The Rationale of Using Calcium Antagonists in the Treatment of Ischaemic Heart Disease
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Journal of Clinical and Basic Cardiology An Independent International Scientific Journal Journal of Clinical and Basic Cardiology 1999; 2 (2), 181-186 The rationale of using calcium antagonists in the treatment of ischaemic heart disease Kickenweiz E, Gasser R, Köppel H, Moosbrugger B Homepage: www.kup.at/jcbc Online Data Base Search for Authors and Keywords Indexed in Chemical Abstracts EMBASE/Excerpta Medica Krause & Pachernegg GmbH · VERLAG für MEDIZIN und WIRTSCHAFT · A-3003 Gablitz/Austria FOCUS ON CA-ANTAGONISTS Calcium antagonists and ischaemic heart disease J Clin Basic Cardiol 1999; 2: 181 The rationale of using calcium antagonists in the treatment of ischaemic heart disease E. Kickenweiz, H. Köppel, B. Moosbrugger, R. Gasser Calcium antagonists were discovered in the late 60s by Albrecht Fleckenstein and co-workers, who also solved the question of the action of calcium antagonists on the slow calcium channel. Since then, enormous developments have taken place and calcium antagonists have found a broad application in the treatment of hypertension as well as coronary heart disease. Drugs such as verapamil and nifedipine have proven useful in the long-term treatment of coronary heart disease. In particular, these drugs did not show any development of tolerance as, for example, nitrates did. Many studies have shown that calcium antagonists have a solid place in the treatment of ischaemic heart disease. They dilate coronary arteries and decrease oxygen consumption. Newer compounds in second and third generation dihydropyridines such as amlodipine, lercanidipine and lacidipine have revolutionized calcium antagonist treatment. These newer drugs do not show an effect on the cardiovascular system like early dihydropyridines did (tachycardia etc.). This article explains the rationale of using calcium antagonists in the treatment of ischaemic heart disease and the mechanisms of the principle underlying this type of treatment. J Clin Basic Cardiol 1999; 2: 181–6. Key words: calcium antagonists, ischaemic heart disease alcium antagonists (Ca-antagonists) have been used for Ca-antagonists during acute myocardial infarction is problem- Cmore than two decades in the treatment of coronary heart atic, in particular in patients with left ventricular dysfunction. disease. Their use was initially promoted for variant angina, In secondary prevention, Ca-antagonists have failed and it but soon expanded to all forms of coronary heart disease en- has been generally accepted that they should not be used. tailing stable and unstable angina. On the basis of promising Ca-antagonists of the dihydropyridine-group increase heart experimental findings, these drugs were also given in the treat- rate and can be effectively combined with betablockers [2]. ment of myocardial infarction, however with disappointing The uses of different types of Ca-antagonists require a differ- results. The same was true for secondary prevention. The basic entiation of patient classes as well as substance classes. principle underlying Ca-antagonist therapy of ischaemic heart Recent research has been directed to the development of disease is the improvement of myocardial oxygen balance. On highly specific and more selective subgroups of Ca-antagonists: the one hand, Ca-antagonists (in particular verapamil and For example, dihydropyridines show little negative effect on diltiazem) reduce myocardial oxygen demand via negative ino- inotropy and tend to decrease reactive neuro-humoral activa- tropic and chronotropic action – on the other hand, the tion which, in turn, is favourable for the treatment of ischae- afterload is reduced by peripheral vasodilatation. In addition, mic cardiomyopathy. This article gives an overview of the vari- coronary dilation improves oxygen delivery, especially during ous types of Ca-antagonists and their use in the treatment of exercise. Ca-antagonists inhibit trans-sarcolemmal calcium coronary heart disease. influx, thus preventing deleterious myocardial calcium over- load, as seen during ischaemia and in atherosclerosis. Indeed, Historical review recent human studies have proven a preventive effect of cal- cium blockers against atherosclerosis. In 1882 Sydney Ringer changed his laboratory assistant. The The discovery of Ca-antagonists and their principle of ac- result was that his isolated perfused Langendorff hearts stopped tion has revolutionized cardiovascular therapy in the course beating. It took some time until Ringer found out that his of more than twenty years. Since their discovery, the thera- former laboratory assistant used the dirty water of the Thames, peutic spectrum of these drugs has constantly increased. It while his new assistant used distilled