Comprehensive Dermatologic Drug

Therapy 4th Edition Edition Stephen

Wolverton
Visit to download the full and correct content document:
https://ebookmass.com/product/comprehensive-dermatologic-drug-therapy-4th-editio
n-edition-stephen-wolverton/
More products digital (pdf, epub, mobi) instant
download maybe you interests ...

Comprehensive Dermatologic Drug Therapy 4th Edition

Stephen E Wolverton Md

https://ebookmass.com/product/comprehensive-dermatologic-drug-
therapy-4th-edition-stephen-e-wolverton-md/

Principles of Pharmacology: The Pathophysiologic Basis

of Drug Therapy 4th Edition, (Ebook PDF)

https://ebookmass.com/product/principles-of-pharmacology-the-
pathophysiologic-basis-of-drug-therapy-4th-edition-ebook-pdf/

Principles of Pharmacology: The Pathophysiologic Basis

of Drug Therapy 4th Edition David E. Golan

https://ebookmass.com/product/principles-of-pharmacology-the-
pathophysiologic-basis-of-drug-therapy-4th-edition-david-e-golan/

Rang et Dale's pharmacology 8th edition Edition Drug

Therapy

https://ebookmass.com/product/rang-et-dales-pharmacology-8th-
edition-edition-drug-therapy/
Drug Use and Misuse 9th Edition Stephen A. Maisto

https://ebookmass.com/product/drug-use-and-misuse-9th-edition-
stephen-a-maisto/

Statistical Issues in Drug Development 3rd Edition

Stephen S. Senn

https://ebookmass.com/product/statistical-issues-in-drug-
development-3rd-edition-stephen-s-senn/

A Comprehensive Russian Grammar 4th Edition Terence

Wade

https://ebookmass.com/product/a-comprehensive-russian-
grammar-4th-edition-terence-wade/

Drug Use and Abuse Stephen A. Maisto

https://ebookmass.com/product/drug-use-and-abuse-stephen-a-
maisto/

Comprehensive Respiratory Therapy Exam Preparation

Guide 3rd Edition, (Ebook PDF)

https://ebookmass.com/product/comprehensive-respiratory-therapy-
exam-preparation-guide-3rd-edition-ebook-pdf/
Comprehensive Dermatologic
Drug Therapy
FOURTH EDITION

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

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

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

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

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

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

Notice

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

Library of Congress Control Number: 2019952758

Senior Content Strategist: Charlotta Kryhl/Nancy Duffy

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

Printed in China

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

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

To my loving wife Stephanie, who lovingly supports my career

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

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

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

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

Kelly A. Foley, PhD

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

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

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

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

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

Katherine Hrynewycz, BS, MD Sa Rang Kim, MD

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

Katherine B. Lee, MD David Martell, DO

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

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

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

Cindy England Owen, MD, MS Naveed Sami, MD

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

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

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

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

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

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

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

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

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

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

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

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

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

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

TABLE
1.3 Definitions and Concepts Central to Understanding Pharmacokinetics

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

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

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

TABLE
1.4 Definitions and Concepts Central to Understanding Pharmacodynamics

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

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

TABLE
1.5 Pharmacodynamics—Selected Receptor Antagonists and Agonists

Drug/Drug Group Receptor Affected Biologic Outcome

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

Hormonal Receptor Agonists

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

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

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

Enzyme Systems Inhibited by Drugs Signal Transduction and Transcription Factors

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

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

Drug/Drug Group Enzyme Inhibited Biologic Outcome

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

Enzymes Important to Microbial Growth and Survival

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

Other Enzymes of Importance to Inflammatory Response

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

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

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

Mr Smith oli kyllästynyt päiviinsä ja koko hoitoon ja ryhtyi

laajasuuntaisiin varusteluihin, päästäkseen varmasti hengestään.

