Milestones in Drug Therapy MDT Series Editors Prof. Dr. Michael J. Parnham Prof. Dr. J. Bruinvels Senior Scientific Advisor Sweelincklaan 75 PLIVA dd NL-3723 JC Bilthoven Prilaz baruna Filipovica 25 The Netherlands HR-10000 Zagreb Croatia Calcium Channel Blockers T. Godfraind with a contribution by E. Erte l Springer Basel AG Theophile Godfraind Universite Catholique de Louvain Avenue Hippocrate 54 - UCL 5410 B-1200 Bruxelles Belgium Advisory Board J.C. Buckingham (Imperial College School of Medicine, London, UK) D. de Wied (Rudolf Magnus Institute for Neurosciences, Utrecht, The Netherlands) F. K. Goodwin (Center on Neuroscience, Washington, USA) G. Lambrecht (J.W. Goethe Universität, Frankfurt, Germany) Library of Congress Cataloging-in-Publication Data Godfraind, T. (Theophile) Calcium channel blockers / T. Godfraind ; with a contribution by Eric Ertel. p. cm.-- (Milestones in drug therapy) Includes bibliographical references and index. ISBN 978-3-0348-9599-6 ISBN 978-3-0348-7859-3 (eBook) DOI 10.1007/978-3-0348-7859-3 1. Calcium—Antagonist—Mechanism of action. I. Title. II. Series. RM666.C243G63 2003 615'.739-dc22 2003063565 Bibliographic information published by Die Deutsche Bibliothek Die Deutsche Bibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data is available in the Internet at <http://dnb.ddb.de>. ISBN 978-3-0348-9599-6 The publisher and editor can give no guarantee for the information on drug dosage and administration contained in this publication. The respective user must check its accuracy by consulting other sources of reference in each individual case. The use of registered names, trademarks etc. in this publication, even if not identified as such, does not imply that they are exempt from the relevant protective laws and regulations or free for general use. This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, re-use of illustrations, recitation, broad casting, reproduction on microfilms or in other ways, and storage in data banks. For any kind of use, permission of the copyright owner must be obtained. © 2004 Springer Basel AG Originally published by Birkhäuser Verlag in 2004 Softcover reprint of the hardcover 1st edition Printed on acid-free paper produced from chlorine-free pulp. TCF °o Cover illustration: Model of voltage-operated Ca"+ channel flanked with typical calcium channel blockers. ISBN 978-3-0348-9599-6 98765432 1 www.birkhasuer-science.com v Contents Preface VII Acknowledgements XIII Historical perspective: from early steps on calcium research to the identification of calcium antagonist prototypes and of the signaling functions of ci+ ............................ . Calcium channel blockers and calcium channels 11 Eric Ertel and Theophile God/raind The action of calcium antagonists on Ca2+ movements in isolated vessels ......................................... 81 The tissue selectivity of calcium antagonists 113 Acute haemodynamic effects of calcium channel blockers ......... 131 Calcium channels and regulation of vascular tone in hypertension ... 151 Long-term effects of calcium antagonists ...................... 161 Blood pressure-independent effects of calcium antagonists 181 From early clinical studies to randomized controlled clinical trials 199 Beyond the cardiovascular system 237 Index ................................................. 255 VII Preface The drugs named calcium channel blockers (CCBs) were initially termed cal cium antagonists (see Chapter 1). They are also designated as calcium entry blockers (CEBs), calcium blockers, calcium channel antagonists, calcium channel inhibitors (and in French anticalciques). As this is reported in several chapters of this book, their main effect is a blockade of calcium entry into cells through voltage operated calcium channels (VOCCs). Chemically related drugs, such as Bay K 8644, exert the opposite effect by increasing the proba bility of calcium channel opening. One of the subcommittees of the Nomenclature Committee (NC-IUPAR) of the International Union of Pharmacology has been devoted to the classification of calcium channels and the site of action of drugs modifying channel function. The members of this Committee are noted for their significant contribution to the field (Tab. 1). A report has been published in 1992 in Pharmacological Reviews [3]. A list of criteria was approved for the identification of distinct drug binding sites on Ca2+ channels. It included: (a) the demonstration of a stereoselective binding site supported by drug interaction studies (competition with other drugs, non-competitive interactions with other sites, reversal of inhibitory effects by channel activators); (b) demonstration of the electrophysiologieal effects of the drug and selectivity of action compared to other sites; (c) deter mination of the affinity for the type and subtype of ion channel. These criteria have identified different classes of Ca antagonists (see Chapter 2). When rec ommending a drug nomenclature, the Committee mentioned that the terms "calcium antagonist" or "calcium entry blocker" have gained historic pharma cological and clinical acceptance when applied to agents inhibiting L-type channel function by acting at specific