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

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 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.
Another random document with
no related content on Scribd:
Comme il y avait, à l’endroit où le bâtiment avait touché, trois pieds
d’eau à peine, le prince et sa suite sautèrent à la mer, tenant leurs
armes au-dessus de leurs têtes, et espérant arriver au village qu’ils
voyaient s’élever à une demi-lieue à peu près dans les terres, sans
avoir besoin d’en faire usage. Mais à peine furent-ils débarqués,
qu’une autre troupe de corsaires qui, prévoyant cette manœuvre,
avait remonté avec une barque le Bufaidone, sortit des roseaux au
milieu desquels le fleuve coule, et coupa au prince la retraite sur
laquelle il comptait. Le combat s’engagea aussitôt; mais tandis que
les campieri du prince avaient affaire à cette première troupe, la
seconde arriva, et toute résistance devenant visiblement inutile, le
prince se rendit, demandant la vie sauve et promettant de payer
rançon pour lui et pour toute sa suite. Au moment où les prisonniers
venaient de déposer leurs armes, on aperçut une troupe de paysans
qui accouraient armés de fusils et de faux. Les corsaires, maîtres de
la personne du prince, et ayant par conséquent atteint le but qu’ils
désiraient, n’attendirent pas les nouveaux arrivans, et
s’embarquèrent avec une telle rapidité qu’ils laissèrent sur le champ
de bataille trois hommes de leur équipage, qu’ils croyaient morts ou
blessés mortellement.
Parmi ceux qui accouraient ainsi se trouvait Pascal Bruno, que
sa vie nomade conduisait vaguement tantôt d’un côté, tantôt d’un
autre, et que son esprit inquiet jetait dans toutes les entreprises
aventureuses. Arrivés sur la plage où le combat avait eu lieu, les
paysans trouvèrent un domestique du prince de Paterno mort, un
autre blessé légèrement à la cuisse, et trois corsaires étendus dans
leur sang, mais respirant encore. Deux coups de fusil eurent bientôt
fait justice de chacun d’entre eux, et un coup de pistolet allait
envoyer le troisième rejoindre ses camarades, lorsque Bruno,
s’apercevant que c’était un enfant, détourna le bras qui allait le
frapper, et déclara qu’il prenait le blessé sous sa protection.
Quelques réclamations s’élevèrent sur cette pitié, qui semblait
intempestive; mais quand Bruno avait dit une chose, il maintenait ce
qu’il avait dit: il arma donc sa carabine, déclara qu’il ferait sauter la
cervelle au premier qui s’approcherait de son protégé; et, comme on
le savait homme à exécuter à l’instant sa menace, on lui laissa
prendre l’enfant dans ses bras et s’éloigner avec lui. Bruno marcha
aussitôt vers le rivage, descendit dans une barque avec laquelle il
faisait habituellement ses excursions aventureuses, et dont il
connaissait si bien la manœuvre qu’elle semblait lui obéir comme un
cheval à son cavalier, déploya sa voile et cingla vers le cap d’Aliga-
Grande.
A peine eut-il vu que la barque était dans sa route, et qu’elle
n’avait plus besoin de son pilote, qu’il s’occupa de son blessé,
toujours évanoui. Il écarta le burnous blanc dans lequel il était
enveloppé, détacha la ceinture à laquelle était passé encore son
yatagan, et vit, aux dernières lueurs du soleil couchant, que la balle
avait frappé entre la hanche droite et les fausses côtes, et était
ressortie près de la colonne vertébrale: la blessure était dangereuse,
mais n’était pas mortelle.
La brise du soir, la sensation de fraîcheur produite par l’eau de
mer avec laquelle Bruno lavait la plaie, rappelèrent l’enfant à lui; il
prononça sans ouvrir les yeux quelque mots dans une langue
inconnue; mais Bruno, sachant que l’effet habituel d’un coup de feu
est de causer une soif violente, devina qu’il demandait à boire et
approcha de ses lèvres une flasque pleine d’eau; l’enfant but avec
avidité, poussa quelques plaintes inarticulées, et retomba dans son
évanouissement. Pascal le coucha le plus doucement qu’il put au
fond de sa barque, et, laissant la blessure à l’air, il continua de
presser, de cinq minutes en cinq minutes, au-dessus d’elle, son
mouchoir imbibé d’eau de mer, remède que les marins croient
efficace à toutes leurs blessures.
Vers l’heure de l’Ave Maria, nos navigateurs se trouvèrent à
l’embouchure de la Ragusa: le vent venait d’Afrique: Pascal n’eut
donc qu’une légère manœuvre à faire pour s’engager dans le fleuve,
et trois heures après, laissant Modica à droite, il passait sous le pont
jeté sur la grande route qui va de Noto à Chiaramonti. Il fit encore
une demi-lieue ainsi; mais alors le fleuve cessant d’être navigable, il
tira sa barque dans les lauriers-roses et les papyrus qui bordent le
rivage, et, reprenant l’enfant dans ses bras, il l’emporta à travers les
terres. Bientôt il atteignit l’entrée d’une vallée dans laquelle il
s’enfonça, et il ne tarda pas à trouver à sa droite et à sa gauche la
montagne taillée à pic comme une muraille, et creusée de distance
en distance, car dans cette vallée sont les restes d’une ancienne cité
de Troglodytes, ces premiers habitans de l’île que civilisèrent les
colonies grecques. Bruno entra dans l’une de ces cavernes, qui
communiquait par un escalier à un étage supérieur, auquel un seul
trou carré, en forme de fenêtre, donnait de l’air; un lit de roseaux
était amassé dans un coin, il y étendit le burnous de l’enfant, le
coucha sur le bournous; puis, redescendant pour allumer du feu, il
remonta bientôt avec une branche de sapin enflammée, qu’il fixa
dans le mur, et, s’asseyant sur une pierre, près de la couche du
blessé, il attendit qu’il revînt à lui.