Antakaamme Amerikan lehden kertoa:

»Hän meni Elk-joen yli vievälle sillalle mukanaan joukko

kuolettavia aseita. Hän valeli vaatteensa öljyllä ja sitoi nuoran sillan
kaiteeseen. Nuoran toisen pään sitoi hän kaulaansa. Hän asetti
paperin jalkainsa juureen ja sytytti sen tuleen. Hän nielasi
annoksen myrkkyä ja ampui revolverilla tähdäten päähänsä. Mutta
sensijaan, että kuula olisi lävistänyt hänen päänsä, katkaisi se
hänen kaulassaan olevan nuoran. Sillä välin olivat vaatteet
alkaneet palaa. Hän kadotti tasapainonsa ja putosi jokeen kuten
palava soihtu. Vedessä sammui tuli vaatteista. Kun Smith nousi
vedenpinnalle, sai hän ankaria oksennuskohtauksia, ja myrkky tuli
ulos vatsasta. Kun hän oli hyvä uimari, onnistui hänen päästä
rantaan. Palohaavoista ja myrkystä ei ollut sen haitallisempia
seurauksia. Viikon kuluttua päästettiin hänet ulos sairaalasta».

Tämän yhtä lyhykäisen kuin uskottavankin kertomuksen antama

opetus siis on, että uimataito on hyvä olla olemassa. Niitä lukijoita,
jotka eivät vielä osaa uida — uimataidottomia on muuten paljon
enemmän kuin uskoisikaan — kehoitetaan senvuoksi opettelemaan
uimaan ensi kesänä.

Kokki Smithinkin henki olisi varmaan ollut vakavassa vaarassa,

ellei hän olisi osannut uida.
 Vaikka kyllä kai hän olisi siinäkin tapauksessa pelastunut jollain
ihmeellisellä tavalla.

Sillä Amerikassa tapahtuu paljon merkillistä.

(1922.)
IHASTUTTAVA YKSIMIELISYYS

Katsokaa meitä!

Näettekö, kuinka poskemme hehkuvat ja silmämme loistavat?

Huomaatteko, kuinka viehättävä olemme kainossa ja
vaatimattomassa kauneudessamme?

Kaikki tämä henkinen ja ruumiillinen kukkeutemme johtuu

yksinomaan siitä, että me katsomme ihastuksella ja luottamuksella
tulevaisuuteen — sekä omaan tulevaisuuteemme, että koko
maailman tulevaisuuteen.

Välistä, havaitessamme kansakuntien ja diplomaattien välillä

melkoisia mielipiteiden eroavaisuuksia, jotka ovat maksaneet,
muiden kustannusten ohella, eräitä miljoonia ihmishenkiä, olemme
me olleet taipuvainen raapimaan oikeaa korvantaustaamme ja
lausumaan mielipiteenämme, että kaikki menee hornan tuuttiin… ja
menköön, senpuolesta, mitäs se meitä liikuttaa!

Mutta nyt me aavistamme, etteivät ne russelilaiset ja hartevalaiset

ja mitä ne lienevät — joita me olemme pitäneet enemmän kuin
luvallisen löylynlyöminä tässäkin löylynlyötyjen maailmassa —
etteivät nämä enemmän tai vähemmän pitkäpartaiset
maailmanlopun prohveetat, jotka näkevät maailmanlopun merkin
siinäkin, jos räystäällä päivänpaisteessa nukkuva kissa sattuu
putoamaan, etteivät ne sentään taidakaan olla niin aivan väärässä
ennustaessaan, että tuhatvuotinen valtakunta on alkamassa, ellei jo
alkanutkin. Me näemme jo julman jalopeuran ja tyhmän lampaan, tai
pässin, kävelevän kaulakkain viheriäisellä kedolla.

Katsokaamme esimerkiksi sitä suurta, omituisen juhlallista ja

huomattavaa yksimielisyyttä, jolla maailman kansat suhtautuvat
meihin. Avatkaa näköttimenne ja suvaitkaa nähdä se
sydäntälämmittävä osanotto, jolla valtakunnat äkkiä ovat alkaneet
harrastaa meitä, kylmän ja pakkasen punanenäisiä lapsia. Mutta
ennen kaikkea se yksimielisyys. Kerrankin on koko maailma, tai
ainakin huomattava osa siitä, yksimielinen edes yhdestä asiasta.

Katsokaamme:

Ruotsin lehdet ovat käsitelleet kysymystä Suomen ja Puolan

liittoutumisesta.

Ruotsin lehdet ovat tulleet siihen tulokseen, että Suomen olisi

edullisempaa liittyä Skandinaviaan.

