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 SECOND
EDITION

“T he first edition of the Clinical Manual of Psychopharmacology in the Medically

in the Medically Ill

Clinical Manual of Psychopharmacology
Ill was an instant must have for all psychiatrists, whether or not they treat pa-
tients with comorbid medical conditions. The updated second edition is even better,
another must have book for all psychiatrists. The evidence supporting the use for or
against a medication in a particular medical illness is reviewed succinctly. I particularly
liked the Key Points at the end of each chapter because they provided a summary of
the take-home messages. Congratulations to the authors and editors for producing
such a valuable textbook.”
Philip R. Muskin, M.D., M.A., DLFAPA, Professor of Psychiatry at CUMC;
Clinical Manual of
Chief of Service, Consultation-Liaison Psychiatry, NYPH-Columbia Campus/

Psychopharmacology
Allen, Lawrence & Milstein Hospitals; and Chair, APA 2017 Scientific Program
Committee

“C linical Manual of Psychopharmacology in the Medically Ill is a timely, highly

pragmatic, thorough, and essential volume for psychosomatic medicine (PSM).
Thoughtfully dedicated to their late colleague and collaborator, James Owen (who in the Medically Ill
was an author on several chapters and coeditor of the first edition), the book takes
a clinically and scientifically grounded approach to the myriad challenges of the
management of comorbid psychiatric and systemic illness. This volume should be
available to every PSM psychiatry service and should also be of interest to the general
psychiatrist who is expected to function in a PSM role on occasion.” S EC O N D E D I T I O N
James A. Bourgeois, O.D., M.D., Clinical Professor, Psychiatry, Weill Institute
for Neurosciences; Department of Psychiatry/Langley Porter Psychiatric Insti-
tute, University of California, San Francisco, San Francisco, California

About the Editors

James L. Levenson, M.D., is Professor of Psychiatry, Medicine, and Surgery and Vice-
Chair for Clinical Services in the Department of Psychiatry at Virginia Commonwealth
University School of Medicine in Richmond, Virginia.

Stephen J. Ferrando, M.D., is Professor of Psychiatry and Chairman of the Depart-

ment of Psychiatry at Westchester Medical Center Health Network of New York Medical
College in Valhalla, New York.
Levenson
Ferrando

Edited by
James L. Levenson, M.D.
Stephen J. Ferrando, M.D.
 Clinical Manual of
Psychopharmacology
in the Medically Ill
Second Edition
 Clinical Manual of
Psychopharmacology
in the Medically Ill
Second Edition

Edited by

James L. Levenson, M.D.

Stephen J. Ferrando, M.D.
Note: The authors have worked to ensure that all information in this book is accurate at
the time of publication and consistent with general psychiatric and medical standards, and
that information concerning drug dosages, schedules, and routes of administration is
accurate at the time of publication and consistent with standards set by the U.S. Food and
Drug Administration and the general medical community. As medical research and practice
continue to advance, however, therapeutic standards may change. Moreover, specific
situations may require a specific therapeutic response not included in this book. For these
reasons and because human and mechanical errors sometimes occur, we recommend that
readers follow the advice of physicians directly involved in their care or the care of a member
of their family.
Books published by American Psychiatric Association Publishing represent the findings,
conclusions, and views of the individual authors and do not necessarily represent the policies
and opinions of American Psychiatric Association Publishing or the American Psychiatric
Association.
If you wish to buy 50 or more copies of the same title, please go to www.appi.org/
specialdiscounts for more information.
Copyright © 2017 American Psychiatric Association Publishing
ALL RIGHTS RESERVED
Second Edition
Manufactured in the United States of America on acid-free paper
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American Psychiatric Association Publishing
1000 Wilson Boulevard
Arlington, VA 22209-3901
www.appi.org
Library of Congress Cataloging-in-Publication Data
Names: Levenson, James L., editor. | Ferrando, Stephen J., editor. | American Psychiatric
Association, issuing body.
Title: Clinical manual of psychopharmacology in the medically ill / edited by James L.
Levenson, Stephen J. Ferrando.
Description: Second edition. | Arlington, Virginia : American Psychiatric Association
Publishing, [2017] | Includes bibliographical references and index.
Identifiers: LCCN 2016026422 (print) | LCCN 2016027149 (ebook) | ISBN
9781585625017 (pb : alk. paper) | ISBN 9781615371075 ()
Subjects: | MESH: Psychotropic Drugs—pharmacokinetics | Psychotropic Drugs—adverse
effects | Drug Interactions | Comorbidity
Classification: LCC RM315 (print) | LCC RM315 (ebook) | NLM QV 77.2 | DDC 615/
.78—dc23
LC record available at https://lccn.loc.gov/2016026422
British Library Cataloguing in Publication Data
A CIP record is available from the British Library.
 Contents
Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xiii
Dedication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xix
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . xxi
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xxiii
James L. Levenson, M.D.
Stephen J. Ferrando, M.D.

Part I
General Principles

1 Pharmacokinetics, Pharmacodynamics, and

Principles of Drug-Drug Interactions . . . . . . . . . . . 3
James A. Owen, Ph.D.
Ericka L. Crouse, Pharm.D.
Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Drug-Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
Appendix: Drugs With Clinically Significant
Pharmacokinetic Interactions . . . . . . . . . . . . . . . . . . . . . . 35

2 Severe Drug Reactions . . . . . . . . . . . . . . . . . . . . . 45

E. Cabrina Campbell, M.D.
Stanley N. Caroff, M.D.
Stephan C. Mann, M.D.
Robert M. Weinrieb, M.D.
Rosalind M. Berkowitz, M.D.
Kimberly N. Olson, CRNP
Central Nervous System Reactions . . . . . . . . . . . . . . . . . . 46
Cardiovascular Reactions . . . . . . . . . . . . . . . . . . . . . . . . . 59
Gastrointestinal Reactions . . . . . . . . . . . . . . . . . . . . . . . . . 66
Renal Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
 Hematological Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . 79
Metabolic Reactions and Body as a Whole . . . . . . . . . . . . 82

3 Alternative Routes of Drug Administration . . . . 101

James A. Owen, Ph.D.
Ericka L. Crouse, Pharm.D.
Properties of Specific Routes of Administration . . . . . . . . 103
Psychotropic Medications . . . . . . . . . . . . . . . . . . . . . . . . . 111
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119

Part II
Psychopharmacology in Organ System
Disorders and Specialty Areas
4 Gastrointestinal Disorders . . . . . . . . . . . . . . . . . 129
Catherine C. Crone, M.D.
Michael Marcangelo, M.D.
Jeanne Lackamp, M.D.
Andrea F. DiMartini, M.D.
James A. Owen, Ph.D.
Oropharyngeal Disorders . . . . . . . . . . . . . . . . . . . . . . . . . 130
Esophageal and Gastric Disorders . . . . . . . . . . . . . . . . . . 132
Intestinal Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
Liver Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
Gastrointestinal Side Effects of Psychiatric Drugs . . . . . . 156
Psychotropic Drug–Induced Gastrointestinal
Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
Psychiatric Side Effects of Gastrointestinal
Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
Drug-Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168

5 Renal and Urological Disorders . . . . . . . . . . . . . 195

James L. Levenson, M.D.
James A. Owen, Ph.D.
 Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196
Pharmacotherapy in Renal Disease . . . . . . . . . . . . . . . . . 198
Psychiatric Adverse Effects of Renal and
Urological Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209
Renal and Urological Adverse Effects of
Psychotropics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211
Drug-Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . 214

6 Cardiovascular Disorders . . . . . . . . . . . . . . . . . . 233

Peter A. Shapiro, M.D.
Differential Diagnostic Considerations . . . . . . . . . . . . . . . 234
Neuropsychiatric Side Effects of Cardiac Medications . . . 235
Alterations in Pharmacokinetics in Heart Disease . . . . . . 236
Psychotropic Medication Use in Heart Disease . . . . . . . . 239
Drug-Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . 253

7 Respiratory Disorders . . . . . . . . . . . . . . . . . . . . . 271

Yvette L. Smolin, M.D.
Catherine Daniels-Brady, M.D.
Wendy L. Thompson, M.D.
James L. Levenson, M.D.
Differential Diagnostic Considerations . . . . . . . . . . . . . . . 272
Neuropsychiatric Side Effects of Drugs Used to
Treat Respiratory Diseases. . . . . . . . . . . . . . . . . . . . . . . . 274
Alteration of Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . 278
Effects of Psychotropic Drugs on Pulmonary Function . . . 279
Prescribing Psychotropic Medications in Respiratory
Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282
Drug-Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . 288

