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Comprehensive Dermatologic
Drug Therapy
FOURTH EDITION

Stephen E. Wolverton, MD
Theodore Arlook Professor of Clinical Dermatology
Department of Dermatology
Indiana University School of Medicine
Indianapolis, Indiana, USA

Associate Editor
Jashin J. Wu, MD
Founder and Course Director
San Diego Dermatology Symposium
May 29-31, 2020;
Founder and CEO
Dermatology Research and Education Foundation
Irvine, California, USA
Elsevier
1600 John F. Kennedy Blvd.
Ste 1800
Philadelphia, PA 19103-2899

COMPREHENSIVE DERMATOLOGIC DRUG THERAPY, FOURTH EDITION ISBN: 978-0-323-61211-1

Copyright © 2021 by Elsevier, Inc. All rights reserved.

No part of this publication may be reproduced or transmitted in any form or by any means, electronic or
mechanical, including photocopying, recording, or any information storage and retrieval system, without
permission in writing from the publisher. Details on how to seek permission, further information about the
Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance
Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions.

This book and the individual contributions contained in it are protected under copyright by the Publisher
(other than as may be noted herein).

Notice

Practitioners and researchers must always rely on their own experience and knowledge in evaluating and
using any information, methods, compounds, or experiments described herein. Because of rapid advances
in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be
made. To the fullest extent of the law, no responsibility is assumed by Elsevier, authors, editors, or con-
tributors for any injury and/or damage to persons or property as a matter of products liability, negligence
or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in
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Library of Congress Control Number: 2019952758

Senior Content Strategist: Charlotta Kryhl/Nancy Duffy

Senior Content Development Specialist: Rae L. Robertson
Publishing Services Manager: Deepthi Unni
Senior Project Manager: Beula Christopher
Design Direction: Brian Salisbury

Printed in China

Last digit is the print number: 9 8 7 6 5 4 3 2 1

 This book is dedicated to the following individuals:
To my wife Cheryl, for her support and help over the past 18 months of the
book development and the editorial process, let alone for our 39 years of marriage.
To our sons Dr. Jay Edward Wolverton (age 33) and Justin David Wolverton (age 31),
who continue to enable us to see the world through their creative minds,
kind hearts, and strong relationships.
To my parents Elizabeth Ann (1924–2000) and Dr. George M. Wolverton Sr.
(1925–2011), for the passion, wisdom, compassion, and encouragement provided
throughout their lives; these traits continue to have a positive influence on my life
on a daily basis.
And lastly to my wonderful (and large) nuclear family with three sisters (Anne, Cynthia,
and Pam) and five brothers (George Jr. [1951–1996], Greg, Jeff, Doug, and Dan),
for their kindness to and consideration for others, and their ongoing
camaraderie and generosity.
Stephen E. Wolverton, MD

To my loving wife Stephanie, who lovingly supports my career

over 10 years of marriage.
To my baby boy Conrad, who I hope grows to be a man of maturity, wisdom,
intellect, and strength.
To my parents Shin Wu, MD and Jane Joaquin-Wu, MD, who installed in me the
value of hard work and perseverance: thank you for all that you have given me.
Jashin J. Wu, MD

v
Contributors
David R. Adams, MD, PharmD
Professor of Dermatology
Department of Dermatology
Penn State Hershey Medical Center
Hershey, Pennsylvania, USA
Stewart Adams, MD, FRCP, FAAD
Clinical Lecturer
Department of Medicine
University of Calgary
Calgary, Alberta, Canada
Mina Amin, MD
Department of Dermatology
Kaiser Permanente Los Angeles Medical Center
Los Angeles, California, USA
Nidhi Avashia-Khemka, MD
Assistant Professor of Clinical Dermatology
Department of Dermatology
Indiana University School of Medicine
Indianapolis, Indiana, USA
Kristen M. Beck, MD
Clinical Fellow
Psoriasis and Skin Treatment Center
University of California
San Francisco, California, USA
Bhavnit K. Bhatia, MD
Physician
Department of Dermatology
The Permanente Medical Group
Richmond, California, USA
Sravya Mallam Bhatia, MD
Resident Physician
Department of Dermatology
Duke University Medical Center
Durham, North Carolina, USA
Tina Bhutani, MD
Assistant Professor
Psoriasis and Skin Treatment Center
University of California
San Francisco, California, USA
vi
Jonathan A. Braue, MD
Staff Dermatologist
Cleveland Clinic Indian River Hospital
Scully-Welsh Cancer Center
Vero Beach, Florida, USA
Robert T. Brodell, MD
Professor and Chair
Department of Dermatology
University of Mississippi Medical Center
Jackson, Mississippi, USA;
Instructor
Department of Dermatology
University of Rochester School of Medicine and Dentistry
Rochester, New York, USA;
Professor
Department of Pathology
University of Mississippi Medical Center
Jackson, Mississippi, USA
David G. Brodland, MD
Assistant Professor
Department of Dermatology,
Assistant Professor
Department of Otolaryngology,
Assistant Professor
Department of Plastic Surgery
University of Pittsburgh
Pittsburgh, Pennsylvania, USA
Candace Broussard-Steinberg, MD, BS
Resident
Department of Dermatology
Indiana University School of Medicine
Indianapolis, Indiana, USA
Jeffrey P. Callen, MD, FACP, MAAD, MACR
Professor of Medicine (Dermatology)
Chief
Division of Dermatology
University of Louisville School of Medicine
Louisville, Kentucky, USA
 Contributors vii

Charles Camisa, MD, FAAD Cynthia M.C. DeKlotz, MD, MASt

Director and Founder Assistant Professor of Clinical Medicine and Pediatrics
Psoriasis Treatment Center Internal Medicine and Pediatrics
Riverchase Dermatology Division of Dermatology
Naples, Florida, USA; Georgetown University School of Medicine;
Affiliate Associate Professor Pediatric and Adult Dermatologist
Department of Dermatology and Cutaneous Surgery Department of Dermatology
University of South Florida MedStar Washington Hospital Center/Georgetown University
Tampa, Florida, USA Hospital
Washington, District of Columbia, USA
Ahmad Chehade, PharmD
Clinical Pharmacist Gabrielle-Eugenie Duprat, MD
Calgary, Alberta, Canada Indiana University School of Medicine
Indianapolis, Indiana, USA
Margot Chima, MC
Resident William H. Eaglstein, MD
Department of Dermatology Professor and Chairman Emeritus
Icahn School of Medicine at Mount Sinai The Doctor Phillip Frost Department of Dermatology and
New York, New York, USA Cutaneous Surgery
University of Miami Miller School of Medicine
Richard A. Clark, MD Miami, Florida, USA
Professor
Department of Biomedical Engineering and Dermatology Carly A. Elston, MD
Stony Brook University Assistant Professor
Stony Brook, New York, USA Department of Dermatology
University of Alabama at Birmingham
Abigail Cline, MD, PhD Birmingham, Alabama, USA
Resident Physician
Department of Dermatology Dirk M. Elston, MD
Metropolitan Hospital Professor and Chair
New York, New York, USA Department of Dermatology
Medical University of South Carolina
Kelly M. Cordoro, MD Charleston, South Carolina, USA
Professor of Dermatology and Pediatrics
University of California Ashley N. Emerson, MD
San Francisco, California, USA Assistant Professor
Department of Dermatology
Julio C. Cruz Ramón, MD University of Mississippi Medical Center
Dermatologist and Dermatopathologist Jackson, Mississippi, USA
Buckeye Dermatology
Dublin, Ohio, USA Stephanie K. Fabbro, MD
Attending Dermatologist
Loretta S. Davis, MD Department of Dermatology
Professor and Chair Buckeye Dermatology
Department of Dermatology, Columbus, Ohio, USA
Residency Program Director
Medical College of Georgia Steven R. Feldman, MD, PhD
Augusta University Professor
Augusta, Georgia, USA Department of Dermatology
Wake Forest School of Medicine
Salma de la Feld, MD Winston-Salem, North Carolina, USA
Assistant Professor
Department of Dermatology Laura K. Ferris, MD, PhD
Emory University Associate Professor of Dermatology
Augusta, Georgia, USA University of Pittsburgh
Pittsburgh, Pennsylvania, USA

Kelly A. Foley, PhD

Medical Research Associate
Department of Dermatology
Mediprobe Research Inc.
London, Ontario, Canada
viii Contributors

Seth B. Forman, MD Aditya K. Gupta, MD, PhD, FRCP(C)

Dermatologist Professor
Dermatology Division of Dermatology, Department of Medicine
Department of ForCare Medical Group University of Toronto
Tampa, Florida, USA Toronto, Ontario, Canada;
Director
Craig Garofola, DO Mediprobe Research Inc.
PGY4 Dermatology Resident London, Ontario, Canada
Virginia College of Osteopathic Medicine/Lewis Gale
Montgomery Anita Haggstrom, MD
Blacksburg, Virginia, USA Associate Professor
Department of Dermatology
Jeffrey R. Gehlhausen, MD, PhD Indiana University
Resident Physician Indianapolis, Indiana, USA
Department of Dermatology
Yale New Haven Hospital Christopher T. Haley, MD
New Haven, Connecticut, USA Clinical Research Fellow
Department of Dermatology
Joel M. Gelfand, MD, MSCE Center for Clinical Studies
Professor of Dermatology and Epidemiology Webster, Texas, USA
Departments of Dermatology and Biostatisitcs, Epidemiology
and Informatics Russell P. Hall III, MD
University of Pennsylvania Perelman School of Medicine J. Lamar Callaway Professor and Chair
Philadelphia, Pennsylvania, USA Department of Dermatology
Duke University Medical Center
Michael Girardi, MD Durham, North Carolina, USA
Professor, Vice Chair, and Residency Program Director
Department of Dermatology Iltefat Hamzavi, MD, FAAD
Yale School of Medicine Senior Staff Physician
New Haven, Connecticut, USA Department of Dermatology
Henry Ford Health System;
Tobias Goerge, MD Clinical Associate Professor
Professor of Dermatology Wayne State University SOM
Department of Dermatology Detroit, Michigan, USA
University of Münster
Münster, Germany Michael P. Heffernan, MD
US Dermatology Lead
Kenneth B. Gordon, MD Department of Dermatology
Professor and Chair Probity Medical Research
Department of Dermatology San Luis Obispo, California, USA
Medical College of Wisconsin
Milwaukee, Wisconsin, USA Yolanda R. Helfrich, MD
Associate Professor
Teri M. Greiling, MD, PhD Department of Dermatology
Assistant Professor University of Michigan Medical School
Department of Dermatology Ann Arbor, Michigan, USA
Oregon Health and Science University
Portland, Oregon, USA Adam B. Hessel, MD
Adjunct Assistant Professor
Erin E. Grinich, MD Department of Dermatology
Resident Physician The Ohio State University
Department of Internal Medicine Columbus, Ohio, USA;
Loma Linda University Medical Center Dermatologist and Dermatopathologist
Loma Linda, California, USA Buckeye Dermatology
Dublin, Ohio, USA
Daniel Grove, MD
Resident Shauna Higgins, MD
Department of Dermatology Clinical Research Fellow
Indiana University Department of Dermatology
Indianapolis, Indiana, USA University of Nebraska Medical Center
Omaha, Nebraska, USA
 Contributors ix

Whitney A. High, MD, JD, MEng Hee Jin Kim, MD

Professor and Vice Chairman Dermatology Resident
Departments of Dermatology and Pathology Department of Dermatology
University of Colorado Icahn School of Medicine at Mount Sinai
Denver, Colorado, USA New York, New York, USA

Katherine Hrynewycz, BS, MD Sa Rang Kim, MD

Dermatology Resident Department of Dermatology
Department of Dermatology Yale School of Medicine
Indiana University New Haven, Connecticut, USA
Indianapolis, Indiana, USA
Melanie Kingsley, MD
Sylvia Hsu, MD Director of Cosmetic Dermatology and Laser Surgery
Professor and Chair Department of Dermatology
Department of Dermatology Indiana University School of Medicine
Temple University Lewis Katz School of Medicine Indianapolis, Indiana, USA
Philadelphia, Pennsylvania, USA
Sandra R. Knowles, BScPhm [Retired]
Michael J. Huether, MD Drug Information Pharmacist
Medical Director Department of Pharmacy
Mohs Micrographic Surgery Sunnybrook Health Sciences Centre
Arizona Skin Cancer Surgery Center, P.C. Toronto, Ontario, Canada
Tucson, Arizona, USA
John Y.M. Koo, MD
Michael J. Isaacs, MD Professor
Physician Psoriasis and Skin Treatment Center
Department of Dermatology University of California
Indiana University School of Medicine San Francisco, California, USA
Indianapolis, Indiana, USA
Carol L. Kulp-Shorten, MD
Michael S. Kaminer, MD Clinical Professor of Medicine (Dermatology)
Associate Clinical Professor Departments of Medicine/Dermatology
Department of Dermatology University of Louisville School of Medicine
Yale Medical School Louisville, Kentucky, USA
New Haven, Connecticut, USA;
Assistant Clinical Professor Megan N. Landis, MD
Department of Dermatology Clinical Associate Professor of Dermatology
Brown Medical School Department of Medicine
Providence, Rhode Island, USA Division of Dermatology
University of Louisville
Prasanthi Kandula, MD Louisville, Kentucky, USA;
Department of Dermatology Dermatologist
SkinCare Physicians Department of Dermatology
Chestnut Hill, Massachusetts, USA The Dermatology and Skin Cancer Center of Southern Indiana
Corydon, Indiana, USA
Swetha Kandula, MD, FAAD
Founder Mark G. Lebwohl, MD
Dermatology and Skincare Arts Chairman
Parsippany, New Jersey, USA Department of Dermatology
Icahn School of Medicine at Mount Sinai
Sewon Kang, MD, MPH New York, New York, USA
Noxell Professor and Chairman
Department of Dermatology Erica B. Lee, MD
Johns Hopkins School of Medicine Department of Internal Medicine
Baltimore, Maryland, USA Santa Barbara Cottage Hospital
Santa Barbara, California, USA
Marshall B. Kapp, JD, MPH
Director and Professor Emeritus
Center for Innovative Collaboration in Medicine and Law
Florida State University
Tallahassee, Florida, USA
x Contributors

Katherine B. Lee, MD David Martell, DO

Assistant Clinical Professor Chief of Dermatology
Department of Dermatology Department of Medicine
University of California, Irvine Irwin Army Community Hospital
Irvine, California, USA; Fort Riley, Kansas, USA
Medical Director
Halcyon Dermatology Rachel R. Mays, BSc
Laguna Hills, California, USA Research Associate
Department of Dermatology
Amy B. Lewis, MD Mediprobe Research Inc.
Clinical Assistant Professor London, Ontario, Canada
Department of Dermatology
Yale University School of Medicine Linda F. McElhiney, PharmD, RPh, MSP
New Haven, Connecticut, USA Team Lead Compounding Pharmacist
Compounding Pharmacy
Geoffrey F.S. Lim, MD Indiana University Health
Medical Director Indianapolis, Indiana, USA
Mohs Micrographic Surgery and Dermatologic Oncology
OptumCare Medical Group Ginat W. Mirowski, DMD, MD
Colorado Springs, Colorado, USA Adjunct Associate Professor
Department of Oral Pathology, Medicine Radiology
Henry W. Lim, MD Indiana University School of Dentistry;
Former Chair Clinical Professor
Department of Dermatology Department of Dermatology
Henry Ford Hospital; Indiana University School of Medicine
Senior Vice President for Academic Affairs Indianapolis, Indiana, USA
Henry Ford Health System
Detroit, Michigan, USA Shoko Mori, MD
Research Fellow
Benjamin N. Lockshin, MD Dermatology Service
Director of the Clinical Trials Center Memorial Sloan Kettering Cancer Center
U.S. Dermatology Partners New York, New York, USA
Rockville, Maryland, USA;
Assistant Professor Kiran Motaparthi, MD
Department of Dermatology Associate Professor
Georgetown University Department of Dermatology
Washington, Maryland, USA University of Florida College of Medicine
Gainesville, Florida, USA
Thomas A. Luger, MD
Professor of Dermatology Uyen Ngoc Mui, MD
Department of Dermatology Clinical Research Fellow
University of Münster Department of Dermatology
Münster, Germany Center for Clinical Studies
Houston, Texas, USA
Jacquelyn Majerowski, MD, BS
Resident, PGY-4 Christian Murray, MD, FRCPC
Department of Dermatology Associate Professor
Medical College of Wisconsin Departments of Dermatology/Medicine
Milwaukee, Wisconsin, USA University of Toronto
Toronto, Ontario, Canada
Lawrence A. Mark, MD, PhD
Associate Professor of Clinical Dermatology Colton Nielson, MD
Department of Dermatology Resident Physician
Indiana University School of Medicine Department of Dermatology
Indianapolis, Indiana, USA University of Florida
Gainesville, Florida, USA
Dana Marshall, MD, FAAD
Board Certified Dermatologist Megan H. Noe, MD, MPH, MSCE
Klinger and Marshall Dermatology Clinical Instructor
Gretna, Louisiana, USA Department of Dermatology
University of Pennsylvania
Philadelphia, Pennsylvania, USA
 Contributors xi

Ginette A. Okoye, MD Dana L. Sachs, MD

Professor and Chair Professor
Department of Dermatology Department of Dermatology
Howard University College of Medicine University of Michigan
Washington, District of Columbia, USA Ann Arbor, Michigan, USA

Cindy England Owen, MD, MS Naveed Sami, MD

Associate Clinical Professor Professor
Department of Dermatology Departments of Internal Medicine and Dermatology
University of Louisville University of Central Florida
Louisville, Kentucky, USA Orlando, Florida, USA

Timothy Patton, DO Marty E. Sawaya, MD, PhD

Assistant Professor of Dermatology President
Department of Dermatology Department of Dermatology
University of Pittsburgh Sujo Co.
Pittsburgh, Pennsylvania, USA Ocala, Florida, USA

Warren W. Piette, MD Courtney R. Schadt, MD

Chair Associate Professor
Division of Dermatology Division of Dermatology
Department of Internal Medicine University of Louisville
John H. Stroger, Jr. Hospital of Cook County; Louisville, Kentucky, USA
Professor
Department of Dermatology William Schaffenburg, MD
Rush University Medical Center Department of Dermatology
Chicago, Illinois, USA Walter Reed National Military Medical Center
Bethesda, Maryland, USA
Sahand Rahnama-Moghadam, MD, MS
Assistant Professor of Dermatology Bethanee J. Schlosser, MD, PhD
Department of Dermatology Assistant Professor
Indiana University Department of Dermatology
Indianpolis, Indiana, USA Northwestern University
Chicago, Illinois, USA
Sarika Manoj Ramachandran, MD, FAAD
Assistant Professor Sahil Sekhon, MD
Yale University School of Medicine Resident Physician
New Haven, Connecticut, USA Department of Dermatology
Howard University
Elizabeth A. Rancour, MD Washington, District of Columbia, USA
Dermatologist
Private Practice Vidhi V. Shah, MD
Missouri Dermatology Laser and Vein Center Department of Dermatology
St. Louis, Missouri, USA University of South Florida
Tampa, Florida, USA
Jaggi Rao, MD, FRCPC
Board Certified Dermatologist Lori E. Shapiro, MD, FRCPC
Clinical Professor of Medicine Staff Physician
University of Alberta Department of Dermatology
Edmonton, Alberta, Canada Department of Clinical Pharmacology
Drug Safety Clinic
Misha Rosenbach, MD Sunnybrook Health Sciences Centre
Associate Professor of Dermatology and Internal Medicine Toronto, Ontario, Canada
Vice Chair, Education and Training
Director, Dermatology Inpatient Consult Service Neil H. Shear, BASc, MD, FRCPC, FACP
Perelman School of Medicine at the University of Pennsylvania Professor
Philadelphia, Pennsylvania, USA Department of Medicine (Dermatology, Clinical Pharmacology)
University of Toronto;
Katherine Roy, MD Dermatologist-in-Chief
Dermatologist, Dermatopathologist Department of Dermatology
Dermatology Group of the Carolinas Sunnybrook Health Sciences Centre
Concord, North Carolina, USA Toronto, Ontario, Canada
xii Contributors

Michael Sheehan, MD Stephen K. Tyring, MD, PhD, MBA

Dermatology Physicians Inc. Clinical Professor
Columbus, Indiana, USA Department of Dermatology
University of Texas Health Science Center;
Eric L. Simpson, MD, MCR Medical Director
Professor Department of Dermatology
Department of Dermatology Center for Clinical Studies
Oregon Health and Science University Houston, Texas, USA
Portland, Oregon, USA
Kaitlin Vogt-Schiavo, MD
Alexandra Snodgrass, MD Department of Dermatology
Department of Dermatology Indiana School of Medicine
University of Florida College of Medicine Indianapolis, Indiana, USA
Gainesville, Florida, USA
Raj Vuppalanchi, MBBS
Nowell Solish, MD FRCP Professor of Medicine
Assistant Professor Department of Medicine–Gastroenterology
Department of Dermatology Indiana University School of Medicine
University of Toronto Indianapolis, Indiana, USA
Toronto, Ontario, Canada
Steve Q. Wang, MD
Ally-Khan Somani, MD, PhD Director of Dermatologic Surgery and Dermatology
Assistant Professor, Dermatology Service
Director of Dermatologic Surgery and Cutaneous Oncology, Memorial Sloan Kettering Cancer Center
Director of Micrographic Surgery and Dermatologic Oncology New York, New York, USA
Dermatology,
Adjunct Assistant Professor of Otolaryngology Gillian Weston, MD
Department of Otolaryngology-Head and Neck Surgery Department of Dermatology
Indiana University School of Medicine University of Connecticut Health Center
Indianapolis, Indiana, USA Farmington, Connecticut, USA

Najwa Somani, MD, FRCPC Stephen E. Wolverton, MD

Assistant Professor Theodore Arlook Professor of Clinical Dermatology
Department of Dermatology Department of Dermatology
Indiana University School of Medicine Indiana University School of Medicine
Indianapolis, Indiana, USA Indianapolis, Indiana, USA

Bruce Strober, MD, PhD Jashin J. Wu, MD

Department of Dermatology Founder and Course Director
Yale University San Diego Dermatology Symposium
New Haven, Connecticut, USA May 29-31, 2020;
Founder and CEO
Mathias Sulk, MD Dermatology Research and Education Foundation
Department of Dermatology Irvine, California, USA
University of Münster
Münster, Germany Ashley Wysong, MD, MS
Founding Chairman
Kathleen C. Suozzi, MD William W. Bruce MD Distinguished Chair of Dermatology
Assistant Professor, Department of Dermatology
Director, Aesthetic Dermatology University of Nebraska Medical Center
Department of Dermatology Omaha, Nebraska, USA
Yale School of Medicine
New Haven, Connecticut, USA John Zic, MD, MMHC
Professor of Dermatology
Michael D. Tharp, MD Department of Dermatology
Chair and Professor Emeritus Vanderbilt University Medical Center
Department of Dermatology Nashville, Tennessee, USA
Rush University Medical Center
Tampa, Florida, USA Jeffrey P. Zwerner, MD, PhD
Assistant Professor
Mary M. Tomayko, MD, PHD Department of Dermatology
Associate Professor Vanderbilt University
Departments of Dermatology and Pathology Nashville, Tennessee, USA
Yale University School of Medicine
New Haven, Connecticut, USA
Preface