Jahah.

Suomen ruotsalaiset ovat äskeisillä puoluepäivillään käsitelleet

kysymystä Suomen ja Puolan liittoutumisesta.

Ruotsalaisemme ovat tulleet siihen tulokseen, että Suomen olisi

lähestyttävä Skandinaviaa.

Jahah.
 Saksalaiset lehdet ovat käsitelleet kysymystä Suomen ja Puolan
liittoutumisesta.

Saksalaiset lehdet ovat tulleet siihen tulokseen, että Suomen olisi

edullisempaa liittyä Skandinaviaan.

Jahah.

Mutta entäs nyt… lukija on ystävällinen ja istuu, ettei putoaisi:

Trotski on käsitellyt kysymystä Suomen ja Puolan liittoutumisesta.

Ja myöskin Trotski on sitä mieltä, että Suomen olisi edullisempaa

liittyä Skandinaviaan.

Rengas on ummessa.

Ruotsalaisen kansanpuolueen puoluepäiviltä on pitkä huippaus

Trotskiin, mutta sittenkin on rengas ummessa, icke desto mindre.

Trotski rakastaa meitä niin lämpimästi, että kai maar tässä on

meidänkin, edes »juutalaisten pelvon tähden», opeteltava
rakastamaan Trotskia. Kunhan hänellä ei olisi niin hirveän pitkä ja
pörröinen tukka. Se tuntuu meistä epäilyttävältä. Tarttis olla
parturikone tai Delila.

Mutta muuten miellyttävä mies, ja hyvin herttainen.

Kuulkaa, mitä hän, hellyydestä värähtelevällä äänellä, on

Moskovan neuvoston juhlakokouksessa puhunut.

Näin on hän puhunut:

 »Tervehdimme ilolla sitä tosiasiaa, että Suomi suuntaisi
politiikkansa
Skandinaviaan sen sijaan, että se suunnattaisiin Puolaan ja
Ranskaan.
Se olisi edullista sekä Suomelle että meille ja myöskin koko
kulttuurin kehitykselle Luoteis-Europassa».

Trotski hellii Suomen tulevaisuutta ja kulttuurin kehitystä

Luoteis-Europassa.

Totisesti on tämä tuhatvuotisen valtakunnan alkua. Julma

jalopeura ja laupias lammas kuhertelevat apilapellossa.
Toivokaamme, ettei laupias lammas osoittautuisi tyhmäksi pässiksi.

Emme sentään juuri ihan vielä lankea uuden ystävämme Trotskin

kaulaan.

Kunhan hän nyt ensin käy parturissakin.

(1922.)
»HARHAANJOHDETTU
TALONPOIKA»

Sallikaa meidän pyyhkiä silmiämme.

Meitä taas itkettää.

Meitä hävettää, että meitä itkettää, isoa miestä, mutta meillä on

niin hellä luonnonlaatu.

Kun me kuulemme tai näemme tai luemme jotain oikein

liikuttavaa, niin itku tahtoo päästä, väkisinkin. Olemme silloin
nauravinamme, salataksemme liikutustamme, mutta kyllä
tarkkasilmäinen henkilö sentään huomaa, mistä todellisuudessa on
kysymys.

Ja juuri nyt, tällä hetkellä, olemme me sydämellisesti liikutettu.

Me olemme lukeneet Kuopion kommunistilehdestä artikkelin

»Harhaanjohdettu talonpoika».

Me ajattelimme ensin, että kommunisti, niinkuin tavallisesti,

kirjoittaa pimeistä talonjusseista, pitkätukkaisista tunkioneuvoksista,
rasvaisista rusthollareista, ihramahaisista isäntämiehistä,
tyhmänpöyhkeistä manttaalipösöistä, leveänaamaisista
lehmäjehuista, työväkeään nylkevistä talokkaista j.n.e. Mutta se oli
erehdys.

Nyt tuli aivan toista.

Esimerkiksi tähän tapaan:

»Jos talonpoika kestää, niin kaikki kestää».

