The Rationale of Using Calcium Antagonists in the Treatment of Ischaemic Heart Disease

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

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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 overload, as seen during ischaemia and in atherosclerosis. Indeed, Historical review recent human studies have proven a preventive effect of calcium 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 calcium 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]. and Ca-antagonists. The multifaceted genesis of angina pectoris requires different strategies and a differentiated use of Classification of Ca-antagonists Ca-antagonists. There are two major groups of Ca-antagonists: Group A Basic pathophysiological principles of (highly specific Ca-antagonists), and group B (less specific coronary artery disease Ca-antagonists) [16, 18, 19]. In this context we would like to point out the different patho- Group A genic principles of coronary artery disease. The basic princi- This group of highly specific Ca-antagonists consists of 3 sub- ple is an imbalance between oxygen delivery and oxygen de- groups: mand. This can be rooted in an increased oxygen demand of 1. Dihydropyridine Ca-antagonists (nifedipine, nicardipine, the myocardium on the one hand, on the other hand, it can nisoldipine, niludipine, isradipine, nitrendipine, amlo- occur secondary to a decreased coronary blood supply. In dipine, flordipine, silvadipine, darodipine and others) most cases, we find a mixed form where reduced coronary 2. Verapamil-type Ca-antagonists (verapamil, gallopamil, ani- flow is unable to provide the substrate and oxygen desired pamil, romipamil, tiapamil and others) and by the myocardium [21–24]. Decreased coronary delivery 3. Benzothiazepine-type Ca-antagonists (diltiazem and deriva- can have various reasons: vasospasm, concentric and eccen- tives) tric coronary stenosis as well as partial or complete coronary All Ca-antagonists have one thing in common: they inhibit occlusion. The different forms of coronary insufficiency the slow trans-sarcolemmal calcium influx without influenc- named can also be mixed. In most cases it remains unclear ing sodium flow. Moreover, these Ca-antagonists are able to which components are predominant. What remains is a strat- suppress “calcium dependent” action potentials without in- egy of trial and error, which, however, underlie certain prin- fluencing “magnesium dependent” membrane phenomena ciples, of course. [16]. These substances allow the suppression of calcium dependent electromechanical coupling in the ventricular myo- Ca-antagonists in the treatment of cardium up to 100 % without influencing sodium influx at coronary artery disease these concentrations. The drugs bind stereo-specifically to characteristic receptor subunits of calcium transport proteins Albrecht Fleckenstein was the first who alluded to the possi- which act as slow calcium channels [16]. bility of a therapeutic use of Ca-antagonists in the treatment The subdivision of this class A of Ca-antagonists in sub- of coronary artery disease [7]. Later work by Maseri and group 1 (verapamil), subgroup 2 (nifedipine) and subgroup 3 co-workers has constantly indicated coronary spasm as one of (benzothiazepine) is based on the WHO classification [18]. A the important causes of myocardial ischaemia. In this con- simplified model allows the understanding of the distinctive text, Ca-antagonists have become an important tool in the actions of Ca-antagonists [20]: dihydropyridine Ca-antagonists strategy of treating coronary artery disease [25]. Moreover, mainly act on vascular smooth muscle cells and have vaso- certain limitations of other coronary therapeutics, for exam- dilatory effect. Verapamil-type Ca-antagonists also tend to di- ple, tolerance development in nitrate therapy demand thera- late vessels, but reduce conduction velocity as well as pacing peutics such as Ca-antagonists. In particular, Ca-antagonists rate. Hence, they lead to a negative inotropic and chronotropic with a negative chronotropic and inotropic effect which at effect. Dihydropyridine Ca-antagonists may cause tachycar- the same time enact a vasodilative effect (verapamil) seem to dia as a result of a quick decrease in blood pressure via the be excellent therapeutics for the treatment of coronary artery baroreceptor reflex. Such a “reflective tachycardia” may cause disease [26, 27]. In this context, we also would like to men- an attack of angina pectoris. Another group of Ca-antagonists tion the combination of dihydropyridines and betablockers. FOCUS ON CA-ANTAGONISTS Calcium antagonists and ischaemic heart disease J Clin Basic Cardiol 1999; 2: 183

The anticalcinotic and antiatherosclerotic effect of Ca-antago- Coronary spasm can be induced by cold, stress and various nists (Fleckenstein) have opened a new era of calcium an- unknown factors. It is likely that also endothelial factors as tagonist therapy in coronary artery disease. Numerous ani- well as platelet borne substances play a role in this context mal experiments, as well as a couple of larger clinical trials, [49, 50]. have underlined this effect of calcium antagonist drugs [1, Neurogenic mechanisms have also been suggested as causal 20, 28–33]. for coronary artery spasm [51–53]. Dihydropyridines constitute an excellent means in order to thwart vasospastic angina. Mechanisms of action and indications for Rafflenbeul has clearly shown the effect of intravenous Ca-antagonists in patients with nifedipine in coronary spasm [54]. Numerous other authors coronary heart disease have confirmed the data and the use of dihydropyridines in the treatment of coronary artery spasm, which nowadays is an established concept [55–57]. However, there are also data that The detailed mode of