45
From the Heart section, Dept. of Medicine, General Hospital, Malmo, Sweden
Clinical Aspects of Ca-blocking Agents.
Bengt W. Johansson
Muscular contraction is caused by the thin actin filaments sliding over the myosin filaments and thus bringing about a shortening of the muscle fibres. The presence of troponin and tropomyosin prevents actin and myosin from reacting together - troponin and tropomyosin is therefore termed “relaxing protein”. The occurrence of calcium, which bonds with troponin, inhibits this relaxing effect, and the reaction between actin and myosin then occurs, resulting in muscular contraction. These reactions are energy-consuming, and the ultimate energy generator is adenosintriphosphate, ATP, which in turn is synthesized by various metabolic processes requiring oxygen. In normal blood supply to the myocardium via normal coronary vessels, the supply of oxygen is sufficient. When the coronary vessels are obstructed, oxygen deficit ensues and with it a shortage of energy for the metabolic processes required for muscular contraction. With moderate obstruction of the coronary vessek, symptoms do not appear until physical or mental effort increases the demand on the blood supply to the myocardium. As obstruction increases, symptoms will also appear in connection with slight exertions or even while the patient is at rest.
It is therefore natural to suppose that Cablockers, which reduce the intensity of muscular contraction and oxygen demand with it, have a favourable effect on patients with symptoms related to a reduced flow of blood via the coronary vessels to the myocardium, i.e. patients with angina pectoris. In fact several studies have confirmed that Ca-blockers have a positive effect on angina pectoris due to an atherosclerotically induced coronary insufficiency. Ca-blockade as an oxygen-reducing mechanism is quite a recent working hypothesis, and when investigations of these compounds were first begun, the main focus of attention was on their vascular expanding effect rather than their Ca-blocking effect. For various reasons it is important to bear this vasodilatory effect in mind. One reason is the renewed attention which in recent years has come to be paid to coronary vascular spasm as a cause of angina pectoris. Another is the sympathetic activation to which vasodilation gives rise, together with the concomitant increase in oxygen consumption. Thus there is reason to ask: what is the net effect of the reduced oxygen consumption caused by the Ca-blockers and the increased oxygen consumption involved. by a higher sympathetic activity.
46 Angina pectoris Several studies have been published showing that Ca-blockers have a positive influence on patients with coronary insufficiency and angina pectoris, judging by the degree of S T reduction in the ECG, the number of anginal attacks, nitroglycerine consumption and physical work capacity (1st International Nifedipine “Adalat” Symposium, University of Tokyo Press, Tokyo 1975; 2nd International Adalat Symposium, Springer Verlag, Berlin 1975; 3rd International Adalat Symposium, Excerpta Medica, Amsterdam 1976; JOHANSSON & JOHNSSON 1971; Angina pectoris - Isoptin, AB Meda 1977; ATTERHOG et al. 1975; EKELUND & O Ri 0 1978; HAGMAN 1977). Not all investigations are equally positive, however, (MC ARTHUR et al. 1975). With Ca-blockers as with G !, blockers, not all angina pectoris patients show a positive response. One reason for this may be that the Ca-blockers, like p-blockers, have multiple and partly contrary pharmacological effects which can be pronounced to different extent in different patients; this can apply, for instance, to the degree of compensatory sympathetic stimulus. Similarly, the negative inotropic effect of the Ca-blockers can have varying results, depending on the degree of the patients’ cardiac decompensation. The possibility of tolerance development is also important in connection with diseases requiring long-term treatment. Several studies have shown that the favourable effect on the anginous symptom persists even after prolonged treatment (CASTRO et al. 1976; MENNA et (11. 1976; ABELIN 1976). On the other hand conflicting results have been obtained concerning the effect on pulse and blood pressure (CASTRO et o f . 1976; MENNA et al. 1976). What drug should then be given to patients with angina pectoris? There is no doubt that nitroglycerine is still the drug of choice. To many people the second drug has been a 8blocker, while to certain people it has been nitroglycerine in a slow-release form. It is clear that Ca-blockers constitute a therapeutic alternative. There is comprehensive clinical documentation underlying the choice of /?-blockers as drugs of second preference (Angina pectoris -