Ce n’était pas la première fois que Bruno visitait cette retraite:
souvent, dans ces voyages sans but qu’il entreprenait à travers la
Sicile pour distraire sa vie solitaire, calmer l’activité de son esprit et
chasser ses mauvaises pensées, il était venu dans cette vallée, et il
avait habité cette chambre creusée dans le roc depuis trois mille
ans; c’est là qu’il se livrait à ces rêveries vagues et incohérentes qui
sont habituelles aux hommes d’imagination auxquels la science
manque. Il savait que c’était une race disparue de la terre qui, dans
des temps reculés, avait creusé ces retraites, et, dévot aux
superstitions populaires, il croyait, comme tous les habitans des
environs, que ces hommes étaient des enchanteurs: au reste, cette
croyance, loin de l’écarter de ces lieux redoutés, l’y attirait
irrésistiblement: il avait dans sa jeunesse entendu raconter nombre
d’histoires de fusils enchantés, d’hommes invulnérables, de
voyageurs invisibles, et son âme, sans crainte et avide de
merveilleux n’avait qu’un désir, c’était celui de rencontrer un être
quelconque, sorcier, enchanteur ou démon, qui, moyennant un pacte
infernal, lui accordât un pouvoir surnaturel qui lui donnerait la
supériorité sur les autres hommes. Mais c’était toujours en vain qu’il
avait évoqué les ombres des anciens habitans de la vallée de
Modica; aucune apparition n’avait répondu à ses désirs, et Pascal
Bruno était resté, à son grand désespoir, un homme comme les
autres hommes; plus cependant, la force et l’adresse, que peu de
montagnards possédaient à un degré qui pût lui être comparé.
 Il y avait une heure à peu près que Bruno rêvait ainsi près de son
jeune blessé, lorsque celui-ci sortit de l’espèce de léthargie dans
laquelle il était plongé; il ouvrit les yeux, regarda autour de lui avec
égarement, et arrêta son regard sur celui qui venait de le sauver,
mais sans savoir encore s’il voyait en lui un ami ou un ennemi.
Pendant cet examen, et par un instinct vague de défense, l’enfant
porta la main à sa ceinture pour chercher son fidèle yatagan; mais
ne l’y trouvant pas, il poussa un soupir.
—Souffres-tu? lui dit Bruno, employant pour se faire entendre de
lui cette langue franque qui est l’idiome universel des côtes de la
Méditerranée, depuis Marseille jusqu’à Alexandrie, depuis
Constantinople jusqu’à Alger, et à l’aide duquel on peut faire le tour
du vieux monde.
—Qui es-tu? répondit l’enfant.
—Un ami.
—Ne suis-je donc pas prisonnier?
—Non.
—Alors comment me trouvé-je ici?
Pascal lui raconta tout, l’enfant l’écouta attentivement; puis,
lorsque le narrateur eut fini son récit, il fixa ses yeux sur ceux de
Bruno, et avec un accent de reconnaissance profonde:
—Alors, lui dit-il, puisque tu m’as sauvé la vie, tu veux donc être
mon père?
—Oui, dit Bruno, je le veux.
—Père, dit le blessé, ton fils s’appelle Ali; et toi, comment
t’appelles-tu?
—Pascal Bruno.
—Allah te protége! dit l’enfant.
—Désires-tu quelque chose?
 —Oui, de l’eau; j’ai soif.
Pascal prit une tasse de terre, cachée dans un enfoncement du
rocher, et descendit puiser de l’eau à une source qui coulait près de
la maison. En remontant, il jeta les yeux sur le yatagan de l’enfant, et
il vit qu’il n’avait pas même songé à le rapprocher de lui. Ali prit
avidement la tasse et la vida d’un trait.
—Allah te donne autant d’années heureuses qu’il y avait de
gouttes d’eau dans cette tasse, dit l’enfant en la lui rendant.
—Tu es une bonne créature, murmura Bruno; dépêche-toi de
guérir, et quand tu seras guéri, tu pourras retourner en Afrique.
L’enfant guérit et resta en Sicile, car il s’était pris pour Bruno
d’une telle amitié, qu’il ne voulut jamais le quitter. Depuis lors, il était
demeuré constamment avec lui, l’accompagnant dans ses chasses
sur les montagnes, l’aidant à diriger sa barque en mer, et prêt à se
faire tuer sur un signe de celui qu’il appelait son père.
La veille, il l’avait suivi à la villa du prince de Carini; il l’attendait
sous les fenêtres pendant son entrevue avec Gemma, et c’était lui
qui avait poussé le double cri d’alarme, la première fois, lorsque le
prince avait sonné à la grille, et la seconde fois, lorsqu’il était entré
dans le château. Il allait monter lui-même dans la chambre pour lui
porter secours, si besoin était, lorsqu’il vit Bruno s’élancer par la
fenêtre. Il le suivit dans sa fuite. Tous deux arrivèrent au rivage, se
jetèrent dans leur canot qui les attendait, et comme la nuit ils ne
pouvaient gagner la haute mer sans éveiller des soupçons, ils se
contentèrent de venir se confondre parmi les barques de pêcheurs
qui attendaient le point du jour pour sortir du port.