This fourth edition of Comprehensive Dermatologic Drug Therapy Section 6—Drug interactions (20 questions)b
has been both a challenge and a joy to edit. The challenge has been Section 7—Miscellaneous issues (6 questions)
primarily in keeping up with the rapidly changing landscape of Appendix 2 The most potentially serious drug interactions con-
dermatologic therapy. The joy has been the continued refinement tains 35 categories of serious/potentially life-threatening drug
of an approach to summarizing vast quantities of information on interactions condensed from the almost 30 fully updated drug
dermatologic drugs in various formats that have been consistently interaction tables throughout this book.
popular with readers. This preface will include describing new
chapters, appendices, and special features to enhance learning and New features in this edition
retrieval of information in this book.
Counting the original book, Systemic Drugs for Skin Diseases, • Drug Risks Profile boxes—at a glance the reader can quickly
published in 1991, the contents have grown from 17 chapters to review a drug’s (a) Contraindications, (b) Boxed Warnings,
70 chapters in this fourth edition of Comprehensive Dermatologic (c) Warnings & Precautions, and (d) Pregnancy Prescribing
Drug Therapy. Status (both traditional ratings and our summation of 2015
US Food and Drug Administration updates)
New chapters in this edition • General updates—include (a) typically 2 to 4 new questions at
the beginning of each chapter, and (b) substantial updating of
Chapter 5 Medical decision- references in all chapters
making principles
Chapter 18 PDE-4 inhibitors apremilast, tofacitinib Traditional features continued in this edition
and JAK inhibitors
Chapter 28 IL 17 inhibitors secukinumab, ixeki-
• Monitoring guidelines boxes: This feature has been a long-term
zumab, brodalumab
favorite for clinicians
• Drug interactions tables: These fully updated tables are derived
Chapter 29 IL 23 inhibitors guselkumab, tildraki-
from Facts and Comparisons e-answers and Hansten and Horn’s
zumab, risankizumab
Top 100 Drug Interactions databases, formatted in a new fash-
Chapter 31 Other biologic dupilumab, omalizum- ion with interactions listed with overall descending order of
agents ab, newer agents risk
Chapter 38 Hedgehog inhibitors vismodegib, sonidegib • Drug structures
• Drug mechanism flow diagrams
• Key pharmacology concepts
New appendices in this edition • Adverse effects boxes
Appendix 1 Core questionsa for understanding systemic derma- … and many other features continued from prior book
tology drugs (“Review test”) editions!
Section 1—Pharmacology basic science (67 questions) Enjoy the learning and information retrieval process!
Section 2—Clinical use (75 questions)
Section 3—Severe adverse effects (61 questions) Stephen E. Wolverton, MD (Senior Editor, SEW)
Section 4—Less serious adverse effects (24 questions) Jashin J. Wu, MD (Associate Editor, JJW)
Section 5—Drug safety monitoring (27 questions)

a280 open-ended high-yield questions selected from the roughly 800 ques-
tions at the beginning of each chapter, many of which have 2 to 4 components
to the questions. Each question lists the book page number(s) for the answer.
bSee also Appendix 2 for the highest-risk drug interactions

xiii
Acknowledgments
We would like to sincerely thank and applaud the following indi-
viduals for their energetic and kind support of our journey through
the book development and editorial process for the fourth edition
of Comprehensive Dermatologic Drug Therapy. We are indebted to
all of you for your time and expertise.
I am very grateful for the expert assistance from my Associate
Editor Jashin J. Wu, MD. Jay was the primary editor for 12 chap-
ters including all but one of the six new chapters. Jay’s extensive
experience in clinical trials was of great value!
To Elsevier
We are most grateful to the book Acquisitions Editors Char-
lotta Kryhl and Nancy Duffy, the Senior Content Development
Specialists Humayra Khan and Rae Robertson and the Project
Manager Beula Christopher. These individuals have been remark-
able in the author communications, attention to detail in editing,
and accommodating to our planning strategies and subsequent
adjustments.
Thanks to Elsevier for the broader role in oversight from the
beginning of book development through marketing the final
product.
To the Indiana University Department of
Dermatology
My colleagues (current and past) from Indiana University Depart-
ment of Dermatology who contributed chapters: Candace Brous-
sard-Steinberg, Gabriella Duprat, Jeff Gehlhausen, Daniel Grove,
Anita Haggstrom, Kate Hrynewicz, Michael Isaacs, Prasanthi
Kandula, Swetha Kandula, Melanie Kingsley, Kathy Lee, Ben
xiv
Lockshin, Lawrence Mark, Ginat Mirowski, Sahand Rahnama,
Elizabeth Rancour, Kaitlin Schiavo, Michael Sheehan, Ally-Khan
Somani, and Najwa Somani.
To the ‘States’ and the World (the authors)
The 128 authors for this edition responded very, very well to the
task of updating earlier chapters and creating totally new ones.
These authors responded in a superb fashion to the challenges
we set for them. In particular, we wish to highlight the following
individuals:
• The five authors who contributed to all five versions of the books
I have edited (including the original title Systemic Drugs from
Skin Diseases, 1991 edition): Jeff Callen, Charles Camisa, Loree
Davis, Marshall Kapp, and Carol Kulp-Shorten.
• The international cast of 12 authors from Canada and Europe:
Stewart Adams, Robert Bissonnette, Tobias Goerge, Aditya
Gupta, Sandra Knowles, Thomas Luger, Christian Murray,
Jaggi Rao, Lori Shapiro, Neil Shear, Nowell Solish, and Math-
ias Sulk.
• The senior authors who contributed to two chapters: Jeff Cal-
len, Charles Camisa, Seth Forman, Melanie Kingsley, John
Koo, Megan Landis, Ben Lockshin, Kiran Motaparthi, Kather-
ine Roy, and Neil Shear.
Thanks to all remaining authors who took time away from
their full-time roles as clinicians and educators, while providing
fresh ideas along with tremendous personal experience and exper-
tise for the remaining chapters of this fourth edition of Compre-
hensive Dermatologic Drug Therapy. We acknowledge the entire list
of authors who spent countless of hours writing and editing their
chapters for this textbook.
 PART I Introduction
1
Basic Principles of
Pharmacology
STEPHEN E. WOLVERTON
QUESTIONS
Q1.1 What are the simplest definitions of ‘pharmacokinetics’,
‘pharmacodynamics’, and ‘pharmacogenetics’? (Pg. 1, Table 1.1)
Q1.2 What are several drugs or drug families for which the absorp-
tion may be altered by (1) food, (2) cations such as iron, calcium,
and magnesium, and (3) variations in gastric pH? (Pg. 2)
Q1.3 What are some of the pros and cons to the decision of
whether to calculate drug dose on (1) actual body weight,
(2) ideal body weight? (Pg. 3)
Q1.4 What are several examples in which sustained exposure to
a drug may give reduced positive or negative pharmacologic
effects at the drug receptor level? (Pg. 4, Table 1.4)
Q1.5 What are several of the most important agonists and
antagonists at the level of specific receptors? (Pg. 4, Table 1.5)
Q1.6 What are several of the most important examples in which
drugs inhibit specific enzymes? (Pg. 6, Table 1.6)
Introduction
This chapter is a relatively brief overview of basic principles of
pharmacology, intended as a primer to maximize understand-
ing of the remaining chapters of the book. There is by design
some overlap with other chapters in the book, in order to address
relevant issues from a number of vantage points. Of particular
relevance to this chapter are the following: Chapter 2 Principles
for Maximizing the Safety of Dermatologic Drug Therapy; Chap-
ter 62 Hepatotoxicity of Dermatologic Drug Therapy (contains
detailed information on hepatic metabolism of drugs); and Chap-
ter 66 Drug Interactions. The reader is encouraged to pursue fur-
ther detailed information and references (cited in the respective
chapters for specific drugs) for drug examples used to illustrate
basic principles of pharmacology in this chapter. In this chapter,
only a bibliography format for references on pharmacologic gen-
eral principles is used.
The primary focus of this chapter will be on pharmacologic
principles related to systemic drugs. A relatively brief section on
percutaneous absorption will conclude the chapter. The basic goal
Q1.7 What are several important examples of active drug and
active metabolite relationships? (Pg. 7, Table 1.9)
Q1.8 What are several of the most important examples of prodrug
and active drug relationships? (Pg. 8, Table 1.8)
Q1.9 Pertaining to drug excretion, (1) what are three important
routes of drug excretion, and (2) what is the overall general
change in the active drug properties that makes excretion
possible? (Pg. 8)
Q1.10 What are five of the most important basic components that
determine percutaneous absorption of topical medications in
general? (Pg. 8)
Q1.11 What are the some of the additional cutaneous properties
and therapeutic maneuvers that alter the degree of percutane-
ous absorption in individual patients? (Pg. 9, Table 1.10)
of this chapter (and for the rest of the book) is to describe and
illustrate pharmacologic principles that will enable the clinician
to maximize the efficacy and minimize the risk (adverse effects
[AE], drug interactions) of dermatologic drug therapy. It is my
hope that this chapter will provide a broad foundation for true
understanding of pharmacology to enable clinicians to achieve:
1. More efficient assimilation of new information on medica-
tions;
2. Adaptability to the many unpredictable responses of patients
to medications;
3. Better long-term retention of important information on all
aspects of drug therapy.
Outline for the Chapter
Q1.1 Traditionally, discussions on basic pharmacology divide
the topic into two domains (Table 1.1): pharmacokinetics (what
the body does to the drug) and pharmacodynamics (what the drug
does to the body). As a relatively novel way of presenting this
information, I will discuss topics in sequence as seen through the
1
2 PA RT I Introduction
TABLE
1.1 Three ‘Entry Level’ Definitions
Term Definition
Pharmacokinetics What the body does to the drug—from entry
into the body until excretion of the drug
and/or its metabolites
Pharmacodynamics What the drug does to the body—once at site
of action; from receptor binding through
the definitive effect (desired or adverse)
Pharmacogenetics Interindividual genetic alterations that
produce variations in both pharmacokinetic
and pharmacodynamic aspects of drug
therapy
‘eyes’ of the drug as it progresses through the human body. In
broad strokes, the sequence will be:
1. Pharmacokinetics (part I—absorption, distribution, bioavail-
ability): the drug must enter the body, travel to, and be ‘avail-
able’ at the site of desired pharmacologic action;
2. Pharmacodynamics: the drug interacts with a receptor/effector
mechanism, producing both desirable and undesirable effects;
3. Pharmacokinetics (part II—metabolism, excretion): the drug
and/or its metabolites must leave the body.
Each of the above steps has a number of variables (with both
predictable and unpredictable components) for which the clini-
cian should have at least a baseline working knowledge. These
variables will be presented and illustrated under each chapter
heading that follows.
Pharmacokinetics—Part I (Tables 1.2 and
1.3)
Drug Absorption (The Drug has to be Absorbed
and Enter Circulation)
The routes of drug administration most pertinent to dermatology,
in order of descending frequency of use, are topical, oral, intra-
lesional, and intramuscular. Intravenous drug administration is
uncommonly ordered by the dermatologist. Typically, drugs must
be relatively lipophilic (nonionized, nonpolar) to ‘enter’ the body
by topical or oral routes, whereas relatively hydrophilic (ionized,
polar) drugs can still ‘enter’ by intramuscular and intravenous
routes. Upon absorption, drugs still must traverse other cell mem-
branes in order to reach the intended destination(s). Again, a drug
with lipophilic qualities is rewarded by the ability to traverse these
lipid bilayers in order to arrive at the site of desired pharmacologic
action.
Several other variables may affect the absorption of drugs by
oral administration. Q1.2 Certain drugs are absorbed less effi-
ciently in the presence of food. In descending order, the impact of
food on tetracycline family drug absorption is as follows: tetracy-
cline > doxycycline > minocycline. Divalent and trivalent cations
in milk (calcium), various traditional antacids (aluminum-, mag-
nesium-, calcium-containing), and iron-containing products can
reduce the absorption of the above tetracyclines, as well as fluo-
roquinolone antibiotics. Gastric pH is yet another variable that
influences drug absorption. An example would be the necessity for
TABLE
1.2 Pharmacokinetics—Major Components
Component Most Important Issues
Absorption Relatively lipophilic drugs are more optimally
absorbed through the gastrointestinal tract;
lipophilic or hydrophilic drugs are relatively
equal for parenteral absorption
Distribution Body compartments to which the drug is dis-
persed; important subcomponents include fatty
tissues and blood–brain barrier
Bioavailability Percentage of administered drug reaching circula-
tion; also relates to free (active drug) vs protein-
bound drug (inactive drug)
Metabolism Lipophilic drugs are converted to more hydrophilic
metabolites to enable excretion
Excretion The above conversion to hydrophilic metabolites
allows renal or biliary excretion; other syn-
onyms—clearance, elimination
These components as related to oral (enteral) or parenteral administered drugs.
a relatively low gastric pH for ketoconazole and itraconazole to be
optimally absorbed, whereas gastric pH is not a critical determi-
nant for fluconazole absorption. The above absorption variables
are the basis for a number of drug interactions that do not involve
the cytochrome P-450 (CYP) system.
A few other points are worth considering under this heading.
Some drugs have negligible absorption with oral administra-
tion, yet can have a pharmacologic effect in the gastrointestinal
(GI) tract. Several examples would be the use of oral cromolyn
sodium (Gastrochrome) for the GI manifestations of masto-
cytosis, as well as the use of nystatin for reduction of bowel
Candida levels. A number of medications are available in sus-
tained-release preparations, in which the drug vehicle is modi-
fied to allow a steady, slow rate of drug absorption. Finally, the
addition of a vasoconstrictor (epinephrine) to local anesthetics
will slow absorption of the anesthetic and, therefore, prolong
the duration of anesthesia after intralesional injection of the
anesthetic.
Distribution (The Drug has to Travel to the Site
of Intended Action or to a Reservoir)
This somewhat mundane component of pharmacokinetics has sev-
eral applications in dermatologic therapeutics. With oral adminis-
tration of drugs for dermatologic purposes, there are at least four
compartments of great interest to which a drug can be distributed:
1. Circulation: important to widespread drug effects, both desir-
able and adverse;
2. Cutaneous: logically of central importance to the desired phar-
macologic effects;
3. Fatty tissue: at both cutaneous and internal sites; very impor-
tant to highly lipophilic drugs, creating a ‘reservoir’ for pro-
longed release of the drug (as with etretinate);
4. Past the ‘blood–brain barrier’: of importance to dermatology
primarily for lipophilic drugs with the potential for sedation or
other central nervous system AE (first-generation H1 antihista-
mines, sedation; minocycline, dizziness).
 CHAPTER 1 Basic Principles of Pharmacology 3

TABLE
1.3 Definitions and Concepts Central to Understanding Pharmacokinetics

Term Definition
Bioactivation Either (1) conversion of prodrug to any active drug, or (2) conversion of the active drug to a reactive, electrophilic meta-
bolic intermediate
Bioequivalencea Generally referring to overall ‘equal’ bioavailability between two comparable drugs; usually between generic and trade
name formulations of a drug
Biotransformation In general, the metabolic change of a lipophilic drug to a more hydrophilic metabolite allowing renal or biliary excretion
Blood–brain barrier Protective mechanism for brain neurons; due to tight junctions (and lack of intercellular pores) in brain capillaries; highly
lipophilic drugs may ‘overcome’ this barrier
Detoxification The metabolic conversion of a reactive, electrophilic intermediate to a more stable, usually more hydrophilic compound
Enteral GI administration of a drug
Enterohepatic recirculation Sequence of initial GI absorption of drug followed by hepatic excretion into bile and small bowel, followed by subsequent
GI reabsorption
First-pass effect Drugs which have significant metabolism in the liver, before widespread systemic distribution—occurs after GI absorp-
tion, by way of portal vein to liver
Half-life Duration of time for 50% of the absorbed and bioavailable drug to be metabolized and excreted
Parenteral Literally ‘around enteral’; either intravenous, intramuscular, or subcutaneous administration
Pharmacogenetics The inherited aspects of drug pharmacokinetics and pharmacodynamics which alter the likelihood of various pharmaco-
logic effects (positive or negative)
Prodrug A pharmacologically inactive precursor of the biologically active ‘drug’
Steady state A balance between the amount of drug being absorbed and the amount being excreted; in general the time to reach
steady state is four to five ‘half-lives’
Terminal elimination Elimination/clearance of drug from all body compartments to which the drug is distributed
Therapeutic index The ratio of (1) the drug dose required to give a desired pharmacologic response, to (2) the drug dose that leads to
significant adverse effects
Therapeutic range Range of circulating drug levels deemed to give optimal efficacy and minimal adverse effects

Tissue reservoirs Body locations to which a given drug is distributed, from which the drug is very slowly released—includes sites such as
fatty tissues, stratum corneum
aThe US Food and Drug Administration definition for ‘bioequivalence’ requires that the bioavailability of the proposed generic drug must have a 95% confidence interval between 80% and 120% of the
trade name drug’s bioavailability.
GI, Gastrointestinal.

Fortunately, there are alternatives to the above drugs that do
not readily cross the blood–brain barrier (second-generation H1
antihistamines; doxycycline, tetracycline).
Q1.3 Many systemic drugs discussed in this book have dos-
ages based on body weight. Included are drugs with doses calcu-
lated per kilogram of body weight (isotretinoin, etretinate) and
dose calculated per meter squared (bexarotene—Targretin). The
question arises as to what to do with dosage calculations for very
obese patients. There are both drug cost implications and poten-
tial AE implications for very high drug doses. I tend to calculate
dosages based more on ‘ideal weight’ for several reasons. Aside
from treatment of panniculitis, there are virtually no indications
for which the site of desired pharmacologic effect is in fatty tis-
sue. Highly lipid-soluble drugs are readily distributed to fatty
tissues, but when a steady state is reached, there is steady release
back into the circulation. When considering efficacy, risk, and
cost, all three point toward maximizing the dosage using cal-
culations based on ideal (or close to ideal) body weight (IBW),
perhaps allowing for a small ‘fudge factor’ on the high side for
very heavy patients who do not respond to traditional doses.
One set of formulas from the life insurance industry for calculat-
ing ‘ideal weight’ is as follows: (1) females IBW = 100 lb for 5 ft
tall + 5 lb/inch over 5 ft, and (2) males IBW = 106 lb for 5 ft tall
+ 6 lb/inch over 5 ft, and (3) an upward ‘adjustment’ up to 10%
based on a ‘large frame.’
Conceptually, there are three drug ‘reservoirs’ of significant
interest to dermatology. The first is in systemic circulation, in the
form of drug-protein binding. The bound drug is pharmacologi-
cally inactive, whereas the unbound drug = free drug = pharmaco-
logically active drug. Acidic drugs are most commonly bound to
albumin, whereas basic drugs bind preferentially to α-1 acidic gly-
coprotein. There are noteworthy exceptions regarding lipophilic
drugs with intracellular physiologic receptor–effector systems
such as corticosteroids (CS) and retinoids. There is a large circula-
tory reservoir for highly protein-bound drugs such as methotrex-
ate. Sudden increases in the free drug levels due to displacement
4 PA RT I Introduction
of methotrexate from circulatory protein-binding sites by aspirin,
nonsteroidal anti-inflammatory drugs, and sulfonamides can
markedly increase the risk for pancytopenia (although the body
can adjust to this drug displacement over time). The second drug
reservoir of interest is in various fatty tissues (including, but not
limited to, subcutaneous fat) for highly lipophilic drugs, as dis-
cussed in the preceding paragraph. The third drug reservoir (the
stratum corneum) pertains just to percutaneous absorption for
topically applied medications. In all three settings the free drug
and the drug in the reservoir are in equilibrium. As the free drug
is metabolized and excreted, corresponding amounts of the drug
in these tissue and circulatory reservoirs are released into the free/
active drug fraction.
Bioavailability (The Drug has to be ‘Available’ at
The Site of Intended Action)
Bioavailability is expressed as the percentage of the total drug
dose administered that reaches the circulation. For a drug taken
orally, the ‘first-pass effect’ of hepatic metabolism reduces bio-
availability. The bioavailability calculations include both free and
bound forms of the drug. A systemic drug with a relatively low
bioavailability is acyclovir; the prodrug for acyclovir, valacyclo-
vir, has at least three times greater bioavailability. At the other
end of the spectrum are the fluoroquinolones, for which oral
absorption (and resultant bioavailability) is so complete that the
oral and intravenous doses for many members of this drug group
are identical. A more optimal method (if it were more practi-
cal) would be to calculate bioavailability at the site of intended
action; for drugs discussed in this book, it would be based on
tissue levels at the site of intended action, the various skin struc-
tures. At present such ‘ideal’ bioavailability calculations are not
routinely available.
For most chapters in this book that discuss systemic drugs there
are tables that present data for the following: (1) % bioavailable
and (2) % protein binding. The ‘% bioavailable’ is typically fac-
tored into ideal oral drug dosage calculations, which will produce
circulating drug levels in a reasonably safe and effective ‘therapeu-
tic range.’ The ‘% protein binding’ is important to the subject of
drug interactions as previously discussed, with methotrexate as an
important example. Changes in albumin levels in disease states
such as severe liver or renal disease will often necessitate drug dos-
age adjustments for drugs (such as methotrexate) that are highly
protein bound.
Creating drug formulations with a more optimal bioavail-
ability is a daunting task for the pharmaceutical industry. In
the past few decades there have been updated formulations of
older drugs with higher bioavailability, more predictable bioavail-
ability, or both. For drugs with a relatively narrow therapeutic
index (cyclosporine, methoxsalen), improved predictability of
the drug absorption and resultant bioavailability are very impor-
tant. The release of Neoral and Gengraf (in place of the previous
cyclosporine formulation, Sandimmune) is an example for both
improved % bioavailability and more predictable bioavailability
of the newer formulation. Likewise, Oxsoralen Ultra demon-
strates improvement in both of these two parameters. In a sepa-
rate example, the need for improved efficacy from griseofulvin
led to the progression from the original griseofulvin formulations
→ microsize formulations → ultramicrosize formulations. Each
step of this progression resulted in improved bioavailability and
smaller griseofulvin dosages required for an adequate therapeutic
response.
Pharmacodynamics (The Drug Produces the
Desired Pharmacologic Effect)
The subject of pharmacodynamics is very complicated. In essence,
this topic is the ‘basic science’ behind drug mechanisms of action.
Considering all the diverse mechanisms of actions discussed
in this book (let alone the diversity of drug mechanisms in the
entirety of medicine), it is not possible to summarize general prin-
ciples behind all of them. In contrast, it is possible to cover a few
areas of central importance to understanding pharmacodynamics.
These include the concepts of drug receptors, enzyme inhibition
by drugs, signal transduction, and transcription factors.
Definitions (Table 1.4)
In general, the definitions used in pharmacodynamics tend to be
less familiar to most clinicians than the comparable terms in phar-
macokinetics. These terms overall tend to relate to factors that:
1. Address aspects of drug binding to receptor (ligand, affinity);
2. Relay the drug ‘signal’ to the definitive effector mechanism
(signal transduction, second messenger);
3. Increase the desired pharmacologic response (drug agonists,
partial agonists);
4. Reduce an undesirable physiologic or pharmacologic response
(drug antagonists or receptor blockers); or
5. Q1.4 Result in a loss of a desirable or undesirable pharmaco-
logic response through repeated use (tolerance, cross tolerance,
refractoriness, downregulation, tachyphylaxis).
Only a proportion of these concepts can be realistically
addressed in the remainder of this section on pharmacodynamics.
Drug Receptors
The broadest definition of a drug receptor is given in Table 1.4.
In this definition, any molecule to which a drug binds, thus ini-
tiating an effector mechanism leading to a specific pharmacologic
response, is a drug receptor. In contrast, proteins involved in drug
‘protein binding’ are merely drug storage (reservoir) or transporta-
tion sites, and thus, are not receptors.
The drug receptor subtypes that are easiest to characterize are
cell surface receptors for endogenous neurohormonal ligands.
Similar receptors are operant for various growth factors and other
cytokines. Q1.5 Such ‘drug’ receptors are common targets in cur-
rent therapeutic strategies and in drug development. In addition,
lipophilic drugs easily absorbed through cellular membranes may
have cytosolic drug receptors. Common examples using these
cytosolic physiologic receptors include both systemic and topi-
cal versions of CS and retinoids. The ‘catch’ regarding receptors
for these two drug categories is that both desirable (therapeutic
effects) and undesirable (AE) effects are mediated through the
same physiologic receptor. A ‘dissociation’ of the drug receptors
for the therapeutic anti-inflammatory benefits of methotrexate
(such as methionine synthetase) and AE (dihydrofolate reductase,
[DHFR]) is of interest. Folic acid (folate) supplementation can
competitively antagonize the DHFR inhibition of methotrex-
ate and minimize the AE of methotrexate without compromis-
ing therapeutic benefits. A few examples of drugs that are either
antagonists or agonists at well-defined cellular receptors are given
in Table 1.5.
Few drugs are ideally specific for a given drug receptor
molecule. The ability of both tricyclic antidepressants (such
 CHAPTER 1 Basic Principles of Pharmacology 5