Isoptin, AB Meda 1977). There is one group where a Ca-blocker should be considered as a drug of second preference, namely those patients in whom a ,+blocker is contraindicated, and this applies particularly to patients with obstructive lung disease. Admittedly these patients tolerate a selective /j-blocker, but the selectivity is not complete and some of these patients develop side effects. Cardiac decompensation is also a contraindication to pblockade as well as AV-block of the second and third degree, but the negative inotropic effect of the Ca-blockers and the effects of certain of these drugs on AV-conduction demands caution in these states. Another group in which Ca-blockers should be tried comprises the patients who d o not respond satisfactorily to /?-blockade (EKELUND & ATTERHOG 1975). The Ca-blockers may provide a therapeutic alternative to the fiblockers, because they act via other mechanisms. Efficacy, of course, is an important factor governing the choice of drug. Certain studies have compared the effect of a Ca-blocker with that of a P-blocker. Various parameters have been chosen for comparison, and the findings vary somewhat, but there are no striking differences between p-blockers and Ca-blockers (EBNER & DONSCHEDE 1976; LIVESLEY et 01. 1973), though in one study verapamil proved to be superior to practolol (FAGHER et 01. 1977). The aim of drug therapy in angina pectoris is to reduce the oxygen consumption of the myocardium. Since p-blockers and Ca-blockers both reduce oxygen consumption but do so in different ways, it ought, theoretically speaking, to be an advantage to combine /?- and Cablockers. There are studies which support this kind of assumption (EKELUND & O R 6 1976; KENMURE & SCRUTON 1976). Theoretically, of course, this also increases the risk of side-effects, but no serious coniplications occurred in the reported series. Nor have they occurred among the limited number of patients on whom I have tested a combination of pand Ca-blockers. Prinzmetal’s variant angina constitutes a special group of patients where the angina symp-
41 toms in certain cases are induced by a spasm in the coronary vessels. Ca-blockers have also been reported to have a positive effect on these patients, but these findings are based on studies without adequate controls (HOSODA & KIMURA 1976). Arrhythmias
ventricular rate is regularly observed (SCHAMROTH et al. 1972). Similar reductions of ventricular rate occur in patients with auricular flutter. One interesting observation is the more regular R-R interval which occurs in patients with auricular fibrillations after the administration of verapamil (SCHAMROTH 197 I : SCHAMROTH et crl. 1972). This equalization of the R-R interval seems to be less pronounced in elderly persons (SCHAMROTH et 01. 1972). The mechanism is not known. There has been conjecture concerning a stabilizing effect on the various degrees of “concealed conduction” in the AV node which may be at the bottom of the regular ventricufar response in cases of auricular fibrillation. No such equalization of the R-R interval occurs after the administration of a /?-blocker, acebutolol (JOHANSSON, unpublished results) (Fig. 1). There is no difference between digoxin and p-methyl-digoxin in terms of equalizing effect (JOHANSSON et al. 1977).
Ca-blockers have also been used as antiarrhytmic agents. Clinical experience is confined t o experience of verapamil. In animal experiments, verapamil has proved antiarrhythmically efficacious against experimentally induced arrhythmias (SCHMID & HANNA 1967; RODRIGUES-PEREIRA & VIANA 1968; SlNGH & WILLIAMS 1972). Increasingly comprehensive clinical documentation has gradually been accumulated, and verapamil has proved effective above all in the treatment of supraventricular arrhythmias (Symposium on Arrhythmias, Meda AB 1974; KRIKLER 1974). A iiricular fibrillation can sometimes be regularized by verapamil, and a reduction of the -14.5
R-R INTERVALL IN MM
a14.5 1s.5
-13.0
R
ACEBUTOLOL
12.0
-
11.0
10.0
GH 17 01 17
P
11.0 YOI
Daua
ion
9.0 8.0 7.0 6.0 5.0 4.0 x
ac
P
3.0
3 .O
2.0 1.0
REST
Nacl
0.l5~1&~0.23%
o.a-t~&
050%
0 . w 12.%’
Fig. I. R-R intervals in patient with atrial fibrillation after increasing dosages of a @-blockingagent,
acebutolol.
