–23.468-
517
Inhalational anesthetics, with the exception
of nitrous oxide, and depolarizing neuromuscu-
lar blocking drugs (skeletal muscle relaxants) are
the drug classes most frequently implicated in
the development of malignant hyperthermia.
The agents most commonly reported to cause
malignant hyperthermia include halothane,
enflurane, isoflurane, and succinylcholine.
Succinylcholine may increase the risk, worsen
the severity, and shorten the onset time of
malignant hyperthermia when used in combina-
tion with inhaled anesthetics.468-471 Succinyl-
choline may also cause malignant hyperthermia
independently.
EPIDEMIOLOGY
Malignant hyperthermia is a genetics-related dis-
order that is observed in all ethnic groups and is
more common in men than in women.518,519 On
average, malignant hyperthermia may be
observed with the third exposure to a triggering
agent, although it is possible to occur with the
first use in a susceptible patient. Malignant
hyperthermia is more common in children under
15 years of age, with an incidence of 1 in 8,000
to 1 in 15,000, as compared with an estimated
incidence of 1 in 40,000 to 1 in 150,000 in
adults.518-520
TABLE 34–23 Agents Implicated in Drug-Induced Malignant Hyperthermia
Drug
ANESTHETICS, INHALED
Desflurane468-476
Enflurane459-479
Halothane480-487
Isoflurane488-502
Methoxyflurane503
Sevoflurane485,504-511
DEPOLARIZING SKELETAL MUSCLE RELAXANTS
Succinylcholine468-471,476,480,485,512-517
NK = not known.
MECHANISMS
Heterogeneic mutations in the ryanodine receptor
(RYR1) gene are involved in the etiology of malig-
nant hyperthermia.521 Although the genetic nature
of the illness has not been fully elucidated, it is
believed that there are two clinical varieties: an
autosomal dominant form that is rare but results in
a more severe form of malignant hyperthermia,
and a more common autosomal recessive form that
may be less severe.518,522-524
The exact mechanism by which malignant
hyperthermia occurs is unknown. However, the
presiding theory is that malignant hyperthermia
occurs because of a defect in the regulation of
intracellular calcium metabolism, such that the
sarcoplasmic reticulum of skeletal muscle releases
calcium inappropriately in response to an inducing
drug.521,525,526 The increase in calcium concentra-
tion may lead to unregulated actin and myosin
cross-bridging, resulting in tetany. This sustained
muscle rigidity results in the excessive heat produc-
tion and muscle damage and the clinical presenta-
tion of malignant hyperthermia.
CLINICAL PRESENTATION AND
DIFFERENTIAL DIAGNOSIS
The classic presentation of malignant hyperther-
mia is sudden, severe hyperthermia with muscle
rigidity, metabolic acidosis, and rhabdomyolysis
(Table 34–24). The onset of symptoms is very rapid,
within minutes to several hours after drug admin-
Incidence Level of Evidence
(see page xii for explanation)
NK C
NK C
NK C
NK C
NK C
NK C
NK C
NK C
NK C
TisdaleC34_644-685 1/12/10 3:35 PM Page 667
TABLE 34–24 Signs and Symptoms Associated
with Drug-Induced Malignant Hyperthermia
• Muscle pain, weakness in jaw, chest, and extremities
• Muscle contraction
• Initial signs
• Increase in end-tidal carbon dioxide
• Masseter-muscle rigidity
• Tachycardia
• Hyperthermia
• Metabolic acidosis
• Signs as syndrome progresses
• Pulmonary edema
• Hypotension
• Hyperkalemia, hypercalcemia, hyperphosphatemia
• Rhabdomyolysis and renal failure
• Metabolic and respiratory acidosis
• Cardiac dysrhythmias
istration. Hyperthermia may be delayed and may
occur after other symptoms (rigidity and tachycar-
dia). Temperature may acutely increase in excess of
1°C every 5 minutes up to maximum temperatures
of 46°C or higher.518,527
Early signs and symptoms of malignant hyper-
thermia include masseter-muscle rigidity (particu-
larly in children), tachycardia, and a sudden,
dramatic increase in end-tidal carbon dioxide
(ETCO2) to greater than 55 mm Hg. The increase in
ETCO2 is a sensitive indicator of the disease but
may be less dramatic and more gradual in patients
who do not receive succinylcholine. Muscle pain,
weakness, and increased tone in the jaw, chest, and
extremities may occur and are often severe and
refractory to therapy with neuromuscular blocking
agents. Muscle contraction and subsequent muscle
damage results in the release of CK and myoglobin,
which may contribute to the development of rhab-
domyolysis and renal failure.
As the syndrome progresses, pulmonary
edema, hypotension, heart failure, electrolyte
abnormalities (hyperkalemia, hypercalcemia,
hyperphosphatemia), metabolic and respiratory
acidosis (pH <7.25 and partial pressure of CO2
[paCO2] >60 mm Hg), and the resultant dysrhyth-
mias may be observed. The paCO2 may exceed 100
mm Hg and pH may decline to <7.0 in severe cases.
A presumptive diagnosis is made based on signs
and symptoms temporally related to the adminis-
tration of inhalational anesthetics or succinyl-
choline. Definitive diagnosis of malignant
hyperthermia requires an in vitro contracture test
(IVCT), also termed a caffeine halothane contrac-
ture test. The test requires a muscle biopsy, which
CHAPTER 34 • Temperature Dysregulation 667
is exposed to halothane or caffeine to determine
the contracture threshold.527 The patient is diag-
nosed as being susceptible to malignant hyperther-
mia based on the threshold at which the muscle is
reactive.528 This test is not necessary as a confirma-
tion of diagnosis for patients in whom the typical
signs and symptoms have developed.529,530 Rather,
optimal use of this test is as a screen for susceptible
individuals (based on family history) prior to use of
triggering agents. Deoxyribonucleic acid (DNA)
testing is also an option for specific, at-risk individ-
uals; guidelines for testing are available.531,532
In addition, a clinical grading scale for malig-
nant hyperthermiahas been developed to aid in
the appropriate diagnosis and for predicting sus-
ceptibility to this drug-induced disease.533 This
scale was developed by an international panel of
malignant hyperthermia experts using anonymous
polling and questionnaires to minimize bias and
subjective influence. Clinical indicators were
developed with points for each indicator as well as
scoring rules. The clinical grading scale allows for
objective determination of the likelihood of a
malignant hyperthermia diagnosis and is an
extremely valuable tool. Differential diagnosis
includes hypoxia due to atelectasis, bronchial
obstruction, sepsis, and pulmonary mechanical
failure, although these conditions are not general-
ly associated with the degree of temperature eleva-
tion that occurs in patients with malignant
hyperthermia (Table 34–25).
RISK FACTORS
Malignant hyperthermia is an idiosyncratic reac-
tion, and therefore is difficult to predict. However,
because the disorder is genetically linked, patients
with a family history of malignant hyperthermia
are at significantly higher risk than those without
a family history (Table 34–26). Younger patients,
TABLE 34–25 Conditions to Consider in the
Differential Diagnosis of Drug-Induced Malignant
Hyperthermia
• Infection
• Sepsis
• Heat stroke
• Endocrine disorders
• Hematologic or solid organ malignancy
• Drug withdrawal (alcohol, benzodiazepines, levodopa)
• Atelectasis
• Bronchial obstruction
• Pulmonary mechanical failure
TisdaleC34_644-685 1/12/10 3:35 PM Page 668
668 SECTION VII • Drug-Induced Endocrine Diseases
TABLE 34–26 Risk Factors for Drug-Induced
Malignant Hyperthermia
• Family history of malignant hyperthermia
• Young age (<15 yr)
• Male sex
• Eye, head, or neck surgeries
• Muscular dystrophies/diseases
males, and those with central core disease tend to
be predisposed to this drug-induced disease. The
type of surgical procedure may also be associated
with differences in incidence of malignant hyper-
thermia. Eye, head, neck, and musculoskeletal sur-
geries are associated with the highest risk.519
Certain muscular diseases, including Duchenne
muscular dystrophy, Becker’s muscular dystrophy,
Wolf–Hirschhorn syndrome, kyphoscoliosis,
myotonic dystrophy, and others have been linked
to a predisposition to malignant hyperther-
mia.534,535 Elevated resting serum CK concentra-
tions have been used in the past for screening
potential patients at risk; however, this has not
been shown to be predictive of the development of
malignant hyperthermia and is no longer recom-
mended.536
MORBIDITY AND MORTALITY
In the past, mortality associated with malignant
hyperthermia was high, exceeding 60%.537,538 With
early recognition and appropriate intervention,
mortality has decreased substantially and currently
may be as low as 7%.539-541 Early implementation of
therapy with dantrolene and shorter duration of
anesthesia (<30 minutes) may be associated with
enhanced survival (87%); patients who receive
anesthesia for longer than 30 minutes have been
found to have lower survival rates (43–61%).542 The
prognosis has been found to be worse for men than
for women for unknown reasons, although an
increased muscle mass may be contributory.518,519
The risk of death has also been associated with
the maximum temperature, the rate of rise of tem-
perature, and the duration of hyperthermia.542
Hyperthermia may cause agitation, confusion, dis-
orientation, combativeness, lethargy, seizures,
coma, and death. Rhabdomyolysis and disseminat-
ed intravascular coagulation may lead to acute
tubular necrosis. Volume depletion, tissue injury,
and hypoxia may lead to shock, organ dysfunc-
tion, and organ failure. Cardiac dysrhythmias,
such as ventricular fibrillation due to hyper-
kalemia, may occur, are often difficult to treat, and
may result in cardiac arrest and death.543,544
PREVENTION
The key to the prevention of malignant hyperther-
mia is avoidance of the use of inhaled anesthetics
and depolarizing neuromuscular blocking agents
in patients with a personal history or a strong fam-
ily history of the condition (Table 34–27).
Appropriate patient screening regarding family
members with a history of malignant hyperther-
mia or death during surgery or general anesthesia
should be performed. Patients at risk should be
given the opportunity for an IVCT to determine
susceptibility to triggering agents. Drugs that have
been used safely in susceptible patients (those with
a history of malignant hyperthermia or those with
a strong family history) include nitrous oxide,
bupivacaine, barbiturates, opiates, and nondepo-
larizing muscle relaxants.512,545,546
It has been suggested that prophylaxis with oral
dantrolene may be effective for the prevention of
malignant hyperthermia in susceptible individuals,
although no data from randomized, controlled tri-
als are available.547-550 In one study, oral dantrolene
was administered to 10 patients who were suscepti-
ble to malignant hyperthermia, at a dose of 5 mg/kg
in three or four divided doses, with the last dose
administered 4 hours preoperatively.548 None of the
patients experienced malignant hyperthermia, but
some experienced drowsiness and weakness due to
dantrolene administration.547 Malignant hyperther-
mia was also prevented via the administration of
dantrolene 100 mg four times daily for 3 days
before surgery and 100 mg on the day of surgery.549
Two cases of malignant hyperthermia despite oral
dantrolene administration have been reported;
however, administered doses were lower than rec-
TABLE 34–27 Approaches to Help Prevent Drug-
Induced Malignant Hyperthermia
• Carefully screen patient and family members prior to
use of anesthesia.
• Use in vitro contracture test in appropriate patients.
• Use genetic testing in specifically targeted patients.
• Avoid use of triggering agents, if possible, in selected
patients.
• Use nitrous oxide, bupivacaine, barbiturates, opiates
and nondepolarizing skeletal muscle relaxants.
• Use medical alerting devices in patients with a histo-
ry of malignant hyperthermia or who are at high risk.
TisdaleC34_644-685 1/12/10 3:35 PM Page 669
ommended.551,552 Dantrolene prophylaxis is not
expected to be completely successful and may cause
significant muscle weakness resulting in temporary
disability, which should be considered in the deci-
sion about whether to attempt prophylaxis.550,553,554
Several cases have been reported in which patients
were successfully anesthetized without prophylac-
tic administration of dantrolene, when triggering
agents were not used and patients were monitored
very closely.546,555 Currently, the use of dantrolene
prophylaxis in susceptible patients is not recom-
mended because of the low risk of malignant hyper-
thermia when triggering agents are avoided and the
potential adverse effects associated with dantro-
lene.
MANAGEMENT
Early recognition and intervention is crucial. All
suspected medications should be immediately dis-
continued, as should the surgical procedure, if fea-
sible (Table 34–28). Control of fever, acidosis,
hypermetabolism, and hypercarbia is imperative.
Patients should receive intravenous fluid therapy
for prevention of acute tubular necrosis and meta-
bolic acidosis from the hypermetabolic state, and
to maintain cardiac output. Hypercarbia and
hypoxemia should be treated with aggressive oxy-
gen management and hyperventilation. Rapid
cooling measures such as cooling blankets, ice
packs, ice water gastric lavage, and intravenous flu-
ids should be implemented. Shivering may occur
from rapid temperature decrease and should be
treated with chlorpromazine, benzodiazepines,
and paralysis with mechanical ventilation for
severe, refractory shivering.
TABLE 34–28 Management of Drug-Induced
Malignant Hyperthermia
• Discontinue suspected agent
• Cooling measures and other supportive care
• Surface cooling
• Cooled intravenous fluids
• Ice water nasogastric or rectal lavage
• Fluid and electrolyte replacement as needed
• Continuous ventilatory management
• Dantrolene 2.5 mg/kg intravenously as needed to
control signs and symptoms (up to 10 mg/kg; doses
up to 30 mg/kg may be used in severe, refractory cases)
• Nondepolarizing neuromuscular blocking drugs, ben-
zodiazepines, chlorpromazine as needed for refracto-
ry shivering or rigidity
CHAPTER 34 • Temperature Dysregulation 669
Dantrolene inhibits calcium release from the
endoplasmic reticulum, which alters the course of
malignant hyperthermia. In one study of 11
patients with malignant hyperthermia to whom
dantrolene was administered, 100% of patients sur-
vived.556 In one retrospective medical record review,
the mortality rate was 8.9% in 79 patients who
received intravenous dantrolene prior to cardiac
arrest, as compared with a mortality rate of 25.4%
in 375 patients who did not receive dantrolene—a
16.6% absolute reduction in mortality.542 Rapid
dantrolene administration after recognition of the
syndrome is critical, as outcome is related to a
shorter elapsed time from symptom onset to time
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
mg/kg until signs and symptoms begin to abate,
which is expected to occur within minutes of
dantrolene administration. Higher doses of up to 30
mg/kg may be administered in severe, refractory
cases. These initial starting doses are higher than
those that were recommended previously (1 mg/kg)
because of diminished circulation in patients with
malignant hyperthermia.482,557 The duration of
treatment in the cases reported has varied consider-
ably, from single-dose therapy to multiple days of
therapy. After the patient has stabilized, dantrolene
may be administered orally at a dose of 50 to 300
mg per day in divided doses or 1 to 2 mg/kg four
times daily for several days (at least 36 hours) to
prevent recurrence.558 Dantrolene has been used
successfully and safely in pregnant patients who are
susceptible to malignant hyperthermia and are
undergoing caesarean section.559-566 Dantrolene
may cause dizziness, diplopia, dysarthria, a sensa-
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
reported cases.517,547,567-571 Procainamide is no
longer recommended for management of malig-
nant hyperthermia unless tachyarrhythmia devel-
ops, in which case procainamide is considered the
drug of choice.
Benzodiazepines, opioid narcotic analgesics,
and in severe cases, neuromuscular blockade with
mechanical ventilation may be required in patients
with severe shivering or refractory muscle contrac-
tion, in an effort to control oxygen utilization.
Close monitoring of improvement of signs and
symptoms as well as any signs of recurrence is
important for a successful outcome for patients
with malignant hyperthermia. Appropriate moni-
toring parameters for patients with malignant
hyperthermia are listed in Table 34–29.
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670 SECTION VII • Drug-Induced Endocrine Diseases
TABLE 34–29 Monitoring Parameters for Patients
with Drug-Induced Malignant Hyperthermia
• Continuous central temperature
• Heart rate
• Respiratory rate
• Pulse oximetry
• End-tidal carbon dioxide
• Blood gases
• Continuous cardiac rhythm
• Coagulation profile
• Serum electrolyte concentrations
• Metabolic panel including serum carbon dioxide
concentration
• Serum blood urea nitrogen and creatinine concentra-
tions
• Serum creatine kinase concentrations
• Urine myoglobin concentrations
• Mental status
• Muscle rigidity
INFORMATION FOR PATIENTS
Patients should be questioned regarding a history of
malignant hyperthermia or a problem with anesthe-
sia and should be instructed to alert all health care
professionals of this risk. In addition, family members
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-
ity to triggering agents. Various options for anesthe-
sia, as well as the risks and benefits of those options
in addition to prophylaxis with dantrolene should be
discussed with patients at risk prior to any surgery. A
medical alerting device is recommended for those
with a history of malignant hyperthermia or who
have a significant family history and positive IVCT in
the event that emergency surgery is needed. Finally,
patients should be offered the opportunity to register
with the Malignant Hyperthermia Association of the
United States (MHAUS) by calling 1-800-MHAUS or
visiting the Web site, at www.mhaus.org. The Web
site provides patient and health care professional
information in addition to resources for susceptibility
testing, hotline contact information, and for obtain-
ing an Emergency Medical Identification Card.
HYPOTHERMIA
CAUSATIVE AGENTS
Baclofen, gamma-hydroxybutyrate (GHB), and
gamma-butyrolactone (GBL), which is converted
to GHB after ingestion, are structurally related to
GABA and may cause hypothermia in overdose.572-
579
GHB is best known as the “date rape” drug but
is also contained within body-building supple-
ments and marketed for recreational purposes. GBL
is found in industrial and household solvents and
other products, including dietary supplements
marketed for sleep and for enhancing sexual and
athletic performance. Although the Food and Drug
Administration requested a voluntary recall of
GBL-containing products in 1999, it may still be
available via the Internet in products labeled as
dietary supplements listed as “dihydro-2(3H)-fura-
none,” “4-butanolide,” “2(3H)-furanone, dihydro,”
“tetrahydro-2-furanone,” and “butyrolactone
gamma.” Street names for both GHB and GBL are
listed in Table 34–30. Drugs associated with
hypothermia are listed in Table 34–31.572-579 It has
been suggested that antipsychotics cause
hypothermia but this has not been clearly substan-
tiated.580
EPIDEMIOLOGY
The incidence of drug-induced hypothermia
among those taking causative drugs is unknown.
Sporadic cases are reported in the literature, but the
total number of individuals taking these drugs can-
not easily be determined.
MECHANISMS
Temperature balance occurs via the anterior hypo-
thalamus, with stimulation and inhibition from a
variety of neurotransmitters in a complex process.
Dopamine and serotonin receptors are involved in
thermoregulatory balance. Although both D1 and
D2 receptor subtypes are involved in temperature
regulation, the more prominent effect of dopamine
receptor stimulation is lowering of temperature,
and the more prominent effect of dopamine recep-
tor antagonism is that of elevating temperature.
Cannabinoid and opioid-induced hypothermia is
mediated via dopaminergic pathways. In addition,
opioids may decrease body temperature through
agonism of opiate receptors in the hypothalamus.
A relative increase in serotonin concentrations
increases temperature. GABA and baclofen inhibit
the release of excitatory neurotransmitters, includ-
ing serotonin and dopamine, resulting in a net
effect of hypothermia. Antipyretic agents such as
acetaminophen, aspirin, and other nonsteroidal
antiinflammatory drugs decrease temperature in
febrile patients in whom the thermoregulatory set
point has been raised. However, these drugs have
no effect on temperature in afebrile patients. Table
TisdaleC34_644-685 1/12/10 3:35 PM Page 671

CHAPTER 34 • Temperature Dysregulation 671

34–32 summarizes the mechanisms of drug-

TABLE 34–30 Street names for gamma-hydroxy- induced hypothermia.
butryrate and gamma-butyrolactone
GAMMA-HYDROXYBUTYRATE (GHB)
• Bedtime Scoop CLINICAL PRESENTATION AND
• Cherry Meth DIFFERENTIAL DIAGNOSIS
• Easy Lay
• Everclear Drug-induced effects other than hypothermia asso-
• Fantasy ciated with overdose of these agents are generally
• “G” more clinically significant (Table 34–33). In one
• G-juice series of cases of intentional baclofen overdose it
• GBH was reported that six of eight patients were
• G-riffic hypothermic (temperature ≤35.5°C).575 Other clin-
• Gamma Oh ical signs included bradycardia, hypertension,
• Gamma Ten hyporeflexia, apnea requiring intubation, and
• Georgia Home Boy coma. Two patients experienced seizures.
• Gook Hypertension and seizures were treated, and
• Great Hormones at Bedtime patients were treated for the possibility of co-inges-
• Grievous Bodily Harm tion of other drugs. Otherwise, treatment was sup-
• Jib portive. All patients recovered without permanent
• Liquid E sequelae within 5 days of ingestion.
• Liquid ecstasy Seventy cases of GHB overdose in which body
• Liquid G temperature was reported have been reviewed.572
• Liquid X The mean (±SD) initial temperature was 35.8±1.1°C
• Organic Quaalude (range, 32–39); 48 patients had an initial tempera-
• Salty water ture of ≤36°C, and 22 had an initial temperature of
• Scoop ≤35°C. Alcohol or other drugs were usually co-
• Sleep ingested, impairing detection of specific drug-
• Sleep-500 induced signs and symptoms. In addition to
• Soap hypothermia, commonly reported clinical signs
• Somatomax and symptoms of GHB and GBL ingestion include
• Vita G hypotension, respiratory depression, central nerv-
GAMMA-BUTYROLACTONE (GBL) ous system depression, bradycardia, nausea, vomit-
• Blue Nitro ing, combativeness, and tremors or twitching.
• Blue Nitro Vitality Co-ingestion of other substances must be strongly
• Fire Water considered in the differential diagnosis.
• GH Revitalizer
• Gamma G
• Re-energize RISK FACTORS
• Remforce
• RenewTrient There are no known risk factors for the develop-
• Revivarant ment of drug-induced hypothermia. Based on the
• Revivarant G cases reported, the disease appears to be dose-relat-

TABLE 34–31 Agents Implicated in Drug-Induced Hypothermia570-579

Drug Incidence Level of Evidence
(see page xii for explanation)
575
Baclofen NK C
Gamma-butyrolactone (GBL)578 NK C
Gamma-hydroxybutyrate (GHB)572-574,576,579 NK C
Cannabinoids578 NK C
Opioids578 NK C
NK = not known.
TisdaleC34_644-685 1/12/10 3:35 PM Page 672

672 SECTION VII • Drug-Induced Endocrine Diseases

TABLE 34–32 Mechanisms of Drug-Induced Hypothermia

Drug Mechanism
Baclofen Inhibits the release of both serotonin and dopamine with a
net effect of lowering temperature
Gamma-butyrolactone (GBL) Gamma-aminobutyric acid (GABA) agonism
Gamma-hydroxybutyrate (GHB) Gamma-aminobutyric acid (GABA) agonism
Cannabinoids Dopaminergic pathways; opiate antagonism in the hypo-
thalamus
Opioids Dopaminergic pathways

TABLE 34–33 Signs and Symptoms of Drug- MANAGEMENT

Induced Hypothermia
• Nausea Hypothermia secondary to ingestion of these drugs
• Vomiting is generally mild and does not require specific
• Hypothermia intervention. Other causes of hypothermia should
• Bradycardia be evaluated and treated, if applicable. Warming
• Hyporeflexia patients is usually not necessary. If hypothermia is
• Respiratory depression severe or if large amounts of fluids are to be admin-
• Hypotension istered, blankets and warmed fluid replacement to
• Combativeness prevent further body cooling may be used.
• Tremors or twitching Supportive measures should be implemented,
including intubation and mechanical ventilation
in patients with severe respiratory depression or for
ed, and therefore individuals taking these products airway protection. Concomitant management of
and drugs in larger quantities or more frequently known or suspected co-ingestants is imperative;
may be at higher risk. toxicology screens should be performed and blood
alcohol concentrations should be determined.

MORBIDITY AND MORTALITY

Most patients with drug-induced hypothermia
recover without permanent sequelae. However,
severe symptoms have developed in some, includ-
ing seizures, apnea, and coma.572-577 In summaries
of reported GBL overdose cases (41 patients) and
GHB cases at a single facility (88 patients), no
deaths were reported.572,576 Most patients fully
recover without significant intervention within
hours of ingestion. Deaths have rarely been report-
ed in other cases of sole GHB ingestion.577,579
INFORMATION FOR PATIENTS
Patient information should include warnings
about the use of illicit drugs, particularly those that
may be available through the Internet, health facil-
ities, and other sources with the potential for hid-
den ingredients. Patients who are hospitalized
because of illicit drug use should receive drug
counseling prior to discharge and be offered infor-
mation regarding treatment programs.

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products available over the Internet and patient
awareness are advisable. Since baclofen is often
used in children and adolescents, secured storage
may help reduce the occurrence of hypothermia
due to overdose of this drug.
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517. Kalow W. Succinylcholine and malignant hyperthermia.
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518. Johnson C, Edleman KJ. Malignant hyperthermia: a
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526. Mickelson JR, Gallant EM, Litterer LA, et al. Abnormal
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527. Dubrow JT, Wackym PA, Abul-Rasool IH, et al. Malignant
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528. Larach MG. Standardization of the caffeine halothane
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538. Jardon OM. Physiologic stress, heat stroke, malignant
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540. Tomarken JL, Britt BA. Malignant hyperthermia. Ann
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TisdaleC35_686-701 1/12/10 3:36 PM Page 686
CHAPTER 35
Sexual Dysfunction
in Males
S exual dysfunction in males can be broadly
classified into five major types: disorders of
libido (increased or decreased sexual drive), erec-
tile dysfunction (penile impotence), ejaculatory
disorders (premature ejaculation, delayed ejacula-
tion, emission failure or anejaculation, decreased
ejaculation volume, or retrograde ejaculation),
priapism (prolonged, painful erection), and infer-
tility. While some patients suffer from only one
type of sexual dysfunction, others may experience
more than one. In some cases, a patient may suf-
fer from one disorder, and then secondarily
another type of sexual dysfunction develops. For
example, an elderly menopausal male patient
may experience decreased libido, and then erec-
tile dysfunction develops secondary to the lack of
sexual drive. Some drugs have the potential to
cause several types of sexual dysfunction. For
example, phenothiazine antipsychotic agents
may cause decreased libido, erectile dysfunction,
or priapism, which may occur together in some
patients or separately in others. This chapter will
focus on drug-induced causes of male sexual dys-
function, including causes, presentation, and
management.
CAUSATIVE AGENTS
Tables 35–1 to 35–5 list the many drugs that have
been commonly reported to cause various types of
sexual dysfunction in males.1-87 Many of the pub-
lished references used to create these tables are
observational studies, case reports, or case series.
Thus, a cause–effect relationship has not been
established for many of the drugs. An effort was
made to include drugs for which a proposed mech-
686
Mary Lee and Roohollah Sharifi
anism for the drug-induced disease could be
described based on the drug’s pharmacologic
effects. Thus, Tables 35–1 to 35–5 should not be
considered exhaustive lists.
Key to the interpretation of the published lit-
erature on drug-induced sexual dysfunction is the
fact that, in some cases, the disease for which the
offending drug was prescribed is itself a risk factor
for sexual dysfunction. For example, diuretics are
a common cause of erectile dysfunction.
However, diuretics are commonly prescribed for
hypertension, which itself may cause erectile dys-
function.
EPIDEMIOLOGY
Up to 25% of cases of erectile dysfunction may be
drug-induced,12 and the most common offending
agents are thiazide diuretics, ␤-blockers, antipsy-
chotic agents, and antidepressants. According to
the Massachusetts Male Aging Study, which was
conducted in male outpatients aged 40 to 70 years,
up to 51% of men have some degree of erectile dys-
function.88 Erectile dysfunction was more common
in men who were taking antihypertensive drugs,
oral hypoglycemic agents, vasodilators, or cardiac
medications. In the 4-year Treatment of Mild
Hypertension Study, patients responded to an
annual survey of sexual function. At the 2-year
point, the incidence of the inability to achieve an
erection was 2.8%, 15.7%, and 4.9% in the doxa-
zosin, chlorthalidone, and placebo groups, respec-
tively.17 In contrast, the incidences of drug-induced
disorders of libido, ejaculation, priapism, or fertili-
ty are not as well studied, and therefore, fewer data
are available (Tables 35–1 to 35–5).
TisdaleC35_686-701 1/12/10 3:36 PM Page 687

CHAPTER 35 • Sexual Dysfunction in Males 687

TABLE 35–1 Agents Implicated in Drug-Induced Decrease in Libido

Drug Incidence Level of Evidence
(see page xii for explanation)

5␣-Reductase inhibitors1 6.4% A

Antidepressants, tricyclic2 NKa C
Antidepressants, selective serotonin reuptake2,3 1–12% A
Antidepressants, other2 4% A
Atypical antipsychotics4,5 0.1–5%, up to 60% A
Carbamazepine6 NK C
Cimetidine7,8 1 –4%b
Cocaine9 NK C
Digoxin10 NK C
Estrogens11 8% B
Ethanol12 NKc C
Gonadotropin-releasing hormone superagonists11 NKd A
Haloperidol11 NK C
Hypnotics, benzodiazepines11 NK C
12,13
Ketoconazole NK B
Lithium14 NK C
Metoclopramide11 NK C
Opiates (natural and synthetic)15 NK C
Phenothiazines16 NKe B
Spironolactone9 NKf B
a
Most common with tertiary amines, as these have the highest incidence of sedative adverse effects.
b
Uncommon. Most often reported with high dose parenteral drug treatment.
c
Common with high doses of ethanol. Low doses may improve libido.
d
Common after the first 2–3 weeks of the start of treatment.
e
Common with highly sedating phenothiazines. Less common with less sedating agents: thiothixene, haloperidol, or loxapine.
f
Common in patients treated with large daily doses (e.g., those with hyperaldosteronism).
NK = Not known

A wide range of prevalence rates has been

reported for sexual dysfunction associated with
specific drugs. These apparently conflicting data
are probably related to variations in patient factors
that directly influence the frequency of reported
sexual dysfunction, including the willingness of
the patient to report the adverse effect, persistence
of the health care provider in questioning the
patient about the adverse effect, patient’s age,
dosage regimen of the offending agent, use of the
offending agent in combination with other drugs
that could also cause sexual dysfunction, and con-
current medical illnesses that could contribute to
sexual dysfunction.89,90
MECHANISMS
Mechanisms of drug-induced sexual dysfunction
are dependent on the type of dysfunction (Table
35–6). A normal male libido is mediated by serum
androgen concentrations. Testosterone is the
chief male androgen, comprising 90% of circulat-
ing androgens, and is produced by the testes.
Serum testosterone concentrations are responsi-
ble for male sexual drive.90,93 The role of dihy-
drotestosterone, the chief active metabolite of
testosterone, in maintaining libido is not clear. In
patients with primary hypogonadism who have
TisdaleC35_686-701 1/12/10 3:36 PM Page 688

688 SECTION VII • Drug-Induced Endocrine Diseases

TABLE 35–2 Agents Implicated in Drug-Induced Erectile Dysfunction

Drug Incidence Level of Evidence
(see page xii for explanation)
17
␣-Adrenergic antagonists 0–2.8% A
5␣-Reductase inhibitors18 8.1–18.5% A
Antihistamines9 NKa C
Antiparkinsonian agents9 NK C
Antidepressants, tricyclic9 NK B
Antidepressants, other19 3.4% A
Antidepressants, tetracyclic16 0.1–1% A
Antidepressants, norepinephrine and serotonin reuptake inhibitors19 1–5% A
Atypical antipsychotics14 0.1–1%b A
Baclofen23 0.2-1.6% A
␤-Adrenergic antagonists17,24,25 6–40%c,d C
Calcium-channel antagonists24-26 <1% A
Celecoxib27 NK C
Central ␣-adrenergic agonists24,28 3–7%, up to 24% A
9,29
Disopyramide 1–3% A
Diuretics, thiazides24,28 10–20% B
Diuretics, loop28,29 NK C
Estrogens11,14 12% A
Gemfibrozil9,30 NK C
Gonadotropin-releasing hormone superagonists31 4% A
Guanethidine28 54% B
Lithium carbonate11,32,33 NK C
Methyldopa28 36%d B
Monoamine oxidase inhibitors9 NK C
Opiates14 Up to 50% B
Phenothiazines14 NKe B
Protease inhibitors34 6% B
Reserpine14 NKd C
Selective serotonin reuptake inhibitors3,19 0–13%f A
Spironolactone14 4–30%d C
NK = not known.
a
Frequency is highest with drugs with the greatest anticholinergic or sedative adverse effects.
b
Of these agents, risperidone has been reported to cause the highest incidence (>5%).
c
Frequency is highest with lipophilic drugs, which cross the blood–brain barrier.
d
Frequency is dose-related.
e
Frequency is highest with thioridazine, which has the greatest anticholinergic potency as compared with other agents.
f
Frequency is lower with antidepressants with low anticholinergic adverse effects (e.g., venlafaxine, bupropion, nefazodone, and tra-
zodone).
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CHAPTER 35 • Sexual Dysfunction in Males 689

TABLE 35–3 Agents Implicated in Drug-Induced Ejaculation Disorders

Drug Incidence Level of Evidence
(see page xii for explanation)
37 a
␣-Adrenergic antagonists 4–5% A
5␣-Reductase inhibitors18 0.1 –7.2% A
Antidepressants, tricyclic38,39 NK C
Antidepressants, tetracyclic39,40 <0.1% A
Antidepressants, norepinephrine and serotonin reuptake inhibitors21 2–3% A
Antidepressants, triazolopyridine41 NK C
Antidepressants, other20 0.1–1%
Antipsychotics, atypical42-44 0.1–5% A
Baclofen35 NK A
Haloperidol45 NK C
Monoamine oxidase inhibitors19,38 NK C
Naproxen35 NK C
Phenothiazines36 NK C
Selective serotonin reuptake inhibitors16,36,46,47 6–28%b A
Thiazide diuretics 48
NKc C
NK = not known.
a
Highest incidences reported with tamsulosin: 8.4% with 0.4 mg/day and 18.1% with 0.8 mg/day.
b
Occurs in up to 50% of patients treated with paroxetine. Paroxetine is associated with the highest incidence as compared with other
agents in this class.
c
Incidence of ejaculation disorders is much lower than those of erectile dysfunction and decreased libido.

serum testosterone concentrations that are below
the normal range, exogenous administration of
testosterone replacement agents restores libido.90
Testicular testosterone production is controlled
by the hypothalamic–pituitary–gonadal–adrenal
axis. Increased release of luteinizing-
hormone–releasing hormone or gonadotropin-
releasing hormone from the hypothalamus
stimulates pituitary release of luteinizing hormone.
Luteinizing hormone stimulates the production of
testosterone in Leydig cells. Therefore, drugs that
suppress hypothalamic release of luteinizing hor-
mone–releasing hormone or pituitary release of
luteinizing hormone, or that directly suppress tes-
ticular testosterone production, may suppress
libido. Similarly, drugs that increase serum pro-
lactin concentrations, which results in a decrease
in testicular androgen production, can indirectly
suppress libido. In addition to the stimulatory
effect of testosterone on libido, males must be con-
scious and receptive to sexual stimuli, which can
be visual, auditory, olfactory, tactile, or gustatory.
As these stimuli are processed in the brain, drugs
that cause sedation or depress the sensorium can
suppress libido.
Theoretically, it follows then that supraphysio-
logic serum testosterone concentrations may
enhance male sexual drive in elderly patients.
However, this has not been demonstrated clinical-
ly. Administration of excessive doses of testos-
terone to elderly male patients, resulting in
supraphysiologic serum testosterone concentra-
tions, is not associated with increased libido.73 The
mechanism for increased sexual drive is poorly
understood and may be due to a combination of
causes, including a supratentorial component.
In order for a penile erection to occur, a patient
must have intact penile vascular and neurologic sys-
tems. The penis is composed of three vascular bod-
ies: two dorsal corpora cavernosa and one corpus
spongiosum. During an erection, the corpora fill
with arterial blood, which must be trapped within
the corpora. Thus, arterial blood flow must be ade-
quate and the degree of arterial inflow must exceed
the degree of venous outflow for penile tumescence
to occur. When compounded by contraction of the
ischiocavernosus muscles surrounding the bulbous
urethra, these effects produce a long, hard penile
shaft suitable for vaginal penetration. Thus, sys-
temic antihypertensive agents, which decrease
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690 SECTION VII • Drug-Induced Endocrine Diseases

TABLE 35–4 Agents Implicated in Drug-Induced Priapism

Drug Incidence Level of Evidence
(see page xii for explanation)
49-51
␣-Adrenergic antagonists <1% A
Alprostadil52,53 0.4%a A
Antidepressants16,54 NK C
Antidepressants, triazolopyridine19,54-56 NK
Antipsychotics, atypical57-65 0.1–1% A
Cocaine66 NK C
Ethanol44 NK C
Fat emulsion, intravenous67 NK C
Heparin68,69 NK C
Hydralazine68 NK C
Papaverine70,71 NKb C
Phenothiazines38,72 NK C
Phentolamine44 NKb C
Phosphodiesterase inhibitors72-75 NK C
76-78
Selective serotonin reuptake inhibitors NK C
Warfarin68,79 NK C
NK = not known.
a
Usually occurs when administered intracavernosally or intraurethrally in large doses, or when used along with other erectogenic
drugs.
b
Usually occurs when administered in large doses intracavernosally, or when used along with other erectogenic drugs.

peripheral blood pressure, or diuretics, which
decrease blood volume, may compromise arterial
blood flow and cause erectile dysfunction.89
Both the central and peripheral nervous systems
can mediate a penile erection. With visual, olfactory,
auditory, tactile, or gustatory sexual stimulation, the
brain sends nerve impulses down the spinal cord.
Preganglionic sympathetic nerve fibers emerge from
the spinal cord at the thoracolumbar vertebra
T11–L2; postganglionic neurotransmission to the cor-
pora is mediated by parasympathetic pathways in the
pelvic plexus. Tactile stimulation of the genitalia can
also stimulate a somatic reflex nerve arc at the level of
the sacral vertebrae S2–S4. In either case, acetyl-
choline is the primary neurotransmitter responsible
for penile tumescence. Acetylcholine probably works
through noncholinergic, nonadrenergic neurotrans-
mitters, such as nitric oxide, and secondary messen-
gers, such as cyclic adenosine monophosphate and
cyclic guanine monophosphate, to mediate corporal
relaxation and blood filling of cavernosal tissue sinus-
es. Therefore, drugs that antagonize acetylcholine at
its receptor, producing anticholinergic effects, can
cause erectile dysfunction.89
In male patients with normal sexual function,
antegrade ejaculation of seminal fluids out of the
urethra occurs at climax. Antegrade ejaculation
requires emission (or the movement of seminal flu-
ids from the prostate, seminal vesicles, and vas def-
erens into the proximal urethra); contraction of the
bladder neck sphincter (to prevent the retrograde
flow of seminal fluids into the bladder); and con-
traction of periurethral skeletal muscles to propel
the ejaculate out of the urethra. Emission and blad-
der neck closure are sympathetically mediated by
norepinephrine.92 Thus, postsynaptic ␣-adrenergic
receptor antagonists (e.g., tamsulosin) block norepi-
nephrine at its receptor, and may lead to retrograde
ejaculation or emission failure.92 The antegrade
propulsion of ejaculate from the posterior urethra
and out of the patient’s body is parasympathetically
mediated. Thus, drugs with anticholinergic effects
may cause delayed ejaculation.44 In addition, stimu-
lation of central serotonin receptors appear to inhib-
it ejaculation. Therefore selective serotonin reuptake
inhibitors are associated with anejaculation.94
The ejaculate is composed of three major compo-
nents: sperm-containing fluid from the vas deferens,
fructose-containing fluid from the seminal vesicles,
and prostatic secretions from the prostate. A normal
ejaculate volume is 2 ml or more. Contributors of
ejaculate volume include the seminal vesicles
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CHAPTER 35 • Sexual Dysfunction in Males 691

TABLE 35–5 Agents Implicated in Drug-Induced Infertility

Drug 14,80 Incidence Level of Evidence
(see page xii for explanation)
80 a
Anabolic steroids NK C
Antineoplastic agents, alkylating14 Up to 100%b B
Carbamazepine81 NK C
Cimetidine14,68 NK C
Cisplatin18 Up to 100%c B
Corticosteroids 100%d B
Erythromycin82 NK C
Estrogens14 NKe C
Ethanol, chronic use83 NKe C
Gonadotropin-releasing hormone superagonists84 NKe B
Ketoconazole NKa,f C
Nitrofurantoin85,86 NKa,f C
Phenothiazines14 NK C
Spironolactone87 NKa C
68
Sulfasalazine NK C
NK=Not known.
a
Frequency is dose-related.
b
Incidence increases with dose and duration of treatment, and if chemotherapy is administered with radiation therapy or in combina-
tion with other chemotherapy known to affect spermatogenesis.
c
Up to 100% of patients become infertile when cisplatin is used to treat testicular cancer. When dose is 0.6 g/m2 or higher, azoosper-
mia develops in most patients.
d
This applies to patients treated with corticosteroids in pharmacologic doses in combination with antineoplastic chemotherapy regi-
mens.
e
Probably common; however, incidence not studied.
f
Not reported with usual therapeutic doses, occurs with large doses.

