Karsten Schrör. Acetylsalicylic Acid

Transcription

1 Karsten Schrör Acetylsalicylic Acid

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3 Karsten Schrör Acetylsalicylic Acid

4 Related Titles Nicolaou, K. C., Montagnon, T. Molecules that Changed the World 2008 ISBN: Corey, E. J., Czakó, B., Kürti, L. Molecules and Medicine 2007 ISBN: Behme, S. Manufacturing of Pharmaceutical Proteins 2008 ISBN: Curtis-Prior, P. (ed.) The Eicosanoids 2004 ISBN:

5 Karsten Schrör Acetylsalicylic Acid

6 The Author Prof. Dr. Karsten Schrör Institut für Pharmakologie und Klinische Pharmakologie Heinrich-Heine-Universität Düsseldorf Universitätsstr Düsseldorf Germany Cover Reproduction of the first commercial Aspirin preparation with kind permission of Bayer Vital GmbH, Cologne. All books published by Wiley-VCH are carefully produced. Nevertheless, authors, editors, and publisher do not warrant the information contained in these books, including this book, to be free of errors. Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadvertently be inaccurate. Library of Congress Card No.: applied for British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library. Bibliographic information published by the Deutsche Nationalbibliothek The Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data are available on the Internet at # 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim All rights reserved (including those of translation into other languages). No part of this book may be reproduced in any form by photoprinting, microfilm, or any other means nor transmitted or translated into a machine language without written permission from the publishers. Registered names, trademarks, etc. used in this book, even when not specifically marked as such, are not to be considered unprotected by law. Typesetting Thomson Digital, Noida, India Printing betz-druck GmbH, Darmstadt Binding Litges & Dopf GmbH, Heppenheim Printed in the Federal Republic of Germany Printed on acid-free paper ISBN:

7 V Contents Preface XI 1 General Aspects History Willow Bark and Leaves as Antipyretic, Anti-Inflammatory Analgesics Salicylates as the Active Ingredient of Willow Bark and Other Natural Sources Synthesis of Acetylsalicylic Acid and First Clinical Studies Mode of Aspirin Action Anti-Inflammatory/Analgesic Actions of Aspirin Aspirin in the Cardiovascular System Current Research Topics Chemistry Structures and Chemical Properties of Salicylates Salicylates in Clinical Use Aspirin Formulations Determination of Salicylates Gas Liquid Chromatography High-Performance Liquid Chromatography Spectrophotometry 30 2 Pharmacology Pharmacokinetics Absorption and Distribution Absorption Particular Aspirin Formulations Distribution Modifying Factors Biotransformation and Excretion Biotransformation of Aspirin Biotransformations of Salicylic Acid Excretion of Salicylates 49

8 VI Contents Modification of Biotransformations and Excretion of Salicylates Cellular Modes of Action Inhibition of Cyclooxygenases Acetylation of Cyclooxygenases and Traditional NSAIDs Modulation of COX-2 Gene Expression Further Actions of Salicylates on Arachidonate Metabolism COX-Independent Actions on Cell Function Kinases Transcription Factors Oxidative Stress and Nitric Oxide Immune Responses Energy Metabolism Fatty Acid b-oxidation Uncoupling of Oxidative Phosphorylation Toxic Actions of Salicylates on the Liver Actions on Organs and Tissues Hemostasis and Thrombosis Platelets Endothelial Cells Plasmatic Coagulation Fibrinolysis Inflammation, Pain, and Fever Inflammation Pain Fever Aspirin and Malignancies COX-Related Antitumor Effects of Aspirin Nonprostaglandin-Related Antitumor Actions of Aspirin Nonspecific Actions of Salicylates Toxicity and Drug Safety Systemic Side Effects Acute and Chronic Toxicity Occurrence and Symptoms Treatment Habituation Bleeding Disorders Prolongation of Bleeding Time by Aspirin Aspirin-Related Bleeding Risk in Surgical Interventions Aspirin, Other Drugs, and Alcohol Prevention and Treatment of Bleedings Safety Pharmacology in Particular Life Situations Pregnancy and Fetal Development The Elderly Patient Organ Toxicity 157

9 Contents VII Gastrointestinal Tract Pathophysiology of GI Injury Prostaglandins and Gastric Mucosal Protection Mode of Aspirin Action Helicobacter pylori Clinical Studies Aspirin and Other Drugs Kidney Analgesic Nephropathy Mode of Aspirin Action Clinical Studies Liver Drug-Induced Liver Injury Mechanisms of Aspirin Action Aspirin and Other Drugs Audiovestibular System Pathophysiology of Hearing and Equilibrium Disturbances Mode of Aspirin Action Aspirin, Arachidonic Acid, and Prostaglandins Clinical Trials Non-Dose-Related (Pseudo)allergic Actions of Aspirin Aspirin Hypersensitivity (Widals Syndrome) Pathophysiology and Clinics Mode of Aspirin Action Clinical Trials Urticaria/Angioedema, Stevens Johnson and Lyell Syndromes Urticaria/Angioedema Stevens Johnson Syndrome and Toxic Epidermal Necrolysis (Lyell Syndrome) Reyes Syndrome Clinics, Laboratory, and Morphological Findings Etiology Clinical Studies Actual Situation Clinical Applications of Aspirin Thromboembolic Diseases Coronary Vascular Disease Thrombotic Risk and Mode of Aspirin Action Clinical Trials: Primary Prevention in Individuals Without Risk Factors Clinical Trials: Primary Prevention in Individuals with Risk Factors Clinical Trials: Stable Angina Pectoris Clinical Trials: Secondary Prevention Clinical Trials: Percutaneous Coronary Interventions Clinical Trials: Coronary Artery Bypass Graft Surgery (CABG) Aspirin and Other Drugs 246