8 Oncology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301
Philip A. Bialer, M.D.
Stephen J. Ferrando, M.D.
Shirley Qiong Yan, Pharm.D., BCOP
Differential Diagnosis of Psychiatric Manifestations of
Cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302
 Psychopharmacological Treatment of Psychiatric
Disorders in Cancer Patients . . . . . . . . . . . . . . . . . . . . . . 303
Adverse Oncological Effects of Psychotropics . . . . . . . . . 309
Neuropsychiatric Adverse Effects of Oncology
Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312
Drug-Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . 316

9 Central Nervous System Disorders. . . . . . . . . . . 341

Adam P. Pendleton, M.D., M.B.A.
Jason P. Caplan, M.D.
Dementia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342
Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 348
Traumatic Brain Injury. . . . . . . . . . . . . . . . . . . . . . . . . . . . 350
Multiple Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 352
Parkinson’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 354
Huntington’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357
Epilepsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 358
Symptoms and Syndromes Common Across
Neurological Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . 360
Adverse Neurological Effects of Psychotropic
Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 362
Adverse Psychiatric Effects of Neurological
Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 365
Drug-Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . 368

10 Endocrine and Metabolic Disorders . . . . . . . . . . 389

Stephen J. Ferrando, M.D.
Sahil Munjal, M.D.
Jennifer Kraker, M.D., M.S.
Diabetes Mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391
Thyroid Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393
Pheochromocytoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396
Antidiuretic Hormone . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396
Reproductive Endocrine System Disorders . . . . . . . . . . . 397
Hypogonadal Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . 397
 Endocrinological Side Effects of Psychiatric
Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 398
Psychiatric Side Effects of Endocrine Treatments. . . . . . . 406
Drug-Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . 411

11 Obstetrics and Gynecology . . . . . . . . . . . . . . . . . 429

Margaret Altemus, M.D.
Mallay Occhiogrosso, M.D.
Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 430
Pharmacotherapy of Premenstrual Mood
Symptoms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 433
Pharmacotherapy of Menopause-Related Depression,
Anxiety, and Insomnia . . . . . . . . . . . . . . . . . . . . . . . . . . . 434
Psychopharmacology in Pregnancy and
Breastfeeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 435
Adverse Obstetric and Gynecological Reactions to
Psychotropic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 450
Psychiatric Effects of Obstetric and Gynecological
Agents and Procedures . . . . . . . . . . . . . . . . . . . . . . . . . . 451
Drug-Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . 454

12 Infectious Diseases . . . . . . . . . . . . . . . . . . . . . . . 471

Christopher P. Kogut, M.D.
Stephen J. Ferrando, M.D.
James L. Levenson, M.D.
James A. Owen, Ph.D.
Bacterial Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 472
Viral Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 474
Treatment of Psychiatric Symptoms in Patients With
HIV/AIDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 490
Viral Infections Other Than HIV . . . . . . . . . . . . . . . . . . . . 497
Parasitic Infections: Neurocysticercosis . . . . . . . . . . . . . . 499
Adverse Psychiatric Effects of Antibiotics . . . . . . . . . . . . . 499
Drug-Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . 499
13 Dermatological Disorders . . . . . . . . . . . . . . . . . . 515
Madhulika A. Gupta, M.D., FRCPC
James L. Levenson, M.D.
Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 517
Pharmacotherapy of Specific Disorders . . . . . . . . . . . . . . 521
Adverse Cutaneous Drug Reactions to Psychotropic
Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 529
Adverse Psychiatric Effects of Dermatological Agents . . . 535
Drug-Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . 538

14 Rheumatological Disorders . . . . . . . . . . . . . . . . . 555

James L. Levenson, M.D.
Stephen J. Ferrando, M.D.
Treatment of Psychiatric Disorders . . . . . . . . . . . . . . . . . . 556
Psychiatric Side Effects of Rheumatological
Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 557
Rheumatological Side Effects of Psychotropic
Medications: Psychotropic Drug–Induced Lupus . . . . . . . 559
Drug-Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . 560

15 Surgery and Critical Care. . . . . . . . . . . . . . . . . . . 565

James L. Levenson, M.D.
Stephen J. Ferrando, M.D.
James A. Owen, Ph.D.
Delirium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 566
Psychotropic Drugs in the Perioperative Period . . . . . . . . 573
Treatment of Preoperative Anxiety . . . . . . . . . . . . . . . . . . 575
Acute and Posttraumatic Stress in the Critical
Care Setting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 577
Adverse Neuropsychiatric Effects of Critical Care and
Surgical Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 578
Drug-Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . 580
16 Organ Transplantation . . . . . . . . . . . . . . . . . . . . . 597
Marian Fireman, M.D.
Andrea F. DiMartini, M.D.
Catherine C. Crone, M.D.
Posttransplant Pharmacological Considerations . . . . . . . 598
Psychotropic Medications in Transplant Patients . . . . . . . 603
Drug-Specific Issues. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 614
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 621

17 Pain Management . . . . . . . . . . . . . . . . . . . . . . . . . 633

Michael R. Clark, M.D., M.P.H., M.B.A.
J. Greg Hobelmann, M.D., M.P.H.
James L. Levenson, M.D.
Psychiatric Comorbidity . . . . . . . . . . . . . . . . . . . . . . . . . . 634
Pain Description and Management. . . . . . . . . . . . . . . . . . 636
Pharmacological Treatment . . . . . . . . . . . . . . . . . . . . . . . 644
Drug-Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . 656

18 Substance Use Disorders . . . . . . . . . . . . . . . . . . 675

Jozef Bledowski, M.D.
Substance Intoxication . . . . . . . . . . . . . . . . . . . . . . . . . . . 676
Substance Use Disorders . . . . . . . . . . . . . . . . . . . . . . . . . 678
Neuropsychiatric Effects of Drugs Used for
Substance-Related Disorders. . . . . . . . . . . . . . . . . . . . . . 699
Drug-Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . 699

Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 713
 Contributors
Margaret Altemus, M.D.
Associate Professor, Department of Psychiatry, Yale University School of Med­
icine, and VA Connecticut Health Care System, West Haven, Connecticut

Rosalind M. Berkowitz, M.D.

Private Practice, Hematology and Oncology, Moorestown, New Jersey

Philip A. Bialer, M.D.

Attending Psychiatrist, Memorial Sloan Kettering Cancer Center; Associate
Professor of Clinical Psychiatry, Weill Cornell Medical College, New York,
New York

Jozef Bledowski, M.D.

Assistant Professor of Psychiatry and Director, STAT/Crisis Stabilization Ser­
vice, Virginia Commonwealth University Health System, Richmond, Vir­
ginia

E. Cabrina Campbell, M.D.

Director, Inpatient Psychiatry, Corporal Michael J. Crescenz Veterans Affairs
Medical Center; Associate Professor of Psychiatry, Perelman School of Medi­
cine at the University of Pennsylvania, Philadelphia, Pennsylvania

Jason P. Caplan, M.D.

Professor and Chair of Psychiatry, Creighton University School of Medicine–
Phoenix Campus, Phoenix, Arizona

Stanley N. Caroff, M.D.

Emeritus Professor of Psychiatry, Perelman School of Medicine at the Univer­
sity of Pennsylvania, Philadelphia, Pennsylvania

xiii
xiv Clinical Manual of Psychopharmacology in the Medically Ill

Michael R. Clark, M.D., M.P.H., M.B.A.

Vice Chair, Clinical Affairs, and Director, Adolf Meyer Chronic Pain Treat­
ment Programs, Department of Psychiatry and Behavioral Sciences, The
Johns Hopkins Medical Institutions, Baltimore, Maryland

Catherine C. Crone, M.D.

Associate Professor of Psychiatry, George Washington University Medical
Center, Washington, D.C.; Vice Chair, Department of Psychiatry, Inova Fair­
fax Hospital, Falls Church, Virginia; Clinical Professor of Psychiatry, Virginia
Commonwealth University School of Medicine, Northern Virginia Branch,
Fairfax, Virginia

Ericka L. Crouse, Pharm.D.

Clinical Pharmacy Specialist—Psychiatry; Clinical Associate Professor, De­
partments of Pharmacy and Psychiatry; Director, PGY2 Psychiatric Pharmacy
Residency, Virginia Commonwealth University Medical Center, Richmond,
Virginia

Catherine Daniels-Brady, M.D.

Assistant Clinical Professor, Department of Psychiatry and Behavioral Sci­
ence, New York Medical College at Westchester Medical Center, Valhalla,
New York

Andrea F. DiMartini, M.D.