TABLE
1.4 Definitions and Concepts Central to Understanding Pharmacodynamics

Term Definition
Active metabolite A drug metabolite which retains the same/similar pharmacologic properties as the parent drug
Affinity (binding) A physical measurement which reflects the attraction of the drug ligand to a given receptor molecule
Agonist Drug which binds to a given receptor initiating an effector mechanism → pharmacologic response
Antagonist Drug which binds to a receptor, but fails to activate the effector mechanism
Cross tolerance (see Tolerance) Reduced pharmacologic effect when exposed to a new, chemically related drug
Downregulation Reduced receptors number/availability, presumably due to a negative feedback mechanism
Inverse agonist Drug which stabilizes receptors which have some constitutive activity to an inactive conformation
Ligand Any molecule (drug) which binds to the drug receptor; binding can be by hydrogen bonds, ionic forces, or covalent forces
Partial agonist Drug which binds to a receptor and weakly initiates an effector mechanism and resultant response
Receptor The molecule to which the drug (ligand) binds to initiate its effector response; location can be cell membrane, cytosolic, or
intranuclear
Refractoriness (synonyms—desensitization, tachyphylaxis) Temporary lack of responsiveness to a drug, subsequent to prior drug efficacy
Second messenger Biochemical mediator (commonly calcium or cyclic adenosine monophosphate) that serves to relay the signal initiated by the
receptor/effector in signal transduction
Signal transduction Cellular biochemical pathways which relays a second messenger ‘signal’ from the receptor to the effector mechanism
Tachyphylaxis A diminished pharmacologic response after repeated drug administration; can be due to down regulation or receptor seques-
tration (transiently ‘unavailable’ to the drug)

Tolerance Diminished effect (generally adverse effect) after repeated drug administration (most common is tolerance to sedating drugs
such as antihistamines)

TABLE
1.5 Pharmacodynamics—Selected Receptor Antagonists and Agonists

Drug/Drug Group Receptor Affected Biologic Outcome

Receptor Antagonists (Receptor ‘Blockers’)
H1 antihistamines H1 antihistamine receptor Antagonize histamine effects via receptor—vasodilation, increased
vascular permeability, etc.
H2 antihistamines H2 antihistamine receptor Antagonize histamine effects via receptor—decreased gastric acid
secretion, suppressor (CD8) T-cell effects
Spironolactone Androgen receptora Antagonize testosterone and dihydrotestosterone effects via receptor—
variable hair effects depending on scalp or face location; also
reduced sebum secretion
Selective serotonin reuptake inhibitors Serotonin transport protein Antagonize serotonin reuptake mechanism (net effect increased persis-
tence of serotonin as neurotransmitter)

Hormonal Receptor Agonists

Corticosteroids Corticosteroid receptor Augment both the desirable pharmacologic effects and the adverse
effects mediated through same receptor
Calcipotriene Vitamin D3 receptor Augment vitamin D3 effects via receptor—include keratinocyte and
fibroblast differentiation

Retinoids Retinoic acid receptor (RAR) Augment various vitamin A-mediated effects via gene response ele-
Retinoid X receptor (RXR) ments
aPrimary pharmacologic (diuretic) effects of spironolactone are mediated through the mineralocorticoid receptor; antiandrogen effects are mediated via the androgen receptor for dihydrotestosterone and
testosterone.
6 PA RT I Introduction

as doxepin) and first-generation H1 antihistamines (such as
diphenhydramine, hydroxyzine) to also bind muscarinic anti-
cholinergic receptors can produce objectionable anticholinergic
AE such as dry mouth, blurred vision, and orthostatic hypo-
tension. Relatively selective drug receptor binding was achieved
in later ‘generations’ of related drug groups. Selective serotonin
reuptake inhibitors (such as fluoxetine, sertraline) and second-
generation H1 antihistamines (such as fexofenadine, loratadine)
have had a significant improvement in the AE profile due to
much more selective drug receptor binding. It is of interest to
note that ‘tolerance’ to the sedative AE can occur with prolonged
use of the first-generation H1 antihistamines.
nucleotide synthesis have significant potential for use in neoplastic
diseases or as immunosuppressants in autoimmune dermatoses.
A number of drugs representing antimicrobial agents for bacte-
rial, viral, and fungal infections capitalize on vital enzyme systems,
which are more readily inhibited in the infectious organism than
in the human host. Finally, a number of drugs inhibit enzyme
systems that contribute important downstream mediators to an
inflammatory response. For all three categories of enzyme listed in
this table, the drug receptor may be the enzyme itself (methotrex-
ate and DHFR) or may work indirectly through another receptor/
effector mechanism (as with CS inhibition of phospholipase A2,
probably mediated through lipomodulin-1).

Enzyme Systems Inhibited by Drugs Signal Transduction and Transcription Factors

Q1.6 For comparison purposes, a number of specific examples These two aspects of pharmacodynamics have a number of concep-
for drugs that selectively inhibit an enzyme system are listed in tual similarities, albeit with very distinctive mechanisms of action.
Table 1.6. Drugs that inhibit enzyme systems of importance to Signal transduction is a series of intermediary steps in relaying a

TABLE
1.6 Pharmacodynamics—Selected Examples of Enzymes that Specific Drugs Inhibit

Drug/Drug Group Enzyme Inhibited Biologic Outcome

Enzymes Important to DNA Synthesis
Methotrexate Dihydrofolate reductase Reduced formation of fully reduced folate precursors for purine and thymi-
dylate synthesis
Mycophenolate mofetil Inosine monophosphate dehy- Inhibition of de novo pathway for purine (guanosine) nucleotide synthesis—
drogenase type II preferentially affects various WBC subsets (other cells can utilize salvage
pathway)

Enzymes Important to Microbial Growth and Survival

Sulfonamides, dapsone Dihydropteroate synthetase Affects bacterial version of this enzyme far more readily than the mammalian
enzyme; first step of two-enzyme pathway essential for folate reduction
Trimethoprim, methotrexate Dihydrofolate reductase Affects bacterial version of this enzyme far more readily than the mam-
malian enzyme; second step of two-enzyme pathway essential for folate
reduction
Itraconazole, fluconazole Lanosterol 14-α demethylase Triazole inhibition of this enzyme inhibits formation of ergosterol, an essential
component of fungal cell wall
Terbinafine, naftifine Squalene epoxidase Allylamine inhibition of this enzyme decreases ergosterol, and increases
squalene accumulation
Acyclovir, valacyclovir, famciclovir DNA polymerase Triphosphorylated forms of these drugsa preferentially inhibit viral DNA
polymerase >> human version of enzyme

Other Enzymes of Importance to Inflammatory Response

Retinoids Ornithine decarboxylase This is rate-limiting enzyme in polyamine pathway, which is initiated by
protein kinase C (PKC) activation
Dapsone Myeloperoxidase This enzyme in neutrophils and macrophages is essential to microbial killing
by these cells (also in eosinophils)
Cyclosporine, tacrolimus Calcineurin This calcium-dependent signal transduction enzyme is key to increased IL-2
production dependent on NFAT-1b
Corticosteroids Phospholipase A2 Inhibition probably mediated through lipomodulin-1; net effect is reduced
prostaglandins, leukotrienes, and other eicosanoids which are important
to inflammatory responses

Apremilast Phosphodiesterase-4 Reduced inflammatory response through alteration of cAMP/cGMP ratio

aSee Table1.8 regarding prodrug and active relationship of these drugs.
bNFAT-1(nuclear factor activated T-cells) is a transcription factor essential to increased T-cell production of IL-2 and upregulation of IL-2 receptors.
cAMP, Cyclic adenosine monophosphate; cGMP; Guanosine monophosphate; DNA, Deoxyribonucleic acid; WBC, White blood cells.

drug-initiated signal or message to the definitive effector mecha-
nism. Tremendous details on the various receptor/signal transduc-
tion categories (six main families) are beyond the scope of this
chapter but are available in the Bibliography. This definitive effector
mechanism is commonly accomplished through deoxyribonucleic
acid (DNA) transcription and subsequent new protein translation.
In many cases the signal transduction ‘passes through’ a DNA tran-
scription factor. This sequence and the resultant overlap of topics
is best illustrated by the so-called ‘signal one’ in activated T-cells
upon T-cell receptor binding to antigen, which is amplified by
subsequent IL-2 binding to the IL-2 receptor. The rough sequence
of steps is as follows: (1) T-cell receptor binding to antigen,
(2) CD3 molecule-based T-cell activation, and (3) calcineurin-
based production of nuclear factor activated T-cell 1 (NFAT-1), a
DNA transcription factor important to IL-2 upregulation. Cyclo-
sporine and tacrolimus both interfere with this signal transduction
pathway through inhibition of calcineurin activity, with a resultant
decrease in activity of the transcription factor NFAT-1.
Second messengers are also important to this discussion.
Probably the two most important second messengers pertinent
to pharmacology are calcium and cyclic adenosine monophos-
phate (cAMP). Calcium is an important component of the above
T-cell signal transduction system in two locations; calcineurin is
a calcium-dependent enzyme, with a calcium-binding protein
(calmodulin) playing an important role as well. Although not
directly related to dermatology, the role of cAMP as a second mes-
senger in the beneficial effects of β-agonists in therapy of asthma
is of interest. The concept of tachyphylaxis as defined in Table 1.4
has been well characterized for β-agonists used in this setting.
Two more examples of important drugs and their effects on
signal transduction (retinoids) and transcription factors (CS) can
be presented. The polyamine pathway creates a process known
as inflammatory hyperplasia, which is an important component
of the pathogenesis of both psoriasis and various malignancies.
Retinoids inhibit the activity of ornithine decarboxylase, the rate-
limiting enzyme in the polyamine pathway. This signal transduc-
tion enzyme inhibition is important to the benefits of systemic
retinoids in both psoriasis therapy and retinoid chemoprevention
of cutaneous malignancies in solid organ transplantation patients.
CS inhibit the actions of the transcription factor, nuclear
factor κB (NFκB) by two mechanisms. CS both increase pro-
duction of the inhibitor of NFκB (known as IκB) and directly
bind to and inactivate NFκB. This transcription factor is piv-
otal in the upregulation of a multitude of cytokines of central
importance in the inflammatory response to a wide variety of
stimuli. There is tremendous amplification potential of the
inflammatory response through this NFκB pathway. Likewise, a
major portion of the anti-inflammatory benefits of CS (topical
or systemic) are probably accomplished through the inhibition
of this important transcription factor. It is unclear whether the
relatively common occurrence of tachyphylaxis noted with class
I topical CS relates to downregulation of receptors involved in
this particular pathway.
Pharmacokinetics—Part II
Metabolism (The Drug Becomes More
Hydrophilic to Favor Renal and Biliary Excretion)
This topic is extensively discussed in Chapter 62 Hepatotoxicity
of Dermatologic Drug Therapy. A relatively brief synopsis will be
presented here. Most drugs are metabolized by phase I (oxidation
CHAPTER 1 Basic Principles of Pharmacology 7
reactions) and phase II (conjugation and detoxification reac-
tions). The initial oxidation reactions in phase I are accomplished
by various CYP isoforms, which are largely present in the liver
(but also available in many other organ sites, including the skin
and GI tract). The result of these enzymes is a somewhat more
hydrophilic (water-soluble) metabolite, which may provide a site
of attachment for subsequent conjugation reactions. To compli-
cate matters, reactive electrophilic intermediates are often created,
which in the absence of adequate phase II detoxification systems
may induce important metabolic or immunologic complications
(Table 1.7). Phase II conjugation reactions (glucuronidation, sul-
fonation, acetylation) and the various detoxification systems (such
as glutathione and epoxide hydrolase) will generally accomplish
the production of both significantly increased hydrophilicity of
the drug metabolites and stabilization of the aforementioned
reactive intermediates, respectively. Q1.7 It is important to note
here that many drug metabolites retain the parent drug’s pharma-
cologic activity (Table 1.8). An example of this principle would
be the itraconazole metabolite hydroxyitraconazole, which also
has significant antifungal activity. In the great majority of drugs
metabolism renders the drug inactive.
The topic of pharmacogenetics largely addresses genetically
based variations in the above metabolic enzyme systems. At times,
these genetic alterations can explain idiosyncratic AE of medica-
tions. Examples pertinent to the above phase I and phase II meta-
bolic systems include the following genetic polymorphisms:
1. CYP2D6 polymorphisms with at least 50-fold variation in the
activity of this important isoform: One result is unexpected
profound sedation from various antidepressants (including
doxepin) and other sedating medications in ‘poor metabolizers.’
2. ‘Slow acetylators’: One result of this polymorphism is more
frequent occurrence of drug-induced lupus erythematosus.
TABLE
Definitions Related to Adverse Effects
1.7
Term Definition
Adverse effect Negative or undesirable effect from a drug
(either at toxic or pharmacologic drug doses)
Idiosyncratic Unexpected adverse effect from a drug
Immunologic Unexpected adverse effect from a drug occur-
idiosyncrasy ring on an immunologic basis (usually due to
hypersensitivity)a
Metabolic idio- Unexpected adverse effect from a drug occur-
syncrasy ring due to a metabolic byproduct (reactive
intermediate)
Pharmacologic Positive or negative effect from a drug,
effect expected at normal doses and/or drug levels
Side effect Synonym for adverse effect (prefer to use
‘adverse effect’ to address undesirable qual-
ity of drug effect)
Toxicity/toxic Undesirable effects expected from a drug due
effect to excessive doses and/or drug levels
aConfusing reality is that immunologic hypersensitivity may occur due to excessive quantities
of a reactive metabolite, rendering immunogenic a previously normal endogenous protein
(see Chapter 62 Hepatotoxicity of Dermatologic Drug Therapy).
8 PA RT I Introduction
TABLE Some Examples of Prodrugs Important to
1.8 Dermatology
Prodrug Active Drug
Antiviral Agents
Valacyclovir Acyclovir
Famciclovir Penciclovir
Corticosteroids
Prednisone Prednisolone
Cortisone Hydrocortisone (cortisol)
Other Immunosuppressants
Azathioprine 6-mercaptopurine → 6-thioguanine
Mycophenolate mofetil Mycophenolic acid
Cyclophosphamide Phosphoramide mustard
Antihistamines
Terfenadine Fexofenadine
3. Glutathione depletion (which in part may be acquired due
to malnutrition or HIV infections): this results in markedly
increased risk of hypersensitivity to sulfonamide medications
in these populations.
The key research agenda for this important topic is the devel-
opment of predictive tests to anticipate which patients are at
increased risk for important AE from drugs. These tests would
be analogous to the baseline glucose-6-phosphate dehydroge-
nase (G6PD) determinations for dapsone patients and baseline
thiopurine methyltransferase determinations for azathioprine
patients, which in both cases enables better prediction of
patients at risk for important AE. Genetic predictive testing for
polymorphisms of CYP2D6, 2C9, and 2C19 are currently com-
mercially available.
The most important numerical parameter under the head-
ing of drug metabolism is the drug ‘half-life.’ The discussion
of the multiple subtypes of drug half-life, such as terminal
elimination half-life, is beyond the scope of this chapter. A
given drug’s half-life is important in determining the time to
reach a steady state once drug therapy is initiated (four to five
half-lives) and the time for virtually complete drug clearance
after drug therapy is discontinued (likewise at least four to five
half-lives).
Q1.8 One flaw of the linear model presented here for dis-
cussing pharmacodynamics between the two sections on phar-
macokinetics relates to prodrugs (Table 1.9). These prodrugs
are pharmacologically inactive until there is ‘metabolic’ con-
version to the active drug, typically through hydrolysis of an
ester or amine linkage. The conversion of prednisone (prodrug)
to prednisolone (active form) is dependent on a hepatic-based
enzyme, which in end-stage liver disease may not produce
therapeutically adequate quantities of the active drug form
prednisolone. Once the prodrug is metabolized to the active
drug, the principles of interest follow through the distribution,
bioavailability, and pharmacodynamics sections as with other
drugs already in active form once absorbed.
TABLE Some Examples of Active Drug, Active
1.9 Metabolite Relationships
Active Drug Active Metabolite(S)
Antihistamines
Hydroxyzine Cetirizine → levo-cetirizine
Loratadine Desloratadine
Antidepressants
Doxepin Nordoxepin
Citalopram Escitalopram
Antifungal
Itraconazole Hydroxyitraconazole
Excretion (The Relatively Hydrophilic Drug
Metabolites Must Leave the Body)
Q1.9 Conceptually there are three common routes by which
systemically administered medications leave the body. These are
(1) renal excretion, (2) biliary excretion of a more hydrophilic
metabolite through the GI tract, and (3) orally administered med-
ications may in part be excreted through the GI tract after failing
to be absorbed. The excreted drug can be the parent drug, drug
metabolites, or combinations of both. Relatively hydrophilic drugs
can be excreted unchanged through the kidney. An example would
be fluconazole, which because of its relatively hydrophilic proper-
ties has a significant portion of the administered drug excreted
through the kidney unchanged. Relatively lipophilic drugs typi-
cally must be rendered more hydrophilic by the aforementioned
phase I and II metabolic steps before excretion is possible through
renal or biliary routes. In particular, greater hydrophilicity favors
renal excretion, which has a much larger overall capacity for drug
excretion than the hepatobiliary route.
In reality, the drugs discussed in this book are frequently
excreted by several of the above routes, both as free drug and
as a variety of metabolites. Refer to the various ‘Pharmacology
Key Concepts’ tables used for systemic drugs in this book for
illustrations of this point. The reader should also be aware that
many drugs conjugated in the liver, and excreted into bile, will
subsequently undergo hydrolysis in the small intestine and be
reabsorbed (enterohepatic recirculation) through many cycles.
Eventually the definitive excretion may be through the kidney.
It is very important to recognize that disease-induced or age-
dependent reduction in renal function should prompt the clini-
cian to significantly reduce dosages of drugs with significant renal
clearance. An example would be the increased risk for pancyto-
penia and other complications with methotrexate when standard
doses are administered to patients with either disease- or age-
related reduction in renal function. Likewise, drugs that have
significant liver metabolism and excretion should have dosage
reductions with advanced liver disease.
Percutaneous Absorption
General Principles
There is a wealth of scientific and practical information in
Tables 1.10 and 1.11. Q1.10 Probably the five most important
 CHAPTER 1 Basic Principles of Pharmacology 9

TABLE
1.10 Percutaneous Absorption Variables

Variable Biologic Result

Drug Variables
Concentration PCA is directly related to concentration, and not volume of topical medication applied to a specific skin site
Lipophilicity Most topically effective drugs are at least somewhat lipophilic
Molecular size Most effective topical medications have a molecular weight < 600 (tacrolimus greater topical absorption than cyclospo-
rine due to lower molecular weight)

Vehicle Variables (see Table 1.11)

Lipid content Ointment is strongest vehicle due to most optimal partition coefficient in transferring drug to stratum corneum lipids
(solution typically weakest vehicle)
Irritancy Irritating vehicles will alter skin barrier function and may ↑ PCA

Innate Skin Variables

Stratum corneum thickness
Cutaneous vasculature
Area of absorptive surface
Mucosal surfaces
Rate-limiting site for PCA; thickness of stratum corneum is inversely related to PCA
Increased cutaneous vasculature can increase both local and systemic drug effects
Increased surface area to which drug is applied will ↑ PCA total overall, but not ↑ PCA at a specific site (concentration
most important variable at a specific site)
Far less innate barrier function, generally less well-developed stratum corneum; consider that any mucosal route of
administration can produce systemic effects

Diseased Skin Variables

Inflamed skin Overall ↑ PCA, due both to altered barrier function and increased vasodilation
Ulceration Topical application responds as if systemic administration of medication (bacitracin or neomycin anaphylaxis risk after
application to a leg ulcer)

Other Variables
Additional skin hydration Hydrating skin (by various means) before application of topical medication will ↑ PCA
Occlusion of medication Topical occlusion locally (food wrap) or widespread (‘sauna suit’) with marked ↑ PCA; conceptually transdermal applica-
tion of ‘systemic medications’ utilizes somewhat similar process

Age of patient Increased total body surface area to body volume ratio in infants and young children; therefore, increased risk of sys-
temic effects from topical therapy due to relatively high absorptive surface

PCA, Percutaneous absorption.

determinants of percutaneous absorption of topical dermatologic
products are:
1. Stratum corneum thickness and integrity of ‘barrier function’;
2. Drug partition coefficient—the ability of the drug to ‘depart
from’ the specific vehicle and enter the stratum corneum;
3. Drug diffusion coefficient—the ability of the drug (due to
innate molecular properties) to penetrate through all layers of
skin once in the stratum corneum;
4. Drug concentration—the specific drug concentration of a
given topical product; and,
5. Superficial dermal vascular plexus—site of systemic absorption
for topically applied drugs.
Q1.11 Measures that increase percutaneous absorption can
always be considered a ‘two-edged sword.’ The desired pharma-
cologic result is enhanced by these measures. For instance, use
of a high-potency topical CS in an ointment base, after skin
hydration, and with total body occlusion will do wonders for
extensive psoriasis. The counterpoint is that all of these measures
will markedly increase systemic absorption of the topical CS,
potentially giving a net prednisone-like effect from the topical
CS. For a short period of time there will be relatively few trade-
offs. After 2 to 3 weeks or more, important systemic AE such as
weight gain, fluid retention, hypertension, hypokalemia, leuko-
cytosis, and cushingoid changes are all possible with this unde-
sirable long-term approach to topical CS administration. It is
important to note here that all topical drug absorption occurs
via passive diffusion.
Topical medications applied in several clinical settings can
produce immediate hypersensitivity (Coombs-Gell type I) reac-
tions. In particular, topical application to ulcerated skin can give
the applied medication almost immediate access to systemic
circulation. There have been reports of anaphylaxis to topical
bacitracin or neomycin in this setting. Likewise, mucosal appli-
cations of medications (such as eyedrops, vaginal suppositories,
and rectal foam or suppositories) can result in significant sys-
temic levels of various drugs and freedom from ‘first-pass effect’
due to the small intestine and liver. Although the risk from
topical application of medications to these above sites is usually
small, the clinician should always be mindful of this systemic
absorption potential.
10 PA RT I Introduction

TABLE
1.11 Clinical Comparisons of Various Vehicles—Generalities

Property Ointments Creams Gels Lotions/Solutions

Composition Water in oil emulsion Oil in water emulsion Semisolid emulsion in Powder in water
alcohol base (some with oil
component)
Relative potency Strong Moderate Strong Low
Hydration or drying properties Hydrating Somewhat hydration Drying Drying (variable)
Variability generic vs trade Relatively low Potentially significant Potentially significant Potentially significant
name
Stage of dermatitis treated Chronic Acute to subacute Acute to subacute Acute

Sensitization risk Very low Significant Significant Significant

Irritation risk Very low Very low Relatively high Low to moderate
Body sites where most useful Nonintertriginous Virtually all sites Oral, scalp Scalp, intertriginous
Body sites to avoid Face, groin, other skin Sites with maceration Fissures, erosions; also Fissures, erosions
folds macerated skin

Patient preference Often dislike greasiness High rate patient accep- Variable High rate patient
tance acceptance