Pendant cette nuit, Ali rendit à son tour, à Pascal, tous les soins
qu’il en avait reçus en pareille circonstance, car le prince de Carini
avait visé juste, et la balle qu’il cherchait vainement dans sa tenture,
avait presque traversé l’épaule de Bruno; de sorte qu’Ali n’eut
qu’une légère incision à faire avec son yatagan, pour la retirer du
côté opposé à celui par lequel elle était entrée. Tout cela s’était
passé presque sans que Bruno s’en mêlât et parût même y penser,
et la seule marque d’attention qu’il donnât à sa blessure, était,
comme nous l’avons dit, de l’humecter de temps en temps avec de
l’eau de mer, tandis que l’enfant faisait semblant de raccommoder
ses filets.
—Père, dit tout-à-coup Ali s’interrompant dans cette feinte
occupation, regarde donc du côté de la terre!
—Qu’y a-t-il?
—Une troupe de gens.
—Où cela?
—Là-bas, sur le chemin de l’église.
En effet, une société assez nombreuse suivait le chemin tortueux
à l’aide duquel on gravit la montagne sainte. Bruno reconnut que
c’était un cortège nuptial qui se rendait à la chapelle de Sainte-
Rosalie.
—Mets le cap sur la terre et rame vivement, s’écria-t-il se levant
tout debout.
L’enfant obéit, saisit de chaque main un aviron, et le petit canot
sembla voler à la surface de la mer. Au fur et à mesure qu’ils
approchaient du rivage, la figure de Bruno prenait une expression
plus terrible; enfin, lorsqu’ils ne furent plus qu’à la distance d’un
demi-mille à peu près...
—C’est Teresa! s’écria-t-il avec un accent de désespoir
impossible à imaginer: ils ont avancé la cérémonie; ils n’ont pas
voulu attendre à dimanche, ils ont eu peur que je ne l’enlevasse d’ici
là!.... Dieu m’est témoin que j’ai fait tout ce que j’ai pu pour que cela
finît bien... Ce sont eux qui n’ont pas voulu; malheur à eux!
A ces mots, Bruno, aidé par Ali, hissa la voile de la petite barque,
qui, tournant le mont Pellegrino, disparut au bout de deux heures
derrière le cap de Gallo.
 I V.

Pascal ne s’était pas trompé. La comtesse, craignant quelque

entreprise de la part de Bruno, avait fait avancer le mariage de trois
jours, sans rien dire à Teresa de l’entrevue qu’elle avait eue avec
son amant; et, par une dévotion particulière, les époux avaient
choisi, pour la célébration du mariage, la chapelle de Sainte-Rosalie,
la patronne de Palerme.
C’est encore un des traits caractéristiques de Palerme, ville toute
d’amour, que de s’être mise sous la protection d’une sainte jeune et
jolie. Aussi sainte Rosalie est-elle à Palerme ce que saint Janvier est
à Naples, la toute-puissante distributrice des bienfaits du ciel; mais,
de plus que saint Janvier, elle est de race française et royale, et
descend directement de Charlemagne[13], ainsi que le prouve son
arbre généalogique, peint au-dessus de la porte extérieure de la
chapelle; arbre dont le tronc sort de la poitrine du vainqueur de
Witikind, et, après s’être divisé en plusieurs rameaux, réunit ses
branches à la cime, pour donner naissance au prince de Sinebaldo,
père de sainte Rosalie. Mais toute la noblesse de sa race, toute la
richesse de sa maison, toute la beauté de sa personne, ne purent
rien sur la jeune princesse. Elle quitta, à l’âge de dix-huit ans, la cour
de Roger, et, entraînée vers la vie contemplative, elle disparut tout-
à-coup sans qu’on sût ce qu’elle était devenue, et ce ne fut qu’après
sa mort qu’on la trouva, belle et fraîche comme si elle vivait encore,
dans la grotte qu’elle avait habitée, et dans l’attitude même où elle
s’était endormie du sommeil chaste et innocent des élus.
Cette grotte était creusée au flanc de l’ancien mont Evita, si
célèbre dans le cours des guerres puniques par les positions
inexpugnables qu’il fournit aux Carthaginois; mais aujourd’hui la
montagne profane a changé de nom. Sa tête stérile a reçu le
baptême de la foi, et on l’appelle le mont Pellegrino, mot qui, dans
sa double signification, veut dire également la colline Précieuse ou le
mont du Pèlerin. En 1624, une peste désolait Palerme; sainte
Rosalie fut invoquée. On tira le corps merveilleux de la grotte, on le
transporta en grande pompe dans la cathédrale de Palerme; et à
peine les ossemens sacrés eurent-ils touché le seuil du monument
demi-chrétien, demi-arabe, bâti par l’archevêque Gauthier, qu’à la
prière de la sainte, Jésus-Christ chassa de la ville non-seulement la
peste, mais encore la guerre et la famine, comme en fait foi le bas-
relief de Villa-Reale, élève de Canova. Ce fut alors que les
Palermitains reconnaissans transformèrent en église la grotte de
sainte Rosalie, établirent le magnifique chemin qui y conduit, et dont
la construction semble remonter à ces époques où une colonie
romaine jetait un pont ou un aqueduc d’une montagne à l’autre,
comme la signature granitique de la métropole. Enfin, le corps de la
sainte fut remplacé par une gracieuse statue de marbre, couronnée
de roses et couchée dans l’attitude où la sainte s’était endormie, à
l’endroit même où elle avait été retrouvée; et le chef-d’œuvre de
l’artiste fut encore enrichi par un don royal. Charles III de Bourbon lui
donna une robe d’étoffe d’or, estimée vingt-cinq mille francs, un
collier de diamans et des bagues magnifiques; et, voulant joindre les
honneurs chevaleresques aux richesses mondaines, obtint pour elle
la grande croix de Malte, qui est suspendue par une chaîne d’or, et
la décoration de Marie-Thérèse, qui est une étoile entourée de
lauriers avec cette devise: Fortitudini.