action of various subtypes of Ca- show that verapamil as well as diltiazem show positive effects antagonists will not be discussed in this context, but can be upon coronary artery spasm [56]. On the other hand, there found in the references [eg, 1, 20, 34, 35]. In brief: are also hints that nifedipine and diltiazem are more effective 1. In principle, Ca-antagonists act via a relaxation of epicar- than verapamil [58]. In summary, we can say that Ca-antago- dial as well as intramyocardial coronary arteries and lead to nists, in particular dihydropyridines, constitute an excellent an increase of oxygen delivery as well as to an inhibition of means for the treatment of vasospastic angina. In serious cases coronary spasm. The latter plays an important role in the of vasospastic angina, the intravenous use of dihydropyridines genesis of angina pectoris [20, 36]. has also been described [59]. 2. Ca-antagonists also cause vascular relaxation by acting di- The advantage of Ca-antagonism lies in the lack of toler- rectly on the smooth muscle cell in the peripheral artery. ance development (unlike nitrates). Thereby, peripheral resistance is decreased and so is Numerous papers allude to the superiority of dihydro- afterload. This, in turn, leads to a reduction of myocardial pyridines over nitrates [eg, 55]. oxygen demand and improves myocardial oxygen balance. The intensity and frequency of angina pectoris attacks will Silent ischaemia hence be decreased [20, 36, 37]. The pathophysiology of silent ischaemia has not been eluci- 3. The blockade of calcium influx in myocytes of the work- dated so far. The spontaneous occurrence in the presence of ing myocardium will decrease ATP consumption, which physical and psychological stress suggests a vasospastic com- leads to a decrease in oxygen- and substrate demand. In ponent. Hence, Ca-antagonists are highly effective in the treat- clinical terms, this leads to a decrease in angina [20, 36]. ment of such episodes. 4. The prolongation of conduction velocity leads to a negative Betablockers, however, have proved superior to Ca-antago- chronotropy of Ca-antagonists, which prolongs the dura- nists in this concern. Rizzon and co-workers have shown that tion of diastole and leads to an improved cardiac output as such silent episodes of ischaemia can well be managed with a result of an improvement in the Franck-Starling mecha- nifedipine (120 mg/day) or verapamil (480 mg/day) both be- nism. In this context, the oxygen consumption is decreased ing superior to nitrates [60]. Repetitive ischaemic episodes also [20, 38]. may lead to “myocardial stunning”, which can be also treated The clinical efficacy of Ca-antagonists in the treatment of very well by Ca-antagonists. coronary heart disease is evidenced by: 1. Subjective decrease in the frequency of angina attacks [24, Stable and exercise induced angina 36, 39, 40] as well as in a decreased use of nitrates [24, 36]. A. Eccentric coronary arteriosclerosis 2. Decrease of heart rate and blood pressure under therapy Stable angina based on eccentric coronary artery disease is well (heart rate may not be decreased in the presence of suited for treatment with dihydropyridine Ca-antagonists. The dihydropyridines, this phenomenon was described and dis- reason for this observation is that eccentric atherosclerosis still cussed first by Loaldi [32] – the lack of decrease of heart has contractible sections of the arterial wall, which can be di- rate is prominent during exercise [24, 36–38]. lated when Ca-antagonists are used. Since this can lead only 3. Increased exercise tolerance, which improves life quality to a partial vasodilation, the combination with a negative ino- for the patient [24, 36–40]. tropic or chronotropic substance like betablockers seems pru- 4. Reduction in exercise induced ST-depression [39, 40]. dent and has various advantages. Therefore, the combination of betablockers and Ca-antagonists has been recommended How, when and which Ca-antagonist to use in because the betablocker component will prevent an increase the treatment of coronary artery disease in heart rate, secondary to a reduction in blood pressure and, at the same time, will reduce oxygen demand [61]. It has also Vasospastic angina been shown that the combination of dihydropyridines with The importance of vasospasm in the genesis of coronary heart betablockers is superior to a combination of nitrates with disease was already described in 1959 by Prinzmetal. Time and betablockers. This combination exerts a favourable influence again we find patients with angina pectoris and a normal coro- upon the left ventricular function during exercise [62]. nary angiogram. In many of these cases, the vasospastic form of Diltiazem has also been used effectively in this context for angina is the predominant cause. However, the pathophysiol- therapy of coronary heart disease. Extensive work in this field ogy of vasospastic angina has not yet been elucidated completely. has been performed by Subramanian [36]. The importance of vasospasm in the context of the development of myocardial infarction has been discussed by numer- B. Concentric coronary arteriosclerosis ous authors [22, 25, 41–46]. In this context, it could be shown In the case of concentric coronary artery sclerosis, Ca-antago- that, in many cases, sudden cardiac death as a result of myocar- nists may have a negative effect [5, 32, 36, 37]: In particular, dial infarction did not occur together with occlusive thrombo- Ca-antagonists of the dihydropyridine class may lead to a pe- sis in any of the coronary arteries [47, 48]. ripheral vasodilatation and, via the baroreceptor reflex, to an FOCUS ON CA-ANTAGONISTS J Clin Basic Cardiol 1999; 2: 184 Calcium antagonists and ischaemic heart disease