48 From a clinical viewpoint this regularizing effect can sometimes be useful in patients with persistent auricular fibrillation who find the irregularity of their cardiac activity unpleasant and disturbing. Paroxysmal siipraventricular tachycardia can often be stopped by the intravenous administration of verapamil (Symposium on Arrhythmias, Meda AB, 1974; KRIKLER 1974) and the oral administration of verapamil reduces the frequency of relapses into paroxysmal supraventricular tachycardia (MIDTBO 1974). Verapamil has proved to have regularizing effect on several patients with auricular tachycardia with AV-block (STORSTEIN & LANDMARK 1975), an arrhythmia which is by no means invariably a manifestation of digitalis intoxication (STORSTEIN & RASMUSSEN 1974). The tachycardias which occur in connection with the Wolff-Pnrkinson-White-syndrome can often be successfully stopped with verapamil. Verapamil is preferable for WPW patients with auricular fibrillation, because the administration of digitalis to such patients is liable to cause ventricular fibrillation.
Hypertension The Ca-blockers have a vasodilatory effect and their acute administration brings about a drop in blood pressure coupled with a rise in the pulse rate. It is therefore natural to discuss the possible role of these drugs in the treatment of hypertension, perhaps not as a single drug, but, on account of the tachycardia, together with p-blockers, i.e. analogously to a combination of p-blockers and hydralazin. Tt is to be hoped that the complication entailed by hydralazin treatment which can be seen in the form of SLE will then be eliminated. Parenterally administered verapamil has proved effective in the treatment of hypertensive crisis (ESSER ef al. 1969). The reduction of blood pressure which was discovered more or less by chance when verapamil was administered orally to slightly hypertensive patients with ischaemic heart disease (LIVESLEY et al. 1973; TSCHIRDEWAHN & KLEPZIG 1963; HOFFMAN 1964) led to further studies of its anti-hypertensive effect. Although preliminary data point to a pressure
reduction following oral administration of verapamil (BENDER 1970; LEVY 1973) further studies are needed. Nifedipine also reduces blood pressure when administered acutely. In a preliminary study of 30 hypertensive patients, nifedipine and placebo double-blind cross-over, respectively, were added in addition to various forms of anti-hypertensive treatment. No further reduction of blood pressure was found to result from nifedipine in a dose of 10 mg t.i.d. for 3 weeks (LAASER et al. 1975).
Reduction of myocardial infarction size In recent years there have been exhaustive discussions of the possibilities of reducing oxygen consumption in a heart affected by an acute infarction and thereby reducing the extent of the infarction (MAROKO & BRAUNWALD 1976). Several interventions in the form of intra-aortic balloon counterpulsation and the administration of several drugs in experimental studies have proved capable of reducing the extent of the infarct. The efficacy of drugs in clinical practice is less apparent. One reason for this may be that drugs are often administered too late in the infarction process, by which time irreversible ischaemic damage has already occurred. Another reason may be that the amount of myocardium salvaged is only marginal. Yet another reason may be that the myocardium thus salvaged becomes a site for arrhythmias or gives rise to other complications, so that the net gain is slight. In view of the reduction of oxygen consumption that is brought about by the Ca-blockers, one is tempted to suppose that they would have a protective influence on an ischaemic myocardium. FLECKENSTEIN et 01. (1974) have shown that isoprenaline-induced myocardial necrosis can be prevented by the simultaneous administration of Ca-blockers. Experiments in dogs have shown that both nifedipine (HENRY 1976) and verapamil (SMITH et 01. 1975) have a cardioprotective effect in experimentally induced cardiac infarction. No convincing clinical series exist as yet. Cardiomyopathies Hereditary cardiomyopathy in hamster is manifested in the form of multifocal degenerative
49 changes, above all myocytolysis and myofibrillary calcinosis, which develop without morphological signs of deteriorated microcirculation. The calcium increase occurring in the myocardium during the prenecrotic stage has been ascribed to a primary defect in the cell organelles, which govern calcium homeostasis, but it may also be the result of changing enzymatic activity in the plasma membranes controlling calcium transport. JASMIN and SOLYMOSS (1975) were able to show that verapamil and prenylamine, and also - to a lesser extent - cinnarizine, were capable of preventing this development or of reducing the gravity of the cardiac lesions in hamsters with cardiomyopathy. FLECKENSTEIN et al. (1974) showed that calcium uptake in the myocardium of these hamsters had risen a great deal higher than the level for normal hamsters. Cardiomyopathy in man constitutes a heterogeneous group which doubtless has a number of different etiologies. Some of these may possibly be of the same nature as the hereditary hamster cardiomyopathies, so that a Ca-blocker might be therapeutically useful.