Professor of Psychiatry and Professor of Surgery, Western Psychiatric Institute;
Consultation Liaison to the Liver Transplant Program, Starzl Transplant In­
stitute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania

Stephen J. Ferrando, M.D.

Professor and Chairman, Department of Psychiatry, Westchester Medical
Center Health Network, New York Medical College, Valhalla, New York

Marian Fireman, M.D.

Clinical Professor of Psychiatry, Oregon Health & Science University, Port­
land, Oregon
 Contributors xv

Madhulika A. Gupta, M.D., FRCPC

Professor, Department of Psychiatry, Schulich School of Medicine and Den­
tistry, University of Western Ontario, London, Ontario, Canada

J. Greg Hobelmann, M.D., M.P.H.

Chief Resident, Department of Psychiatry and Behavioral Sciences, The
Johns Hopkins Medical Institutions, Baltimore, Maryland

Christopher P. Kogut, M.D.

Assistant Professor, Department of Psychiatry, Virginia Commonwealth Uni­
versity, Richmond, Virginia

Jennifer Kraker, M.D., M.S.

Private Practice in Psychiatry, New York, New York

Jeanne Lackamp, M.D.

Assistant Professor, Department of Psychiatry, and Director, Division of Psy­
chiatry and Medicine, University Hospitals Case Medical Center, Cleveland,
Ohio

James L. Levenson, M.D.

Rhona Arenstein Professor of Psychiatry and Professor of Medicine and Sur­
gery and Vice-Chair of Psychiatry, Virginia Commonwealth University
School of Medicine, Richmond, Virginia

Stephan C. Mann, M.D.

Lenape Valley Foundation, Doylestown, Pennsylvania

Michael Marcangelo, M.D.

Associate Professor, Department of Psychiatry and Behavioral Neuroscience,
and Director of Medical Student Education in Psychiatry, Pritzker School of
Medicine, University of Chicago, Chicago, Illinois

Sahil Munjal, M.D.

Resident in Psychiatry, New York Medical College, Valhalla, New York
xvi Clinical Manual of Psychopharmacology in the Medically Ill

Mallay Occhiogrosso, M.D.

Clinical Assistant Professor, Department of Psychiatry, Weill Cornell Medical
College, New York, New York

Kimberly N. Olson, CRNP

PENN Rodebaugh Diabetes Center, Clinical Practices of the University of
Pennsylvania, Philadelphia, Pennsylvania

James A. Owen, Ph.D. (deceased)

Associate Professor, Department of Psychiatry and Department of Pharma­
cology and Toxicology, Queen’s University; Director of Psychopharmacology,
Providence Care Mental Health Services, Kingston, Ontario, Canada

Adam P. Pendleton, M.D., M.B.A.

Chief Resident for Inpatient Services, Department of Psychiatry, Vanderbilt
University School of Medicine, Nashville, Tennessee

Peter A. Shapiro, M.D.

Professor of Psychiatry at Columbia University Medical Center, Columbia
University; Director, Fellowship Training Program in Psychosomatic Medi­
cine; Associate Director, Consultation-Liaison Psychiatry Service, New York
Presbyterian Hospital–Columbia University Medical Center, New York, New
York

Yvette L. Smolin, M.D.

Director, Psychosomatic Medicine Service and Fellowship, Department of
Psychiatry and Behavioral Science, New York Medical College at Westchester
Medical Center, Valhalla, New York

Wendy Thompson, M.D.

Clinical Professor, Department of Family and Community Medicine, New
York Medical College at Westchester Medical Center, Valhalla, New York
 Contributors xvii

Robert M. Weinrieb, M.D.

Director, Psychosomatic Medicine and Psychosomatic Medicine Fellowship
Program, and Associate Professor of Psychiatry, Perelman School of Medicine
at the University of Pennsylvania, Philadelphia, Pennsylvania

Shirley Qiong Yan, Pharm.D., BCOP

Pediatric Hematology/Oncology Clinical Pharmacy Specialist, Department
of Pharmacy, Memorial Sloan Kettering Cancer Center, New York, New York

Disclosure of Interests
The following contributors to this book have indicated a financial interest in or
other affiliation with a commercial supporter, a manufacturer of a commercial
product, a provider of a commercial service, a nongovernmental organization,
and/or a government agency, as listed below:
E. Cabrina Campbell, M.D. Grant: Sunovion.
Stanley N. Caroff, M.D. Research Grant: Sunovion. Consultant: Auspex.
The following contributors to this book have no competing interests to re­
port:
Rosalind M. Berkowitz, M.D.; Jozef Bledowski, M.D.; Catherine C.
Crone, M.D.; Stephen J. Ferrando, M.D.; Marian Fireman, M.D.; Madhu­
lika A. Gupta, M.D., FRCPC; James L. Levenson, M.D.; Stephan C. Mann,
M.D.; Kimberly N. Olson, CRNP; Wendy L. Thompson, M.D; Robert M.
Weinrieb, M.D.; Shirley Qiong Yan, Pharm.D., BCOP
 Dedication

The editors would like to dedicate this edition of the manual to James
Owen, Ph.D., our former coeditor and friend. Jim was diagnosed with a se­
vere cardiomyopathy shortly after the publication of the first edition and
passed away prematurely on November 7, 2013. As was always our experience
of Jim, he dealt with his illness in a steadfast and calm manner. Jim was the
consummate gentleman and scholar. He was instrumental not only in provid­
ing the highest-quality information on psychopharmacology but also in ce­
menting and motivating our editorial team, always with energy and
enthusiasm. The pleasure he took in the academic aspects of psychopharma­
cology was infectious, with a lasting impact on both of us, as was his dedica­
tion to the highest quality and safety of patient care. We have missed him
greatly in the preparation of this edition of the manual, although his presence
continues to be felt both in content and in spirit.

James L. Levenson, M.D.

Stephen J. Ferrando, M.D.

xix
 Acknowledgments

The editors would collectively like to acknowledge multiple individuals for

their support, encouragement, and thoughtful input during the preparation
of this book. We thank our original contributors, who have undertaken to up­
date their original contributions, and welcome our newest authors for their
high-quality contributions. We continue to appreciate the wisdom and dedi­
cation of Dr. Robert E. Hales, Editor-in-Chief of American Psychiatric Asso­
ciation (APA) Publishing, as well as John McDuffie and the editorial staff of
APA Publishing, for their enthusiastic encouragement to produce a second
edition.
Dr. Levenson would like to thank his wife and family for their support and
his father, Milton Levenson, whose lifelong dedication to his profession has
been an inspiration throughout his own.
Dr. Ferrando would like to thank his wife, Maria, and his children, Luke,
Nicole, Marco, and David, for all of their support.

xxi
 Introduction
James L. Levenson, M.D.
Stephen J. Ferrando, M.D.

The mission of this second edition is the very same as the first: to serve as
a clinical manual and educational tool for specialist and nonspecialist clini­
cians for the psychopharmacological treatment of patients with medical ill­
ness. There was great interest in the first edition, with the first printing selling
out in less than a year. We are pleased that many fellowship programs ap­
proved by the Accreditation Council for Graduate Medical Education have
adopted this book as a core reference and text for teaching the principles and
practice of prescribing psychotropic medication to psychiatrically and medi­
cally ill patients. Further, physicians in other specialties of medicine, includ­
ing primary care specialties, have found the manual to be useful.
Since the publication of the first edition, the importance of the co-occurrence
of psychiatric and medical illness has become even more evident. There is in­
creasing recognition that patients with medical and psychiatric comorbidity
have more functional impairment, disability days, emergency department use,
rehospitalization, and other medical care costs than do those without such co­
morbidity (Druss and Reisinger Walker 2011). Government-based reform ef­
forts, such as the Delivery System Reform Incentive Payment Program (New
York State Department of Health 2016) in New York State, have begun to in­
centivize health care systems to develop new and innovative models of popu­
lation-based care that integrate medical and psychiatric care in an effort to
increase quality and prevention while decreasing use of expensive services such

xxiii
xxiv Clinical Manual of Psychopharmacology in the Medically Ill

as emergency department visits and hospitalizations. In this context, a broader

array of physician and nonphysician practitioners will be called on to pre­
scribe psychiatric medications to individuals with medical illness, taking into
account neuropsychiatric, metabolic, and other side effects as well as drug­
drug and drug-disease interactions. Of further importance is the fact that out­
patient practitioners will be called on to take care of sicker patients more than
ever before, making issues of safe prescribing even more critical. It is our hope
that this manual will continue to fill a key need for up-to-date and practical
information.