(75–80% of the total volume) and prostate (10% of
the total volume), both of which are androgen-
dependent tissues.44 Thus, medications that interfere
with testosterone stimulation of these target tissues
(e.g., finasteride) can decrease ejaculate volume.18,36
Following climax and ejaculation, the penis
returns to a flaccid state. For detumescence to occur,
venous outflow must exceed arterial inflow.
Detumescence is sympathetically mediated.
Therefore, norepinephrine normally causes arterio-
lar vasoconstriction, thereby decreasing arteriolar
inflow and causing cavernosal vasoconstriction.
This improves venous outflow, and the penis even-
tually becomes flaccid. ␤2-Adrenergic stimulation of
peripheral blood vessels causes venodilation, which
improves venous outflow and blood emptying from
the corpora cavernosa. When detumescence does
not occur, and the penile erection is sustained in the
absence of sexual stimulation, priapism can devel-
op. Penile pain may result from blood sludging
within and hypoxia of cavernosal tissue. Permanent
cavernosal injury may develop if priapism does not
resolve on its own or is not treated appropriately.
The mechanism of drug-induced priapism is
poorly understood. Priapism may result from drug-
induced increased arteriolar inflow to the caver-
nosa (e.g., hydralazine), drug-induced decreased
venous outflow mediated by inhibition of ␣-adren-
ergic tone (e.g., phentolamine, phenothiazines,
trazodone), blood sludging in the corpora because
of platelet or clotting factor dysfunction (e.g.,
heparin, warfarin), or some other mechanism.
The fertility of a male is dependent on multiple
physiologic functions: adequate quantitative and
qualitative production of sperm and effective emis-
sion of sperm into the prostatic urethra. Luteinizing
hormone and follicle-stimulating hormone (FSH) are
essential for the induction of sperm production at
puberty. After puberty, maintenance of spermatogen-
esis is dependent on FSH stimulation of Sertoli cells
TisdaleC35_686-701 1/12/10 3:36 PM Page 692

692 SECTION VII • Drug-Induced Endocrine Diseases

TABLE 35–6 Mechanisms of Drug-Induced Sexual Dysfunction in Males2-6,9-12,14,16,18,19,30,34-39,41,50-53,55,56,58-60,62-65,

67-71,76-79,82,85,86,91,92,97

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)
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CHAPTER 35 • Sexual Dysfunction in Males 693

TABLE 35–6 Mechanisms of Drug-Induced Sexual Dysfunction in Males2-6,9-12,14,16,18,19,30,34-39,41,50-53,55,56,58-60,62-65,

67-71,76-79,82,85,86,91,92,97
(Continued)

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
694 SECTION VII • Drug-Induced Endocrine Diseases
TABLE 35–6 Mechanisms of Drug-Induced Sexual Dysfunction in Males2-6,9-12,14,16,18,19,30,34-39,41,50-53,55,56,58-60,62-65,
67-71,76-79,82,85,86,91,92,97
(Continued)
Drugs
Sulfasalazine
Nitrofurantoin
Erythromycin
FSH = Follicle-stimulating Hormone; HT = Hydroxytryptamine; LH = Luteinizing hormone; AMP = Adenosine monophosphate; GMP =
Guanosine monophosphate
and the presence of adequate concentrations of
testosterone in the seminiferous tubules so that sper-
matogonia can undergo differentiation and matura-
tion into spermatozoa.94 Normal semen parameters
include a semen volume of 2 to 6 mL, a sperm con-
centration of at least 20 million per milliliter, at least
50% to 60% motile sperm, and at least 30% of sperm
with normal morphology.94,95 Although variably
defined, infertility refers to the inability of the female
partner to become pregnant after 1 year or more of
purposeful attempts to conceive.76 Infertility can be
due to an inadequate number of sperm in the semen;
abnormal sperm morphology, which interferes with
their motility; or their ability to penetrate an egg.
Thus, drug-induced infertility can result from dam-
age to the Sertoli cells (e.g., antineoplastic alkylating
agents, radiation therapy), interference with the mat-
uration of sperm (e.g., antiandrogens), or motility of
sperm (e.g., sulfasalazine, vaginal spermicides).14 The
extent of damage to the germinal epithelium by anti-
neoplastic agents is dependent on the pharmacolog-
ic class of agent used (alkylating agents are the most
potent, followed by antimetabolites, vinca alkaloids,
procarbazine, and cisplatin), dose used (higher doses
cause worse damage than lower doses), combined
use of alkylating agents (worse than monotherapy),
age of the patient (prepubertal males tend to be more
resistant to the effects of antineoplastic chemothera-
py than adult patients), and combined use with radi-
ation (worse than with chemotherapy alone).
CLINICAL PRESENTATION AND
DIFFERENTIAL DIAGNOSIS
Symptoms of drug-induced sexual dysfunction in
males are similar to those of patients with dysfunc-
tion due to other causes (Table 35–7). With decreased
libido, patients may report no desire for or interest in
sexual intercourse. Patients commonly profess to be
busy with work, engaged in other activities, or to not
feel well, and use these as excuses for having no desire
for sexual intercourse. Often, patients with decreased
Mechanism
Decreases sperm production, maturation, and motility.
Inhibits sperm maturation and protein synthesis, which
interferes with sperm motility.
Decreases sperm motility and sperm number.
libido present with a recent history of divorce, separa-
tion from a loved one, death of a spouse, sudden job
loss, or performance anxiety. Patients with increased
libido usually do not come to the attention of a clini-
cian unless the patient’s sexual desires are inappropri-
ate, such as in precocious puberty.
Patients with erectile dysfunction present with
failure to achieve a penile erection sufficient for
vaginal penetration. Although periodic erectile
dysfunction is generally acceptable, a patient who
experiences erectile dysfunction in more than 50%
of attempts at sexual intercourse should seek med-
ical treatment if he wishes to be sexually active.
Patients with ejaculatory dysfunction may pres-
ent with a variety of symptoms, including prema-
ture ejaculation, reduced ejaculation volume,
retrograde ejaculation, delayed ejaculation, anejacu-
lation (no ejaculation), or emission failure. With
premature ejaculation, the patient ejaculates
within 1 minute of vaginal penetration or before cli-
max is reached, often rapidly followed by detumes-
cence.44 A chief problem is spousal dissatisfaction
with the patient’s sexual performance. Alternatively,
some patients report reduced ejaculatory volume.
Confirmation of the existence of the problem
requires measurement of ejaculatory volume prior
to and after the supposed disorder developed, which
is rarely performed in clinical practice. Thus, this is
more often a subjective report by the patient. On
the other hand, in patients with retrograde ejacula-
tion, the patient usually reports “dry sex” and no
antegrade flow of seminal fluid during climax.
Instead, during the first urine voiding after inter-
course, the patient may produce cloudy urine,
which indicates the presence of seminal fluid in the
urine. The presence of sperm in the urine can be
confirmed by microscopic examination of a poste-
jaculation urine sample. Anejaculation is a failure to
ejaculate, which may be due to a disorder of emis-
sion or a delay in emission. The patient may present
similarly to those with retrograde ejaculation.
Patients with priapism often have a sickle cell
anemia or chronic granulocytic leukemia, use erec-
TisdaleC35_686-701 1/12/10 3:36 PM Page 695
TABLE 35–7 Signs and Symptoms Associated
with Drug-Induced Sexual Dysfunction in Males
Decreased libido
• Decreased or absent desire for sexual intercourse,
depressed mood.
• Symptoms are temporally related to start of
causative drug.
• Gynecomastia, small testicles, decreased muscle
mass, hot flashes, and subphysiologic serum
testosterone concentrations.
Erectile dysfunction
• Inability to achieve a penile erection sufficient for
successful intercourse. Partner may express dissat-
isfaction or frustration with patient.
• Symptoms are temporally related to start of
causative drug.
• Inability to achieve a penile erection with stimulation.
Patient may have a medical illness that also causes
erectile dysfunction for which the causative drug is
being taken. For example, the patient may suffer from
depression and need to take an antidepressant.
• Absence of penile curvature or palpable plaques
• No signs of infection
Ejaculation disorder
• Absent, decreased, or delayed ejaculation. Patient
reports dry sex or lack of sexual
satisfaction/enjoyment during climax. If retrograde
ejaculation, patient reports cloudy urine immedi-
ately after intercourse. If premature ejaculation,
patient reports ejaculation before intercourse or
before climax is reached. Partner may express dis-
satisfaction or frustration with patient.
• Symptoms are temporally related to start of
causative drug.
• If delayed or retrograde ejaculation, microscopical
examination of urine after intercourse shows
sperm. If decreased ejaculation, semen volume is
less than 2–6 ml.
Priapism
• Prolonged erection in the absence of sexual stimu-
lation. Penis is painful and may be bluish in color.
• Symptoms are temporally related to start of the
causative drug.
• Physical exam shows a rigid, hard dorsal surface of
penis, and a soft ventral surface.
Infertility
• Female partner is unable to conceive despite 1 year
of trying.
• Symptoms are temporally related to start of the
causative drug.
• Semen analysis shows an abnormality: volume is less
than 2–6 ml, <50–60% of sperm are motile, sperm
count is less than 20 million per milliliter, less than
30% of sperm have normal morphology. Increased
serum concentrations of follicle-stimulating hor-
mone.
CHAPTER 35 • Sexual Dysfunction in Males 695
togenic drugs, or have a history of unusually pro-
longed sexual activity or drug abuse. Because of a
persistent painful erection for several hours, the
patient will present for urgent or emergency care.
Because priapism more commonly involves the
corpora cavernosa as opposed to the corpus spon-
giosum, the dorsal surface of the penis will be hard,
but not the ventral surface.
In a patient with infertility, the failure to suc-
cessfully impregnate his female partner after 1 year’s
time is obvious. However, the diagnostic assessment
to determine the cause generally requires an exten-
sive workup, as the cause could be multifactorial.
In the diagnostic evaluation of patients with sex-
ual dysfunction, it is important to take a careful his-
tory of present illnesses, past medical problems and
surgical procedures, and concurrent medications. In
many cases, information should also be obtained
from the spouse or significant other, so that sensitive
data collected from the patient regarding the nature
of the sexual dysfunction can be corroborated.
Knowledge of past medical problems and concurrent
prescription and nonprescription medications is key
to rule out diseases or other drugs or drug combina-
tions that could be contributing to the patient’s cur-
rent symptoms. Conditions to consider in the
differential diagnosis of drug-induced sexual dysfunc-
tion are listed in Table 35–8. Patients with erectile dys-
function should be asked to complete a standardized,
validated, self-assessment survey of sexual function,
such as the International Index of Erectile Function
or Brief Sexual Function Inventory.96 This should be
done at baseline and after a corrective measure has
been instituted. Physical examination should include
gross examination of the external genitalia, and
assessment of pelvic nerve function, including assess-
ment of genitoperineal pain sensation, the bulbocav-
ernosal reflex, and anal sphincter tone.89
Patients being evaluated for drug-induced dimin-
ished libido should undergo two serial measurements
of serum testosterone concentrations, obtained in the
morning at the same time each day. Repeated morn-
ing measurements are recommended because of the
circadian pattern of endogenous testosterone secre-
tion and because of substantial variability in serum
testosterone concentrations throughout the day. In
addition, the patient should be checked for physical
signs of hypogonadism, including gynecomastia,
decreased muscle mass, and undersized testes.
In patients with erectile dysfunction, no specific
diagnostic tests are usually performed. With the
availability of phosphodiesterase inhibitors (e.g.,
sildenafil), which are effective in the majority of
patients with erectile dysfunction independent of
the cause, diagnostic testing is not necessary.
Nocturnal penile tumescence testing, penile Doppler
ultrasound, cavernosography, and cavernosometry
TisdaleC35_686-701 1/12/10 3:36 PM Page 696
696 SECTION VII • Drug-Induced Endocrine Diseases
TABLE 35–8 Conditions to Consider in the
Differential Diagnosis of Drug-Induced Sexual
Dysfunction in Males
Decreased libido
• Primary hypogonadism due to testes removal
(postorchiectomy) or injury (e.g., mumps orchitis)
• Secondary hypogonadism due to hypothalamic or
pituitary disorder
• Hyperprolactinemia
Erectile dysfunction
• Vascular disorders (e.g., hypertension, arterioscle-
rotic cardiovascular disease, peripheral vascular
disease)
• Neurologic disorders (e.g., diabetes mellitus, spinal
cord injury, stroke, post–radical prostatectomy,
post–pelvic trauma with pelvic nerve injury, chron-
ic alcoholism, peripheral neuropathy, Parkinson’s
disease)
• Psychiatric disorders (e.g., depression, schizophre-
nia, performance anxiety)
• Hormonal disorders (e.g., primary or secondary
hypogonadism, hyperprolactinemiaa)
• Penile disorders (e.g., Peyronie’s disease, penile
trauma, previous priapism)
Ejaculation disorder
• If premature or delayed ejaculation, performance
anxiety
• If retrograde ejaculation, post–radical prostatecto-
my, surgical injury to the bladder neck or diabetes
mellitus
Priapism
• Sickle cell disease
• Chronic granulocytic leukemia
• Coagulopathy
• Excessive sexual activity
• Drug abuse
• Spinal cord injury
Infertility
• Extensive radiation therapy to pelvis
• Testicular cancer
• Absent or nonfunctional testes
• Primary or secondary hypogonadism
• Hyperprolactinemia
• Cryptorchidism
• Obstruction of epididymis or vas deferens (e.g.,
congenital cystic fibrosis)
a
These disorders produce decreased libido and secondary
erectile dysfunction.
are generally reserved for patients in whom there is
no response to phosphodiesterase inhibitors or in
those in whom specific surgically correctable organic
causes of sexual dysfunction are suspected.
Patients with ejaculatory dysfunction should
be requested to provide two semen samples under
controlled conditions in the clinic. Each sample
should be collected on a different day, and sample
collection should be preceded by 3 days of sexual
abstinence. The specimen should be checked for
ejaculate volume, and sperm motility and mor-
phology. If retrograde ejaculation is suspected, a
postejaculation urine specimen should also be
evaluated for the presence of sperm.
Patients with infertility are diagnosed with
semen analysis and FSH serum concentrations.
Patients with drug-induced infertility due to testicu-
lar damage present with increased FSH, azoosper-
mia/oligospermia, decreased semen volume,
abnormal sperm motility and morphology, or all of
these. Antineoplastic chemotherapy is one of the
most common causes of infertility. The usual onset is
8 to 12 weeks after the start of chemotherapy. The
incidence and duration of infertility are greater with
the use of alkylating agents in high doses in repeated
cycles, which are associated with extensive damage
to spermatogonia.97 Recovery of fertility is depend-
ent on the number of remaining functional sper-
matogonia after chemotherapy. Significant delays in
recovery, up to several years after the last dose of
chemotherapy, are due to extensive reduction in the
numbers of spermatogonia and stem cells.
RISK FACTORS
Specific risk factors for drug-induced sexual dys-
function in males have been proposed, but not
confirmed. Possible risk factors for drug-induced
sexual dysfunction in males are listed in Table
35–9. Several factors associated with diminished
sexual function include age >40 years, smoking,
drinking excessive amounts of alcohol, coronary
artery disease, hypertension, diabetes mellitus,
spinal cord injury, stroke, and cancer.100 In addi-
tion, the risk of drug-induced sexual dysfunction
is greater in patients taking combinations of
drugs that are known to cause sexual dysfunction.
MORBIDITY AND MORTALITY
Except for priapism, drug-induced sexual dysfunc-
tion is largely a benign disease98. Patient morbidity
is largely related to the negative impact of drug-
induced sexual dysfunction on the quality of life of
affected patients and their partners.101,102
Depression, performance anxiety, and lack of self-
confidence or diminished self-esteem can result.
Priapism can be painful.
Decreased libido, erectile dysfunction, and ejacu-
latory disorders do not result in mortality. However,
untreated priapism or priapism that responds poorly
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CHAPTER 35 • Sexual Dysfunction in Males 697

mented if necessary. Taking complete and careful

TABLE 35–9 Risk Factors for Drug-Induced medical and medication histories is best for initial
Sexual Dysfunction in Males9,25,89,98 screening. This should be followed by evaluation of
Vascular risk factors pertinent physical examination findings.
• Arteriosclerotic cardiovascular disease Laboratory tests such as measurement of serum
• Hyperlipidemia testosterone concentrations and semen analyses
• Hypertension should not be obtained routinely in patients for
• Smoking whom a drug is prescribed that has been associated
• Sickle cell anemia with sexual dysfunction; such laboratory tests
• Peripheral vascular disease should be obtained only if the patient has a medical
Neurologic risk factors history and symptoms that are consistent with
• Diabetes mellitus drug-induced sexual dysfunction (Table 35–7).
• Chronic alcohol use Table 35–10 describes a general approach to prevent
• Pelvic trauma with nerve injury drug-induced sexual dysfunction and infertility.
• Post–radical prostatectomy or retroperitoneal
surgery
• Spinal cord injury MANAGEMENT
• Stroke
• Parkinson’s disease Treatment options for the management of drug-
Hormonal risk factors induced sexual dysfunction are presented in Table
• Primary or secondary hypogonadism 35–11. When drug-induced sexual dysfunction
• Hyperprolactinemia occurs, it is recommended that the causative agent
• Hyperthyroidism be discontinued. After an adequate washout period,
• Hypothyroidism the patient should be reassessed to determine
Psychogenic risk factors whether sexual dysfunction is still present. If the
• Depression offending agent cannot be discontinued, dose
• Anxiety disorder reduction is often helpful. For certain types of drug-
• Strained relationship with significant other induced sexual dysfunction, specific treatments
• Psychosis have been described in the literature. However, in
Other risk factors many cases, no direct comparison studies have been
• Penile disorder (e.g., Peyronie’s disease, penile injury)
• Cancer
• Obesity TABLE 35–10 Approaches to Help Prevent Drug-
• Liver failure Induced Sexual Dysfunction in Males
• Kidney failure • Maintain heart-healthy lifestyle: do not smoke, avoid
excessive alcohol, maintain ideal body weight, and
exercise regularly.
to drug or surgical intervention may result in penile
• If patient has hypertension or diabetes mellitus, he
fibrosis, which can lead to irreversible erectile dys-
should optimize treatment of these conditions.
function. In one rare case of papaverine-induced pri-
• If the patient is older than 50 years of age, he should
apism, a pulmonary embolus developed.70
undergo an annual urologic evaluation to check for
genitourinary tract disorders (e.g., benign prostatic
hypertrophy, prostate cancer) that could affect sexu-
PREVENTION al function.
• If the patient will need to take a medication that may
Minimizing risk factors associated with drug-induced
cause sexual dysfunction or infertility, the health care
sexual dysfunction may prevent the disease. Drugs
professional should consider any of the following meas-
known to cause sexual dysfunction should be avoid-
ures, if possible, to minimize the risk of drug-induced
ed in young, sexually active males, if possible. If this
sexual dysfunction: use the lowest effective dose of the
is not possible, these drugs should be used at the low-
medication, change the timing of the medication so
est effective dose for the shortest period of time.
that the peak serum concentration does not occur
Comorbid conditions that have been associated
when the patient wants to be sexually active (this works
with sexual dysfunction should be treated optimal-
for medications with short half-lives or that cause seda-
ly. Lifestyle modifications, such as smoking cessa-
tion), or switch the patient from a medication with a
tion, weight loss, and avoidance of excessive
higher prevalence of sexual dysfunction to a medication
alcohol use (which decreases libido and secondarily
with a lower prevalence of sexual dysfunction.
produces erectile dysfunction) should be imple-
TisdaleC35_686-701 1/12/10 3:36 PM Page 698
698 SECTION VII • Drug-Induced Endocrine Diseases
performed to determine whether one specific treat-
ment is more effective than another. In addition,
implementation of drug therapy to treat a disease
caused by another drug is never a preferred manage-
ment approach, as it adds to the patient’s drug costs
and is usually associated with additional adverse
effects. Pharmacotherapy for the purpose of treating
sexual dysfunction induced by another drug should
be implemented only when other measures fail or
are not feasible. Furthermore, a key component in
the treatment of patients with drug-induced sexual
dysfunction is replacing the causative agent with a
drug that is associated with a lower likelihood of
causing sexual dysfunction (Table 35–11).
INFORMATION FOR PATIENTS
Practitioners who counsel patients with drug-induced
sexual dysfunction should have a clear understanding
of the categories of sexual dysfunction, so there is no
confusion in discussing the specific problem with the
patient.105 Patients should be advised that drug-
induced sexual dysfunction (with the exception of
alkylating agent–induced infertility) is usually
reversible following discontinuation of the culprit
drug. Patients who are taking drugs that may cause
sexual dysfunction should be counseled regarding the
specific type(s) of dysfunction that could occur and
the specific symptoms that may result. Patients
should be advised to implement lifestyle changes
(e.g., quitting smoking, reducing alcohol consump-
tion) that may minimize the risk of drug-induced sex-
ual dysfunction. Patients should be instructed to
consult their pharmacist or physician if sexual dys-
function that interferes with their lifestyle or nega-
tively impacts their quality of life occurs. Patients
should be instructed to avoid using nonprescription
medications, illicit drugs, and some herbal medicines,
including those that may cause sedation, produce
anticholinergic effects, have antiandrogenic effects,
or inhibit hepatic metabolism of the offending drug,
as these factors can worsen the degree of drug-
induced sexual dysfunction. In addition, patients
should inform the pharmacist and physician of any
new medications, so that these can be checked for
interactions with existing medications that may
cause or exacerbate drug-induced sexual dysfunction.
If the patient has risk factors for priapism (e.g., the
patient has sickle cell anemia or is using erectogenic
drugs) he should be instructed to seek medical atten-
tion immediately if an erection persists for 4 hours or
more. Because extensive radiation therapy and
chemotherapy for cancer may cause irreversible dam-
age to the testes and infertility, patients should be
advised to bank semen before chemotherapy. After
chemotherapy, to minimize teratogenic effects due to
persistent drug-induced mutations to sperm, patients
should be advised to delay conception for 6 months
to 2 years after the last dose of chemotherapy.94,97,108
Practitioners caring for patients with drug-
induced sexual dysfunction should talk to these
patients, respond to their questions, and anticipate
their concerns. These cases must be handled with
the utmost confidentiality. Counseling should take
place in a quiet, secure area. The practitioner should
project an attitude of caring and respect, and be
nonjudgmental in handling the patient’s issues.
Some patients find it difficult to discuss their con-
cerns regarding drug-induced sexual dysfunction.
Practitioners can be helpful and proactive. For exam-
ple, pharmacists can initiate a follow-up consultation
session when refilling a prescription by stating, “This
medication may cause changes to your sexual func-
tion when used in usual doses. Has this been a prob-
lem for you?” Such a statement immediately puts the
patient at ease because the patient is reminded up
front that the problem is not unique and occurs com-
monly. Also, some patients who experience drug-
induced sexual dysfunction may refuse to continue to
take necessary medications. In this case, the pharma-
cist should discuss the benefits and risks of taking the
medication, notify the prescriber of the problem, and
offer options for management of the patient’s primary
problem and for his drug-induced sexual dysfunction.
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CHAPTER 35 • Sexual Dysfunction in Males 699

TABLE 35–11 Approaches to Manage Drug-Induced Sexual Dysfunction in Males

In all cases of drug-induced sexual dysfunction, management should include:
• Discontinuation or reduction of dose of offending agent, if possible.
• Switching to another drug that does not cause sexual dysfunction.
• Initiating a specific drug to treat sexual dysfunction only if first two steps do not work or cannot be implemented.
Type of Dysfunction Additional Management Approaches
Decreased libido • Psychotherapy or counseling.
• If patient has low serum testosterone concentration, con-
sider testosterone supplementation, provided the patient has
no contraindications (e.g., testosterone cypionate or testos-
terone enanthate 200 mg intramuscularly every 3–4 wk)90
Erectile dysfunction • Initiate a phosphodiesterase inhibitor (e.g., sildenafil
25–50 mg orally 1 hour before intercourse)103,104
• If oral agents are unsuccessful or contraindicated, initiate
intracavernosal alprostadil (e.g., alprostadil 10 mcg
intracavernosally 30 minutes before intercourse)
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• Surgical implantation of a penile prosthesis is a treatment
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more potential adverse effects than medical treatments.
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imipramine 25–50 mg daily for 7 days prior to planned
sexual activity, or pseudoephedrine 60 mg four times a
day for 3 days prior to planned sexual activity.35
• If premature ejaculation, manual squeezing of the glans
penis may be helpful.94 Alternatively, application of 2%
lidocaine jelly to the glans penis may decrease sensitivity
of penis to tactile stimulation. Administration of sertra-
line 50 mg daily for 1 or 2 weeks or clomipramine 25–50
mg daily for 1 or 2 weeks, which produces anejaculation,
has been used with some success.35,105-107
Priapism • Sedate patient to reduce central nervous system
stimulation that might be causing or exacerbating priapism.
• Put the patient in a quiet, darkened room.
• Apply ice packs to the penis.
• Aspirate and irrigate sludged blood from corpora, if
necessary.
• Initiate surgical arteriovenous shunts of the corpora as a
treatment of last resort.
Infertility • Reassure the patient that after a significant time after the
last dose of chemotherapy, fertility may return. However,
the time to recovery is highly dependent on the degree
of damage to the germinal cells. If the patient is receiving
antineoplastic chemotherapy for cancer, the benefit of
continuing treatment outweighs the risk of this adverse
effect.105
• Sometimes, this adverse effect can be minimized by using
lower doses of drugs in combination, and using combina-
tions of drugs with a lower potential to cause infertility.
• Although a variety of hormonal therapies have been tried
(e.g., testosterone supplements, clomiphene citrate, human
chorionic gonadotropin), none has been uniformly effective.
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CHAPTER 36

Gynecologic Diseases and

Infertility in Women

Judith A. Smith

D rug-induced gynecologic diseases and infertility

in women can have an enormous impact on the
quality of life for those afflicted. The true incidence
of drug-induced gynecologic diseases, dysfunctions,
and disorders is difficult to estimate because of sig-
nificant under-reporting. The drug-induced gyneco-
logic diseases have an insidious and inconsistent
onset that can make prevention and diagnosis a
challenge in most cases. Moreover, women often do
not identify the relationship between the use of the
offending agent and the onset of the gynecologic
disease, dysfunction, or condition. Although appro-
priate interventions may successfully manage and
relieve the symptoms associated with the various
drug-induced gynecologic diseases discussed in this
chapter, many result in irreversible outcomes such
as sexual dysfunction or infertility.
OVARIAN HYPERSTIMULATION
CAUSATIVE AGENTS
Drug-induced ovarian hyperstimulation occurs
after repeated or prolonged use of ovulation-induc-
tion agents such as antiestrogens (clomiphene cit-
rate or tamoxifen), gonadotropins (gonadorelin,
human chorionic gonadotropin [hCG]), or
gonadotropin-releasing agonists (goserelin
acetate). Drugs implicated in ovarian hyperstimu-
lation are listed in Table 36–1).1-36
EPIDEMIOLOGY
Ovulation-induction medications were introduced
over 30 years ago. Drug-induced ovarian hyperstim-
702
ulation has been reported to occur in up to 27.7% of
patients receiving ovulation-induction drugs, with
severe cases occurring in less than 2% of patients.3-6
Mechanisms
Gonadotropins or gonadotropin-releasing agonists
are used in the follicular phase of the ovarian cycle to
increase serum concentrations of follicle-stimulating
hormone (FSH) and luteinizing hormone (LH), for
the purpose of increasing the maturation of multiple
ovarian follicles resulting in multiple ovulations.7
Antiestrogen agents interact with estrogen receptors
at the hypothalamus, displacing endogenous estro-
gen, thereby disrupting the endogenous estrogen
negative feedback loop effect.7 Ultimately, this
results in stimulation of the release of FSH and LH,
increasing the maturation of multiple ovarian folli-
cles, producing multiple ovulations. Endogenous
and exogenous hCG (or both) also likely play a role
in the pathogenesis of ovarian hyperstimulation.8 It
is believed that hCG stimulates continuous ovula-
tion, and it may also increase ovarian capillary per-
meability.8 Mechanisms of drug-induced ovarian
hyperstimulation are described in Table 36–2.
CLINICAL PRESENTATION AND
DIFFERENTIAL DIAGNOSIS
Signs and symptoms associated with ovarian hyper-
stimulation are listed in Table 36–3. This drug-
induced disease may occur either early (within 7
days) or late (within 2 weeks) after initiation of drug
therapy. The primary sign of ovarian hyperstimula-
tion is significant enlargement of the ovary that
leads to the leakage of protein-rich fluid from ovari-
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CHAPTER 36 • Gynecologic Diseases and Infertility in Women 703

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)
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704 SECTION VII • Drug-Induced Endocrine Diseases

TABLE 36–1 Agents Implicated in Drug-Induced Gynecologic Diseases and Infertility in Women (Continued)

Drug Incidence Level of Evidence

SEXUAL DYSFUNCTION109-112, 117-122
Antiepileptic drugs NK C
Antihypertensive agents 11% B
Antidepressants 16–57% B
Antipsychotics 28–93% B
Amphetamines NK C
Bromocriptine NK C
Cimetidine NK C
Digoxin NK C
Granisetron NK C
Indinavir 40% C
Ketamine NK C
Methadone NK C
Methazolamide NK C
Naproxen NK C
Norethandrolone NK C
INFERTILITY131-144
Alkylating agents <60% A
Antiepileptic drugs 12–59% B
Anthracyclines <60% B
Bleomycin <60% C
Caffeine NK, dose-dependent A
Etoposide <60% B
Fluorouracil <60% B
Methotrexate <60% A
Platinum analogues <60% B
Thalidomide <60% A
Vinca alkaloids <60% C
NK = not known
a
Occurs in up to 27.7% of patients receiving ovulation-induction drugs, with severe cases occurring in less than 2% of patients
b
Approximately 17-39% of gynecologic office visits are associated with cases of vulvovaginal candidiasis.
c
The incidence of dysmenorrhea in menstruating women ranges from 3-90%.

an capillaries into the peritoneal space.9 Drug-
induced ovarian hyperstimulation may be associated
with multiple nonspecific symptoms related to the
accumulation of this peritoneal fluid and including
abdominal distention, pain or a pulling sensation in
the pelvis, nausea, vomiting, diarrhea, dyspnea, and
chest pain.4 In addition to enlargement of the ovary,
specific signs suggestive of ovarian hyperstimulation
include ascites, oliguria, tachycardia, and, in severe
cases, pleural effusion.6,11 These signs and symptoms
of drug-induced ovarian hyperstimulation must be
differentiated from other conditions that may result
in similar symptoms, such as gastrointestinal compli-
cations of ovarian cysts, endometriosis, and ectopic
pregnancy. Conditions to consider in the differential
diagnosis of ovarian hyperstimulation are presented
in Table 36–4.
RISK FACTORS
Specific risk factors for the development of drug-
induced ovarian hyperstimulation are not well-
established (Table 36–5). Younger patients tend to be
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CHAPTER 36 • Gynecologic Diseases and Infertility in Women 705

TABLE 36–2 Mechanisms of Drug-Induced Gynecologic Diseases and Infertility in Women

Drug Mechanism
OVARIAN HYPERSTIMULATION1-36
Clomiphene citrate Disrupts endogenous estrogen negative feedback loop at the
hypothalamic level by blocking estrogen receptors inducing
ovulation
Gonadotropins Increase FSH and LH inducing multiple ovulations
Gonadotropin-releasing agonists Increase FSH and LH inducing multiple ovulations
Tamoxifen Disrupts endogenous estrogen negative feedback loop at
the hypothalamic level by blocking estrogen receptors
inducing ovulation
VULVOVAGINAL CANDIDIASIS37-46
Antibiotics (systemic) Alter normal flora (lactobacilli) of vagina resulting in
overgrowth of Candida
Corticosteroids Increase glycogen content, increasing pH and promoting
growth of Candida
Hormone-replacement therapy Increases glycogen content, increasing pH and promoting
growth of Candida
Oral contraceptives Increase glycogen content, increasing pH and promoting
growth of Candida
Tamoxifen Increases glycogen content, increasing pH and promoting
growth of Candida
VAGINAL BLEEDING DISORDERS: AMENORRHEA/OLIGOMENORRHEA55-61
Antiepileptic drugs Increase hormone-binding globulin, resulting in decreased
binding of estradiol leading to ovarian dysfunction
Antihypertensive agents Microvascular instability inducing breakthrough bleeding
Platinum analogues Direct toxic effects on oocytes that halts ovulation,
inducing amenorrhea
Chlorambucil Direct toxic effects on oocytes that halts ovulation, inducing
amenorrhea
Alkylating agents Direct toxic effects on oocytes that halts ovulation,
inducing amenorrhea
Danazol Indirect inhibition of negative feedback loop of the
hypothalamic–pituitary pathway, decreasing FSH/LH
release and altering ovarian function
Doxorubicin Direct toxic effects on oocytes that halts ovulation, inducing
amenorrhea
Estrogen Indirect inhibition of negative feedback loop of the
hypothalamic–pituitary pathway, decreasing FSH/LH
release and altering ovarian function
Etoposide Direct toxic effects on oocytes that halts ovulation, inducing
amenorrhea
Goserelin Indirect inhibition of negative feedback loop of the
hypothalamic–pituitary pathway, decreasing FSH/LH
release and altering ovarian function
Medroxyprogesterone Direct effect on uterine lining
Methyldopa Increases prolactin concentrations; indirect effect on LH secretion
(Continued)
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706 SECTION VII • Drug-Induced Endocrine Diseases

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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CHAPTER 36 • Gynecologic Diseases and Infertility in Women 707

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
recruitable follicles and gonadotropin receptors.11,12
Although some data suggest that women with a his-
tory of polycystic ovarian syndrome may have an
increased risk for drug-induced ovarian hyperstimu-
lation, in most cases this drug-induced disease is not
predictable.13-16 Repeated or prolonged cycles as well
as high doses of clomiphene citrate and
gonadotropins contribute to an increased risk of
drug-induced ovarian hyperstimulation.17-21
MORBIDITY AND MORTALITY
Early or mild drug-induced ovarian hyperstimulation
typically resolves without intervention and with no
significant sequelae. However, severe cases of drug-
induced ovarian hyperstimulation and those which
are diagnosed late can be life-threatening.4 In the
short term, the fluid shifts can result in significant
ascites, intravascular volume depletion, and pleural
effusion that may lead to significant breathing diffi-
culties and, in rare cases, acute respiratory distress
syndrome. Ascitic fluid can put pressure on the infe-
rior vena cava and lead to decreased cardiac output.4
Severe cases of drug-induced ovarian hyperstimula-
tion have been associated with significant throm-
boembolic events.5,6 In addition, patients are at risk
of ovarian torsion or cyst rupture that may lead to
potentially fatal hemorrhage.5,6 Ovarian hyperstimu-
lation associated with fertility drugs may be associat-
ed with the development of ovarian cancer.18-29
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708 SECTION VII • Drug-Induced Endocrine Diseases

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-
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CHAPTER 36 • Gynecologic Diseases and Infertility in Women 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
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710 SECTION VII • Drug-Induced Endocrine Diseases
the luteal phase.30,31 Another option is the intra-
venous administration of 25% albumin during
follicular aspiration; however, the effectiveness
of this approach for prevention of drug-induced
ovarian hyperstimulation has been variable.30,32-34
MANAGEMENT
Treatment options for drug-induced ovarian hyper-
stimulation are described in Table 36–7. Mild cases
in which patients present with some discomfort
and for which the only physical finding is mild
abdominal distention will resolve without any
intervention.4 Fluid shifts can occur because of sig-
nificant ascites, intravascular volume depletion,
and pleural effusions. To help prevent progression
and adverse sequelae related to these fluid shifts,
patients should be instructed to increase fluid
intake. Patients with moderate drug-induced ovar-
ian hyperstimulation often present with increasing
abdominal girth, pain, nausea and vomiting, diar-
rhea, shortness of breath, or any combination of
these. Moderate ovarian hyperstimulation can be
treated on an outpatient basis, but close monitor-
ing and follow-up is required. These patients
should be instructed to increase oral hydration and
may benefit from a short course of intravenous
hydration. Outpatients with moderate drug-
induced ovarian hyperstimulation should be on
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-
istration of a gonadotropin-releasing–hormone
agonist (intramuscular leuprolide 7.5 mg once
monthly) has been reported to be successful for the
treatment of tamoxifen-induced ovarian hyper-
stimulation.35
Patient with life-threatening cases of ovarian
hyperstimulation present with significant ascites,
intravascular volume depletion, possible pleural
effusions, severe hemoconcentration, potential
renal failure, risk for acute respiratory distress syn-
drome, or thromboembolic events. Hospital admis-
sion with immediate interventions is often
required. Aggressive intravenous fluid hydration is
required in patients with severe cases of drug-
induced ovarian hyperstimulation characterized by
dehydration with a hematocrit >45%.4 The rate of
infusion should be adjusted to maintain urine out-
put >30 mL/hr. All diuretics, antihistamines,
angiotensin-converting enzyme inhibitors, and
nonsteroidal antiinflammatory drugs (NSAIDs)
should be discontinued and avoided. Once the
patient’s condition has been stabilized, paracente-
sis may be used, if necessary, to remove ascites fluid
to alleviate pelvic pain and dyspnea. Because these
patients are at risk for thromboembolic events,
anticoagulation therapy with heparin (5,000 U
subcutaneously every 12 hours) or low-molecular-
weight heparin (e.g., enoxaparin 40 mg subcuta-
neously once daily) with or without sequential
compression device therapy should be considered
for the duration of the patient’s confinement to
bed. Surgical interventions may be required to pre-
vent ovarian torsion or cyst rupture that may lead
to intraperitoneal hemorrhage.4
When drug-induced ovarian hyperstimulation
is detected early and interventions and treatment
can be performed on an outpatient basis, symp-
toms usually resolve within 1 week.6 In moderate
to severe cases, patients typically require hospital-
ization, and complete symptom resolution may
take 10 days or more.6,36
INFORMATION FOR PATIENTS
Patients should be informed that while undergoing
ovarian-stimulation therapy, they should be close-
ly monitored by their physician. Patients should be
told that if symptoms such as abdominal discom-
fort, shortness of breath, diarrhea, nausea, or vom-
iting occur, they should seek medical attention
immediately.
VULVOVAGINAL CANDIDIASIS
CAUSATIVE AGENTS
Drug-induced vulvovaginal candidiasis most often
results from the use of systemic antibiotics that
alter the normal flora of the vaginal canal allowing
for an overgrowth of Candida species. Drugs asso-
ciated with drug-induced vulvovaginal candidiasis
are listed in Table 36–1.37–42
EPIDEMIOLOGY
Vaginal symptoms are one of the most common
reports of women during annual gynecologic office
visits.42 Approximately 17% to 39% of these office
visits are associated with cases of vulvovaginal can-
didiasis.43,44 The majority of women (>75%) experi-
ence at least one case of vulvovaginal candidiasis
during their lifetime and many (up to 50%) suffer
from recurrent or persistent cases of vulvovaginal
candidiasis.42,45
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CHAPTER 36 • Gynecologic Diseases and Infertility in Women 711

TABLE 36–7 Management of Drug-Induced Gynecologic Diseases and Infertility in Women

Ovarian Vulvovaginal Vaginal Bleeding Sexual Infertility
Hyperstimulation Candidiasis Disorders Dysfunction
IV fluids as appropri- Topical (intravaginal) Amenorrhea and Topical estrogen Gonadotropin releas-
ate Miconazole oligomenorrhea: (intravaginal): ing hormone agonist
• Diuretics (e.g., • 2% cream 5g daily x • Combination oral • Estropipate cream (e.g. leuprolide 3.75 mg
furosemide 20–40 7 days contraceptives of (0.15%) 2-4 g once IM once monthly)
mg PO/IV) • 100 mg supp daily x preference (e.g. 35 - daily x 21 days, one Oral Contraceptives
• Antihistamines (e.g., 7 days 50 mcg ethinyl week off Cryopreservation
diphenhydramine 50 • 200 mg supp daily x estradiol with 0.5–1 • Estradiol vaginal • Embryo Freezing
mg IV every 4 hours 3 days mg norethindrone) cream (0.01%) 2-4 g • Oocyte Freezing
as needed) Clotrimazole Menorrhagia and once daily x 2 • Ovarian Cortex
• Bed rest • 1% cream 5g daily x Menometrorrhagia: weeks, 2 weeks off. Freezing
• Antiemetic of 7-14 days • Combination oral • Conjugated estro- • Follicle Freezing
choice (e.g., • 100 mg tablet daily contraceptives of gens cream (0.0625%)
ondansetron 8 mg x 7 days preference (e.g. 35 -50 0.5 – 2 g once daily x
IV every 8 hours) • 2- 100 mg tablets mcg ethinyl estradiol 21 days, one week off
• Analgesics (e.g., daily x 3 days with 0.5–1 mg • Dienestrol cream
acetaminophen 500 • 500 mg tablet x 1 day norethindrone) (0.01%)
mg every 6 hours as • Tioconazole • SSRI of choice (e.g. 2-4 g once daily x 2
needed) • 6.5 % ointment 5 g x fluoxetine 20 mg weeks, then 1 g 3 x
• Gonadotropin 1 dose daily or sertraline weekly
releasing hormone Terconazole 50-100 mg daily) • Estradiol vaginal ring
agonist (leuprolide • 0.4% cream 5g daily 0.05 – 0.1 mg per
Dysmenorrhea: day; replace every 3
7.5 mg IM once x 7 days
• NSAID of choice (i.e months.
monthly) • 0.8 % cream 5g daily
ibuprofen 400-800 • Vaginal lubricants or
• Anticoagulation x 3 days
mg every 6 hr with moisturizers as
therapy (heparin • 80 mg supp daily x 3
food or naproxen needed
5000 units SC every days
250-500 mg twice • Sildenafil citrate 50
12 hours or enoxa- Oral: daily as needed for mg ~ 60 minutes
parin 40 mg SC • Fluconazole
pain) prior to activity
once daily) • 150 mg orally x 1
• Celecoxib 200 mg • Vibrator or mechan-
dose
once daily ical stimulation

IM = Intramuscularly; IV = Intravenously; SC = subcutaneously; supp = vaginal suppository; SSRI = Selective serotonin reuptake inhibitor;
NSAID = Non-steroidal antiinflammatory drugs.