»Talonpoika on niin tärkeä tekijä taloudellisessa elämässä, että

ilman sitä ei yhteiskunnallinen taloutemme pysy pystyssä, talonpoika
on yksi tärkeimpiä perus- ja kulmakiviä
yhteiskuntarakennuksessamme. Tästä jo seuraa itsestään, että
talonpoika on työntekijä».

Talolliset kuuntelevat silmät pystyssä ja korvat hörössä tällaista

puhetta sellaiselta taholta. Se olisi jotain ennenkuulumatonta, ellei
samanlaista kieltä olisi käyttänyt — sittenkun punakaartin asiat
alkoivat arveluttavasti kääntyä päin mäntymetsää —
kapinanaikainen »Työmies»-lehti. Silloin sekin heltyi yhteen
otteeseen ja selitti, että sosialistit ovat aina hellästi rakastaneet juuri
talonpoikaa, vaikka joitakin väärinkäsityksiä aikaisemmin lieneekin
tapahtunut. Mutta nyt ne ovat selvinneet. Lyökäämme siis kädet
käsihin…

Suomalainen talonpoika ei silloin ottanut tätä tarjousta vastaan.

Saamme nähdä, onko se nyt alkavassa vaalitaistelussa siihen
halukkaampi.

Mutta kuunnelkaamme edelleenkin, kyynel silmäkulmassa, niitä

hellyttäviä sointuja, jotka hiljalleen kajahtelevat kommunistisesta
kantelosta: »Mitäpä muuta talonpojan elämä onkaan kuin alituista
raatamista. Aamusta varhain iltaan myöhään täytyy hänen tehdä
raskasta työtä pysyäkseen leipä suussa. Kadehdittavaa ei suinkaan
talonpojan elämä ole».

Ja niin edespäin palstamääriä. Tuleepa kirjoittaja lopuksi jo

siihenkin tulokseen että kun kaikki ympäri käy, niin on talonpojan
elämä vaivaloisempaa ja työläämpää kuin palkkatyöläisen.
Vähintäänkin on talonpoikien elämä »yhtä kurjaa ja sorrettua kuin
palkkaustyöläistenkin. Molemmat ovat kohtalotovereita».

Näin ollen olisi aivan luonnollista, että talonpojat olisivat

kommunisteja ja liittyisivät »yhteiseen taistelurintamaan». Ettei niin
ole tapahtunut, johtuu siitä, että »talonpoika, korvenraataja, on jäänyt
henkisessä kehityksessään takapajulle» kommunisteista, ja eksynyt
väärille poluille. Sillä porvalit, perhanat, »ovat viekkaudella ja
kavaluudella onnistuneet talonpoijan eksyttämään harhateille
poliittisessa elämässä».

Kommunismin leveä ja lämmin syli on kuitenkin nyt, vaalien

lähestyessä, avoin myöskin talonpojille. Heidän ei tarvitse muuta
kuin äänestää polsuja eduskuntaan, kyllä nämä sitten vuorostaan
pitävät lopusta huolen.

Niinkuin sanottu, olemme me syvästi liikutettu. Näin kaunista

puhetta emme ole pitkiin aikoihin lukeneet talonpojasta.

Me vain hieman epäilemme, mahtaneeko maataviljelevä

väestömme sulaa yhtä helposti kyyneleihin. Se on luullaksemme
vähän paksunahkaisempaa. Sitä nahkaa ovat kommunistit itse
ankarasti peitonneet ja parkinneet, ja »korvenraatajalla» on hyvä
muisti, vaikkapa hän, kommunistisella kyynärkepillä mitattuna,
olisikin »jäänyt henkisessä kehityksessään takapajulle».

Siihen tarvittaisiin nyt paljon pehmikettä.

Epäiltävää on, tokko siihen bolshevikkien rahoilla kustannettujen

lehtien palstat ja sanavarasto riittävät.

(1922.)
KYLLÄ TOVERI LENIN…

Usko on vahva uskallus niihin, joita toivotaan, j.n.e.

Suomalaisesta on sanottu, ettei hän usko ennenkuin koettelee,

eikä aina sittenkään. Vaan se on nyt sekin kuinka sen ottaa.