* * * The muscle-relaxing effect of nifedipine has been used, with a certain measure of success, in the treatment of patients with complaints of the urinary tract. Renal calculus pains are said to be relieved and patients with prostate adenoma are reported to be less inconvenienced by pollakisuria and nycturia. Similarly, there were improvements in patients suffering from neurogenic disturbances of the bladder; these were also reflected by an increase in bladder capacity (BODEKER et al. 1976). Incipient miscarriages are tending more and more frequently to be treated with sympathicomimetics. This quite often produces cardiovascular side-effects, which have been treated with verapamil with a certain degree of success (GUMMERUS 1975). MC MURTRY et (11. (1976) established that the pulmonary vasoconstriction occurring in hypoxia was due to a transmembranic influx of extracellular calcium. It is therefore open to question whether Ca-blockers can have a pressure-reducing effect in the narrow circle of patients with pulmonary hypertension.
REFERENCES 1st International Nifedipine “Adalat” Symposium: New Therapy of Ischemic Heart Disease. Ed K. Hashimoto, E. Kimura & T. Kobauashi, University of Tokyo Press, Tokyo 1975. 2nd International Adalat Symposium: New Therapy of Ischemic Heart Disease. Ed W. Lochner. W. Braasch & G. Kroneberg, Springer Verlag, Berlin 1975. 3rd International A d d a t Symposium: New Thera-
py of Ischemic Heart Disease. Ed A. Domingos Jatene & Paul R. Lichtlen, Excerpta Medica, Amsterdam 1976. Bengt W. Johansson & Gillis Johnsson: Liikemedel vid Angina Pectoris. Socialstyrelsens KommittC for Lakemedelsinformation, 2:1, maj 1971. Angina Pectoris - Isoptin. Ed J.-H. Atterhog, L. Sparre Hermann & J. Sieverts, AB Meda, Goteborg 1977. Symposium on Arrhythmias - Isoptin. Ed J.-H. Atterhog, A. Haakana & B. Nording, AB Meda. Goteborg 1974. Abelin, J.: From “Discussion” 3rd International Adalat Svmoosium, Excerpta Medica. p. 244, Amsterdam 1976. Mc Arthur. J . D.. R. G. Murrav. A. Tweddel & T. D. V.’ Lawrie: Comparison-of the Effect of Adalat and Propranolol on Exercise Tolerance in Patients with Angina Pectoris, 2nd lnternational Adalat Symposium, Springer Verlag, p. 315, Berlin 1975. Atterhog, J.-H., L.-G. Ekelund & A.-L. Melin: Effect of nifedipine on exercise tolerance in patients with angina vectoris. Eurou. J . Clin. Phnrmacol. 1975, 8 125.
Bender. F.: Die Behandlung der Tachvcarden Arrhythmien und der Art&iellen Hyiertonie mit Verapamil. Arzneimittel-Forsch, 1970, 20, 1310. Bodeker, J., S. A. Salim & R. Nagel: Wirkungen von Nifedipine bei Urologischen Patienten. Dtsch. Med. Wschr. 1976, 101, 1866.