tions and indirectly alter the natural flora of the

MECHANISMS vaginal canal.48

Vulvovaginal candidiasis is a common fungal

infection that is caused by an overgrowth of
Candida albicans, C. tropicalis, C. glabrata, or C.
parapsilosis resulting from environmental
changes in the vagina that alter the natural
flora.37,44 Drug-induced vulvovaginal candidiasis
most often results from the use of systemic
antibiotics that alter the normal flora of the vagi-
nal canal, allowing for an overgrowth of Candida
species (Table 36–2).37-46 Oral contraceptives, cor-
ticosteroids, and hormone-replacement therapy
can increase the pH and glycogen content of the
vaginal canal, favoring Candida infection. 47
Retinoids such as acitretin alter vaginal secre-
CLINICAL PRESENTATION AND
DIFFERENTIAL DIAGNOSIS
Symptoms in patients presenting with drug-
induced vulvovaginal candidiasis are no different
from those in patients presenting with sponta-
neous cases of vulvovaginal candidiasis (Table
36–3). The most common presenting symptom is
vaginal pruritus, which may or may not be accom-
panied by a white, curd-like, thick vaginal dis-
charge often described by patients as “cottage
cheese–like.” The infection typically originates in
TisdaleC36_702-726 1/20/10 11:46 PM Page 712
712 SECTION VII • Drug-Induced Endocrine Diseases
the vaginal canal and spreads to the vulva. The
vulva and vaginal tissue may develop erythema,
edema, or both because of local irritation and
inflammation. The onset of signs or symptoms of
drug-induced vulvovaginal candidiasis varies. As
the infection progresses, symptoms increase and
patients may report burning, soreness, and dys-
pareunia.
When a patient presents with these vaginal
symptoms, a vaginal smear (culture) should be
obtained to determine whether the symptoms are
a result of bacterial vaginosis, trichomoniasis, or
candidiasis.51 Urinary tract infections should also
be ruled out. Patients are often tested for gonor-
rhea or chlamydia, although neither has been
closely associated with vaginal discharge.50,51 Table
36–4 describes the conditions that should be con-
sidered in the differential diagnosis of drug-
induced vulvovaginal candidiasis.
RISK FACTORS
A number of factors have been identified that pre-
dispose women to drug-induced vulvovaginal can-
didiasis (Table 36–5). These include comorbid
diseases or conditions, including diabetes, obesity,
and pregnancy.46 Environmental factors such as
increased moisture and heat or tight clothing may
also increase a women’s risk of drug-induced vulvo-
vaginal candidiasis.52 Sexual intercourse has not
been reported as a means of transmission of vulvo-
vaginal candidiasis.45
MORBIDITY AND MORTALITY
The majority of episodes of drug-induced vulvo-
vaginal candidiasis are uncomplicated. In these
cases, symptoms resolve within 48 to 72 hours fol-
lowing initiation of appropriate therapy.
Uncomplicated vulvovaginal candidiasis is not
associated with morbidity. However, approximate-
ly 10% of cases of vulvovaginal candidiasis are
more severe and are associated with significant ery-
thema, edema, pruritus, and dyspareunia. Left
untreated, drug-induced vulvovaginal candidiasis
eventually resolves after the restoration of normal
vulvovaginal flora.
PREVENTION
Methods to prevent drug-induced vulvovaginal
candidiasis are described in Table 36–6. Behavior
modification, such as wearing loose clothing and
cotton undergarments and wiping away from the
vulvovaginal area after bowel movements, can
help prevent episodes of drug-induced disease.52 It
has been suggested that consuming yogurt with
live bacteria or taking lactobacillus acidophilus
capsules to maintain the balance of the normal
flora in the vaginal tract may prevent drug-induced
vulvovaginal candidiasis infections.41 Patients with
a history of vulvovaginal candidiasis may choose
to eat yogurt “with activated cultures” when initi-
ating antibiotic therapy to help prevent drug-
induced vulvovaginal candidiasis. Therapy with
vitamin C (250 mg intravaginally for 6 days),
which is available by prescription, may increase
vaginal secretions and reduce infection53 and may
help prevent drug-induced vulvovaginal candidia-
sis. Douching with vinegar and water, yogurt, or
potassium sorbate may help prevent reinfection by
restoring the acidic pH to the vulvovaginal canal.41
For patients who routinely experience episodes
of vulvovaginal candidiasis when taking systemic
antibiotics, prophylactic antifungal treatment
should be considered. Preventive treatment should
be initiated simultaneously with the first dose of
antibiotics.45 A topical azole drug (miconazole,
clotrimazole, ticonazole, terconazole) may be
administered for 3 to 7 days as indicated, or two
doses of fluconazole 150 mg may be administered
72 hours apart.47 Measures for prevention of drug-
induced vulvovaginal candidiasis may improve
adherence to and completion of prescribed antibi-
otic regimens.44,52
MANAGEMENT
Drug-induced vulvovaginal candidiasis can be
effectively treated with antifungal topical cream or
vaginal suppositories administered for 1, 3, 7, or up
to 14 days in severe cases when symptoms do not
resolve after one course of treatment (Table
36–7).45 The most common topical antifungal
agents used in the treatment of vulvovaginal can-
didiasis include miconazole and clotrimazole, both
of which are available without a prescription, and
terconazole, which is currently available by pre-
scription only.47 For both prescription and nonpre-
scription topical regimens, the recommended
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
symptoms persist after one course. Another effec-
tive option is a single 150 mg oral dose of flucona-
zole. This treatment approach also requires a
prescription.45 The strategies discussed above for
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CHAPTER 36 • Gynecologic Diseases and Infertility in Women
prevention of drug-induced vulvovaginal candidia-
sis may also have some benefit for treatment.
Patients with significant erythema, edema, and
local irritation may require more prolonged treat-
ment (up to 14 days) to achieve a complete
response and eradication of all symptoms.45,51
Although topical therapy provides more immedi-
ate relief of symptoms as compared with oral treat-
ment, either route will successfully eradicate
vulvovaginal candidiasis.45,51,54
INFORMATION FOR PATIENTS
Patients can reduce the risk of drug-induced vulvo-
vaginal candidiasis by wearing loose clothing and
cotton undergarments to limit excessive moisture
to the vulva area.51 Exposure to the Candida organ-
isms can be minimized if patients remember to
wipe away from the vulva area after a bowel move-
ment.51 Patients should seek medical attention for
diagnosis of their first vulvovaginal candidiasis
infection.44,45 However, patients with recurrent
drug-induced vulvovaginal candidiasis infections
should learn to recognize the symptoms and begin
early self-treatment with nonprescription medica-
tions.41,44
VAGINAL BLEEDING DISORDERS
AMENORRHEA AND
OLIGOMENORRHEA
Causative Agents
Agents that alter hormone balance directly or indi-
rectly are associated with drug-induced amenor-
rhea (cessation of menses), oligomenorrhea
(irregular menses), or intermenstrual bleeding.55-61
Drugs that are known to be toxic to actively divid-
ing cells may induce premature or temporary ovar-
ian failure that presents as drug-induced
amenorrhea/oligomenorrhea.56 For example, drug-
induced amenorrhea is an unfortunate long term
consequence of chemotherapy used to treat cancer
and autoimmune disorders such as systemic lupus
erythematosus.62-67 Other agents may affect
microvascular stability or hormone production/
release, causing drug-induced amenorrhea/oligo-
menorrhea (Table 36–1).55-61
Epidemiology
A menstruation disorder is often the primary reason
for a woman to seek medical attention. Both amen-
713
orrhea and oligomenorrhea are often symptoms of
more complex endocrine, gynecologic, or metabolic
disorders.70 Intermenstrual bleeding, often described
as “breakthrough bleeding,” is bleeding that occurs
between regular menses and is usually associated
with nonadherence with oral contraceptives or
inadequate doses of oral contraceptives based on
endogenous, baseline hormone concentrations that
may vary between individuals.70,71
Antiepileptic drugs such as phenytoin, valproic
acid, and carbamazepine alter various aspects of
endocrine function, although endocrine dysfunc-
tion has itself been associated with epilepsy. From
12% to 59% of women receiving antiepileptic
drugs experience amenorrhea/oligomenorrhea.75
More than 60% of women receiving cytotoxic
chemotherapy have experienced one or more
symptoms of ovarian failure.64 The incidence of
amenorrhea/oligomenorrhea associated with other
drugs is unknown, as the evidence is published pri-
marily in the form of case reports.
Mechanisms
Drugs can affect uterine function through direct
effects on the endometrium, such as causing
microvascular instability that leads to break-
through bleeding.71 Antineoplastic drugs exert a
direct toxic effect on oocytes, decreasing follicular
formation and halting ovulation, leading to amen-
orrhea.56 Drugs can also indirectly inhibit the neg-
ative feedback loop of the hypothalamic–pituitary
pathway via modulation of serum hormone con-
centrations. This leads to decreased FSH and LH
release, resulting in decreased ovarian function and
induction of amenorrhea/oligomenorrhea.68-74
Antiepileptic drugs such as phenytoin and car-
bamazepine have been reported to increase serum
concentrations of hormone-binding globulin,
resulting in decreased binding of estradiol, leading
to amenorrhea/oligomenorrhea.75-79 The mecha-
nism of valproic acid–induced amenorrhea is not
well understood, but it is thought to be related to
weight gain, elevated serum insulin concentra-
tions, and decreased serum concentrations of
insulin-like growth factor I, leading to decreased
ovarian androgen synthesis.75,79-81 Mechanisms of
drug-induced amenorrhea and oligomenorrhea are
described in Table 36–2.55-61
Clinical Presentation
and Differential Diagnosis
Patients with drug-induced amenorrhea/oligomen-
orrhea present with no menses or irregular bleed-
ing. These symptoms may occur at any time after
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714 SECTION VII • Drug-Induced Endocrine Diseases
therapy with the causative drug is initiated.
Amenorrhea is a common presenting symptom of
ovarian failure, and is typically not the only symp-
tom that patients may experience related to the
hormonal imbalances. Other symptoms include
mood swings, irritability, vaginal dryness, dyspare-
unia, decreased cervical mucus, and thinning of
the vaginal mucosa (Table 36-3).53
Drug-induced amenorrhea/oligomenorrhea
must be distinguished from other causes, including
endocrine disorders, metabolic disorders, anorexia
nervosa, pituitary or hypothalamus tumors, or
excessive psychological or emotional stress (Table
36-4).60
Risk Factors
Women who have advanced in age to the peri-
menopausal stage are more susceptible to drug-
induced amenorrhea/oligomenorrhea.55 The
probability of permanent chemotherapy-induced
amenorrhea or menopause increases proportional-
ly with advancing age.55 Poor nutritional status
caused by crash diets or anorexia nervosa can also
influence the susceptibility to drug-induced amen-
orrhea/oligomenorrhea.60 Physiologic stress such
as excessive exercise (i.e., marathon training pro-
grams) and psychological stress (i.e., anxiety,
work/school/family pressure) also increases the risk
of drug-induced amenorrhea/oligomenorrhea
(Table 36–5).60
Morbidity and Mortality
Drug-induced amenorrhea/oligomenorrhea is not
associated with increased mortality but can signifi-
cantly impact quality of life. Drug-induced amen-
orrhea/oligomenorrhea may interfere with the
ability to plan conception as well as to conceive
and can be associated with numerous other unde-
sirable symptoms that interfere with daily activities
and relationships, including vaginal dryness,
moodiness, and painful intercourse.53,60,70 Drug-
induced amenorrhea/oligomenorrhea may disguise
underlying gynecologic and endocrine conditions
requiring medical evaluation, including polycystic
ovarian syndrome and hypothyroidism.60,82
Prevention
No specific studies have addressed the prevention
of drug-induced amenorrhea/oligomenorrhea. Oral
contraceptives and gonadotropin-releasing hor-
mone (GnRH)-a inhibit ovarian function, primari-
ly ovulation, which, in theory, decreases
susceptibility to the gonadotoxic effects of
chemotherapy.60,61,64,83 The use of oral contracep-
tives or GnRH-a during courses of cytotoxic
chemotherapy has demonstrated some benefit in
the prevention of drug-induced ovarian
failure/amenorrhea; this preventive strategy is suc-
cessful primarily in younger patients.60,61,80 GnRH-
a has shown limited benefit for the prevention of
chemotherapy-induced amenorrhea/ovarian fail-
ure in perimenopausal women.60,61 Maintenance of
a well-balanced diet with regular exercise may help
reduce the risk of developing drug-induced amen-
orrhea/oligomenorrhea (Table 36–6).
Management
Treatment options for drug-induced amenorrhea/
oligomenorrhea vary depending on the causative
agent. Drug-induced amenorrhea/oligomenorrhea
associated with the use of progesterone implants
can be reversed by discontinuation of the implant
and selection of an alternative contraceptive agent,
such as oral contraceptives, or use of alternative
modes of contraception such as barrier meth-
ods.66,72 Breakthrough bleeding can be decreased
by encouraging better patient adherence or use of
oral contraceptive agents with higher estrogen
content (up to 50 mcg ethinyl estradiol).60 Once
the causative agent is discontinued or doses modi-
fied, drug-induced amenorrhea/oligomenorrhea
usually resolves within 4 to 6 weeks (Table 36–7).
GnRH-a (e.g., leuprolide 7.5 mg intramuscular-
ly once monthly) may promote the reversal of
chemotherapy-induced amenorrhea/ovarian fail-
ure in some younger patients.61,64,80 However,
because chemotherapy-induced amenorrhea (ovar-
ian failure) is often permanent, in most cases it is
advisable to discuss alternative options to compen-
sate for future infertility, such as cryopreservation
of embryos, unfertilized ova, or ovarian tissue
before chemotherapy administration.60
Information for Patients
Patients receiving drugs that may induce amenor-
rhea or oligomenorrhea should be counseled that
amenorrhea is the absence of menstrual bleeding
and oligomenorrhea is the presence of
infrequent/irregular menstrual cycles, and that if
these symptoms occur they should be evaluated by
a health care provider. Patients who will be receiv-
ing cancer chemotherapy agents that may cause
amenorrhea and ovarian failure should be
informed of the potential for occurrence of this
drug-induced disease and that options for future
child-bearing should be discussed before
chemotherapy administration.64,65,80,81
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CHAPTER 36 • Gynecologic Diseases and Infertility in Women
MENORRHAGIA AND
MENOMETRORRHAGIA
Menorrhagia is prolonged menses or excessive
bleeding that occurs at regular intervals.
Menometrorrhagia is prolonged menses or exces-
sive bleeding that occurs at irregular intervals.
Causative Agents
Drug-induced menorrhagia has been reported with
the use of selective serotonin reuptake inhibitors
(SSRIs), hormones (estrogen and progesterone),
intrauterine contraceptive devices (IUDs), and
prostaglandins (Table 36–1).81-88 Drug-induced
menometrorrhagia has been found to be associated
with the oral and topical use of ginseng and the
investigational agent recombinant human relaxin,
which is a disease-modifying agent that has
demonstrated benefit in the treatment of scleroder-
ma.87,88
Epidemiology
The incidences of drug-induced menorrhagia or
menometrorrhagia have not been clearly deter-
mined. There are few cases reports or reviews that
describe the risk.70,89-91 In one large study evaluat-
ing the associated risk of bleeding caused by SSRIs,
the incidence of drug-induced menorrhagia or
menometrorrhagia was <1%.92 As many as 50% of
women receiving maintenance therapy with
methadone experience drug-induced menorrhagia
or menometrorrhagia.70 Historically, menorrhagia
and menometrorrhagia are among the most com-
mon reasons for discontinuing IUD use, as the inci-
dence of these diseases increases by 70% to 100%
in association with the insertion of copper-con-
taining IUDs. However, the incidence of menorrha-
gia or menometrorrhagia is only approximately 2%
to 4% in patients using the levonorgestrel-releasing
IUD.72
Mechanisms
Serotonin receptors, those specific for 5-hydrox-
ytryptamine2a, are expressed on platelets.
Serotonin is released during platelet activation and
binds to these receptors, contributing to platelet
aggregation and thrombus formation.
Administration of SSRIs results in a relative
decrease in clotting function, resulting in potential
episodes of drug-induced menorrhagia.81,82 The
cause of increased blood loss in association with
IUDs is unclear. When exposed to IUDs, concentra-
715
tions of hydrogen peroxide and prostaglandins in
uterine tissue increase, but whether or not this is
related to menorrhagia is uncertain.83,89
The mechanism of ginseng-induced meno-
metrorrhagia is not known. Relaxin-induced
menometrorrhagia results from the induction of
vascular endothelial growth factor receptor expres-
sion in the endometrial cell.85 Table 36–2 describes
the mechanisms for drug-induced menorrhagia
and menometrorrhagia.
Clinical Presentation
and Differential Diagnosis
Patients with drug-induced menorrhagia present
with a chief symptom of heavy or prolonged men-
strual cycles which may occur at any time after the
initiation of treatment with the culprit agent
(Table 36–3). Drug-induced menorrhagia or
menometrorrhagia may lead to the development
of anemia and fatigue.
Drug-induced menorrhagia or menometrorrha-
gia must be distinguished from non-drug-induced
causes, including common uterine complications
such as fibroids or polyps or endometriosis.93-97
Patients with menorrhagia or menometrorrhagia
should undergo a complete physical exam and an
endometrial biopsy to determine the primary
cause. Endometrial biopsy can detect abnormal
hyperplasia or cancer, but cannot differentiate
between a drug-induced and a non-drug-induced
cause (Table 36–4).
Risk Factors
There are no known risk factors for drug-induced
menorrhagia or menometrorrhagia.
Morbidity and Mortality
If drug-induced menorrhagia or menometrorrhagia
is left untreated, it may lead to more significant
health complications including anemia, thrombo-
cytopenia, shortness of breath, altered nutritional
status, and episodes of syncope. The majority of
these symptoms can be directly associated with
blood loss. Diminished nutritional status is an
indirect result of fatigue associated with anemia
that leads to decreased appetite and weight loss.
Prevention
Oral contraceptive therapy may be instituted pro-
phylactically in patients undergoing treatment
with SSRIs to prevent the development of menor-
rhagia.86,96 Oral contraceptives may also help pre-
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716 SECTION VII • Drug-Induced Endocrine Diseases
vent recurrent episodes of bleeding in patients
with a history of menorrhagia/menometrorrha-
gia.98 Avoidance of other platelet-inhibiting agents
such as aspirin, may decrease the risk of drug-
induced menorrhagia or menometrorrhagia (Table
36–6).97
Management
Drug-induced menorrhagia can be effectively treat-
ed with combination oral contraceptive therapy.
Product selection is generally based on patient and
physician preference.86,96 Patients who have had
menorrhagia for an extended time may also
require iron-replacement therapy until the hemo-
globin concentration returns to normal. In
patients with IUDs, therapy with the antioxidant
vitamin E (100 IU once every other day for 14 days)
has been successful in attenuating menorrhagia.83
Drug-induced menometrorrhagia can be effectively
treated with GnRH agonists such as leuprolide (7.5
mg intramuscularly once monthly) or goserelin
(3.6 mg intramuscularly once monthly).94,96 When
a patient is experiencing drug-induced menorrha-
gia or menometrorrhagia, the risks and benefits of
discontinuation of the causative agent should be
weighed. If the causative agent is discontinued, it
may take up to 3 months for symptoms to resolve
completely.
Information for Patients
Patients receiving drugs that may cause menorrha-
gia or menometrorrhagia should be counseled that
heavy or prolonged menstrual cycles (at regular or
irregular intervals) may occur and that this should
prompt them to seek medical attention.
DYSMENORRHEA
Causative Agents
Drug-induced dysmenorrhea is associated with
agents such as oxytocin, which is a known uterine
stimulant, and vasopressin (antidiuretic hormone),
a known vasoconstrictor (Table 36–1).102 Estrogen
and progesterone are also believed to be associated
with some cases of drug-induced dysmenorrhea.
100,101
Epidemiology
Dysmenorrhea is one of the most common gyneco-
logic symptoms of menstruating women, with an
incidence ranging from 3% to 90%.101 The inci-
dence and magnitude of drug-induced dysmenor-
rhea is unknown. It is possible that dysmenorrhea
has been overlooked as a drug-induced condition,
and occurrences therefore may be under-reported.
Mechanisms
Dysmenorrhea occurs often with normal ovulation
because of the release of arachidonic acid, which
promotes release of prostaglandins and
leukotrienes, initiating inflammation that pro-
duces cramps, bloating, and abdominal discom-
fort.102 Elevations occur in serum concentrations of
prostaglandin-2␣, which is an active metabolite of
arachidonic acid that mediates vasoconstriction
and uterine contractions which can result in
cramping.102 Drug-induced dysmenorrhea associat-
ed with the administration of the combination of
oxytocin and vasopressin occurs as a result of vaso-
pressin-related antidiuretic effects that alter the
uterine contractions stimulated by oxytocin into a
dysrhythmic and painful pattern (Table 36–2).101
The mechanism of estrogen- and progesterone-
induced dysmenorrhea is not well understood. It
has been suggested that the rapid fluctuations in
serum hormone concentrations, primarily proges-
terone withdrawal, activates the inflammation cas-
cade, causing pelvic congestion (swelling) and
contributing to the development of dysmenorrhea
(Table 36–2).103,104
Clinical Presentation
and Differential Diagnosis
Dysmenorrhea is a pelvic pain that occurs in rela-
tionship to menses. It is associated with a variety of
symptoms, including nausea, vomiting, diarrhea,
bloating, headache, backache, syncope, dizziness,
breast tenderness, abdominal cramping, mood
changes, nervousness, and fatigue (Table 36–3).
Symptoms typically present within 24 to 48 hours
before menstruation begins and usually continue
for 48 to 72 hours after menstruation com-
mences.101 Drug-induced dysmenorrhea must be
distinguished from other causes of dysmenorrhea.
Pelvic pain with menses can be a natural physio-
logic occurrence in association with ovulation or
premenstrual syndrome or may have other primary
or secondary causes, including adverse effects of
drugs (Table 36–4).101,102
Risk Factors
Diets high in omega-6 fatty acids, including most
Western diets, increase the release of arachidonic
acid after progesterone withdrawal, and may result
TisdaleC36_702-726 1/20/10 11:46 PM Page 717
CHAPTER 36 • Gynecologic Diseases and Infertility in Women
in inflammation and cramping (Table 36–5).101
Early menarche and heavier menstrual blood flow
are both associated with an increased risk of drug-
induced dysmenorrhea.103,104 Individuals who have
more than one first-degree relative with dysmenor-
rhea have a higher risk of drug-induced dysmenor-
rhea.101,105
Morbidity and Mortality
Dysmenorrhea is one of the most common gyneco-
logic symptoms associated with repeated absen-
teeism from school or work.102 Dysmenorrhea is
not associated with mortality.
Prevention
Drug-induced dysmenorrhea may be prevented by
avoiding the use of uterine-stimulation drugs in
women predisposed to dysmenorrhea. In women
with a history of dysmenorrhea, prophylactic use
of NSAIDs such as ibuprofen 400 to 800 mg once
every 6 hours, or cyclooxygenase (COX)-2
inhibitors such as celecoxib 200 mg once daily,
may be effective in decreasing and controlling
symptoms of drug-induced dysmenorrhea (Table
36–6).102,103,106
Management
Management of drug-induced dysmenorrhea
should be individualized to the patient’s pain
threshold, contraception goals, and overall health
status. NSAIDs (e.g., ibuprofen 400 to 800 mg once
every 6 hours) or COX-2 inhibitors (e.g., celecoxib
200 mg once daily) are effective for alleviation of
pain, and therapy should be continued until the
end of menses (Table 36–7).102,105 In patients with
lower pain thresholds, short term use of combina-
tion opioid products can be considered.103,105
Acetaminophen is not as effective in controlling
the inflammation and symptoms associated with
dysmenorrhea.106
Information for Patients
Patients taking medications that may cause dys-
menorrhea should be informed of the possibility
and should be instructed to take antiinflammatory
medications at the first symptoms. Prompt treat-
ment will help control the pain and can prevent
the development or more significant discomfort.
Patients should take NSAIDs with food to avoid
development of gastrointestinal distress. Patients
with sulfa allergies should avoid the use of COX-2
inhibitors.
717
SEXUAL DYSFUNCTION
Human sexual response can be classified into five
phases: desire, excitement, plateau, orgasm, and
resolution.107 Sexual desire is an innate component
of human social well-being. Any impairment or
abnormality in the human sexual response is
defined as “sexual dysfunction.”
CAUSATIVE AGENTS
Drug-induced sexual dysfunction often con-
tributes to patient nonadherence to important
medications, including antihypertensives, anti-
depressants, antipsychotics, sedatives, antiretro-
viral agents, androgen antagonists, and
narcotics.107-111 Alcohol may also interfere with
sexual function. Sexual dysfunction can be classi-
fied into two categories: disorders of libido and
disorders of excitement and orgasm. Disorders of
libido are generally mediated by neuronal fac-
tors, whereas disorders of excitement and orgasm
generally involve the genital organs. Drugs asso-
ciated with sexual dysfunction are listed in Table
36–1.101-112, 117-122
EPIDEMIOLOGY
Drug-induced sexual dysfunction in women is
often underreported, but is one of the contributing
factors to nonadherence to prescribed pharma-
cotherapy and decreased quality of life.111 It is dif-
ficult to distinguish drug-induced sexual
dysfunction from the effects of specific diseases on
sexual function. This is especially true with psychi-
atric disorders, where the disease itself has pro-
found effects on social and sexual function.112
Since the success of sildenafil and similar drugs for
the treatment of erectile dysfunction, there has
been increased attention to the incidence of drug-
induced sexual dysfunction.112 Antidepressants
have been associated with decreased libido and
sexual dysfunction, with an incidence in women
ranging from 16.3% to 57%.113-115 Antipsychotic
agents such as haloperidol, risperidone, and thior-
idazine have been associated with a 28% to 93%
incidence of drug-induced sexual dysfunction in
women.116-121 Antiretroviral agents are associated
with an incidence of drug-induced sexual dysfunc-
tion of 40%.110 The incidence of drug-induced sex-
ual dysfunction associated with the use of
antihypertensive agents in women is approximate-
ly 11%.122
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718 SECTION VII • Drug-Induced Endocrine Diseases
MECHANISMS
Drug-induced sexual dysfunction is associated with
agents that affect the autonomic and central nerv-
ous systems and with agents that elevate serum
prolactin concentrations (Table 36–2). For exam-
ple, antipsychotic agents are known to elevate
serum prolactin concentrations via inhibition of
dopamine-2 receptors that are responsible for
blocking prolactin secretion.123-125 The mechanism
by which prolactin diminishes libido and causes
orgasm disturbances is not well under-
stood.110,111,116,122,125 Elevated serum prolactin con-
centrations have been associated with decreasing
serum testosterone concentrations, which may
contribute to diminished libido.126
Drug-induced sexual dysfunction, primarily loss
of libido and orgasm dysfunction, has been associat-
ed with all classes of antidepressant agents.112,125,127
Although the mechanism involved is not well under-
stood, antidepressants may cause sexual dysfunction
by altering central serotonergic activity and indirect-
ly influencing adrenergic activity. Alterations in cen-
tral serotonergic activity may disrupt
hypothalamic–pituitary axis regulation of hormone
release, including the release of testosterone. Indirect
effects on adrenergic activity may contribute to
direct effects on gonads, leading to decreases in mus-
cle tension, vaginal lubrication, or both.
Antihypertensive agents are more often associ-
ated with erectile dysfunction and diminished
libido in men. However, these drugs may also
decrease libido in women via antiandrogenic and
antidopaminergic activity. The mechanism by
which antiretroviral agents induce sexual dysfunc-
tion is not well understood. Collazos and colleagues
confirmed that serum hormone concentrations are
not altered in patients receiving antiretroviral
agents, suggesting that the mechanism of antiretro-
viral-induced sexual dysfunction involves a yet to
be determined non-hormone-related pathway.110
CLINICAL PRESENTATION AND
DIFFERENTIAL DIAGNOSIS
Identifying the individuals who have drug-induced
sexual dysfunction can be difficult because
patients are often embarrassed and hesitant to dis-
cuss sexual complications.128 Health care providers
should specifically ask questions regarding sexual
activity and relations and should volunteer infor-
mation to dispel misconceptions that patients may
have about sexuality to alleviate their fear, guilt, or
frustration regarding sexual dysfunction.
Once comfortable, patients may begin to vol-
unteer information regarding symptoms they are
experiencing. These may include vaginismus,
dyspareunia, or loss of libido or desire (Table
36–3). Dyspareunia can often be attributed to
physical disorders of the vagina, such as
decreased lubrication, infections, or local irrita-
tion, which could be drug-induced as discussed
earlier in this chapter. Patients with loss of libido
or desire often present with other psychological
symptoms including depression, fatigue, anxiety,
anger, or fear (Table 36–4). Again, extensive
counseling and discussion is necessary to sort
through the vague symptoms. A close evaluation
of the medication profile is necessary to deter-
mine whether sexual dysfunction can be attrib-
uted to a drug. Drug-induced sexual dysfunction
usually occurs within 2 weeks of the initiation of
therapy with the culprit agent, although sexual
dysfunction induced by SSRIs may take longer to
manifest.
RISK FACTORS
Specific disease-related factors may increase the
risk of drug-induced sexual dysfunction. These
include endocrine disorders associated with hor-
mone imbalances such as hypogonadism or
hypothyroidism, neurologic/psychiatric impair-
ments such as schizophrenia or depression, surgery
such as hysterectomy, oophorectomy, or vulvo-
vaginal resections or pelvic irradiation that direct-
ly alters ovarian function or the structure or
function of the vagina.129 The patient’s psycholog-
ical ability to tolerate and discuss symptoms asso-
ciated with sexual dysfunction may be
compounded by anxiety, stress, depression, or sub-
stance abuse (Table 36–5).
Drug-induced sexual dysfunction is not always
dose-related, but in some cases, especially with
antihypertensive agents or SSRIs, using lower doses
or instituting “drug holidays” may help minimize
symptoms.112,122
MORBIDITY AND MORTALITY
The physical complications of drug-induced sexual
dysfunction are not life-threatening. However, the
psychological stress generated from these compli-
cations can significantly impact mental health
(depression, anxiety, disposition) and quality of
life associated with relationships with partners,
family, and friends.
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CHAPTER 36 • Gynecologic Diseases and Infertility in Women
PREVENTION
Education is the most important component of pre-
vention and may help lead to acceptance and
improve the ability of the patient to communicate
their concerns regarding sexual dysfunction.
Counseling should include education regarding the
potential for sexual complications associated with
prescribed therapy and possible alternative treat-
ment options for the management of symptoms.
The risk of drug-induced sexual dysfunction should
be weighed against the potential therapeutic bene-
fit of the drug being prescribed and the availability
of alternative treatment options. Avoidance of
causative agents is recommended if alternative
agents for treatment are available (Table 36–6).
MANAGEMENT
The first step in the management of drug-induced
sexual dysfunction is completion of a thorough
physical examination to determine any possible
physical causes that could be contributing to symp-
toms. The patient’s medication profile should be
closely evaluated to identify drugs that may be caus-
ing sexual dysfunction. Once a drug is identified to
be the likely source of sexual complications, alterna-
tive medical treatment options should be considered.
It is sometimes reasonable to substitute therapy with
other agents within the same class to determine
whether symptoms improve. Although symptoms
generally improve within 2 weeks after discontinua-
tion of the causative agent, in some cases sexual
function may not completely return to normal with-
out additional interventions to treat the sexual dys-
function. This is often the case with sexual
dysfunction associated with antipsychotic agents,
where treatment of the drug-induced disease may be
confounded by the underlying psychiatric disor-
der.125
Topical estrogen (estradiol 0.05 to 0.1 mg vaginal
ring inserted once every 3 months, or estradiol
0.01% cream 2 to 4 g once daily for 2 weeks followed
by once-weekly maintenance) may help improve
arousal dysfunction by increasing vaginal secretions
and engorgement.128 Other pharmacotherapy to
increase libido could include phosphodiesterase-5
inhibitors such as sildenafil citrate (50 mg orally 1
hour before sexual activity). In addition, vaginal
lubricants and moisturizers may be used to relieve
vaginal dryness and improve genital arousal (Table
34–7).128 Mechanical stimulatory devices, such as
vibrators, that increase blood flow to the vaginal
719
muscle can be used in conjunction with pharmaco-
logic interventions to optimize relief of symptoms.128
When treating a patient with drug-induced
sexual dysfunction, it is extremely important to be
sensitive and supportive. Psychological support
and assurance can be extremely effective in allevi-
ating the stress and anxiety experienced by
patients with drug-induced sexual dysfunction.129
INFORMATION FOR PATIENTS
Sexual function is an important component of
adult relationships. Patients who are taking
antipsychotic agents, antidepressants, antihyper-
tensive agents, or other drugs associated with sex-
ual dysfunction should be counseled regarding the
potential for occurrence of this drug-induced dis-
ease and should be instructed to discuss symptoms
such as painful intercourse, vaginal dryness, lack of
or decreased orgasm, or diminished libido with
their health care provider.
INFERTILITY IN WOMEN
CAUSATIVE AGENTS
Drug-induced infertility is a tragic yet predictable out-
come associated with treatment with cytotoxic
chemotherapy agents. Although there is potential for
drug-induced infertility after treatment with any cyto-
toxic agent, the most common classes of agents that
cause infertility include the alkylating agents, plat-
inum analogues, antitumor antibiotics, antimetabo-
lites, and vinca alkaloids (Table 36–1).131-144 Even
patients who may resume normal menses after com-
pletion of cytotoxic chemotherapy may not have a
viable ovarian follicular reserve.132 Whereas cytotoxic
agents are associated with permanent infertility, caf-
feine, often not considered a drug, is associated with a
reversible or transient infertility.133-137 Caffeine is com-
monly found in many beverages and is an additive in
both prescription and nonprescription medications.
In addition to infertility, caffeine has also been associ-
ated with a dose-related increased risk of miscarriages
in the first trimester.138 Finally, many antiepileptic
drugs have been associated with endocrine dysfunc-
tion and drug-induced infertility.78-80,88,139-144
EPIDEMIOLOGY
Women with cancer are most often afflicted with
drug-induced infertility after completion of their
TisdaleC36_702-726 1/20/10 11:46 PM Page 720
720 SECTION VII • Drug-Induced Endocrine Diseases
cytotoxic chemotherapy regimen. However, lower
doses of these same cytotoxic agents are used in
treatment of systemic lupus erythematosus or
other autoimmune disorders and can cause drug-
induced infertility in these situations as well. In
addition, the prevalent use of caffeine in today’s
society could put many women at risk for
reversible drug-induced infertility.
MECHANISMS
Antineoplastic drugs have a direct toxic effect on
oocytes, decreasing follicular formation and halt-
ing ovulation resulting in permanent drug-induced
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
the serum concentration of hormone-binding
globulin, resulting in decreased binding of estradi-
ol, which can result in drug-induced infertility.75-79
The mechanism of drug-induced infertility is not
as well understood for caffeine (Table 36–2).
CLINICAL PRESENTATION AND
DIFFERENTIAL DIAGNOSIS
Drug-induced infertility associated with cytotoxic
agents is fairly easy to recognize, since it is associ-
ated with a majority of these drugs. Conversely, the
diagnosis of reversible drug-induced infertility
associated with caffeine is more difficult to estab-
lish and requires a detailed medication and diet
history. The obvious and primary symptoms of
drug induced infertility include inability to con-
ceive and/or frequent miscarriages (Table 36–3).
Patients may also have cessation of menses or irreg-
ular menses. Underlying or contributing endocrine
or metabolic conditions should be ruled out as well
as possible early menopause. Conditions to consid-
er in the differential diagnosis of drug-induced
infertility are presented in Table 36–4.
RISK FACTORS
The probability of permanent drug-induced infer-
tility after chemotherapy increases proportionally
with advancing age.144,145 In patients with autoim-
mune disorders, there are specific disease-related
factors that may increase the risk of drug-induced
infertility, including the presence of antiovarian
antibodies, polyglandular insufficiency, and viral
infections.146-148 Epilepsy also has been associated
with an increased risk for endocrine disorders
resulting in infertility (Table 36–5).149
MORBIDITY AND MORTALITY
As with drug-induced sexual dysfunction, the
physical complications of drug-induced infertility
are not life-threatening. However, finite and pre-
dictable infertility can be associated with signifi-
cant psychological stress reflected in a diminished
mental health (i.e., depression, reduced self-
esteem) and quality of life associated with relation-
ships with partners, family, and friends.
PREVENTION
Drug-induced infertility associated with caffeine
can be prevented simply by reducing or eliminat-
ing the frequent consumption of caffeine-contain-
ing beverages and medications. Patients will find
that fertility is regained within months after the
discontinuation of caffeine consumption.
Permanent drug-induced infertility is less likely to
be prevented. Some studies have suggested the use
of oral contraceptives during chemotherapy in
younger patients may help prevent permanent
drug-induced infertility by temporarily halting
ovulation.144 Another pharmacologic option that
has been proposed, although still controversial, is
the prophylactic use of GnRH analogs to prevent
permanent drug-induced infertility (Table
36–6).61,150,151
MANAGEMENT
Management strategies for drug-induced infertili-
ty are listed in Table 36–7. Prior to receiving cyto-
toxic chemotherapy, patients need to be made
aware of the high risk and likelihood of drug-
induced infertility, which in most cases will be
permanent. These patients need to consider mul-
tiple options for cryopreservation to preserve fer-
tility options once treatment is completed.
Factors that can influence this decision include
time restraints (how quickly treatment needs to
be initiated), the type of cancer or disease being
treated (specifically if estrogen-sensitive),
whether or not the patient has a partner, desire to
have (more) children, and the patient’s age. For
those with a partner and enough time before
cytotoxic therapy begins, cryopreservation of
TisdaleC36_702-726 1/20/10 11:46 PM Page 721
CHAPTER 36 • Gynecologic Diseases and Infertility in Women
embryos is preferred and has the highest success
rate.152 Other cryopreservation options include
freezing of oocytes, ovarian cortex, or folli-
cles.152,153 Although these options do not require
a partner and can be accomplished in less time
than cryopreservation of embryos, the potential
of achieving viable pregnancies is less than with
cryopreservation of embryos.
For patients receiving antiepileptic drugs, infer-
tility is often, but not always, reversible once the
culprit agent is removed and endocrine function is
allowed to normalize. Unfortunately, the option to
discontinue medications is generally available only
for patients whose seizure disorder can be managed
effectively by an alternative, newer antiepileptic
agent.149
INFORMATION FOR PATIENTS
Infertility is a highly sensitive and emotional topic
for most women. In some cases, fertility is the
essence of a women’s identity. Patients about to
receive cytotoxic chemotherapy need to be educat-
ed regarding the multiple methods available to pre-
serve child-bearing options after completion of
treatment. Once treatment is completed and resid-
ual treatment-related toxicities have resolved,
patients should be encouraged to exercise fertility
options at that time to avoid additional complica-
tions with pregnancy. In patients receiving
antiepileptic drugs, the potential for infertility
should be discussed prospectively and alternative
agents should be considered. Patients should
understand that there is no guarantee that fertility
will return after removal of the offending agent.
Finally, patients inflicted with drug-induced infer-
tility associated with caffeine intake should be
counseled on the benefits of the short term cessa-
tion of all caffeine products and caffeine-contain-
ing medications. Patients should be reminded the
caffeine withdrawal side effects are temporary and
resolve quickly and that the potential benefit of
regaining fertility and the prevention of miscar-
riages outweighs any short-term discomfort.
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112. Montgomery SA, Baldwin DS, Riley A. Antidepressant
medications: a review of the evidence for drug-induced
sexual dysfunction. J Affect Disord. 2002;69:119-140.
113. Ashton AK, Hamer R, Rosen RC. Serotonin reuptake
inhibitor-induced sexual dysfunction and its treatment: a
large-scale retrospective study of 596 outpatients. J Sex
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114. Balon R, Yeragani VK, Pohl R, et al. Sexual dysfunction
during antidepressant treatment. J Clin Psychiatry.
1993;54:209-212.
115. Zajecka J, Mitchell S, Fawcett J. Treatment-emergent
changes in sexual function with selective serotonin
reuptake inhibitors as measured with the Rush Sexual
Inventory. Psychopharmacology. 1997;33:755-760.
116. Bobes J, Gare A-Portilla MP, Rejas J, et al. Frequency of
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117. Smith SM, O’Keane V, Murray R. Sexual dysfunction in
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119. Kotin J, Wilbert DE, Verburg D, et al. Thioridazine and
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the phenothiazines. Dis Nerv Syst. 1967;28:240-244.
121. Teusch L, Scherbaum N, Bohme H, et al. Different
patterns of sexual dysfunctions associated with
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122. Grimm RH Jr, Grandits GA, Prineas RJ, et al. Long-term
effects on sexual function of five antihypertensive drugs
and nutritional hygienic treatment in hypertensive men
and women: treatment of mild hypertension study
(TOMHS). Hypertension. 1997;29:8-14.
123. Hummer M, Kemmler G, Kurz M, et al. Sexual
disturbances during clozapine and haloperidol
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124. Halbreich U, Kinon BJ, Gilmore JA, et al. Elevated
prolactin levels in patients with schizophrenia:
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125. Culter AJ. Sexual dysfunction and antipsychotic
treatment. Psychoneuroendocrinology. 2003;28:69-82.
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127. Schiavi RC, Segraves RT. The biology of sexual function.
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128. Kanaly KA, Berman JR. Sexual side effects of SSRI
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induced female sexual dysfunction. Curr Womens Health
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129. Carmack Taylor CL, Basen-Engquist K, Shinn EH, et al.
Predictors of sexual functioning in ovarian cancer
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130. Meirow D. Reproduction post-chemotherapy in young
cancer patients. Mol Cell Endocrinol. 2000;169:123-131.
131. Maltaris T, Seufert R, Fischl R, et al. The effect of cancer
treatment on female fertility and strategies for preserving
fertility. Eur J Obstet Gynecol Reprod Biol. 2007;130:148-155.
132. Meirow D, Epstein M, Lewis H, et al. Administration of
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135. Williams MA, Monson RR, Goldman MB, et al. Coffee
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137. Williams MS, Mittendorf R, Stubblefield PG, et al.
Cigarettes, coffee, and preterm premature rupture of the
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138. Weng X, Odouli R, Li DK. Maternal caffeine
consumption during pregnancy and the risk of
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139. Isojarvi JIT, Laatikainen TJ, Pakarinen AJ, et al. Polycystic
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Depression of the serum protein-bound iodine level by
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141. Isojarvi JIT. Serum steroid hormones and pituitary
function in female epileptic patients during carbazepine.
Arch Neurol. 1989;46:1175-1178.
142. Isojarvi JIT, Laatikainen TJ, Pakarinen AJ, et al. Menstrual
disorders in women with epilepsy receiving
carbamazepine. Epilepsia. 1995;36:676-681.
143. Isojarvi JIT, Tauboll E, Pakarinen AH, et al. Altered
ovarian function and cardiovascular risk factors in
valproate-treated women. Am J Med. 2001;111:290-296.
144. Meirow D, Nugent D. The effects of radiotherapy and
chemotherapy on female reproduction. Hum Reprod
Update. 2001;7:535-543.
145. Behringer K, Breuer K, Reineke T, et al. A report from the
German Hodgkin’s Lymphoma Study Group: secondary
amenorrhea after Hodgkin’s lymphoma is influence by
age at treatment, stage of disease, chemotherapy regimen
and the use of oral contraceptives during therapy. J Clin
Oncol. 2005;23:7555-7564.
146. Moncayo-Naveda H, Moncayo R, Benz R, et al. Organ-
specific antibodies against ovary in patients with
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systemic lupus erythematosus. Am J Obstet Gynecol.
1989;160:1227-1229.
147. Pasto SG, Viana VST, Mendonca BB, et al. Anti-corpus
luteum antibody: a novel serological marker for ovarian
dysfunction in systemic lupus erythematosus? J
Rheumatology. 1999;26:1087-1093.
148. Lieman H, Santoro N. Premature ovarian failure: a
modern approach to diagnosis and treatment.
Endocrinology. 1997;7:314-321.
149. Isojarvi JIT. Reproductive dysfunction in women with
epilepsy. Neurology. 2003;61(6) Suppl 2:S27-S34.
150. Pereya PB, Mendez Ribas JM, Milone G, et al. Use of
GnRH analogs for functional protection of the ovary and
preservation of fertility during cancer treatment in
725
adolescents: a preliminary report. Gynecol Oncol.
2001;81:391-397.
151. Blumenfield Z, Avivi I, Linn S, et al. Prevention of
irreversible chemotherapy-induced ovarian damage in
young women with lymphoma by a gonadotropin-
releasing hormone agonist in parallel to chemotherapy.
Hum Reprod. 1996;11:1620-1626.
152. Sim AA. Fertility preservation in female cancer patients:
current developments and future directions. Fertil Steril.
2006;85(1):1-11.
153. Maltaris T, Seufert R, Fischl F, et al. The effect of cancer
treatment on female fertility and strategies for preserving
fertility. Eur J Obstet Gynecol. 2007;130:148-155.
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TisdaleC37_727-737 1/20/10 11:35 PM Page 727

SECTION VIII

DRUG-INDUCED
GASTROINTESTINAL DISEASES

CHAPTER 37 Upper Gastrointestinal Ulceration

CHAPTER 38 Diarrhea

CHAPTER 39 Constipation

CHAPTER 40 Hepatic and Cholestatic Disease

CHAPTER 41 Pancreatitis

CHAPTER 42 Nausea, Vomiting and Anorexia

TisdaleC37_727-737 1/20/10 11:35 PM Page 728
TisdaleC37_727-737 1/20/10 11:35 PM Page 729
C H A P T E R 37
Upper Gastrointestinal
Ulceration
T he upper gastrointestinal (GI) tract consists of
the mouth, pharynx, esophagus, and stomach.
Drug-induced ulcerations of the upper GI tract can
occur in any of these areas, but the esophagus and
stomach are primary targets. Patients may present
with signs and symptoms that range from benign
lesions with no sequelae to serious complications
including GI bleeding, strictures, perforation, and
obstruction. Distinguishing characteristics of drug-
induced mucosal damage of the upper GI tract are
typically evident on endoscopy. Understanding the
mechanisms of risk factors for drug-induced upper
GI ulceration can help clinicians minimize and
manage the complications that may occur.
CAUSATIVE AGENTS
Medications that have been reported to cause
upper GI ulceration are listed in Table 37-1.
Overall, nonsteroidal antiinflammatory drugs
(NSAIDs) and aspirin are the most common
causative agents. Other medications that are com-
monly associated with upper GI ulceration
include ferrous sulfate, quinidine, doxycycline,
selective serotonin reuptake inhibitors (SSRIs),
and corticosteroids (especially when used in com-
bination with other medications that can cause
ulceration).
The mucosa of the esophagus is particularly
vulnerable to the direct mucosal injury that can
occur with many medications. Over 70 medica-
tions have been associated with esophageal dam-
age, including certain bisphosphonates (e.g.,
alendronate), potassium chloride, aspirin, clin-
damycin, ferrous sulfate, quinidine, valproic
Dianne B. Williams and J. Russell May
acid (sustained-release), and tetracyclines. 1,2
Esophageal perforation has been reported with
sustained-release valproic acid, aspirin-caffeine
products and sustained-release ferrous sulfate.2
While anticoagulant and antiplatelet medica-
tions may increase the risk of bleeding, they are
not generally considered major culprits in upper
GI ulceration.
EPIDEMIOLOGY
The true incidence of drug-induced upper GI
ulceration is difficult to determine because of pos-
sible underreporting or misdiagnosis. Many
patients self-medicate, making it impossible to
know actual exposure rates. In addition, some
patients in whom ulceration develops have mini-
mal sequelae or are asymptomatic. Dyspepsia, for
example, is present in less than 50% of patients
taking NSAIDs who present with life-threatening
complications such as GI bleeding or perforation.3
Another factor that complicates the collection and
interpretation of incidence data is the use of dif-
fering definitions for the diagnosis of drug-
induced upper GI ulceration that appear in
published literature. Knowing the criteria that
were used to define ulceration is important when
comparing study results.
Notwithstanding the difficulties described
above, NSAIDs appear to be the most common
cause of upper GI ulceration.4 More serious GI
complications may also develop in patients receiv-
ing NSAIDs including bleeding, stricture forma-
tion, and perforation.3,4 The incidence of
hospitalization for upper GI bleeding induced by
729
TisdaleC37_727-737 1/20/10 11:35 PM Page 730

730 SECTION VIII • Drug-Induced Gastrointestinal Diseases

TABLE 37-1 Agents Implicated in Drug-Induced Upper Gastrointestinal Ulceration

Drug Incidence Level of Evidence
(see page xii for explanation)
2,20
Ascorbic acid NK C
Aspirin21,22 10–15% A
Bisphosphonates (oral)4,20,21,29,30 0.2–0.4% A
Clindamycin1 NK C
Clopidogrel17 NK B
Corticosteroids4,14 0.4% B
Erythromycin4 NK C
Ferrous sulfate2,20 5% B
Nonselective NSAIDs3,5 10–25% A
Potassium chloride2,20 8–19% A
Quinidine2,20 NK C
Selective COX-2 NSAIDs8 5–8% A
Selective serotonin reuptake inhibitors6,18 NK B
Sulfasalazine4 NK C
2,4
Tetracyclines NK B
Valproic acid2 NK C
NK = not known; NSAIDs = nonsteroidal antiinflammatory drugs; COX = Cyclooxygenase.