increase of heart rate and, more importantly, to the so-called acting dihydropyridines, benzothiazepines and verapamil type steal phenomenon: of Ca-antagonists. Here, one would prefer nitrates and ACE The vascular bed in other sections of the coronary artery inhibitors. that are not affected by atherosclerosis is dilated – as a result, Often such patients suffer from an adrenergic overdrive blood is “stolen” from the areas that are situated distally from that leads to tachycardia. Betablockers have been used effec- the concentric atherosclerotic lesion. The latter is stiff and tively to counteract this adrenergic overdrive. This results in can not be dilated [63, 64]. Hence, Ca-antagonists are less an improved diastolic filling and thus in an improved haemo- likely to be successful in the treatment of this type of coro- dynamic situation of the heart. Some studies using newer gen- nary artery disease. However, in combination with beta- erations of Ca-antagonists are on the way and results are not blockers, dihydropyridines can be given as well as diltiazem yet available. As far as secondary prevention of myocardial in- [61, 62]. farction is concerned, Yusuf and Fuhrberg published a Ca-antagonists of the benzothiazepine-type as well as vera- meta-analysis of long and short term investigations and showed pamil are well suited for this type of coronary artery disease in an increased mortality (6 %) in patients who have been treated stable angina [36, 38–40, 65]. The following drugs have been with Ca-antagonists after myocardial infarction. This analysis shown as ideally suited compounds: gallopamil, verapamil and shows no favourable effects of Ca-antagonists in secondary diltiazem. prevention. Currently, the evidence for positive effects in cer- However, the main effect of these drugs in this particular tain subgroups of Ca-antagonists is scant and therefore we subtype of coronary artery disease is the decrease in oxygen would currently not recommend those drugs in the treatment consumption of the myocardium as a result of negative of myocardial infarction. chronotropic and negative inotropic effects. More than 10 years ago, the combined use of verapamil and propanolol Primary prevention was propagated [66, 67], however, this combination seems dangerous, because it can lead to AV-block III and asystoly Larger primary prevention studies for Ca-antagonists are rare. [68, 69]. Lichtlen [31] looked at normotensive patients with coronary It should also be noted that during physical exercise, the artery disease after 3 year’s treatment with nifedipine and could relative tension of the arterial wall can be increased (possibly show a certain degree of prevention of atherosclerotic plaque a result of increased catecholamines) [70] and, as a result, coro- development. A number of experimental studies alluded to nary artery dilation via Ca-antagonists could be even more the antiatherosclerotic effect of Ca-antagonists. The link be- effective under exercise than at rest [70, 71]. This results in tween arterial wall cholesterol and Ca++ is, however, still improved oxygen delivery and could be the main source of missing. Cardiovascular events such as myocardial infarction the antianginal effect of nifedipine [2, 71]. Another impor- or sudden cardiac death were not reduced in this study, pro- tant patho-mechanism in ischaemic heart disease is increased gression of coronary artery disease was also not affected. These “diastolic stiffness” of the myocardium, which is an early mani- results have been supported by a Canadian study using festation of ischaemia [2, 72]. Verapamil improves left ven- nicardipine [81]. Klein [29] and co-workers as well as Kober tricular filling, but does not affect diastolic ventricular func- and co-workers (personal communication) have found cer- tion to the same extent [72–74]. tain indications that diltiazem and verapamil would cause a regression of atherosclerotic plaques. However, these were re- Unstable angina trospective analyses. Unstable angina may be very different from stable angina as The recently published follow up data of the INTACT trial far as its pathophysiology is concerned. It is largely rooted in show a remarkable retardation of progression of coronary ar- vasospastic forms of angina and in intermittent coronary tery disease while, however, no favourable clinical effects of thrombus formation [75–77]. Clinically, it appears as angina long term dihydropyridine administration have been seen in at rest and requires hospitalization of the patient with intrave- these patients and the number of cardiac deaths and non-fatal nous therapy in order to avoid progression to myocardial inf- cardiac events was equal in both groups (patients with and arction. Dependent upon the possibilities and the severity of without nifedipine). The vision of primary prevention of coro- unstable angina, the intracoronary and the intravenous ad- nary heart disease using Ca antagonists will certainly take much ministration of Ca-antagonists have proven useful [54, 55]. more time to manifest itself in the real world of day to day In a “cross-over study” with intravenous nifedipine the re- practice. A lot of further clinical trials will be needed in order sults were better than those with intravenous nitroglycerine. to allow a solid final statement on primary prevention with It was shown that ischaemic episodes can be better controlled Ca-antagonists. [78]. Previtali and co-workers have treated patients with a ten- References dency to spastic angina using oral nifedipine, diltiazem and 1. Gasser R. Antiarteriosklerotische Wirkung von Calciumantagonisten und coronare Herzkrankheit. Monographie. Fakultas, Wien, 1990. verapamil as well as in unstable forms of angina. All 3 types of 2. Opie LH. Calcium channel antagonists. 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