CRC - Aspirin and Related Drugs

Organization: CRC
Publication Date: 28 October 2004
Page Count: 802


In my book Aspirin and the Salicylates (Butterworths, London, 1984) I wrote of my fascination with the salicylates. Now, two decades later, I can say that the fascination has grown, especially as we learn more about the mechanisms of action of these drugs and, through this, a wider range of uses for them. Advances in the past decade or so regarding the molecular biology of inflammatory diseases, the neurobiology of pain and fever and the physiopathology of thromboembolic diseases have given great insights into the molecular and cellular mechanisms of aspirin and salicylates, as well as the many non-steroidal anti-inflammatory and analgesic drugs - the latter often being compared with the salicylates for their actions, safety and efficacy. In fact, the salicylates are often used as a basis of comparison in laboratory as well as clinical studies. This reflects the extent of knowledge of these drugs and their past and present utility as antipyretic, analgesic, anti-inflammatory and, with some like aspirin, anti-thrombotic effects.

Since its introduction a century ago, aspirin has enjoyed waves of popularity in its use as well as in its application in new therapeutic areas. The remarkable thing about aspirin is that despite challenges from many other non-steroidal anti-inflammatory drugs and non-narcotic as well as weak narcotic analgesics, it is still extensively used to control pain, fever and inflammation. Its popularity in highly competitive markets where it is sold extensively on a non-prescription (or over-the-counter) basis, such as in the USA, is testimony to its recognition by the public as a very effective drug. Issues about its safety, especially regarding the gastrointestinal tract and kidneys, have long been recognised, but with careful use and the development of novel formulations these adverse reactions can be regarded as relatively rare - especially for occasional use by adults. The possible risk of Reye's syndrome in children is still a vexed question, as can be seen in Chapter 9. It still seems odd that the syndrome appears not to have been recognised or to have caused appreciable fatalities in children until several decades ago. No doubt the decline in fatalities associated with Reye's syndrome has reflected the reduction in the intake of aspirin, but there may be many other factors involved in this decline.

The popular use of aspirin as anti-thrombotic agent, which arose from the recognition that the antiplatelet aggregating effects of this drug could be responsible for gastrointestinal bleeding, was quickly turned to good therapeutic use. With careful studies to identify the requirement for low dosage to obtain selective effects on the platelets' thromboxane production without markedly influencing prostaglandin production by blood vessels, it was possible to obtain a degree of selectivity in therapy or prophylaxis of thromboembolic diseases. Thus, aspirin is undoubtedly the drug of choice in prophylaxis of cardiovascular conditions in subjects at potential risk of developing myocardial infarction. However, gastrointestinal bleeding can still present a problem at low doses of this drug, although for many this adverse reaction is of low grade and possibly an acceptable risk. Despite its popularity and wide acceptance, there is still research ongoing to identify safer anti-thrombotic agents. The major reason for the success of aspirin as a prophylactic or therapeutic agent for cardiovascular conditions is that it is cheap as well as effective. Cheapness and reliability also account for its widespread use by the lay public, although ibuprofen and paracetamol (acetaminophen) are potent competitors and both have lower risks for developing gastrointestinal and possibly renal adverse reactions. It is because of the competitive aspects of use of these analgesics and other non-steroidal and analgesic agents that aspects of comparison of their actions and use are considered in this book alongside those of aspirin and salicylates.

The major focus in this book is on the key aspects concerning the historical uses and developments of the salicylates, their chemistry and occurrence, pharmacological and toxicological effects, adverse drug reactions and clinical uses. The '. . . and Related Drugs' part of the title is intended to refer to comparisons with other analgesics, non-steroidal anti-inflammatory drugs (NSAIDs) or alternative classes of therapeutic agents that represent competitors, or where there are other important reasons for comparing their actions or adverse reactions. This book has to some extent been modelled on the format of my earlier book, Aspirin and the Salicylates, and a few sections in some of the chapters I have written have been taken, because of historical content, and updated from this book.

In attempting to present a comprehensive account of the salicylates I have enlisted the help of and contributions from leading researchers and physicians in the field. The content emphasis of their contributions has been largely their own, while I have attempted to give an overview. I accept there are some areas of overlap or even differing views; I believe that it is important to have the former because of the need for a comprehensive account within an area of review and discussion for the sake of readability. It is also important to present differing views because this reflects our state of knowledge and the dynamic state of the subject area. To have a homogeneous presentation might help some readers, but for those requiring a critical analysis it is imperative to bring out the contrasts and controversies.

Although the term 'related drugs' logically covers some of the commonly used analgesics, especially ibuprofen and paracetamol, there has been no attempt here to present a comprehensive account that includes these drugs, aside from chapters on their pharmacokinetics and comparisons with the salicylates and some historical aspects. The reader is referred to comparison monographs from the publisher - Professor Prescott's excellent book Paracetamol. A Critical Bibliographic Review, and Ibuprofen. A Critical Bibliographic Review, which was edited by myself and intended to be to some extent a comparison monograph. Perhaps the present volume will be regarded as completing the triad of the most popular or most extensively used analgesic, anti-inflammatory and antipyretic agents. It is recognised that there are some other significant drugs in this class that probably deserve a volume in themselves, but we have attempted broad comparisons with these and have included the newer non-steroidal anti-inflammatories as well.