10 VIII Contents Actual Situation Cerebrovascular Diseases Thrombotic Risk and Mode of Aspirin Action Clinical Trials: Primary Prevention Clinical Trials: Secondary Prevention Aspirin and Other Drugs Actual Situation Peripheral Arterial Disease Thrombotic Risk and Mode of Aspirin Action Clinical Trials: Primary Prevention Clinical Trials: Secondary Prevention Clinical Trials: Peripheral Transluminal Angioplasty (PTA) Aspirin and Other Drugs Actual Situation Venous Thrombosis Thrombotic Risk and Mode of Aspirin Action Clinical Trials Actual Situation Preeclampsia Thrombotic Risk and Mode of Aspirin Action Clinical Trials Clinical Trials in Pregnancy-Induced Hypertension: Reasons for Data Variability Actual Situation Aspirin Resistance Definition and Types of Pharmacological Aspirin Resistance Detection of Aspirin Resistance Pharmacological Mechanisms of Aspirin Resistance Clinical Trials Pain, Fever, and Inflammatory Diseases Aspirin as an Antipyretic Analgesic Fever, Pain, and Antipyretic/Analgesic Actions of Aspirin Clinical Trials Aspirin and Other Drugs Actual Situation Arthritis and Rheumatism Pathophysiology and Mode of Aspirin Action Clinical Trials Aspirin and Other Drugs Actual Situation Kawasaki Disease Pathophysiology and Mode of Aspirin Action Clinical Trials Aspirin and Other Drugs Actual Situation Further Clinical Indications 343

11 Contents IX Colorectal Cancer Etiology and Pathophysiology of Intestinal Adenomas, Colorectal Cancer, and Mode of Aspirin Action Clinical Trials: Epidemiological Studies Clinical Trials: Randomized Prospective Prevention Trials Aspirin and Other Drugs Actual Situation Alzheimers Disease Pathophysiology and Mode of Aspirin Action Clinical Trials Aspirin and Other Drugs Actual Situation 363 Appendix A 367 Appendix B 369 Index 371

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13 XI Preface Acetylsalicylic acid, best known by its first trade name aspirin, belongs to the small and steadily decreasing number of therapeutic agents that are well known to both the health professional and the layman and enjoy a good reputation with both. Aspirin is not only one of the most intensively studied but also one of the most frequently used and cheapest drugs in the world, with an immense annual production rate. Ironically, the first clinical investigator to study the drug more than 100 years ago did so with not little distress. What are the reasons behind this exciting development? Certainly in the beginning, there was an urgent need for an effective and well-tolerated antipyretic analgesic that became invaluable during the large flue pandemia in In the following decades, aspirin soon became very popular as a household remedy for almost any condition associated with flu, feverish discomfort, or any kind of malaise take an aspirin. Another breakthrough was the discovery of its novel mode of action inhibition of injury-induced prostaglandin biosynthesis. This offered a plausible mechanistic explanation for its multitude of pharmacological activities. Later, the antiplatelet/antithrombotic properties of aspirin came in focus and opened a new and broad therapeutic field for the prevention of atherothrombotic events. Aspirin is still a treatment of first choice in many of these indications, most notably the prevention of myocardial infarction and stroke. Experimental and clinical research on aspirin is still ongoing with current issues including investigation of transcriptional effects of aspirin on gene regulation, specifically in inflammation and malignancies, as well as possible new clinical indications, such as colorectal carcinoma. This book provides an overview of all aspects of therapeutically relevant aspirin actions and the underlying mechanisms with specific focus on the unique structural property of the compound consisting of two bioactive molecules, that is, a reactive acetyl group and the salicylate moiety, each with different pharmacokinetic and pharmacodynamic properties that synergize in many cases. This and the resulting possible benefits and risks in clinical use are discussed in four main chapters, each divided into several subsections. A list of selected references is provided in each section and includes reports that have been published up to The preparation of this manuscript would not have been possible without the continuous help and assistance of a number of individuals. The first person to mention is my wife Elke. I thank her for her patience and continuous support during the last 4 years while this manuscript was prepared. I also like to thank all of my friends and colleagues in Australia, Germany, and the rest of Europe, Taiwan, and the United States for critical reading of parts of the manuscript and providing many valuable suggestions.

14 XII Preface Many thanks also to Erika Lohmann and Petra Kuger in Düsseldorf for typing and carefully reading the manuscript as well as preparing figures and tables. As a young research scientist in the mid-1970s, I had the privilege to work for some time in the laboratory of Sir John Vane in Beckenham (England). This was an exciting period, when several important discoveries were made in this laboratory: detection of prostacyclin and the demonstration that aspirin inhibits injury-induced prostaglandin biosynthesis. The significance of these findings was acknowledged when Sir John Vane was awarded the Nobel Prize in Medicine in When this book project was still in progress, I asked Sir John whether he would be willing to write a preface and he kindly agreed to do so. Unfortunately, he passed away before the project was finished. He would have celebrated his 80th birthday in March This book is dedicated to him. Düsseldorf, October 2008 Karsten Schrör

15 1 General Aspects 1.1 History 1.2 Chemistry 2 Pharmacology 2.1 Pharmacokinetics 2.2 Cellular Modes of Action 2.3 Actions on Organs and Tissues 3 Toxicity and Drug Safety 3.1 Systemic Side Effects 3.2 Organ Toxicity 3.3 Non-Dose-Related (Pseudo)allergic Actions of Aspirin 4 Clinical Applications of Aspirin 4.1 Thromboembolic Diseases 4.2 Pain, Fever, and Inflammatory Diseases 4.3 Further Clinical Indications