sites and that these terms will undoubt edly continue to be used to describe the classic pharmacological properties of this type of agent. However, it was clear at that time that new pharmacological profiles were expected from interactions with other types of calcium channel, or even from new binding sites on the L-type channel, quite different from the profile associated with, for example, nifedipine. For the Committee, the term "calcium channel modulator" was preferred for agents interacting with calci um channels. The term "calcium agonist" was considered inappropriate, and agents such as Bay K 8644 were referred to as calcium channel activators and inhibitory compounds were referred to as calcium channel blockers. More recently NC-IUPHAR has established a new subcommittee devoted to calcium channels classification (Tab. 2), which has published a Compendium in 2002 [1]. The IUPHAR recommended classifications have been followed in this book, which is divided in ten chapters. All chapters can be independently read. VIII Preface Table 1. Composition of the temporary section of the Nomenclature Committee (NC-IUPAR) of the International Union of Pharmacology devoted to the classification of calcium channels and the site of action of drugs modifying channel function R. Paoletti J. Moss President: Institute of Pharmacol. Sciences, Professor of Anesthesia and Critical Care Via Balzaretti 9 The University of Chicago Medical Center 20133 Milan, Italy Chicago, IL 60637, USA M. Spedding S. Murata Institut de Recherches Servier Department II Suresnes, France Pharmacological Research Laboratory Tanabe Seiyaku Co Ltd 2-2-50, Kawagishi, Toda-Shi Saitarna, Japan F. R. Buhler J. Olesen Department of Internal Medicine Department of Neurology University Hospital Gentofte Hospital CH-4031 Basel, Switzerland University of Copenhagen 2900 Copenhagen, Denmark M. O. Christen L. H. Opie Lab. de Therapeutique Medeme L. T. M University of Capetown Latema Sarbach Heart Research Unit and Hypertension Clinic 42, Rue Rouget-de-Lisle Department of Medicine Medical School, 92151 Suresne Cedex, France Observatory 7925, South Africa S. Ebashi A. Schwartz Director-General and Professor Professor and Chairman National Institute for Physical Sciences Department of Pharmacology and Cell Myodaiji, Okazaki 444, Japan Biophysiology University of Cincinnati College of Medicine Cincinnati, OH 45267-0575, USA C. Fieschi B. Siesjo Cattedara di Clinica Neurologica University of Lund Viale delI'Universita 90 Laboratory for Experiment University of Rome Brain Research, Lund Hospital S-22185 Lund, Sweden A. Fleckenstein (t) and G. Fleckenstein-Grun R. W. Tsien Albert Ludwigs Universitiit Department of Molecular Cell Physiology Physiologisches Institut Stanford University Herman Herder Strasse 7 B 105 Beckman Centre D-7800 Freiburg, Germany Stanford, CA, USA T. Godfraind P. M. Vanhoutte Laboratoire de Pharmacodynamie Baylor College of Medicine Generale et de Pharmacologie Centre for Experimental Therapeutics Universite Catholique de Louvain One Baylor Plaza Avenue Mounier 73-U. C. L 7350 Houston, TX 77030, USA B-1200 Bruxelles, Belgium B. E. G. Johansson J. M. Van Nueten AB Hassle Research Labs International Research Council 8-431 83 Molndal Janssen Research Foundation Sweden Turnhoutseweg 30 B-2340 Beerse, Belgium (Continued on next page) Preface IX Table I. (Continued) S. Kazda P. A. Van Zwieten Bayer A. G.-Institute fuer Pharmacologie Departments of Pharmacotherapy, Postfach 10 1709 Pharmacology and Cardiology D-5600, Wuppertal, Germany Academic Medical Centre and Academic Hospital University of Amsterdam I 105 AZ Amsterdam, The Netherlands R. J. Miller Department of Pharmacology University of Chicago 947 E. 58th Street Chicago, IL 60637, USA Chapter 1 deals with an historical perspective: from early steps on calcium research to the identification of calcium antagonist prototypes and of the sig naling functions of Ca2+. Chapter 2 is a review dealing with the various iden tified calcium channels: receptor-activated, ligand-gated, and voltage-operat ed. Special attention is devoted to voltage-operated calcium channels that are targets of calcium antagonists. Chapter 3 deals with the action of calcium antagonists on Ca2+ movements in isolated vessels. Our initial hypothesis [2] was that the reduction of blood pressure by calcium antagonists is the result of a decrease of peripheral resistance due to vasodilatation within the arterial beds. Therefore, a large body of experimental work has been concerned with studies of the mechanism of action of CCBs in arteries. Earliest studies have addressed the mechanism of action of calcium antagonists in the vasculature by considering their interaction with Ca2+ activator of the contractile machin ery. Such approaches have required the characterization of calcium movements in the absence and in the presence of calcium antagonists. Chapter 4 deals with the tissue selectivity of calcium antagonists, which has some interest for phar macotherapy. Analytical pharmacology studies of various CCBs that have sup ported the concepts of tissue and action selectivity are reported in this chapter. Chapter 5 deals with acute haemodynamic