Castro, I., S. W. Rocha & R. Rodrigues: Antianginal Efficacy and Tolerance of Adalat (BAY a 1040). Results of a Six-month Trial. 3rd International Adnlat Symposium, Excerpta Medica, p. 255, Amsterdam 1976. Ebner, F. & H. B. Dunnschede: Haemodynamics, Therapeutic Mechanism of Action and Clinical Findings of Adalat Use based on Worldwide Clinical Trials. 3rd International Adnlat Symposium, Excerpta Medica, p. 283, Amsterdam 1976.
Ekelund, L.-G., & J.-H. Atterhog: Adalat and Beta Blockers; the Mechanism Studied with two Serie5 of Work Tests in two Groups of Patients with Angina Pectoris. 2nd International Adalut Symposium, Springer Verlag, p. 169, Berlin 1975. Ekelund, L.-G. & L. Oro: Antianginal Efficiency of Adalat with and without a Beta-blocker. A Subacute Study with Exercise Tests. 3rd International Adalat Symposium, Excerpta Medica, p. 218, Amsterdam 1976. Ekelund, L.-G. & L. Oro: Antianginal efficiency of nifedipine (Adalat) with and without a betablocker, studied with exercise tests. A subacute study. Submitted to publication 1978.
50 Esser, W., W. Herms & E. Wetzels: Die Wirkung verschiedener Koronardilatierender Pharmaka auf die Nierenfunktion. Ed B. Watschinger, Verlag der Wiener Medizinischen Akademie, p. 593, Wien 1969. Fagher, B., S. Persson & S. E. Svensson: Doubleblind Comparison of Verapamil and Practolol in the Treatment of Angina Pectoris. Postgrad. Med. J . 1977, 53, 61. Fleckenstein, A., J. Janke, H. J. Doring & 0. Leder: Myocardial Fiber Necrosis due to IntracelM a r Ca Overload a New Principle in Cardiac Pathophysiology. Recent A d v . Stud. Cardiac Struct. Metab. 1974, 4, 563-580. Gummerus, M.: Hemmung der drohenden Fruhgeburt mit Nylidrin und Verapamil. Z . Geburtsh. Perinat. 1975, 179, 261. Hagman, M: Effekt of BAY a 1040 jamfort med Aptin vid behandling av angina pectoris. Submitted to publication 1977. Henry, P. D.: Protection of Ischemic Myocardium by Nifedipine. 3rd International Adalat Symposium, Excerpta Medica, p. 55, Amsterdam 1976. Hoffman, P.: Behandlung Koronarer Durchblutunnsstorunnen mit Isoutin in der Praxis. Med. Klin. 1964,-59, 1387. Hosoda. S. & E. Kimura: Efficacv of Nifediuine in the Variant Form of Angina Pectoris. 3 r a International Adalat Symposium, Excerpta Medica, p. 195, Amsterdam 1976. Jasmin, G. & B. Solymoss: Prevention of Hereditary Cardiomyopathy in the Hamster by Verapamil and Other Agents. Proc. SOC. Exp. Biol. Med. 1975, 149, 193. Johansson, B. W.: Unpublished results. Johansson, B. W., K.-E. Anderson, H. Ledermann, H. von Schenk & 1. J . Thorell: The Effects of Digoxin and Beta-methyl-digoxin on the Heart Rate of Decornpensated Patients with Atrial Fibrillation. Europ. J . Clin. Investig. 1977, 7, 3. Kenmure, A. C. F. & J. H. Scruton: A Doubleblind Controlled Trial of the Antianginal Efficacy of Nifedipine Compared with Propranolol. 3rd International Adalat Symposium, Excerpta Medica, p. 268, Amsterdam 1976. Krikler, D.: Verapamil in Cardiology, Europ. J . Cardiol. 1974, 2, 3. Laaser, U., K. A. Meurer, H. Kriiger & W. Kaufmann: Clinical Studies on the Combined Effect of Various Antihypertensive Agents and Adalat, 2nd International Adalat Symposium, Springer Verlag, p. 285, Berlin 1975. Levy, L.: Treatment for Hypertension. S. A f r . Med. J . 1973, 47:676. Livesley, B., P. F. Carley, R. C. Campell & S. Oram: Double-blind Evaluation of Verapamil, Propranolol and Isosorbide Dinitrate against a Placebo in the Treatment of Angina Pectoris. Brit, Med. J . 1973, 1, 375.