water in order to pro- covers certain forms of arrhythmias as well as hypertension duce the solutions for the perfusate. The dirty river Thames and coronary heart disease. In this context important devel- contained enough soluble calcium to allow contractibility. opments have taken place. The positive effect of Ca-antagonists From this laboratory accident results our knowledge that cal- is attributed to the reduction of afterload via a decrease of cium is needed for electromechanical coupling [3]. Thirty peripheral resistance, the lowering of myocardial oxygen de- years later, Cow investigated the effect of calcium on isolated mand and the inhibition of calcium overload in cardiac and smooth muscle. Ebashi later described the interdependence vascular tissue. The anti-atherosclerotic effect of these drugs between actin, myosin, troponin and ATP-activity together has also been discussed. The latter has been evidenced in nu- with calcium [4]. merous animal experiments and by a number of multicenter Ca-antagonists have been used for a long time in order to trials in patients [1]. treat coronary heart disease. More than three thousand years Ca-antagonists can be effectively used in the treatment of ago, the Chinese started to use tea from a plant called Dan the following conditions: stable as well as unstable angina, hy- Shen, that contains a naturally available Ca-antagonist called pertensive heart disease and transient ischaemia as well as myo- “Tanshinone”. The drug was used in Chinese medicine in cardial “stunning”. The specific Ca-channel blocker diltiazem order to treat angina pectoris [5]. has been used effectively in order to treat acute non-transmu- In 1963 Albrecht Fleckenstein was asked to investigate a ral infarction. Other studies, however, point out that the use of substance called “iproveratril” (later verapamil) and “prenyl- From the Department of Cardiology, University of Graz, Austria. Correspondence to: Dr. med. E. Kickenweiz, I. Med. Kardiologie-Ambulanz, Karl-Franzens-Universität Graz, Auenbruggerplatz15, A-8036 Graz FOCUS ON CA-ANTAGONISTS J Clin Basic Cardiol 1999; 2: 182 Calcium antagonists and ischaemic heart disease amin”. Fleckenstein and co-workers found that these sub- has properties between group 1 and group 2: the so-called stances affect myocardial contractility as well as smooth mus- benzothiazepine Ca-antagonists and their derivatives. Diltiazem cle tone. This effect could be compared to the effect of cal- is not only cardiodepressive but also a strong vasodilator. cium withdrawal: When calcium was added to the solution, contractility recovered [6]. Fleckenstein was the first to pos- Group B tulate the principle of calcium antagonist action [7]. Only ten This group represents the less specific Ca-antagonists. Among years later, Lewis and co-workers [8] began to use these drugs these are prenylamine, fendiline, terodiline, caroverine, per- in the treatment of hypertension. Around the same time, the hexiline, cinnarizine, flunarizine and bepridil [16, 20]. These first dihydropyridine Ca-antagonist was discovered. It was a substances have a lower affinity to the calcium channels and substance called “Bay a 1040”, which was used earlier as a the calcium antagonist activity is less pronounced than in group yellow colouring pigment. Fleckenstein and co-workers then A. They also affect the fast sodium current. Various papers [9] showed that the substance has a highly specific vasodila- have shown that this group of Ca-antagonists also affects tor effect. In 1975 Nikajima and co-workers [10] found that magnesium-dependent bioelectrical membrane phenomena. there was another class of highly specific Ca-antagonists re- Fleckenstein used this criterion as the second important prin- lated to benzothiazepines: diltiazem. The blockade of slow ciple of this differentiation between group A and group B of calcium channels as a fundamental principle of calcium an- Ca-antagonists [16, 20]. Group B of Ca-antagonists is only tagonism was first postulated by Kohlhart and Fleckenstein in rarely used in clinical treatment today. 1972 [11]. Their work confirmed the earlier concept of cal- cium antagonist action as a slow channel blocker. Livsley and Coronary artery disease and Ca-antagonists co-workers were the first to introduce Ca-antagonists for the treatment of angina pectoris [12]. Glossman and associates The therapeutic spectrum of drugs that is available in order to described receptor binding at the calcium channel for these treat coronary heart disease has various options. Not only in- substances in 1984 [13]. Several authors later described cal- terventional cardiology and bypass surgery, but also pharma- cium antagonist myocardial protection, mainly Bourdellion, cotherapy is used. The latter consists of nitrates, betablockers Henry, Clark and Fleckenstein [14–17].