Vehicles application of a class I TCS to minimally inflamed skin (without

Much of the art and science of dermatology revolves around choos-
ing the appropriate vehicle for topical medications (Table 1.11).
In general, the choice of vehicle is just as important as choosing
the proper active ingredient. Two common consequences of cer-
tain vehicles are the following:
1. Irritancy: most notably from high concentrations of propyl-
ene glycol; other ‘alcohols’ or certain acidic vehicle ingredients
also may be irritants, particularly when applied to diseased skin
with altered barrier function.
2. Contact allergy/sensitization: common with preservatives
in various water-based (creams, lotions, solutions) topical
products, and include various parabens along with ‘formalin
releasers’ (such as quaternium-15, imidazolidinyl urea, and dia-
zolidinyl urea).
The astute clinician will be mindful of the potential AE of the
vehicle, particularly if the patient fails to improve or worsens with
topical therapy. The simplest and safest way to minimize the risk
of these vehicle-induced AE is to choose topical products that lack
the most common potential irritants and allergens. See Chapter
45 Topical Corticosteroids and Chapter 56 Irritants and Aller-
gens: When to Suspect Topical Therapeutic Agents for additional
information on this topic.
Tachyphylaxis
In my experience, tachyphylaxis is a relatively common clini-
cal event with very high-potency (class I) topical corticosteroids
(TCS) and seldom seen with lower potency products. (See Chap-
ter 4 Adherence with Drug Therapy for some ‘counterpoints’
on this controversial topic.) The measures previously discussed,
which can produce excessive systemic absorption, also predispose
to diminished therapeutic benefit from the topical drug over time.
The clinician should be aware that continued daily or twice-daily
any other maneuvers to increase percutaneous absorption) at times
leads to tachyphylaxis after 2 to 4 weeks of continuous therapy.
The good news is that this is an easily reversible process, particu-
larly if the clinician is mindful of the potential for tachyphylaxis.
Weekend-only or alternate-day applications of these high-potency
topical products typically prevents tachyphylaxis; a week or so off
therapy altogether allows upregulation of the CS receptor mole-
cules and a resultant return of the desired therapeutic benefit upon
resumption of the high-potency TCS.
Transdermal Medication Formulations
One final routine of topical administration of medications that
is tangentially related to dermatology deserves mention here. The
potential for certain drugs to have reduced bioavailability through
excessive hepatic and small intestine first-pass metabolism can be
circumvented by transdermal administration. An excellent example
would be transdermal estrogen administration, which allows the
drug to be absorbed directly into systemic circulation. This avoids
the significant first-pass metabolism typical of orally administered
estrogens, with resultant improved drug bioavailability. There are
numerous other medications that can be administered in various
transdermal delivery systems for steady, continuous percutaneous
delivery of the active ingredient.
Summary
Given the central importance of understanding percutaneous
absorption, the interested reader is encouraged to pursue further
information on this subject from the chapters listed in the Bib-
liography. Hopefully through the principles, clinical examples,
and tables presented on this subject, all readers can achieve an
adequate basic understanding of the most important concepts
of percutaneous absorption and the importance of the drug

vehicle to the optimal clinical response. Each chapter in the three
major book sections on topical medications (Chapters 41–57)
will expand on and illustrate these principles of percutaneous
absorption.
Bibliography: Important Reviews and Chapters
Systemic drugs
Buxton ILO, Benet LZ. Pharmacokinetics: the dynamics of drug absorp-
tion, distribution, metabolism, and elimination. In: Brunton LL,
Chabner BA, Knollman BC, eds. Goodman and Gilman’s The Phar-
macologic Basis of Therapeutics. 12th ed. New York: McGraw Hill;
2011:17–39.
Blumenthal DK, Garrison JC. Pharmacodynamics: molecular mecha-
nisms of drug action. In: Brunton LL, Chabner BA, Knollman BC,
eds. Goodman and Gilman’s The Pharmacologic Basis of Therapeutics.
12th ed. New York: McGraw Hill; 2011:41–72.
CHAPTER 1 Basic Principles of Pharmacology 11
Gonzales FJ, Coughtrie M, Tukey RH. Drug metabolism. In: Brunton
LL, Chabner BA, Knollman BC, eds. Goodman and Gilman’s The
Pharmacologic Basis of Therapeutics. 12th ed. New York: McGraw Hill;
2011:123–143.
Relling MV, Giacomina KM. Pharmacogenetics. In: Brunton LL, Chab-
ner BA, Knollman BC, eds. Goodman and Gilman’s The Pharmacologic
Basis of Therapeutics. 12th ed. New York: McGraw Hill; 2011:145–
168.
Percutaneous Absorption
Burkhart C, Morell D, Goldsmith L. Dermatogic pharmacology. In:
Brunton LL, Chabner BA, Knollman BC, eds. Goodman and Gilman’s
The Pharmacologic Basis of Therapeutics. 12th ed. New York: McGraw
Hill; 2011:1803–1832.
2
Principles for Maximizing
the Safety of Dermatologic
Drug Therapy
STEPHEN E. WOLVERTON
QUESTIONS
Q2.1 What four words characterize the overall approach to
maximizing drug safety, and what general concepts are
represented by these words? (Pg. 12)
Q2.2 How are the ‘standards of care’ for drug therapy monitoring
determined? (Pg. 13)
Q2.3 What are several of the typical characteristics of the most
worrisome adverse effects to systemic drug therapy (Pg. 13)
Q2.4 In general, what are the most important issues to discuss
with a patient before initiating systemic drug therapy which has
a significant element of risk? (Pg. 14)
Q2.5 What are three broad categories for mechanisms for drug
interactions which can assist clinicians in anticipating important
potential drug interactions? (Pg. 15)
Q2.6 What are three to four examples of major drug risks
‘discovered’ many years after the drug’s release? (Pg. 15)
Introduction
This chapter is unique in the context of the entire book. The prin-
ciples that follow are a blend of science, literature reports, personal
experience, and common sense. Rather than provide references
for the principles and examples used in this chapter, the reader
is encouraged to selectively pursue more detailed information
and literature references pertaining to examples cited here in the
various chapters devoted to the respective drug or drug category.
Most of the examples provided deal with systemic drug therapy in
dermatology, given that the systemic drugs commonly prescribed
pose a significantly greater potential risk to the patient than topi-
cal or intralesional therapeutic options.
Q2.1 Four words summarize the proactive approach to maxi-
mizing the safety of dermatologic drug therapy discussed in this
chapter: anticipation, prevention, diagnosis, and management. The
primary goals of maximizing drug safety are:
12
Q2.7 When considering a ‘teamwork’ approach to maximize drug
safety, name at least five different ‘individuals’ with a key role in
this drug safety process for a given patient. (Pg. 17)
Q2.8 What are the most important common clinical scenarios
which require more frequent (compared with normal
monitoring frequencies) laboratory monitoring? (Pg. 18)
Q2.9 What are some important examples of ‘thresholds of
concern’ and ‘critical values’ for laboratory tests commonly used
in drug monitoring (Table 2.1)? (Pg. 18)
Q2.10 What are several important clinical strategies available for a
specific abnormal lab value? (Pg. 18)
Q2.11 In the event a potentially serious complication of drug
therapy does occur, what are some of the most important
management options available to clinicians? (Pg. 19)
1. Anticipation of which patients (comorbidities and other drugs
the patient receives) and which drug regimens are at risk for
various important adverse effects (AE);
2. Prevention of AE of potential concern by taking appropriate
proactive safety measures;
3. Diagnosis at an early, reversible stage should an AE occur;
and
4. Management of the AE in a safe and effective, and often col-
laborative, manner.
I will present a number of general principles regarding how to
maximize the safety and efficacy of systemic drug therapy. Each
principle will be illustrated with several pertinent drug examples.
Unlike many medical specialties, dermatologists in general must
take greater precautions with systemic drug therapy, for the following
reasons. Systemic drugs used in this field have typically been devel-
oped for specialties such as rheumatology, oncology, infectious dis-
eases, and transplantation surgery. These specialties in general care for
 CHAPTER 2 Principles for Maximizing the Safety of Dermatologic Drug Therapy
patients with more serious, possibly life-threatening, illnesses than the
majority of conditions for which dermatologists prescribe the various
systemic drugs. Clinicians in any field are obliged to avoid creating
a greater risk with drug therapy than the innate risk (in that specific
patient) of the underlying disease to be treated. This statement is the
underlying principle behind the need for careful monitoring of sys-
temic drug therapy in dermatology. It is essential to maximize the
safety and minimize the risk of this drug therapy.
How to optimally anticipate, prevent, diagnose, and manage
specific drug AE to maximize drug safety is a central theme of
this chapter and of the book as a whole. This is a broader view-
point than merely ‘monitoring’ for AE. The goals of this broader
approach are to (1) maximize overall drug safety for the patient, (2)
improve the ‘emotional comfort’ of systemic drug therapy for the
patient and physician, and (3) follow the appropriate ‘standards
of care’ to minimize medicolegal risk. These overlapping goals are
interdependent. For example, when appropriate standards of care
are followed, the patient safety is the focus of these standards. In
addition, when the patient’s safety and emotional comfort during
drug therapy are truly of central importance to the physician, the
medicolegal risk is negligible. This is particularly true if the patient
assumes an active role in the decision making process for all aspects
of any systemic drug therapy regimen, in turn forming a ‘therapeu-
tic partnership’ with the prescribing physician.
It is somewhat challenging to define the definitive sources of
these so-called ‘standards of care.’ Q2.2 In general, such stan-
dards come from one or more of the following sources:
1. Specialty-based formal guidelines such as the American Acad-
emy of Dermatology ‘Guidelines of Care’;
2. Individual pharmaceutical company guidelines for specific
drugs, such as the therapeutic guidelines and informed consent
packet for isotretinoin (iPLEDGE) in women of childbearing
potential;
3. The US Food and Drug Administration (FDA) Advisory Com-
mittee recommendations, such as those guidelines proposed in
the early 1980s for monitoring the hematologic complications
of dapsone;
4. Consensus conference publications, such as the consensus
guidelines published in 2004 for isotretinoin therapy in acne
patients; and
5. ‘Dear Health Care Professional’ letters (formerly ‘Dear
Doctor’ letters) from pharmaceutical companies, with care-
ful oversight by the FDA, updating physicians and other
health care providers nationally regarding recent findings
for specific AE.
The reality is that the standards of care for a given drug are
often a blend of several of these sources, with a certain amount of
ambiguity as would be expected from such a mix.
Historically, these standards of care were based on local prac-
tices in the ‘community’ in which the physician practiced. Cur-
rently the realities of the ‘information age’ in which we practice
tend to create a trend towards national, if not global, standards
of care. Such standards should be considered guidelines, and not
mandates, with room for flexibility as the patient’s individual cir-
cumstances, clinician’s experience, and scientific ‘evidence’ justify.
As far as possible, special efforts must always be made to ensure
that the most serious adverse effects (SAE) ‘never’ occur. Q2.3
Characteristics of the most SAE given the highest priority in this
chapter, and throughout the book, include at least several of the
following:
1. a sudden, precipitous onset;
2. no early warning symptoms;
13
3. no predictive laboratory tests;
4. potentially irreversible; and
5. a potentially serious outcome.
Examples of such high-priority AE include (1) hematologic
complications (pancytopenia from azathioprine or methotrexate,
agranulocytosis from dapsone), (2) isotretinoin teratogenesis, (3)
corticosteroid (CS) osteonecrosis, (4) opportunistic infections
from tumor necrosis factor (TNF) inhibitors and other biologic
therapeutics, and progressive multifocal leukoencephalopathy
from rituximab and efalizumab (off the market). Principles to
minimize the likelihood of these and other complications follow
in the four major sections of this chapter.
First, a few ‘baseline concepts.’ No matter how careful a physi-
cian may be, sooner or later ‘bad things’ will happen to a patient
from drug therapy that he or she initiates. No medical risk reduc-
tion system is perfect, given the unpredictabilities of the human
body. If the patient and physician can form a strong therapeu-
tic partnership, and if the physician continues to work with the
patient to promptly diagnose and manage any drug-induced
complications, there can be a number of positive results: (1) the
patient’s medical outcome is optimized, (2) the physician’s ethical
obligations are met, and (3) the medicolegal risk is minimized.
Nevertheless, the physician must take a ‘lifelong learner’ approach
to any such unexpected complications, carefully analyzing the
events leading to the specific drug complication, and learning how
to minimize the likelihood of a similar therapeutic outcome in the
future.
On the following pages of this chapter, 33 ‘principles,’ with
over 90 specific drug therapy examples, are used to illustrate
the clinical approach for maximizing the safety of dermatologic
drug therapy.
Anticipation
This section is broken down into five subsections: (1) patient selec-
tion, (2) patient education, (3) baseline laboratory and related
tests, (4) concomitant drug therapy—drug interactions, and
(5) evolving guidelines—risk factors.
Patient Selection
Principle #1. Carefully compare the ‘risk’ of the disease to be
treated with the ‘risk’ of the drug regimen planned (in that
particular patient); thus a ‘risk–risk’ assessment:
• The risk of high-dose systemic CS in severe pemphigus vul-
garis versus the risk from the same CS regimen in patients with
either pemphigus foliaceus or localized epidermolysis bullosa
acquisita.
• The risk of 6 to 12 months of cyclosporine for a patient with
limited plaque-type psoriasis versus the risk of the same regi-
men in a patient with debilitating and extensive pyoderma gan-
grenosum.
• The risk of 1 to 2 weeks of cyclosporine for a patient with Ste-
vens-Johnson syndrome versus the risk of burn unit therapy.
• The risk of an interleukin IL-17 or IL-23 inhibitor in a patient
with severe psoriasis with components of metabolic syndrome
versus therapy with methotrexate or cyclosporine.
Principle #2. Choose patients who can comprehend and com-
ply with important instructions for preventing and monitor-
ing the most serious potential complications of systemic drug
therapy. Examples in which this principle is most important
include the following:
14 PA RT I Introduction