Suomalaista on hiukan vaikea saada uskomaan sellaista, mitä hän

syystä tai toisesta ei halua uskoa. Taikka oikeammin sanoen on se
kerrassaan ylivoimainen tehtävä. »Mutta enpä saa päähäni, ettei
minun oman käteni painamaa puumerkkiä tarvittaisi tässä kirjassa».
Taikka: »enkeli taivaasta ei tee parempaa saapasta kuin minä!»
Siinä ei auta silloin koetteleminenkaan. Vähän yli neljä vuotta
takaperin koeteltiin tässä maassa oikein olan takaa, mutta vaikuttiko
se erääseen uskoon? Eipä paljon. Lukekaapa kommunistilehtiä! Ne
olisivat erittäin suositeltavaa lukemista juuri tähän aikaan kaikille
laiskansitkoille porvareille, jotka eivät pidä niin erikoista väliä sillä,
tuleeko heidän käytyä äänestämässä vai ei. Koska hekin ovat näitä
meitä yksiä samoja suomalaisia kuin sosialistit ja kommunistitkin,
niin ovat hekin vahvat ja rauhalliset uskossaan, että kyllä ne asiat
taas jotenkuten itsestäänkin pysyvät oikealla tolallaan, kun ne kerran
on saatu sille kääntymään. Joutavat toiset äänestää ja rehkiä
puolueasioissa.
 Tämä on juuri sitä kaikkein harmittavinta joukkoa. Jota on
valitettavasti paljon. Typerintä ja itsekkäintä ainesta koko
luomakunnassa, ja vielä typerämpää kuin itsekästä. Sillä jos
itsekkyys veisi voiton typeryydestä, niin juuri se itsekkäisyys panisi
ajattelemaan, että tässä alkaa olla oma raha ja paha maha
vaarassa.

Kommunistit ovat nekin sekä typeriä että itsekkäitä, mutta aivan

toisella tavalla. Ne eivät lepää n.s. laakereillaan. Ne ovat
semmoisessa puuhassa, että liepeet liehuvat. Lakkoliike laajenee
laajenemistaan, mitä lähemmäksi vaalit lähenevät, ja uhka on
olemassa semmoinen, että ajetaan asiat yhtä kyytiä suurlakkoon
asti. Kun sitten on joutilasta sakkia tarpeeksi, niin… mitä sitten
tapahtuu, sitä ei aivan selvästi sanota semmoisissa paikoissa, joissa
se voi tulla porvarinkin kuuluville. Mutta arvaahan sen sanomattakin.
Iskekäämme vain ovelasti silmää ja nyökäyttäkäämme päätä. Kyllä
me ymmärrämme toinen toisemme tarkoitukset, vaikka välistä
haastelemmekin esikuvien ja tunnustähtien kautta. Emme ole niin
tyhmiä.

Varkaudessa, niinkuin tiedämme, on ollut käynnissä suuret

lakkomeiningit. Niihin liittyy seuraava eräästä Kuopion lehdestä
lipsauttamamme pikku-uutinen:

»Varkaudessa ovat poliisiviranomaiset kuulustelleet erästä

henkilöä, joka oli ollut lakkokokouksessa, jossa muuan
lakkokiihoittaja esiintyi. Tämä henkilö on kertonut, että kiihoittaja,
jota hän ei tunne ja joka tuskin lienee mitään nimeä käyttänytkään,
oli kehoittanut työläisiä vankasti pysymään lakossa, sillä, oli
kiihoittaja kehunut, kyllä rahaa saadaan, toveri Lenin sitä lähettää
ja on jo lähettänyt 25 milj. mk, lisää tulee, niin että voitte huoletta
olla lakossa. Kautta maan, niin oli agitaattori edelleen ilmoittanut,
pannaan pyörät seisomaan».

Tämä on sitä kommunistista uskoa, joka kyllä menee erääseen

osaan työväkeä kuin häkä huonoon päähän. Ja meistä se ei ole
niinkään perusteetonta kuin se tylsä porvarillinen usko, josta edellä
huomautimme.