Quant à la grotte elle-même, c’est une excavation creusée dans
un noyau primitif recouvert de couches calcaires, à la voûte de
laquelle pendent de brillantes stalactites; à gauche est un autel dans
le bas duquel est couchée la statue de la sainte, que l’on voit à
travers un treillage d’or, et derrière l’autel coule la fontaine où elle se
désaltérait. Quant au portique de cette église naturelle, il est séparé
d’elle par un intervalle de trois ou quatre pieds, par lequel pénètre le
jour et descendent les festons de lierres; de sorte que les rayons du
soleil séparent comme un rideau lumineux le desservant de ses
auditeurs.
C’est dans cette église que Teresa et Gaëtano furent mariés.
La cérémonie terminée, la noce redescendit à Palerme, où des
voitures attendaient les convives pour les conduire au village de
Carini, fief princier dont Rodolfo tirait son nom et son titre. Là, par les
soins de la comtesse, tous les apprêts d’un repas magnifique
avaient été faits; les paysans des environs avaient été invités; il en
était venu de deux ou trois lieues à la ronde, de Montreale, de
Capaci et de Favarota; et parmi toutes ces jeunes paysannes qui
avaient fait assaut de coquetterie villageoise, on reconnaissait celles
de Piana de Greci à leur costume moraïte, qu’elles ont
religieusement conservé, quoique la colonie qui le leur a légué et qui
le tenait de ses pères ait quitté depuis douze cents ans la terre
natale pour une nouvelle patrie.
Des tables étaient dressées sur une esplanade ombragée par
des chênes verts et des pins parasols, embaumée par les orangers
et les citronniers, et ceinte par des haies de grenadiers et de figuiers
d’Inde, double bienfait de la Providence, qui, pensant à la faim et à
la soif du pauvre, a semé ces arbres comme une manne sur toute
l’étendue de la Sicile. On arrivait à cette esplanade par un chemin
bordé d’aloës, dont les fleurs géantes, qui semblent de loin des
lances de cavaliers arabes, renferment un fil plus brillant et plus
solide que celui du chanvre et du lin; et tandis qu’au midi la vue était
bornée par le palais, au-dessus de la terrasse duquel s’élevait la
chaîne de montagnes qui sépare l’île en trois grandes régions, à
l’occident, au nord et à l’est, à l’extrémité de trois vallées on revoyait
trois fois cette magnifique mer de Sicile qu’à ses teintes variées on
eût prise pour trois mers; car, grâce à un jeu de lumière produit par
le soleil qui commençait à disparaître à l’horizon, du côté de Palerme
elle était d’un bleu d’azur; autour de l’île des Femmes, elle roulait
des vagues d’argent, tandis qu’elle brisait des flots d’or liquide contre
les rochers de Saint-Vito.
Au moment du dessert, et lorsque le festin nuptial était dans
toute sa joie, les portes du château s’ouvrirent, et Gemma, appuyée
sur l’épaule du prince, précédée de deux domestiques portant des
torches, et suivie d’un monde de valets, descendit l’escalier de
marbre de la villa et s’avança sur l’esplanade. Les paysans voulurent
se lever, mais le prince leur fit signe de ne pas se déranger. Gemma
et lui commencèrent le tour des tables et finirent par s’arrêter
derrière les fiancés. Alors un domestique tendit une coupe d’or,
Gaëtano la remplit de vin de Syracuse, le domestique présenta la
coupe à Gemma, Gemma fit un vœu en faveur des nouveaux époux,
effleura de ses lèvres la coupe d’or et la passa au prince, qui, la
vidant d’un trait, y versa une bourse pleine d’onces[14], et la fit porter
à Teresa, dont c’était le présent de noce; au même instant les cris de
vive le prince de Carini! vive la comtesse de Castel-Nuovo! se firent
entendre; l’esplanade s’illumina comme par enchantement, et les
nobles visiteurs se retirèrent, laissant après eux, comme une
apparition céleste, de la lumière et de la joie.
A peine étaient-ils rentrés dans le château avec leur suite, qu’une
musique se fit entendre; les jeunes gens quittèrent les tables et
coururent à l’endroit préparé pour la danse. Comme d’habitude,
Gaëtano allait ouvrir le bal avec sa fiancée, et déjà il s’avançait vers
elle, lorsqu’un étranger arrivant par le chemin des Aloës, parut sur
l’esplanade: c’était Pascal Bruno, vêtu du costume calabrais que
nous avons déjà détaillé; seulement, une paire de pistolets et un
poignard étaient passés à sa ceinture, et sa veste, jetée sur son
épaule droite, comme une pelisse de hussard, laissait voir la
manche ensanglantée de sa chemise. Teresa fut la première qui
l’aperçut: elle jeta un cri, et, fixant sur lui ses yeux épouvantés, elle
resta pâle et droite comme à l’aspect d’une apparition. Chacun se
retourna vers le nouveau venu, et toute cette foule demeura dans
l’attente, silencieuse et muette, devinant qu’il allait se passer
quelque chose de terrible.—Pascal Bruno marcha droit à Teresa, et,
s’arrêtant devant elle, il croisa les bras et la regarda fixement.
—C’est vous, Pascal? murmura Teresa.
—Oui, c’est moi, répondit Bruno d’une voix rauque: j’ai appris à
Bauso, où je vous attendais, que vous alliez vous marier à Carini, et
je suis venu à temps, je l’espère, pour danser la première tarentelle
avec vous.
—C’est le droit du fiancé, interrompit Gaëtano s’approchant.