-
Maroko, P. R. & E. Braunwald: Effects of Metabolic and Pharmacologic Interventions on Myocardial Infarct Size Following Coronary Occlusion. Circulation 1976, 53, suppl. 1 , 162. Menna, J., M. Traina, E. Ferreiros & J. C. Cassera: Long-term Doubleblind Cross-over Study on the Antianginal Efficacy of Adalat Compared with Placebo. 3rd International Adalat Symposium, Excerpta Medica, p. 282, Amsterdam 1976. Midtbo, K.: Isoptin, a Prophylactic Agent in Paroxysmal Supraventricular Tachyarrhythmias. A Double-blind Trial. Symposium on Arrhythmias - Isoptin, AB Meda, p. 100, Goteborg 1974. Mc Murtry, J . F., A. B. Davidson, J. T. Reeves & R. F. Grove: Inhibition of Hypoxic Pulmonary Vasoconstriction by Calcium Antagonists in isolated Rat Lungs. Circulation Res. 1976, 38, 99. Rodrigues-Pereira, E. & A. P. Viana: The Actions of Verapamil on Experimental Arrhythmias. Arzneimittel-Forsch. 1968, 18, 175. Schamroth, L., D. M. Krikler & C. Garrett: Immediate Effects of Intravenous Verapamil in Cardiac Arrhythmias. Brit. M e d . J . 1972, 1, 660. Schamroth, L.: Immediate Effects of Intravenous Verapamil on Atrial Fibrillation. Cardiovasc. Res. 1971, 5, 419. Schmid, J. R. & C. Hanna: A Comparison of the Antiarrhythmic Actions of two Synthetic Compounds, Iproveratril and MJ 1999, with Quinidine and Pronethalol. J . Pharmacol. Exp. Ther. 1967, 156, 331. Singh, B. N. & E. M. Vaughan Williams: A Fourth Class of Anti-dysrhythmic Action? Effect of Verapamil on Ouabain Toxicity, on Atrial and Ventricular Intracellular Potentials, and on Other Features of Cardiac Function. Cardiovesc. Res. 1972, 6, 109. Smith, H. J., B. N. Singh, H. D. Nisbet & R. M. Norris: Effects of Veraparnil on Infarct Size Following Experimental Coronary Occlusion. Cardiovasc. Res. 1975, 9, 569. Storstein, 0. & K. H. Landmark: Verapamil in the Treatment of Atrial Tachycardia with Block. Acra Med. Scand. 1975, 198, 483. Storstein, 0. & K. Rasmussen: Digitalis and Atrial Tachycardia with Block. Brit. Heart J . 1974, 36, 171. Tschirdewahn, B. & H. Klepzig: Klinische Untersuchung uber die Wirkung von Isoptin und Isoptin S bei Patienten mit Koronarinsuffizienz. Dtsck. Med. Wschr. 1963, 88, 1702.
From the Heart section, Dept. of Medicine, General Hospital, Malmo, Sweden
Clinical Aspects of Ca-blocking Agents.
Bengt W. Johansson
Muscular contraction is caused by the thin actin filaments sliding over the myosin filaments and thus bringing about a shortening of the muscle fibres. The presence of troponin and tropomyosin prevents actin and myosin from reacting together - troponin and tropomyosin is therefore termed “relaxing protein”. The occurrence of calcium, which bonds with troponin, inhibits this relaxing effect, and the reaction between actin and myosin then occurs, resulting in muscular contraction. These reactions are energy-consuming, and the ultimate energy generator is adenosintriphosphate, ATP, which in turn is synthesized by various metabolic processes requiring oxygen. In normal blood supply to the myocardium via normal coronary vessels, the supply of oxygen is sufficient. When the coronary vessels are obstructed, oxygen deficit ensues and with it a shortage of energy for the metabolic processes required for muscular contraction. With moderate obstruction of the coronary vessek, symptoms do not appear until physical or mental effort increases the demand on the blood supply to the myocardium. As obstruction increases, symptoms will also appear in connection with slight exertions or even while the patient is at rest.