How to Use This Manual

The organization of the second edition is the same as the first. We aim to pro­
vide clinically relevant information regarding psychopharmacology in patients
who are medically ill, including pharmacokinetic and pharmacodynamic prin­
ciples, drug-drug interactions, and organ system disease–specific issues. Chap­
ters are authored and updated by experts in the field, with editorial input to
maintain consistency of format and style.
The manual has two sections. Part I, “General Principles,” provides fun­
damental background information for prescribing psychotropic drugs across
medical disease states and is suggested reading prior to advancing to the dis­
ease-specific information in the second section. Part I includes discussion of
pharmacodynamics and pharmacokinetics, principles of drug-drug interac­
tions, major systemic adverse effects of psychotropic drugs, and alternative
routes of psychotropic drug administration.
Part II, “Psychopharmacology in Organ System Disorders and Specialty
Areas,” includes chapters on psychopharmacological treatment in specific or­
gan system diseases, such as renal and cardiovascular disease, as well as other
relevant subspecialty areas, such as critical care, organ transplantation, pain,
and substance use disorders. With some variation, chapters are structured to
include the following elements: key differential diagnostic considerations, in­
cluding adverse neuropsychiatric side effects of disease-specific medications;
disease-specific pharmacokinetic principles in drug prescribing; review of ev­
idence for psychotropic drug treatment of psychiatric disorders in the specific
disease state or specialty area; disease-specific adverse psychotropic drug side
 Introduction xxv

effects; and interactions between psychotropic drugs and disease-specific

drugs. Each chapter has tables that summarize information on adverse neuro­
psychiatric side effects of disease-specific medications, adverse disease-specific
side effects of psychotropic drugs, and drug-drug interactions. Chapters are
heavily referenced with source information should readers wish to expand
their knowledge in a specific area. Finally, each chapter ends with a list of key
summary points pertaining to psychotropic prescribing in the specific medical
disease(s) or specialty area covered in the chapter.
With this structure, we hope that we have contributed a comprehensive
yet practical guide for psychotropic prescribing for patients who are medically
ill. We will consider this manual a success if it proves useful for a broad range
of specialists, such as the psychosomatic medicine specialist caring for a delir­
ious patient with cancer, the general psychiatrist in the community mental
health clinic whose patient with schizophrenia develops liver disease in the set­
ting of alcohol dependence and hepatitis C infection, and the general medical
practitioner prescribing an antidepressant to a diabetic patient who recently
had a myocardial infarction. We hope that this manual, beyond serving as a
clinical guide, will also become a mainstay of curricula in general psychiatric
residency programs, in psychosomatic medicine fellowships, and in nonpsy­
chiatric residency training programs that seek to provide training in psycho­
pharmacology for medically ill patients.

References
Druss BG, Reisinger Walker R: Mental Disorders and Medical Comorbidity. Research
Synthesis Report No 21. Princeton, NJ, The Synthesis Project, Robert Wood
Johnson Foundation, February 2011. Available at: www.integration.samhsa.gov/
workforce/mental_disorders_and_medical_comorbidity.pdf. Accessed February
21, 2016.
New York State Department of Health: Delivery System Reform Incentive Payment
(DSRIP) Program. Available at: www.health.ny.gov/health_care/medicaid/redesign/
dsrip/. Accessed February 21, 2016.
 PA R T I

General Principles
 1
Pharmacokinetics,
Pharmacodynamics, and
Principles of Drug-Drug
Interactions
James A. Owen, Ph.D.
Ericka L. Crouse, Pharm.D.

Psychotropic drugs are commonly employed in the management of pa­

tients who are medically ill. At least 35% of psychiatric consultations include
recommendations for medication (Bronheim et al. 1998). The appropriate
use of psychopharmacology in medically ill patients requires careful consider­
ation of the underlying medical illness, potential alterations to pharmacoki­
netics, drug-drug interactions, and contraindications. In this chapter, we
review drug action, drug pharmacokinetics, and drug interactions to provide

3
4 Clinical Manual of Psychopharmacology in the Medically Ill

a basis for drug-drug and drug-disease interactions presented in later disease­

specific chapters.
The effects of a drug—that is, the magnitude and duration of its therapeutic
and adverse effects—are determined by the drug’s pharmacodynamic and phar­
macokinetic characteristics. Pharmacodynamics describes the effects of a drug on
the body. Pharmacodynamic processes determine the relationship between drug
concentration and response for both therapeutic and adverse effects. Pharma­
cokinetics describes what the body does to the drug. It characterizes the rate and
extent of drug absorption, distribution, metabolism, and excretion. These phar­
macokinetic processes determine the rate of drug delivery to and the drug’s con­
centration at the sites of action. The relationship between pharmacokinetics
and pharmacodynamics is diagrammed in Figure 1–1.

Pharmacodynamics
For most drugs, the pharmacological effect is the result of a complex chain of
events, beginning with the interaction of drug with receptor. Pharmacody­
namic response is further modified—enhanced or diminished—by disease
states, aging, and other drugs. For example, the presence of Parkinson’s disease
increases the incidence of movement disorders induced by selective serotonin
reuptake inhibitors. Pharmacodynamic disease-drug interactions are reviewed
in the relevant chapters; pharmacodynamic drug-drug interactions are dis­
cussed later in this chapter in the subsection “Pharmacodynamic Drug Inter­
actions.”
A drug’s spectrum of therapeutic and adverse effects is due to its interac­
tion with multiple receptor sites. The effects produced depend on which re­
ceptor populations are occupied by the drug; some receptor populations are
readily occupied at low drug concentrations, whereas other receptor sites require
high drug levels for interaction. In this way, different responses are recruited in
a stepwise manner with increasing drug concentration. As drug levels increase,
each effect will reach a maximum as all active receptors responsible for that ef­
fect are occupied by the drug. Further increases in drug concentration cannot
increase this response but may elicit other effects. Figure 1–2 illustrates three
pharmacological effects produced by a drug in a concentration-dependent
 Pharmacokinetics Pharmacodynamics
What the body is doing to the drug What the drug is doing to the body

Drug in
tissues of
distribution

Drug in Drug at site

Dose of drug Bioavailability systemic
administered of action
circulation
Pharmacological
effect

Drug
metabolized
or excreted
Pharmacokinetics and Pharmacodynamics

Figure 1–1. Relationship between pharmacokinetics and pharmacodynamics.

5
 Therapeutic range of
concentrations

Minimum therapeutic Minimum toxic

concentration concentration

100%

R
e
s Effect A Effect B Effect C
p Adverse effect Therapeutic Toxic effect
o effect
n
s
e
6 Clinical Manual of Psychopharmacology in the Medically Ill

Drug concentration at site of action

Figure 1–2. Concentration-response relationship (see text for details).

 Pharmacokinetics and Pharmacodynamics 7

manner. In this example, Effect B is the primary therapeutic effect, Effect A is

a minor adverse effect, and Effect C is a significant toxic effect. Low drug con­
centrations recruit only Effect A; the patient experiences a nuisance side effect
without any therapeutic gain. As drug concentration increases, Effect B is en­
gaged, and Effect A is maximized. Clearly, for this drug, except in the rare sit­
uation where Effect B antagonizes Effect A (e.g., where the initial sedating
effect of a drug is counteracted by stimulating effects recruited at a higher con­
centration), Effect A will always accompany a therapeutically effective dose
because it is recruited at a lower concentration than that required for the ther­
apeutic effect. Further increases in drug concentration improve the therapeu­
tic effect until reaching its maximum, but these increases also introduce toxic
Effect C.
Optimum therapy requires that drug concentrations be confined to a
therapeutic range to maximize the therapeutic effect and minimize any ad­
verse and/or toxic effects. Developing a dosage regimen to maintain drug lev­
els within this therapeutic range requires consideration of pharmacokinetic
processes.
Drug-receptor interactions produce effects on several timescales. Immediate
effects are the result of a direct receptor interaction. Several psychoactive drugs,
including benzodiazepines, have immediate therapeutic effects and therefore are
useful on an acute or as-needed basis. However, many psychoactive drugs, such
as antidepressant and antipsychotic agents, require chronic dosing over several
weeks for a significant therapeutic response. These drugs appear to alter neu­
ronal responsiveness by modifying slowly adapting cellular processes. Unfor­
tunately, many adverse effects appear immediately—the result of a direct
receptor interaction. Medication adherence may be eroded when adverse ef­
fects are experienced before therapeutic effects are realized. Table 1–1 lists
strategies to maximize medication adherence.

Pharmacokinetics
Drug response, including the magnitude and duration of the drug’s therapeu­
tic and adverse effects, is significantly influenced by the drug’s pharmacoki­
netics (absorption from administration sites, distribution throughout the
body, and metabolism and excretion). Individual differences in constitutional
8 Clinical Manual of Psychopharmacology in the Medically Ill

Table 1–1. Strategies to maximize medication

adherence
Provide patient education
Inform the patient about potential adverse effects, their speed of onset, and whether
tolerance will develop over time.
Indicate the time for onset of the therapeutic effect. Many psychotropic drugs have a
considerable delay (weeks) before the appearance of significant therapeutic effects
yet give rise to adverse effects immediately. Patients not aware of this temporal
disconnect between adverse and therapeutic effects may consider the medication a
failure and discontinue the drug if only adverse effects and no therapeutic effects
are initially experienced.
Select drugs with a convenient dosing schedule
Select drugs with once-daily dosing (i.e., those with a suitably long half-life or
available in an extended-release formulation) to maximize adherence.
Consider the use of long-acting injectable formulations for antipsychotic agents.
Depending on the agent, they may be dosed every 2 or 4 weeks. A new formulation
of paliperidone palmitate is available as a once every 3 months injection. Adherence
can be confirmed from administration records. However, the patient must have
undergone a successful trial of the equivalent oral formulation to verify therapeutic
response and tolerance to adverse effects and to establish the appropriate dose.
Minimize adverse effects
Select drugs with minimal pharmacokinetic interaction where possible (e.g., avoid
cytochrome P450 inhibitors or inducers).
Gradually increase drug dosage to therapeutic levels over several days or weeks (“start
low, go slow”) so that patients experience minimal adverse effects while gradually
developing tolerance.
Use the minimum effective dose.
Select a drug with an adverse-effect profile the patient can best tolerate. Drugs within
a class may be similar therapeutically but differ in their adverse-effect profile.
Patients may vary in their tolerance of a particular effect.
Reduce peak drug levels following absorption of oral medications. Many adverse
effects are concentration dependent and are exacerbated as drug levels peak
following oral dosing. Consider administering the drug with food or using divided
doses or extended-release formulations to reduce and delay peak drug levels and
diminish adverse effects.
 Pharmacokinetics and Pharmacodynamics 9

Table 1–1. Strategies to maximize medication

adherence (continued)
Minimize adverse effects (continued)
Schedule the dose so the side effect is less bothersome. If possible, prescribe activating
drugs in the morning and sedating drugs or those that cause gastrointestinal distress
in the evening.
Utilize therapeutic drug monitoring
Keep in mind that therapeutic drug monitoring is available for many psychotropic
drugs. This is valuable for monitoring adherence and ensuring that drug levels are
within the therapeutic range.
Check for patient adherence
Schedule office or telephone visits to discuss adherence and adverse effects for newly
prescribed drugs.

factors, compromised organ function, and disease states and the effects of
other drugs and food all contribute to the high variability in drug response ob­
served across patients. Understanding the impact of these factors on a drug’s
pharmacokinetics will aid in drug selection and dosage adjustment in a ther­
apeutic environment complicated by polypharmacy and medical illness.

Absorption and Bioavailability

The speed of onset and, to a certain extent, the duration of the pharmacolog­
ical effects of a drug are determined by the route of administration. Bioavail­
ability of a drug formulation describes the rate and extent of drug delivery to
the systemic circulation from the formulation. Intravenous or intra-arterial
administration delivers 100% of the drug dose to the systemic circulation
(100% bioavailability) at a rate that can be controlled if necessary. For drugs
delivered by other routes, bioavailability is typically less than 100%, often
much less.
Drug absorption is influenced by the characteristics of the absorption site
and the physiochemical properties of a drug. Specific site properties affecting
absorption include surface area, ambient pH, mucosal integrity and function,
and local blood flow, all of which may be altered by, for example, peptic ulcer
disease or inflammatory bowel disease and the drugs used to treat the disease.
10 Clinical Manual of Psychopharmacology in the Medically Ill

Orally administered drugs face several pharmacokinetic barriers that limit

drug delivery to the systemic circulation. Drugs must dissolve in gastric fluids
to be absorbed, and drug dissolution in the stomach and gut may be incom­
plete (e.g., after gastric bypass surgery). Drugs may be acid labile and degrade
in the acidic stomach environment, or they may be partially metabolized by
gut flora. Some medications require food to enhance absorption. For example,
the bioavailability of ziprasidone is enhanced almost twofold with food, and
lurasidone exposure (area under the curve [AUC]) is doubled in the presence
of food. Drugs absorbed through the gastrointestinal tract may be extensively
altered by first-pass metabolism before entering the systemic circulation (see
Figure 1–3). First-pass metabolism refers to the transport and metabolism of
drugs from the gut lumen to the systemic circulation via the portal vein and
liver. Drug passage from the gut lumen to the portal circulation may be lim­
ited by two processes: 1) a P-glycoprotein (P-gp) efflux transport pump,
which serves to reduce the absorption of many compounds (some P-gp sub­
strates are listed in the appendix to this chapter) by countertransporting them
back into the intestinal lumen, and 2) metabolism within the gut wall by cy­
tochrome P450 3A4 (CYP3A4) enzymes. Because P-gp is co-localized with
and shares similar substrate affinity with CYP3A4, drug substrates of
CYP3A4 typically have poor bioavailability. Bioavailability may be further de­
creased by hepatic extraction of drugs as they pass through the liver before
gaining access to the systemic circulation. Sublingual and topical drug admin­
istration minimizes this first-pass effect, and rectal delivery, although often re­
sulting in erratic absorption, may reduce first-pass effect by 50%.
Bioavailability can be markedly altered by disease states and drugs that al­
ter gut and hepatic function. As with the CYP and uridine 5′-diphosphate
glucuronosyltransferase (UGT) enzyme systems involved in drug metabo­
lism, drugs can also inhibit or induce the P-gp transporter. Common P-gp in­
hibitors include paroxetine, sertraline, trifluoperazine, verapamil, and proton
pump inhibitors. Because intestinal P-gps serve to block absorption in the gut,
inhibition of these transporters can dramatically increase the bioavailability of
poorly bioavailable drugs. For example, oral fentanyl absorption in humans is
increased 2.7-fold when the drug is administered with quinidine, a known in­
testinal P-gp inhibitor (Kharasch et al. 2004). P-gp inhibitors are listed in the
appendix to this chapter. For drugs administered chronically, the extent of
drug absorption is the key factor in maintaining drug levels within the thera­
 Portal vein

Liver
Oral dose
P-gp

CYP
3A4
Small
intestine
Bioavailable
drug to
circulation

Gut wall Hepatic

Fecal metabolism metabolism
elimination

First-pass effect

Figure 1–3. First-pass metabolism of orally administered drugs.

Many drugs undergo a first-pass effect as they are absorbed from the intestinal lumen before they are delivered to the systemic circulation.
Pharmacokinetics and Pharmacodynamics

The first-pass effect limits oral bioavailability through countertransport by P-glycoprotein (P-gp) back into the intestinal lumen and by
gut wall (mainly cytochrome P450 3A4 [CYP3A4]) and hepatic metabolism.
11
12 Clinical Manual of Psychopharmacology in the Medically Ill

peutic range. In situations where bioavailability may be significantly altered,

parenteral administration of drugs may be preferable.
Drug formulation, drug interactions, gastric motility, and the character­
istics of the absorptive surface all influence the rate of absorption, a key factor
when rapid onset is desired. Oral medications are absorbed primarily in the
small intestine because of its large surface area. Delayed gastric emptying or
drug dissolution will slow absorption and therefore blunt the rise in drug lev­
els following an oral dose. In this way, the occurrence of transient concentra­
tion-related adverse effects following an oral dose may be reduced by
administering a drug with food, whereas the common practice of dissolving
medications in juice may produce higher peak levels and exacerbate these
transient adverse reactions.

Distribution
Following absorption into the systemic circulation, the drug is distributed
throughout the body in accordance with its physiochemical properties and the ex­
tent of protein binding. Volume of distribution describes the relationship between
the bioavailable dose and the plasma concentration. Lipophilic drugs, including
most psychotropic medications, are sequestered into lipid compartments of the
body. Because of their low plasma concentrations relative to dose, these drugs ap­
pear to have a large volume of distribution. In contrast, hydrophilic drugs (e.g.,
lithium, oxazepam, valproate), being confined mainly to the vascular volume and
other aqueous compartments, have a high plasma concentration relative to dose,
suggesting a small volume of distribution. Volume of distribution is often unpre­
dictably altered by disease-related changes in organ and tissue perfusion or body
composition. Edema (e.g., in congestive heart failure, cirrhosis, nephrotic syn­
drome) causes expansion of the extracellular fluid volume and may significantly
increase the volume of distribution for hydrophilic drugs. Lipophilic drugs expe­
rience an increase in volume of distribution with obesity, which is sometimes iat­
rogenic (e.g., with corticosteroids or antipsychotics), and age-related increases in
body fat. P-gp, a major component of the blood-brain barrier, may limit entry of
drugs into the central nervous system (CNS). Many antiretroviral agents have lim­
ited CNS penetration because they are P-gp substrates (see the appendix to this
chapter). Besides the P-gp efflux transport pump, the blood-brain barrier itself
presents a physical barrier through tight junctions that limits the movement of
agents into the CNS.
 Pharmacokinetics and Pharmacodynamics 13

Most drugs bind, to varying degrees, to the plasma proteins albumin or α1

acid glycoprotein. Acidic drugs (e.g., valproic acid, barbiturates) bind mostly
to albumin, and more basic drugs (e.g., phenothiazines, tricyclic antidepres­
sants, amphetamines, most benzodiazepines) bind to globulins.
Drug in plasma circulates in both bound and free (unbound to plasma
proteins) forms. Generally, only free drug is pharmacologically active. The
amount of drug bound to plasma proteins is dependent on the presence of
other compounds that displace the drug from its protein binding sites (a pro­
tein-binding drug interaction) and the plasma concentration of albumin and
α1 acid glycoprotein. Medical conditions may alter plasma concentrations of
albumin or α1 acid glycoprotein (see Table 1–2) or increase the levels of en­
dogenous displacing compounds. For example, uremia, chronic liver disease,
and hypoalbuminemia may significantly increase the proportion of free drug
relative to total drug in circulation (Dasgupta 2007).
Changes in drug protein binding, either disease induced or the result of a
protein-binding drug interaction, were once considered a common cause of
drug toxicity because therapeutic and toxic effects increase with increasing con­
centrations of free drug. These interactions are now seen as clinically significant
only in very limited cases involving rapidly acting, highly protein bound
(> 80%), narrow therapeutic index drugs with high hepatic extraction
(propafenone, verapamil, and intravenous lidocaine) (Benet and Hoener
2002; Rolan 1994). For drugs with low hepatic extraction, such as warfarin
(Greenblatt and von Moltke 2005) and phenytoin (Tsanaclis et al. 1984) (see
Table 1–3 later in this chapter), metabolism is not limited by hepatic blood
flow, and a reduction in protein binding serves to increase the amount of free
drug available for metabolism and excretion. Consequently, hypoalbuminemia
or the presence of a displacing drug enhances drug elimination, which gener­
ally limits changes in circulating unbound drug levels to only a transient, and
clinically insignificant, increase. (Many warfarin drug interactions previously
thought to be protein-binding interactions are now recognized as pharmaco­
dynamic and CYP2C9 and CYP1A2 metabolic interactions.) However, al­
though free drug levels may remain unchanged, changes in protein binding will
reduce plasma levels of total drug (free+bound fractions). Although of no con­
sequence therapeutically, therapeutic drug monitoring procedures that mea­
sure total drug levels could mislead the clinician by suggesting lower, possibly
subtherapeutic, levels and might prompt a dosage increase with possible toxic
14 Clinical Manual of Psychopharmacology in the Medically Ill

Table 1–2. Conditions that alter plasma levels of albumin and

α1 acid glycoprotein
Decrease albumin
Surgery
Burns
Trauma
Pregnancy
Alcoholism
Sepsis
Bacterial pneumonia
Acute pancreatitis
Uncontrolled diabetes
Hepatic cirrhosis
Nephritis, nephrotic syndrome, and renal failure
Malnutrition
Increase albumin
Hypothyroidism
Decrease α1 acid glycoprotein
Pancreatic cancer
Pregnancy
Uremia
Hepatitis, cirrhosis
Cachexia
Increase α1 acid glycoprotein
Stress response to disease states
Inflammatory bowel disease
 Pharmacokinetics and Pharmacodynamics 15

Table 1–2. Conditions that alter plasma levels of albumin and

α1 acid glycoprotein (continued)
Increase α1 acid glycoprotein (continued)
Acute myocardial infarction
Trauma
Epilepsy
Stroke
Surgery
Burns
Cancer (except pancreatic)
Acute nephritic syndrome, renal failure
Rheumatoid arthritis and systemic lupus erythematosus
Source. Compiled in part from Dasgupta 2007; Israili and Dayton 2001.

effects. For this reason, in patients with uremia, chronic hepatic disease, hypo­
albuminemia, or a protein-binding drug interaction, the use of therapeutic
drug monitoring for dose adjustment requires caution; clinical response to the
drug (e.g., international normalized ratio for warfarin), rather than laboratory­
determined drug levels, should guide dosage (Nadkarni et al. 2011). Where
therapeutic drug monitoring is employed, methods selective for unbound drug
should be used, if available, for phenytoin, valproate, tacrolimus, cyclosporine,
amitriptyline, haloperidol, and possibly carbamazepine (Dasgupta 2007). Clin­
ically free phenytoin levels are the most widely utilized, especially in the elderly
and malnourished populations.
Disease-related changes to a drug’s protein binding have little effect on
steady-state plasma concentrations of free drug as long as the disease does not
affect metabolic and excretory processes (Benet and Hoener 2002). However,
most diseases that affect protein binding also affect metabolism and excretion,
with clinically significant consequences, especially for drugs with a low ther­
apeutic index.
16 Clinical Manual of Psychopharmacology in the Medically Ill

Drug Elimination: Metabolism and Excretion

The kidney is the primary organ of drug excretion, with fecal and pulmonary
excretion being of less importance. Hydrophilic compounds are removed
from the body through excretion into the aqueous environment of urine and
feces. In contrast, lipophilic drugs, including most psychoactive medications,
are readily reabsorbed through the intestinal mucosa (enterohepatic recircu­
lation) and renal tubules, which limits their excretion. Because all drugs un­
dergo glomerular filtration, lipophilic drugs would experience significant
renal elimination were it not for renal resorption. Renal resorption, and thus
the elimination, of several drugs, including amphetamines, meperidine, and
methadone, can be significantly changed by altering urine pH (discussed later
in the subsection “Pharmacokinetic Drug Interactions”).
The general function of metabolism is to convert lipophilic molecules
into more polar water-soluble compounds that can be readily excreted. Al­
though biotransformation often results in less active or inactive metabolites,
this is not always true. For some drugs, metabolites have pharmacological ac­
tivities similar to, or even greater than, the parent compound, and thus con­
tribute to the therapeutic effect. Indeed, some metabolites are separately
marketed, including paliperidone (principal active metabolite of risperidone)
and temazepam and oxazepam (both metabolites of diazepam). Some drugs
are administered as prodrugs—inactive compounds requiring metabolic acti­
vation—including lisdexamfetamine (metabolized to dextroamphetamine),
tramadol, codeine (metabolized to morphine), clopidogrel, fosphenytoin,
primidone (metabolized to phenobarbital), and tamoxifen (metabolized to
endoxifen). Other drug metabolites may have pharmacological effects consid­
erably different from those of the parent drug and may cause unique toxicities
(e.g., the meperidine metabolite normeperidine has proconvulsant activity,
and carbamzepine 10, 11 epoxide is a toxic metabolite of carbamazepine).

Metabolism
Biotransformation occurs throughout the body, with the greatest activity in
the liver and gut wall. Most psychotropic drugs are eliminated by hepatic me­
tabolism followed by renal excretion. Hepatic biotransformation processes are
of two types, identified as Phase I and Phase II reactions. Phase I reactions typ­
ically convert the parent drug into a more polar metabolite by introducing or
 Pharmacokinetics and Pharmacodynamics 17

unmasking a polar functional group in preparation for excretion or further

metabolism by Phase II pathways. Phase II metabolism conjugates the drug or
Phase I metabolite with an endogenous acid such as glucuronate, acetate, or
sulfate. The resulting highly polar conjugates are usually inactive and are rap­
idly excreted in urine and feces (see Figure 1–4).

Phase I metabolism. Phase I reactions include oxidation, reduction, and

hydrolysis. Most Phase I oxidation reactions are carried out by the hepatic
CYP system, with a lesser contribution from the monoamine oxidases
(MAOs). CYP enzymes exist in a variety of body tissues, including the gastro­
intestinal tract, liver, lung, and brain. Approximately 12 enzymes within three
main families, CYP1, CYP2, and CYP3, are responsible for the majority of
drug metabolism (Zanger and Schwab 2013). These families are divided into
subfamilies identified by a capital letter (e.g., CYP3A). Subfamilies are further
subdivided into isozymes on the basis of the homology between subfamily
proteins. Isozymes are denoted by a number following the subfamily letter
(e.g., CYP3A4, CYP2J2).
In humans, CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 are
the most important enzymes for drug metabolism. These enzymes exhibit
substrate specificity. Functional deficiencies in one CYP enzyme will impact
the metabolism of only those compounds that are substrates for that enzyme.
Because some of these enzymes exist in a polymorphic form, a small percent­
age of the population, varying with ethnicity, has one or more CYP enzymes
with significantly altered activity. For example, polymorphisms of the 2D6
gene give rise to populations with the capacity to metabolize CYP2D6 sub­
strates extensively (normal condition), poorly (5%–14% of whites, ~1% of
Asians), or ultraextensively (1%–3% of the population) (Zanger and Schwab
2013; Zanger et al. 2004). CYP enzyme activity can also be altered (inhibited
or enhanced through induction) by environmental compounds or drugs, giv­
ing rise to many drug-drug interactions (discussed in the section “Drug-Drug
Interactions” later in this chapter).
Phase II metabolism. Phase II conjugation reactions mainly involve en­
zymes belonging to the superfamily of UGTs. UGT enzymes are located he­
patically (primarily centrizonal) (Debinski et al. 1995) and in the kidney and
small intestine (Fisher et al. 2001). The UGT enzyme superfamily is classified
18 Clinical Manual of Psychopharmacology in the Medically Ill

Phase I metabolism
Primary systems:
Oxidation by cytochrome P450 enzymes
mainly in gut and liver
Most drugs Secondary systems:
Monoamine oxidases
Dehydrogenases
Hydrolysis by esterases and amidases

Phase I metabolites
may be active or inactive

Phase II metabolism
Lorazepam, Hepatic and intestinal conjugation enzymes
oxazepam, Primary systems:
temazepam, UGTs
lamotrigine, Secondary systems:
and others Sulfotransferases
Methyltransferases

Phase II metabolites are generally

inactive, with the exceptions of
morphine and codeine 6-glucuronides

Lithium,
gabapentin, Renal and biliary excretion
pregabalin,
and others

Fecal and urinary excretion

Figure 1–4. General pathways of metabolism and excretion.

UGTs=uridine 5′-diphosphate glucuronosyltranferases.
Another random document with
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The Project Gutenberg eBook of Peck's Bad Boy in
an airship
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and most other parts of the world at no cost and with almost no
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Title: Peck's Bad Boy in an airship

Author: George W. Peck

Illustrator: Charles Lederer

Release date: November 27, 2023 [eBook #72237]

Language: English

Original publication: Chicago: Stanton and Van Vliet Co, 1908

Credits: Stephen Hutcheson, Gísli Valgeirsson, Rod Crawford, Dave

Morgan and the Online Distributed Proofreading Team at
https://www.pgdp.net

*** START OF THE PROJECT GUTENBERG EBOOK PECK'S BAD

BOY IN AN AIRSHIP ***
PECK’S BAD BOY IN AN
AIRSHIP
“Take That from Your Little Hennery.”
 Peck’s Bad Boy
in an Airship
By Hon. Geo. W. Peck
Author of Peck’s Bad Boy, Peck’s Bad Boy Abroad, Peck’s Bad Boy
With the Circus, Peck’s Bad Boy With the Cowboys, Etc.

Humorous and Interesting

A story relating the adventures of Peck’s Bad Boy and
His Pa who are sent to Europe to investigate airships
with an idea of using them in the United States Navy.
Tells of their adventures in Europe also in South Africa
where the airship is used in hunting wild animals.

Illustrated by Charles Lederer

The Celebrated Illustrator and Cartoonist
 Copyright, 1908
By W. G. CHAPMAN

Copyright, 1908
By THOMPSON & THOMAS
 CONTENTS.

CHAPTER I.
The Bad Boy Wants to Be an Orphan—The Bad Boy Goes to an Orphan
Asylum—The Government Gives the Bad Boy’s Pa an Appointment to
Travel Over the World and Get Information About Airships, Dirigible
Balloons and Everything to Help Our Government Know What Other
Governments are Doing in Case of War 15

CHAPTER II.
No Encouragement for Inventive Genius in Orphan Home—The Boy Uses
His New Invention, a Patent Clothes Wringer, in Milking 28

CHAPTER III.
The Boy Escapes from Orphan Asylum—The Boy and His Chum Had Red
Letter Days—The Boy is Adopted by New Friends 42

CHAPTER IV.
A Bad Railroad Wreck—The Boy Contrasts Their Ride to One in a Parlor
Car—The Lawyer is the Greatest Man on Earth—The Boy Settles His
Claim for $20 55

CHAPTER V.
The Bad Boy Leaves St. Louis in a Balloon—The Boy Makes a Trip to San
Francisco and Joins Evans’ Fleet—The Police Arrest Boy and Tie Up
Balloon 67

CHAPTER VI.
The Balloon Lands in Delaware—The Boy Visits the Battleships—They 78
Scour the Boy With a Piece of Brick and Some Laundry Soap—The Boy
Investigates the Mechanism of the Battleships—The Boy Goes With the
Ships as a Mascot

CHAPTER VII.
A Storm Comes from the Coast of Cuba—Everyone Goes to Sleep on the
Ship Except the Watchman and Pilot—The Bad Boy is Put in the
Dungeon—The Captain Says to Throw the Boy Overboard to Feed the
Sharks 91

CHAPTER VIII.
The Boy Dresses Up in His Sunday Clothes and Tells the Captain He is
Ready to Die—The Crew Throw a Steer Overboard to Feed a School of
Sharks—The Boy Produces His New Electric Battery—The Bad Boy
Makes a Trip to France to Meet His Pa 104

CHAPTER IX.
The Bad Boy Arrives in France—The Boy’s Pa is Suspected of Being an
Anarchist—The Boy Finds Pa Seated at a Large Table Bragging About
America—He Told Them the Men in America Were All Millionaires and
Unmarried 131

CHAPTER X.
Pa Had the Hardest Time of His Life in Paris—Pa Drinks Some Goat Milk
Which Gives Him Ptomaine Poison in His Inside Works—Pa Attends the
Airship Club in the Country—Pa Draws on American Government for
$10,000 145

CHAPTER XI.
The Boy and His Pa Leave France and Go to Germany, Where They Buy
an Airship—They Get the Airship Safely Landed—Pa and the Boy With
the Airship Start for South Africa—Pa Shows the Men What Power He
Has Over the Animal Kingdom 157

CHAPTER XII.
All Kinds of Climates in South Africa—Pa Hires Men to Capture Wild
Animals—The Boy and His Pa Capture Some Tigers and a Big Lion—
They Have a Narrow Escape from a Rhinoceros 170
 CHAPTER XIII.
Pa Was a Hero After Capturing Two Tigers and a Lion—Pa Had an Old
Negro With Sixty Wives Working for Him—Pa Makes His Escape in
Safety—Pa Goes to Catch Hippopotamusses 181

CHAPTER XIV.
Pa Was Blackmailed and Scared Out of Lots of Money—Pa Teaching the
Natives to Speak English—Pa Said the Natives Acted Like Human
Beings—Pa Buys Some Animals in the Jungle 194

CHAPTER XV.
The Idea of Airships is All Right in Theory, but They are Never Going to Be
a Reliable Success—Pa Drowns the Lions Out With Gas—The Bad Boy
and His Pa Capture a Couple of Lions—Pa Moves Camp to Hunt Gorillas 207

CHAPTER XVI.
The Boy’s Pa Shows Bravery in the Jungles in Africa—Four Gorillas Chase
Pa—The Boy and His Pa Don’t Sleep Much at Night—The Boy
Discovers a Marsh Full of Wild Buffaloes 220

CHAPTER XVII.
The Boy’s Experience With an African Buffalo—The Boy’s Pa Shoots
Roman Candles to Scare the Buffaloes—The Boy’s Pa Tames the Wild
Animals 234

CHAPTER XVIII.
The Boy and His Pa Start for the Coast in an Airship—Pa Saluted the
Crowd as We Passed Over Them—The Airship Lands Amid a Savage
Tribe—The King of the Tribe Escorts Pa and the Boy to the Palace 246

CHAPTER XIX.
The Boy’s Pa Becomes King over the Negroes—Pa Shows the Natives
How to Dig Wells—Pa Teaches the Natives to become Soldiers—The
Boy Uses a Dozen Nigger Chasers and Some Roman Candles—The
Boy, His Pa and the Natives Assist at the 4th of July Celebration 258
 ILLUSTRATIONS.

Gee, My Ideas of an Orphan Home Got a Shock.

The Way Freshmen Do in College When They’re Being
Murdered.
Gosh, But I Never Had Such an Excursion.
Grabbed the Balloon Rope and Gave it a Hitch Around the
Pole.
Any Man That Lays Hands on the Government Mail Can
Be Imprisoned for Life for Treason.
Hit the Chief of Police With a Bottle.
They Pulled Me Through the Forty-Foot Gun to Swab it
Out.
When it Exploded the Jap Was the Scaredest Person I
Ever Saw.
The Boss of the Boat Ordered Me Pulled Out With a Boat
Hook.
I Am Thy Father’s Ghost—Come on in, the Water’s Fine.
The Captain Got Upon a Chair and Pulled a Revolver and
Was Going to Shoot.
I Gave Him a Squeeze That Sent a Shock Through Him
That Loosened His Teeth.
Pa’s Face Was Scratched So They Sent Him to the Pest
House.
After Pa Had Been Ducked in the Fountain They Charged
for Two Ducks He Killed by Falling on Them.
The Fireworks Went Off. The Woman Threw a Fit and Pa
Raised Out of the Smoke.
Up She Went With the Inventor Steering and Pa Hanging
on for Dear Life.
Pa Gave a Honk Honk Like an Auto, But the Lion Wasn’t
Frightened So You Would Notice.
When Pa Found the Snake Coiled Up on His Blanket He
Threw a Fit.
Looking Him Square in the Face I began to Chant, Ene-
Mene-Miny-Mo.
Pa Astride of a Zebra, Has Frightened the Elephants Into a
Stampede by Playing “A Hot Time” on a Mouth Organ.
Pa Made a Lunge and Fell on Top of the Little Elephant,
Which Began to Make a Noise Like a Baby.
“There’s Your Lions, About a Dozen, Captured Down in
That Hole; Help Yourselves,” Said Pa.
“Get in There, You Measly Cur Dog,” Said Pa, Kicking the
Big Lion at Every Jump.
Pa Stopped the Music and Repeated an Old Democratic
Speech of His, and They Acted Just Like a Caucus.
All He Had to Do Was Play “Supper is Now Ready in the
Dining Car.”
Some of Those Negroes are Running Yet, and Will, No
Doubt, Come Out at Cairo, Egypt.
Pa Had to Put His Foot on Their Necks and Acknowledge
Him Their King and Protector.
Peck’s Bad Boy in an Airship.
 CHAPTER I.
The Bad Boy Wants to Be an Orphan—The Bad Boy Goes to an
Orphan Asylum—The Government Gives the Bad Boy’s Pa an
Appointment to Travel Over the World and Get Information About
Airships, Dirigible Balloons and Everything to Help Our Government
Know What Other Governments Are Doing in Case of War.

I have always wanted to be an orphan and I guess now I have got

my wish.
I have watched orphans a whole lot and they have seemed to me to
have the easiest job outside of politics.
To see a good mess of orphans at an Orphan Asylum, with no
parents to butt in and interfere with your enjoyment has seemed to
me to be an ideal existence.
When a boy has a father that he has to watch constantly to keep him
from going wrong he has no time to have any fun, but to belong to a
syndicate of orphans, with an easy old maid matron to look after the
whole bunch, an individual orphan who has ginger in him can have
the time of his young life. At least that is the way it has always
seemed to me.
They set on the food at an orphanage, and if you have a pretty good
reach, you can get enough corralled around your plate to keep the
wolf from the door, and when it comes to clothes, you don’t have to
go to a tailor, or a hand me down store, and take something you
don’t want because it is cheap, but you take any clothes that are
sent in by charitable people, which have been worn enough so there
is no style about them, and no newness to wear off by rolling in the
grass, and you put them on and let it go at that, if they do smell of
moth balls.
Pa has skipped and I am left alone and I shall enter as a freshman in
an Orphan Asylum, and later go out into the world and travel on my
shape.
Pa took me to Washington and for a week he was visiting the
different Departments, and nights he would talk in his sleep about air
ships and balloons, and forts and battleships, and about going
abroad, until I thought he was getting nutty.
One day he called me up to our room in the hotel and after locking
the door, and plugging up the keyhole with chewed paper he said:
“Now, Hennery, I want you to listen right out loud. The government
has given me an appointment to travel over the world and get
information about air ships, divagable balloons, and everything that
will help our government to know what other governments are doing
in inventing things to be used in case of war. I am to be the Billy
Pinkerton of the War Department and shall have to spy in other
governments, and I am to be the traveling diplomat of the
government, and jolly all nations, and find out how things are running
everywhere.
“You will have to stay home this time because you would be a dead
give away, so I will send you to a nice orphan home where you will
be taught to work, and where guards will keep you on the inside of
the fence, and put you to bed in a straight jacket if you play any of
your jokes, see?” and Pa gave me a ticket to an orphans’ home, and
a letter of introduction to the matron and the next day I was an
inmate, with all the degrees coming to me. What do you think of that,
and Pa on the ocean, with a government commission in his pocket?
Gee, but my ideas of an orphans’ home got a shock when I arrived
at the station where the orphans’ home was located. I thought there
would be a carriage at the train to meet me, and a nice lady dressed
in white with a cap on her head, to take me in her arms and hug me,
and say, “Poor little boy, I will be a sister to you,” but there was no
reception committee, and I had to walk a mile with my telescope
valise, and when I found the place and went in the door, to present
my letter to the matron, a man with a scar on his face, and one eye
gone, met me and looked over my papers, and went, one eye on me,
and called an assistant private and told him to take me and give me
the first or entered apprentice degree.

Gee, My Ideas of an Orphan Home Got a Shock.

The private took me by the wrist and gave me a jerk and landed me
in the laundry, and told me to strip off, and when I had removed my
clothes and folded them and laid them on a table, he took the clothes
away from me, and then told me to climb into a laundry tub, and he
turned cold water on me and gave me a bar of yellow laundry soap,
and after I had lathered myself he took a scrubbing brush, such as
floors are scrubbed with, and proceeded in one full swoop to peel the
hide off of me with a rough crash towel till you could see my veins
and arteries, and inside works as well as though you had used X-
rays, and when I was ready to die and wanted to, I yelled murder,
and he put his hand over my mouth so hard that he loosened my
front teeth, and I guess I died right there or fainted, for when I came
to, and thought the resurrection morning, that they used to tell me
about in the Sunday School, had come. I found myself dressed in a
sort of combination shirt and drawers, like a bunny nightie, made of
old saddle blankets, and he told me that was the uniform of the
orphanage and that I could go out and play for fifteen minutes, after
which the bell would ring and I could go from play to work. Gosh, but
I was glad to get out doors, but when I began to breathe the fresh air,
and scratch myself where the saddle blanket clothes pricked me,
about fifty boys, who were evidently sophomores in the orphanage,
came along, and made a rush for me, to haze me as a freshman.
Well, they didn’t do a thing to me. They tied a rope around one
ankle, and threw the rope over a limb, and pulled me off the ground,
and danced a war dance around me and run thistles up my trouser’s
legs, and spanked me with a board with slivers in it, and let me down
and walked over me in a procession, singing “There’ll be a hot time
in the old town to-night.” I laughed all the time, because that is the
way freshmen do in college when they are being murdered, and I
thought my new associates would like me better if I died game. Just
before I died game the bell rang, and the one eyed pirate and his
chief of staff came out and said we would go to work, and the boys
were divided into squads and put to work, some husking corn, others
sweeping up dead leaves, others milking cows, and doing everything
necessary around a farm.
Before I was set to work I had a few minutes of silent reflection, and I
thought of my changed condition from my porcelain lined bath tub
with warm water and soft towels, to that bath in the laundry, and the
skinning process of preparing a boy for a better life.

The Way Freshmen Do in College When They’re Being

Murdered.

Then what do you suppose they set me to work at? Skinning bull
heads and taking out the insides. It seems the boys catch bull heads
in a pond, and the bull heads are used for human food, and the
freshest boys were to dress them. Well, I wasn’t going to kick on
anything they gave me for a stunt, so I put on an apron, and for four
hours I skinned and cut open bull heads in a crude sort of way, until I
was so sick I couldn’t protect myself from the assaults of the live bull
heads, and the cook said I done the job so well that she would ask to