Tosin ei tunnu uskottavalta, että toveri Leniniltä enää kovinkaan

paljon riittää miljoonia kaiken maailman lakkolaislaumojen
elättämiseksi. Toveri Leninillä on peijakkaan paljon murhetta
omienkin laumojensa elättämisestä, ja kirkkojen tultua ryöstetyiksi
alkaa Venäjä olla kutakuinkin kaput kullasta ja muusta sopivasta
maksuvastineesta. Sitäpaitsi on toveri Leninin terveys tätä nykyä
arveluttavasti rempallaan, niin että Moskovassakin on mahdollisesti
jotakin muuta ajattelemista kuin savolaisten kommunistijätkien
onnellistuttamista uusilla suurlahjoituksilla.

Mutta varmaankin ovat tämänkaltaiset »pyörien seisottajat»

aikaisemmin saaneet suurelta toveriltaan tuntuviakin avustuksia, niin
ettei ole ihme, jos he kukaties vieläkin ovat siinä luulossa, että toveri
Leninillä on Aladdinin taikalamppu, jonka henget kantavat hänelle
vaunulastittain uutta kultaa, kun entinen loppuu.

Mutta olipa kuinka tahansa: typerintä ja itsekkäintä ainesta koko

luomakunnassa ovat ne porvarit, jotka tällaisena aikana eivät ota
äänellään osaa isänmaansa tukemiseen. Sellainen joukko olisi
ainakin joka kolmas vuosi kylmässä vedessä pieksettävä.

(1922.)
KURKI EI HALUA KUOLLA

Välistä kuuluu tapahtuvan niin, että kurkiparka ennättää kuolla

kutkahtaa ennenkuin suo sulaa.

Se on tietysti kova koettelemus kurjelle, sillä oma suu hänelläkin

on lähempänä kuin kontin suu, mistä viimeksimainitusta kurjella
sitäpaitsi lienee hämärä käsitys.

Kurki seisoo pitkänä ja kylmänä keväänä vuoroin toisella, vuoroin

toisella jalallaan jään ja roudan peittämällä suolla, ja ajattelee pää
kallellaan ja silmissä uneksiva ilme kaikkia niitä herkullisia aarteita,
joita suo, kerran sulaksi päästyään, on sille tarjoava, pitkiä, liukkaita
madonloikareita, jotka niin suloisesti luistavat alas pitkästä kurkusta,
ja ennenkaikkea lihavia, mulkosilmäisiä sammakoita, ihania
sammakoita, hurmaavia sammakoita, taivaallisia sammakoita. Mutta
kevät on pitkä ja kylmä. Suo ei jaksa sulaa. Ja eräänä aamuna
aurinko ylösnoustessaan näkee kurkiraukan kuukahtaneen sen
jäätyneen mättään juurelle, jonka päällä se on uneksinut viimeiset
sammakkounelmansa. Se kurki ei enää koskaan tarvitse
sammakoita. Meillä tässä suuressa Suomaassa on myöskin eräs
kurki, jolle on alkanut tulla uskon puutos.
 Mutta se ei halua enää odottaa suon sulamista. Se on saanut siitä
odottamisesta enemmän kuin kyllikseen.

Ja henki on sillekin rakas.

Se kurki on meidän viehättävä ja eräiltä näkökulmilta katsottuna ei

ainoastaan mielenkiintoinen, vaan tavallaan huvittavakin
kommunistinen puolueemme.

Jos kaikki tämän puolueen toilaukset, meiningit ja edesottamiset

kirjaan kirjoitettaisiin, niin tulisi siitä paksu romaani.

Mutta niitä ei ole tarpeellista kirjoihin kirjoittaa. Ne ovat

enimmäkseen sitä laatua tavaraa, jota siistissä pakinatyylissä
sanotaan tuomaskuonaksi, mikä tosin on suuri ja ansaitsematon
loukkaus tuomaskuonaa kohtaan. Sillä tuomaskuona on hyödyllistä
ja tarpeellista ainetta, jota ei suinkaan voi sanoa kommunismin
tuotteista.