NSAIDs has been reported to be as high as 2.2%
annually in patients with rheumatoid arthritis.5
The highest risk for upper GI ulceration in
patients receiving NSAIDS appears to occur when
these agents are used in combination with other
medications also known to cause GI ulceration.
When combined with even low doses of aspirin
(less than 325 mg/day), the risk of upper GI bleed-
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
patients receiving corticosteroids and selective
serotonin reuptake inhibitors alone, the combina-
tion of these drugs with an NSAID increases the
risk for ulceration considerably. Patients taking a
selective serotonin reuptake inhibitor concurrent-
ly with an NSAID had as much as a 3.6-fold
increase in the risk of upper GI bleeding.6 The inci-
dence of ulceration appears to be least common
with ibuprofen, especially at doses <1,200 mg/24
hours. Selective cyclooxygenase (COX)-2 NSAIDs
also are associated with a lower incidence of med-
ication-induced ulceration ranging from 5% to
8%.7
While GI damage due to NSAIDs and aspirin
are most common at sites distal to the esophagus,
they can cause esophageal damage as well. One
review of medications associated with drug-
induced esophageal injury showed NSAIDs, includ-
ing aspirin, to be responsible for 40% of cases. This
was followed by tetracyclines (22%), potassium
chloride (10%), and bisphosphonates (9%).
Antimicrobials, quinidine, and ascorbic acid were
responsible for the remainder of cases.2
MECHANISMS
Various mechanisms are responsible for drug-
induced upper GI ulceration, ranging from simple
direct irritation of the GI lining to more complex
interactions with mucosal cells and prostaglandin
inhibition. Since ulceration can occur in the
absence of direct contact with the GI tract, no
route of administration can be considered com-
pletely safe with respect to this drug-induced dis-
ease. An understanding of mechanisms is
important in preventing or minimizing adverse
effects in patients at greatest risk. Table 37-2 lists
causative agents with their proposed mechanism.
With some drugs, more than one mechanism may
be involved.
TisdaleC37_727-737 1/20/10 11:35 PM Page 731
TABLE 37-2 Mechanisms of Drug-Induced Upper Gastrointestinal Ulceration
Drug
Aspirin4
Bisphosphonates (oral)2,4
Clindamycin1
Clopidogrel17
Corticosteroids4
Erythromycin4
Ferrous sulfate2
Nonsteroidal anti inflammatory drugs4
Potassium chloride4,20
Selective serotonin reuptake inhibitors6,18
Tetracyclines2,4
COX = cyclooxygenase
Aspirin and NSAIDs have long been thought
to cause upper GI ulceration through their inhibi-
tion of COX, a major enzyme needed for the syn-
thesis of prostaglandins. Prostaglandins have a
strong cytoprotective effect on the GI mucosa.
They help maintain mucosal blood flow, increase
secretion of mucus and bicarbonate, and augment
epithelial defense against cytotoxic injury.2 There
are at least two subtypes of the COX enzyme,
COX-1 and COX-2. COX-1 is the predominant
subtype found in the stomach. NSAIDs that pref-
erentially inhibit COX-2, therefore, might be
expected to cause fewer adverse GI effects than
those that inhibit COX-1. Indeed, when COX-1
inhibitors were directly compared with COX-2
inhibitors, it was found that patients experienced
fewer minor GI problems with the COX-2
inhibitors.8 Unfortunately, the long-term use of
COX-2 inhibitors is limited because they have
also been associated with greater cardiovascular
toxicity. Nonacetylated salicylates, such as sal-
salate, are weaker inhibitors of cyclooxygenase
activity and therefore less damaging to the GI
tract.
The relationship between Helicobacter pylori
positivity and the incidence of NSAID ulceration
appears to depend on when NSAID therapy was
started. New users of NSAIDs have been shown
to have fewer ulcers and ulcer-associated com-
plications if they are Helicobacter pylori-nega-
tive. 9 However, long-term users with healed
CHAPTER 37 • Upper Gastrointestinal Ulceration 731
Mechanism
COX inhibition
Platelet effects
Direct irritant
Direct irritant
Direct irritant
Platelet effects
Impair mucosal healing
Direct irritant
Direct irritant
COX inhibition
Direct irritant
Platelet effects
Direct irritant
Platelet effects
Direct irritant
gastric ulcers have a lower incidence of recur-
rence if they are Helicobacter pylori-positive.10,11
Whether the presence of one affects the mecha-
nism of ulceration of the other is unknown.
These are likely independent risk factors for
ulceration.12
Corticosteroids have been implicated in GI
ulceration, but the exact mechanism is unclear.
These drugs may impair mucosal healing through
the reduction of epithelial regeneration.13
Corticosteroids may pose a greater risk to the lower
GI tract than to the upper GI tract.2 Studies have
failed to confirm the mechanism or quantify the
actual risk.14
“Pill-induced” esophagitis, a localized ulcer of
variable depth, can occur when capsules or tablets
do not clear the esophagus in a timely manner.
Gelatin capsules can become sticky and lodge in
the esophagus if not taken with adequate water. In
addition, tablets may be difficult to swallow or
contain a caustic coating that causes direct mucos-
al irritation. The pH and concentration of the med-
ication may also be contributing factors.
Pill-induced esophagitis occurs commonly with
oral bisphosphonates, such as alendronate.
Potassium chloride may induce irritation in a local-
ized area of the esophagus or stomach because of
the high salt concentration. The slow-release, wax
matrix formulations are more likely to cause dam-
age than the microencapsulated forms. In most
cases the esophageal injury is caused by the pro-
TisdaleC37_727-737 1/20/10 11:35 PM Page 732
732 SECTION VIII • Drug-Induced Gastrointestinal Diseases
longed contact of drug, resulting in direct damage
to the esophageal wall.15
A number of other mechanisms for drug-
induced upper GI bleeding exist. Vascular shunt-
ing due to an increased osmotic load of sorbitol
has led to ischemic necrosis in patients taking
sodium polystyrene.16 Clopidogrel may cause
rebleeding in patients with a history of bleeding
because of its antiplatelet effect.17 There is some
evidence suggesting that selective serotonin reup-
take inhibitors increase the risk of upper GI bleed-
ing by possibly decreasing platelet serotonin and
interfering with platelet aggregation.18 This effect
is potentiated when selective serotonin reuptake
inhibitors are administered with NSAIDs or low-
dose aspirin.6
CLINICAL PRESENTATION AND
DIFFERENTIAL DIAGNOSIS
Patients with drug-induced GI ulceration may be
asymptomatic or may present with life-threaten-
ing complications including bleeding, perfora-
tion, and strictures. The most common signs and
symptoms of upper GI ulceration are listed in
Table 37-3. Heartburn, dyspepsia, cramps, and
abdominal pain are common, but do not always
correlate with ulceration. As previously noted,
dyspepsia was reported by less than 50% of
patients presenting with life-threatening bleeding
due to NSAID use in one series.3 Hematemesis
and/or black, tarry stools may be signs of bleeding
and should be carefully evaluated. Likewise, dys-
phagia, odynophagia, weight loss, or severe
abdominal pain may be indicative of severe com-
plications or malignancy and warrant careful
evaluation.
NSAIDs most commonly cause ulceration in
the stomach, followed by ulceration in the small
intestines. Less commonly they may cause ulcera-
tions in the esophagus. Of note, indomethacin,
diclofenac, piroxicam, and aspirin have been
shown to induce esophageal injury.1 There appears
to be a correlation between NSAID use and the
development of esophagitis and esophageal stric-
tures.19 While esophageal injury may not be as
common with NSAIDs, when it does occur it can
have serious consequences, including bleeding and
stricture formation.
Patients with pill-induced esophagitis, as
occurs with doxycycline or alendronate, may pres-
ent with sudden, painful swallowing shortly after
the offending agent is taken. It can also be
TABLE 37-3 Signs and Symptoms Associated with
Drug-Induced Upper Gastrointestinal Ulceration2,20
• Hematemesis
• Hematochezia
• Abdominal tenderness
• Burning in the back or stomach
• Heartburn
• Abdominal pain
• Nausea/ vomiting
• Indigestion
• Cramps
• Odynophagia
• Dyspepsia
described as a dull aching pain in the shoulder or
chest.20 Sequelae from this type of injury can
include severe ulceration and strictures.
Hemorrhage is rare. Symptoms generally resolve
within 7 to 10 days following discontinuation of
the culprit drug.20 Pill-induced esophagitis should
be suspected whenever patients present with the
above symptoms and especially in those without
previous esophageal symptoms.
Patients with esophageal injury due to potassi-
um chloride tend to have progressive dysphagia
with little pain.1 The connection between drug and
injury can be difficult to recognize, since symp-
toms may progress over months or even years. In
many cases, strictures develop because of the
chronic nature of injury. Clinicians should be alert
for pill-induced esophagitis or gastritis in elderly
patients who require potassium supplements while
being treated with diuretics for heart failure.
Quinidine may cause production of an exudate
and edema in the upper GI tract that must be dis-
tinguished from carcinoma.1
Many of the signs and symptoms associated
with upper GI ulceration are also common with
other diseases. It is important, therefore, to distin-
guish drug-induced upper GI ulceration from other
ulcerative, erosive, or inflammatory conditions, as
well as trauma, tumors, or other diseases. Table 37-
4 lists conditions that should be considered in the
differential diagnosis of drug-induced upper GI
ulceration.
Patients presenting with weight loss, recurrent
emesis, and dyspepsia may have gastric outlet
obstruction. Patients who present with chest pain
or pain that radiates to the shoulder should be
evaluated for cardiovascular causes. Dysphagia,
odynophagia and weight loss may be indicative of
carcinoma and patients with these symptoms
require careful evaluation.
TisdaleC37_727-737 1/20/10 11:35 PM Page 733
TABLE 37-4 Conditions to Consider in the
Differential Diagnosis of Drug-Induced Upper
Gastrointestinal Ulceration2
• Reflux esophagitis
• Infectious cause of esophagitis (herpes, candida, HIV,
cytomegalovirus)
• Esophageal stricture
• Gastric outlet obstruction
• Perforation
• Peptic ulcer disease (gastric and duodenal ulcer)
• Crohn’s disease
• Chest pain secondary to cardiovascular disease
• Malignancy
• Stevens-Johnson syndrome
• Sclerotherapy
• Nasogastric intubation
HIV = Human Immunodeficiency Virus
It is difficult to distinguish pill-induced
esophagitis from herpes esophagitis, since both
may present radiographically as shallow ulcera-
tions in the mid or distal esophagus.
Differentiation can sometimes be made by deter-
mining the presence or absence of a temporal rela-
tionship between drug ingestion and the onset of
symptoms. Patients with herpes-induced ulcers are
usually immunocompromised, and their esoph-
ageal lesions tend to be more widely distributed
than those in patients with pill-induced esophagi-
tis.1 Reflux esophagitis generally causes ulcers in
the more distal segment of the esophagus.
There are several characteristic morphologic
and pathophysiologic changes that can help differ-
entiate drug-induced GI ulceration from other con-
ditions.16 Candidal esophagitis is characterized by
its “shaggy” appearance due to plaque formation.1
Crohn’s disease is usually distinguished by evi-
dence of the disease in other parts of the GI tract,
including the small and large bowel.1 An exuda-
tive, ulcerative esophagitis may develop in patients
receiving alendronate. The exudate shows translu-
cent crystalline material, with multinucleated
giant cells seen in as many as 30% of cases, a
process indicative of pill-induced esophagitis. Iron-
induced GI injury occurs most commonly in the
esophagus, but the stomach may also be affected.16
The injury manifests as a chemical burn with ero-
sive injury and is characterized by brown-black
crystalline material within the epithelium.16
Elderly patients are at increased risk for this
because of low saliva production. Those who are in
a recumbent position for extended periods are also
at risk for this type of injury. Iron can also deposit
CHAPTER 37 • Upper Gastrointestinal Ulceration 733
in the stomach epithelium, causing damage.
Patients with uremia are very susceptible to vascu-
lar shunting because of the sorbitol osmotic load in
sodium polystyrene. Basophilic crystalline material
may be evident on morphologic evaluation.
Ischemic necrosis has been reported. Most upper
GI lesions due to sodium polystyrene are reversible
and do not generally lead to serious sequelae.16
RISK FACTORS
Our knowledge of the risk factors associated with
GI bleeding caused by aspirin and NSAIDs and
those for bisphosphonate-induced esophageal
damage provide excellent guidance when consider-
ing the risk associated with any of the medications
described in this chapter. Risk factors for drug-
induced upper gastrointestinal ulceration are listed
in table 37-5.
Factors that increase the risk for GI bleeding
with aspirin include dose, history of ulcer or upper
GI bleeding, age >70 years, and concomitant use of
NSAIDs.21 Other risk factors for GI bleeding with
aspirin, even low-dose aspirin, are the concomitant
use of corticosteroids or anticoagulants.22
A history of GI complications is the most
important predictor of NSAID-induced GI toxici-
ty.23,24 Other risk factors include a history of
TABLE 37-5 Risk Factors for Drug-Induced Upper
Gastrointestinal Ulceration2,4
• History of ulceration
• History of gastrointestinal bleeding
• Concomitant use of two NSAIDs (including low-dose
aspirin)
• Prolonged NSAID use
• High NSAID dose
• Concomitant anticoagulation
• Concomitant corticosteroid use
• Increasing age
• Helicobacter pylori infection (see text, controversial)
• Specific risks for pill-induced esophagitis:
• Inadequate fluid intake
• Swallowing abnormalities (e.g., stroke, dysmotility,
anatomic abnormalities)
• Returning to a supine position too soon after med-
ication administration
• Fasting
• Decreased saliva production (including dry mouth
as a drug side effect)
NSAID = nonsteroidal antiinflammatory drug.
TisdaleC37_727-737 1/20/10 11:35 PM Page 734
734 SECTION VIII • Drug-Induced Gastrointestinal Diseases
uncomplicated peptic ulcer; age >75 years; con-
comitant use of aspirin, corticosteroids, or warfarin;
the dose of NSAID; a history of dyspepsia; and the
disease being treated (e.g., patients treated for
rheumatoid arthritis have higher prevalence of GI
events than those treated for osteoarthritis).23 The
duration of NSAID use may also be an important
factor in the development of GI toxicity. Short-term
use (<1 week) in healthy patients is unlikely to be
problematic, but longer-term use is associated with
increased GI toxicity. GI complications are most
common within the first 3 months of the initiation
of NSAID therapy.
Because COX-1 produces prostaglandins that
are known to protect the GI mucosa, it is thought
that NSAIDs with greater COX-1 inhibitory activi-
ty would present a greater risk of GI toxicity. This
idea is supported by evidence that ketorolac, the
NSAID with the greatest COX-1 inhibitory effects,
produces the highest risk for GI bleeding of all the
medications in this class.25,26 COX-2 inhibiting
agents (e.g., celecoxib) have a minimal effect on
COX-1 and theoretically present a lower risk of GI
bleeding. However, no NSAID is completely free of
ulceration risks and associated complications. Most
of the factors that raise the risk for GI complica-
tions in patients taking NSAIDs also increase the
likelihood of GI complications in non-NSAID-
treated patients.7 As a result, patients may be at
continued risk for GI complications even after
being switched to alternative medications. In addi-
tion, the incidence of cardiovascular toxicities has
been shown to be higher with COX-2 inhibitors, so
proper patient selection following evaluation of
the risks and benefits is extremely important.
Patients who have undergone transplantation
have multiple risk factors for GI ulceration, includ-
ing the stress of surgery, use of NSAIDs and corti-
costeroids, and increased gastric acid secretion
during dialysis post-transplantation.27 Also con-
tributing is the possible impairment of native GI
cytoprotection due to azathioprine or mycopheno-
late-induced slowing of intestinal cell turnover.
Ulcers can be asymptomatic with the symptoms
masked by the use of corticosteroids. Risk factors
for bleeding following transplantation include
NSAID use for at least 1 week post-transplantation,
high-dose intravenous corticosteroids used for
acute rejection, and cyclosporine use.27
Patients with a history of GI bleeding may also
be at increased risk of rebleeding when taking clopi-
dogrel.17 Nine of 70 such patients (14%) had signif-
icant GI bleeding after a median follow-up of 1 year.
All except one lesion was identical to the previous
lesion, suggesting that clopidogrel causes rebleed-
ing only in patients with underlying mucosal
defects or scarring. Clinicians should be alert to the
fact that patients with a history of aspirin-induced
GI bleeding are at high risk for the development of
the same outcome with clopidogrel.
Clopidogrel has been reported to have a favor-
able GI safety profile as compared with aspirin,
although patients who were studied received only
325 mg doses of nonbuffered and nonenteric coat-
ed aspirin. In addition, prescribers were permitted
to exclude any patient they defined as being
“aspirin-intolerant.”28
Patients at risk for pill-induced esophagitis are
those who do not take enough fluids with their
medications, those with swallowing abnormalities
due to stroke or esophageal dysmotility, and those
with anatomic abnormalities such as strictures.20
Other risk factors include fasting, decreased pro-
duction of saliva, age > 70 years, and polypharma-
cy.1 In most case reports of bisphosphonate-related
ulcerative esophagitis or esophageal stricture, the
patient took alendronate with little to no water or
returned to a supine position too soon after swal-
lowing the tablet.29 Women with a history of upper
GI disease or patients with gastroesophageal reflux
disease also appear to be at greater risk for
esophageal complications from bisphosphonates.30
When used in combination, NSAIDs and bisphos-
phonates appear to have a synergistic effect on the
risk for the development of gastric ulceration.31
MORBIDITY AND MORTALITY
While some drug-induced upper GI ulceration may
be relatively insignificant and transient, there is
always a risk of severe complications including per-
foration, penetration of an ulcer from the stomach
or duodenum into an adjacent organ, GI obstruc-
tion, and bleeding. Any of these complications can
necessitate hospitalization with possible surgical
intervention and can be life-threatening.
The highest rates of complication are associat-
ed with aspirin and the NSAIDs. Problems range
from minor but common side effects such as dys-
pepsia and abdominal pain to the more severe
complications of ulceration, perforation, and
bleeding. While the more serious complications are
relatively uncommon, they are a major public
health concern because of the large numbers of
patients who are exposed each year to aspirin and
NSAIDs. With an estimated 60 million Americans
taking NSAIDs, the reported 1% to 2% rate of sig-
nificant upper GI events results in a large number
of patients requiring care.32,33 Although estimates
vary, NSAID-related mortality has been reported to
be as high as 16,500 per year in the United States.5
TisdaleC37_727-737 1/20/10 11:35 PM Page 735
Studies have attempted to determine hospital-
ization rates due to NSAID-induced complications.
Patients with upper GI symptoms who were admit-
ted through emergency departments were more
likely to be NSAID users as compared with controls
(odds ratio, 2.4).34 Blood transfusion requirements
were also higher. Another population-based study
completed in Scotland reported a hospitalization
rate of 2% over a 3-year period among NSAID users
>50 years old.35 Eighteen hospitals in Spain and
Italy participated in a study of risk for upper GI
bleeding. The incidence was 401.4 per million
inhabitants aged 18 and older, with 38% of the
cases attributable to NSAIDs.36 An observational
study of NSAID-related GI complications and death
included patients in more than 200 hospitals in
the Spanish National Health System, which pro-
vides care for 80% of the country.37 The mortality
was 15.3 deaths per 100,000 NSAID users.
PREVENTION
Approaches to help prevent drug-induced upper
gastrointestinal ulceration are listed in Table 37-6.
The first and most important step is to avoid
agents known to increase the risk of disease in
patients who already have known risk factors.
Whenever possible, an alternative drug with little
or no risk for upper GI ulceration should be used in
these patients. An example might be using aceta-
minophen instead of aspirin to treat osteoarthritis
in an elderly patient.
When the use of a drug known to cause upper
GI ulceration cannot be avoided, using the lowest
possible dose is helpful. Upper GI injury may be
minimized in patients who require NSAID therapy
by using one of the following strategies. In low-risk
patients (those having no known risk factors), use
the lowest dose possible and avoid concomitant
use of other agents known to cause upper GI ulcer-
ation.24 An increased risk of GI toxicity has been
seen when aspirin (even low-dose aspirin) is com-
bined with NSAIDs. Likewise, corticosteroids have
a low incidence of GI ulceration when used alone;
however, the incidence increases significantly
when combined with NSAIDs.
In patients at moderate risk (one or two risk
factors), concomitant treatment with acid suppres-
sion therapy, such as a proton pump inhibitor
(PPI), or misoprostol should be considered.24 PPIs
prevent upper GI toxicity associated with NSAIDs
and are generally well tolerated as compared with
misoprostol. While effective in increasing mucosal
blood flow and stimulating mucus and bicarbonate
production in the upper GI tract, misoprostol is
CHAPTER 37 • Upper Gastrointestinal Ulceration 735
TABLE 37-6 Approaches to Help Prevent Drug-
Induced Upper Gastrointestinal Ulceration
Aspirin2,4
• Use lowest possible dose
• Avoid other ulcerogenic medications
Bisphosphonates 4,20
• Take with 8 oz of water
• Remain upright for at least 30 minutes after taking
medication
Corticosteroids20
• Avoid concomitant use of NSAIDs or aspirin, if pos-
sible
NSAIDs4,20
• Use lowest possible dose
• Use least ulcerogenic NSAID
• Consider addition of proton pump inhibitor or
misoprostil
• Avoid other ulcerogenic medications
• Treat Helicobacter pylori if found
Potassium chloride4
• Microencapsulated formulation preferred
• Avoid slow-release, wax-matrix formulations
Selective serotonin reuptake inhibitors6,18
• Use alternative class of antidepressant
• Avoid concomitant use of NSAIDs, if possible
Tetracyclines20
• Use tablet formulation rather than capsule formulation
NSAID = nonsteroidal antiinflammatory drug.
associated with numerous adverse effects, such as
diarrhea, which can limit its routine use. The use of
a selective COX-2 inhibitor, such as celecoxib, may
be considered in some patients. Selective COX-2
inhibitors reduce the incidence of GI toxicity as
compared with traditional NSAIDs. However, the
other toxicities, such as cardiovascular risk, associ-
ated with COX-2 selective inhibitors must be
weighed against the potential benefit.
Other options include using NSAIDs that
undergo less enterohepatic circulation, such as
nabumetone or etodolac.3 High-risk patients (>3
risk factors or concomitant use of aspirin, corticos-
teroids, or warfarin) may benefit from the addition
of a proton pump inhibitor or misoprostil.24 In the
highest-risk patients (history of recent ulcer com-
plications) it is best to avoid NSAIDs altogether. If
avoidance is not possible, these patient should
receive the same treatment as those in the high-
risk category.24
With other medications that cause upper GI
ulceration, changing to an agent less likely to cause
injury may be an option. In patients requiring
potassium supplementation, switching to a
TisdaleC37_727-737 1/20/10 11:35 PM Page 736
736 SECTION VIII • Drug-Induced Gastrointestinal Diseases
microencapsulated form may be preferable to a
slow-release, wax-matrix form. Patients requiring a
bisphosphonate for osteoporosis may tolerate rise-
dronate better than alendronate, since it appears to
be less ulcerogenic.
Education is important in pill-induced
esophagitis. Patients should sit or stand upright
and take medications with ample fluids. They
should remain upright for at least 15 minutes after
taking the medication. Careful selection of the
dosage form of the medication may also help pre-
vent mucosal injury. Liquid or tablet formulations
may be less problematic than capsules.
In addition to the steps outlined above,
patients at risk for upper GI ulceration should be
educated regarding important lifestyle modifica-
tions, including avoidance of acidic beverages (e.g.,
citrus juices) and irritating foods (e.g., onions,
spicy foods).
MANAGEMENT
The first step in the management of drug-induced
upper GI ulceration is to reassess the need for the
offending agent. Changing to an alternative med-
ication is often ideal; however, if this is not possi-
ble, the lowest possible dose of the offending agent
should be used. Gastric ulceration should be con-
firmed via endoscopy and, when present, treated
with acid-suppressing therapy such as a proton-
pump inhibitor. Treatment of Helicobacter pylori
infections should be considered. Surgery may be
necessary to treat strictures.
Treatment of pill-induced esophagitis damage
consists mostly of supportive therapy, and acid
suppression may be used as an adjunct. Symptoms
usually improve within 2 to 6 days after stopping
the medication, and antacids may give fast relief of
pain.1 When possible, discontinuation of the
offending agent is the best option. Use of acid sup-
pressing therapy (e.g., a proton pump inhibitor) is
beneficial if gastroesophageal reflux is present,
since the refluxed material may worsen pill-
induced esophagitis.1 Avoiding foods or beverages
(e.g., citrus, alcohol) that might exacerbate symp-
toms may also be helpful in selected patients.1
Drinking plenty of water is also helpful in prevent-
ing tablets or capsules from adhering to the
mucosa and causing damage.
INFORMATION FOR PATIENTS
Counseling is critical for the safe use of the med-
ications discussed in this chapter. As previously
noted, one of the biggest risk factors for drug-
induced upper GI ulceration is the concomitant
use of aspirin or NSAIDs with any other medica-
tion known to cause upper GI ulceration. Because
many NSAIDs are available over the counter under
a variety of brand names and as combination
products, an informed patient may be the best
protection against these adverse events. Patients
should be reminded to carefully read labels of
non-prescription medications to avoid inadver-
tently purchasing products containing NSAIDs. A
discussion of potentially harmful non-prescription
medications should be conducted with all patients
receiving a prescription for any of the causative
drugs.
For NSAIDs, patients should take the recom-
mended dose for the indicated length of time. If
prescribed for a chronic condition, patients should
be regularly reminded of the warning signs of
ulceration. They should report any nausea, abdom-
inal pain or tenderness, or coffee-ground or bloody
emesis or stools immediately to their health care
provider. Patients must realize that even low-dose
aspirin can result in complications.
Patients taking bisphosphonates should strictly
adhere to recommendations regarding administra-
tion, including taking the medication first thing in
the morning at least 30 minutes before eating or
drinking anything, taking the medication with a
full glass of water, and staying in a sitting or stand-
ing position for at least 30 minutes following
ingestion. Any medication known to cause pill-
induced esophagitis should be taken with suffi-
cient fluid every time a dose is administered.
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11. Hawkey CJ, Karrasch JA, SzczepanskiL, et al. Omeprazole
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12. Huang JQ, Sridhar S, Hunt RH. Role of Helicobacter pylori
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13. Gore RM, Levine MS, Ghahremani GG. Drug-induced
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14. Carpani DK, Rentsch R, Levi S, et al. Corticosteroids
reduce regenerative repair of epithelium in experimental
gastric ulcers. Gut. 1995;37:613-616.
15. Boyce HW. Drug-induced esophageal damage: diseases of
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16. Parfitt JR, Driman DK. Pathological effects of drugs on
the gastrointestinal tract: a review. Hum Pathol.
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17. Ng FH, Wong SY, Chang CM, et al. High incidence of
clopidogrel-associated gastrointestinal bleeding in
patients with previous peptic ulcer disease. Aliment
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18. Yuan Y, Tsoi K, Hunt RH. Selective serotonin reuptake
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19. McCord GS, Clouse RE. Pill-induced esophageal
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20. Tolstoi LG. Drug-induced gastrointestinal disorders.
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33. Silverstein FE, Faich G, Goldstein JL, et al.
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35. MacDonald TM, Morant SV, Robinson GC, et al.
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36. Laporte JR, Lbanez L, Vidal X, et al. Upper
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TisdaleC38_738-759 1/12/10 3:40 PM Page 738
CHAPTER 38
Diarrhea
D iarrhea is a relatively frequent adverse drug
effect. Symptoms may be mild and transient,
disappearing within days, or severe and life-threat-
ening. Because even healthy individuals may expe-
rience symptoms of diarrhea from time to time, the
identification of drug-induced diarrhea can be
challenging. In addition, drug-induced diarrhea
may present after months of uncomplicated, rou-
tine drug use, further complicating its recognition.
CAUSATIVE AGENTS
Drugs frequently implicated as a cause of drug-
induced diarrhea are listed in Table 38-1. However,
this list should not be interpreted as exhaustive,
since diarrhea can be a side effect of a multitude
of drugs.1-304 Commonly prescribed drugs with
lower incidences of drug-induced diarrhea include
␣-glucosidase inhibitors,305-308 antidepressants,
305,309,310
histamine2 blockers,305,311-313 hypolipidem-
ic drugs, 305,314-320
and nonsteroidal antiinflammato-
ry drugs.305,321-323
Antineoplastics represent a class of drugs asso-
ciated with a high incidence of drug-induced diar-
rhea, referred to as cancer treatment–induced
diarrhea (CTID).324-328 The actual incidence of diar-
rhea associated with individual antineoplastic
drugs is difficult to identify because most
chemotherapeutic regimens use combination ther-
apies. The potential for CTID increases with the
number of antineoplastic agents administered and
when radiation therapy is used.305,324,328
Antibiotics also represent a class of drugs with
a high incidence of drug-induced diarrhea, referred
to as antibiotic-associated diarrhea (AAD).305,329-333
The incidence of AAD is similar with oral and par-
738
Jane M. Gervasio
enteral antibiotic administration.333 AAD due to
Clostridium difficile (C. diff) is a common complica-
tion.331,333 C. diff colitis and pseudomembranous
colitis are used synonymously to refer to the spec-
trum of the disease attributed to C. diff. However,
pseudomembraneous colitis specifically describes
the formation and proliferation of membranous
exudates in the colon resulting in diarrhea.
Diarrhea associated with C. diff or pseudomembra-
neous colitis is termed C difficile–associated diar-
rhea (CDAD). Clindamycin, cephalosporins, and
penicillins are most frequently associated with
CDAD. CDAD frequently results in hospitalization
and, if untreated, death.331,333 Drugs associated
with CDAD are included in Table 38–1.
Herbal agents are also known to induce diar-
rhea and must be considered when evaluating a
patient with this disorder. Unfortunately, many
patients do not consider herbal medications to be
drugs and may not reveal their use when giving a
medication history. Questions specifically ad-
dressing herbal agents may be necessary for iden-
tification. Although limited research makes it
difficult to ascertain the exact incidence of diar-
rhea associated with the use of herbal products,
some of the more commonly used culprits
include chondroitin sulfate,334 glucosamine sul-
fate,334 coenzyme Q10,335 creatine,336 echinacea,337
flaxseed (oil),338 milk thistle,339 saw palmetto,340
and St. John’s Wort.341
EPIDEMIOLOGY
The epidemiology of diarrhea varies between
developed and developing countries. In the United
States, it is estimated that 375 million episodes of
TisdaleC38_738-759 1/12/10 3:40 PM Page 739

CHAPTER 38 • Diarrhea 739

TABLE 38–1 Agents Implicated in Drug-Induced Diarrhea

Drug Incidence Level of Evidence
(see page xii for explanation)
2
Albendazole (Clostridium difficile–associated diarrhea) NK C
Alizapride3,4 12–50% A
Amoxicillin6,7 5–29% A
Amoxicillin (Clostridium difficile–associated diarrhea)8,9 NK C
Amoxicillin–clavulanate10-13 10–25% A
Ampicillin8,9,14,15 5–21% A
Ampicillin (Clostridium difficile–associated diarrhea)16 NK C
Ampicillin/sulbactam (Clostridium difficile–associated diarrhea)8,16,17 <1% C
Auranofin (gold salt)18-20 15–50% A
Azathioprine21 10–39.4% A
Azithromycin7,22-24 5–11.6% A
Aztreonam (Clostridium difficile–associated diarrhea)25 <1% C
Bevacizumab26,27 2–34% A
Bortezomib28-32 32–57% A
33
Busulfan 1 –75% A
Calcitonin34 >10% A
Capecitabine35,36 55–61.7% A
Carbenicillin (Clostridium difficile–associated diarrhea)37,38 <1% C
Cefamandole (Clostridium difficile–associated diarrhea)39 <1% C
Cefixime40-44 15–20% A
Cefazolin (Clostridium difficile–associated diarrhea)44 <1% C
Cefmetazole (Clostridium difficile–associated diarrhea)45 <1% C
Cefonicid (Clostridium difficile–associated diarrhea)46 <1% C
Cefoperazone (Clostridium difficile–associated diarrhea)47 <1% C
Cefotaxime (Clostridium difficile–associated diarrhea)48 <1% C
Cefotetan (Clostridium difficile–associated diarrhea)49 <1% C
Cefoxitin (Clostridium difficile–associated diarrhea)50 <1% C
Ceftazidime (Clostridium difficile–associated diarrhea)51,52 <1% C
Cefuroxime (Clostridium difficile–associated diarrhea)53 <1% C
Cephalexin54,55 <1% C
Cephalothin (Clostridium difficile–associated diarrhea)56 NK C
Cephapirin (Clostridium difficile–associated diarrhea)57 <1% C
Cephradine (Clostridium difficile–associated diarrhea)58 <1% C
Cetuximab59-61 19–39% A
Chloramphenicol (Clostridium difficile–associated diarrhea)62 <1% C
Chlorpropamide (Clostridium difficile–associated diarrhea)63 NK C
Cilostazol64-66 12–19% A
Ciprofloxacin (Clostridium difficile–associated diarrhea)67 <1% C
Cisapride (investigational limited access)68,69 4–18% A
Cisplatin (Clostridium difficile–associated diarrhea)70,71 NK C
(Continued)
TisdaleC38_738-759 1/12/10 3:40 PM Page 740

740 SECTION VIII • Drug-Induced Gastrointestinal Diseases

TABLE 38–1 Agents Implicated in Drug-Induced Diarrhea (Continued)

Drug Incidence Level of Evidence

Clindamycin72-75 2–31% A
Clindamycin (Clostridium difficile–associated diarrhea)8,9,76,77 1–13% B
Cocaine (Clostridium difficile–associated diarrhea)78 NK C
Colchicine79-81 8–10% A
Cyclophosphamide82,83 10–50% A
Cytarabine84,85 10–12% A
Cytarabine (Clostridium difficile–associated diarrhea)86 NK C
Dalbavacin87,88 2.5–21.2% A
Darbepoetin89 16–22% A
Darunavir90,91 2.3–12% A
Dasatinib92 23–37% A
Daunorubicin93 >10% A
Decitabine94 17–34% B
Dexrazoxane95,96 11% B
Diacerein97 37% A
Diclofenac (Clostridium difficile–associated diarrhea)98,99 <1% C
Dicloxacillin (Clostridium difficile–assoicated diarrhea)100 <1% C
Didanosine101-103 17.2–34% A
Docetaxel104-106 32.8–42.6% A
Doxyrubicin30,106 20.9–46% A
Doxyrubicin (Clostridium difficile–associated diarrhea)107,108 NK C
Duloxetine109-111 7–13% A
Epirubicin112-114 7–25% A
Erythromycin24,115,116 >10% A
Erythromycin (Clostridium difficile–associated diarrhea)8,9,117 <1% C
Erythropoietin118 6–21% A
Erlotinib119,120 55–68% A
Esomeprazole121-123 1–10% A
Etidronate (Clostridium difficile–associated diarrhea)124 NK C
Etoposide125,126 1–13% A
Exenatide127 13% A
Flavopiridol128,129 50% A
Fluorouracil35,130-133 10–80% A
Fluorouracil (Clostridium difficile–associated diarrhea)134 NK C
Fluvoxamine135,136 11–18% A
Galantamine137 6–12% A
Gefitinib138,139 40–60% A
Gentamicin (Clostridium difficile–associated diarrhea)140 <1% C
Hydroxyurea141,142 10–13% A
Idarubicin84,143 9–22% A
Ifosfamide144,145 >10% A
(Continued)
TisdaleC38_738-759 1/12/10 3:40 PM Page 741

CHAPTER 38 • Diarrhea 741

TABLE 38–1 Agents Implicated in Drug-Induced Diarrhea (Continued)