—C’est le droit de l’amant, répondit Bruno. Allons, Teresa, c’est
le moins que vous puissiez faire pour moi, ce me semble.
 —Teresa est ma femme, s’écria Gaëtano en étendant le bras
vers elle.
—Teresa est ma maîtresse, dit Pascal en lui tendant la main.
—Au secours! cria Teresa.
Gaëtano saisit Pascal au collet; mais au même instant il poussa
un cri et tomba, le poignard de Pascal enfoncé jusqu’au manche
dans la poitrine. Les hommes firent un mouvement pour s’élancer
vers le meurtrier, qui tira froidement un pistolet de sa ceinture et
l’arma; puis, avec son pistolet, il fit signe aux musiciens de
commencer l’air de la tarentelle. Ils obéirent machinalement: chacun
demeura immobile.
—Allons, Teresa! dit Bruno.
Teresa n’était plus un être vivant, mais un automate dont le
ressort était la peur. Elle obéit, et cette horrible danse près d’un
cadavre dura jusqu’à la dernière mesure. Enfin les musiciens
s’arrêtèrent, et comme si cette musique eût seule soutenu Teresa,
elle tomba évanouie sur le corps de Gaëtano.
—Merci, Teresa, dit le danseur la regardant d’un œil sec; c’est
tout ce que je voulais de toi. Et maintenant, s’il est quelqu’un ici qui
désire savoir mon nom, afin de me retrouver autre part, je m’appelle
Pascal Bruno.
—Fils d’Antonio Bruno, dont la tête est dans une cage de fer au
château de Bauso, dit une voix.
—C’est cela même, répondit Pascal; mais si vous désirez l’y voir
encore, hâtez-vous, car elle n’y restera pas longtemps, je vous le
jure!
A ces mots, Pascal disparut sans qu’il prît envie à personne de le
suivre; d’ailleurs, soit crainte, soit intérêt, tout le monde s’occupait de
Gaëtano et de Teresa.
L’un était mort, l’autre était folle.
 Le dimanche suivant était le jour de la fête de Bauso: tout le
village était en joie, on buvait à tous les cabarets, on tirait des boîtes
à tous les coins de rue. Les rues étaient pavoisées et bruyantes, et,
entre toutes, celle qui montait au château était pleine de monde qui
s’était amassé pour voir les jeunes gens tirer à la cible. C’était un
amusement qui avait été fort encouragé par le roi Ferdinand IV,
pendant son séjour forcé en Sicile; et plusieurs de ceux qui se
livraient en ce moment à cet exercice avaient eu récemment, à la
suite du cardinal Ruffo, occasion de déployer leur adresse sur les
patriotes napolitains et les républicains français; mais pour le
moment, le but était redevenu une simple carte, et le prix un gobelet
d’argent. La cible était placée directement au-dessous de la cage de
fer où était la tête d’Antonio Bruno, à laquelle on ne pouvait atteindre
que par un escalier qui, de l’intérieur de la forteresse, conduisait à
une fenêtre en dehors de laquelle était scellée cette cage. Les
conditions du tirage étaient, au reste, des plus simples; on n’avait
besoin, pour faire partie de la société, que de verser dans la caisse
commune, qui devait servir à payer le prix du gobelet d’argent, la
modique somme de deux carlins pour chaque coup que l’on désirait
tirer, et l’on recevait en échange un numéro amené au hasard, qui
fixait l’ordre dans lequel le tour devait arriver; les moins adroits
prenaient jusqu’à dix, douze et quatorze balles; ceux qui comptaient
sur leur habileté se bornaient à cinq ou six. Au milieu de tous ces
bras tendus et de toutes ces voix confuses, un bras s’étendit qui jeta
deux carlins, et une voix se fit entendre qui demanda une seule
balle. Chacun se retourna étonné de cette pauvreté ou de cette
confiance. Ce tireur qui demandait une seule balle, c’était Pascal
Bruno.
Quoique depuis quatre ans il n’eût point paru dans le village,
chacun le reconnut; mais nul ne lui adressa la parole. Seulement,
comme on le savait le chasseur le plus habile de toute la contrée, on
ne s’étonna point qu’il n’eût pris qu’une seule balle: elle portait le no
11. Le tir commença.
Chaque coup était accueilli par des rires ou par des
acclamations; et au fur et à mesure que les premières balles
s’épuisaient les rires devenaient moins bruyans. Quant à Pascal,
appuyé triste et pensif sur sa carabine anglaise, il ne paraissait
prendre aucune part à l’enthousiasme ou à l’hilarité de ses
compatriotes; enfin son tour vint; on appela son nom; il tressaillit et
leva la tête comme s’il ne s’attendait pas à cet appel; mais, se
rassurant aussitôt, il vint prendre place derrière la corde tendue qui
servait de barrière. Chacun le suivit des yeux avec anxiété: aucun
tireur n’avait excité un tel intérêt ni produit un pareil silence.
Pascal lui-même paraissait sentir toute l’importance du coup de
fusil qu’il allait tirer, car il se posa d’aplomb, la jambe gauche en
avant, et assurant son corps sur la jambe droite, il épaula avec soin,
et prenant sa ligne d’en bas, il leva lentement le canon de sa
carabine; tout le monde le suivait des yeux, et ce fut avec
étonnement qu’on le vit dépasser la hauteur de la cible, et, se levant
toujours ne s’arrêter que dans la direction de la cage de fer: arrivés
là, le tireur et le fusil restèrent un instant immobiles comme s’ils
étaient de pierre; enfin le coup partit, et la tête, enlevée de la cage
de fer[15], tomba du haut du mur au pied de la cible!... Un frisson
courut parmi les assistans, et aucun cri n’accueillit cette preuve
d’adresse.