Kommunistien aatokset ovat sinkoilleet tässä maassa niinkuin

niinsanotut sittapörriäiset pörräävät ilmassa, matalalla lentäen,
poutaa ennustavana kesäiltana. Sattuu sitten sellaista, että
lentolinjaan osuu aidanseiväs. Sittapörriäiselle ominaisella
suoraviivaisella yksitoikkoisuudella lentää pörriäinen päänsä
aidanseipääseen ja makaa seuraavassa silmänräpäyksessä maassa
selällään, sääriään sätkytellen ja odotellen onnenpotkausta, joka
kääntäisi sen jälleen luonnolliseen asentoonsa, jotta se pääsisi taas
lentoon ja seuraavaa aidanseivästä etsimään. (Siitä on syntynyt
aatepitoinen sananlasku: »Käypä yhtyy johonkin, sanoi sittapörri,
kun päänsä seipääseen lensi».)
 Enemmän kuin neljä vuotta ovat tämän maan oikeauskoiset
kommunistit, jonka ydinjoukon muodostavat ne punakaartilaiset,
jotka eivät osaa ottaa terveellistä oppia yhdestä eikä
useammastakaan vakavahenkisestä elämäntapahtumasta,
odottaneet silmä kovana vallankumousta. Sekä paikallista että
yleismaailmallista.

Ryssät, jotka maailman sivu ovat pitäneet tyhmempiään

narreinaan ja kyntäneet hulluilla, ovat elättäneet ja ruokkineet
Suomen kommunistipuoluetta henkisesti ja aineellisesti tällä
maailmanvallankumoustoivollaan. Bolshevikkiryssät, jotka eivät ole
pitkään aikaan enää itse uskoneet tuohon heidän heleillä
punaväreillä maalailemaansa yleismaailmalliseen kumoukseen —
jos ovat tosissaan uskoneet milloinkaan — ovat olleet onnellisia
voidessaan löytää aivan Rajajoen takana taajalukuisen lauman
sellaisia pässinpäitä, jotka jaksavat uskoa mainittuun uneen,
sittenkun kaikki muut kokomaailman pöllötkin ovat lakanneet siihen
uskomasta. Nämä jalot, mutta kokolailla naurettavat uskonsankarit
ovat suomalaisia kommunisteja. Niistä ei karise usko muuten kuin
jos he joutuvat sinne Ryssän paratiisiin. Mutta sitten se kariseekin
niistä vähän jumalattoman nopeasti.

Näyttää kuitenkin siltä, että meidänkin sitkeä kurkemme alkaa

pitkistyä odotukseen. Tietysti ei se vieläkään epäile näkevänsä sitä
autuasta päivää, jolloin nirri on otettu pois viimeiseltä porvarilta, ja
eloonjätetyt nosket raastavat kahle kintussa kommunistien orjina,
jotka viimeksimainitut luonnollisesti ovat kaikki komissaareja.

Mutta viidettä vuotta odotettuaan päivästä päivään tuota uutta

yleistä hulinaa, luvattuaan joukoille sen tuloa ihan just-justiinsa
siinäpaikassa ja hohotettuaan kylmää kommunistinaurua kaikille
noskeille ja heidän parlamenttaarisuudelleen, ovat kommunistit,
olojen Venäjällä kehittyessä yhä kepulimmiksi, oikealla
kommunistisella ympäripyörähdyksellä kääntyneet itsekin
parlamenttarismin poluille.

Ja ottavat he nyt omana puolueena osaa eduskuntavaaleihin.

Väärinkäsitysten välttämiseksi he tosin suhkavat joukkojensa

korviin, että tarkoitus on vain kenkkuilla myöskin eduskunnassa ja
siunatun »vallankumouksen» hyväksi. Mutta tosiasia on, että
kommunistiagitaattoreille tulee näistäpuolin pitkä nälkä ja hoitajansa
laiminlyömän kilin ajatukset, elleivät he mitä pikimmin pääse
eduskunnan leipiin.

Se on aivan samantekevää, mitä he vaalikiihoituksessaan

sohlaavat vallankumouksesta, sotaväestä, suojeluskunnista ja
»ohranasta». Se on pantu vain palstan täytteeksi, pääasia on, että
joukko jäätyneelle suolle jääneitä nälkäkurkia pääsisi taas vähän
varmemmalle ja aivan porvarilliselle taloudelliselle pohjalle.

Mutta voi vaivaisia niitä yksinkertaisia harjastukkaisia

proletäärijoukkoja, jotka haaskaavat kalliin äänioikeutensa moisen
sakin hyväksi!