Drug Incidence Level of Evidence

Imatinib146 3–70% A
Imipenem/cilastatin (Clostridium difficile–associated diarrhea)147 <1% B
Interferon-alfa-2B149,150 2–45% A
Irinotecan151-153 60–90% A
Itraconazole (Clostridium difficile–associated diarrhea)154 NK C
Ixabepilone155,156 22–44% A
Lanreotide157-159 26–65% B
Lansoprazole (Clostridium difficile–associated diarrhea)160 NK C
Lapatinib161,162 40–60% A
Leflunomide163-165 17–32.6% A
Levamisole166,167 13% A
Levocarnitine168-170 9–35% A
Lincomycin (Clostridium difficile–associated diarrhea)171-174 NK C
Magnesium175-177 5–46% A
Meclofenamate178-180 10–33% A
Metformin181-183 12.5–30% A
Metoclopramide184,185 >10% A
Methotrexate186 11% A
Methotrexate (Clostridium difficile–associated diarrhea)187 NK C
Metronidazole (Clostridium difficile–associated diarrhea)188,190 NK C
Miglitol191-193 15–49% A
Misoprostol194-196 14.6–50% A
Mitoguazone197-202 30% A
Mitomycin203,204 10–52% A
Mitoxantrone205 20% A
Mycophenolic acid21,206-209 27.6–51.3% A
Naltrexone210-212 13% A
Nelarabine213,214 22% B
Nelfinavir215-218 61% A
Nevirapine219,220 37– 41% A
Nilotinib221,222 19–22% A
Olsalazine223-225 16–35% A
Orlistat226-231 11–20% A
Oxacillin (Clostridium difficile–associated diarrhea)100,232,233 NK C
Paclitaxel234-236 8–14% A
Paclitaxel (Clostridium difficile–associated diarrhea)237 NK C
Panitumumab238,239 21–58% A
Peginterferon alfa-2a240-242 19–31% A
Penicillin V (Clostridium difficile–associated diarrhea)8,9 NK C
Piperacillin/tazobactam243,244 10–12% A
Piperacillin/tazobactam (Clostridium difficile–associated diarrhea)8,9 <1% C
(Continued)
TisdaleC38_738-759 1/12/10 3:40 PM Page 742

742 SECTION VIII • Drug-Induced Gastrointestinal Diseases

TABLE 38–1 Agents Implicated in Drug-Induced Diarrhea (Continued)

Drug Incidence Level of Evidence

Posaconazole245 2–12% A
Procarbazine246-248 5–25% A
Quinidine249,250 8–30% A
Rifampin (Clostridium difficile–associated diarrhea)251-255 1–10% C
Satraplatin256-259 29–59% A
Sorafenib260 33–55% A
Spiramycin (Clostridium difficile–associated diarrhea)261 NK C
Sulfasalazine (Clostridium difficile–associated diarrhea)8 NK C
Sultamicillin (Clostridium difficile–associated diarrhea)262 NK C
Sunitinib263-265 20–58% A
Tacrolimus (Clostridium difficile–associated diarrhea)266 NK C
Tedisamil267,268 3.6–59% A
Telithromycin269,270 11–20% A
Temozolomide271 16% A
Temsirolimus272-274 27% A
Testolactone275 1–25% B
Tetracycline276-279 1–10% A
8
Tetracycline (Clostridium difficile–associated diarrhea) NK C
280,281
Thioguanine 1–51% A
Tigecycline282-285 12.7–21.3% A
Ticlopidine286,287 12.5–20% A
288,289
Tipranavir 15% A
290,291
Topotecan 14–36% A
Trastuzumab292,293 25% A
294,295
Treprostinil 25% A
296,297
Trimethoprim–sulfamethoxazole (Clostridium difficile–associated diarrhea) NK C
298
Vancomycin (Clostridium difficile–associated diarrhea) NK C
Vinorelbine299,300 20% A
Vorinostat301-304 52.3% B
NK = Not know

acute diarrhea occur annually, with children

younger than 5 years of age experiencing the
majority of episodes. Diarrhea accounts for 4% of
children’s hospital admissions.342,343
Drug-induced diarrhea accounts for approxi-
mately 7% of all adverse drug events. More than
700 drugs are associated with diarrhea, and about
25% of those are antimicrobials.305 Elderly individ-
uals and children are more susceptible to drug-
induced diarrhea and have a greater risk for severe
complications because of declining and underde-
veloped gastrointestinal (GI)-tract function, respec-
tively.
MECHANISMS
Diarrhea arises from one of two basic mechanisms:
decreased absorption of water and electrolytes or
increased active secretion in the GI tract.344,345
Drug-induced diarrhea is generally caused by a
derivative of one of these two basic mechanisms
(Table 38–2).
Decreased absorption of water may occur in
association with drug-induced osmotic and secre-
tory diarrhea. Drugs such as lactulose, mannitol,
sorbitol, and magnesium affect the lumen of the
TisdaleC38_738-759 1/12/10 3:40 PM Page 743

CHAPTER 38 • Diarrhea 743

TABLE 38–2 Mechanisms of Drug-Induced Diarrhea344-346

Drug Mechanism
Lactulose, sorbitol, fructose, mannitol Osmotic
Magnesium
Antibacterials (ampicillin)
␣-Glucosidase inhibitors
Antibacterials Secretory
Antineoplastics
Auranofin (gold salts)
Biguanides
Calcitonin
Colchicine
Diacerein
Nonsteroidal antiinflammatory drugs
Olsalazine
Prostaglandins (misoprostol)
Ticlopidine
Cisapride Motility
Colchicine
Antimicrobials (erythromycin)
Metoclopramide
Ticlopidine
Antibacterials Exudative (increased active secretion)
Antineoplastics
Nonsteroidal antiinflammatory drugs
Simvastatin
Ticlopidine
Antibiotics (aminoglycosides, tetracyclines) Malabsorption of fat (steatorrhea)
Auranofin (gold salts)
Biguanides
Cholestyramine
Colchicine
Highly active antiretroviral therapy
Octreotide
Orlistat
Antibacterials Microbial proliferation
Antineoplastics
Immunosuppressive agents
Nonsteroidal antiinflammatory drugs
Antibacterials Clostridium difficile/pseudomembranous colitis;
Antineoplastics colonization of the human gut flora after the normal gut
flora has been altered because of bowel wall edema,
erythema, friability, inflammation

gut and promote retention of water and elec-
trolytes. Drug-induced secretory diarrhea occurs
when a medication increases secretions or decreas-
es absorption of large amounts of water and elec-
trolytes in the gut lumen.344,345
Drugs that decrease the amount of time during
which chyme is exposed to intestinal epithelium
cause abnormal absorption and secretion, which
can result in diarrhea. Prokinetic medications
including metoclopramide and the antibiotic
erythromycin are associated with this type of direct
effect on the intestine.344,345
Drug-induced diarrhea has been attributed to
fat malabsorption, or steatorrhea. Drugs can pre-
vent absorption of fatty acids in the small intes-
tine. When non-absorbed fatty acids reach the
TisdaleC38_738-759 1/12/10 3:40 PM Page 744
744 SECTION VIII • Drug-Induced Gastrointestinal Diseases
colon, they inhibit fluid absorption, and diarrhea
ensues.344,345 Highly active antiretroviral therapy is
known to cause steatorrhea. Orlistat, a gastroin-
testinal lipase inhibitor, uses this principle to
inhibit absorption of dietary fats for the purpose of
weight loss.
Drugs that increase active secretion alter intes-
tinal motility and may cause diarrhea. Drug-altered
intestinal motility is attributed to reduction of con-
tact time in the small intestine, premature empty-
ing of the colon or bacterial overgrowth.344,345 An
increase in active secretion is associated with
drugs, such as antineoplastics, that destroy the
mucosa of the small and large intestine. This
exudative process causes discharge of mucus,
serum proteins, and blood into the gut.
Antineoplastic drugs may also suppress normal GI
flora resulting in microbial overgrowth and colo-
nization of the intestines with pathogenic bacteria
(e.g., C. diff). In addition, antineoplastics can affect
the absorptive, secretory, or motility functions of
the gut.344,345
AAD occurs as a result of the overgrowth of
antibiotic-resistant bacteria, fungi, or toxin-pro-
ducing C. diff. C. diff secretes enterotoxin A and
cytotoxin B. Enterotoxin A adheres to the brush-
border membrane of enterocytes, inducing lesions
and an inflammatory response. Cytotoxin B may
also cause GI mucosal damage. Both toxins are nec-
essary for the full tissue damage associated with
CDAD. 305,344-346
CLINICAL PRESENTATION AND
DIFFERENTIAL DIAGNOSIS
Diarrhea is defined as an increased frequency of
bowel movements (≥3/24 hr), decreased stool con-
sistency, and/or increased stool weight (>200 g/24
hr).344,345 Because bowel habits, stool characteris-
tics, and daily stool output vary considerably
among individuals and populations, diarrhea,
including drug-induced diarrhea, should always be
evaluated in light of the patient’s age, weight and
comorbid conditions.344 Patients with prolonged,
voluminous, bloody diarrhea or severe abdominal
pain from diarrhea should be carefully evaluated. A
patient may present with weight loss, weakness,
orthostatic hypotension, tachycardia, electrolyte
imbalances and acid–base disturbances. Signs and
symptoms of drug-induced diarrhea are listed in
Table 38–3.
The clinical presentation of diarrhea may be
acute or chronic, and drugs have been recognized
as a cause of both processes. Diarrhea subsiding
within 72 hours of onset is usually considered
TABLE 38–3 Signs and Symptoms Associated
with Drug-Induced Diarrhea
• Abdominal pain
• Acid–base disorders
• Anorexia
• Chills
• Cramping
• Dehydration
• Dizziness
• Electrolyte imbalance
• Fever
• Headache
• Hyperactive bowel sounds
• Hyperperistalsis
• Hypotension
• Light-headedness
• Local tenderness
• Malaise
• Nausea/vomiting
• Tachycardia
• Thirst
• Weakness
• Weight loss
acute. Patients with acute diarrhea may experience
abrupt onset of nausea, vomiting, abdominal pain,
headache, fever, chills, and malaise. There may be
generalized or local abdominal tenderness with
hyperactive bowel sounds. Bowel movements are
frequent, usually not bloody, and episodes may last
12 to 72 hours.347
Chronic diarrhea involves frequent attacks
over extended periods, making its identification
more difficult.347 With chronic diarrhea, physical
examination is often less revealing and diagnostic
tests play a bigger role.347
Malabsorption of fat results in pale and volu-
minous stool with a stool fat content greater than
6 g per day and a stool weight greater than 200 g
per day. A stool sample is necessary to diagnosis
stool fat content and weight. If possible, a 3- to 5-
day collection period is preferred to reduce errors
and variability, since slight increases in fecal fat not
associated with fat malabsorption have been iden-
tified in patients with diarrhea.
Because of the difficulty in obtaining a 3- to 5-
day collection of stool, other diagnostic tests are
often used. The Sudan III stain, acid steatocrit, and
the near infrared reflectance analysis offer accurate
and simplified alternatives for diagnosing steator-
rhea.348-351
Carbohydrate malabsorption is associated with
watery diarrhea and increased flatulence.
Diagnostic tests to identify carbohydrate malab-
TisdaleC38_738-759 1/12/10 3:40 PM Page 745
sorption include acidic stool pH, stool osmotic gap,
and increased breath hydrogen. The D-xylose test
and lactose-tolerance test may also be used to iden-
tify malabsorption and lactose intolerance.351 Drug
formulations containing sucrose, lactose, or fruc-
tose may cause or exacerbate diarrhea in patients
who have carbohydrate malabsorption.
Chemotherapeutic agents, particularly fluo-
rouracil and irinotecan, are well recognized to
cause drug-induced diarrhea.326-328 Two National
Cancer Institute–sponsored cooperative group tri-
als of irinotecan plus high-dose fluorouracil and
leucovorin for advanced colorectal cancer led to
the recognition of a life-threatening GI syndrome,
with symptoms including severe diarrhea, nausea,
vomiting, anorexia, and abdominal cramping.326-
328
These symptoms were associated with severe
dehydration, neutropenia, fever and electrolyte
imbalance. Severe abdominal cramping appeared
to be an important early warning sign of imminent
diarrhea. Early detection and treatment of diarrhea
is imperative to prevent life-threatening complica-
tions.326
AAD and CDAD may occur from a few days
after antibiotic therapy is initiated to 8 weeks after
discontinuation of the drug. Patients with CDAD
present with profuse diarrhea (rarely with blood)
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
way to diagnosis CDAD, it is extremely costly and
should generally not be used as a first-line diag-
nostic test for most patients. On endoscopy, C. diff
lesions appear as raised white to yellow plaques
covering a normal or moderately erythematous
colonic mucosa.305 Diagnostic tests should initial-
ly include testing a stool specimen for C. diff and
its toxin. The standard for the laboratory diagno-
sis of C. diff is a cell culture to detect the specific
cytopathic effects of toxin B.332,333 In addition,
many institutions use enzyme immunoassay (EIA)
tests for detection of toxin A or B. Unfortunately,
the accuracy of these tests is not optimal, and a
negative EIA test for toxin A or B does not rule out
the diagnosis of CDAD. A second or third stool
specimen should be sent to the laboratory when
initial results are negative but diarrhea persists.331-
333
Differentiating between drug-induced diarrhea
and non–drug-induced diarrhea can be challeng-
ing. Practitioners should seek to identify any
changes in drug therapy that have occurred recent-
ly and any new drugs (prescription, nonprescrip-
tion, herbal and nutritional supplements) to which
the patient has been exposed. Since diarrhea may
CHAPTER 38 • Diarrhea 745
result from drug therapy started as long as 4 weeks
prior to the onset of symptoms and 8 weeks follow-
ing discontinuation, the temporal relationship
between onset and changes in drug therapy must
be carefully and thoroughly explored. Additive or
synergistic effects from possible drug–drug interac-
tions must also be considered. To help rule out
common non-drug causes of diarrhea, eating
habits, alcohol and caffeine consumption, and
illicit drug use as well as psychosocial factors that
might be affecting the patient all must be consid-
ered. Any environmental changes in the patient’s
home or office, recent travel or exposure to possi-
ble sources of bacterial or viral pathogens, disease
processes or comorbid complications must all be
identified. Conditions to consider in the differen-
tial diagnosis of drug-induced diarrhea are listed in
Table 38–4.
RISK FACTORS
General risk factors for diarrhea are listed in Table
38–5. Although specific risk factors for drug-
induced diarrhea have not been identified, it can
reasonably be assumed that patients are at
increased risk for drug-induced diarrhea when one
TABLE 38–4 Conditions to Consider in the
Differential Diagnosis of Drug-Induced Diarrhea
• Celiac disease
• Crohn’s disease
• Diverticulitis
• Gastroenteritis
• Infectious diarrhea/traveler’s diarrhea
• Campylobacter
• Cryptosporidium
• Cyclospora infections
• Enterotoxigenic Escherichia coli
• Giardia lamblia
• Isospora belli
• Microsporidia
• Plesiomonas shigelloides
• Rotavirus
• Salmonellosis
• Shigella
• Irritable bowel syndrome
• Ischemic bowel disease
• Malabsorption syndrome
• Microbial foodborne disease
• Psychiatric disease
• Psychosocial/psychological disorders
• Ulcerative colitis
TisdaleC38_738-759 1/12/10 3:40 PM Page 746
746 SECTION VIII • Drug-Induced Gastrointestinal Diseases
TABLE 38–5 Risk Factors for Drug-Induced
Diarrhea
• Age (pediatric and elderly)
• Diet (high-fat, high-fiber)
• Female sex
• Malnutrition
• Pain
• Poor/unsanitary conditions
or more of the general risk factors are present or if
multiple agents known to cause diarrhea are used
concomitantly. Furthermore, since changes in
bowel function or a developing GI tract put the
elderly and infants at increased risk for diarrhea,
health care providers must recognize that the
potential for drug-induced diarrhea is increased in
these populations as well.
MORBIDITY AND MORTALITY
The morbidity and mortality of drug-induced diar-
rhea is unknown. Severe diarrhea may result in
dehydration, electrolyte abnormalities, and shock,
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-
plications secondary to the use of irinotecan, fluo-
rouracil, and leucovorin in cancer patients.327,328
PREVENTION
Techniques for decreasing the risk of drug-induced
diarrhea are listed in Table 38–6. Although proper
diet and adequate fluid intake should be encour-
aged in all individuals, implementing specific pre-
ventive measures in all patients receiving a drug
with the potential to induce diarrhea may be
overzealous. It is more effective for health care
providers to implement preventive measures in
patients with a history of intolerance to medica-
tions or in patients receiving medications associat-
ed with a high incidence of diarrhea. Whenever
possible, health care providers should attempt to
minimize drug-induced diarrhea in their patients
by avoiding the use of medications with high sor-
bitol content or high tonicity,352 using alternative
medications with lower incidences of causing diar-
rhea, using low doses and slowly increasing the
dose of drugs known to cause diarrhea, and judi-
ciously prescribing antibiotics.
TABLE 38–6 Approaches to Help Prevent Drug-
Induced Diarrhea
• Adjust dosage to patient-specific parameters (e.g.,
age, weight, renal/hepatic function).
• Avoid foods with artificial sweeteners (e.g., sorbitol,
mannitol, fructose).
• Encourage fluid and proper diet.
• Encourage rational antimicrobial use; prescribe
antibiotics only when necessary; reserve broad-spec-
trum antibiotics where possible.
• Identify any drug intolerance or allergy previously
experienced.
• Identify liquid medications with high-sorbitol content
and substitute the tablet/capsule form when possible.
• Implement probiotic therapy (further investigation
necessary).
• Instruct patient to eat low-residual diet (e.g. bananas,
rice, applesauce, toast).
• Instruct patients to consume low-fat meals (e.g., with
orlistat).
• Instruct patients to eat frequent, small meals.
• Instruct patients to take medication with meals (if
not contraindicated).
• Progressively increase dose (if able).
• Use alternative medications with a lower risk of diar-
rhea when available.
In addition to general measures, drug-specific
preventive measures are sometimes available.
Patients prescribed orlistat may decrease the inci-
dence of diarrhea by consuming low-fat meals.
Patients experiencing GI cramping and diarrhea
associated with iron therapy or multivitamins
may benefit from taking these preparations with
meals. Smaller, more frequent meals may be help-
ful in patients with chemotherapy-induced diar-
rhea.
Probiotics have been investigated for the pre-
vention of AAD.353-356 A meta-analysis of nine ran-
domized, double-blind, placebo-controlled studies
found probiotics to be effective for the prevention,
but not treatment, of antibiotic-induced diar-
rhea.353 While these biologic agents may have a
place in therapy, larger trials and further investiga-
tion are needed before their routine use can be rec-
ommended.
MANAGEMENT
Approximately 90% of cases of acute diarrhea
require no intervention and are self-limiting.342
Drug-induced diarrhea usually spontaneously
TisdaleC38_738-759 1/12/10 3:40 PM Page 747

CHAPTER 38 • Diarrhea 747

resolves within a few days after withdrawal of the
drug and, in some cases, resolves even with contin-
ued use of the causative agent.306
When diarrhea persists, identification of the
offending agent is imperative to direct appropriate
therapy. Patients should be asked specifically
about new medications, including antibiotics
taken within the previous 4 weeks, any nonpre-
scription medications, herbal medications, illicit
drugs, alcohol, and caffeine. The content of sor-
bitol or other sugar substitutes in liquid medica-
tions or “sugar-free” formulations, as well as the
tonicity, usually found in the product labeling,
should be identified.
Whenever possible, the culprit drug should be
discontinued or changed to an agent less likely to
cause diarrhea. Solid oral dosage forms may be con-
sidered when sorbitol-containing liquid medica-
tions or high-tonicity formulations are associated
with diarrhea. Another option, if a formulation
change is not feasible, is to dilute the liquid med-
ication with water. When therapy with the offend-
ing agent must be continued, some of the
preventive measures described in Table 38–6 may
be helpful. Antidiarrheal medications should gen-
erally not be thought of as first-line therapy for
drug-induced diarrhea; however, if the culprit drug
cannot be changed or discontinued and preventive
measures do not resolve the diarrhea, antidiarrheal
drugs may be used.
Patients with chemotherapy-induced diarrhea
are a population in which antidiarrheal medica-
tions may be indicated as first-line therapy, espe-
cially in situations in which it would be
detrimental to discontinue or lower the dose of the
culprit chemotherapeutic agent. CTID has been
recognized as a severe and life-threatening compli-
cation for which vigilant monitoring and aggres-
sive therapy is warranted.324,325 An expert multidis-
ciplinary panel developed guidelines for the
treatment of CTID in 2000, and even more aggres-
sive recommendations were published in
2004.324,325 Patients with uncomplicated, grade 1 or
2 CTID (Table 38–7) should be treated with lop-
eramide 4 mg initially followed by 2 mg every 4
hours (or after every unformed stool). Patients
should be reassessed after 12 to 24 hours, and, if
diarrhea persists, the loperamide dose should be
increased to 2 mg every 2 hours and therapy with
an oral antibiotic (see below) initiated. For patients
with unresolved diarrhea after an additional 12- to
24-hour period, loperamide should be discontin-
ued and octreotide 100 to 150 mcg given subcuta-
neously three times daily. The dose may be
increased up to 500 mcg three times daily as
required based on the patient’s response.
Patients presenting with grade 3 or 4 CTID
should be admitted to the hospital and given intra-
venous fluids and antibiotics (see below).
Octreotide in subcutaneous doses as outlined
above or intravenously in a dose of 25 to 50 mcg
per hour should be administered. Cytotoxic
chemotherapy should be discontinued until all
symptoms have resolved; afterward, chemotherapy
should be at reinstituted at reduced dosages.
Oral antibiotics are used in CTID to prevent
superinfections from widespread necrosis of crypt
stem cells, especially in patients with immunosup-
pression or neutropenia. Superinfections can wors-
en diarrhea via direct secretory effects on the
intestinal mucosa and destruction of the intestinal
epithelium. Antibiotic therapy should be targeted
at opportunistic pathogens, including C. diff,
Clostridium perfringens, Bacillus cereus, Giardia lam-

TABLE 38–7 Criteria for Grading Severity of Diarrhea324,3256

Grade 1 Grade 2 Grade 3 Grade 4
Patients without Increase of Increase of Increase of ≥7 >10 stools/day.
a colostomy <4 stools/day over 4–6 stools/day stools/day. Grossly bloody
pretreatment. or nocturnal stools. Severe cramping diarrhea and need for
No other symptoms Moderate cramping, and incontinence, parenteral support.
not interfering with interfering with
normal activity. daily activities.
Patients with Mild increase in Moderate increase Severe increase Physiologic
a colostomy loose, watery in loose, watery in loose, watery consequences
colostomy output colostomy output colostomy output requiring intensive
compared with compared with compared with care; hemodynamic
pretreatment. pretreatment, but pretreatment, collapse.
not interfering with interfering with
normal activity. normal activity.
TisdaleC38_738-759 1/12/10 3:40 PM Page 748
748 SECTION VIII • Drug-Induced Gastrointestinal Diseases
blia, Cryptosporidium, Salmonella, Shigella, and
Campylobacter and guided by local patterns of sen-
sitivity and resistance.325
Oral metronidazole or vancomycin should be
used to treat patients with C. diff and resulting
CDAD. Metronidazole is considered first-line ther-
apy, and it should be given orally in doses of 250
mg four times a day or 500 mg three times a day for
7 to 10 days. Although oral metronidazole is pre-
ferred, intravenous metronidazole may be used
when the oral route is not available. Vancomycin
may be used as a second-line agent or as a first-line
agent in severe disease and is given orally in doses
of 125 to 500 mg four times daily.330-333
Intravenous vancomycin is not indicated in treat-
ment of CDAD. Rifampin has been used alone and
in combination with oral metronidazole but has
lost favor after a study demonstrating increased
mortality in patients receiving the combination of
rifampin and metronidazole as compared with
metronidazole alone.357 Other antibiotic agents
that have been used to treat CDAD include rifax-
imin, an antibiotic similar to rifampin but lacking
the GI absorption (making it a safer treatment) and
nitazoxanide, a synthetic antibiotic and antipara-
sitic. Both antibiotics are considered as adjunctive
treatment in recurrent C. diff infections. Rifaximin
is administered orally at 400 to 800 mg two to
three times daily and nitazoxanide, also given oral-
ly, is administered at 500 mg twice daily.
Additional antibiotics under investigation for the
treatment of CDAD include ramoplanin,
teicoplanin, and oritavancin.358
Treatment directed at binding the C. diff toxin
has included use of the bile acid–binding resin
cholestyramine. Studies, however, failed to show a
high success rate with cholestyramine, and it has
been relegated to adjunct treatment status for
patients who have no response to antibiotics.
Cholestyramine is administered at 4 g three to four
times a day. If given with vancomycin, administra-
tion should be separated by 2 hours.358
Intravenous immunoglobulin (IVIG) has been
used to bolster the immune response to C. diff tox-
ins.358 Although case reports have described its
effectiveness randomized trials have not been con-
ducted. Smaller studies have reported 100% and
60% response rates to IVIG in children and adults,
respectively, with recurrent C. diff infections.359,360
The usual dosing regimen of IVIG is 300 to 500
mg/kg daily until resolution or to a maximum of
six doses. IVIG is reserved for patients as an
adjunct to antibiotic therapy in severe refractory or
recurrent C. diff infections.358
Probiotics have also been studied for the treat-
ment of diarrhea, specifically treatment of infectious
diarrhea, including CDAD. A meta-analysis361 evalu-
ating studies using probiotics for CDAD treatment
showed a significant therapeutic benefit; however,
the Cochrane Review362 suggested only a modest ben-
efit with Saccharomyces boulardii when this probiotic
was used as an adjunct to antibiotics. Lactobacillus
rhamnosus GG and Lactobacillus plantarum did not
appear to provide any benefit.362 The Cochrane
Review concluded that evidence is insufficient to rec-
ommend probiotic therapy as an adjunct to antibiot-
ic therapy and that no evidence supports the use of
probiotics alone in the treatment of CDAD.362
In patients with CDAD, antidiarrheal medica-
tions that inhibit peristalsis (e.g., diphenoxylate)
are contraindicated, since these agents may pro-
long the course of illness and have been associated
with the serious complication of toxic megacolon.
Agents such as bismuth subsalicylate are preferred
in CDAD if antidiarrheal treatment is necessary.
The most common complication of severe diar-
rhea is dehydration. Patients with mild or moder-
ate dehydration can nearly always be rehydrated
with oral rehydration solution (ORS). An appropri-
ate ORS contains sodium, potassium, chloride, cit-
rate, and glucose to address electrolyte and
bicarbonate losses.363 The rehydration volume for
mildly dehydrated patients is approximately 50
mL/kg and approximately 75 mL/kg for those with
moderate dehydration. Additional volumes may be
necessary to account for continuing stool losses. 363
Intravenous fluid is recommended for patients
with severe dehydration or when oral rehydration
is contraindicated. Volumes of 100 mL per kilo-
gram of body weight or more may be required for
rehydration. Rapid replacement of fluid and elec-
trolyte losses is necessary to prevent shock and sub-
sequent death. A poly-electrolyte solution such as
Ringer’s lactate is considered appropriate for this
purpose. Normal saline is a poorer choice for rehy-
dration in these patients because it does not correct
the acidosis or hypokalemia that may result from
severe diarrhea.363
INFORMATION FOR PATIENTS
Patients who are prescribed drugs that may cause
clinically relevant diarrhea should be warned of
the potential for this adverse effect prior to the ini-
tiation of therapy. To help anticipate and avoid
complications, patients should always be carefully
questioned regarding any adverse drug reactions
previously experienced.
Adequate fluid intake and a proper diet should
be recommended for any patient who might expe-
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-
bitol or mannitol sweeteners. Patients at risk for
drug-induced diarrhea should be cautioned to
avoid or at least reduce the consumption of alco-
hol, which may itself cause diarrhea. Patients with
drug-induced diarrhea should take medication
with food if not contraindicated. If the patient is
receiving orlistat, consuming low-fat meals is
advised.
Patients should be aware that most inci-
dences of drug-induced diarrhea are self-limiting
and resolve within a few days. However, if symp-
toms are chronic or severe (e.g., presence of
blood, existence of fever, excruciating pain), the
patient should notify the health care provider
immediately.
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C H A P T E R 39
Constipation
C onstipation is a common gastrointestinal dis-
order and is frequently drug-induced. Signs
and symptoms vary over a wide range.
Constipation may be relatively mild and simply
interfere to some extent with a patient’s quality of
life, or it can be become severe. Constipation can
cause a patient to discontinue critical drug therapy
and can even lead to life-threatening situations. All
people, whether healthy or ill, experience symp-
toms of constipation from time to time, making
the identification of drug-induced constipation
challenging. In addition, there can be significant
interindividual variation among both patients and
health professionals regarding what actually con-
stitutes constipation.
CAUSATIVE AGENTS
Commonly used drugs known to be associated
with a 10% or greater incidence of causing con-
stipation are listed in Table 39–1.1-85 This listing
should not be considered exhaustive, however,
since constipation is a common adverse effect of
a large number of drugs. Drugs with anticholin-
ergic effects, including antidepressants and
antipsychotics and neurally active agents, espe-
cially the opiate drugs, account for the majority
of cases of drug-induced constipation.
Commonly prescribed drugs with lower inci-
dences of drug-induced constipation include
anticonvulsants, antihistamines, calcium chan-
nel blockers, diuretics, nonsteroidal antiinflam-
matory drugs, vinca alkaloids, calcium
supplements and aluminum-containing
antacids. 86-97 Herbal medications, including
chondroitin sulfate, glucosamine sulfate, echi-
760
Jane M. Gervasio
nacea, and saw palmetto have also been reported
to cause constipation.98-111
EPIDEMIOLOGY
Constipation is the most common digestive symp-
tom in the United States (U.S.), affecting 4.53 mil-
lion people per year and accounting for 2.5 million
physician visits annually.112-115 This corresponds to
a prevalence of 1.2% in the general popula-
tion.113,114 Approximately 28% of otherwise
healthy individuals report one or more symptoms
of chronic constipation.112 Constipation is three
times more common in women than in men,
shows a marked increase after the age of 65 years,
and appears to affect nonwhites 1.3 times more fre-
quently than whites. In addition, constipation is
more frequently reported in people living in the
South than elsewhere in the U.S. and in people
with lower income or less education.115 While
drugs are well recognized as a cause of constipa-
tion, the incidence of drug-induced constipation is
unknown.
MECHANISMS
Mechanisms of constipation are broadly separated
into two categories: anatomic and functional.
Anatomic constipation (e.g., from tumor or volvu-
lus) is not drug-related. Functional constipation
results from abnormalities in colonic neural regula-
tion or motor function. Drug-induced constipation
is usually associated with these types of functional
abnormalities.87 Normally, elimination from the
colon occurs within 4 days. However, colonic dys-
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CHAPTER 39 • Constipation 761

TABLE 39–1 Agents Implicated in Drug-Induced Constipation

Drug Incidence Level of Evidence
(see page xii for explanation)
2
Alosetron 32% A
Aripiprazole3-5 5–13% A
Atomoxetine6 3–10% A
Bicalutamide7-9 22% A
Bortezomib10-13 30–43% B
Bupropion14,15 5–10% A
Cholestyramine16,17 20% A
Clonidine18,19 1–10% A
Clozapine20,21 14% A
Codeine22-26 10–21% A
Colesevelam27 8.7–11% A
Colestipol28,29 10% A
Dalbavancin30 18.2% A
Decitabine31 35% A
31,32
Doxorubicin Hydrochloride liposome 31% A
Duloxetine33,34 5–15% A
Fentanyl35-37 8–26% A
Fluoxetine38,39 4–17.9% A
Granisetron40-43 3–18% A
Guanfacine44 10–15% A
Hydrocodone26,45 10–29% A
Hydromorphone46 29% A
Imipramine47,48 20% A
Iron preparations49,50 15.6% A
Ixabepilone51 16–22% A
Levomethadyl52,53 20% A
Methadone52,53 20% A
Meclobemide14,47 10–13% A
Morphine34-36,53,54 5.1–57% A
Nilotinib55,56 18–21% B
Olanzapine20,21 5–15% A
Oxycodone46,53,54,57-60 6.1–23% A
Oxymorphone46,57,60,61 4.1–27.6% A
Paroxetine14,48,62 18–25% A
Quetiapine63,64 8–10% A
Reboxetine65,66 10–16.8% A
Satraplatin67,68 18.5–47% B
Sibutramine69 11.5% A
Solifenacin70,71 13–16% A
Sorafenib72,73 14–15% A
(Continued)
TisdaleC39_760-770 1/12/10 3:41 PM Page 762
762 SECTION VIII • Drug-Induced Gastrointestinal Diseases
TABLE 39–1 Agents Implicated in Drug-Induced Constipation
Drug
Temsirolimus74
Thalidomide75-77
Venlafaxine14,78
Verapamil79-82
Vorinostat83
Zoledronic acid84,85
function increases colonic transit time.111 Under
these circumstances, colon contents may not be
expelled for 10 days or longer.116 Drug-induced
constipation may be multifactorial, and common
mechanisms are listed in Table 39–2.
CLINICAL PRESENTATION AND
DIFFERENTIAL DIAGNOSIS
Constipation may be defined as hard stools, fewer
than three bowel movements per week, or inabil-
ity to expel stool. Patients may report too infre-
quent defecation, stools too hard or too small,
and incomplete rectal evacuation. Discomfort,
pain, and straining may also accompany poor
defecation. The American Gastroenterological
Association, in their Medical Position Statement:
Guidelines on Constipation, state that practition-
ers must also consider straining, stools that are
excessively hard, unproductive urges, infrequency
and a feeling of incomplete evacuation when
evaluating patients for constipation.117 Signs and
symptoms associated with drug-induced constipa-
tion are presented in Table 39–3.
Constipation may be acute or chronic.89 The
Rome III diagnostic criteria for functional constipa-
TABLE 39–2 Mechanisms of Drug-Induced Constipation
Drug
Opioids and related compounds
Drugs with anticholinergic properties
(examples include: antihistamines,
antidepressants, antiparkinsonian agents,
antispasmodics, and antipsychotics)
(Continued)
Incidence Level of Evidence
20% A
54.9% A
15% A
7.3–42% A
15.1% B
6–31% B
tion are met when two or more of the following are
present: straining during ≥25% of defecations,
lumpy or hard stools in ≥25% of defecations, sen-
sation of incomplete evacuation in ≥25% of defeca-
tions, sensation of anorectal obstruction/blockage
in ≥25% of defecations, manual maneuver to facil-
itate defecation (digital manipulations, pelvic floor
support) is required in ≥25% of defecations, less
than three evacuations per week, or loose stools are
rarely present without use of laxatives.118,119
Patients must experience these symptoms for at
least 3 months, and onset must occur ≥6 months
prior to diagnosis.118,119 Chronic constipation in
patients receiving long-term opioid therapy is
termed “opioid-induced bowel dysfunction” and is
often diagnosed in oncology patients. A subset of
these patients presenting with worsening, severe
constipation, abdominal pain and distention, nau-
sea, and vomiting from large, chronic doses of nar-
cotics are said to have narcotic bowel syndrome
(NBS).86 NBS is due to a prolonged intestinal tran-
sit time combined with increased electrolyte and
water absorption and an impaired defecation
response and/or increased anal sphincter tone.
Drug-induced constipation rarely requires hos-
pitalization unless the complications of bowel
obstruction or perforation occur. Patients with
Mechanism
Prolongation of intestinal transient time (reduced peristalsis)
Increased anal sphincter tone
Increased electrolyte and water reabsorption
Impaired defecation response
Parasympatholytic actions affecting innervation of many regions of
the gastrointestinal tract
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CHAPTER 39 • Constipation 763

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
764 SECTION VIII • Drug-Induced Gastrointestinal Diseases
MORBIDITY AND MORTALITY
Constipation interferes with daily activity, affect-
ing mood (44%), mobility (37%), work (42%),
recreation (47%), and enjoyment of life
(58%).113,114 Constipation associated with opioid
use has been reported in as many as 50% to 60% of
cancer patients admitted to palliative-care units.86
Severe constipation may result in small bowel
obstruction, impaction, and gastrointestinal perfo-
ration requiring hospitalization and possible surgi-
cal intervention.119
The estimated cost of ambulatory and inpa-
tient care for constipation in the U.S. was $235
million in 2001. Laxatives, the mainstay of treat-
ment for constipation, are prescribed for more
than 3 million people per year with an estimated
cost of over $800 million.89,111
PREVENTION
Techniques for decreasing the risk of drug-induced
constipation are listed in Table 39–6. Patients may
decrease their risk by staying active, maintaining a
routine bowel habit schedule, never ignoring the
urge to defecate, drinking plenty of fluids and eat-
ing a balanced, high-fiber diet.87,89,113,116,118,119
Health care providers may further decrease or pre-
vent drug-induced constipation by adjusting doses
of causative agents with respect to specific patient
parameters, using the lowest possible dose of the
drug to effectively treat the patient, slowly escalat-
TABLE 39–6 Approaches to Help Prevent Drug-
Induced Constipation
• Adjust dosage to patient specific parameters (e.g. age,
weight, renal/hepatic function)
• Employ an alternative route of administration
• Encourage activity (exercise, especially aerobic)
• Encourage fluids and high-fiber diet (25–35 g/day for
adults)
• Encourage patients to avoid postponing defecation
• Identify any intolerance already experienced to drugs
• Instruct patients to add a bulk-forming agent (e.g.,
psyllium), if necessary
• Maintain a routine bowel habit schedule
• Rotate among opioid medications, if possible
• Slowly escalate doses to allow for better patient tol-
erance, if possible
• Use alternative medications with a lower risk of con-
stipation, if possible
• Use the lowest possible dose
ing the doses of medications to allow for better tol-
erance and using alternative medications with a
lower risk of constipation. Additional techniques
may be used in patients receiving opioids, includ-
ing rotating among opioids and alternating routes
of administration. Because opioid cross-tolerance is
incomplete, switching to a lower equianalgesic
dose of a different opioid may allow for continued
analgesia with the potential for a lower likelihood
of constipation. Opioids such as fentanyl are asso-
ciated with decreased constipation. In addition,
alternating oral delivery of opioids with transder-
mal or intravenous delivery may help alleviate
constipation.86
MANAGEMENT
Whenever possible and appropriate, the culprit
drug should be discontinued and an alternative
agent less likely to cause constipation substituted.
When that is not possible, lowering the dose of the
drug can sometimes help relieve symptoms.
Lifestyle modifications, including dietary changes
(increasing consumption of food fiber, fruits, and
vegetables and decreasing consumption of dairy
products such as cheese), increasing fluid con-
sumption, increasing physical activity, especially
aerobic exercise, and adding additional fiber (e.g.,
psyllium) can sometimes also be helpful.
Pharmacotherapy may be implemented if
dietary and lifestyle modifications do not relieve
the constipation. Table 39–7 lists available agents,
dosages, and mechanisms of action. Bulk-forming
agents, emollient laxatives, osmotic laxatives, and
saline laxatives modify the characteristics of stool
to increase bulk, decrease consistency, or facilitate
passage through the digestive tract and anus.
Stimulant laxatives cause propulsive motor con-
tractions that may decrease transit time and facili-
tate evacuation of stool from the rectal
vault.87,119-121
Bulk-forming agents and osmotic laxatives
are generally used first, however, stimulant laxa-
tives may be used when patients do not respond
adequately to bulk or osmotic laxatives given
alone. Stimulant laxatives can be combined with
bulk or osmotic laxatives given in sufficient
amounts to soften the stool, or they can be used
alone, based on clinical circumstances. The dose
of stimulant laxatives should be titrated to
effect. Though rare, stimulant laxatives may
cause abdominal cramping and should be dis-
continued if the patient experiences this compli-
cation.87,116-121
Exaggerated concerns regarding stimulant lax-
ative abuse have led to hesitation on the part of
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CHAPTER 39 • Constipation 765

TABLE 39–7 Drugs Used to Treat Drug-Induced Constipation116-118

Agent Generic Name Brand Name Dosages Mechanism of Action
Fiber, bulk-forming Methylcellulose Citrucel™ 1 tsp up to 3 times daily Increase stool weight
laxatives Calcium polycarbophil FiberCon™ 2–4 tablets daily Modify stool
Psyllium Metamucil™ 1 tsp up to 3 times daily consistency
Emollient Docusate sodium Colace™ 100 mg twice daily Surfactant properties
laxatives Soften stool
Stimulate net
intestinal secretion
Osmotic laxatives Glycerin Daily as needed Attract and retain
Lactulose Chronulac™ 15-30 mL 1–2 times daily water in intestinal
Phosphate salts Fleet enema™ 1 unit/enema daily lumen
Polyethylene glycol Golytely, Miralax™ 8–32 oz daily Increases intraluminal
pressure
Exert an osmotic
effect
Stimulate colonic
motility (lactulose)
Saline laxative Magnesium salts Milk of magnesia™ 15–30 mL 1–2 times daily Fluid osmotically
drawn into small-
bowel lumen; chole-
cystokinin-stimulated
Lubricant laxatives Mineral oil 15-45 mL once Facilitates transit
by coating feces
Stimulants Bisacodyl Dulcolax™ 10 mg rectally 3 times/wk Stimulate intestinal
Anthraquinones Senokot™ 2–4 tablets 1–2 times daily motor activity
(senna, cascara) Stimulate net
intestinal secretion
Increase stool
volume/weight
Induces urge to
defecate
Nonselective Naloxone Narcan™ Not FDA-approved Opioid receptor
opioid antagonist Nalmefene Revex™ for treatment of antagonist in the
constipation gastrointestinal tract.
Crosses the blood–
brain barrier and may
reverse opioid
analgesic effects
Selective opioid Methylnaltrexone Relistor™ Not FDA-approved Opioid receptor
antagonist (under Alvimopam Entereg™ for treatment of antagonist in the
investigation for constipation gastrointestinal tract.
treatment of Neither crosses the
opioid-induced blood–brain barrier
constipation) nor reverses opioid
analgesic effects
FDA = United States Food and Drug Administration