effects of calcium channel block- Table 2. NC-IUPHAR Subcommittee on calcium channels William A. Catterall (Chairman), Department of Pharmacology, University of Washington School of Medicine, Box 357280, Seattle WA 98195-7280, USA; E-mail: [email protected] Joerg Striessnig, Abteilung Pharmakologie und Toxikologie, Institut fUr Pharmazie, Universitat Innsbruck, A-6020 Innsbruck, Austria Terrance P. Snutch, Biotechnology Laboratory, University of British Columbia, Vancouver, British Columbia V6T IZ3, Canada Edward Perez-Reyes, Department of Pharmacology, University of Virginia, Charlottesville VA 22908, USA x Preface ers. The examples taken in this chapter are illustrative of the actions of CCBs in general, even if all drugs have not been examined. Owing to the complexi ty of haemodynamic reflexes and the tissue selectivity of CCBs at the level of the various vascular beds, it might be anticipated that those drugs may exhib it variations in action according to the vascular bed or the species so far con sidered. Because of the importance of CCBs for the therapy of coronary dis eases, hypertension and stroke, their actions have been studied in coronary, renal and cerebral circulations. Chapter 6 deals with calcium channels and the regulation of vascular tone in hypertension. Regulation of the contractile activ ity of vascular smooth muscle cells in the systemic circulation is dependent on a complex interplay of vasodilator and vasoconstrictor stimuli from circulating hormones, neurotransmitters, endothelium-derived factors, and blood pres sure. All these signals are integrated by vascular muscle cells to determine the activity of the contractile apparatus of the muscle cells and hence resistance of a blood vessel. Calcium antagonists produce a hypotensive effect more pro nounced in hypertensive than in normotensive humans and animals. How the disease modifies the target is the purpose of this chapter. Chapter 7 deals with long-term effects of calcium antagonists. Indeed, patients are treated for life with those drugs, which prevent both in hypertensive humans and animals the alterations of various organs including heart and kidneys. Analysis of the long term effects has been done in experimental animals showing how calcium channel blockers prevent tissue remodeling and the activation of endothelin and renin-angiotensin systems in salt-sensitive species. Such studies raise the question of whether the reduction of blood pressure is the sole mechanism responsible for the therapeutic long-term effects. Therefore, in Chapter 8 we examine the blood pressure-independent effects of calcium channel blockers as potential mechanisms of tissue protection, which have not reached full acceptance because of poor evidence from clinical studies. Evidence for such mechanisms is provided by various studies: analytical pharmacology showing that prevention of cardiac remodeling is not directly related to reduction of blood pressure, effects on hypertrophic stimuli in cardiac cells in culture, blockade of the renin-angiotensin system, inhibition of the translocation of protein-kinase, interaction with the L-arginine-NO pathway and the anti-oxi dant properties of some molecules that could account for a therapeutic action in atherosclerosis. Chapter 9 deals with early clinical trials and with random ized control trials (RCTs) in cardiovascular medicine, considering cardiac ischaemia, cardiac arrhythmias, hypertension and atherosclerosis. Questions raised by meta-analyses are also examined in the light of results obtained from ALLHAT, the largest RCT so far organized in the treatment of hypertension. Chapter lOis entitled 'Beyond the cardiovascular system' . Blockade of L-type calcium currents by dihydropyridines, phenylalkylamines and benzoth iazepines forms the basis for treatment of cardiovascular diseases. A number of other agents that either un selectively or selectively target neuronal and other calcium channels have been described. Some of them have been introduced in therapy to treat gastro-intestinal or neuronal disorders and more recently, some Preface XI blockers have become the subject of intense interest regarding their potential ity for the treatment of chronic and neuropathic pain. This appears promising for a variety of pain conditions. Those various aspects are examined. In the final section of this chapter it is assumed that although the future is by defini tion imperceptible, it is likely that powerful medicines will be identified with in a novel generation of calcium channel blockers. New chemical and biolog ical technologies are emerging in the field of calcium channels pharmacology that may help the discovery of novel compounds more active in diseases insuf ficiently controlled by the actual calcium channel blockers. References 1 Catterall WA, Chandy KG and Gutman GA. The IUPHAR Compendium of voltageg ated ion chan nels. Leeds: IUPHAR Media, 2002 2 Godfraind T. Nouveaux aspects de la pharmacologie du muscle lisse vasculaire. Prod Prob! Pharmac26: 117-125,1971 3 Spedding M and Paoletti R. Classification of calcium channels and the sites of action of drugs modifying channel function. Pharmacal Rev 44: 363-376, 1992