Au milieu de ce silence, Pascal Bruno alla ramasser la tête de
son père, et prit, sans dire un mot et sans regarder une seule fois
derrière lui, le sentier qui conduisait aux montagnes.
 V.

Un an à peine s’était écoulé depuis les événemens que nous

venons de raconter dans notre précédent chapitre, et déjà toute la
Sicile, de Messine à Palerme, de Céfalu au cap Passaro, retentissait
du bruit des exploits du bandit Pascal Bruno. Dans les pays comme
l’Espagne et l’Italie, où la mauvaise organisation de la société tend
toujours à repousser en bas ce qui est né en bas, et où l’âme n’a
pas d’ailes pour soulever le corps, un esprit élevé devient un
malheur pour une naissance obscure; comme il tend toujours à sortir
du cercle politique et intellectuel où le hasard l’a enfermé, comme il
marche incessamment vers un but dont mille obstacles le séparent,
comme il voit sans cesse la lumière, et qu’il n’est point destiné à
l’atteindre, il commence par espérer et finit par maudire. Alors il
entre en révolte contre cette société pour laquelle Dieu a fait deux
parts si aveugles, l’une de bonheur, l’autre de souffrances; il réagit
contre cette partialité céleste et s’établit de sa propre autorité le
défenseur du faible et l’ennemi du puissant. Voilà pourquoi le bandit
espagnol et italien est à la fois si poétique et si populaire: c’est que,
d’abord, c’est presque toujours quelque grande douleur qui l’a jeté
hors de la voie; c’est qu’ensuite son poignard et sa carabine tendent
à rétablir l’équilibre divin faussé par les institutions humaines.
On ne s’étonnera donc pas qu’avec ses antécédens de famille,
son caractère aventureux, son adresse et sa force extraordinaire,
Pascal Bruno soit devenu si rapidement le personnage bizarre qu’il
voulait être. C’est que, si l’on peut parler ainsi, il s’était établi le
justicier de la justice; c’est que, par toute la Sicile, et spécialement
dans Bauso et ses environs, il ne se commettait pas un acte
arbitraire qui pût échapper à son tribunal: et, comme presque
toujours ses arrêts atteignaient les forts, il avait pour lui tous les
faibles. Ainsi, lorsqu’un bail exorbitant avait été imposé par un riche
seigneur à quelque pauvre fermier, lorsqu’un mariage était sur le
point de manquer par la cupidité d’une famille, lorsqu’une sentence
inique allait frapper un innocent, sur l’avis qu’il en recevait, Bruno
prenait sa carabine, détachait quatre chiens corses, qui formaient sa
seule bande, montait sur son cheval de Val-de-Noto, demi-arabe et
demi-montagnard comme lui, sortait de la petite forteresse de
Castel-Nuovo, dont il avait fait sa résidence, allait trouver le
seigneur, le père ou le juge, et le bail était diminué, le mariage
conclu, le prisonnier élargi. On comprendra donc facilement que tous
ces hommes auxquels il était venu en aide lui payaient leur bonheur
en dévoûment, et que toute entreprise dirigée contre lui échouait,
grâce à la surveillance reconnaissante des paysans, qui le
prévenaient aussitôt, par les signes convenus, des dangers qui le
menaçaient.
Puis, des récits bizarres commençaient à circuler dans toutes les
bouches; car plus les esprits sont simples, plus ils sont portés à
croire au merveilleux. On disait que, dans une nuit d’orage, où toute
l’île avait tremblé, Pascal Bruno avait passé un pacte avec une
sorcière, et qu’il avait obtenu d’elle, en échange de son âme, d’être
invisible, d’avoir la faculté de se transporter en un instant d’un bout
de l’île à l’autre, et de ne pouvoir être atteint ni par le plomb, ni par le
fer, ni par le feu. Le pacte, disait-on, devait durer pendant trois ans,
Bruno ne l’ayant signé que pour accomplir une vengeance à laquelle
ce terme, tout restreint qu’il paraissait, était suffisant. Quant à
Pascal, loin de détruire ces soupçons, il comprenait qu’ils lui étaient
favorables, et tâchait, au contraire, de leur donner de la consistance.
Ses relations multipliées lui avaient souvent fourni des moyens de
faire croire à son invisibilité en le mettant au fait de circonstances
qu’on devait penser lui être parfaitement inconnues. La rapidité de
son cheval, à l’aide duquel, le matin, il se trouvait à des distances
incroyables des lieux où on l’avait vu le soir, avait convaincu de sa
faculté locomotive; enfin, une circonstance dont il avait tiré parti avec
l’habileté d’un homme supérieur, n’avait laissé aucun doute sur son
invulnérabilité. La voici:
Le meurtre de Gaëtano avait fait grand bruit, et le prince de
Carini avait donné des ordres à tous les commandans de
compagnie, afin qu’ils tâchassent de s’emparer de l’assassin, qui, du
reste, offrait beau jeu à ceux qui le poursuivaient par l’audace de sa
conduite. Ils avaient, en conséquence, transmis ces ordres à leurs
agens, et le chef de la justice de Spadafora fut prévenu un matin que
Pascal Bruno était passé dans le village pendant la nuit pour aller à
Divieto. Il plaça, les deux nuits suivantes, des hommes en
embuscade sur la route, pensant qu’il reviendrait par le même
chemin qu’il avait suivi en allant, et que, pour son retour, il profiterait
de l’obscurité.