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
766 SECTION VIII • Drug-Induced Gastrointestinal Diseases
antagonists have been successfully used, though
their place in therapy is still being debated.
Nonselective opioid receptor antagonists, such as
naloxone and nalmefene, reverse both peripheral
and central opioid effects, thereby relieving symp-
toms of opioid-induced constipation but may also
reverse the intended opioid analgesic effects.123,124
The bioavailability of oral naloxone is approxi-
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-
temic opioid effects, as long as hepatic first-pass
capacity is not exceeded.123 Low oral doses of
naloxone (9–36 mg) have been successful in reliev-
ing symptoms of constipation, but appropriate oral
starting doses, individual titration of the dose, and
clinical vigilance is necessary to avoid opioid with-
drawal symptoms.124 Because its effectiveness is
variable and its use poses the risk of opioid rever-
sal, the routine use of naloxone for the treatment
of opioid-induced constipation is not recommend-
ed. However, the drug may be helpful if conven-
tional treatments fail.
Two selective opioid receptor antagonists,
methylnaltrexone and alvimopan (currently not
approved for use in the U.S. to treat opioid-induced
constipation), are being investigated for their use in
restoring relaxation of the gastrointestinal tract
while avoiding reversal of analgesia.125-133
Methylnaltrexone is a derivative of the opioid antag-
onist naltrexone. The additional methyl group
results in high selectivity for peripheral opioid recep-
tors, and the drug does not cross the blood–brain
barrier. Some studies have reported that methylnal-
trexone is useful in relieving opioid-induced side
effects while not affecting opioid analgesia.125-129
Another selective opioid receptor antagonist,
alvimopan, has been reported to reverse the opi-
oid-induced slowing of the gastrointestinal-tract
transit time, relieving constipation without antag-
onizing the analgesic effect of opioid analgesics or
precipitating withdrawal in opioid-dependent
patients.130-133
Patients presenting with chronic constipation,
severe pain, hematochezia, or fever should be eval-
uated for small-bowel obstruction, impaction, or
gastrointestinal perforation.
INFORMATION FOR PATIENTS
Fluids and a proper diet, including fiber consump-
tion of 25 g/day, should be recommended for any
patient at risk for drug-induced constipation.
Patients should be instructed to maintain regular
bowel habits and to not ignore the urge to defe-
cate. Increased activity and exercise should be
encouraged. Laxatives may be necessary if and
when these lifestyle and dietary measures do not
resolve constipation. If symptoms of abdominal
distention, severe pain, or fever occur, the patient
should notify a health care provider immediately
for evaluation and assistance.
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TisdaleC40_771-799 1/12/10 3:42 PM Page 771
CHAPTER 40
Hepatic and
Cholestatic Diseases
T he liver plays a major role in metabolizing and
removing drugs and other chemicals from the
body and is susceptible to toxicity from these
agents. Many drugs taken in overdose cause hepat-
ic and cholestatic (hepatocholestatic) injury and
some cause damage even when used in normal
therapeutic doses. Herbal agents, illicit drugs, and
environmental chemicals can also cause hepato-
toxicity. Although medicinal agents are the focus
of this chapter, herbal remedies, illicit drugs, and
environmental chemicals are discussed when
appropriate.
CAUSATIVE AGENTS
Agents implicated as the cause of drug-induced
hepatic and cholestatic diseases are listed in Table
40–1.1-41 Over 1,100 medicinal agents, herbal reme-
dies, illicit drugs, and environmental chemicals are
recognized as causing hepatocholestatic injury.
Drug-induced hepatocholestatic diseases are best
categorized according to the predominant patho-
logic pattern of injury: hepatitis, which is also
termed hepatocellular or cytotoxic (necrosis, apop-
tosis, steatosis); cholestatic; vascular; and neoplas-
tic (Table 40–2).1-19,42-48 Each type of injury may be
the result of short- or long-term exposure, and
injuries may be mixed (e.g., hepatocellular and
cholestatic or hepatocholestatic).
EPIDEMIOLOGY
The incidence of drug-induced hepatocholestatic
disease is increasing, largely because of the growing
number of agents that have been introduced into
Robert MacLaren
clinical practice. Hepatotoxicity is the main reason
for postmarketing drug withdrawal.49 The annual
incidence of drug-induced hepatotoxicity ranges
between 1.27 and 40.6 cases per 100,000 per-
sons.50-52 Worldwide, the overall frequency of drug-
induced liver diseases as a percentage of all drug
reactions is 3% to 9%.53 Among hospitalized
patients, the incidence of drug-induced hepatotox-
icity is between 0.7% and 1.4%.54
Although the frequency of drug-induced liver
injury for any particular medication varies from 1
in 1,000 to 1 in 100,000 patients,3 approximately
10% of cases of mild–to-moderate alterations of
hepatic biochemical/laboratory profiles are attrib-
uted to medicinal agents.54 In patients >50 years of
age, 40% of cases of mild-to-moderate hepatic
injury are due to medicinal agents.54 About 2,000
cases of fulminant (end-stage) hepatic failure occur
each year in the United States, 50% of which are
due to medicinal agents.55 Idiosyncratic reactions
represent about 15% of all cases of drug-induced
heptotoxicity.56-58 In the geriatric population,
medicinal agents are responsible for 20% of cases
of jaundice and 25% of cases of fulminant hepatic
failure.59
MECHANISMS
The purpose of hepatic biotransformation is to pro-
duce polarized metabolites that are more
hydrophilic so that they may enter the circulation
and be excreted in the urine or be directly secreted
in the bile. The sinusoids of the liver are lined with
endothelial cells that contain open pores (fenestra-
tions) through which most blood proteins actively
or passively diffuse into the hepatocyte.60 The
771
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772 SECTION VIII • Drug-Induced Gastrointestinal Diseases

TABLE 40–1 Agents Implicated in Drug-Induced Hepatic and Cholestatic Diseases

Drug Incidence Level of Evidence
(see page xii for explanation)

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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CHAPTER 40 • Hepatic and Cholestatic Diseases 773

TABLE 40–1 Agents Implicated in Drug-Induced Hepatic and Cholestatic Diseases (Continued)

Drug Incidence Level of Evidence

Griseofulvin17,18 NK C
Hydroxychloroquine1-14,21,24,25 NK C
Isoniazid1-14,20,22,24-26 1% B
NNRTIs1-16,20,22-25,27 <15% B
NRTIs1-16,20,22-25,27 <16% A
Nitrofurantoin1-14,17,18,24,25 0.03% B
Pentamidine1-14,24,25 NK C
Protease inhibitors1-16,20,22-25,27 <3% B
Pyrazinamide1-14,20,22,24-26 NK C
Ribavirin1,21 NK C
Rifampin1-14,17,18,20,22,24-26 1.4% B
Sulfonamides1-14,17,18,24,25 NK C
Telithromycin1-14,20,24,25 NK C
Terbinafine1-14,17,18,24,25 0.02% C
Tetracyclines1-18,20,24,25 NK B
Thiabendazole17,18 NK C
CARDIOVASCULAR AGENTS
ACE inhibitors1-14,17,18,21,28 NK C
Ajmaline17,18 NK C
Aprindine17,18 NK C
Amiodarone1-16,20-22,28 0.6–3% B
Angiotensin-receptor blockers1-14,17,18,21,28 NK C
␤-Blockers1-18,28 NK C
Calcium-channel blockers1-18,28 NK C
Disopyramide17,18,28 NK C
Hydralazine1-14,17,18,28 NK C
Loop diuretics1-14,28 NK C
Methyldopa1-14,17,18,28 <0.1% B
Procainamide17,18,28 NK C
Propafenone17,18,28 NK C
Quinidine1-14,17,18,28 2% B
Spironolactone1-14,28 NK C
Thiazide diuretics17,18,28 NK C
CHEMOTHERAPEUTIC AGENTS
Actinomycin1-14 NK C
Aminoglutethimide17,18 NK C
Amsacrine1-14,17,18 NK C
Asparaginase1-16 NK C
BCNU/CCNU1-14 NK C
Bleomycin1-14 NK C
Bortezomib20 NK C
(Continued)
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774 SECTION VIII • Drug-Induced Gastrointestinal Diseases

TABLE 40–1 Agents Implicated in Drug-Induced Hepatic and Cholestatic Diseases (Continued)

Drug Incidence Level of Evidence

Busulfan1-14 NK C
Capecitabine1-14 NK C
Carboplatin1-14 NK C
Carmustine1-14 NK C
Chlorambucil1-14 NK C
Cisplatin1-14 NK C
Cyclophosphamide1-14 NK C
Cyclosporine1-14,17,18,22 NK C
Cyproterone acetate1-14,21 NK C
Cytarabine1-14,17,18 NK C
Dacarbazine1-14 NK C
Daunorubicin1-14 NK C
Doxorubicin1-14 NK C
Erlotinib20 NK C
Etoposide1-14 NK C
Floxuridine17,18 NK C
Fluorouracil20 NK C
Flutamide1-14,20,21 NK C
Gemcitabine1-14,17,18 NK C
Hydroxyurea1-14 NK C
Imatinib mesylate1-14,20 NK C
Interleukin-217,18 NK C
Mercaptopurine1-14,17,18,20,23 NK C
Mitomycin1-16 NK C
Procarbazine1-14 NK C
Riluzole1-16 NK C
Streptozocin1-14 NK C
Tamoxifen15-18,21,22 7% B
Temozolomide20 NK C
Teniposide1-14 NK C
Thalidomide21 NK C
Thioguanine1-14,21,22 NK C
Thiotepa1-14 NK C
Topotecan1-14 NK C
Toremifene1-14 NK C
Vinca alkaloids1-14 NK C
ENDOCRINE AGENTS
Alendronate20 NK C
Androgens17,18 NK C
Carbimazole21 NK C
(Continued)
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CHAPTER 40 • Hepatic and Cholestatic Diseases 775

TABLE 40–1 Agents Implicated in Drug-Induced Hepatic and Cholestatic Diseases (Continued)

Drug Incidence Level of Evidence

Corticosteroids15,16 NK C
Cyclofenil1-14 NK C
Danazol1-14 NK C
Fenofibrate1-14,21,22,28,32 NK C
Gemfibrozil21 NK C
Levothyroxine20 NK C
Metformin1-14,17,18,28,32 NK C
Methimazole17,18 NK C
Niacin1-14,20,21,28,32 NK C
Orlistat1-14,28 NK C
Propylthiouracil1-14,22,28 NK C
Repaglinide1-14,28 NK C
Sex steroids15-18 0.025% C
Sibutramine22 NK C
Statins1-14,17,18,23,24,28,32,33 <0.0003% B
Sulfonylureas1-14,,17,18,28,32 NK C
Thiazolidinediones1-14,20-23,28,32,34,35 NK B
Voglibose17,18 NK C
ENVIRONMENTAL CHEMICALS
Aflatoxin (found in foods such as nuts)1-16 NK C
Allyl compounds1-14 NK C
Amanitin15,16 NK C
Aniline derivatives17,18 NK C
Arsenicals17,18 NK C
Beryllium1-14 NK C
Carbon tetrachloride1-16 NK C
Chloroform15,16 NK C
Chromium15,16 NK C
Cycad nut1-14 NK C
Dichloroethylate15,16 NK C
Dimethylacetaminde1-14 NK C
Dimethylformamide1-14 NK C
Dioxane1-14 NK C
Ethionine15,16 NK C
Ethyl bromide/chloride, methyl bromide/chloride/dichloride15,16 NK C
Hexachlorethane21 NK C
Nitroaliphatic compounds1-14 NK C
Nitroaromatic compounds1-14 NK C
Orotic acid15,16 NK C
Paraquat17,18 NK C
Phosphorus1-16 NK C
(Continued)
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776 SECTION VIII • Drug-Induced Gastrointestinal Diseases

TABLE 40–1 Agents Implicated in Drug-Induced Hepatic and Cholestatic Diseases (Continued)

Drug Incidence Level of Evidence

Selenium15,16 NK C
Tannic acid15,16 NK C
Tetrachloroethylene/trichloroethylene15,16 NK C
Tripelannamine17,18 NK C
Uranium15,16 NK C
Urethane1-14 NK C
Vinyl chloride1-14 NK C
GASTROINTESTINAL AGENTS
Alverine1-14 NK C
Histamine2-receptor antagonists1-14,17,18,21 NK C
Mesalamine17,18 NK C
Octreotide1-14 NK C
p-Aminosalicylic acid1-14 NK C
Proton pump inhibitors1-14,22 NK C
Sulfasalazine1-14 NK C
GENERAL ANESTHETICS
Desflurane20,22 NK C
Enflurane1-14 NK C
Halothane1-14 0.03–0.01% B
Isoflurane1-14,21 NK C
Sevoflurane20,22 NK C
HERBAL AGENTS
Aloe vera20 NK C
␤-Carotene17,18 NK C
Black cohosh1-14,21,22,38-41 NK C
Cade oil22 NK C
Camphor1-16,38-41 NK C
Carp capsules (cyprinol) 1-14,21,38-41 NK C
Cascara sagrada17,18 NK C
Celandine17,18 NK C
Chaparral leaf1-14,17,18,38-41 NK C
Chaso1-14,38-41 NK C
Colpachi20 NK C
Comfrey38-41 NK C
Garlic21 NK C
Germander1-14,38-41 NK C
Gordoloba tea38-41 NK C
Impila1-14,38-41 NK C
Ju bu huan1-14,17,18,38-41 NK C
Kava1-14,38-41 NK C
Linghzi17,18 NK C
Lipokinetix1-14,38-41 NK C
(Continued)
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CHAPTER 40 • Hepatic and Cholestatic Diseases 777

TABLE 40–1 Agents Implicated in Drug-Induced Hepatic and Cholestatic Diseases (Continued)

Drug Incidence Level of Evidence

Lantana camara20 NK C
Ma-huang1-14,38-41 NK C
Margosa oil15,16,22 NK C
Mediterranean glue thistle1-14,38-41 NK C
Mistletoe1-14,38-41 NK C
Noni21,22 NK C
Oil of cloves1-14,38-41 NK C
Pennyroyal oil1-14,38-41 NK C
Prostata1-14,38-41 NK C
Sairei-to20 NK C
Sassafras38-41 NK C
Senna fruit22,23` NK C
Shark cartilage1-14,38-41 NK C
Shen-min21 NK C
Sho-saiko-to1-18,38-41 NK C
Skullcap38-41 NK C
Teucrium polium20 NK C
Valerian root1-14,38-41 NK C
Venencapsan15,16 NK C
ILLICIT AGENTS
Amphetamines (including MDMA)1-14 NK C
Cocaine1-16 NK C
Mushroom poisoning1-14 NK C
Phencyclidine1-14 NK C
NEUROPSYCHIATRIC AGENTS
Amantadine15,16 NK C
Barbiturates17,18 NK C
Benzodiazepines1-14 NK C
Carbamazepine1-14,17,18 0.03% B
Chlormethiazole1-14 NK C
Chlopromazine15-18 1% C
Clozapine1-14,17,18 0.001% B
Dantrolene1-14 0.5% B
Disulfiram1-14,21 NK C
Duloxetine21 NK C
Felbamate1-14 NK C
Fluphenazine17,18 NK C
Gabapentin17,18 NK C
Haloperidol17,18 NK C
Lamotrigine1-14 NK C
(Continued)
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778 SECTION VIII • Drug-Induced Gastrointestinal Diseases

TABLE 40–1 Agents Implicated in Drug-Induced Hepatic and Cholestatic Diseases (Continued)

Drug Incidence Level of Evidence

Loxapine17,18 NK C
Monoamine oxidase inhibitors1-14,29-31 NK C
Methylphenidate1-14 NK C
Molindone17,18 NK C
Nefazodone1-14,20,29-31 NK C
Olanzapine1-14,21 NK C
Pemoline1-14 NK C
Phenytoin1-14,17,18,21 0.03% B
Prochlorperazine17,18 NK C
Promazine17,18 NK C
Riluzole15,16 NK C
Risperidone17,18 NK C
Selective serotonin-reuptake inhibitors1-14,17,18,20,23,29-31 NK C
Tacrine1-16 2–25% A
Thioridazine15-18 NK C
Tolcapone1-14,20 NK B
Topiramate1-14,21 NK C
Trazodone1-14,17,18,29-31 NK C
Tricyclic antidepressants15-18,,29-31 1% C
Valproic acid1-16,21,23 NK B
Venlafaxine1-14,21,29-31 NK C
OTHERS
Allopurinol17,18 NK C
Azathioprine17,18 NK C
Bosentan1-14,22 3–7% A
Cetirizine23 NK C
Chlorpheniramine15,16 NK C
Clopidogrel1-14,21-23,28 NK C
Colchicine23 NK C
Cyclizine15,16 NK C
Cyproheptadine17,18 NK C
Ethanol15,16 NK B
Etretinate1-14 <1% B
Fenfluramine15,16 NK C
Ferrous salts1-14 NK C
Gold17,18 NK C
Infliximab21 NK C
Interferon1-14,21 NK C
Loratadine1-14 NK C
Methotrexate15,16 NK C
Montelukast1-14,37 NK C
(Continued)
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CHAPTER 40 • Hepatic and Cholestatic Diseases 779

TABLE 40–1 Agents Implicated in Drug-Induced Hepatic and Cholestatic Diseases (Continued)

Drug Incidence Level of Evidence

Parenteral lipid15,16 NK B
Penicillamine17,18 NK C
Pentoxifylline1-14,28 NK C
Probenecid1-14 NK C
Ritodrine1-14 NK C
Sirolimus22,23 NK C
Tacrolimus17,18 NK C
Terbutaline1-14 NK C
Terfenadine17,18 NK C
Ticlopidine15-18,20 NK C
Tiopronin17,18 NK C
Trimethobenzamide17,18 NK C
Vitamin A15,16 NK B
Warfarin15,16,22 NK C
Ximelagatran1-14,20 7.9% A
Zafirlukast1-14,37 NK C
ACE = angiotensin-converting enzyme; BCNU = bischloroethylnitrosourea; CCNU = 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea; MDMA
= 3,4-methylenedioxymethamphetamine; NNRTIs = nonnucleoside reverse-transcriptase inhibitors; NRTIs = nucleoside reverse-tran-
scriptase inhibitors; NK = Not Known.

enzymes responsible for converting nonpolar pathophysiologic mechanisms of drug-induced

(lipophilic) xenobiotics to polar (hydrophilic) com-
pounds are mostly attached to the endoplasmic
reticulum of hepatocytes. Reactions catalyzed by
these enzymes are described as phase 1 or phase 2.
Phase 1 reactions involve oxidation or demethyla-
tion by cytochrome P-450 (CYP) enzymes. Phase 2
reactions involve covalent binding (conjugation)
of the xenobiotic or product of phase 1 metabolism
to polar ligands such as glucuronic acid, sulfate, or
glutathione. Baseline phase 1 and 2 enzymatic
activities vary considerably within any given pop-
ulation, sometimes because of genetic polymor-
phism (e.g., CYP2D6, CYP2C19, type 2
N-acetyltransferase).54,60 Even hepatic transport
systems of drugs may be influenced by genetic
polymorphisms. Examples include import mecha-
nisms such as organic anion transport polypep-
tides, organic anion transporter 2, organic cation
transporter, and export mechanisms such as mul-
tidrug-resistant–associated proteins and bile salt
export pump.47 In addition, the metabolic activity
of many enzymes may be induced or inhibited by
xenobiotics.54,60
Although a few drugs (e.g., acetaminophen,
methotrexate) are known to cause direct hepato-
toxicity, most drug-induced hepatocholestatic
injuries are idiosyncratic. There are four complex
hepatocholestatic diseases: hepatocellular or cyto-
toxic injury, cholestasis, vascular injury, and neo-
plasms (Table 40–2).1-18,42-48 A particular agent may
cause more than one type of injury, and mecha-
nisms of injury may act concurrently or serially to
overlap.
Hepatocellular or cytotoxic injuries can be
metabolic or immune-mediated, with some degree
of overlap. Metabolic injury commonly occurs
when the drug or metabolite binds covalently to
intracellular proteins (e.g., glutathione) or deoxyri-
bonucleic acid (DNA) to disrupt cellular functions.
Metabolic mechanisms may involve the down-
stream formation of free radicals, reactive oxygen
species, or electrophilic radicals that cause oxida-
tive stress and disrupt ionic gradients, cell mem-
branes, actin, and adenosine triphosphate (ATP)
generation.1-3,42-44,60-63 Yet another mechanism of
metabolic injury involves the sensitization of the
liver cells to cytokines, such as tumor necrosis fac-
tor (TNF).1-3,42-44,60-63 Hepatocellular death from
metabolic injury may result from necrosis or apop-
tosis.1-3,42-44,60-63 Necrosis is characterized by cell
swelling and lysis, usually due to mitochondrial
dysfunction and ATP depletion.1-3,42-44,60-63
Accumulation of cytosolic ionized calcium acti-
vates nonspecific hydrolases (proteases, nucleases,
TisdaleC40_771-799 1/12/10 3:42 PM Page 780

780 SECTION VIII • Drug-Induced Gastrointestinal Diseases

TABLE 40–2 Mechanisms of Drug-Induced Hepatic and Cholestatic Diseases

Predominant Injury Agents or Class of Agents
HEPATOCELLULAR1-16,42-46
Cytotoxic ACE inhibitors (primarily captopril, enalapril, lisinopril), acetaminophen, actinomycin,
aflatoxin (found in foods such as nuts), afluzosin, alendronate, allyl compounds, aloe
vera, alverine, amiodarone, amoxicillin/ampicillin, amphetamines (including MDMA),
amphotericin (primarily lipid-based), amsacrine, angiotensin-receptor blockers (prima-
rily irbesartan, losartan), azole antifungals (primarily ketoconazole but others too),
azole antiparasitics (albendazole, mebendazole, ornidazole), ␤-blockers (primarily
propranolol, metoprolol, acebutalol, labetolol), BCNU/CCNU, benzodiazepines,
beryllium, black cohosh, bleomycin, bortezomib, bosentan, cade oil, camphor,
capecitabine, carbamazepine, carboplatin, carmustine, carp capsules (cyprinol),
caspofungin, calcium-channel blockers, carbon tetrachloride, ceterizine, chaparral
leaf, chaso, chlorambucil, chloramphenicol, chlormethiazole, cisplatin, clindamycin,
cloxacillin/nafcillin, clopidogrel, clozapine, cocaine, colchicine, colpachi, cotrimoxa-
zole, cycad nut, cyclofenil, cyclophosphamide, cyclosporine, cyproterone acetate,
cytarabine, dacarbazine, danazol, dantrolene, dapsone, desflurane, diclofenac,
daunorubicin, dimethylacetaminde, dioxane, disulfiram, doxorubicin, duloxetine,
enflurane, ertotinib, ethionamide, etodolac, etoposide, etretinate, felbamate, fenofi-
brate, ferrous salts, flutamide, fluoroquinolones (primarily ciprofloxacin, tro-
vofloxacin), flucytosine, fluorouracil, garlic, gemcitabine, germander, halothane,
hexachloroethane, histamine2-receptor antagonists, hydralazine, hydroxychloroquine,
hydroxyurea, ibuprofen, imatinib mesylate, impila, indomethacin, interferons, isoflu-
rane, isoniazid, ju bu huan, kava, lamotrigine, lantana camara, leflunamide, lipokinetix,
loop diuretics (primarily furosemide), loratadine, ma huang, monoamine oxidase
inhibitors, Mediterranean glue thistle, mercaptopurine, metformin, methyldopa,
methylphenidate, minocycline, mistletoe, mitomycin, montelukast, mushroom poi-
soning, nefazodone, niacin, nimesulide, nitroaliphatic compounds, nitroaromatic
compounds, NNRTIs (primarily nevirapine, abacavir), noni, NRTIs (primarily zidovu-
dine, didanosine, stavudine), nitrofurantoin, octreotide, oil of cloves, olanzapine, orli-
stat, oxaprozin, p-aminosalicylic acid, pemoline, pennyroyal oil, pentamidine,
pentoxifylline, phencyclidine, phenylbutazone, phenytoin, phosphorus, piroxicam,
proton pump inhibitors (primarily omeprazole, rabeprazole), probenecid, procar-
bazine, propionic acid derivatives (bromfenac, fenoprofen, ketoprofen), propylth-
iouracil, protease inhibitors (primarily ritonavir, indinavir), pyrazinamide, quinidine,
repaglinide, rifampin, riluzole, ritodrine, sairei-to, senna fruit, sevoflurane, shark carti-
lage, shen-min, sho-saiko-to, sirolimus, spironolactone, SSRIs (primarily fluoxetine,
fluvoxamine, sertraline), statins (all), streptozocin, sulfasalazine, sulfonamides, sul-
fonylureas (primarily acetohexamide, gemfibrozil, gliclazide), tacrine, telithromycin,
temozolomide, teniposide, terbinafine, terbutaline, teucrium polium, thalidomide,
thiazolidinediones (primarily pioglitazone, rosiglitazone, troglitazone), thioguanine,
thiotepa, tienilic acid, tolcapone, topiramate, topotecan, trazodone, urethane, valer-
ian root, valproic acid, venlafaxine, vinca alkoloids, ximelagatran, zafirlukast
STEATOSIS1-3,15,16
Microvesicular Aflatoxin (found in foods such as nuts), antimonial antiparasitics, asparaginase,
aspirin, camphor, cocaine, dimethylformamide, ibuprofen, margosa oil, NNRTIs, NRTIs,
piroxicam, protease inhibitors (primarily ritonavir and indinavir), riluzole, selenium,
sho-saiko-to, tetrabamate, tolmetin, tetracyclines (primarily minocycline), ticlopidine,
valproic acid, venencapsan, vitamin A, zidovudine
Macrovesicular Amanitin, asparaginase, calcium-channel blockers, carbon tetrachloride, chloroform,
chromium, corticosteroids, dichloroethylate, ethanol, ethionine, ethyl bromide/chloride,
methotrexate, methyl bromide/chloride/dichloride, mitomycin, orotic acid, parenteral
lipid, phosphorus, sex steroids, tamoxifen, tannic acid, tetrachloroethylene/trichloroeth-
ylene, toremifene, uranium, warfarin
(Continued)
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CHAPTER 40 • Hepatic and Cholestatic Diseases 781

TABLE 40–2 Mechanisms of Drug-Induced Hepatic and Cholestatic Diseases (Continued)

Predominant Injury Agents or Class of Agents

Phospholipidosis Amantadine, amiodarone, chloroquine, chlorpheneramine, chlorpromazine, cotrimox-
azole, cyclizine, fenfluramine, propranolol, sex steroids, tacrine, TCAs, thioridazine,
tripelennamine
CHOLESTASIS17,18,19,47,48
Pure cholestasis Anabolic steroids, azathioprine, cyclosporine, cytarabine, fosinopril, infliximab, mer-
captopurine, sex steroids, tamoxifen
Canalicular ACE inhibitors (primarily captopril), allopurinol, aminoglutethimide, amoxicillin/clavu-
lanic acid, anabolic steroids, aniline derivatives, arsenicals, atenolol, azathioprine, bar-
biturates, carbamazepine, carbapenems, carbimazole, ceftriaxone, chloramphenicol,
chlorpropamide, citalopram, clindamycin, cotrimoxazole, cyclosporine, cyprohepta-
dine, cytarabine, diltiazem, disopyramide, flucytosine, fusidic acid, glibenclamide,
glipizide, gold compounds, griseofulvin, haloperidol, histamine2-receptor antagonists,
hydralazine, irbesartan, ketorolac, methyldopa, naproxen, penicillamine, phenytoin,
propafenone, propoxyphene, rifampin, risperidone, sex steroids, sho-saiko-to, sulin-
dac, tacrolimus, tricyclic antidepressants, terfenadine, thiazide diuretics, ticlopidine,
trazodone, trimethobenzamide, tripelannamine, voglibose
Hepatocanalicular ACE inhibitors, acetohexamide, amsacrine, azathioprine, ␤-carotene, carbamazepine,
carbimazole, cephalosporins, cascara sagrada, celandine cetirizine, chaparral leaf,
chlorpromazine, clozapine, dapsone, erythromycins (primarily estolate salt), floxuri-
dine, fluphenazine, gabapentin, gemcitabine, gemfibrozil, glimepiride, infliximab,
interleukin-2, jin bu huan, linhgzi, loxapine, mercaptopurine, metformin, methimazole,
methyldopa, molindone, nitrofurantoin, phenylbutazone, phenytoin, procainamide,
prochlorperazine, promazine, quinidine, risperidone, sertraline, statins (primarily
cerivastatin, pravastatin), thioridazine, tolazamide, tolbutamide
Cholangiodestructive Ajmaline, amoxicillin/clavulanic acid, aprindine, azathioprine, barbiturates, chlorpro-
mazine, chlorpropamide, cimetidine, clindamycin, cotrimoxazole, COX2I (primarily
celecoxib), cyproheptadine, fluoroquinolones, glibenclamide, gold compounds,
h onazole, ibuprofen, mesalamine, nitrofurantoin, paraquot, penicil-
lamine, phenytoin, prochlorperazine, semisynthetic penicillins, sex steroids, sulfon-
amides, tricyclic antidepressants (primarily amitriptylline, imipramine), terbinafine,
tetracycline, thiabendazole, thiazide diuretics, ticlopidine, tiopronin, tolazamide,
tolbutamide
VASCULAR1-14,42-46
Hepatic vein thrombosis Contraceptive steroids, comfrey, gordoloba tea, parenteral lipid
Veno-occlusion Actinomycin, arsenicals, azathioprine, busulfan, carmustine, comfrey, cyclophos-
phamide, cytarabine, dacarbazine, daunorubicin, floxuridine, gordoloba tea, insecti-
cides, mitomycin, nitrosoureas, pyrrolizidine alkaloids, skullcap, thioguanine,
trovafloxacin, urethane, vinca alkaloids
Peliosis hepatis Anabolic steroids, arsenicals, azathioprine, sex steroids, tamoxifen, thioguanine, vita-
min A
NEOPLASM1-3,42-44
Benign (adenoma) Anabolic steroids, antineoplastic agents, octreotide, sex steroids, sassafras
Malignant Anabolic steroids, sex steroids, vinyl chloride (carcinoma)
ACE = angiotensin-converting enzyme; BCNU = bischloroethylnitrosourea; CCNU = 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea; COX2I
= cyclooxygenase-2 inhibitor; MDMA = 3,4-methylenedioxymethamphetamine; NNRTIs = nonnucleoside reverse-transcriptase
inhibitors; NRTIs = nucleoside reverse-transcriptase inhibitors; SSRIs = selective serotonin-reuptake inhibitors.
TisdaleC40_771-799 1/12/10 3:42 PM Page 782
782 SECTION VIII • Drug-Induced Gastrointestinal Diseases
and phospholipases) causing cell membrane break-
down and localized inflammation. Apoptosis is
characterized by cell shrinkage, nuclear disassem-
bly, and cell fragmentation into discrete bodies
with intact cell membranes.1-3,42-44,60-63
Phagocytosis of these bodies occurs so that local-
ized inflammation is minimized. Histologically,
cell death may be zonal or nonzonal (diffuse).1-3,42-
44,60-63
Zonal injury means that necrosis/apoptosis
is limited to specific zones of the hepatic acinus,
which is determined by the relative concentration
of the enzyme system responsible for degrading
the xenobiotic. Diffuse injury causes lobules to col-
lapse so that lobular arrangements disappear. Most
idiosyncratic reactions produce centrilobular or
nonzonal injuries.
Immune-mediated cytotoxicity results from the
biotransformation of the xenobiotic to produce
adducts or haptens (known as haptenization) that
migrate to the cell membrane of Kupffer cells to
evoke an immune response via major histocompati-
bility complexes I and II.1-3,42-46,60-63 Both humoral
and cellular immune responses of innate and adap-
tive immunity lead to inflammation and produce
liver damage. Several recognized antibodies exist:
anti–liver/kidney microsomal (LKM) antibody that
specifically targets CYP2C9 of the liver and kidney;
anti–liver microsomal (LM) antibody (e.g., as
induced by carbamazepine) that targets CYP1A2, an
isoenzyme not found in the kidney; antimitochon-
drial antibody (e.g., as induced by isoniazid); antimi-
crosomal epoxide hydrolase (e.g., as induced by
germander); anti-CYP 1A2 (e.g., as induced by
hydralazine); and anti-CYP 2E1 (e.g., as induced by
halothane). The inflammatory reaction is mediated
by several inflammatory cytokines, including inter-
leukin (IL)-1, TNF, nitric oxide, and interferon-␥.1-
3,42-46,60-63
Other cytokines, such as IL-6, IL-10, and
some prostaglandins are hepatoprotective. All
cytokines may be expressed differently according to
genetic polymorphisms. Animal models have
demonstrated hepatotoxicity to nontoxic doses of
agents when inflammation is present, suggesting
that the inflammatory state at baseline may precipi-
tate or enhance the risk of immune-mediated hepa-
totoxicity.42-46 Some agents activate macrophages to
produce fibrosis or form granulomas. Immune-
mediated toxicity causes cell death by apoptosis that
produces piecemeal zonal injury (regions of inflam-
mation surrounded by fibrous strands that extend
into the periportal area).1-3,42-46,60-63
Acetaminophen is the classic example of an
agent that causes cytotoxicity and, as understand-
ing of its mechanisms of injury continues to
evolve, is a good example of the complexity of
drug-induced hepatotoxicity. Approximately 90%
of ingested acetaminophen is conjugated through
glucuronidation and sulfation to nontoxic inactive
metabolites that are excreted in the urine. About
5% to 10% undergoes oxidative conversion by CYP
to the toxic metabolite, N-acetyl-p-benzo-
quinoneimine (NAPQI). NAPQI is a highly reactive
two-electron moiety that can act as an electrophile
or oxidant. It is rapidly metabolized by conjuga-
tion to intracellular glutathione.42,43,45 Excessive
doses of acetaminophen saturate the conjugation
pathways, shunting more acetaminophen into the
CYP system to generate more NAPQI. Hepatic glu-
tathione stores may be depleted in an attempt to
detoxify NAPQI. In the absence of glutathione,
NAPQI binds covalently to the cysteine residues of
hepatocyte macromolecules such as mitochondrial
proteins. Mitochondrial destruction and loss of
ATP occurs, resulting in altered calcium homeosta-
sis, DNA damage, and intracellular protein modifi-
cation.42,43,45 Glutathione depletion further
contributes to cellular oxidative stress.42,43,45
Covalent binding to hepatic proteins in isolation
does not produce hepatotoxicity. Evidence suggests
that inflammatory mediators (e.g., interferon-␥)
trigger the innate immune system, leading to an
influx of Kupffer cells, non-Kupffer cells, neu-
trophils, and macrophages that participate in the
development and propagation of injury.42,43,45
The accumulation of fatty acids in the mito-
chondria is termed “steatosis.”15,16,64,65 The two
major pathways of fatty acid elimination are
microsomal triglyceride transfer protein (MTP) that
forms triglyceride-rich very-low-density lipopro-
tein particles that are secreted and mitochondrial
oxidation.15,16,64,65 Xenobiotics can cause steatosis
by inhibiting MTP activity to block the movement
of fat from the liver or impairing fatty acid oxida-
tion through various mechanisms, including the
sequestration of coenzyme A, the inhibition of
mitochondrial ␤-oxidation, the disruption of
oxidative phosphorylation to deplete cellular ATP,
or the formation of reactive oxygen species.15,16,64,65
Impaired hepatic protein synthesis or cross linking
of structural proteins contribute to steatohepatitis.
For example, malondialdehyde and 4-hydrox-
ynoneal, two products of lipid peroxidation, are
capable of cross linking structural proteins in the
hepatocyte and may explain the transition from
steatosis to hepatitis.15 Steatosis may occur in the
vicinity of zonal necrosis or may be associated with
inflammation and apoptosis.15,16,64,65 Steatosis is
described as microvesicular (hepatocytes that are
occupied by many tiny fat droplets that do not dis-
place the nucleus) or macrovesicular (hepatocytes
that are occupied by few large fat droplets that dis-
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
the coalescence of small fat vesicles to form
macrovesicular steatosis usually represents chronic
injury.15,16,64,65 Phospholipidosis is the trapping
and accumulation of phospholipids in the lyso-
somes of hepatocytes by xenobiotics.15,16
Cholestatic injury is frequently due to selective
interference with excretion of substances into the
bile canaliculus or direct bile duct injury from a
xenobiotic or its metabolite.17-19,47,66 Some xenobi-
otics or metabolites disable ATP-dependent bile salt
transport proteins (e.g., bile salt export protein) by
disrupting actin filaments to cause cholestasis.17-
19,47,66
Several ATP-dependent transport pumps
(multidrug-resistant polypeptide and multidrug-
resistant P-glycoprotein) located on the canalicular
domain of the hepatocyte are responsible for the
excretion of bilirubin and other organic substances
including xenobiotics and their conjugates.
Cholestatic injury may be caused when these trans-
port pumps are disrupted.17-19,47,66 Few agents pro-
duce pure cholestatic injuries. Mixed
hepatocholestatic injury is usually the result of an
immune-mediated reaction with parenchymal
injury and portal inflammation or the failure of
canalicular pumps to allow toxic bile acids to accu-
mulate and cause secondary hepatocyte injury.
Direct injury to cells lining the bile duct causes
cholangiodestructive cholestasis and is character-
ized by interlobular bile duct destruction (vanish-
ing bile duct syndrome).17-19,47,66
Drug-induced vascular injuries may produce
hepatotoxicity by blocking the efferent blood flow
(veno-occlusion) and causing congestive hepatopa-
thy or by dilation of hepatic sinusoids producing
blood-filled cavities within the liver (peliosis
hepatis).1-3,42-44,60-63 Congestive hepatopathy may
result from thrombosis of the hepatic veins or
occlusion of the hepatic venules.1-3,42-44,60-63 Some
agents may alter DNA to produce benign or malig-
nant neoplasms.1-3,42-44,60-63
CLINICAL PRESENTATION AND
DIFFERENTIAL DIAGNOSIS
Drug-induced hepatocholestatic injury is best cate-
gorized according to the predominant type of
injury: hepatocellular (cytotoxic), cholestatic, vas-
cular, or neoplastic (Table 40–2).1-19,42-48 Several
general relationships exist between the pharmaco-
logic category and the pattern of hepatic injury.
General anesthetics, drugs used to treat rheumatic
or musculoskeletal diseases, hydrazine antidepres-
sants, and most anticonvulsants produce hepato-
cellular injury.2 Neuroleptic agents, most
CHAPTER 40 • Hepatic and Cholestatic Diseases 783
antithyroid agents (except propylthiouracil), and
some antidiabetic agents produce predominantly
cholestatic injury.2 The diversity of agents used in
cardiovascular and infectious diseases precludes
generalizations. Some agents produce mixed hepa-
tocholestatic injuries. However, even mixed
injuries usually have a predominant cytotoxic or
cholestatic feature.
In patients with acute drug-induced hepatoc-
holestatic injury, the onset of symptoms and labo-
ratory abnormalities may occur within days,
weeks, or months following initiation of therapy.67-
71
Near-immediate onset is typical of direct hepatic
injury. An onset of several days to weeks is typical
of immune-mediated injuries or microvesicular
steatosis, and a delayed onset of months is indica-
tive of metabolic idiosyncrasies or macrovesicular
steatosis.1-19,67-71 Some agents, however, have a
latency of 3 to 12 months between exposure and
onset of symptoms (e.g., isoniazid or troglitazone)1-
19,67-71
and in some cases, injury may even occur
weeks after the medication is discontinued (e.g.,
amoxicillin/clavulanic acid, erythromycin,
trovafloxacin).1-19,67-71 A chronic injury is defined
as 3 months of consistent hepatic or cholestatic
injury.1-19
Signs and symptoms of hepatocholestatic
injuries are presented in Table 40–31-19 and patterns
of biochemical features of acute hepatocholestatic
injuries are presented in Table 40–4.1-19,67-71 Many
agents are associated with asymptomatic, mild ele-
vations (<3 times the upper limit of the normal
range) of aspartate aminotransferase (AST) and ala-
nine aminotransferase (ALT) concentrations that
return to normal over time while continuing the
agent. This has been termed “hepatic adaptation”
and potentially represents minor degrees of non-
progressive injury to organelles that do not induce
cell death or inflammation but rather activate pro-
tective mechanisms such as antioxidant and anti-
apoptotic pathways.1-19,67-71
Early cytotoxic injury may also be associated
with asymptomatic elevations of AST and ALT con-
centrations; however, in most cases of injury, AST
and ALT are substantially elevated (>10 times the
upper limit of the normal range).1-19,67-71 Serum
alkaline phosphatase (ALP) and 5´-nucleotidase,
two enzymes that reflect cholestasis, may be mini-
mally elevated, and serum bilirubin concentrations
are variably elevated. If hyperbilirubinemia is pres-
ent with hepatocellular injury, usually unconjugat-
ed (indirect) bilirubin concentration is elevated
rather than conjugated (direct) because bilirubin
undergoes hepatic conjugation. Depressed concen-
trations of plasma coagulation factors are charac-
teristic of necrosis or apoptosis. More severe injury
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784 SECTION VIII • Drug-Induced Gastrointestinal Diseases

mortality rate of 10%.72-74 Hypoalbuminemia and

TABLE 40–3 Signs and Symptoms Associated hypotransferrinemia are rare in the acute phase of
with Drug-Induced Hepatic and Cholestatic cytotoxic injuries but may be present with suba-
Diseases1-19 cute or chronic liver injury. Immune-mediated
• Decreased albumin cytotoxic reactions may present with rash,
• Increased ALP/ GGT eosinophilia, lymphocytosis, fever, arthralgias, and
• Anemia liver-specific antibodies (e.g., LKM, LM).1-15,45,46,61-63
• Increased AST/ALT Similarly, autoimmune serum markers (antinuclear
• Asterixis antibody, anti–smooth-muscle antibody, lupus ery-
• Presence of autoimmune serum markers (e.g., antinu- thmatosus, antimitochondrial antibody) and
clear antibody, anti–smooth-muscle antibody, lupus hyperglobinemia are often present.1-15,45,46,61-63
erythmatosus, antimitochondrial antibody) Other common manifestations of cytotoxic injury
• Increased bilirubin include nausea, vomiting, abdominal pain,
• Caput medusae hepatomegaly, anorexia, fatigue, and pruritus.
• Coagulopathy These patients may experience symptoms of portal
• Epigastric valvular murmur (Cruveilhier–Baumgarten hypertension including ascites, encephalopathy,
syndrome) and varices. Alternatively, there may be periods of
• Eosinophilia remission between episodes of symptomatic hepa-
• Fever titis. Steatotic injury is commonly associated with
• Finger clubbing steatorrhea and occasionally with pancreatitis.
• Fetor hepaticus (sweet- pungent smell on breath) Hallmark manifestations of cholestatic injury
• Hepatomegaly are jaundice and pruritus. Occasionally, anorexia,
• Hypoglycemia or hyperglycemia fatigue, and malaise occur, but these tend to be
• Hypogonadism more common with chronic cholestasis.17-19,66
• Hyponatremia Serum aminotransferase concentrations are mildly
• Lactic acidosis to moderately elevated, with the highest concen-
• Presence of liver-specific antibodies (e.g., LKM, LM) trations occurring during acute hepatocholestatic
• Nodular liver injury. Hyperbilirubinemia is due to elevated con-
• Palmar erythema jugated (direct) bilirubin concentration, although
• Spider angioma the unconjugated (indirect) bilirubin concentra-
• Splenomegaly tion is also frequently high. In addition, serum
• Thrombocytopenia and leukopenia ALP, 5´-nucleotidase, and cholesterol concentra-
• White nails tions are usually elevated to ≥3 times the upper
• Abdominal pain limit of the normal range in acute cholestatic
• Ascites injury.
• Anorexia, weight loss, fatigue, malaise Distinguishing cytotoxic, cholestatic, and
• Encephalopathy mixed injuries may be aided by the differential ele-
• Gynecomastia, loss of hair in males vations of ALT and ALP when adjusted for their
• Hepatorenal syndrome upper limits of the normal range (ULN) by the
• Hepatopulmonary syndrome equation ALT/ULN ÷ ALP/ULN. Values ≥5 are
• Pruritus indicative of cytotoxic injuries, values ≤2 are
• Rash indicative of cholestatic injuries, and values
• Steatorrhea between 2 and 5 represent mixed injuries.1-19,69-71
• Jaundice, scleral icterus Veno-occlusive disease presents as severe right
• Varices upper quadrant abdominal pain, rapid weight gain,
• Weight gain ascites, lower extremity edema, pleural effusions,
ALP = alkaline phosphatase; ALT = alanine aminotransferase; nausea, vomiting, jaundice, and portal hyperten-
AST = aspartate aminotransferase; GGT = ␥-glutamyltrans- sion potentially leading to variceal hemorrhage
ferase; LKM = anti–liver/kidney microsomal antibody; LM = (Table 40–3).1-19 Serum aminotransferase concentra-
anti–liver microsomal antibody. tions are moderately elevated, and serum bilirubin
and ALP concentrations are variably elevated. In
cases of thrombosis, markers of fibrin degradation
associated with cytotoxic insults is represented may be evident (e.g., D-dimer, fibrin split products).
clinically by prolonged clotting times, the presence Alteration of DNA may produce benign or
of jaundice, the presence of lactic acidosis, or any malignant neoplasms.1-14 Examples include adeno-
combination of these. Jaundice is associated with a ma (benign), angiosarcoma (malignant), and hepa-
 785
CHAPTER 40 • Hepatic and Cholestatic Diseases

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

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786 SECTION VIII • Drug-Induced Gastrointestinal Diseases
tocellular or cholangiocarcinoma (malignant).
Abdominal pain, presence of a palpable mass,
anorexia, weight loss, and fatigue are the most
common manifestations.
Drug-induced hepatocholestatic diseases are
usually detected by finding abnormalities in hepat-
ic-associated liver enzymes or by the development
of hepatitis-like symptoms or jaundice. Several val-
idated causality scales are available but are rarely
used clinically because of their complicated scoring
schemes and their inability to detect less common
or atypical toxicities. Unfortunately, fulminant
hepatic failure may be the first manifestation of
acute liver injury, and patients may present with
pruritus, coagulopathy, malabsorption of fat-solu-
ble vitamins (vitamins A, D, E, K), hypoglycemia or
hyperglycemia, ascites, spontaneous bacterial peri-
tonitis (SBP), other infectious processes,
encephalopathy with increased intracranial pres-
sure (ICP), variceal hemorrhage, hepatorenal syn-
drome (HRS), electrolyte abnormalities, or any
combination of these. Chronic injury usually pro-
duces similar patterns of enzyme abnormalities,
but enzyme elevations tend to be milder.
Definitive diagnosis of drug-induced liver dis-
ease is virtually impossible. The presumptive diag-
nosis is usually made by the exclusion of other
plausible causes, presence of a temporal relation-
ship of onset, reversal of signs and symptoms on
discontinuation of the causative agent, and simi-
TABLE 40–5 Situations Indicating Xenobiotics as
a Likely Cause of Hepatocholestatic Disease1-48,67-71
• The patient has recently started a new medication,
herbal, etc (<6 mo).
• Presence of extrahepatic manifestations, especially
rash, lyphadenopathy, eosinophilia.
• Acute hepatitis or cholestasis not readily accounted for
by other causes, such as viruses, other infections, gall-
stones, alcohol, metabolic or immunologic disorders.
• Atypical features of liver disease are present, such as
mixed hepatocholestatic injury or microvesicular
steatosis.
• Cholestasis with normal bile duct caliber on imaging.
• Histologic features representative of drug-induced
hepatic injury (see text).
• Chronic hepatitis without autoantibodies or hyper-
globulinemia.
• Abnormal results on liver tests in complex medical
situations.
• Obscure or poorly explained liver disease among
those taking long-term steroids (anabolic or sex
steroids), immunosuppressive agents, or other drugs
(including herbal agents).
larity to other reported cases. Table 40–51-19,67-71
outlines situations in which drug-induced liver
toxicity may be particularly likely. Other potential
causes of hepatocholestatic injury should always
be investigated (Table 40–6).1-19 A thorough med-
ical history must be obtained and should include a
review of the patient’s disease states, social habits,
and environmental exposures (occupational,
household, food). The medication history should
include the patient’s use of prescription and non-
prescription drugs, herbal products, nutritional
supplements, and illicit drugs. The clinician should
search for temporal relationships between the
onset of symptoms and history of chemical expo-
sure or changes in drug therapy.
Extrahepatic manifestations may be evident
with some agents that cause hepatic injury. Allergic
hypersensitivity reactions are associated with fever,
rash, arthralgias, and eosinophilia.1-19, 45,46,61-63
Some agents produce relatively specific clinical
syndromes that can provide evidence for causality
(Table 40–7).1-19
Although liver biopsy can allow characteriza-
tion of a patient’s specific hepatic injury, it may
not be diagnostic for drug-induced hepatic or
cholestatic disease since the various patterns of
injury may have multiple causes.2 Nevertheless,
biopsy is frequently performed for the purpose of
pathologic diagnosis. Similarly, ultrasound or com-
puted tomography scans may aid with the clinical
diagnosis of hepatic disease and be helpful in mon-
itoring patients over time, but are not specific for
drug-induced hepatic or cholestatic disease.
RISK FACTORS
Table 40–8 lists the various risk factors for drug-
induced hepatic and cholestatic diseases.54,70 Genetic
predisposition, sex, age, and alcohol consumption
play important roles. In certain cases, the magnitude
of a single dose (as can be the case in acetaminophen
overdose) or cumulative dose (as may occur with
amiodarone or methotrexate) may cause hepatic
injury. Patients with chronic viral infections (e.g.,
human immunodeficiency virus infection) may be
predisposed to immune-mediated cytotoxicity from
agents such as isoniazid.42-46 Pharmacokinetic or
pharmacodynamic interactions may enhance sus-
ceptibility to hepatocholestatic injuries. Illicit drug
use, including cocaine, 3,4-methylenedioxymetham-
phetamine (nonliquid “ecstasy”), and toxic mush-
rooms are directly linked to fulminant hepatic
failure. Food exposures and household or occupa-
tional exposure to chemical agents associated with
construction, agriculture, printing, plastic fabrica-
TisdaleC40_771-799 1/12/10 3:42 PM Page 787

CHAPTER 40 • Hepatic and Cholestatic Diseases 787

tion, plumbing, and horticulture may independent-

TABLE 40–6 Conditions to Consider in the ly produce hepatic dysfunction.54,71
Differential Diagnosis of Drug-Induced Hepatic Little evidence exists for cross sensitivity
and Cholestatic Diseases1-19 between agents within a class with the exception
Cytotoxic of the antiepileptics (phenytoin and carba-
• Autoimmune disorders mazepine), which exhibit approximately 80% like-
• Epstein–Barr virus lihood of causing hepatic insufficiency when one
• Heat stroke has already caused hepatotoxicity, the inhaled
• Ischemic liver anesthetics (isoflurane, halothane, and enflurane),
• Leukemia/lymphoma and the histamine2-receptor antagonists.54,71 The
• Neoplasms use of oral contraceptives has been described as a
• Pregnancy risk factor for veno-occlusive hepatic dysfunction,
• Reye syndrome and this risk appears to be dose-dependent.
• Sea anemone stings Patients with diabetes, obesity, or hyperlipidemia
• Trauma are at increased risk of steatohepatitis.15,16
• Varicella–zoster In general, patients with mild-to-moderate
• Viral hepatitis chronic liver disease are not at increased risk of
• Wilson disease idiosyncratic drug-induced liver diseases.1-3
Cholestasis Exceptions include patients who receive methotrex-
• Acquired immunodeficiency syndrome ate, tolcapone, pemoline, niacin, troglitazone, and
• Allograft rejection trovafloxacin. Patients with severe liver disease or
• Bacterial infections cirrhosis have altered pharmacokinetic profiles
• Bile duct strictures (absorption, metabolism, volume of distribution)
• Biliary atresia and may be at increased risk of drug-induced liver
• Cholangitis injury. However, many enzyme systems are pre-
• Cholecystitis served, particularly phase 2 conjugation reactions.
• Congenital abnormalities (e.g., porphyrias, Byler syn- Regardless, dose adjustment of some hepatically
drome, ␣1-antitrypsin deficiency) eliminated agents will be required.75
• Cystic fibrosis Malnutrition may contribute to hepatic dys-
• Graft-versus-host disease function. Patients with cirrhosis are prone to renal
• Lymph node compression (lymphoma) dysfunction, and caution must be exercised when
• Neoplasms renally toxic agents are used in this population.
• Pancreatitis An understanding of the risk factors associated
• Portal vein thrombosis with acetaminophen toxicity provides good insight
• Postoperative cholestasis into the complexities of drug-induced hepatic dis-
• Viral hepatitis ease and how various factors can work individually
or collectively to influence toxicity. CYP2E1 is the
Vascular enzyme primarily responsible for the production of
• Behçet’s disease NAPQI, and its activity is enhanced twofold with
• Cirrhosis chronic alcohol ingestion.42,43,45 Tobacco use is an
• Collagen vascular diseases independent risk factor for mortality following
• Constrictive pericarditis acetaminophen exposure, presumably because
• Hypercoagulation states tobacco smoke contains inducers of CYP1A2.42,43,45
• Infections Isoniazid also induces CYP2E1 and the common
• Inflammatory bowel disease antiepileptics (phenytoin, carbamazepine, barbitu-
• Myeloproliferative disorders, sarcoidosis rates) induce CYP3A4 to also possibly increase
• Polycystic liver disease NAPQI. Children have increased capacity for sulfa-
• Pregnancy tion to reduce acetaminophen exposure to the CYP
• Systemic lupus erythematosus system, and individuals taking zidovudine or
• Total-body irradiation trimethoprim–sulfamethoxazole may have
• Trauma increased toxicity, since these agents compete for
Neoplasm glucuronyl transferase to shunt more acetamino-
• Metastatic neoplasms phen to the CYP system.42,43,45 Poor nutritional sta-
• Primary neoplasm of liver, pancreas, gastrointestinal tus contributes to diminished glucuronidation,
tract induction of CYP2E1, and glutathione depletion to
possibly enhance toxicity. Genetic polymorphisms
TisdaleC40_771-799 1/12/10 3:42 PM Page 788
788 SECTION VIII • Drug-Induced Gastrointestinal Diseases
TABLE 40–7 Extrahepatic Syndromes Associated with Drug-Induced Hepatocholestatic Diseases1-19
Drug
Dapsone
Dapsone, carbamazepine, minocycline,
phenytoin, sulfonamides
Intravenous tetracycline, valproic acid
Amoxicillin/clavulanic acid, chlorpromazine,
erythromycin estolate
Carbamazepine, phenytoin
Clofibrate
Methyldopa, oxyphenisatin
Diphenylhydantoin, para-aminosalicylate,
sulfonamides
Anticonvulsants, chloramphenicol, gold salts,
propylthiouracil, phenylbutazone
Nitrofurantoin, amiodarone
Gold salts, methoxyflurane, paraquat, penicillamine
exist for the conjugative and CYP systems that may
influence the metabolism of acetaminophen and
alter the risk of toxicity.42,43,45
MORBIDITY AND MORTALITY
Drug-induced liver diseases account for 2% to 3%
of all hospital admissions.76 Only 20% to 25% of
patients with acute idiosyncratic fulminant hepat-
ic failure survive 3 weeks without liver transplanta-
tion.56 The causes of death include cerebral edema,
sepsis, multiorgan failure, cardiac arrhythmia or
arrest, and respiratory failure.56 As suggested by
associated signs and symptoms (Table 40–3), mild-
to-moderate liver dysfunction can cause significant
morbidity, however, mortality is rare.1-19 Patients
with preexisting liver disease, however, have
increased morbidity and mortality.72-74 Prognosis is
worse the longer a patient is exposed to the hepa-
totoxin. AST, bilirubin, female sex, and age are
associated with higher mortality in patients who
experience hepatocellular reactions, whereas only
bilirubin is predictive of mortality in patients with
cholestatic injuries.72-74
PREVENTION
Table 40–9 lists approaches to help prevent drug-
induced hepatic and cholestatic diseases.1-9,76,77
Recognition and rapid discontinuation of the
Syndrome
Fever, jaundice, rash, anemia (sulfone syndrome)
Fever, rash, perspiration, lymphadenopathy
(mononucleosis syndrome)
Anorexia, nausea, vomiting, somnolence, encephalopathy
resembling fatty liver of pregnancy
Obstructive jaundice
Fever, rash, atypical lymphocytosis, lymphadenopathy
Mylagias, stiffness, weakness, elevated creatine kinase
Autoimmune hemolysis
Fever, rash, lymphadenopathy, arthralgias (serum
sickness syndrome)
Associated bone marrow injury
Associated pulmonary injury
Associated renal injury
agent is the best preventive measure. A patient
reporting that a new medicine “does not agree
with him” may be all that is required for early
detection of a preventable toxic exposure. Patients
with risk factors should not receive hepatotoxic
agents if and when alternative agents are available.
Many manufacturers of drugs known to cause
hepatic injury provide guidelines for monitoring
liver enzymes while patients are receiving the
potential hepatotoxin (e.g., isoniazid, etretinate,
synthetic retinoids, ketoconazole, methotrexate,
pemoline, tacrine). Monthly monitoring of liver-
associated biochemistry may be cost-effective for
drugs that produce serious liver dysfunction in 1%
to 2% of exposures, but not for drugs that are less
frequently associated with this drug-induced dis-
ease.54
MANAGEMENT
Most cases of drug-induced hepatocholestatic dys-
function are reversible. In general, discontinuation
of the hepatotoxin results in rapid reversal of signs
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-
cellular, but this degree of improvement may take
6 months or longer if the injury is cholestatic.1-19,72-
74
Recovery following discontinuation of drugs
with long half-lives may be prolonged or incom-
plete.
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CHAPTER 40 • Hepatic and Cholestatic Diseases 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
790 SECTION VIII • Drug-Induced Gastrointestinal Diseases
TABLE 40–9 Approaches to Help Prevent Drug-
Induced Hepatic and Cholestatic Diseases.1-9,76,77
Global
• Preclinical drug testing in animals.
• Serial biochemical assessment during clinical studies.
• Post-marketing surveillance and reporting.
• Restricted availability (e.g. blister packaging of non-
prescription medication).
Patient-Specific
• Appropriate use of medicinal agent.
• Adherence to dosing guidelines.
• Avoid use of agents in patients with known risk fac-
tors (Table 42-8).
• Avoid polypharmacy and herbal medicines.
• Serial biochemical monitoring in high risk patients or
with agents known to cause injury.
• Rapid recognition of injury and associated extrahep-
atic syndromes (Table 42-7).
• Maintain nutrition.
• Minimize alcohol consumption, occupational expo-
sures, and illicit drug use.
• Control other disease states (e.g. hyperthyroidism,
diabetes mellitus, hyperlipidemia).
• Future: genomic testing for potential susceptibility.
associated enzymes should be monitored daily to
weekly during rechallenge.
The agent should be permanently discontin-
ued if fulminant hepatocholestatic injury or
immune-mediated injuries are present. To prevent
further injury, agents with dose-dependent toxicity
should be removed, if possible, by aspiration, acti-
vated charcoal, or dialysis. Determination of serum
concentrations of the culprit drug, when available,
can help gauge the success of removal strategies.
These concentrations should be obtained at least
daily, but more frequent monitoring may be neces-
sary in cases of severe hepatotoxicity.
In most cases, management of drug-induced
liver dysfunction is limited to supportive care, as
therapeutic treatment is applicable in only a
small number of situations. Table 40–10
describes management of drug-induced hepa-
tocholestatic diseases and associated complica-
tions.76-170 Mevalonic acid prevents and amelio-
ates cholestatic injury due to hydroxymethylglu-
taryl coenzyme A reductase inhibitors in ani-
mals, but it is not available for human use.78
Folic acid is protective against methotrexate-
induced hepatotoxicity when given within 24
hours of exposure and when administered in a
dose of 0.25–0.5 mg per milligram of methotrex-
ate given.79
The only therapy proven to be effective for the
treatment of drug-induced hepatitis is N-acetylcys-
teine (NAC) for patients with acetaminophen toxi-
city. Although the agent is usually administered
within 24 hours of acetaminophen ingestion, a
randomized, placebo-controlled study showed that
NAC infusions of 6.25 mg/kg/hr reduced mortality,
the incidence of cerebral edema, and vasopressor
requirements in patients with acetaminophen-
induced fulminant liver failure who presented >24
hours after ingestion.80 All patients had unde-
tectable serum acetaminophen concentrations
when NAC was initiated, suggesting that NAC may
have therapeutic effects other than supplying
exogenous glutathione.
Pennyroyal oil and carbon tetrachloride cause
the depletion of glutathione, and case series indi-
cate that administering NAC shortly after exposure
to these agents is beneficial.81-85 Case reports also
indicate that NAC may be beneficial in the treat-
ment of acute hepatic failure caused by valproic
acid and sulfasalazine.86,87
In theory, NAC may be beneficial for other
drug-induced causes of direct hepatotoxicity
because it supplies glutathione, acts as an antioxi-
dant, decreases inflammation by reducing leuko-
cyte chemotaxis and suppressing the expression of
nuclear factor-␬B, and enhances the synthesis of
nitric oxide to increase oxygen delivery.88,89 Studies
have demonstrated benefits of treatment in certain
cases of non–acetaminophen–induced hepatic
injury.90-92 However, until further research is com-
pleted, intravenous NAC should generally be
reserved for use in the situations described above.
Corticosteroids reduce the inflammatory
response to toxic stimuli. Prednisone 10–80 mg
daily may reduce the inflammatory reaction associ-
ated with immune-mediated hypersensitivity reac-
tions.93,94 Azathioprine 50–150 mg daily may be
substituted or added.93,94 Because corticosteroids
are possibly effective for alcohol-induced hepatitis,
several studies have investigated their clinical use
for other causes of hepatitis.95-98 Unfortunately, no
trial has specifically studied drug-induced hepati-
tis. The results of a multicenter study that enrolled
a total of 62 patients with acute hepatic failure
found that 9 of 10 patients with drug-induced liver
failure (6 due to halothane, 2 to methyldopa, 1 to
isoniazid, 1 to propylthiouracil) died despite daily
therapy with hydrocortisone 40 to 800 mg.99 Until
additional studies are conducted, corticosteroids
cannot be routinely recommended for the treat-
ment of drug-induced hepatitis. They may, howev-
er, have a role in certain case-specific scenarios,
including use in patients with lesions resembling
immune-mediated hypersensitivity reactions or
TisdaleC40_771-799 1/12/10 3:42 PM Page 791

CHAPTER 40 • Hepatic and Cholestatic Diseases 791

TABLE 40–10 Management of Drug-Induced Hepatocholestatic Diseases and Associated Complications76-170

Agent or Symptom Management
Methotrexate79 Folic acid 0.25–0.50 mg/mg of methotrexate intravenously
or enterally daily until resolution
Carbon tetrachloride, pennyroyal oil, acetaminophen N-acetylcysteine intravenously 150 mg/kg over 15 min, then
(unintentional or chronic), other cytotoxic agents 50 mg/kg over 4 hr, then 6.25 mg/kg/hr until resolution
(case-specific)78,80-92
Macrovesicular steatosis (case-specific)77 Prednisone 40–80 mg enterally daily for 4–6 wk or
pentoxiphylline 400 mg enterally three times daily
Immune-mediated hypersensitivity reaction Prednisone 10–80 mg enterally daily for 4–6 wk
(case-specific)93-100,102 ⫾ azathioprine 50–150 mg enterally daily
Valproic acid and other causes of microvesicular L-Carnitine 50–300 mg/kg intravenously daily
steatosis (case-specific)101,103-105 (bioavailability of oral carnitine is 25%) until resolution
Cholestasis106-110 Ursodiol 300–600 mg enterally daily until resolution
Veno-occlusive or veno-thrombotic111-116 Stent placement, or angioplasty ⫾ thrombolysis (rTPA 2 mg
then 0.5–1 mg/hr infused locally for 24 hr) ⫾ anticoagulation
Pruritus122 Cholestyramine 4 g enterally twice daily or colestipol 5 g
enterally twice daily (titrate to relief or diarrhea) ⫾ rifampin
600 mg enterally daily ⫾ phenobarbital 60–120 mg enteral-
ly daily ⫾ chlorpromazine 150–300 mg orally daily ⫾
naloxone 20 mg subcutaneously daily ⫾ ondansetron 8 mg
intravenously or enterally once
Coagulopathy (international normalize ratio ⱖ1.5)123-136 Vitamin K 10 mg intravenously, subcutaneously, or enterally
daily ⫾ fresh-frozen plasma ⫾ platelets (to keep platelet
count ⱖ50⫻109/L) ⫾ desmopressin acetate 0.4 ␮g/kg
intravenously ⫾ factor VIIa 40 ␮g/kg intravenously (usually
reserved for refractory hemorrhage)
Vitamin deficiency77,137 Individual administration of a multivitamin containing vita-
min A 5,000 IU, vitamin D 50,000 IU, vitamin E 10,000 IU,
and vitamin K 10 mg daily
Hypoglycemia127-132 Dextrose 50% intravenously
Hyperglycemia127-132 Short-acting (regular) insulin intravenously or subcutaneously
Ascites127-132,138-144, Fluid restriction 1–2 L/day and sodium restriction 1–2 g/day
and furosemide 40 mg intravenously or enterally daily and
spironolactone 100 mg enterally daily (diuretics titrated to
remove 0.5–2 kg/day) ⫾ large-volume paracentesis if diuretic-
refractory, abdominal pain, or breathing difficulties
Spontaneous bacterial peritonitis138-148 Antibiotic (third-generation cephalosporin, fluoroquinolone,
or extended-spectrum penicillin) for 5–7 days, and albumin
1.5 g/kg intravenously at diagnosis then 1 g/kg intravenous-
ly 3 days later
Encephalopathy149-157 Lactulose enterally or rectally 30 mL as needed to produce
2 stools daily, and protein restriction <1 g/kg daily ⫾
branched-chainamino acids in severe cases of encephalopa-
thy) ⫾ enteral antibiotic (rifaximin 200–400 mg three times
daily or metronidazole 500 mg two to four times daily)
(Continued)
TisdaleC40_771-799 1/12/10 3:42 PM Page 792
792 SECTION VIII • Drug-Induced Gastrointestinal Diseases
TABLE 40–10 Management of Drug-Induced Hepatocholestatic Diseases and Associated Complications76-170
(Continued)
Agent or Symptom
Cerebral edema with increased intracranial pressure127-132,158-164 Minimize agitation, hyperthermia, pain, hypoxia, and acido-
Variceal hemorrhage143-145,165-167,170
Hepatorenal syndrome 117-121,168,169
169
Electrolytes
pCO2 = partial pressure of arterial carbon dioxide; rTPA; recombinant tissue plasminogen activator.
macrovesicular steatosis caused by agents other
than alcohol, including methotrexate, parenteral
lipids, and warfarin.
Typically, corticosteroids are initiated in
patients with chronic hepatitis who show minimal
or slow clinical or biochemical improvement
despite other therapies. Approximately one-third
of patients with acute hepatic failure, irrespective
of the cause, have concomitant relative adrenal
insufficiency. This condition can be diagnosed
with the adrenocorticotropic hormone–stimula-
tion test, where a serum cortisol increase of ≤9
mg/dL 60 minutes after the administration of 0.25
mg of corticotrophin is considered positive.100
These patients may benefit from short-term admin-
istration of supplemental corticosteroid (daily
administration of hydrocortisone 200–300 mg or
equivalent).
Other agents that have been successfully used
in the treatment of alcohol-induced hepatitis or
reported to be of benefit in the treatment of other
causes of hepatitis include colchicine, propylth-
iouracil, gemfibrozil, betaine glucuronate, ursodi-
ol, pentoxifylline, ␣-tocopherol, nitric oxide,
methionine, vitamin E, L-carnitine, and silymarin
(milk thistle).101,102 Only L-carnitine and silymarin
have been studied for reversal of drug-induced liver
dysfunction. L-Carnitine induces ureagenesis,
reduces inflammation by inhibiting TNF, and facil-
itates fatty acyl transport. The results of a retro-
spective study of 92 patients with apparent
fulminant liver failure secondary to valproic acid
Management
sis ⫾ mannitol 25-5- g intravenously as needed for intracra-
nial pressure > 20 mm Hg and serum osmolarity < 320
mOsm/Kg (or hypertonic saline to keep serum sodium
145–155 mEq/L) ⫾ hyperventilation for pCO2 near 35 mm
Hg ⫾ pentobarbital or thiopental 250 mg intravenously as
needed for intracranial pressure >20 mm Hg ⫾ hypothermia
32–35°C
Hemodynamic resuscitation, and endoscopy (banding pre-
ferred) and octreotide 50 U intravenously then 50 U/hr for
3–5 days ⫾ transjugular intrahepatic portosystemic shunt
Renal replacement therapy ⫾ vasopressin 0.1–0.4 U/min (or
midodrine 2.5–10 mg enterally three times daily +
octreotide)
Correct hypokalemia, hypomagnesemia, and
hypophosphatemia
showed that L-carnitine therapy at unspecified
doses improved survival from 10% to 48% in
patients receiving standard treatment.103,104 It
should be noted, however, that specific data
describing the patients, severity of liver injury, and
morphologic and histologic pathologies were not
presented. Moreover, the beneficial effect of
increased survival was observed only when L-carni-
tine was administered intravenously (67% vs. 29%
with enteral administration). The typical dose of
intravenous L-carnitine is 50 to 100 mg/kg/day
given in divided doses every 6 to 8 hours, and ther-
apy should be initiated as soon as possible after
exposure. Silymarin, an herbal supplement com-
monly used by patients to protect the liver when
they are taking known hepatotoxic agents, is
reported to possess antioxidant, antiinflammatory,
and antifibrotic activities that protect hepatocytes
from lipid peroxidation. However, a meta-analysis
of 14 trials of silymarin used in patients with
chronic liver disease (two studies of drug-induced
liver diseases) found that ALT was reduced by only
9 U/L (P = 0.05).105 AST, albumin, and prothrombin
time were not altered. Silymarin, therefore, should
not be used to treat cases of hepatotoxicity until
additional information supports its use for this
indication. Only case reports or in vitro data sup-
port the use of other agents for drug-induced liver
failure.
Drug-induced cholestasis may require long-term
daily treatment with ursodiol 300–600 mg, which
aids in the dissolution of cholesterol gallstones and
TisdaleC40_771-799 1/12/10 3:42 PM Page 793
inhibits apoptosis.18,19,106-110 Anticoagulation thera-
py, thrombolytic therapy, or both should be initiated
after stent placement or angioplasty for drug-
induced veno-occlusive or veno-thrombotic dis-
eases.111-116 Monitoring of bleeding times is difficult
in patients with fulminant hepatic failure, so serum
drug concentrations should be used to guide therapy
if underlying coagulopathy is present. Patients with
veno-occlusive or veno-thrombotic disorders should
receive minimal sodium (<2 g/day) and may require
diuretics for the removal of accumulated fluid, simi-
lar to the treatment of ascites.111-116
Ultimately, patients with fulminant liver fail-
ure who do not respond to the measures described
above will likely require liver transplantation to
survive. Unfortunately, only 50% of patients with
drug-induced liver failure receive a liver transplant,
primarily because of the relatively short timeframe
in which a transplant is required and the limited
availability of organs.56,57 The use of liver-assist
devices or hepatic regeneration therapy with
agents such as malotilate is not common, and most
data supporting their use are from case reports.117-
121
Extracorporeal liver-assist devices may be artifi-
cial or cell-based.119 Artificial devices use either
conventional dialysis along with hemodialysis
against a 5% to 10% albumin dialysate solution
over an albumin-impermeable membrane or a frac-
tionated plasma separation technique that uses a
membrane with a 250-kDa cutoff between circuits,
thereby making the membrane permeable to albu-
min and hence albumin-bound toxins.119 Cell-
based devices incorporate hepatocytes from
various sources and have the theoretical advantage
of not only providing blood purification through
dialysis, but also providing hepatocyte-specific
functions such as protein synthesis, ureagenesis,
gluconeogenesis, and detoxification through CYP
activity.119 A meta-analysis showed that liver-assist
devices may reduce the incidence of encephalopa-
thy by 33% but do not alter mortality.117 They may,
however, increase the likelihood that a patient will
survive until transplantation is possible.118
Transjugular intrahepatic portosystemic shunt
(TIPS) may provide time until a liver transplanta-
tion can be performed, but it is associated with
worsening encephalopathy.170
Liver dysfunction may be associated with pru-
ritus, coagulopathy, malabsorption of fat-soluble
vitamins (vitamins A, D, E, K), hypoglycemia or
hyperglycemia, ascites, SBP or other infectious
processes, encephalopathy with increased ICP,
variceal hemorrhage, HRS, electrolyte abnormali-
ties, metabolic acidosis, hyperventilation, and car-
diovascular collapse. Biliary dysfunction may cause
osteoporosis and hypercholesterolemia.
CHAPTER 40 • Hepatic and Cholestatic Diseases 793
Pruritus in patients with liver dysfunction is
likely due to the accumulation of bile acids, even
though the concentration of bile acids in the skin
does not correlate with the degree of pruritus.122
Management of this condition is difficult because
traditional histamine1-receptor antagonists such as
promethazine, while possibly helpful as sleep aids,
typically offer little relief from itching. First-line
treatment is the administration of a bile acid
sequestrant such as cholestyramine or colestipol.122
Doses are initially low (cholestyramine 4 g or
colestipol 5 g daily or twice daily) and increased
over a period of several weeks until symptomatic
relief is achieved or diarrhea develops. Both of
these agents may bind and reduce the gastrointesti-
nal absorption of other drugs. Consequently, dos-
ing schedules should be adjusted so that other
drugs are given 1 hour before or 6 hours after the
sequestrant. In cases in which the bile-acid seques-
trant is ineffective or not tolerated, therapy with
rifampin in a dose of 600 mg daily may be tried
with caution.122 Symptomatic relief usually occurs
within 1 to 3 weeks of initiating rifampin, likely
due to enzyme induction and enhanced clearance
of bile acids. Serum concentrations of hepatic-asso-
ciated enzymes and bilirubin should be obtained
within 2 weeks of initiating rifampin therapy to
ensure that the drug is not worsening the patient’s
hepatic disease. Phenobarbital alleviates pruritus
and also provides sedation. Chlorpromazine 25 to
100 mg every 6 hours produces variable results. As
with rifampin, serum concentrations of hepatic-
associated enzymes and bilirubin should be deter-
mined within 2 weeks of initiating
chlorpromazine. Daily subcutaneous administra-
tion of naloxone 20 mg has been shown to be
effective.122 A single intravenous dose of
ondansetron 8 mg has been shown to alleviate pru-
ritus within 24 hours of administration, presum-
ably by blocking serotonin (5-hydroxytryptamine
type 3) receptors on sensory nerve endings.122
Hepatic dysfunction alters coagulation and fib-
rinolysis through several mechanisms, including
reducing concentrations of coagulation factors V,
VII, IX, X, XI, prothrombin, thrombin-activatable
fibrinolysis inhibitor, endogenous anticoagulants
(proteins C, S, Z; heparin cofactor II; Z-dependent
protease inhibitor; antithrombin), producing
defective vitamin K–dependent coagulation factors
(VII, IX, X, prothrombin), and increasing concen-
trations of tissue plasminogen activator, plasmino-
gen activator inhibitor, and von Willebrand
factor.123,124 Renal dysfunction frequently accom-
panies hepatic dysfunction and usually imparts
enhanced bleeding risk because of acquired platelet
dysfunction and abnormal platelet–vessel-wall
TisdaleC40_771-799 1/12/10 3:42 PM Page 794
794 SECTION VIII • Drug-Induced Gastrointestinal Diseases
interaction.123,124 Hepatic injury prevents efficient
use of vitamin K, and a dose of 10 mg of vitamin K
reverses coagulopathy to some extent in many
patients with mild-to-moderate liver dysfunc-
tion.125-132 However, the treatment of coagulopathy
secondary to drug-induced hepatic dysfunction
frequently necessitates the administration of
exogenous clotting factors such as fresh-frozen
plasma or cryoprecipitate.127-132 Exogenous
platelets should only be administered when throm-
bocytopenia is present.133 Intravenous desmo-
pressin acetate at 0.4 mcg/kg promotes the release
of factor VIII from platelets and reverses coagu-
lopathy with variable success.133 Intravenous
recombinant factor VIIa in a dose of 40 mcg/kg
rapidly reverses coagulopathy and may alleviate
hemorrhagic episodes, but these effects last less
than 6 hours and, since the agent is extremely
expensive, it is usually reserved for cases of refrac-
tory hemorrhage.134,135 Higher doses may be associ-
ated with thrombosis.136 In general, the
international normalized ratio should be kept <1.5
and the platelet count ≥50,000 per cubic millime-
ter. However, reversing coagulopathy may require
substantial fluid administration that can induce
ascites and intracranial hypertension and may
negate the ability to use coagulopathy as a prog-
nostic marker.127-132 Although the production of
endogenous thrombopoietin is frequently dimin-
ished in patients with severe liver dysfunction,
additional evidence is needed before the routine
use of exogenous thrombopoietin can be recom-
mended in these patients.133 Fat-soluble vitamins
(A, D, E, K) should be administered with careful
attention to the dose of vitamin A, since it may
induce liver failure at high doses or worsen existing
injury at therapeutic doses by producing hepatic
inflammation and depleting the antioxidant
capacity of the liver.137
Hypoglycemia is a common manifestation of
liver dysfunction because the production of
glucagon is impaired and hepatic glycogen stores
are minimal.127-132 Patients with fulminant liver
dysfunction are often hypervolemic, so the intra-
venous administration of high concentrations of
dextrose (50%) may be needed to correct hypo-
glycemia without adding volume. Patients may
have hyperglycemia due to peripheral insulin
resistance and the inability of the liver to convert
glucose to glycogen.127-132 Short-acting insulin can
be used to control hyperglycemia.
Portal hypertension and arterial vasodilation
produce ascites by activating the renin–angio-
tensin–aldosterone–vasopressin system to increase
intravascular blood volume.138-144 Peritoneal fluid
collects when an elevated hepatosplanchnic pres-
sure forces the passage of fluid from the sinusoidal
lumen into the interstitial spaces because the
endothelial cells that line the sinusoids are com-
promised.138-144 Therefore, ascites should be treated
with fluid restriction (1–2 L/day), sodium restric-
tion (1–2 g/day), and the administration of diuret-
ics, preferably furosemide and spironolactone in
doses of 40 mg and 100 mg daily, respectively.127-
132,138-144
These doses may be increased to 160 mg
and 400 mg, respectively. The goal of diuretic ther-
apy is to remove fluid at a rate of 0.5 kg/day in
patients without peripheral edema and 2 kg/day in
patients with peripheral edema. Large-volume
paracentesis (>5 L) may be performed if the patient
has severe abdominal pain or breathing difficul-
ty.138-144 Albumin (8 g for each liter of ascitic fluid
removed) administered during or immediately
after paracentesis can help prevent circulatory and
renal dysfunction.127-132,139-144
A small-volume paracentesis (<2 L) is used to
evaluate patients with new-onset ascites for the
presence of SBP, and an ascitic fluid polymor-
phonuclear count of ≥250 cells per cubic millime-
ter is considered diagnostic.138-147 SBP occurs when
bacteria translocate from the intestinal tract to the
peritoneum via the mesenteric lymphatic system.
This complication of hepatic disease is secondary
to impaired gastrointestinal motility, damage to
the intestinal mucosa, gastrointestinal bacterial
overgrowth, low concentrations of protein and
complement in the ascitic fluid, impaired activity
of the reticuloendothelial system including Kupffer
cells, and reduced neutrophil function.146,147
Antibiotic therapy for 5 to 7 days is indicated for
the treatment of patients with SPB.138-147 Therapy
should be designed to cover the most likely organ-
isms and penetrate the ascitic fluid. Coverage for
Escherichia coli, Streptococcus pneumoniae, Klebsiella
species, and other enteric gram-negative organisms
should be provided. Third-generation cephalo-
sporins (cefotaxime, ceftriaxone), extended-spec-
trum penicillins (ampicillin/sulbactam), and
fluoroquinolone agents are all effective in eradicat-
ing these organisms, with resolution rates
≥90%.146,147 Albumin in a dose of 1.5 g/kg given at
the time of diagnosis and 1 g/kg 3 days later has
been shown to reduce the incidences of renal
impairment and hospital mortality in patients
with SBP.148 Prophylactic antibiotics for the preven-
tion of SBP in patients with ascites may be warrant-
ed when fulminant liver failure is present.142-147
Encephalopathy is a metabolic disorder of
mentation, neuromuscular function, and con-
sciousness associated with hepatic disease. It is
believed to be caused by the accumulation of sub-
stances such as ammonia that are efficiently
TisdaleC40_771-799 1/12/10 3:42 PM Page 795
metabolized under normal conditions but accumu-
late with liver dysfunction.149-151 Single measure-
ments of serum ammonia concentrations do not
reflect the degree of encephalopathy, but trends in
serial measurements correlate with the progression
or reversal of encephalopathy.149-151 Initial treat-
ment of encephalopathy should include the rever-
sal of precipitating factors, including hemorrhage,
excess dietary protein, azotemia (as induced by
diuretics or renal failure), infection, constipation,
and metabolic/electrolyte disturbances and the dis-
continuation of central nervous system depres-
sants.149-151 Pharmacotherapy of encephalopathy
may be initiated with enteral/rectal lactulose (30
mL as often as hourly until stool is produced and
then 3–4 times daily as needed to produce 2–3 soft
stools per day) and/or enteral rifaximin (200–400
mg 3 times daily) or metronidazole (500 mg 2–4
times daily).127-132,149-152 Meta-analysis has shown
that lactulose improves encephalopathy.153
Neomycin (1–2 g 4 times daily) may be used, but
caution is warranted, as it may be associated with
nephrotoxicity.152 Daily protein should be restrict-
ed to 1 g/kg in patients with encephalopathy, and
nutritional products containing branched-chain
amino acids may further reduce the degree of
encephalopathy, although other outcomes such as
returning to baseline mental status, length of hos-
pital stay, and survival are not affected.154-156
Intravenous flumazenil (0.2–0.5 mg) temporarily
reduces the extent of encephalopathy.157
Altered mental status should be investigated
using computed tomography to rule out intracra-
nial hemorrhage. Insertion of an ICP monitoring
device should be considered but may constitute an
unacceptable risk for the patient when coagulopa-
thy is present.158,159 The use of an ICP monitor is
associated with hemorrhage but enhances the rate
of successful transplantation.160 Treatment of
increased ICP should include minimizing agitation
with short-acting benzodiazepine agents, provid-
ing analgesia with short-acting opioid agents, con-
trolling hyperthermia, and minimizing acidosis
and hypoxia.127-132,158,159 Cerebral edema and
increased ICP may be treated with intravenous
mannitol 25–50 g as needed to keep the ICP <20
mm Hg and the serum osmolarity between
310–320 mOsm/kg.149-151,158,159 Mannitol may accu-
mulate in astrocytes if renal failure is present and
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
mannitol but may contribute to serum sodium
irregularities.161 Hyperventilation to maintain the
partial pressure of arterial carbon dioxide near 35
mm Hg should reduce ICP without substantially
CHAPTER 40 • Hepatic and Cholestatic Diseases 795
compromising cerebral blood flow, but the effect is
limited to several hours.127-132,162 Intravenous
thiopental or pentobarbital 250 mg may be used if
mannitol is unsuccessful or contraindicated.127-
132,158,159
Mild hypothermia (32–35°C) is also used
in the treatment of elevated ICP; this therapy
maintains hepatic function by decreasing
ischemic-reperfusion injury and the inflammatory
response; however; it is associated with coagulopa-
thy, electrolyte abnormalities, altered hemody-
namics, variable glucose control, and rebound
intracranial hypertension during rewarming.163,164
Variceal hemorrhage and HRS are rarely associ-
ated with idiosyncratic drug reactions. Varices are
caused by portal hypertension and develop when
the portal pressure gradient exceeds 10 mm Hg,
resulting in the development of portosystemic col-
lateral circulation.143-145,165,166 A variceal hemor-
rhage should be treated with endoscopic
procedures (banding is preferred) followed by the
administration of octreotide (50-U bolus followed
by intravenous infusion of 25–50 U/hr for 3–5
days).143-145,165,166 Octreotide reduces the rate of
rebleeding and transfusion requirements.167 Acute
renal failure may require renal dialysis, but HRS
may be temporarily alleviated by intravenous vaso-
pressin infusion (0.1–0.4 U/min) or the combina-
tion of octreotide and midodrine (2.5–10 mg 3
times daily).168
Common electrolyte abnormalities associated
with liver dysfunction include hypophos-
phatemia, hypokalemia, and hypomagnesemia,
and electrolyte replacement may be required.
Hypervolemic hyponatremia is common and usu-
ally asymptomatic even when sodium concentra-
tions are profoundly low; however, it may indicate
the onset of HRS.169 Diuretic therapy combined
with fluid restriction usually improves serum sodi-
um concentrations.169 Intravenous sodium chlo-
ride should be administered only when patients
are symptomatic (e.g., when seizures are present),
as increases in serum sodium concentrations are
transient and the excess fluid may precipitate
ascites. In the future, therapy for hyponatremia
may involve the administration of antagonists to
vasopressin receptor2 (antidiuretic hormone) to
reduce hypervolemia, but these approaches have
not been evaluated for hyponatremia associated
with acute liver disease.169
INFORMATION FOR PATIENTS
Patients taking agents that may cause hepatoc-
holestatic injury should be instructed to consult
their physician or pharmacist if they experience
TisdaleC40_771-799 1/12/10 3:42 PM Page 796
796 SECTION VIII • Drug-Induced Gastrointestinal Diseases
nausea, vomiting, unexplained weight loss, or
abdominal pain that lasts several days and cannot
be attributed to other causes. Patients with altered
mental status, increased abdominal girth, peripher-
al edema, bleeding episodes, protracted pruritus,
jaundice, or reduced urine production should
receive immediate medical attention. Patients
should be instructed not to take any nonprescrip-
tion medications or herbal products without first
consulting their physician or pharmacist. Patients
should inform their physician and pharmacist of
all agents (including herbal remedies) they are tak-
ing to avoid interactions and should be cautioned
about risk factors including ethanol use, illicit-drug
use, and environmental exposures. Finally, appro-
priate monitoring to avoid the development of
hepatocholestatic injury or to prevent further dam-
age in patients already experiencing mild injury
must be conducted.
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TisdaleC41_800-818 1/12/10 3:43 PM Page 800
CHAPTER 41
Pancreatitis
P ancreatitis is an inflammatory process of the
pancreas. It may be described as acute, in which
the normal function of the pancreas returns, or
chronic, in which the damage to pancreatic func-
tion is irreversible.1 Drug-induced pancreatitis is
most often acute in nature. Several mechanisms
have been hypothesized, including immune-medi-
ated, direct pancreatic toxicity, pancreatic-duct
constriction, thrombosis, and metabolic effects.
Although a number of drugs have been reported to
cause pancreatitis, cause and effect relationships
are often difficult to verify.
CAUSATIVE AGENTS
Table 41–1 lists agents that have a definite or prob-
able association with drug-induced pancreatitis.
Drugs typically cause acute pancreatitis, although
there are reports of drug-induced chronic pancre-
atitis as well. Drug-induced pancreatitis has no fea-
tures that allow it to be differentiated from other
forms of the disorder.2 Mallory and Kern classified
drugs that may cause pancreatitis into three
groups: those with a definite, probable, or ques-
tionable association with pancreatitis.3 Drugs are
classified as having a “definite association” with
pancreatitis if the disease develops during treat-
ment with the drug, disappears after the drug is
withdrawn, and returns when the patient is rechal-
lenged. Drugs are classified as having a “probable
association” with pancreatitis if an association is
thought to be likely and some, but not all, of the
“definite association” criteria are met. Drugs are
classified as having a “questionable association” if
supporting evidence is inadequate or contradicto-
ry. A similar classification has been proposed that
800
Pramodini B. Kale-Pradhan and Sheila M. Wilhelm
categorizes drug-induced pancreatitis in five classes
based on the number of reports and rechallenge
results.4
EPIDEMIOLOGY
The overall incidence of drug-induced pancreatitis
has been estimated to be 0.1%,5 and drugs may be
the cause in approximately 1.4% to 2% of patients
who are diagnosed with the disease.5-8 Drugs are
responsible for 13% to 30% of cases of pancreatitis
in children.9,10 The incidence of acute, drug-
induced pancreatitis is higher in patients who have
disease states that predispose them to the develop-
ment of the disease, including human immunode-
ficiency virus (HIV), acquired immune deficiency
syndrome (AIDS), renal transplantation (immuno-
compromised patients), and inflammatory bowel
disease (autoimmune diseases).8
Drug-induced pancreatitis has a much higher
incidence (approximately 20%) in patients who are
HIV-positive and in those treated with didanosine
the incidence varies from 7.45 to 23.5%.11-16 In
contrast, the incidence of didanosine-induced pan-
creatitis is substantially lower in patients without
HIV (1.5–9%).17-19 Numerous reports demonstrate
an association of didanosine with pancreatitis, and
the incidence of pancreatitis in phase I trials was
up to 9%.14,17,19-34 In phase II trials, the National
Institute of Allergy and Infectious Diseases, report-
ed that pancreatitis developed in only 1.5% of
patients receiving didanosine, and the onset of
pancreatitis after didanosine initiation was 10 to
20 weeks.15,35
Angiotensin-converting enzyme (ACE) inhibi-
tors were implicated as the cause of pancreatitis in
TisdaleC41_800-818 1/12/10 3:43 PM Page 801