• The importance of avoiding abrupt cessation of long-term, what would a ‘reasonable patient’ want to know as a rough
high-dose prednisone therapy—risk of hypothalamo-pituitary guide.
axis (HPA) complications such as an addisonian crisis.
Principle #5. Use patient handouts, written at a very under-
• The pregnancy prevention measures which are of central
standable level, to reinforce important information and instruc-
importance in isotretinoin therapy for women of childbearing
tions concerning the drug therapy chosen:
potential.
• The physician must emphasize the key information contained
• The importance of avoiding significant amounts of alcohol
in the handout, but handouts are never a substitute for appro-
with long-term methotrexate therapy for severe psoriasis or in
priate physician-patient communication.
women of childbearing potential on long-term acitretin ther-
• The patient should be instructed to notify the physician if there
apy for psoriasis.
are any questions pertinent to the handout provided.
Principle #3. All patients are not ‘created equal’ regarding the risk • The patient should be instructed to report any significant new
for various AE. Examples of patients at significantly increased symptoms that may develop subsequently (even if they are not
risk for the following AE (beyond the specifics of the drug sure these symptoms are attributed to the specific drug).
regimen) include: • Sources for these handouts include National Psoriasis Founda-
• Methotrexate hepatotoxicity: obesity, alcohol abuse, diabetes tion (major systemic therapies for psoriasis, including biolog-
mellitus, renal insufficiency. ics), various pharmaceutical companies (acitretin/Soriatane),
• CS osteoporosis: postmenopausal women, especially those who the American Medical Association (CS and many others), and
are thin and inactive. various online sources. Consider creating your own personal-
• CS osteonecrosis: recent significant local trauma, alcohol ized patient education handouts regarding specific drugs you
abuse, cigarette smoking, and presence of underlying hyperco- commonly prescribe.
agulable conditions.
Principle #6. Educate your patients regarding groups or clus-
• TNF inhibitor use in patients with a personal or family history
ters of symptoms, which together are important for the detec-
of multiple sclerosis.
tion of potentially serious drug-induced complications. The
The bottom line is that individual patients must be carefully
grouping of these symptoms may not be emphasized in the
‘matched’ with the safest and most effective drug regimen for the
above-mentioned handouts:
unique presentation of their dermatosis. This ‘match’ hinges on
• CS osteonecrosis: focal, significant joint pain (especially hip,
the various risk factors and demographic variables with which a
knee, shoulder) with decreased range of motion of the affected
specific patient presents. Perhaps the best example is the lesson
joint.
provided by the specialty of rheumatology regarding the apparent
• Isotretinoin pseudotumor cerebri: headache, visual change,
lesser risk of methotrexate in rheumatoid arthritis (RA) patients
nausea, and vomiting.
compared with the historical risk of the same methotrexate ther-
• All current biologic therapeutics and opportunistic infections:
apy in psoriasis patients. This risk reduction was accomplished by
fever plus localizing symptoms such as a cough.
(1) more careful patient selection of patients by rheumatologists,
• Dapsone (or minocycline) hypersensitivity syndrome (DRESS):
and (2) by the much lower risk of ‘metabolic syndrome’ in RA
fever, fatigue, sore throat, adenopathy, and morbilliform eruption.
patients than in psoriasis patients.
A ‘two-way street’ of open communication between patient
and physician is essential in maximizing the safety of systemic
Patient Education drug therapy. Any extra time the physician spends in this com-
munication process should pay great dividends with regard to
The multiple variables regarding a given course of systemic drug
improved therapeutic outcomes.
therapy are often very difficult for physicians to master. Thus,
it should come as no surprise that the specific drug regimens
and risks of these various therapies discussed are much more Baseline Laboratory and Related Tests
difficult for patients (who typically lack medical training) to
Any organ system with potential for drug-induced complications
understand. Q2.4 The patient needs to understand at least the
requires a baseline evaluation before initiating therapy. There are
following information: (1) how to take the medication, specifi-
very few exceptions to this principle. It stands to reason that exist-
cally the correct dose and timing, (2) the expected AE, (3) what
ing pathology in an organ system, for which a given drug has the
symptoms to report, and (4) the specific monitoring using labora-
potential to induce abnormalities, will increase the likelihood of
tory and related diagnostic tests. Particularly when significant risks
further injury to this organ system.
to important organs or body systems are discussed, the under-
standable emotional reaction of most patients makes long-term Principle #7. Assess the baseline status of any potential target
retention very difficult. The above points and other concepts form organ or site of excretion for a given drug. Similarly, if a drug
the basis of the following principles. can induce a metabolic abnormality, check for baseline presence
of this metabolic defect if such testing is currently available:
Principle #4. Careful and reasonably thorough patient educa-
• Baseline liver function tests and hepatitis viral serology: metho-
tion is essential to truly ‘informed consent’ (see Chapter 68):
trexate hepatotoxicity (methotrexate ‘target’ organ) and with
• Patients need to be active participants in therapeutic decision-
the full spectrum of biologics.
making, which requires physicians to present the information
• Baseline renal function assessment; at least testing serum cre-
in an understandable fashion.
atinine, and possibly creatinine clearance: methotrexate hepa-
• In addition, the patient must be provided the opportunity to
totoxicity or pancytopenia (site of methotrexate excretion).
ask questions and be given adequate time to consider the thera-
• Baseline (at least in the first month) comprehensive eye exami-
peutic options presented.
nation, including visual fields, in patients to receive hydroxy-
• The ‘perpetual’ question of what risks need to be discussed dur-
chloroquine therapy.
ing informed consent always needs to be carefully considered;
 CHAPTER 2 Principles for Maximizing the Safety of Dermatologic Drug Therapy
• Baseline testing for hyperglycemia or hyperlipidemia: pred-
nisone therapy (metabolic abnormalities aggravated by pred-
nisone).
• Baseline testing for latent tuberculosis for all biologic therapeu-
tics regardless of the indication. The choice of tuberculosis test-
ing method (tuberculin test or interferon-γ release assay such
as T-spot TB or Quantiferon Gold) is not yet fully clarified.
Principle #8. Use the most optimal tests that predict which
patients are at increased risk for a specific AE. Typically such
tests are ordered only at baseline. (Ideally many more of these
predictive tests will be available in the future.):
• Baseline glucose-6-phosphate dehydrogenase (G6PD) level:
predicts magnitude of risk for dapsone hemolysis. (This test
does not predict which patients are at risk for dapsone agranu-
locytosis or dapsone hypersensitivity syndrome.)
• Baseline thiopurine methyltransferase level: predicts risk for
azathioprine hematologic complications as well as guiding
optimal azathioprine dosing. (This test does not predict azathi-
oprine hepatotoxicity or hypersensitivity syndrome reactions.)
There are a few select tests for which a baseline determination
is not required. Near the end of long-term high-dose prednisone
therapy, a morning cortisol determination (usually ∼8:30 AM)
may be of value in assessing HPA function; a baseline determina-
tion is virtually never indicated. Some tests may require a delayed
baseline determination. I formerly requested a ‘delayed baseline’
ultrasound-guided liver biopsy for methotrexate patients after 6 to
12 months of therapy, once it is clear that the patient tolerates the
drug, benefits from the drug, and requires long-term methotrexate
therapy. In current practice, a fibroscan after 6 to 12 months of
therapy is appropriate. Still, overall the general rule holds: if you
plan on monitoring a specific test during therapy with a given
systemic drug, it is prudent to determine the baseline status of that
specific test.
Concomitant Drug Therapy—Drug Interactions
Chapter 66 is devoted entirely to the subject of drug interac-
tions of importance to the dermatologist and other physicians
using similar medications. However, a few principles must still
be addressed in this setting. The vast majority of drug interac-
tions can be anticipated, and thus prevented. Truly life-threat-
ening drug interactions are quite uncommon and virtually
always have been well publicized. Q2.5 The following are
principles dealing with three categories of drug interactions of
central importance to maximizing the safety of systemic drug
therapy.
Principle #9. Anticipate (and avoid) drug combinations that
have overlapping target organs of potential toxicity:
• Tetracycline or minocycline plus isotretinoin: pseudotumor
cerebri.
• Hydroxychloroquine plus chloroquine: antimalarial retinopathy.
(It is acceptable practice to combine quinacrine with either of these
two drugs, as quinacrine alone does not induce a retinopathy.)
• Methotrexate and a second-generation retinoid (previously
etretinate, now acitretin): probably an increased risk for hepa-
totoxicity.
Principle #10. Anticipate interactions involving two drugs that
alter the same metabolic pathway:
• Methotrexate and trimethoprim/sulfamethoxazole: increased
risk for pancytopenia, given that these drugs inhibit folate
metabolism.
15
• Azathioprine and allopurinol or febuxostat: increased risk for
hematologic complications, as these drugs affect parallel purine
metabolic pathways.
Principle #11. Anticipate (and avoid) drug combinations metab-
olized by the same cytochrome P-450 (CYP) pathway, particu-
larly if there is a narrow therapeutic index for one of the drugs
involved:
• Rifampin (CYP3A4 enzyme inducer) plus hormonal contra-
ceptives: loss of efficacy of the contraceptive with the potential
for an unintended pregnancy.
• Ketoconazole or erythromycin (CYP3A4 enzyme inhibitors)
plus cyclosporine: increased risk for renal toxicity because of
increased cyclosporine blood levels.
This area of medicine is very complicated and it is very difficult
to stay ‘current’ (see Chapter 66). At times, recently released drugs
have important, potentially life-threatening interactions which are
discovered only years later. The potential for torsades de pointes with
life-threatening cardiac arrhythmias from terfenadine, astemizole, or
cisapride (elucidated several years after the drugs’ release) in the pres-
ence of certain CYP enzyme inhibitors illustrates this point. Do your
best to stay current: liberally use the numerous electronic resources
for information on drug interactions. As a backup, use of your hos-
pital’s drug information pharmacists is highly recommended to
more effectively deal with this challenging area of medicine.
Evolving Guidelines—Risk Factors
Typically, with the passage of time the magnitude of risk for vari-
ous systemic drugs becomes clarified. The level of concern can
go in one of two directions: over time there is either increased
concern or decreased concern about various risks subsequent upon
the publication of new data. Furthermore, specific new risk factors
can be elucidated as new scientific information is reported.
Principle #12. Q2.6 Certain risks or risk factors for systemic
therapies may be discovered many years after a specific drug is
released. It is imperative to ‘stay tuned’ regarding standards of
care, as discussed in the Introduction:
• Psoralen and Ultraviolet A (PUVA) therapy: an increased risk
for squamous cell carcinoma of the male genitalia (specific risk
factor—male gender, without clothing protection for the groin
region during PUVA treatments).
• PUVA-induced melanoma: probably an increased risk in patients
receiving more than 250 to 350 treatments over a lifetime (spe-
cific risk factor—very large number of PUVA treatments).
• Minocycline drug reaction with eosinophils and systemic
symptoms (DRESS) or minocycline-induced lupus erythema-
tosus: the magnitude of risk for these complications was not
clarified until over a decade after the drug’s release.
• Ketoconazole hepatotoxicity: magnitude of risk overall and
potential for fatal outcomes were not clarified until several
years after the drug’s release.
• Boxed warnings for tumor necrosis factor (TNF) inhibitors concern-
ing ‘opportunistic’ (bacterial, fungal, and parasitic) infections were
expanded in the package insert many years after the drugs’ release.
Principle #13. In contrast, the perceived magnitude of risk for
a particular AE may decrease over time as new scientific evi-
dence accumulates:
• Antimalarial retinopathy: markedly lower risk than originally
perceived, largely because of more careful antimalarial dosing
schemes, and perhaps also to greater use of hydroxychloro-
quine rather than chloroquine.
16 PA RT I Introduction
• PUVA cataracts: primarily a risk in patients who fail to comply
with current regimens regarding Ultraviolet A (UVA)-protec-
tive wraparound sunglasses.
• Prednisone bursts and osteonecrosis risk: although this issue
is still cloudy in the legal system, the scientific evidence ‘rules
against’ there being a true risk of this bone complication with
short courses (‘bursts’) of systemic CS.
Principle #14. In many clinical scenarios, physicians must
make decisions about measures to prevent important potential
drug risks before all necessary information is published con-
cerning whether there truly is an increased risk of a specific
complication:
• TNF inhibitors (etanercept, adalimumab, infliximab, certoli-
zumab) and IL-12/23, IL-17, and IL-23 inhibitors tuberculosis
(TB) risk: at least order a baseline purified protein derivative
(PPD) or interferon-γ release assay such as T-spot TB (and
selectively order a chest x-ray in higher-risk patients or in posi-
tivity with the above tests) before initiating therapy.
• TNF inhibitors (etanercept, adalimumab, infliximab, cer-
tolizumab) and risk of demyelinating diseases: at least check
personal and family history closely for multiple sclerosis and
related demyelinating disorders before initiating therapy.
• Isotretinoin, apremilast, and brodalumab risk of suicide; in
each case all three drugs may at least induce severe depression
if patient baseline depression is present (even if population
studies do not show a direct connection with these drugs and
suicide). Avoid these drugs when moderate-severe depression
(or a history of same) is present.
As challenging as it may be, physicians are obliged to stay ‘cur-
rent’ with the latest published information on the magnitude of
risk from the drugs we use. Truly important ‘new risks’ tend to
be widely and repeatedly disseminated to physicians, with the so-
called ‘Dear Health Care Professional’ letters from the FDA being
a common vehicle for the dissemination of such information.
Prevention
This section of the chapter will be divided into three subsections
as follows: (1) patient measures to reduce risks, (2) therapeutic
interventions to minimize drug risk, and (3) timing of risk and
medication errors.
Patient Measures to Reduce Risks
Principle #15. Patients should take all reasonable protective
measures to prevent important AE:
• Prevention of squamous cell carcinoma of male genitalia caused
by PUVA therapy: wearing a ‘jockstrap’ or underwear during a
PUVA treatment.
• Prevention of cataracts in PUVA therapy: wearing opaque
goggles during the PUVA treatment and wearing wraparound
UVA-protective sunglasses when exposed to outdoor light, at
least until sundown the day of the PUVA treatment.
Therapeutic Interventions to Minimize Drug Risk
There are many occasions in which the patient would benefit from
a specific systemic drug, yet there are worrisome risk factors for a
given AE. If the drug regimen is essential for the patient, concomi-
tant medical therapy to reduce the negative impact of the AE is
logical and appropriate in most cases.
Principle #16. Use all reasonable adjunctive therapeutic mea-
sures to minimize the risk of various AE:
• Daily folic acid therapy in patients receiving methotrexate:
prevention of gastrointestinal (GI) AE and minimization of
pancytopenia risk. (Ideally, folic acid should be used in all
methotrexate patients; the benefits easily outweigh the theo-
retical risk of loss of efficacy in psoriasis.)
• Calcium, vitamin D, and possibly estrogens, bisphosphonates,
PTH analogs or nasal calcitonin: use in patients receiving long-
term systemic CS therapy at or above physiologic doses. (Use
a greater number of these preventative therapies in higher-risk
patients.)
Timing of Risk and Medication Errors
The prevention of many AE requires either heightened awareness
with more frequent monitoring (drugs with a specific timing of
greatest risk) or careful patient education (for potentially serious
medication errors). In either setting a proactive physician style is
preferred to maximize safety.
Principle #17. For the most potentially SAE of systemic drugs,
learn the timing of greatest risk for the drug-induced compli-
cation while monitoring the patient most carefully during this
period:
• Dapsone agranulocytosis or dapsone-induced DRESS is pri-
marily an issue between weeks 3 and 12 of therapy. (Minocy-
cline-induced DRESS: timing of greatest risk is roughly in the
same interval, particularly in the first 2 months of therapy.)
• Methotrexate or azathioprine pancytopenia: the risk is greatest
primarily in the first 4 to 6 weeks of therapy, unless a drug inter-
action is a precipitating factor later in the course of therapy.
• Prednisone osteonecrosis: the risk begins to increase substan-
tially by months 2 to 3 of pharmacologic dose CS therapy.
(This risk tends to parallel the overall development of cushin-
goid changes in the patient.)
• Timing of rituximab-induced expected CD20 marked reduc-
tion and recovery in pemphigus vulgaris therapy; the recovery
may help determine the optimal timing of a subsequent ritux-
imab course.
Principle #18. Medication errors are largely preventable with
careful patient education and, if necessary, cross-checks on
potentially unreliable patients. These medication errors can be
caused by either dose omissions or dose duplications:
• Methotrexate weekly dosing scheme: the literature has many
reports of pancytopenia caused by inadvertent daily dosing of
methotrexate. If necessary, another caregiver or family member
should place the drug in the slot for just one specific day each
week in a weekly pill container, particularly for older patients.
• Hormonal contraceptives and isotretinoin or thalidomide:
pregnancy prevention is critical in women of childbear-
ing potential. Omission of oral contraceptives for even a day
can lead to unintended pregnancy in women of childbearing
potential prescribed these potent teratogens.
Diagnosis
This section is divided into five subsections as follows: (1) evolving
guidelines for monitoring, (2) a teamwork approach for maximiz-
ing the safety of drug therapy, (3) use of the most optimal diagnos-
tic tests, (4) higher-risk scenarios, and (5) efficient and thorough
record keeping.
 CHAPTER 2 Principles for Maximizing the Safety of Dermatologic Drug Therapy
Evolving Guidelines for Monitoring
As discussed under the section ‘Anticipation’, newer scientific evi-
dence commonly leads to new or revised guidelines for standards
of care. As before, the level of concern can increase or decrease
over time with the release of this new scientific information.
Principle #19. Stay current with changing guidelines for diag-
nosing important complications of systemic drug therapy at
an early, reversible stage:
• Methotrexate chest x-rays for pneumonitis: pneumonitis from
methotrexate is a significant risk in RA patients. In contrast,
the negligible risk for this complication in psoriasis patients led
to elimination of a previous yearly requirement for chest X-rays
in more recent methotrexate guidelines.
• TNF inhibitors (etanercept, adalimumab, infliximab, cer-
tolizumab) and subsequent biologics and tuberculin skin test
or interferon-γ releasing assay (IGRA): the somewhat recent
overall resurgence in incidence of TB and the TNF-α role in
stabilizing granulomatous responses leads to this guideline for
screening patients for TB before initiating therapy.
• There is inconsistent package insert requirements for follow-up of
latent TB screening for all four subgroups of biologics for moder-
ate-severe psoriasis. A significant number of clinicians (including
myself) have adopted yearly latent TB screening for all biologic
therapeutics (and most oral immunosuppressive agents).
A Teamwork Approach for Maximizing the Safety
of Drug Therapy
Despite recent trends in managed care to fragment care and limit
access to various medical specialties in the name of cost savings,
a teamwork approach for risk reduction is imperative. Q2.7 A
‘team’ consisting of the prescribing physician, the patient (includ-
ing their family), and, in many cases, the patient’s primary physi-
cian or another specialist, is of central importance. In addition,
pharmacists and members of the physician’s office staff have key
roles in this team. Each member of the team has an important role
in maximizing the safety of systemic drug therapy.
Principle #20. In addition to the importance of patient aware-
ness of reporting symptoms suggesting the early phases of
selected complications, the patient often has a role in home
monitoring for selected complications:
• Cyclosporine or CS and hypertension: with a growing number
of patients using home blood pressure cuffs or electronic blood
pressure monitoring devices, this is a relatively easy area of home
surveillance for AE. The patient merely needs to be told what
levels of blood pressure elevation should be reported to the pre-
scribing physician and/or primary physician.
• CS and home glucose monitoring: even though the history of
diabetes mellitus should lead to careful scrutiny regarding the
appropriateness of systemic CS, there are many circumstances
in which prednisone therapy is essential in diabetic patients.
Home glucose monitoring provides for relatively easy surveil-
lance and follow-up.
• CS and weight gain: the simple bathroom scale can provide
useful information on the progression of cushingoid changes or
for signs of increasing fluid overload in patients with previously
well-compensated congestive heart failure.
Principle #21. The prescribing physician’s examination is essen-
tial for detection or verification of important early signs of
various drug complications:
17
• Full skin examination for PUVA/NB-UVB (narrow-band
ultraviolet B) or patients on systemic immunosuppressive ther-
apy: detection of melanoma, squamous cell carcinoma, and
basal cell carcinoma (and precursors thereof ).
• Neurologic examination (screening style) for dapsone motor
neuropathy or thalidomide sensory neuropathy: screening
done by the prescribing physician, possibly verified by a con-
sultant.
• Morbilliform eruption and related DRESS syndrome findings
caused by dapsone, minocycline, or azathioprine: reported by
the patient but verified by the prescribing physician.
Principle #22. Comanagement with another consultant is com-
monly an essential part of this ‘teamwork’ approach to maxi-
mizing the safety of systemic drug therapy:
• Gastroenterologist: for recent trend of using fibroscans in
detection of fatty liver or fibrosis in long-term methotrexate
therapy.
• Ophthalmologist: integral part of monitoring guidelines for
PUVA and antimalarial therapy.
• Primary physician: for management decisions regarding ele-
vated blood glucose or blood pressure with CS therapy or for
management of hyperlipidemia in patients on long-term sys-
temic retinoid or cyclosporine therapy.
Use of Optimal Diagnostic Tests
Principle #23. Stay current regarding optimal diagnostic tests
that have improved sensitivity and precision for early diagno-
sis of important AE at a reversible stage:
• CS osteonecrosis diagnosis: magnetic resonance imaging is far
superior to conventional X-rays for early diagnosis, and can
allow timely performance of core decompression to salvage the
affected bone or joint.
• CS osteoporosis diagnosis: dual-energy X-ray absorptiometry
(Dexascan) has much greater sensitivity than conventional
X-rays for early recognition of bone density loss.
• Methotrexate hepatotoxicity diagnosis: as discussed previously
with fibroscan largely replacing ultrasound-guided liver biopsies.
Principle #24. Realize that many diagnostic tests provide com-
plementary information for the clinician:
• Transaminase values and liver histology for methotrexate
hepatotoxicity: one method of testing (transaminases) assesses
hepatocellular toxicity, whereas the other method (liver biopsy/
histology) assesses the potential for slow progression from fatty
liver changes to focal fibrosis to cirrhosis; both tests in combi-
nation are essential for proper hepatic monitoring.
• Ordering both transaminases (SGOT/AST and SGPT/ALT) for
detection of dapsone, azathioprine, and methotrexate hepatotoxic-
ity: improved sensitivity and specificity when ordering both tests;
subsequently, tests for hepatobiliary obstruction (bilirubin, alka-
line phosphatase, gamma-glutamyl transpeptidase) can be useful
adjuncts if significant transaminase elevation has already occurred.
Higher-Risk Scenarios
As discussed earlier, patients are not ‘all created equal’ when it
comes to risk factors for AE from systemic drug therapy. The
more a physician knows about relatively high-risk clinical sce-
narios (with corresponding increased surveillance for AE in these
settings), the more that physician can maximize the safety of the
drug therapy in that particular patient.
18 PA RT I Introduction

Principle #25. Q2.8 Laboratory monitoring and related
diagnostic tests should be performed more frequently with
(1) higher-risk patients, (2) abnormal test results, and (3) at
high-risk periods—typically early in therapy:
Principle #26. Q2.9 Become familiar with ‘thresholds of con-
cern’ (levels at which to consider dose reduction and/or more
frequent monitoring) and ‘critical values’ (levels at which
therapy should be stopped, possibly indefinitely) for various
laboratory tests and related monitoring procedures (Table 2.1):
Q2.10 It is of tremendous importance for the reader to realize
that the test result ranges in Table 2.1 are merely rough guide-
lines for clinicians to use. The rapidity of change and the overall
trend of the laboratory values are of at least equal importance to
recognize. Regardless of the actual laboratory test abnormality or
the rapidity of change, the clinician should be mindful of four
possible options (depending on the clinical circumstances in an
individual patient):
1. Discontinue the drug therapy temporarily or indefinitely;
2. Reduce the drug dose;
3. Increase the frequency of test monitoring; and
4. Treat the AE while carefully continuing the therapy.
These are not mutually exclusive options: generally, several of
the above steps are instituted simultaneously. Again, the key is to
know which circumstances constitute a high-risk clinical scenario,
and subsequently to proceed therapeutically with greater caution
in these clinical settings.
Efficient and Thorough Record Keeping
It is quite difficult to stay ‘current’ regarding scientific advancements
related to drug safety in dermatologic therapeutics. It is at least an
equal challenge to keep track of the following aspects of medical
record keeping for the five general steps of maximizing safety pre-
sented in this chapter. The issues here include (to name a few):
1. Documenting informed consent discussions;
TABLE Thresholds of Concern and Critical Values for
2.1 Diagnostic Tests
Threshold of
Test concern
WBC count <3500
(#/mm3)
Hemoglobin (g/dL) 10–11
Platelet count <100,000
(#/mm3)
Triglycerides (mg/dL) <400–500
Creatinine 30% increase
AST/ALT 1.5–2.0 times
increase (above
the upper
normal value)
Dexascan T-score: –1.0 to
–2.5
ALT, Aalanine aminotransferase; AST, aspartate aminotransferase; WBC, white blood cell.
2. The changing frequency of laboratory tests any given patient
should have, depending on the stage of therapy and the dose of
the drug;
3. Keeping track of which patients did not have laboratory tests
performed when scheduled;
4. Notifying patients about laboratory test results, particularly
abnormal results, and the resultant algorithm describing how
to respond to these abnormal results; and
5. How to efficiently document steps 2 through 4 above.
What is a busy clinician to do?
Fortunately, the electronic/information era in which we prac-
tice has provided some solutions. I previously kept written test
result flow sheets on patients I followed in the 1980s, but through
the 1990s and into the 21st century most laboratories are capable
of printing (or simply displaying) computer-generated flow sheets
of test results. Similarly, most electronic medical records (EMR)
can provide a summary of test results over time. If a clinician can
readily find the last 2 to 3 sets of test results, most decision making
proceeds without much difficulty.
There should be a cross-check system regarding missed appoint-
ments and missed laboratory tests for patients on systemic drug
therapy. I personally believe this is an area of potential medicolegal
risk. In general, it is helpful to have a patient call about test results
(in a specified time frame) if not previously notified about test
results by mail or a phone call from the physician’s office. A less
time-consuming step is a policy that only severely abnormal test
results require phone notification of the patient; otherwise com-
munication with a letter is sufficient. The reality is that even with
normal test results, the physician (or physician’s staff) must com-
monly contact the patient about drug dose changes, and hence the
need to document and to communicate this decision.
A few principles need to be listed, some of which overlap with
other chapters (such as Chapter 68 Informed Consent and Risk
Management).
Principle #27. An important medicolegal dictum states that ‘if
it was not written, it was not done.’ An individual physician
needs to find a balance of thoroughness and efficiency. Person-
ally, I believe that dictated chart notes more readily allow this
optimal balance—I believe voice recognition software is the
most efficient manner of documenting important informed
Critical value consent discussions:
<2500–3000 Principle #28. When possible, with relatively high-risk medica-
tions, create backup systems in case the patient, the physician,
<10
the office staff, or the laboratory personnel have (hopefully
rare) oversights:
<50,000 • One option is a log for high-risk medication patients kept by
nursing staff, with the expected date for follow-up lab test-
>700–800 ing; there should be an electronic or phone notification if any
patients are delayed in the required testing.
>40%–50% • The traditional strategy of giving the patient just enough medi-
(increase from the cation to last until the next appointment has a couple pitfalls.
baseline value)
One is the common tendency for other ‘well-meaning’ pro-
>2.5–3.0 times viders to extend the patient prescription supply without being
increase (above aware of monitoring plans. Two is patient no-shows or, in par-
the upper normal ticular, cancellations in advance of the appointment date with-
value) out rescheduling (easily happens with ‘robo-calls’).
T-score < –2.5 Principle #29. Use any electronic means available to keep track
of important information needed to maximize the safety of
systemic drug therapy:
 CHAPTER 2 Principles for Maximizing the Safety of Dermatologic Drug Therapy
Management
This section of the chapter will be divided into two subsections
as follows:
1. What to do if problems arise—relatively minor complications;
and
2. What to do if problems arise—potentially serious complica-
tions.
What to do if Problems Arise—Relatively Minor
Complications
The vast majority of complications from systemic drug therapy
are relatively minor and are fixable. Provided that communication
channels are kept open, the physician remains nondefensive and a
solutions-based approach to these complications is used, keeping
the patient’s best interests in mind, serious medical complications
and adverse medicolegal outcomes are relatively unlikely. This
relatively brief section will address a general approach to man-
aging AE if the ‘anticipation’ and ‘prevention’ steps are not fully
successful. Parenthetically, these same principles also apply to any
complication of topical or intralesional therapy.
Principle #30. When in doubt, have the patient stop the drug
in question if a potentially SAE has occurred. The physician
generally has at least a few days (subsequent to discontinua-
tion of the drug) to consider the management options, and to
communicate with the necessary consultants. Important fac-
tors in this decision-making process include:
• The severity of the underlying disease being treated.
• The magnitude of risk from the AE the patient experienced,
particularly if the complication can worsen precipitously with
continued use of the responsible drug.
• Whether the drug in question is uniquely effective for the dis-
ease being treated.
• Whether there is a significant risk caused by abrupt discontinu-
ation of the responsible drug—most notably the risk of abrupt
cessation of high-dose, long-term systemic CS therapy and the
potential for an addisonian crisis.
Principle #31. With less serious medical complications in the
setting of a systemic drug essential for the patient, specific medi-
cal therapy directed at this complication is quite acceptable:
• Retinoid or CS hyperlipidemia: concomitant treatment with
‘statins’ or gemfibrozil.
• CS or cyclosporine hypertension: any of a wide variety of med-
ical options for blood pressure control. One should be mindful
that the therapeutic choice for cyclosporine-induced hyperten-
sion needs to preserve optimal renal blood flow as well. (see
Chapter 17)
• Hepatitis B reactivation in patients on biologics and traditional
immunosuppressive therapy: comanagement with GI physi-
cian for antiviral therapy.
What to do if Problems Arise—Potentially Serious
Complications
Principle #32. Q2.11 More serious complications generally have
a specific remedy, although frequently these management steps
come at significant cost or present a lifelong risk to the patient:
• CS osteonecrosis: core decompression (if diagnosed relatively
early) or joint replacement surgery (if there is more advanced
osteonecrosis).
19
• Methotrexate pancytopenia: if recognized early, ‘leucovorin
rescue’ will be quite effective, as is routine for high-dose meth-
otrexate therapy in oncology settings.
• Methotrexate, ketoconazole, dapsone liver failure: worst-case
scenario is that the patient may require a liver transplantation.
• CS or PUVA cataracts: this outcome is far less catastrophic
than even a decade or two ago, given the availability of safe and
reliable lens implants after cataract extraction.
Principle #33. A few complications cannot be ‘fixed’ and should
be avoided at all costs:
• Retinoid or thalidomide teratogenesis: absolute and complete
pregnancy prevention is essential.
• Antimalarial retinopathy: although therapeutic and monitor-
ing approaches used in the current era fortunately minimize the
likelihood of this complication. Early retinopathy (‘premacu-
lopathy’) is potentially reversible, whereas more advanced
retinopathy can lead to scotomata/visual field defects that are
likely irreversible. The above complications are possibly more
likely now with newer more infrequent visit guidelines.
Parting Thoughts
The bottom line is as follows: it would be an ideal goal that clini-
cians reading this chapter, and who used the principles presented,
never had a patient suffer a major complication from systemic
drug therapy in their respective careers. In reality, this is not likely.
The mindset that is more realistic is as follows:
1. The physician should thoroughly learn the measures necessary
to anticipate the most important risk factors and strive to pre-
vent important complications of systemic drug therapy;
2. When important AE rarely occur, which is inevitable despite
meticulously following all principles discussed in this chapter,
the clinician should move quickly to diagnose the condition at
an early and potentially reversible stage;
3. Once diagnosed, management of these complications of therapy
should proceed in an efficient manner, using appropriate consul-
tants when necessary; the patient’s best overall wellbeing is always
first and foremost a guide to this medical decision making;
4. The more potentially serious and less reversible the complica-
tion, the greater the efforts should be made to be sure that this
complication never occurs (retinoid or thalidomide teratogen-
esis as examples); and
5. With a proactive mindset for prevention of and monitoring
for AE, and forming a true therapeutic partnership with the
patient, the medicolegal risks of systemic drug therapy become
significantly reduced.
6. Should an important drug complication occur (virtually inevi-
table in any physician’s career) the most successful and profes-
sional approach has three parts:
• ‘Stand by’ and work with the patient’s management, regard-
less of the circumstances;
• For future patients’ benefit, learn everything possible from
the undesirable therapeutic outcome; and
• Focus on the numerous patients who have benefited from
(and will continue to benefit from) the same drug or thera-
peutic approach throughout your career.
The gratification that patients and physicians alike receive
from successful outcomes of carefully planned and appropriately
monitored systemic drug therapy is immense. Please use the prin-
ciples discussed in this chapter carefully and effectively, reinforced
by additional strategies detailed in specific chapters throughout
this book, and look forward to the numerous safe and successful
20 PA RT I Introduction