Fatigués d’avoir veillé deux nuits, le matin du troisième jour, qui
était un dimanche, les miliciens se réunirent à un cabaret situé à
vingt pas de la route; ils étaient en train d’y déjeuner, lorsqu’on leur
annonça que Pascal Bruno descendait tranquillement la montagne,
du côté de Divieto. Comme ils n’avaient pas le temps d’aller
reprendre leur embuscade, ils attendirent où ils étaient, et lorsqu’il
ne fut plus qu’à cinquante pas de l’auberge, ils sortirent et se
rangèrent en bataille devant la porte, sans cependant paraître faire
attention à lui. Bruno vit tous ces préparatifs d’attaque sans paraître
s’en inquiéter, et au lieu de rebrousser chemin, ce qui lui aurait été
facile, il mit son cheval au galop et continua sa route. Lorsque les
miliciens virent quelle était son intention, ils préparèrent leurs armes,
et, au moment où il passait devant eux, toute la compagnie le salua
d’une décharge générale; mais ni le cheval, ni le cavalier n’en furent
atteints, et l’homme et l’animal sortirent sains et saufs du tourbillon
de fumée qui les avait un instant enveloppés. Les miliciens se
regardèrent en secouant la tête, et allèrent raconter au chef de la
justice de Spadafora ce qui venait de leur arriver.
Le bruit de cette aventure se répandit le même soir à Bauso, et
quelques imaginations, plus actives que les autres, commencèrent à
penser que Pascal Bruno était enchanté, et que le plomb et le fer
s’aplatissaient et s’émoussaient en frappant contre lui. Le
lendemain, cette assertion fut confirmée par une preuve irrécusable:
on trouva accrochée à la porte du juge de Bauso, la veste de Pascal
Bruno percée de treize coups de feu, et contenant dans ses poches
les treize balles aplaties. Quelques esprits forts soutinrent bien, et
parmi ceux-ci était César Alletto, notaire à Calvaruso, de la bouche
duquel nous tenons ces détails, que c’était le bandit lui-même qui,
échappé miraculeusement à la fusillade, et voulant mettre à profit
cette circonstance, avait suspendu sa veste à un arbre, et avait tiré
les treize coups de feu dont elle portait la marque; mais la majorité
n’en demeura pas moins convaincue de l’enchantement, et la crainte
qu’inspirait déjà Pascal s’en augmenta considérablement. Cette
crainte était telle, et Bruno était si convaincu que des classes
inférieures elle avait gagné les classes supérieures, que, quelques
mois avant l’époque où nous sommes arrivés, ayant eu besoin, pour
une de ses œuvres philantropiques (il s’agissait de rebâtir une
auberge brûlée), de deux cents onces d’or, il s’était adressé au
prince de Butera pour faire l’emprunt de cette somme, lui indiquant
un endroit de la montagne où il irait la prendre, en l’invitant à l’y
enfouir exactement, afin que, pendant une nuit qu’il désignait au
prince, il pût l’aller chercher; en cas de non exécution de cette
invitation, qui pouvait passer pour un ordre, Bruno prévenait le
prince que c’était une guerre ouverte entre le roi de la montagne et
le seigneur de la plaine; mais que si, au contraire, le prince avait
l’obligeance de lui faire le prêt, les deux cents onces d’or lui seraient
fidèlement rendues sur la première somme qu’il enlèverait au trésor
royal.
Le prince de Butera était un de ces types comme il n’en existe
plus guère dans nos époques modernes: c’était un reste de la vieille
seigneurie sicilienne, aventureuse et chevaleresque comme ces
Normands qui ont fondé leur constitution et leur société. Il s’appelait
Hercule, et semblait taillé sur le modèle de son antique patron. Il
assommait un cheval rétif d’un coup de poing, brisait sur son genou
une barre de fer d’un demi-pouce d’épaisseur, et tordait une piastre.
Un événement où il avait fait preuve d’un grand sang-froid, l’avait
rendu l’idole du peuple de Palerme. En 1770, le pain avait manqué
dans la ville, une émeute s’en était suivie; le gouverneur en avait
appelé à l’ultima ratio, le canon était braqué dans la rue de Tolède, le
peuple marchait sur le canon, et l’artilleur, la mèche à la main, allait
tirer sur le peuple, lorsque le prince de Butera alla s’asseoir sur la
bouche de la pièce, comme il aurait fait sur un fauteuil, et de là
commença un discours tellement éloquent et rationnel, que le peuple
se retira à l’instant même, et que l’artilleur, la mèche et le canon
rentrèrent vierges à l’arsenal. Mais ce n’était pas encore à ce seul
motif qu’il devait sa popularité.
 Tous les matins il allait se promener sur la terrasse qui dominait
la place de la Marine, et comme, au point du jour, les portes de son
palais étaient ouvertes pour tout le monde, il y trouvait toujours
nombreuse compagnie de pauvres gens; il portait ordinairement
pour cette tournée un grand gilet de peau de daim, dont les
immenses poches devaient tous les matins être remplies, par son
valet de chambre, de carlins et de demi-carlins qui disparaissaient
jusqu’au dernier pendant cette promenade, et cela avec une manière
de faire et de dire qui n’appartenait qu’à lui: de sorte qu’il semblait
toujours prêt à assommer ceux auxquels il faisait l’aumône.
—Excellence, disait une pauvre femme entourée de sa famille,
ayez pitié d’une pauvre mère qui a cinq enfans.
—Belle raison! répondait le prince en colère: est-ce moi qui te les
ai faits?—Et, avec un geste menaçant, il laissait tomber dans son
tablier une poignée de monnaie.
—Signor principe, disait un autre, je n’ai pas de quoi manger.