TABLE 41–1 Agents Implicated in Drug-Induced Pancreatitis

Drug Incidence Level of Evidence
(see page xii for explanation)

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
TisdaleC41_800-818 1/12/10 3:43 PM Page 802
802 SECTION VIII • Drug-Induced Gastrointestinal Diseases
209 of the 2749 reports of drug-induced pancreati-
tis received by the World Health Organization
(WHO) from 1968 to 1993.36 More recently, over
300 cases of drug-induced pancreatitis were associ-
ated with enalapril or captopril.37 The estimated
incidence of ACE inhibitor-associated pancreatitis
ranges from 0.3% to 1.07%.38 A retrospective
cohort study of 174,824 elderly patients prescribed
ACE inhibitors reported an incidence of 9 per
10,000 person-years, which was not significantly
different from that in control groups receiving war-
farin or calcium-channel blockers (classes of drugs
with either a weak association or with no associa-
tion with pancreatitis).39 Several cases of ACE
inhibitor and angiotensin II receptor
antagonist–induced pancreatitis have been report-
ed.40-53 In one such case, pancreatitis developed
with no known cause other than a 10-month his-
tory of lisinopril therapy and mildly elevated
serum triglyceride concentrations, highlighting the
possibility that pancreatitis may develop several
months after the initiation of ACE inhibitor thera-
py.38 In another case, pancreatitis developed three
times after initiation and rechallenge with lisino-
pril. The latency period ranged from 4 to 25
months.54 ACE inhibitors are associated with an
increased risk of acute pancreatitis (approximately
50%), particularly in the first 6 months of thera-
py.55
During the period from 1968 to 1993, the
WHO received reports of 127 cases of pancreatitis
associated with histamine-2 (H2) receptor antago-
nists.56 The association between cimetidine and
pancreatitis is probable, and there are numerous
published case reports.57-59 A retrospective cohort
study of patients taking acid-suppressive therapies
(cimetidine, famotidine, nizatidine, ranitidine,
lansoprazole, omeprazole) identified 36 cases of
acute pancreatitis, 5 of which occurred in patients
taking cimetidine.60 One case report of ompera-
zole-induced pancreatitis has been reported in the
literature.61 Pancreatitis developed 2 months after
the initiation of therapy and recurred after rechal-
lenge with omeprazole. However, a retrospective,
case-control study including more than 180,000
subjects did not find an increased risk associated
with acid-suppressive therapy.60
There are at least six well-documented cases of
metronidazole-induced pancreatitis.62-67 In these
cases, the onset of symptoms ranged from 12 hours
to 7 days after initiation of therapy and resolved
after discontinuation of the drug. Metronidazole-
induced acute pancreatitis was reported in a 46-
year-old female.68 Another case of metronida-
zole-related acute pancreatitis occurred during a
relapse of ulcerative colitis.69 In addition, a popula-
tion based case–control Danish study reported a
threefold increased risk of acute pancreatitis in
patients receiving metronidazole.70
There are numerous reports of 3-hydroxy-3-
methyl-glutaryl-CoA (HMG-CoA) reductase
inhibitor (or statin)–induced pancreatitis in the lit-
erature.71,72 A meta-analysis of two pooled studies
showed an odds ratio of 1.41 (95% confidence
interval, 1.15–1.74) for the risk of pancreatitis
developing while a patient is receiving statins.72
Pancreatitis can occur at any time, but may be
more likely after many months of treatment with
statins.
Azathioprine and 6-mercaptopurine are potent
immunosuppressive agents that are associated with
pancreatitis.73-88 The incidence of pancreatitis with
6-mercaptopurine is approximately 3.3%,73 where-
as the incidence of azathioprine-induced pancre-
atitis ranges from 4.4% to 5.3%.73–75 Pancreatitis
developed within approximately 1 month of initi-
ation of 6-mercaptopurine therapy, with a range of
8 to 32 days. Pancreatitis developed within 2
weeks, often within 1 to 2 days, in all 7 of the 13
patients who were rechallenged. Three additional
patients with azathioprine-induced pancreatitis
subsequently did well with 6-mer- captopurine.89
L-asparaginase induces pancreatitis in 2% to
16% of patients, and approximately 2% to 5% of
children treated with L-asparaginase experience
life-threatening pancreatitis.90-94 Two other prepa-
rations of asparaginase have become available:
Erwinia carotovora-derived L-asparaginase and poly-
ethylene glycol-L-asparaginase (PEG-asparaginase,
Oncaspar). Erwinia asparaginase may be associated
with a lower incidence of pancreatitis as compared
with the native L-asparaginase product (0% vs. 2%,
respectively) although this has not been thorough-
ly investigated.95-97 There are numerous case
reports of L-asparaginase-induced pancreatitis with
or without fatalities.98-110 Pancreatitis induced by L-
asparaginase usually occurs during administration
of the drug, but in some cases pancreatitis second-
ary to L-asparaginase therapy may occur as long as
10 weeks after therapy has been discontin-
ued.3,90,92,99,110-112 The incidence of pancreatitis
associated with PEG-asparaginase is similar to that
with native L-asparaginase (0–15%).113-118 The
onset of pancreatitis associated with PEG-asparagi-
nase is within a few days or up to 6 weeks after
PEG-asparaginase administration.
The incidence of hypercalcemia-induced pan-
creatitis is approximately 7%.119 Two of 112 cases
(1.8%) of drug-induced pancreatitis reported
through 1977 were attributed to calcium thera-
py.120 Intravenous calcium administration has
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
total parenteral nutrition has also been report-
ed.121-124 In a prospective study of patients who had
undergone cardiopulmonary bypass, the risk of
pancreatic injury correlated with a dose of calcium
chloride >800 mg/m2, and calcium chloride admin-
istration was an independent predictor of pancre-
atic injury.121 Hypercalcemia-related pancreatitis is
more common in patients who have undergone
renal transplantation, with an approximate inci-
dence of 11%.125
The incidence of pancreatitis induced by nons-
teroidal antiinflammatory drugs (NSAIDs) appears
low. In a population-based study of over 100,000
users of piroxicam, naproxen, or diclofenac, only
one case of pancreatitis occurred (in a patient
receiving piroxicam).126 In contrast, there are
numerous reports of sulindac-induced pancreatitis,
including reports of recurrence after rechal-
lenge.127-134 Pancreatitis may develop within 2
weeks to 9 months after the initiation of sulindac
therapy.134,135
Salicylate-induced pancreatitis has also been
reported, particularly in poisonings.136,137 Of 112
cases of drug-induced pancreatitis reported
through 1977, 1 (0.9%) was attributed to salicylate
therapy.120 Sulfasalazine is composed of sulfapyri-
dine and 5-aminosalicylic acid (5-ASA). Intestinal
bacteria cleave the diazo bond between the two
components, releasing the active moiety, 5-ASA.
Pancreatitis has been reported in association with
both sulfapyridine and 5-ASA.138-151 Sulfasalazine-
induced pancreatitis has recurred after rechallenge
with 5-ASA. Although serum 5-ASA concentrations
are higher when the drug is administered orally,
pancreatitis has been reported in association with
5-ASA administered by either the oral or the rectal
route. In a retrospective analysis of serious adverse
events, pancreatitis was reported seven times more
frequently with mesalamine than with sul-
fasalazine.152 However, in a retrospective study,
patients with inflammatory bowel disease who
received 5-ASA and sulfasalazine did not show an
increased risk of pancreatitis.153
Cisplatin, cytarabine, ifosfamide, and the vinca
alkaloids have been associated with pancreatitis,
but the incidence is unknown.154-167 Many cases of
drug-induced pancreatitis have been reported dur-
ing concurrent cytarabine and L-asparaginase
administration. Pancreatitis developed within 10
days after the first cytarabine dose in 7 of 134
patients undergoing treatment for acute myeloge-
nous leukemia at two tertiary care centers; recur-
rent pancreatitis developed in one of six patients
who were rechallenged.160 Another case described
the development of acute pancreatitis in a patient
CHAPTER 41 • Pancreatitis 803
treated with vincristine, methotrexate, mitomycin
C, fluorouracil, and cyclophosphamide for
advanced-stage ovarian carcinoma. Pancreatitis
recurred during the sixth cycle, although cholecys-
tography confirmed gallbladder disease, a con-
founding variable.158 Another patient who received
cisplatin, bleomycin, and vinblastine experienced
recurrence of pancreatitis during the second cycle
of chemotherapy.164 Pancreatitis developed in a
patient treated with cyclophosphamide, doxoru-
bicin, vincristine, and prednisone for immunoblas-
tic lymphoma before the initiation of prednisone;
pancreatitis recurred during later cycles of treat-
ment, and asymptomatic hyperamylasemia also
occurred during a later chemotherapy cycle.156
During the 1950s, corticosteroids became the
first drugs to be implicated in drug-induced pan-
creatitis. Steroids and adrenocorticotropic hor-
mone (ACTH) accounted for 51 of 112 (45.5%)
cases of pancreatitis reported in the literature as of
1977.120 A more recent report described a patient
being treated with hydrocortisone for exacerbation
of ulcerative colitis in whom pancreatitis later
developed.168 This patient experienced a second
exacerbation of ulcerative colitis and was again
treated with hydrocortisone; acute pancreatitis
developed again.
In 1963, Barrett and Their reported the first
case of sulfonamide-induced pancreatitis.169 More
recently, there have been three reported cases of
pancreatitis secondary to trimethoprim–sul-
famethoxazole treatment, in which the disease
developed within 5 days to 10 weeks after the ini-
tiation of therapy.17,140,170-172
Ober and Lecompte reported the earliest case of
tetracycline-induced pancreatitis in a patient in
whom acute fatty liver of pregnancy also devel-
oped.173 Other reports of pancreatitis secondary to
tetracycline have also been associated with liver
disease.174-176 There are three other reports of tetra-
cycline-induced pancreatitis in patients without
liver disease.177-179 Also, two reports of minocy-
cline-induced pancreatitis have been des-
cribed.180,181 Tigecycline, a newer agent related to
the tetracyclines, has been implicated in drug-
induced pancreatitis in two case reports.182,183
A number of cases of aerosolized and injectable
pentamidine-induced pancreatitis have been
reported, the majority of which have been in the
HIV/AIDS population, including a report of recur-
rence after rechallenge.17,184-199 Pancreatitis second-
ary to pentamidine typically occurs in the second
week of treatment and resolves within 10 days after
discontinuation, although there have been some
reports of pancreatitis persisting after the discon-
tinuation of therapy. Persistence may be explained
TisdaleC41_800-818 1/12/10 3:43 PM Page 804
804 SECTION VIII • Drug-Induced Gastrointestinal Diseases
by the lipophilic properties of pentamidine, a
cumulative dose effect on the pancreas, or
both.190,192 In a report of five cases of pentamidine-
induced pancreatitis, all patients experienced
episodes of hypoglycemia or hyperglycemia. Sepsis
developed in four of the five.192 Glucose abnormal-
ities, renal insufficiency, nonspecific abdominal
pain, and nausea and/or vomiting after the initia-
tion of pentamidine may be early warning signs of
pancreatitis.184
One case report supports a probable association
between pancreatitis and ampicillin.200 Pancreatitis
developed 6 days after the initiation of therapy;
the patient recovered 5 days after discontinuation
and had a relapsed 4 days after ampicillin therapy
was reinstituted.
The incidence of methyldopa-induced pancre-
atitis is unknown. Symptoms of methyldopa-
induced pancreatitis generally occur within 1 week
after the initiation of therapy.201-204
There are numerous reports of estrogen-
induced pancreatitis (with and without concomi-
tant progesterone therapy).205-211 Estrogen-induced
pancreatitis begins 2 to 78 weeks after the initia-
tion of therapy, and symptoms usually resolve
approximately 10 days after discontinuation.17 In
addition, there is a case report of clomiphene (an
estrogen analogue)-induced pancreatitis.212
Although there are case reports of estrogen-
induced pancreatitis, a population-based case–con-
trol study did not support a substantial association
between pancreatitis and postmenopausal hor-
mone therapy.213
Several cases of furosemide-induced pancreati-
tis have been reported.214-219 The doses that were
administered in these cases ranged from 40 to 1000
mg daily, and symptoms occurred within 2 to 5
weeks after the initiation of therapy.17 In one case,
pancreatitis occurred in a patient with malignant
hypertension within 24 hours of the initiation of
therapy with furosemide 750 mg per day.218
Pancreatitis resolved after the discontinuation of
furosemide and recurred upon rechallenge. In
addition, other loop diuretics, bumetanide and
ethacrynic acid, have been associated with pancre-
atitis.218,220,221
Chlorothiazide, hydrochlorothiazide, and
chlorthalidone have all been reported to cause
pancreatitis.222-236 Thiazide-induced pancreatitis
develops within 2 weeks to as long as 1 year or
more after the initiation of therapy.
Pancreatitis associated with valproic acid was
first recognized in 1979,237 and since then there
have been many reports of valproic acid induced
pancreatitis, in both adults and children.238-267 The
estimated incidence is 1 in 40,000.268 In view of the
case reports and the potential severity of this drug-
induced disease the United States Food and Drug
Administration (FDA) instituted new “black box”
warnings regarding the risk of pancreatitis in pack-
age inserts for valproic acid in July, 2000.258
Although valproic acid induced pancreatitis is
most common during the first year of therapy, in
some cases the disease has appeared more than 1
year after the initiation of treatment. There have
also been cases suggestive of valproic acid induced
chronic pancreatitis.260,261 In a retrospective, case-
control trial, valproic acid significantly increased
the risk for pancreatitis; however, the risk was no
different from that of other antiepileptic agents.269
There are at least five case reports of drug-
induced pancreatitis with clozapine.270-274 In one of
these reports, pancreatitis remitted upon clozapine
withdrawal but recurred when clozapine was reini-
tiated.272 In another report, pancreatitis resolved
after withdrawal of clozapine but did not recur
after a rechallenge with a lower dose.273 Other
reports describe a syndrome of “asymptomatic”
pancreatitis and eosinophilia induced by clozap-
ine, although asymptomatic hyperamylasemia
usually is not diagnostic of pancreatitis.275,276
MECHANISMS
The pancreas has two functions: endocrine and
exocrine.1 The endocrine function is to secrete
insulin, glucagon, somatostatin and other
polypeptides via the pancreatic ␤-cells. The
exocrine pancreas consists of lobular subunits
called acini, which secrete pancreatic fluid that
contains water, electrolytes, and enzymes for diges-
tion. The major enzymes secreted by the pancreas
include proteolytic (trypsinogen, chymotrypsino-
gen, proelastase, procarboxypeptidases A and B),
amylolytic (amylase), lipolytic (lipase, prophos-
pholipase A1 and A2, esterase), nucleolytic
(deoxyribonuclease and ribonuclease), and others,
such as trypsin inhibitor. The proteolytic enzymes
are secreted as zymogens (enzymes requiring acti-
vation, such as proenzymes) in the pancreas and
require an extrapancreatic trigger for activation.
Enterokinase in the duodenum transforms
trypsinogen to trypsin, which activates all other
zymogens. The pancreas protects itself from
autodigestion by secreting proenzymes and low
concentrations of trypsin inhibitor. Acute pancre-
atitis results from premature activation of prote-
olytic enzymes within the pancreas.
Drugs may induce pancreatitis through several
mechanisms, including pancreatic duct hyperten-
sion secondary to intraluminal or extraluminal
TisdaleC41_800-818 1/12/10 3:43 PM Page 805

CHAPTER 41 • Pancreatitis 805

duct blockage, increased viscosity of pancreatic
fluid leading to peripheral duct rupture, and proen-
zyme release.2 Data from studies in animals have
shown that reduced exocytosis and premature
fusion of zymogen granules to lysosomes in pan-
creatic exocrine cells may activate pancreatic
proenyzmes and lead to cellular autodigestion.
Drugs could play a role in this process.
Predisposition to infection through immunosup-
pression may also be involved in pancreatitis
caused by drugs such as corticosteroids and other
immunosuppressants.2 Table 41–2 lists additional
mechanisms that have been proposed for drugs
known to be associated with pancreatitis.
Antimicrobial Agents
Metronidazole-induced pancreatitis may occur as a
result of a redox cycling reaction that occurs under
aerobic conditions, yielding hydrogen peroxide
and other oxygen free radicals.277,278 These redox
active compounds are toxic to pancreatic ␤-cells
and cause pancreatitis in animal models. The exact
mechanism of tetracycline-induced pancreatitis is
not completely understood; however, it may be
related to a toxic metabolite of tetracycline.279 The
precise mechanism of pentamidine-induced pan-
creatitis likewise is not known, but animal studies
suggest a direct toxic effect on the pancreas.280
Pentamidine is known to cause hypoglycemia or
hyperglycemia, which is possibly due to damaged
pancreatic ␤-cells.17
Estrogen
A possible mechanism of estrogen-induced pancre-
atitis is hyperlipidemia, a well-known cause of pan-
creatitis. In a report by Glueck and colleagues,

TABLE 41–2 Mechanisms of Drug-Induced Pancreatitis

Drug Mechanism
Angiotensin-converting enzyme inhibitors Bradykinin-induced inflammation; autoantibodies
5-Acetylsalicylic acid Immune-mediated reaction
L-Asparaginase Inhibition of protein synthesis through the hydrolysis of the
amino acid L-asparagine
Azathioprine/6-mercaptopurine Allergic reaction direct toxic effect, or both
Didanosine Hypersensitivity or mitochondrial toxicity
Estrogen Unknown (potentially hyperlipidemia)
Furosemide Direct toxic effect, diuretic-induced pancreatic stimulation,
ischemia related to impaired pancreatic blood flow due to
volume contraction.
Hydrochlorothiazide Increased serum calcium concentration leads to calculi in
the pancreatic ducts; direct toxic effect secondary to
increased parathyroid hormone concentrations or increased
calcium concentrations may accelerate the conversion of
trypsinogen to trypsin, causing pancreatitis; or thiazides
lead to hypotension and pancreatic ischemia
Methyldopa Unknown
Metronidazole Undergoes redox cycling reaction yielding hydrogen perox-
ide and other oxygen free radicals that are toxic to pan-
creas
Pentamidine Direct toxic effect on the pancreas
Statins Immune-mediated inflammatory response, metabolic effect
o cellular toxicity
Sulfonamide Hypersensitivity
Sulindac Hypersensitivity
Tetracycline Unknown (potentially toxic metabolite)
Valproic acid Hypersensitivity
TisdaleC41_800-818 1/12/10 3:43 PM Page 806
806 SECTION VIII • Drug-Induced Gastrointestinal Diseases
pancreatitis developed in 4 of 12 women with
hypertriglyceridemia who received estrogen-
replacement therapy.205 However, pancreatitis has
also developed in patients without elevated serum
lipid concentrations who are receiving estrogens,
suggesting that hypertriglyceridemia may not be
the only factor in estrogen-induced pancreatitis.206
Thiazide Diuretics
Several potential mechanisms of thiazide-induced
pancreatitis have been suggested. Thiazides may
have a direct toxic effect on the pancreas.223 Also,
thiazides are known to cause hypercalcemia and
hypophosphatemia, which are also present in
patients with primary hyperparathyroidism, a con-
dition known to increase the risk of pancreatitis.222
Increased serum concentrations of parathyroid
hormone may be present in patients treated with
thiazide diuretics and can result in pancreati-
tis.223,224 In addition, elevated serum calcium con-
centrations may lead to calculi within the
pancreatic ducts, may accelerate the conversion of
trypsinogen to trypsin, or both, causing pancreati-
tis.281 It has also been suggested that thiazides may
cause pancreatitis as a result of thiazide-induced
hyperlipidemia224 and that thiazide-induced reduc-
tions in blood pressure may lead to pancreatic
ischemia.1
Antiinflammatory Agents
Sulfasalazine-induced pancreatitis may occur
because of an immune-mediated reaction.282 An
allergic reaction is also a possible mechanism of
sulindac-induced pancreatitis.283
Valproic Acid
Pancreatitis associated with valproic acid may be
related to a hypersensitivity reaction and recurs
after rechallenge with the drug.237-241 It has been
theorized that valproic acid may cause depletion of
the free radical scavengers superoxide dismutase,
catalase, and glutathione peroxidase, resulting in
an excess of free radicals that may promote
endothelial permeability and lipid peroxidation,
ultimately leading to tissue damage.284-286
L-Asparaginase
L-Asparaginase-induced pancreatitis may occur as a
result of the inhibition of protein synthesis
through hydrolysis of the amino acid L-
asparagine.287, 288 Organs with high rates of protein
synthesis, such as the liver and pancreas, are more
severely affected. The presence of glutaminase or
an endotoxin cannot be excluded as a mechanism
because L-asparaginase is extracted from Escherichia
coli.289,290
ACE Inhibitors
Several mechanisms have been proposed for ACE
inhibitor-induced pancreatitis. ACE inhibitors
increase serum bradykinin concentrations.
Bradykinin acts as a mediator of inflammation that
may lead to localized angioedema and obstruction
of pancreatic ducts.291 Bradykinin also increases
vascular permeability in early-stage pancreatitis
induced by cerulein.292 Bradykinin antagonists
such as HOE-140 have been shown to have a pro-
tective role in pancreatitis.293 Induction of local
angioedema, which obstructs the pancreatic duct,
is a likely phenomenon when pancreatitis occurs
rapidly after drug initiation.294 Other possible
mechanisms are ACE inhibitor-induced hypo-
glycemia resulting in toxic effects on the pancreas
and the effects of combined toxins, including ACE
inhibitors and alcohol.40,295,296
Studies in animals suggest that ACE inhibitors
may increase pancreatic secretion as a possible or
contributing mechanism.41 Another theory is that
ACE inhibitors induce the formation of autoanti-
bodies, which then attack pancreatic cells.40 Both
captopril and enalapril have been found to induce
the production of autoantibodies to many tissues,
including the pancreas, although the pancreas is
less commonly affected.297
Clozapine
The mechanism by which clozapine induces acute
pancreatitis is unknown. Clozapine may have toxic
effects on the pancreas, or clozapine-induced pan-
creatitis may occur as a result of an allergic reac-
tion.271,272
H2 Receptor Antagonists
The H2 receptor antagonists may affect pancreatic
secretory stimuli through reduction of gastric and
duodenal acidity, may cause pancreatitis through
an idiosyncratic reaction, or both.2,56
NSAIDs and ASA
The probable mechanism of ASA- or NSAID-
induced pancreatitis is inhibition of prostaglandins
that otherwise may cause pancreatic duct constric-
tion.2,298 Aspirin has been shown to increase pan-
creatic duct permeability in animals.299,300 Admin-
TisdaleC41_800-818 1/12/10 3:43 PM Page 807
istration of intravenous aspirin increases calcium
secretion from the pancreas, which is considered a
marker of pancreatic damage.301 Experimental
studies suggest that prostaglandins may have a pro-
tective effect on pancreatic cells. Administration of
prostaglandin E2 in a mouse model of experimen-
tal pancreatitis was associated with an improved
survival rate as compared with the 100% mortality
reported in controls. Membrane stabilization of
pancreatic cells may be the mechanism behind the
cytoprotection conferred by prostaglandins.302
Calcium
It is possible that hypercalcemia may induce
chronic pancreatic exocrine secretion changes that
may affect ductal epithelium.120 Intracellular calci-
um in pancreatic zymogen granules is important in
the maintenance of granule stability, and factors
disrupting this delicate balance may contribute to
calcium-induced pancreatitis.303
Corticosteroids
Corticosteroids may induce pancreatitis through
toxic effects, immune suppression, or increased vis-
cosity of pancreatic fluids.120 The viscosity of pan-
creatic secretions was greater in steroid-treated
glands in an ex vivo study of perfused canine pan-
creas exposed to high doses of methylpred-
nisolone.304 Steroids stimulate both exocrine and
endocrine pancreatic secretions, which may con-
tribute to the development of drug-induced pan-
creatitis.305
Statins
The exact mechanism of statin-induced pancreati-
tis is not clear. Some hypothesized mechanisms
include an immune-mediated inflammatory
response, a metabolic effect, or direct cellular toxi-
city.72 The safety profile among the statins may dif-
fer based on their inhibitory effects on cytochrome
P-450 and their lipophilicity.
CLINICAL PRESENTATION AND
DIFFERENTIAL DIAGNOSIS
The clinical presentation of drug-induced pancre-
atitis is similar to that of acute pancreatitis second-
ary to other causes.2 Table 41–3 summarizes the
usual signs and symptoms associated with drug-
induced pancreatitis. Typically, patients with
acute pancreatitis present with abdominal pain,
nausea, vomiting, abdominal distention, and low-
CHAPTER 41 • Pancreatitis 807
TABLE 41–3 Signs and Symptoms Associated with
Drug-Induced Pancreatitis1
• Abdominal pain (95%)
• Nausea/vomiting (80%)
• Abdominal distention (75%)
• Low-grade fever (75%)
• Pain radiating to back (50%)
• Hypotension (30%)
• Mental aberrations (25%)
• Jaundice (20%)
grade fever. The presentation may also include
pain that radiates to the back, hypotension, men-
tal aberrations, and jaundice. Complications may
include the development of pancreatic abscess,
pseudocyst formation and the development of
subcutaneous fat necrosis and bluish discoloration
of the abdominal wall (Grey-Turner’s or Cullen’s
sign).306
Diagnosis is usually based on clinical and lab-
oratory data. Typical laboratory parameter abnor-
malities that may occur in patients with
drug-induced pancreatitis include leukocytosis,
hyperglycemia, hypoalbuminemia, mild hyper-
bilirubinemia, elevated blood urea nitrogen and
serum creatinine concentrations, elevated hemo-
globin, elevated hematocrit, hypocalcemia,
thrombocytopenia, and prolongation of pro-
thrombin time and the international normalized
ratio (INR).1 Serum amylase concentrations usual-
ly increase within 24 hours of the onset of symp-
toms and return to normal over a period of 3 to 4
days. Persistent elevation is suggestive of exten-
sive pancreatic necrosis or related complications
or both. Serum amylase concentrations do not
correlate with severity of disease or cause. In con-
trast, lipase originates in the pancreas, making it
a more specific marker for pancreatitis than serum
amylase. Serum lipase concentrations are usually
elevated in patients with pancreatitis. Elevations
of serum lipase concentration persist longer (7 to
10 days) than serum amylase elevations. Imaging
techniques such as ultrasound may be indicated
in patients with suspected biliary involvement.
Contrast-enhanced computed tomography may
be useful in determining the severity of the
inflammatory process, and it also provides an esti-
mate of risk for systemic and local complica-
tions.307,308
Because the clinical presentation of drug-
induced pancreatitis is similar to that of pancreatitis
due to other causes, drug-induced pancreatitis is
usually diagnosed after other, more common causes
have been ruled out. A careful medication history
TisdaleC41_800-818 1/12/10 3:43 PM Page 808
808 SECTION VIII • Drug-Induced Gastrointestinal Diseases
should always be taken and helpful in differential
diagnosis. Most commonly, acute pancreatitis
occurs secondary to alcohol ingestion or cholelithi-
asis. Less common causes include abdominal trau-
ma, exposure to toxins, hyperlipidemia, pancreatic
tumor, complications of surgery, infection, vascular
abnormalities, and other miscellaneous condi-
tions.309 Endoscopic retrograde cholangiopancre-
atography, which is used to diagnose pancreatitis,
can also, ironically, cause pancreatitis in up to 40%
of patients who undergo the procedure.310 Table
41–4 lists conditions to consider in the differential
diagnosis of drug-induced pancreatitis.
In patients with drug-induced pancreatitis, the
time from the initiation of therapy to the onset of
pancreatitis symptoms varies depending on the
causative drug. No generalizations can be made,
and for most drugs, pancreatitis can occur from
within a short time after administration of the first
dose to years after therapy begins.
RISK FACTORS
Risk factors for drug-induced pancreatitis are pre-
sented in Table 41–5. Any disease state that predis-
poses patients to hypercalcemia, such as
hyperparathyroidism, malignancy, thyrotoxicosis,
or multiple myeloma, as well as circumstances
such as hard water syndrome, tumor lysis syn-
drome, and cholecalciferol overdose, increase the
risk of drug-induced pancreatitis.166,311-316 In addi-
tion, the risk of drug-induced pancreatitis is
increased in patients receiving a drug with a defi-
nite or probable association with pancreatitis for
management of a disease state that is also inde-
pendently associated with pancreatitis.317 For
example, immunosuppression increases the risk of
infection, and infectious processes are often associ-
ated with pancreatitis; patients with disease states
associated with immunosuppression including
TABLE 41–4 Conditions to Consider in the
Differential Diagnosis of Drug-Induced
Pancreatitis309
• Cholelithiasis
• Abdominal trauma
• Toxins
• Hyperlipidemia
• Pancreatic tumor
• Surgery
• Endoscopic retrograde cholangiopancreatography
• Infection
• Vascular abnormalities
TABLE 41–5 Risk Factors for Drug-Induced
Pancreatitis
• Hypercalcemia
• Hyperparathyroidism
• Malignancy
• Thyrotoxicosis
• Multiple myeloma
• Hard water syndrome
• Tumor lysis syndrome
• Cholecalciferol overdose
• Immunosuppression
• Renal transplantation
• HIV/AIDS
• Autoimmune disease
• Crohn’s disease
• Hyperlipidemias
• Concurrent estrogen therapy
AIDS = Acquired immunodeficiency syndrome; HIV = Human
immunodeficiency virus
renal transplantation and HIV/AIDS have an
increased incidence of drug-induced pancreatitis.2
Autoimmune diseases such as inflammatory bowel
disease have also been linked to pancreatitis, and
patients with these conditions are at increased risk
for drug-induced pancreatitis when treated with
drugs that have definite or probable associations
with the disease.8,318
Specific risk factors for didanosine-associated
pancreatitis in the AIDS population have been
identified. These include severity of HIV disease
(CD4 count <200 cells/mcL), didanosine dose >9.6
mg/kg/day, drug-related hyperlipidemia, therapy
longer than 10 weeks, history of pancreatitis, con-
comitant alcohol use, and concomitant use of pen-
tamidine.14,19,319 In addition to pentamidine,
concomitant use of other drugs known to cause
pancreatitis, particularly hydroxyurea and stavu-
dine, increases the risk of didanosine-induced pan-
creatitis.26,27,29 Ribavirin should be used with
extreme caution in patients receiving didanosine,
because of the risk of fatal lactic acidosis and pan-
creatitis.31 Previous exposure to didanosine is a risk
factor for pentamidine-induced pancreatitis.198
MORBIDITY AND MORTALITY
Drug-induced pancreatitis may be mild to severe.
The majority of patients recover without any long-
term morbidity, but 5% to 15% of patients ex-
perience life-threatening complications. 2 A
retrospective study including data from 42 Ger-
man centers of gastroenterology found that the
TisdaleC41_800-818 1/12/10 3:43 PM Page 809
majority of drug-induced pancreatitis cases run
a benign course; no patients experienced
pseuodocyst development or required mechani-
cal ventilation.8 However, the mean hospital
stay was 25.5 days (range, 2–78 days). Of the
cases of suspected drug-induced pancreatitis
reported to the Danish Committee on Adverse
Drug Reactions from 1968 through 1999, 68%
required hospitalization for treatment and the
mortality rate was 9%.5 Another Dutch study
reported a 15% mortality rate associated with
drug-induced pancreatitis.56
Ranson’s criteria may be used to assess the
severity of an episode of drug-induced pancreatitis
and may also be used to predict mortality (Table
41–6).306 The presence of three or more of these cri-
teria indicates a more severe attack with a higher
risk of mortality. Severe acute pancreatitis is associ-
ated with an Acute Physiology and Chronic Health
Status Evaluation (APACHE) score >8, associated
organ failure, or >30% pancreatic necrosis viewed
on a computed tomography scan, and with a
Ranson’s score >3.319 There have been fatalities due
to pancreatitis reported with many drugs, with a
seemingly higher incidence of mortality in patients
with pancreatitis due to azathioprine, didanosine,
furosemide, and hydrochlorothiazide. Many fatal
cases involving azathioprine occurred after renal
transplantation, and most didanosine-related cases
occur in patients with AIDS in whom the inci-
dence of pancreatitis is greater.8 In severe cases, cir-
culatory, pulmonary, and renal complications may
occur and ultimately result in death.306
TABLE 41–6 Severity of Pancreatitis Based on
Ranson’s Criteria306
At Hospital Admission or Diagnosis
• Age >55 yr
• White cell count >16,000 cells/mm3
• Blood glucose >200 mg/dL
• Serum lactate dehydrogenase >350 IU/L
• Serum aspartate aminotransferase >250 IU/dL
During First 48 Hours after Admission or Diagnosis
• Fall in hematocrit of >10% (absolute %)
• Rise in blood urea nitrogen of >5 mg/dL
• Serum calcium <8 mg/dL
• Arterial oxygen pressure <60 mm Hg
• Base deficit of >4 mEq/L
• Estimated fluid sequestration of >6 L
Each item in the list is valued at 1 point. The points are added to
produce a score. If the score ⱖ3, severe pancreatitis is likely; If the
score < 3, severe pancreatitis is unlikely. Predicted mortality is as
follows: Score 0 to 2 – 2% mortality; Score 3 to 4 – 15% mortal-
ity; Score 5 to 6 – 40% mortality; Score 7 to 8 – 100% mortality
CHAPTER 41 • Pancreatitis 809
PREVENTION
Drug-induced pancreatitis is a rare, idiosyncratic dis-
ease. It is important for clinicians to be aware of this
potential adverse event and to consider medications
as potentially causative when other causes of pancre-
atitis are not present. Measurement of serum lipase
and amylase concentrations should be performed in
patients in whom abdominal discomfort develops
and who are taking medications associated with pan-
creatitis.38,197,275,319 Indications for monitoring serum
amylase and lipase concentrations in the absence of
symptoms are less clear. Some suggest monitoring
these parameters in patients taking ACE
inhibitors.320 Routine monitoring has also been sug-
gested for patients receiving mirtazepine treatment.
Particularly when upward dose adjustments are
made. However, this recommendation is based on
only one confirmed case of pancreatitis and two
other reports that describe only asymptomatic eleva-
tions in serum lipase and amylase concentrations.321
Serial serum amylase concentration monitoring and
sonography are not helpful in making an early diag-
nosis of pancreatitis in patients receiving L-asparagi-
nase therapy.98,322-324 In patients with a preexisting
pancreatic disorder, L-asparaginase is contraindicated
because of its well-known pancreatic toxicity.325
The National Institute of Allergy and Infectious
Diseases recommends screening all patients for a
history of pancreatitis before initiating therapy
with didanosine. Patients taking didanosine
should avoid alcohol or other drugs that cause pan-
creatitis. Didanosine therapy should be discontin-
ued during therapy and for 1 week after treatment
with pentamadine or sulfonamides for Pneumo-
cystis jiroveci pneumonia. The dose of didanosine
should be reduced from 400 mg to 250 mg in
patients weighing <60 kg.31,33 Table 41–7 lists some
approaches that can be helpful in the prevention
of drug-induced pancreatitis.
Except in those specific situations described
above, clinical judgment should guide decisions re-
garding whether or not to monitor serum pancreatic
enzyme concentrations in patients receiving drugs
known to induce pancreatitis. In most cases, routine
monitoring is not warranted unless symptoms devel-
op that are suggestive of pancreatitis. The risk for
drug-induced pancreatitis is relatively low. In addi-
tion, asymptomatic (and therefore clinically unim-
portant) hyperamylasemia occurs in association with
many drugs. If abdominal pain, nausea, and vomit-
ing occur in patients being treated with drugs known
to cause pancreatitis, prompt laboratory evaluation
of serum pancreatic enzyme concentrations and
other diagnostics should be initiated.
TisdaleC41_800-818 1/12/10 3:43 PM Page 810
810 SECTION VIII • Drug-Induced Gastrointestinal Diseases
TABLE 41–7 Approaches to Help Prevent Drug-
Induced Pancreatitis
Didanosine
• Adjust dose for weight <60 kg
• Avoid alcohol or other drugs that can cause
pancreatitis
• Avoid use with Pneumocystis jiroveci therapy
Hypercalcemia
• Treat the underlying condition (hyperparathy-
roidism, malignancy, thyrotoxicosis)
Immunosuppressive agents
• Use lowest effective dose of immunosuppressive
agents (tacrolimus, cyclosporine, sirolimus)
Azathioprine, 6-mercaptopurine, mesalamine, cor-ticos-
teroids, metronidazole for inflammatory bo-wel disease
• For patients with abdominal pain, consider pancrea-
titis as part of the differential diagnosis
MANAGEMENT
When drug-induced pancreatitis is suspected, prompt
discontinuation of the suspect agent is necessary.
Traditional therapeutic management of pancreatitis
should be initiated, including administration of intra-
venous fluids, administering nothing by mouth and
providing adequate analgesia.2 Traditionally, meperi-
dine has been used as an analgesic agent in patients
with pancreatitis, as it has been reported to cause less
constriction of the sphincter of Oddi.1 The clinical
importance of this potential advantage has been
debated, however, and morphine may be considered
in patients who require more than 600 mg of meperi-
dine for pain relief or in patients with renal insuffi-
ciency.
INFORMATION FOR PATIENTS
Patients taking medications with an association with
pancreatitis should be instructed to report the onset
of acute abdominal pain immediately to their health
care provider. Some clinicians recommend advising
patients to discontinue the suspected causative drug
immediately and to seek medical attention if they
experience abdominal pain, nausea, or vomiting. If
possible, patients should avoid drugs that have
caused pancreatitis for them in the past.
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