therapeutic results for your patients. With the markedly increased Recent References
focus on physician burnout, ‘releasing’ oneself from long-term Noe MH, Gelfand JM. Research techniques made simple: pharmaco-
self-blame and rumination about mistakes or complications goes a epidemiology research methods in dermatology. J Invest Dermatol.
long way to reduce the risk of burnout. 2018;138(2):e13–e18.
Reich K, Mrowietz U, Radtke MA, et al. Drug safety of systemic treat-
ments for psoriasis: results from the German Psoriasis Registry Psobest.
Bibliography: Important Reviews and Arch Dermatol Res. 2015;307(10):875–883.
Chapters
Wolverton SE. Major adverse effects from systemic drugs: defining the
risks. Curr Probl Dermatol. 1995;7:1–4.
Wolverton SE. Monitoring for adverse effects from systemic drugs used in
dermatology. J Am Acad Dermatol. 1992;26(5Pt1):661–679.
Wolverton SE. Systemic drugs for psoriasis. The most critical issues. Arch
Dermatol. 1991;127(4):565–568.
3
Polymorphisms: Why
Individual Drug Responses
Vary
WILLIAM C. SCHAFFENBURG, BENJAMIN N. LOCKSHIN AND
CYNTHIA M.C . DEKLOTZ
QUESTIONS
Q3.1 How are ‘polymorphism’ and ‘variability’ defined in the
most basic sense? (Pg. 22)
Q3.2 Regarding the cytochrome P-450 (CYP) isoforms discussed
in this chapter, (1) which isoforms are most important to
drug interactions, and (2) which of these isoforms have
polymorphisms? (Pg. 22)
Q3.3 Which three CYP isoforms are most important for drug
metabolism based on the percentage of drugs metabolized by
the respective isoform? (Pg. 23, Table 3.2)
Q3.4 What are the terms regarding the rate of drug metabolism (and
their respective abbreviations) for the four major groups in various
populations, given that a polymorphism is present? (Pg. 23)
Q3.5 Regarding the CYP2C9 isoform, what are (1) the frequency of
polymorphisms in various populations, and (2) the key alleles
affecting drug metabolism (and the clinical result)? (Pg. 24,
Table 3.4, Table 3.5)
Q3.6 Regarding the CYP2C19 isoform, what are (1) the frequency
of polymorphisms in various populations, and (2) the key alleles
affecting drug metabolism (and the clinical result)? (Pg. 25,
Table 3.6, Table 3.7)
Introduction
This chapter focuses on the intrinsic and extrinsic factors that
affect systemic medications. Adverse drug reactions (ADR) are
often associated with drug toxicity, but can also account for
decreased drug efficacy. An understanding of drug interactions
and drug metabolism is imperative for selecting the appropriate
medications.
The WHO defines ADR as ‘a response to a drug that is nox-
ious and unintended and occurs at doses normally used in man
for the prophylaxis, diagnosis or therapy of disease, or for modi-
fication of physiological function.’1 Cutaneous ADR represent
Q3.7 Regarding the CYP2D6 isoform, what are (1) the frequency
of polymorphisms in various populations, and (2) the key alleles
affecting drug metabolism (and the clinical result)? (Pg. 25,
Table 3.8)
Q3.8 Regarding thiopurine methyltransferase (TPMT), what are
(1) the frequency of polymorphisms in various populations,
and (2) the net clinical effect of the polymorphisms? (Pg. 28,
Table 3.10)
Q3.9 Regarding N-acetyl transferase (NAT2), what are (1) the
frequency of polymorphisms in various populations, and
(2) the net clinical effect of the polymorphisms? (Pg. 29,
Table 3.11)
Q3.10 Regarding glucose-6-phosphate dehydrogenase
(G6PD), what are (1) the frequency of polymorphisms in
various populations, and (2) the net clinical effect of the
polymorphisms? (Pg. 29, Table 3.12, Table 3.13)
Q3.11 What are several of the most important polymorphisms
which can help predict which patients are likely to develop a
serious cutaneous drug reaction with systemic features? (Pg. 31,
Table 3.14)
around a fifth of all reported ADR, with morbilliform eruptions
being reported as the majority of clinical presentations, and
severe cutaneous adverse drug reaction (SCAR) accounting for
around 2%.1,2
ADR occur frequently and result in a substantial cost burden
on the healthcare system. In a prospective study of over 18,000
patient admissions by Pirmohamed and associates,3 ADR were
responsible for 6.5% of all hospital admissions. Furthermore, it
has been speculated (in a very controversial study) that 100,000
deaths each year in the United States are caused by ADR, with
a cost-estimated ADR of US$5000 per reaction reported in the
early 2000s.4,5
21
22 PA RT I Introduction
Given that the primary focus of this chapter is on polymor-
phisms, it is important to provide a clear-cut definition of the
terms variability and polymorphism. Q3.1 The definitions can
relate to receptor affinity/avidity and a variety of other biologic
properties, although for the purposes of this chapter the defini-
tions will be applied to activity for phase I and phase II enzymes
important for drug metabolism. Conceptually, ‘variability’ is
defined by a single ‘bell-shaped curve,’ whereas ‘polymorphism’ is
defined by two or more (usually three) distinct ‘bell-shaped curves’
for drug metabolism rates in various populations. Genetically this
correlates with specific mutations of a single allele (single nucleo-
tide polymorphism [SNP]). A ‘polymorphism’ is a variation that
occurs in more than 1% of the studied population.6 Additional
terms that are useful to define include pharmacogenetics and
pharmacogenomics. Initially defined in 1959, pharmacogenet-
ics is the relationship between genetic polymorphisms and drug
response. Pharmacogenomics further encompasses the interrela-
tionships between epigenetics, transcription, and metabolism in
response to medication.7
Evaluating the Patient
Initial patient evaluation should include a detailed history with
focus on the patient’s demographics, comorbidities, current medi-
cations, and allergies. Renal function declines with age, accounting
for decreased clearance of many medications. In addition to evaluat-
ing renal function, any presence of liver dysfunction or disease must
be determined before administration of most medications. Ethnic-
ity can occasionally help predict genetic variability in enzyme levels
responsible for drug metabolism. A complete list of the patient’s
prescription medications along with all vitamins, herbals, and
over-the-counter (OTC) medications is imperative. When seeking
information on a given patient’s drug allergies, inquire if there are
any medications that the patient cannot take, and what specifically
happens when the medication is taken. This will help distinguish
between potential life-threatening ADR and drug intolerances.
Factors That Influence Medication Effects
(Including Adverse Effects)
There can be considerable variability in virtually every point along
a medication’s course from absorption to excretion. It is important
to be aware of the pharmacogenetic and pharmacokinetic factors
that can ultimately affect the patient’s medication tolerability and
treatment outcomes.
Absorption
Gastrointestinal Tract. Extrinsic and intrinsic factors can result
in altered absorption in the gastrointestinal (GI) tract. Antacids
raise the stomach’s pH, which can influence medication absorp-
tion. Ketoconazole is a classic example of a medication that is
better absorbed in an acidic environment (Table 3.1).8 Other
medications can act as binding resins in the GI tract, and thus
inhibit absorption. There is evidence that iron will bind myco-
phenolate mofetil, thereby inhibiting its absorption (see Table
3.1).9 GI transit times are thought to play only a small role in
drug absorption variability.8 Anticholinergic agents and opioids
can slow down transit times, whereas infections and some medical
conditions such as Crohn’s disease and ulcerative colitis can mark-
edly increase transit times.
TABLE
3.1 Absorption of Important Dermatologic Drugs8,9
Absorption
Drug Location Take Home Point
Ketoconazole GI tract Improved absorption in an
acidic environment
Mycophenolate GI tract Do not give with iron: binds
mofetil with iron, which inhibits
absorption
Cyclosporine PGP Affects bioavailability
GI, Gastrointestinal; PGP, P-glycoprotein.
P-Glycoprotein. P-glycoprotein (PGP), a membrane-bound
transport protein, affects drug absorption in the GI tract. Func-
tioning as part of the ‘first-pass effect’ in the gut, PGP acts as
a pump to remove drugs from the cell through active adenosine
triphosphate (ATP) hydrolysis.10 Cyclosporine is just one example
of a medication in which PGP can affect drug bioavailability (see
Table 3.1).8 High levels of PGP are also found in the kidneys and
liver, where it functions in drug elimination.
Phase I and Phase II Drug Metabolism
Drug metabolism is a process that facilitates drug clearance by
(1) increasing solubility, or (2) being responsible for converting
prodrugs to their active drug form (along with the formation of
potentially toxic metabolites).8 Classically, drug metabolism is
divided into two general components, designated as phase I and
phase II reactions. Despite the nomenclature, there is no set order
in which these reactions take place. Phase I reactions involve intra-
molecular modifications: oxidation, reduction, and hydrolysis;
whereas phase II reactions result in conjugation of the drug with
an endogenous substance by acetylation, glucuronidation, sulfa-
tion (also called sulfonation), and methylation. Most commonly,
the phase I oxidative reactions create a site for subsequent attach-
ment of larger polar side chains in phase II reactions. Both phase
I and II reactions function to make the drug more hydrophilic,
thereby facilitating renal or hepatobiliary excretion.
Drug Metabolism—Phase I Reactions
Cytochrome P-450 Enzyme System Overview
The cytochrome P-450 (CYP) enzyme group plays a paramount
role in drug metabolism. Various CYP enzymes are responsible for
catalyzing 70% to 80% of all phase I reactions.11 These enzymes
are located within the endoplasmic reticulum of most cells, but
are found in variable concentrations, with hepatocytes having the
greatest concentration of CYP enzymes.
Nomenclature. CYP enzymes are classified by a hierarchical
nomenclature system. The first number represents the enzyme
family followed by a letter designating the subfamily. The final
number is for the individual gene. There is at least 40% homology
in amino acid sequences within a family, whereas subfamilies have
77% or more homology.
Q3.2 Although there are more than 50 families of CYP
enzymes, only a few CYP isoforms (CYP1A2, 2B6, 2C9,
2C19, 2D6, 2E1, 3A4) appear to play a significant role in drug
 CHAPTER 3
TABLE Fraction of Drugs Metabolized by Various
3.2 Cytochrome P-450 Isoforms11
Percentage of All Drugs
CYP Isoform Metabolized by Isoform
CYP1A2a,b 5 are noncompetitive inhibitors that result in CYP alteration, inac-
CYP2A6 2 Induction of a CYP isoform causes an increase in its metabolic
CYP2B6 2–4
CYP2C8 1 to a week or more) process than CYP enzyme inhibition, because
CYP2C9a,b 10
CYP2C19a,b 5
CYP2D6a,b 20–30
CYP2E1 2–4
CYP3A4a 40–45
CYP3A5 <1
aCYP isoforms most commonly involved in drug interactions.
bCYP isoforms with polymorphisms.
CYP, Cytochrome P-450.
metabolism (Table 3.2).11 Of these isoforms, all but CYP2E1 play
a prominent role in drug interactions important in the special-
ized field of dermatology. CYP1A2, 2B6, 2C9, 2C19, and 2D6 all
have polymorphisms.11 Q3.3 Based on the percentage of drugs
metabolized by the respective isoforms, CYP2C9, 2D6, and 3A4
are most important for drug metabolism (see Table 3.2).11
CYP Polymorphisms. Q3.4 Many CYP isoforms show sig-
nificant genetic polymorphism. Approximately 40% of human
CYP-dependent drug metabolism is carried out by polymorphic
CYP enzymes.12 This can translate into variable enzyme activity
between individuals. Depending on the enzyme activity, individu-
als are designated as:
1. ‘Poor metabolizers’ (PM) if they have very low to no enzyme
activity.
2. ‘Intermediate metabolizers’ (IM) if there is reduced activity.
3. ‘Normal metabolizer’ or ‘extensive metabolizer’ (NM/EM) if
there is average enzyme activity with at least one functional
allele.13
4. ‘Ultrarapid metabolizers’ (UM) if there is exceptionally high
enzyme activity.8,11,13
This has important clinical relevance for medications that have
a narrow therapeutic index. For example, if a clinician could pre-
dict how a patient would metabolize a specific medication, then
the starting dose could be altered to avoid unwanted adverse
effects (AE). In a PM, the starting dose would be lower than in
an EM. However, if the patient was a UM, a clinician could more
aggressively uptitrate a medication to reach a therapeutic level
with a greater assurance that the patient could safely tolerate the
more aggressive dosing.
Aside from the genetic variability of CYP isoforms, drug
metabolism can be influenced by other medications, as well as
physical factors. Medications can affect the various CYP isoforms
by either inhibition or induction of enzyme activity, making an
individual more susceptible to developing a cutaneous ADR.
Drug Inhibition or Induction of CYP Isoforms. Drug-induced
inhibition of various CYP isoforms plays an important role in
Polymorphisms: Why Individual Drug Responses Vary 23
many ADR. Inhibition reduces the metabolizing effects of the
affected cytochrome. In turn, CYP inhibition increases drug levels
and toxicity. This can occur after just 1 to 2 doses of a medica-
tion, with maximal inhibition being observed once steady state is
achieved.8 Inhibition is typically competitive; however, few drugs
tivation, or destruction.
activity by increasing either the enzyme amount or level of its
activity resulting in reduced drug levels. This is a much slower (up
induction relies on synthesis of additional CYP enzyme. Once an
inducing agent is removed, the duration of enzyme induction is
dependent on the degradation of the newly formed enzyme.
CYP1A2 Polymorphism
CYP1A2 functions primarily to metabolize several antipsychotic
medications and theophylline. Environmental and genetic factors
are shown to influence the activity of CYP1A2. These can account
for up to a 60-fold difference in activity. Tobacco byproducts pro-
duced from smoking and oral contraceptive steroids have been
well established as CYP1A2 inducers.14 Caffeine is a common
substrate of CYP1A2.14 Polymorphisms have been observed in the
gene encoding CYP1A2, accounting for 16 known alleles. These
genetic factors account for approximately 35% to 75% of the
variation in CYP1A2 activity.14 The frequency of these polymor-
phisms varies between different ethnic groups. A lower CYP1A2
activity has been found in Asian and African populations than in
Caucasian populations. Among nonsmokers, the frequency of PM
was found to be 5% in Australian, 14% in Japanese, and 5% in
Chinese people.14
CYP2B6 Haplotype Variation
CYP2B6 is an isoenzyme involved in the metabolic hydroxylation
and plasma concentrations of nevirapine.15 In African-American
human leukocyte antigen (HLA)-Cw*04 carriers, the CYP2B6
516TT allele, a marker for the slow metabolizing haplotypes of
CYP2B6, results in lowered CYP2B6 expression and function.15
A large study in Malawian and Ugandan HIV-infected patients
showed an association between nevirapine-induced ADR and the
983C>T polymorphism of CYP2B6 gene.16 CYP2B6 is expressed
by epidermal keratinocytes, and it was hypothesized that nevirap-
ine concentrations in the skin are associated with polymorphisms
that may contribute to the development of cutaneous ADR.16
CYP3A4 Variability
CYP3A4 is responsible for 40% to 45% of all phase I metabolism
and accounts for up to 70% of gastrointestinal CYP activity.8,11
CYP3A4 is coexpressed with PGP in the liver and intestines.17
Despite little genetic variability between populations, there
appears to be as much as a 20-fold interindividual ‘variability’ of
enzyme activity.8 CYP3A4*1B appears to be the most common
variant allele (Table 3.3) and is associated with decreased CYP3A4
activity.17 Obesity has been shown to reduce CYP3A4 activity,
resulting in increased substrate activity. A number of medica-
tions and supplements can influence the activity. In addition to
numerous other medications, ivermectin is a known substrate for
CYP3A4.17 See Chapter 66 on Drug Interactions for additional
details on CYP3A4 substrates, inhibitors, and inducers.
24 PA RT I Introduction

CYP2C9 Polymorphism to significantly reduce substrate affinity through inhibiting CYP

activity (Table 3.4). Only the homozygote CYP2C9*3/*3, com-
Overall, 10% of drug metabolism is carried out by CYP2C9. prising 0.5% of most populations, is considered to have marked
Q3.5 Although there have been over 100 SNP identified, only clinical significance with very low CYP2C9 activity.18 The
two allelic variants (CYP2C9*2 and CYP2C9*3) have been shown CYP2C9*3 variant may also play a role in phenytoin-induced
cutaneous adverse drug reactions (see ADR section).19 With
TABLE regard to the activity of CYP2C9, the *1/*1 genotype demon-
3.3 Prevalence of CYP3A4 Variant Alleles17
strates normal activity; the *1/*2 genotype has a minor reduction
in activity; and the *2/*2, *1/*3, and *2/*3 genotypes all show
Population CYP3A4*1B CYP3A4*3
moderately reduced activity (see Table 3.4).18 Epidemiologic stud-
Caucasian (%) 4–9 2 ies show varying prevalence in the different CYP2C9 genotypes
African (%) 69–82 0
among different ethnic populations (Tables 3.4 and 3.5). Cau-
casians show marked variability in CYP2C9, with *2 being the
Ghanaian (%) 71 0 most common mutant allele, whereas people of African and Asian
descent have predominantly normal activity with the presence of

TABLE
3.4 CYP2C9 Polymorphism Activity: Frequency in Various Populations18

Moderate Reductiona
Normal Activitya (EM) Minor Reductiona (IM) (CYP2C9*2/*2, Very Low Activitya
Population # Studied (CYP2C9*1/*1) (IM) (CYP2C9*1/*2) *1/*3, *2/*3) (PM) (CYP2C9*3/*3)
African 150 87 8.7 4.3 0
African-American 100 97 2 1 0
Caucasian 1383 65.3 20.4 13.9 0.4
Chinese 115 96.5 0 3.5 0
Japanese 218 95.9 0 4.1 0

Spanish 157 49.7 15.9 34.3 0

aThe number in this column represents the percentage of the given ethnic group with this level of CYP2C9 activity.

TABLE
3.5 Prevalence of CYP2C9 Genetic Polymorphisms20,21,24

Population CYP2C9 *1*1 CYP2C9 *1*2 CYP2C9 *1*3 CYP2C9 *2*2 CYP2C9 *2*3 CYP2C9 *3*3
White (average) 65a 20 12 1 2 1
Asian (average) 96 0 4 0 0 0
African 93.6 4.2 2.1 0 0 0
Chinese-Mongolian 93 0 7 0 0 0
Egypt 66.3 19 12 2.4 0 0.4
Greek 62 20 13.5 1.5 2.8 0
Iran 82 10.5 0 7.5 0 0
Southern Iranian 41.2 37.8 9.5 10.1 1.3 0
Italian 62 17.2 14.5 2.7 2.2 1.3
Japan 95 0 4 0 0 1
Russian 68 18.2 11.3 0.6 1.2 0.3
Sweden 66.7 18.6 11.6 0.4 1.6 0.6

UK 69.9 19 0.06 0.003 0.006 0

aThe number in each column represents the percentage of the given ethnic group with this CYP isoform.
CYP, Cytochrome P-450; UK, United Kingdom.
 CHAPTER 3 Polymorphisms: Why Individual Drug Responses Vary 25

the *1/*1 genotype.20,21 There are no allelic variants known to observed in 1% to 23% of persons, with Asians having the highest
be inducers. Warfarin is the most clinically significant substrate incidence, and African-Americans and Caucasians having the low-
for CYP2C9. Fluconazole inhibition of CYP2C9 can result in est (Table 3.6).23 Detailed prevalence of some of the CYP2C19
markedly elevated levels of warfarin, with a resultant risk of hem- genotypes may be seen later, where *2/*2, *2/*3, and *3/*3 are the
orrhage. Missense variant CYP2C9*3 is also known to be signifi- PM (Table 3.7).21,24
cantly associated with phenytoin-related ADR in Asian people as In addition to acting as a strong CYP3A4 inhibitor, ketocon-
a result of delayed clearance and accumulation of metabolites.1 azole inhibits the CYP2C19 isoform, although it is not a sub-
strate of this isoform. This dual inhibition is important, given that
many medications metabolized by the CYP2C19 isoform are also
CYP2C19 Polymorphism metabolized by CYP3A4.23
General Issues. Proton pump inhibitors and numerous anti-
convulsants are the primary substrates metabolized by the CYP2D6 Polymorphism
CYP2C19 isoform. This isoform comprises approximately 5% of
all drug metabolism. General Issues. CYP2D6 shows significant pharmacogenetic
Specific Alleles of Importance. Q3.6 There are several allelic variation (polymorphism) and is integral in the metabolism of
variants22 (CYP2C19*2–8) that show no enzymatic activ- numerous medications, especially psychiatric, narcotic, and car-
ity, which translates into a PM phenotype. This phenotype is diac medications. Q3.7 With over 90 documented allelic variants
reported, CYP2D6 displays remarkable polymorphism, some-
TABLE CYP2C19 Poor Metabolizer Frequency in
times with whole gene duplication. Overall, 20% to 30% of drugs
3.6 are metabolized through this pathway, with more than 50 drug
Various Populations23 substrates known (see Table 3.2).2,8,11 Because of these important
Population # Studied PM (%) issues, CYP2D6 has been extensively studied.25 In contrast to
Japanese 399 19.5
CYP2C9, CYP2D6 alleles that alter enzymatic activity are com-
mon. The enzymatic activity can vary up to 1000-fold between
Korean 309 12.1 allele types.11 Clinically this translates to at least a 50-fold dif-
Filipino 52 23.1 ference in drug doses tolerated between various individuals; this
principle is illustrated by the wide dosing range of the CYP2D6
Chinese 538 15.6 substrate doxepin and various β-blockers. Research has also gone
Middle East 537 3.0 into CYP2D6 and its effects on estrogen-responsive breast cancer
treatment with tamoxifen, with conclusions still being contested
African 684 3.9 as to clinical significance.26
White—European 2291 2.9 Specific Alleles of Importance. CYP2D6 polymorphisms are
classified according to level of activity: PM, IM, EM/NM, and
African-American 291 1.4 UM.13,27 The EM phenotype, which is expressed by the major-
White—American 422 2.6 ity of the population, is considered the norm. In Europeans, four
alleles, CYP2D6*3, *4, *5, and *6, are most closely associated
PM, Poor metabolizer. with the reduced enzyme, also known as PM phenotypes.25,28
These PM phenotypes are seen in 1.5% to 10% of Caucasians,

TABLE
3.7 Prevalence of CYP2C19 Genetic Polymorphisms21,24

Population CYP2C19 *1*1 CYP2C19 *1*2 CYP2C19 *1*3 CYP2C19 *2*2 CYP2C19 *2*3 CYP2C19 *3*3
China 36.7a 38.2 5.8 5.8 11 1.4
Chinese-Mongolian 51 35 6 6 1 1
Colombia 83.5 15.3 0 1 0 0
Egypt 78.5 20 0.4 0.8 0 0
Greek 76 22 0 2 0 0
India 35 55 0 10 0 0
Iran 75 22 0 3 0 0
Southern Iranian 74 25 0.6 0.6 0 0
Italian 79.4 18.8 1.6 0 0 0
Russian 76.6 19 0.3 1.7 0.3 0