Pimitetyn kansan silmät aukenevat kyllä lopuksi.

Vähän hitaasti ne tosin aukenevat niinkuin sokeana syntyneen

kissanpoikasen silmät. Mutta aukenevat kumminkin.

Se on ainakin vankka toivomme.

(1922.)
TRI PERETTIN KÄSILAUKKU

Tohtori Perettin käsilaukusta ei vieläkään kuulu sen enempää.

Ei ainakaan allekirjoittanut ole mistään huomannut, että se olisi

löytynytkään.

Ja bolshevikit, ollen kaikkien rosvojen ja varkaiden ystäviä ja

hengenheimolaisia, ovat nyt jo useampia viikkoja olleet kovasti
huolissaan ei tri Perettin vaan varkaan vuoksi.

Emme tiedä, onko Peretti itse bolshevikki, mutta ainakin kuuluu

hän ryssien terveydenhoitokomissariaattiin. Hän oli ollut matkoilla
nälkäalueella, ja oli matkalla takaisin Moskovaan.

Hänellä oli muassaan käsilaukku, jota hän säilytti kuin

silmäteräänsä, mutta Jaroslavin asemalla jätti hän sen hetkeksi
kädestään, ja silloin se varastettiin. Tietysti.

Tri Peretti nosti heti helun ja meni valittamaan ensimmäiselle

komissariolle, jonka käsiinsä sai.

— Mikä on hätänä, hospodin tavaristsh? kysyi komissario.

— Varastivat, ryökäleet, minun käsilaukkuni!

 — Ikävä asia, toveri, sanoi komissario, sivellen punertavaa
partaansa.
— Mutta semmoista sattuu. Ihmeellistä kyllä, sattuu semmoista
täällä
Neuvosto-Venäjälläkin. Mutta minkäs sille tekee?

— Varas on otettava kiinni! huusi tri Peretti kiihtyneenä.

— Aa! toveri! nauroi komissario. — Helposti sanottu: ota kiinni!

Mutta
Venäjänmaa on suuri ja avara… kuin rannaton meri. Kuljet, kuljet,
a ei tule laitaa vastaan. Ja väkeä on paljon, sata miljoonaa sielua.
Kuinka otat kiinni? Näytä meille varas, ka kohta otamme kiinni.

— Minä valitan tästä Moskovassa! sanoi hra Peretti vihaisesti.

— Mistä?

— Varkaudesta!

— Käsilaukun varkaudesta?

— Niin juuri!

Komissario nauroi. Kädellään huiskautti:

— Vot valita, veikkonen! Valita varkaudesta Moskovassa! Ha ha

ha!

Tri Peretti saapui Moskovaan.

Kiiruhti korkeimpaan paikkaan mihin pääsi.

 Valituksen teki: semmoinen ja semmoinen oli asia. Käsilaukun
varastivat!

Bolshevikit nauroivat:

— Olisit pitänyt paremmin silmällä! Yksilö laukku meillä on

varastettu! Meikäläiset varastivat koko Venäjän, eikä tullut sen
kummempaa, sinä, veikkonen, semmoisen metelin siitä
käsilaukustasi… juokse suolle!

— Tiedättekö, mitä siinä käsilaukussa oli? kysyi tri Peretti.

— Kuinkas sen voisimme tietää, veliseni? Kukaties kultaa,

jalokiviä… kukaties vain yöpaita ja hammasharja.

— Ei, sanoi tri Peretti. — Siinä oli viljeltyjä lavantaudin basilleja

tieteellisiä tutkimuksia varten. Miljardeja basilleja. Elinvoimaisia,
parhaassa kunnossa olevia basilleja. Jos ne pääsevät irti, niin
saattaa tapahtua, että puolet Neuvosto-Venäjän väestöstä saadaan
haudata.

Silloin muuttui ääni bolshevikkien kellossa.

Syntyi suuri hälinä.

Bolshevikkien sähkösanomatoimisto sai tehtäväkseen määrätä

kaikki lehdet varoittamaan varasta.

Sillä kannalla ovat asiat.

Eikä tri Perettin käsilaukusta ole mitään kuulunut.

Bolshevikeilla on nyt n.s. kylmä rengas: