54589_C000.fm Page i Tuesday, September 4, 2007 10:22 AM Half Title Page Pharmacokinetics and Pharmacodynamics of Abused Drugs 54589_C000.fm Page ii Tuesday, September 4, 2007 10:22 AM 54589_C000.fm Page iii Tuesday, September 4, 2007 10:22 AM Title Page Pharmacokinetics and Pharmacodynamics of Abused Drugs Edited by Steven B. Karch, MD, FFFLM Consultant Pathologist and Toxicologist Berkeley, California Boca Raton London New York CRC Press is an imprint of the Taylor & Francis Group, an informa business 54589_C000.fm Page iv Tuesday, September 4, 2007 10:22 AM CRC Press Taylor & Francis Group 6000 Broken Sound Parkway NW, Suite 300 Boca Raton, FL 33487-2742 © 2008 by Taylor & Francis Group, LLC CRC Press is an imprint of Taylor & Francis Group, an Informa business No claim to original U.S. Government works Printed in the United States of America on acid-free paper 10 9 8 7 6 5 4 3 2 1 International Standard Book Number-13: 978-1-4200-5458-3 (Hardcover) This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. 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For orga- nizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. Visit the Taylor & Francis Web site at http://www.taylorandfrancis.com and the CRC Press Web site at http://www.crcpress.com 54589_C000.fm Page v Tuesday, September 4, 2007 10:22 AM Contents Chapter 1 Pharmacokinetics: Basic Concepts and Models........................................................1 Amanda J. Jenkins, Ph.D. Chapter 2 Pharmacokinetic Modeling and Pharmacokinetic–Pharmacodynamic Correlations..............................................................................................................15 Amanda J. Jenkins, Ph.D. Chapter 3 Toxicokinetics and Factors Affecting Pharmacokinetic Parameters.......................21 Amanda J. Jenkins, Ph.D. Chapter 4 Pharmacokinetics of Specific Drugs........................................................................25 Amanda J. Jenkins, Ph.D. Chapter 5 Pharmacodynamics: Effects of Abused Drugs on Human Performance: Laboratory Assessment............................................................................................65 Stephen J. Heishman, Ph.D. and Carol S. Myers, Ph.D. Chapter 6 Performance-Based Assessment of Behavioral Impairment in Occupational Settings..............................................................................................97 Thomas H. Kelly, Ph.D., Richard C. Taylor, M.A., Stephen J. Heishman, Ph.D., and Jonathan Howland, Ph.D. Chapter 7 Pupillometry and Eye Tracking as Predictive Measures of Drug Abuse.............127 Wallace B. Pickworth, Ph.D. and Rudy Murillo, B.A. Chapter 8 Abuse of Marketed Medications............................................................................143 Kenzie L. Preston, Ph.D., David H. Epstein, Ph.D., John P. Schmittner, M.D., and Sharon L. Walsh, Ph.D. Index..............................................................................................................................................175 54589_C000.fm Page vi Tuesday, September 4, 2007 10:22 AM 54589_C000.fm Page vii Tuesday, September 4, 2007 10:22 AM Preface This volume discusses pharmacokinetics and pharmacodynamics. Chapters 1 through 4 discuss aspects of pharmacokinetics. Chapters 5 through 8 discuss aspects of pharmacodynamics. Pharmacokinetics is defined as the study of the quantitative relationship between administered doses of a drug and the observed plasma/blood or tissue concentrations. The field of pharmaco- kinetics is concerned with drug absorption, distribution, biotransformation, and excretion or elim- ination. These processes, in addition to the dose, determine the concentration of drug at the effector or active site and, therefore, the intensity and duration of drug effect. The practice of pharmacokinetics has been used in clinical medicine for many years in order to optimize the efficacy of medications administered to treat disease. Through a consideration of pharmacokinetics, physicians are able to determine the drug of choice, dose, route, frequency of administration, and duration of therapy in order to achieve a specific therapeutic objective. In the same manner, study of the pharmacokinetics of abused drugs aids investigators in addiction med- icine, forensic toxicology, and clinical pharmacology in understanding why particular drugs are abused, factors that affect their potential for abuse, how their use can be detected and monitored over time, and also provides a rational, scientific basis for treatment therapies. Pharmacodynamics is the study of the physiological and behavioral mechanisms by which a drug exerts its effects in living organisms. An effect is initiated by the drug binding to receptor sites in a cell’s membrane, setting in motion a series of molecular and cellular reactions culminating in some physiological (e.g., opioid-induced analgesia) or behavioral (e.g., alcohol-induced impair- ment) effect. Drugs typically have multiple effects. For example, a benzodiazepine will produce its primary anxiolytic effect, but may also cause side effects of sedation and impaired performance. The question of the behavioral effects of abused drugs has been the focus of research by behavioral pharmacologists for many decades. Because of the widespread use of psychoactive drugs throughout society, employers have become increasingly concerned about drugs in the workplace and the potential for impaired job performance and onsite drug-related accidents. There are now computerized tests that employers can use to aid in the detection of impaired employees. Some drugs of abuse also produce characteristic effects on the visual system, and for this reason, devices that detect eye movement and function are also being tested for their ability to predict drug ingestion and potential impairment in the workplace. Knowledge of both pharmacokinetics and pharmacodynamics is central to an understanding of drug abuse and its treatment. 54589_C000.fm Page viii Tuesday, September 4, 2007 10:22 AM 54589_C000.fm Page ix Tuesday, September 4, 2007 10:22 AM The Editor Steven B. Karch, M.D., FFFLM, received his under- graduate degree from Brown University. He attended grad- uate school in anatomy and cell biology at Stanford Univer- sity. He received his medical degree from Tulane University School of Medicine. Dr. Karch did postgraduate training in neuropathology at the Royal London Hospital and in cardiac pathology at Stanford University. For many years he was a consultant cardiac pathologist to San Francisco’s Chief Med- ical Examiner. In the U.K., Dr. Karch served as a consultant to the Crown and helped prepare the cases against serial murderer Dr. Harold Shipman, who was subsequently convicted of murdering 248 of his patients. He has testified on drug abuse–related matters in courts around the world. He has a special interest in cases of alleged euthanasia, and in episodes where mothers are accused of murdering their children by the trans- ference of drugs, either in utero or by breast feeding. Dr. Karch is the author of nearly 100 papers and book chapters, most of which are concerned with the effects of drug abuse on the heart. He has published seven books. He is currently completing the fourth edition of Pathology of Drug Abuse, a widely used textbook. He is also working on a popular history of Napoleon and his doctors. Dr. Karch is forensic science editor for Humana Press, and he serves on the editorial boards of the Journal of Cardiovascular Toxicology, the Journal of Clinical Forensic Medicine (London), Forensic Science, Medicine and Pathology, and Clarke’s Analysis of Drugs and Poisons. Dr. Karch was elected a fellow of the Faculty of Legal and Forensic Medicine, Royal College of Physicians (London) in 2006. He is also a fellow of the American Academy of Forensic Sciences, the Society of Forensic Toxicologists (SOFT), the National Association of Medical Examiners (NAME), the Royal Society of Medicine in London, and the Forensic Science Society of the U.K. He is a member of The International Association of Forensic Toxicologists (TIAFT).