Slovenian 68.2 30 0.7 0.7 0 0

aThe number in each column represents the percentage of the given ethnic group with this CYP isoform.
CYP, Cytochrome P-450.
26 PA RT I Introduction

but in only 0% to 1.2% of many Asian populations (Thai, Chi- resulting in very low drug levels with standard drug dosing. Peri-
nese, Japanese) (Table 3.8). Importantly, 6% of Caucasians lack odically checking morning doxepin levels (which include active
the CYP2D6 enzyme altogether as a result of the presence of two metabolite nordoxepin) as the dose is increased is of value to reach
null alleles (therefore are PM).6 a clinically effective and safe drug level. Population studies reveal
Many individuals, particularly those in certain African and considerable variation in the prevalence of CYP2D6*2 gene dupli-
East Asian regions, have the IM genotype.28 Among those with cation. Genotypic studies of CYP2D6*2 gene duplication in vari-
IM, CYP2D6*10 is common in East Asians and CYP2D6*17 is ous European countries demonstrate a prevalence of 1% to 10%,
common among African populations.28 depending on the country studied. Up to 29% of black Ethiopians
Gene Duplication. Gene duplication occurs with the and 21% of Saudi Arabians have CYP2D6*2 gene duplication.25
CYP2D6*2 allele, which generally confers an UM phenotype,
CYP2D6 Testing
TABLE CYP2D6 Polymorphism Frequency in Various Despite the fact that CYP2D6 polymorphisms have been known
3.8 Populations25,27 for over 30 years, genotyping still has not entered routine clinical
practice.28 Interestingly, a patient’s tolerance of diphenhydramine
Population PM (%) IM (%) EM (%) UM (%) (a CYP2D6 substrate) can reasonably predict doxepin tolerance.
White
American 6.86–7.7 9.8 83.33 4.3 Sources for Additional Information on CYP-
British 8.9 14.7 77 –
Based Interactions
Physicians should be cognizant of potential CYP-based drug inter-
Polish 8.3 –
actions when prescribing systemic medications. The website www.
Swiss 10 – drug-interactions.com is a valuable reference tool evaluating for
Danish – 0.8
CYP-based interactions.29 It has a comprehensive list of medica-
tions that are substrates, inducers, or inhibitors for the major CYP
German 7.7 0.8 isoforms of clinical significance.29 This website links the reader to
Swedish – 1 pertinent references for the interactions listed.29
Databases courtesy of the Pharmacogenomics Research Net-
Spanish – 10 work (PGRN), and commercially available testing (see section
Turkish 1.5 8.7 on Databases and Tests for Genetic Polymorphisms) are available
on a widespread basis for the major CYP isoforms with currently
Croatian 3.0 4.0 known clinically significant polymorphisms. Currently, approval
African for testing through insurance is limited, and based on a tier-based
African- 1.9–8 29.78 63.11 4.9
drug-gene pair of importance system in a reactive fashion; certain
American medical research centers within the PGRN (see Pharmacogenom-
ics section) have implemented ‘pre-emptive’ alerts based on elec-
Nigerian 0–8.1 – tronic health records, but this is not widespread.17,30
Ghanaian 6.0 –
Ethiopian 1.8 29 Dihydropyrimidine Dehydrogenase
South African 19 – Another example of phase I drug metabolism involves the metab-
olism of 5-fluorouracil (5-FU).31 5-FU is a chemotherapeu-
Asian tic agent used to treat solid tumors, with topical formulations
Japanese 0 – – designed to treat some cutaneous premalignant lesions (actinic
Chinese <1.0 – 0.9 keratoses) and nonmelanoma skin cancers. Treatment can be lim-
ited by unwanted ADR. A number of functional genetic variants
Thai 1.2 – – are present in the main enzyme that metabolizes 5-FU, dihydro-
Indian 1.8–4.8 – – pyrimidine dehydrogenase (DPD), and in the target of 5-FU,
thymidylate synthase ([TS]; see next section for details on TS
Saudi Arabian 1–2 [3–9]a 21.0 polymorphisms).32,33
Hispanic As more than 80% of a given dose of 5-FU is rapidly metabo-
Colombian 6.6 1.7 lized by DPD, it is not surprising that patients with DPD defi-
ciency have been reported to have severe neurotoxicity from
Mexican 3.2 – 5-FU treatment.32 Severe GI and hematological toxicity has been
Panamanian 2.2–4.4 – reported in a DPD-deficient patient who applied topical 5-FU to
the scalp.34 As a result, topical 5-FU is contraindicated in patients
(Amerindian) 3–6 – with DPD deficiency.35
Nicaraguan Many genetic variants in the DPD gene have been described.
aThisrepresents the percentage of diminished activity of CYP2D6 found in this group with IM. The most common polymorphism is a splice site mutation, recog-
CYP, Cytochrome P-450; EM, extensive metabolizer; IM, intermediate metabolizer; PM, poor nized as the DPD*2A allele, which leads to an enzymatically defi-
metabolizer; UM, ultrarapid metabolizer. cient DPD.32 The DPD*2A allele is associated with 5-FU-induced
toxicity, specifically leukopenia and mucositis.32 In a study, this
 CHAPTER 3 Polymorphisms: Why Individual Drug Responses Vary 27

effect depended strongly on gender, given that heterozygosity for
DPD*2A was associated with 5-FU-induced toxicity in men, but
not in women.32
Genetic testing for the DPD*2A allele may be performed in
many laboratories. Additionally, a DPD enzyme deficiency test
may be carried out in specific laboratories. One example is the
DPD enzyme assay performed by LabCorp laboratories, which
cost US$441 in 2018 (https://www.labcorp.com).36 Approxi-
mately 1% of the population is heterozygous for the DPD poly-
morphism31; however, the clinical relevance or indications for
DPD genetic testing remain unclear at present. Currently, rou-
tine screening for DPD enzyme deficiency is not standard of care
before the topical application of 5-FU.
Drug Metabolism—Phase II Reactions
(TABLE 3.9)
P-Glycoprotein
General Issues. Permeability-glycoprotein (P-glycoprotein,
PGP), an ATP-activated pump, has gained increased attention in
the past few years because of its role in multidrug resistance, in
particular to chemotherapeutic agents. Essentially, PGP involves
pumping molecules from intracellular to extracellular spaces,
counteracting the effects of passive diffusion, most notably in the
GI tract, with a resultant decrease in net drug absorption.37 This
has been shown to have a greater effect on drug absorption than
clearance.
Polymorphisms of PGP. Genetic polymorphisms have been
identified in the multidrug resistance-1 (MDR1) gene that encodes
PGP. Various alleles have been linked to lower PGP expression in
the small intestine. This decreased PGP expression correlated with
increased drug concentration when digoxin was administered in a
study by Hoffmeyer and coworkers.38
Ethnic variability has been demonstrated in the MDR1 gene.
Testing for MDR1 gene expression may help identify populations
who are at increased risk for PGP drug interactions.39
Clinical Importance of PGP Polymorphisms. There appears
to be significant overlap of substrate specificity between PGP
and CYP3A4.40 This overlap has complicated assessment of the
role of PGP polymorphisms and drug interactions. Although
evidence suggests that PGP likely has a significant role in

TABLE
3.9 Polymorphisms of Phase II Enzymes6,12,32,39,42–44,52,57,62,63,65

Phase II reaction Polymorphism Drugs, Clinical Importance Available Tests

P-glycoprotein (PGP) MDR1 gene Affects absorption, distribution, MDR1 gene expression
and elimination of several
drugs
Thiopurine methyltransfer- High (normal) TPMT activity: TMPT*1 Azathioprine (ADR: bone mar- (1) phenotyping: measure TPMT
ase (TPMT) (seen in 89–90% Caucasian population) row suppression), 6-mer- activity in erythrocytes though
Decreased TPMT activity: TPMT*3C, *3A, captopurine (6-MP), and peripheral red blood cell lysates
and *2 (present in 0.3% population, thioguanine (2) genotyping: DNA-microarray
*3A in Caucasians and *3C in Asians study
and Africans) (3) genetic allele testing: rapid
Intermediate activity: heterozygous for PCR-RFLP TPMT*3A and *3C
TPMT*1 and TPMT*3C, *3A, or *2 allele testing
(seen in 10–11% population)
N-acetyltransferase-2 Rapid acetylators: NAT2*4, *12, *13 Isoniazid, procainamide, NAT2 polymorphisms testing;
(NAT2) Slow or intermediate acetylation: hydralazine, sulfonamides; unclear clinical practicality of
NAT2*5, *6, *7, *14S (ADR: varied) testing
Glucose-6-phosphate Gene coding for G6PD Sulfones (particularly dapsone), (1) fluorescent spot test, measures
dehydrogenase (G6PD) sulfonamides, primaquine; G6PD activity in population of
ADR: hemolytic anemia erythrocytes
Less effect on other antima- (2) methemoglobin or Nile blue
larials (chloroquine and sulfate reduction G6PD studies,
hydroxychloroquine) evaluate individual erythrocytes
(3) G6PD genotyping
Glutathione S-transferase GSTM1-null genotype, in ∼50% of Coal tar topically to skin, Genotyping for GSTM1 via PCR
(GST) European Caucasians GSTM1-null individuals have analysis
greater mutagen exposure

Thymidylate synthase TS 5-UTR 3R/3R Methotrexate (TS 3R/3R, TS 6bp Genotyping to 5-UTR repeats,
TS 3′-UTR 6bp deletion del, RFC 80A: increased ADR) limited availability
RFC 80A 5-FU (TS 2R/2R: increased
toxicity; TS 2R/3R, TS 3R/3R:
protective effect against
diarrhea)

5-FU, 5-Fluorouracil; ADR, adverse drug reaction; MDR1, multidrug resistance-1; PCR, polymerase chain reaction; RFC, reduced folate carrier; RFLP, restriction fragment length polymorphism; TS,
thymidylate synthase; UTR, untranslated region.
28 PA RT I Introduction

Red blood cell

Liver HGPRT
AZA 6-MP 6-TGN DNA & RNA

Salvage TPMT
XO TPMT pathway and
recycling

6-Thiouric acid 6-MMP Inactive

metabolites

• Fig. 3.1Azathioprine metabolic pathways. 6-MP, 6-mercaptopurine; 6-MMP, 6-methyl mercaptopurine;

6-TGN, 6-thioguanine nucleotides; AZA, azathioprine; HGPRT, hypoxanthine-guanine phosphoribosyl-
transferase; TPMT, thiopurine methyltransferase; XO, xanthine oxidase, (From El-Azhary RA. Azathioprine:
current status and future considerations. Int J Dermatol. 2003;42[5]:335–341.)

drug–drug interactions, this currently appears to be of limited
clinical application, with minor effects seen in cyclosporine
pharmacokinetics.41
Thiopurine Methyltransferase
General Issues. Q3.8 TPMT functions as a catalyst for the
metabolism and inactivation of azathioprine, 6-mercaptopurine
(6-MP), and thioguanine. The enzyme functions by convert-
ing 6-MP to inactive methylmercaptopurine nucleotides and by
converting 6-thioguanine to inactive metabolites (Fig. 3.1).42,43
Decreased TPMT activity results in increased 6-thioguanine lev-
els, leading to increased hematologic toxicity.44 Specifically, high
levels of accumulated 6-thioguanine nucleotides (6-TGN) seen
in patients with TPMT deficiency appear to be associated with
myelosuppression.45 Conversely, TPMT deficiency leads to a
decreased amount of 6-methyl mercaptopurine (6-MMP) nucleo-
tides because TPMT is not available to convert 6-MP to 6-MMP.
Because 6-MMP is correlated with azathioprine-induced hepato-
toxicity, TPMT-intermediate and TPMT-deficient patients are at
a lower risk for developing hepatotoxicity.45 For these reasons, it is
important to determine TPMT activity before dosing these immu-
nosuppressive agents. This is recommended to ensure therapeutic
drug levels and to reduce the risk of potentially life-threatening AE.
Polymorphism of TPMT. TPMT displays genetic polymor-
phism accounting for variable phenotypes. Approximately 89%–
90% of the general Caucasian population has high (normal)
TPMT activity, which corresponds with homozygous expression
of TPMT*1.6,43 Approximately 17 allelic variants of TPMT have
been identified.46 Of these, three mutant alleles (TPMT*3C,
*3A, and *2) account for over 95% of individuals with decreased
TPMT activity. TPMT*3A is the predominant mutant allele in
Caucasians, whereas TPMT*3C is the most common mutant
allele in Asians and Africans.43 Heterozygous expression of any of
these alleles, along with TPMT*1, results in intermediate TPMT
activity.43 Approximately 10% to 11% of the general population
falls into this intermediate category.6 Low to no TPMT activity is
seen in approximately 0.3% of the Caucasian population. These
persons are either homozygous or heterozygous with two mutant
alleles with decreased enzyme activity and are at high risk for severe
bone marrow suppression during treatment with azathioprine.6,43
Epidemiologic studies show these percentages to vary significantly
among various ethnic groups (Table 3.10).46–51
Specific Testing Methods for TPMT Polymorphism and Clinical
Applications. Patient evaluation is becoming more accessible to
community physicians. There are a number of reference labora-
tories performing TPMT evaluation. Two general testing methods
are available: (1) TPMT phenotypes can be assessed by measuring
the TPMT activity in erythrocytes, through peripheral red blood
cell lysates,44 and (2) DNA-microarray studies can be performed,
which have resulted in more rapid and cost-effective TPMT geno-
typing. TPMT assays based on enzyme activity or genotype are
both valuable screening tools that are available in selected laborato-
ries12; however, each has drawbacks and limitations. Enzyme activ-
ity can be influenced by physiological or environmental factors:
medications, recent blood transfusions, tobacco use, and impaired
renal function all can cause an inaccurate result.46 TPMT genotyp-
ing studies have shown some discordance between phenotype and
genotype, which was most commonly observed in the intermediate
activity groups. Studies have noted concordance rates from 76%
to 99%. With DNA-microarrays including an increasing number
of less common alleles, genotyping studies appear to be better cor-
related with phenotype testing.46 Also, newly introduced rapid
genetic polymerase chain reaction (PCR)-restriction fragment
length polymorphism (RFLP) TPMT*3A and *3C allele tests are
likely available in standard laboratories.52 In one Paris study, a Phe-
nome Wide Association Study combined electronic medical records
with genotyping to associate phenotypes with TMPT activity levels
(see section on pharmacogenetic databases).2,53 It is thought that
these association tests should allow more widespread screening of
TPMT polymorphisms to be performed before treatment with aza-
thioprine, but, unlike TPMT phenotyping and genotyping, they
are currently not performed in routine clinical practice.
Recommended doses of azathioprine have been determined,
based upon the patient’s genetic TPMT polymorphisms. If a
patient is homozygous for the wild type, TPMT*1, then a stan-
dard dose titrated to of 2–2.5 mg/kg daily, depending on clinical
response, may be administered.43 In patients who are hetero-
zygous with one TPMT*1 allele and one mutant allele (inter-
mediate activity), the dose of azathioprine should be reduced
by 15% to 50%. Limited case reports have demonstrated both
improved efficacy and safety in treating severe atopic dermatitis
in heterozygote TPMT-deficient children with azathioprine at
50% reduced doses.45 For patients found to have two ‘mutant’
alleles with known associated markedly decreased TPMT activ-
ity (TPMT*3A, *3C, or *2), it is recommended that they not be
 CHAPTER 3 Polymorphisms: Why Individual Drug Responses Vary 29

TABLE Thiopurine Methyltransferase Polymorphisms TABLE N-acetyl Transferase Polymorphisms in Various

3.10 in Various Populations46–51 3.11 Populations55
Population # Studied EM (%) IM (%) PM (%) Rapid Slow
Acetylator Acetylator
Egyptian 200 97 3 0
Population # Studied Alleles (%) Alleles (%)
White 1222 89.2a 10.2 0.6
Americans Whites, US 421 24 76

Japanese 522 97.1 2.5 0.4 Whites, Europe 434 26 74

Italian 103 87 13 0 Whites, Spain 504 22 72

French 468 91.9 7.9 0.2 African- 214 35 65

Caucasian American
Hispanics 148 40 61
Chinese 426 99.8 0.2 0
Native Africans 102 27 73
a1.8% of this population had ‘very high’ TPMT activity, hence were UM (ultrarapid metabolizers).

EM, Extensive metabolizer; IM, intermediate metabolizer; PM, poor metabolizer; TPMT, thio- Japanese 224 67 33
purine methyltransferase.
Chinese 254 53 47
Korean 85 68 32
Filipino 100 40 61
treated with azathioprine or, if they must be treated, treatment
should be at an azathioprine dose reduced by 90% (see also Chap- Aborigines 49 41 59
ter 15, Azathioprine).43 (Australian)

N-Acetyltransferase damage by oxidative stress.57 Because erythrocytes lack mitochon-

General Issues. N-acetyltransferase-2 (NAT2) is responsible for
acetylation of numerous xenobiotic substances. The addition of
an acetyl group to a parent compound increases the drug’s water
solubility, facilitating drug elimination.
Polymorphism of NAT2. In the 1950s, high variability in indi-
vidual rates of excretion of isoniazid was found among patients
being treated for tuberculosis.6 This was later determined to be
caused by polymorphisms in NAT2, which metabolizes isoniazid.
Q3.9 At least 25 allelic variants of the NAT2 gene have been
identified, some being correlated with altered enzyme activity that
varies in prevalence among different ethnic populations (Table
3.11).54,55 NAT2 enzyme activity is often reported as rapid, interme-
diate, or slow (analogous to EM/NM, IM, PM). Rapid acetylation
is seen in persons who are homozygous for NAT2*4, NAT2*12,
and NAT2*13.6 Rapid acetylators require higher doses of medica-
tions to minimize the likelihood of treatment failure. NAT2*5, *6,
*7, *14S comprise virtually all of the alleles associated with slow
or intermediate acetylation.6 These slow acetylators are more likely
to develop toxic AE, including drug-induced lupus erythematosus
from procainamide and hydralazine, neuropathy from isoniazid,
and toxic epidermal necrolysis from sulfonamides.6 Studies have
also demonstrated that slow acetylators may have an increased risk
for certain solid tumors and for some IgE-mediated food allergies
seen in children.56 However, as approximately 40%–70% of Cau-
casians are slow acetylators, and as severe ADR are rare, there are
likely other underlying factors that contribute to these associations
and ADR.12 Hence, the practicality of routine testing for these
NAT2 polymorphisms is questionable in daily clinical practice.
Glucose-6-Phosphate Dehydrogenase
General Issues. G6PD catalyzes the first reaction in the pentose
phosphate pathway (PPP), leading to the reduction of NADP to
NADPH throughout the body. NADPH plays an important role
in reducing glutathione, which is central to preventing cellular
dria, the PPP is the only source of NADPH, thus making G6PD-
deficient erythrocytes exquisitely sensitive to oxidative stressors,
resulting in significant hemolysis. This became clinically evident
when primaquine caused hemolysis in some patients with malaria.
Polymorphism of G6PD. In the 1950s, polymorphisms of the
G6PD gene on the X chromosome were noted to be the genetic
cause for anemia, occurring in a certain subset of African patients
taking primaquine. Affected individuals had low levels of the
functioning activity of the G6PD enzyme.6 The cause of this
decreased activity was found in a single base substitution, aspara-
gine to aspartic acid, resulting in hemolytic anemia.
Q3.10 Although there are over 400 identified variants, only
30 SNP mutations are associated with altered G6PD function.58
Epidemiologic studies have identified higher incidences of G6PD
deficiency in areas where malaria is endemic, because of its protec-
tive role against this infection (Table 3.12).59–61
Specific Drugs of Importance to G6PD. Approximately two
dozen drugs have been shown to cause varying degrees of hemo-
lysis in G6PD-deficient patients (Table 3.13).57 This is germane
to dermatologists who use sulfones (particularly dapsone) and sul-
fonamides, as these drugs rely on G6PD for phase II metabolism.
Although primaquine (8-aminoquinoline) causes hemolysis in
G6PD-deficient patients, there appears to be minimal hemolysis
with other antimalarial medications used in dermatology (chlo-
roquine and hydroxychloroquine which are 4-aminoquinolines).
(See Chapter 21, Antimalarial Agents.) Fava beans, infections, and
physiological stressors have also been noted to induce hemolysis in
G6PD-deficient persons.
Specific G6PD Testing Methods and Limitations. Screening for
G6PD deficiency has become regular practice before starting dap-
sone and other medications that increase oxidative stress on eryth-
rocytes. Quantitative evaluation is the most common method of
screening for a G6PD deficiency. G6PD activity is measured by
its ability to reduce NADP to NADPH in erythrocytes.62 The
fluorescent spot test, which allows for direct visualization of a
30 PA RT I Introduction

TABLE Glucose-6-Phosphate Dehydrogenase family members; they can function as a reliable surrogate, as there
3.12 Deficiency in Various Populations59–61 are very low rates of spontaneous mutations in the G6PD gene.
Another option is to genotype the patient. This is reliable in all
Population # Studied Deficiency (%) patient populations provided the mutation is already known.62
African-Americans 6366 11.4 (males)
2.5 (females) Glutathione S-Transferase
Kuwait 1080 6.5 Glutathione S-transferase (GST) is an enzyme involved in the
United Arab Emirates 496 9.1 detoxification of carcinogenic derivatives of coal tar.12 Approxi-
mately 50% of European Caucasians have low or absent activity
Mexican 4777 0.71 of GST owing to the presence of the GSTM1-null genotype.12
Indian 3166 10.5 After applying 2% coal tar topically to the skin, GSTM1-null
individuals were found to have twice the amount of urinary
Caucasian Italians 85,437 0.9 1-hydroxypyrene excreted as individuals with normal enzyme
Nigeria (Yoruba) 721 23.9 (males) activity.12 Hence, when GSTM1-null individuals are treated with
4.6 (females) topical coal tar, they have a greater mutagen exposure.12 Genotyp-
ing for GSTM1 may be performed via PCR analysis in selected
research laboratories.63

TABLE Drugs With Phase II Metabolism Altered

Thymidylate Synthase and Other Polymorphisms
3.13 by Glucose-6-Phosphate Dehydrogenase in the Folate Pathway
Deficiency57 Methotrexate, a drug frequently used in dermatology, is a struc-
tural analog of folic acid which competitively inhibits dihydrofo-
Drug Category Specific Examples late reductase (DHFR).64 Methotrexate also directly inhibits TS.
Antimalarials Primaquine Via downstream effects of DHFR, methotrexate also influences
the activity of methylene tetrahydrofolate reductase (MTHFR),
Sulfonamides Sulfanilamide
Sulfacetamide
which converts homocysteine to methionine. Methotrexate-asso-
Sulfapyridine ciated ADR, including hepatotoxicity, GI symptoms, and acute
Sulfamethoxazole myelosuppression, result in up to 30% of patients discontinu-
ing therapy.64,65 These ADR have been associated with polymor-
Other antimicrobial agents Nitrofurantoin phisms of TS and MTHFR.
Spiramycin
Evidence suggests that a polymorphism in the promoter
Sulfones Dapsone region of the TS gene may affect methotrexate metabolism and
Triazolesulfone clinical response.65 The TS 5-untranslated region (UTR) 3R/3R
Other drugs Acetanilide
homozygous genotype has been significantly linked with ADR
Furazolidone in psoriasis patients taking methotrexate when folic acid is not
Glibenclamide administered.44,65 Additionally, the TS 5′-UTR 3R allele has been
Isobutylnitrite associated with a poor therapeutic response to methotrexate.65
Niridazole The TS 3′-UTR 6 base pair deletion allele has also been associ-
Phenylhydrazine ated with increased methotrexate-induced toxicity,44,65 including
Phenazopyridine up to an 8-fold increased risk of developing elevated transaminase
Related chemicals Aniline dyes
(ALT) levels in the absence of folic acid supplementation.65 The
Methylene blue importance of folic acid administration was confirmed as patients
Naphthalene (mothballs) not receiving it were twice as likely to discontinue methotrexate,
Toluidine blue and many of the ADR attributed to these polymorphisms were
Urate oxidase attenuated or resolved with folic acid supplementation.65
5-FU is a chemotherapeutic medication that strongly inhibits
TS, which is considered to be its major drug target.32 In contrast
to methotrexate, the TS 2R/3R or 3R/3R genotypes have been
fluorescently tagged NADPH, is the most commonly employed associated with a lower risk for 5-FU-induced ADR, specifically
testing method. However, inaccurate G6PD test results can occur diarrhea.32 The TS 2R/2R genotype, on the other hand, has been
in certain patient populations. For example, because of chromo- reported to increase the risk for 5-FU-induced toxicity.32
some X inactivation, women with a heterozygous G6PD muta- The C677T polymorphism of MTHFR, observed in 8% of the
tion can have two populations of erythrocytes, one with and the normal population, leads to a thermolabile variant subsequently
other without G6PD activity.62 reducing its activity to about 30% of the wild type.64 The C677T
In contrast to the fluorescent spot test, which measures the polymorphism has been associated with an increased risk of dis-
activity in a population of erythrocytes, methemoglobin or Nile continuing methotrexate because of ADR, mainly elevated liver
blue sulfate reduction studies are more accurate because they enzymes,64 postulated to be related to increased homocysteine lev-
evaluate individual erythrocytes.62 Nonetheless, recent hemoly- els.64 However, different studies have yielded conflicting results,
sis and blood transfusions can both yield inaccurate results. In some which show no association between MTHFR C677T and
these situations, G6PD determination can be made by testing methotrexate toxicity.65
 CHAPTER 3
Additionally, studies on the effects of MTHFR polymorphisms
in regard to treatment with fluorouracil have yielded varying clini-
cal results. Some studies suggest that MTHFR 677C>T is cor-
related with better clinical response to FU; however, the impact
of MTHFR polymorphisms on severe FU-induced toxicity seems
negligible based on prospective data.32
Because methotrexate interacts with the folate pathway, stud-
ies analyzing the effects of reduced folate carrier (RFC) polymor-
phisms have been performed. The RFC 80A allele has recently
been associated with methotrexate-induced toxicity.65
Tests for Genetic Polymorphisms and Clinical
Significance
Q3.11 A rapidly developing area of laboratory testing relevant to
dermatology involves prediction of SCAR related to various ethnic
groups. This topic is addressed adequately in Chapter 67, Cutane-
ous Drug Reactions with Systemic Features. Table 3.14 summa-
rizes the most important HLA polymorphisms pertaining to these
potentially serious cutaneous drug reactions. Testing for specific
polymorphisms could help address ADR in approximately 10% to
20% of patients.44 Although many of the tests for such polymor-
phisms are not widely accessible, several have become more readily
available in recent years, with clinical practice guidelines being
updated yearly based on drug and known HLA or CYP polymor-
phisms (Tables 3.9 and 3.15).66 For example, a DNA microarray
analyzing genetic polymorphisms of CYP2D6 has been developed
in recent years.67 Also, in 2008, the US Food and Drug Admin-
istration (FDA) issued a safety warning to all healthcare profes-
sionals that ‘serious and sometimes fatal hypersensitivity reactions
caused by abacavir therapy are significantly more common in
patients with a particular HLA allele, HLA-B*5701.’ The name of
the pharmacogenetics test for the HLA-B*5701 polymorphism is
the ‘HLA-B5701 test.’33
The FDA has issued similar recommendations for other medi-
cines, including azathioprine, topical 5-FU and carbamazepine.
Imuran (azathioprine) drug label recommends that genotype or
TABLE
3.14 Human Leukocyte Antigen Genetic Markers for Severe Cutaneous Adverse Drug Reactions
Drug Genetic Marker for Severe ADR
Abacavir HLA-B*5701, HLA-DQ3, HLA-DR767
Allopurinol HLA-B*5801
Azathioprine TPMT
Carbamazepine HLA-B*1502
HLA–A*3101
HLA-B*1511
Doxepin CYP2D6 and CYP2C19
Nevirapine HLA-Cw*041
HLA-B*1402
HLA-Cw8
HLA-B*3505 (rash)
HLA-DRB1*0101 (hypersensitivity syndrome
± rash)
ADR, Adverse drug reactions; HLA, human leukocyte antigen; SJS, Stevens-Johnson Syndrome; TEN, toxic epidermal necrolysis.
Polymorphisms: Why Individual Drug Responses Vary 31
phenotype for TPMT should be considered in patients.33 Test-
ing for TPMT may be performed in several ways (see section on
TPMT previously), one of which is to order a test called ‘Pro-
metheus TPMT Genetics.’
On the Efudex (topical 5-FU) drug label there is a warning
that the medicine ‘should not be used in patients with dihydropy-
rimidine dehydrogenase (DPD) deficiency.’33 The DPD and TS
polymorphisms may be tested by ordering the ‘TheraGuide 5-FU’
test. Testing for DPD deficiency is described in the previous sec-
tion on DPD.
Finally, on the Tegretol (carbamazepine) label, the package
insert states that genetically at-risk patients should be screened for
HLA-B*1502 before starting treatment.33 Specifically, the FDA
has concluded that Asian patients should be screened before initi-
ating treatment with carbamazepine. This may be done by order-
ing an ‘HLA-B*1502 carbamazepine sensitivity’ test.
It is our hope that similar genetic tests for all clinically sig-
nificant polymorphisms will become readily available in the near
future so that future severe ADR may be minimized. Until then,
clinicians must focus on family and personal histories as a means
of screening patients that might be at high risk for ADR and
optimize the judicious use of available genetic tests in high-risk
patients.67
Pharmacogenomic Databases
Pharmacogenomics is an emerging field that applies information
and technology gained from the Human Genome Project towards
the goal of optimizing drug efficacy, minimizing ADR, facilitating
drug development, and reducing healthcare costs.44 SNP libraries
have been developed in addition to gene mapping, with the Phar-
macogenomics Knowledgebase (PharmaGKB) consisting of phar-
macogenomic variants, along with the individual drug responses.
Originally devised at Stanford, this database analyzes patient’s risk
of an adverse drug event through an individual’s genotype, based
on genes with known reproducible associations.2 PharmaGKB also
has a haplotype database that involves combinations of SNP for
further risk stratification, and has collaborated with ClinVar, the
Ethnic Associations Reaction Type
Hypersensitivity
Han Chinese, Japanese, Thai, European SJS/TEN
Myelosuppression
Han Chinese40,67 SJS/TEN
Caucasian, Japanese, Han Chinese1
Japanese, Korean1
Intoxication
Han Chinese1 Hypersensitivity
Sardinian
Japanese
HIV-infected Thai (B*3505)
32 PA RT I Introduction
TABLE
3.15 Clinically Relevant Available Tests for Genetic Polymorphisms
Genetic Polymorphism
CYP2D6 polymorphisms
CYP2C19 polymorphisms
CYP2C9 polymorphisms
General HLA polymorphisms
Specific HLA polymorphisms
HLA-B*5701 polymorphism
HLA B*1502
Thiopurine methyltransferase (TPMT)
Dihydropyrimidine dehydrogenase (DPD)
polymorphisms
Glucose-6-phosphate dehydrogenase (G6PD)
HLA, Human leukocyte antigen PCR, polymerase chain reaction; RFLP, restriction fragment length polymorphism.
National Institute of Health clinically relevant pharmacogenomic
variant database, to form the PGRN.2,30 Initially founded in 2000,
the PGRN is on its fourth iteration, with inclusion of various aca-
demic institutions to continuously develop clinical testing pro-
grams for pharmacogenomics, with examples including the Scripps
Genomic Health Initiative, the Indiana Institute for Personalized
Medicine, and the Polyphen tool at Harvard University, to assess
rare gene variants and predict their impact on downstream protein
products.2,7 Electronic Medical Records and Genomics (eMERGE)
grants from the National Human Genome Research Institute have
also driven access to genome-wide association study and next-
generation sequencing, and have also acted as a strong stimulus
for the clinical implementation of pharmacogenomics.30 Build-
ing upon genome association studies, phenome-wide association
studies (PheWAS) have been developed in an attempt to combine
genotype with phenotype response when taking specific drugs, and
to investigate whether genetic polymorphisms associated with a
phenotype are also associated with other diagnoses; in other words,
PheWAS start with a single genotype and analyze many phenotypes
to find an association.2,25,27 The Paris study found an association
with high TMPT activity and iron deficient anemia as well as dia-
betes mellitus.53 For ethical and legal reasons, pharmacogenomic
profiling should only predict patients’ responses to drugs and not
test specifically for disease-causing genetic mutations.12
Although pharmacogenomics is important for future drug
development, its applications in drug approval processes are still
being debated, with cost analyses based on testing vs treatment
Test
DNA-microarray analysis67
DNA-microarray analysis13
Genotyping assay
PCR-based HLA typing
Sequence-based typing
Specific HLA typing
HLA-B5701 test33
HLA-B*1502 ‘carbamazepine sensitivity’ test
Phenotyping: measures TPMT activity in erythrocytes though peripheral red blood cell lysates44
Genotyping12
DNA-microarray study
PCR, ‘Prometheus TPMT Genetics’ (www.mayomedicallaboratories.com)
Genetic allele testing: rapid PCR-RFLP TPMT*3A and *3C allele testing52
Genetic testing for DPD*2A allele; e.g., ‘TheraGuide 5-FU’ test (full sequencing of DPD, and analysis of
TYMS gene (www.myriadtests.com)
DPD enzyme deficiency test, e.g., the DPD enzyme assay performed by LabCorp laboratories (cost
US$441 in 2018) (www.labcorp.com)
Fluorescent spot test, measures G6PD activity in population of erythrocytes62
Methemoglobin or Nile blue sulfate reduction G6PD studies, evaluate individual erythrocytes62
G6PD genotyping62
response showing support for particular drugs. Authorities in the
USA (FDA), Europe (European Medicines Agency), and Japan
(Ministry of Health, Labour and Welfare) have issued guidelines
for new drug development that address the genetic heterogene-
ity of target patient populations.44 In particular, the FDA has
approved modifications on 58 drug labels that contain pharmaco-
genetic information.33 Additionally, since March 2008, through
the Public Law No. 110–85, 121 Stat. 823, the FDA has the
power to mandate that a genetic test be performed as part of a
plan to optimize safety or efficacy of a new drug.33 With the cost
of whole genome sequencing continuing to shrink, this technol-
ogy is becoming more clinically applicable. The Clinical Pharma-
cogenomic Implementation Consortium (CPIC) guidelines have
been available since 2010, giving recommendations in a tier-based
system as to whether specific genetic tests are indicated and/or
reimbursable through insurance.2,22,24 Six gene-drug pairs that
institutions are recommended to first test include: HLA-B and
abacavir and carbamazepine; CYP2C19 and clopidogrel; TPMT
and azathioprine, mercaptopurine, and thioguanine; CYP3A5
and tacrolimus; CYP2D6 and opioids; and CYP2C9/VKORC1
and warfarin.13
Conclusions and Future Directions
An understanding of drug metabolism and drug interactions is of
paramount importance in an era when many patients are taking
multiple medications. This chapter presents a brief overview of
 CHAPTER 3
how genetic factors can alter the likelihood of various drug inter-
actions, and related AE in the absence of drug interactions from
a genotype and drug centric point of view. New information on
drug metabolism, including polymorphisms, is constantly being
accrued. New tests that have clinical application are being devel-
oped and commercialized at a staggering pace. Electronic and
print sources for this information are essential for all clinicians. A
general understanding of how drugs are metabolized, along with
recognition of the genetic, phenomic, and environmental factors
that can influence drug metabolism and their clinical effects, will
prove to be an invaluable asset when choosing appropriate sys-
temic and topical medications.
Bibliography: Important Reviews and Chapters
Borroni Riccardo G. Role of dermatology in pharmacogenomics: drug-
induced skin injury. Pharmacogenomics. 2015;16(4):401–412.
Correia MA. Drug biotransformation. In: Katzung BG, Masters SB,
Trevor AJ, eds. Basic & Clinical Pharmacology. 11th ed. New York:
McGraw Hill/Lang; 2009:53–66.
Crettol S, Petrovic N, Murray M. Pharmacogenetics of phase I and phase
II drug metabolism. Curr Pharm Des. 2010;16(2):204–219.
Ingelman-Sundberg M, Sim SC, Gomez A, Rodriguez-Antona C. Influ-
ence of cytochrome P450 polymorphisms on drug therapies: pharma-
cogenetic, pharmacoepigenetic and clinical aspects. Pharmacol Ther.
2007;116(3):496–526.
Johansson I, Ingelman-Sundberg M. Genetic polymorphism and toxicol-
ogy – with emphasis on cytochrome p450. Toxicol Sci. 2011;120(1):1–
13.
Mooney SD. Progress towards the integration of pharmacogenomics in
practice. Hum Genet. 2015;134(5):459–465.
Wecker L. Pharmacokinetics: absorption, distribution, metabolism, and
elimination. In: Wecker L, Crespo L, Dunaway G, et al., eds. Brody’s
Human Pharmacology. 5th ed. Philadelphia: Elsevier; 2010:17–28.
Zhou SF, Liu JP, Chowbay B. Polymorphism of human cytochrome P450
enzymes and its clinical impact. Drug Metab Rev. 2009;41(2):89–295.
Polymorphisms: Why Individual Drug Responses Vary 33
References*
8. Shapiro LE, Shear NH. Drug interactions: proteins, pumps, and P-450s. J
Am Acad Dermatol. 2002;7:467–484; quiz 485–486.
10. Evans WE, McLeod HL. Pharmacogenomics – drug disposition, drug targets,
and side effects. N Engl J Med. 2003;348:538–549.
12. Ameen M, Smith CH, Barker JN. Pharmacogenetics in clinical dermatology.
Br J Dermatol. 2002;146(1):2–6.
19. Lee AY, Kim MJ, Chey WY, Choi J, Kim BG. Genetic polymorphism of
cytochrome P450 2C9 in diphenylhydantoin-induced cutaneous adverse
drug reactions. Eur J Clin Pharmacol. 2004;60(3):155–159.
24. Yang ZF, Cui HW, Hasi T, Jia SQ, Gong ML, Su XL. Genetic polymor-
phisms of cytochrome P450 enzymes 2C9 and 2C19 in a healthy mongolian
population in China. Genet Mol Res. 2010;9(3):1844–1851.
27. Bernard S, Neville KA, Nguyen AT, Flockhart DA. Interethnic differences in
genetic polymorphisms of CYP2D6 in the U.S. population: clinical implica-
tions. Oncologist. 2006;11(2):126–135.
29. Flockhart DA. Drug Interactions: Flockhart TableTM. Indiana University
School of Medicine; 2009. Available at: https://drug-interactions.medicine.
iu.edu/Main-Table.aspx. Accessed January 8, 2019.
32. Schwab M, Zanger UM, Marx C, et al. Role of genetic and non-genetic factors
for fluorouracil treatment-related severe toxicity: a prospective clinical trial
by the german 5-FU toxicity study group. J Clin Oncol. 2008;26(13):2131–
2138.
33. Flockhart DA, Skaar T, Berlin DS, Klein TE, Nguyen AT. Clinically avail-
able pharmacogenetic tests. Clin Pharmacol Ther. 2009;86(1):109–113.
44. Pincelli C, Pignatti M, Borroni RG. Pharmacogenomics in dermatology: from
susceptibility genes to personalized therapy. Exp Dermatol. 2009;18:337–
349.
67. Pereira FA, Mudgil AV, Rosmarin DM. Continuing medical education: toxic
epidermal necrolysis. J Am Acad Dermatol. 2007;56:181–200.
* Only a selection of references are printed here. All other refer-
ences in the reference list are available online at www.expertcon-
sult.com.
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*** START OF THE PROJECT GUTENBERG EBOOK THE YALE

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Vol. LXXXVIII No. 6

The
Yale Literary Magazine
Conducted by the
Students of Yale University.

“Dum mens grata manet, nomen laudesque Yalenses

Cantabunt Soboles, unanimique Patres.”

March, 1923.
 New Haven: Published by the Editors.
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Price: Thirty-five Cents.

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 A Story of Progress
At the close of the fiscal year, July, 1921, the total membership
was 1187.
For the same period ending July, 1922, the membership was
1696.
On January 18th, 1923, the membership was 1905, and men
are still joining.
Why stay out when a membership will save you manifold times
the cost of the fee.
 THE YALE LITERARY
MAGAZINE

Contents
MARCH, 1923

Leader Maxwell E. Foster 181

A Drama for Two Russell W. Davenport 184
Five Sonnets Maxwell E. Foster 187
This Modern Generation Russell W. Davenport 192
The Soul of a Button L. Hyde 207
Book Reviews 213
Editor’s Table 220
 The Yale Literary Magazine

Vol. LXXXVIII MARCH, 1923 No. 6

EDITORS

MAXWELL EVARTS FOSTER

RUSSELL WHEELER DAVENPORT WINFIELD SHIRAS
ROBERT CHAPMAN BATES FRANCIS OTTO MATTHIESSEN

BUSINESS MANAGERS

CHARLES EVANDER SCHLEY HORACE JEREMIAH VOORHIS

 Leader
“... being firmly persuaded that every time a man smiles,—
but much more so, when he laughs that it adds something to
this Fragment of Life.”—Dedication to Tristam Shandy.

There is, of course, the Campus and Osborn Hall. There is Mory’s.
There is Yale Station. There is the Bowl. Enumeration is
unnecessary. That will serve well enough at the twenty-fifth reunion.
For the moment we are affluent in detail, and comprehend
suggestion. We still remember a great deal about Yale.
But there is a wistfulness about even specific memories that hardly
expresses our attitude. For we take with us something we are glad to
have. The Comic Spirit has quietly insinuated its existence into our
point of view. Undoubtedly we have found cherished mansions set
on fire and destroyed, but in general we have discovered the delights
of roast pig amidst their ruins. You will find the Senior more capable
of laughing at the serious than the Freshman. He sees the humor
abroad, and is more sensitive to the divine comedy.
Comedy particularizes, whereas tragedy deals in the general.
When one laughs one is beginning to see things in detail. In
Freshman year one contents oneself with the infinite, but in Senior
year one becomes concerned with the finite. The Freshman poet will
write about Death and Eternity, the Senior about life. After all the
latter is merely more sincere.
For Yale does not influence one to become a golden mean, or to
idealize a mens sana in corpore sano. It has a more brilliant bit of
philosophy than that. It satirizes the affectations out of a man, so that
he learns the proportion of the everyday and of the eternal, and
adapts his decisions to that proportion. He is capable of rendering
unto Caesar the things that are Caesar’s, because he has learned to
recognize what things are Caesar’s. He has won his scales.
 Seeing things in proportion is not materialism, any more than it is
idealism. It is seeing with sincerity. Material things are not then
idealized, and ideals are not made material. Each is treated in its
own terms, the question of emphasis and relativity being left to the
temperament. Shelley, for instance, in most of his writing,
exemplifies a disproportioned point of view of life. It is not quite real,
because it is not quite sincere. He died at the point where he was
beginning to imagine balance. Chaucer lived long enough to find it
and employ it in his art. He is the greater. For it is just as foolish to
think that the soul is without a body, as to think that the body is
without a soul; or to fancy a man as completely aetherial, when it is
perfectly obvious that he walks with feet of clay.
I may seem to have maligned the Freshman, and the Freshman of
feeling will be hurt. But I am using the sobriquet as generic. It really
applies to most of the outside world. Experience there is a hard task-
master, and only the exception finds mirth under her schooling. The
majority there remain Freshmen always, lacking the knowledge of
the comic. At Yale there are few who remain so. Ultimately they are
laughed out of their position.
Yale has always fastened its banner to this criticism of life. For
years it was “Harvard affectation” that Yale ridiculed. To-day freaks
are not seriously condemned; it is the dilettante who plays into the
hands of satire. Insincerity is the unpardonable sin. But the method
of punishing is humor. The world crushes the apocryphal with an iron
heel, but Yale kicks it deftly out of a college window. It is the
intelligent method. And naturally. For common sense has become
almost a Yale idiom.
Maxwell E. Foster.
 A Drama for Two

I
“ f men are dust, I do not understand
What women are. What language does she speak,
Who plays with me as children with the sand,
Who shapes me with a gesture of her hand,
And floods me in the crimson of her cheek?
Our fingers in our passion did entwine,
Like ivy growing in the lap of Spring:
A moment, and she was a deathless thing—
A woman? Nay, the spirit of the vine!”

“Ah, but I did not love to make him glad;

But, if I could, to make him more than wise.
I found, in the strange silence of his eyes,
The same unuttered fear that Dante had,
Lest Beatrice should die and he go mad!
And so I let him dream a paradise
Upon my lips; and with love’s quick disguise
Appeared in white robes and in roses clad.”

“I think that love is like a leaning sail

Swept toward a far horizon, swift in flight.
The seas are blue. But soon the wind must fail,
And all of Heaven’s will cannot avail
To keep the ship from drifting toward the night.
I am not sure of this: but yesterday
There was no eager passion in her lips;
And so I said, ‘My dear, we are but ships
Passing away in time—leaning away’.”

“How quickly do our blushes leave the cheek:

How like a withered ghost goes modesty!
I loved him not. The devil played with me,
And still plays on—instructing me to speak
In soft words—sounding truer in a shriek.
Would I had vanished into destiny!
Ah, God! When they pretend that love is free,
The women buy the freedom that they seek.”

“Of Beauty in immortal guise beware!—

For even women’s bodies are of dust.
I do not hate her, but I cannot bear
The subtle isolation of her stare,
As though she’d changed ‘I love’ into ‘I must’.
But in me there’s no sorrow or regret,
I am not by a jealousy distraught;
Love’s neither here nor there—for I have sought,
And found, and lost—and now I can forget.”

“Ah, when I told him everything, he said:

‘I love you still, but not as yesterday.
Life is a laughing art. Our passions play
So madly that it is in vain to wed.
I’m glad you feel the way I do,’ he said.
And had he washed my body quite away
In tears, I would not have had less to say.
I merely smiled, pretending I was dead.”

“Then where is Beauty, now that she had fled,

And where is Paradise without her arms?
Surely I did not know how much I said,
When I complained that the old love was dead:
’Tis thinking of to-morrow that disarms!
How her remembered hair makes sadness live,
And how her absent voice is young with power!
Yea, for the recollection of one hour
Turns the soul nightward, like a fugitive.”

“I find that being in the house alone

Is gruesome, for the worn and creaky floors,
The wind outside, the rain, the empty doors,
Sing with a wild and ghostly undertone—
Not quite articulate—but yet a moan.
Often I long for the white surf that roars,
Or for the rapture of the gull that soars,
Or for the splendor of a silent throne.”

RUSSELL W. DAVENPORT.
 Five Sonnets
I.

Perplex me not with words I understand,

Nor gracefully demolish the unborn.
You tell me that my fantasies are torn,
But I have only written them on sand.
You answer with a gesture of your hand
Though I have asked not, I have only sworn.
Would you then burn green shoots with withered scorn?
My lady, you do waste your flaming brand.

I draw the pictures you desire to hide,

When you return such compliments for mine,
For love makes bitter poison into sweet.
And there’ll be memory, when our quick eyes meet,
To stir into a bubbling the gay wine.
—Which of us will have fallen in our pride?

II.

But is it pride that motivates the play,

Or brings the climax and the curtain call?
—I question the new lilies that are tall,
For wiser than a Solomon are they.
But they have only parables to say,
And only nod against the mossy wall,
Pale blossoms of the sacrifice and gall,—
They do not answer those who cannot pray?

Their quick renascence from the tragedy

We do not act. We play the witty parts,
And do not veil with curtains our decease.
It is a trifle of a comic piece?
We wear upon our sleeves our naked hearts?
—Pride is not on, for we are two, not three.

III.

But there’s the dialogue that must confuse.

It is not swift or brilliant otherwise.
We make a parody of paradise,
That it may fascinate, not to amuse.
I grant it’s a lost quaint, uncommon ruse.
But if it serves to open wide our eyes,
Would it be well to fancy or devise
New strange unheard of fables to abuse.

Love is a clever scene that you have set,

You the beginning, I will do the end.
—It is a bargain of an enemy?
Perhaps, but as a bargain let it be,
For it is fair I should not be your friend
—Now the dénouement of the cruel coquette.

IV.

You laugh again at this my imagery,

But I will turn your laughter from my soul,
Explain this love has humor as its goal,
That you are quainter than the simile.
You who have bound yourself so to be free,
You who will lose the part to keep the whole,
You who will quench with fire the living coal,—
O strange and unaccounted mystery.

Yes, I have flung you back your worn derision,

Cast to you all my precious, secret oaths.
Now as the curtain’s falling, take the applause.
Foolish to fight with bastard natural laws,
Even the ones that all of nature loathes.
Lady, you have the worth of their decision.

V.

Charming?—A little long-drawn out?—or dead?

It matters not. Open the exit doors,
And let them out, and sweep the theatre floors,
The dazzle of the footlights takes my head.
—Good-night, and I shall totter off to bed.
To-morrow’s play? God, how these lines are bores!
You say it’s just the thing the crowd adores?
—It likes the pretty ending where we’re wed?

Thank God for night that is not made with lights,

Stars that are quiet, unpainted, distant things,
Wind that is dustless, fresh, and water-cool.
—Some day I shall give over my new school,
Permit myself the luxury of wings,—
Yes, I can hear you: “And a pair of tights?”
MAXWELL E. FOSTER.
 This Modern Generation
What is more exasperating, more insistent, and still more
exasperating because of its insistence, than a telephone ringing
beside one’s bed at two A. M.? There is indeed some doubt as to
whether these modern appliances, together with the modern world
which they purport to make happy, are not altogether out of place on
this earth. In striving to be great, perhaps we mortals have obscured
our immortality. At any rate, Mr. Harrow thought so, as he hurled his
corpulent shape from the bed, crashed into the small table upon
which the offensive instrument rested, swore, and put the receiver to
his ear. A terrific buzzing ensued, and a vibration which was actually
painful.
“Dammit,” he said, “hello, dammit.”

And now the reader will excuse us if we leave Mr. Harrow

struggling with this all too mortal instrument, and proceed to an
explanation of the causes of his disturbance; which task will require
the remainder of the story for its consummation.
Betty Harrow lived with her father in this very modest house
somewhere in New York City. The two of them were an affectionate
pair, in spite of a large discrepancy in their characters. For, while the
implacable gruffness of Mr. Harrow prevented him from
understanding the youth and the beauty of his daughter’s emotions,
still he was able to make allowances for what seemed to him too
modern and dashing in her character. She filled a place in the old
gentleman’s life which the death of his wife had left vacant. If Mr.
Harrow had ever understood his wife, he was the only person that
believed it. But there is a kind of understanding which arises from a
tender and lasting affection, and which is really the main prerequisite
to a happy married life. This Mr. Harrow possessed to a degree. He
never tired of watching his wife manage the house, and never failed
to kiss her tenderly, after an argument, even when his impatience