—Imbécile! répondait le prince en lui allongeant un coup de poing
qui le nourrissait pour huit jours, est-ce que je fais du pain, moi? va-
t’en chez le boulanger[16].
Aussi quand le prince passait par les rues, toutes les têtes se
découvraient, comme lorsque monsieur de Beaufort passait par les
halles; mais, plus puissant encore que le frondeur français, il n’aurait
eu qu’un mot à dire pour se faire roi de Sicile; il n’en eut jamais
l’idée, et il resta prince de Butera, ce qui valait bien autant.
Cette libéralité avait cependant trouvé un censeur, et cela dans la
maison même du prince: ce censeur était son maître d’hôtel. On doit
comprendre qu’un homme du caractère que nous avons essayé
d’indiquer devait surtout appliquer à ses dîners ce luxe et cette
magnificence qui lui étaient si naturels; aussi tenait-il littéralement
table ouverte, et tous les jours avait-il à sa table vingt-cinq ou trente
convives au moins, parmi lesquels sept ou huit lui étaient toujours
inconnus, tandis que d’autres s’y asseyaient au contraire avec la
régularité de pensionnaires de table d’hôte. Parmi ces derniers, il y
avait un certain capitaine Altavilla, qui avait gagné ses épaulettes en
suivant le cardinal Ruffo de Palerme à Naples, et qui était revenu de
Naples à Palerme avec une pension de mille ducats.
Malheureusement, le capitaine avait le défaut d’être tant soit peu
joueur, ce qui eût rendu sa retraite insuffisante à ses besoins, s’il
n’avait trouvé deux moyens à l’aide desquels son traitement
trimestriel était devenu la part la moins importante de son revenu: le
premier de ces moyens, et celui-là, comme je l’ai dit, était à la portée
de tout le monde, le premier de ces moyens, dis-je, était de dîner
tous les jours chez le prince, et le second, de mettre religieusement,
chaque jour, en se levant de table, son couvert d’argent dans sa
poche. Cette manœuvre dura quelque temps sans que cette
soustraction quotidienne fût remarquée: mais si bien garnis que
fussent les dressoirs du prince, on commença de s’apercevoir qu’il
s’y formait des vides. Les soupçons du majordome tombèrent
aussitôt sur le santa-fede[17]; il l’épia avec attention, et il ne lui fallut
qu’une surveillance de deux ou trois jours pour changer ses
soupçons en certitude. Il en avertit aussitôt le prince, qui réfléchit un
moment, puis qui répondit que, tant que le capitaine ne prendrait que
son couvert, il n’y avait rien à dire; mais que, s’il mettait dans sa
poche ceux de ses voisins, il verrait alors à prendre une résolution.
En conséquence, le capitaine Altavilla était resté un des hôtes les
plus assidus de son excellence le prince Hercule de Butera.
Ce dernier était à Castrogiovanni, où il avait une villa, lorsqu’on
lui apporta la lettre de Bruno; il la lut et demanda si le messager
attendait la réponse. On lui dit que non, et il mit la lettre dans sa
poche avec le même sang-froid que si c’était une missive ordinaire.
La nuit fixée par Bruno arriva: l’endroit qu’il avait désigné était
situé sur la croupe méridionale de l’Etna, près d’un de ces mille
volcans éteints qui doivent leur flamme d’un jour à sa flamme
éternelle, et dont l’existence éphémère a suffi pour détruire des
villes. On appelait celui-là le Montebaldo; car chacune de ces
collines terribles a reçu un nom en sortant de la terre. A dix minutes
de chemin de sa base, s’élevait un arbre colossal et isolé appelé le
Châtaignier des cent chevaux, parce qu’à l’entour de son tronc, qui a
cent soixante-dix-huit pieds de circonférence, et sous son feuillage,
qui forme à lui seul une forêt, on peut abriter cent cavaliers avec
leurs montures. C’était dans la racine de cet arbre que Pascal venait
chercher le dépôt qui devait lui être confié. En conséquence, il partit
sur les onze heures de Centorbi, et vers minuit il commença, aux
rayons de la lune, à apercevoir l’arbre gigantesque et la petite
maison bâtie entre les tiges différentes de l’arbre, et qui sert à
renfermer la récolte immense de ses fruits. Au fur et à mesure qu’il
approchait, Pascal croyait distinguer une ombre debout contre un
des cinq troncs qui puisent leur sève à la même racine. Bientôt cette
ombre prit un corps; le bandit s’arrêta et arma sa carabine en criant:
—Qui vive?
—Un homme, parbleu! dit une voix forte; as-tu cru que l’argent
viendrait tout seul?
—Non, sans doute, reprit Bruno; mais je n’aurais pas cru que
celui qui l’apporterait serait assez hardi pour m’attendre.
—Alors c’est que tu ne connaissais pas le prince Hercule de
Butera, voilà tout.
—Comment! c’est vous-même, monseigneur? dit Bruno, rejetant
sa carabine sur son épaule et s’avançant le chapeau à la main vers
le prince.
—Oui, c’est moi, drôle; c’est moi qui ai pensé qu’un bandit
pouvait avoir besoin d’argent comme un autre homme, et qui n’ai
pas voulu refuser ma bourse, même à un bandit. Seulement il m’a
pris fantaisie de la lui apporter moi-même, afin que le bandit ne crût
pas que je la lui donnais par peur.
—Votre excellence est digne de sa réputation, dit Bruno.
—Et toi, es-tu digne de la tienne? répondit le prince.
—C’est selon celle qu’on m’a faite devant vous, monseigneur; car
je dois en avoir plus d’une.
—Allons, continua le prince, je vois que tu ne manques ni d’esprit
ni de résolution; j’aime les hommes de cœur partout où je les