To achieve a comprehensive account of many areas concerning the mode of action and therapeutics of the salicylates, it is important to cover much important earlier literature that was published in the first half or so of the twentieth century, during which there were important formative data and observations published on aspirin, the salicylates and related drugs. It would be easy simply to cover the most recent literature, but this ignores highly significant and important information that has led to modern development of these drugs. Indeed, there have been numerous examples where revisiting an earlier area of investigation has enabled a new view to be developed, based on this earlier information. For example, the importance of the mitochondrial actions of the salicylates in the development of induced cellular death (apoptosis) brings together the observations of the 1950s and 1960s regarding the effects of salicylates on the uncoupling of oxidative phosphorylation and their effects on intermediary metabolism, with more recent data on the activation of caspases and cytochrome c release from mitochondria. This may be important, along with the newer information on the actions of these drugs on oxyradical and cytotokine-mediated signal transduction events, in understanding the protective effects of aspirin and related drugs in colon and other cancers as well as the mode of action of these drugs in the development of gastrointestinal ulceration and bleeding. As a further example, the longdebated and important therapeutic question regarding the efficacy of high-dose aspirin compared with that of salicylic acid, its dimer, salsalate, or the sodium salt in the long-term treatment of pain and inflammation in rheumatic diseases has been revisited again with evidence that the major antiinflammatory and analgesic actions of aspirin reside in the salicylate that is produced therefrom. Recent studies on the molecular pharmacology of aspirin versus salicylate give further support to this view. The question is an important one therapeutically because the serious gastrointestinal adverse reactions from salicylate (and possibly certain formulations thereof ) have long been recognised as less than those from aspirin. Yet why is it that aspirin is still, despite competition from paracetamol, ibuprofen and other NSAIDs (including the new COX-2 selective inhibitors), used so exclusively in self-medication of chronic, if episodic, arthritic disease as well as in acute states? The simple answer is that many consider that the drug works, and it is cheap. Maybe too many think only of its limitations concerning adverse effects in the major organ systems. We should not forget the old German adage 'Bitter im Mund, gesund im Korper', or 'Bitter in the mouth, healthy in the body' (from Familiar Medical Quotations, edited by M.B. Strauss, published by Little Brown, 1968) for this, as Professor Watson Buchanan has pointed out, is a reflection that you need to experience some adverse reactions to know that a drug works!

The previous question has relevance to the actions of competitors of aspirin, both new and old. Current interest in the COX-2 selective NSAIDs highlights important competitive issues for the salicylates - amongst the oldest of the analgesics. Aspirin and the salicylates have faced such competition in the past, including from ibuprofen and paracetamol. However, one single outstanding therapeutic action in the prevention of coronary vascular disease and stroke, which resulted from the discovery of the antiplatelet effects of the drug over three decades ago, has given aspirin a new lease of life. Intense interest in the mode of action of aspirin (which stems from recent understanding of the molecular biology of the cyclo-oxygenases, apoptosis and other components of the regulation of cell cycle and growth) coupled with clinico-epidemiological evidence that it might prevent colon and maybe other cancers now gives further scope for the therapeutic use of aspirin and others of its class.

With these new(er) discoveries has come recognition that the salicylates are employed as 'bench', 'gold' or 'clinical' standards for comparison with newer agents.

A number of outstanding books and reviews have been written about aspirin and the salicylates, and some of these are listed at the end of the preface. Many of the books have long been out of print, and their availability from libraries is limited or declining. Where possible, many of the points from earlier key literature have been included in this book so that it will provide an important source of information on the salicylates.

I would especially like to thank Mrs Veronica Rainsford-Köchli for her help with translating texts from German and French and for secretarial assistance in preparing this book, and my secretary, Mrs Marguerite Lyons, and Mrs Ann Shepherd for their secretarial support. My thanks too to Mr Richard Seabrook and Miss Kate Maybury, for assistance with obtaining references, and to the libraries of the Royal Society of Medicine and Sheffield Hallam University for the immense help given in obtaining articles and books - some of them from very remote locations.

This book is dedicated to the many colleagues and friends who have willingly shared their views and opinions with me over the years and who have given much valued advice in preparing this book. I especially appreciate the impartial advice, criticism and valuable comments from colleagues and friends, among them Professors Watson Buchanan, Richard Hunt and Walter Kean, (McMaster University, Canada), Dr Michael Whitehouse and Professor Michael Roberts (University of Queensland, Australia), Professor Garry Graham (University of New South Wales, Australia), Dr Michael Powanda (M/P Biomedical Consultants LLC, California, USA) and Dr Brian Callingham (University of Cambridge, UK). I am also most grateful to Dr Callingham for his valuable help in editing the text and for discussing some issues and controversies. This book is also dedicated to the memory of the late Professor Derek Willoughby, who did much pioneering work in the field of inflammation science, and who sadly passed away on 13 March 2004 just as this book was going to press.