It is therefore natural to suppose that Cablockers, which reduce the intensity of muscular contraction and oxygen demand with it, have a favourable effect on patients with symptoms related to a reduced flow of blood via the coronary vessels to the myocardium, i.e. patients with angina pectoris. In fact several studies have confirmed that Ca-blockers have a positive effect on angina pectoris due to an atherosclerotically induced coronary insufficiency. Ca-blockade as an oxygen-reducing mechanism is quite a recent working hypothesis, and when investigations of these compounds were first begun, the main focus of attention was on their vascular expanding effect rather than their Ca-blocking effect. For various reasons it is important to bear this vasodilatory effect in mind. One reason is the renewed attention which in recent years has come to be paid to coronary vascular spasm as a cause of angina pectoris. Another is the sympathetic activation to which vasodilation gives rise, together with the concomitant increase in oxygen consumption. Thus there is reason to ask: what is the net effect of the reduced oxygen consumption caused by the Ca-blockers and the increased oxygen consumption involved. by a higher sympathetic activity.
46 Angina pectoris Several studies have been published showing that Ca-blockers have a positive influence on patients with coronary insufficiency and angina pectoris, judging by the degree of S T reduction in the ECG, the number of anginal attacks, nitroglycerine consumption and physical work capacity (1st International Nifedipine “Adalat” Symposium, University of Tokyo Press, Tokyo 1975; 2nd International Adalat Symposium, Springer Verlag, Berlin 1975; 3rd International Adalat Symposium, Excerpta Medica, Amsterdam 1976; JOHANSSON & JOHNSSON 1971; Angina pectoris - Isoptin, AB Meda 1977; ATTERHOG et al. 1975; EKELUND & O Ri 0 1978; HAGMAN 1977). Not all investigations are equally positive, however, (MC ARTHUR et al. 1975). With Ca-blockers as with G !, blockers, not all angina pectoris patients show a positive response. One reason for this may be that the Ca-blockers, like p-blockers, have multiple and partly contrary pharmacological effects which can be pronounced to different extent in different patients; this can apply, for instance, to the degree of compensatory sympathetic stimulus. Similarly, the negative inotropic effect of the Ca-blockers can have varying results, depending on the degree of the patients’ cardiac decompensation. The possibility of tolerance development is also important in connection with diseases requiring long-term treatment. Several studies have shown that the favourable effect on the anginous symptom persists even after prolonged treatment (CASTRO et al. 1976; MENNA et (11. 1976; ABELIN 1976). On the other hand conflicting results have been obtained concerning the effect on pulse and blood pressure (CASTRO et o f . 1976; MENNA et al. 1976). What drug should then be given to patients with angina pectoris? There is no doubt that nitroglycerine is still the drug of choice. To many people the second drug has been a 8blocker, while to certain people it has been nitroglycerine in a slow-release form. It is clear that Ca-blockers constitute a therapeutic alternative. There is comprehensive clinical documentation underlying the choice of /?-blockers as drugs of second preference (Angina pectoris -
Isoptin, AB Meda 1977). There is one group where a Ca-blocker should be considered as a drug of second preference, namely those patients in whom a ,+blocker is contraindicated, and this applies particularly to patients with obstructive lung disease. Admittedly these patients tolerate a selective /j-blocker, but the selectivity is not complete and some of these patients develop side effects. Cardiac decompensation is also a contraindication to pblockade as well as AV-block of the second and third degree, but the negative inotropic effect of the Ca-blockers and the effects of certain of these drugs on AV-conduction demands caution in these states. Another group in which Ca-blockers should be tried comprises the patients who d o not respond satisfactorily to /?-blockade (EKELUND & ATTERHOG 1975). The Ca-blockers may provide a therapeutic alternative to the fiblockers, because they act via other mechanisms. Efficacy, of course, is an important factor governing the choice of drug. Certain studies have compared the effect of a Ca-blocker with that of a P-blocker. Various parameters have been chosen for comparison, and the findings vary somewhat, but there are no striking differences between p-blockers and Ca-blockers (EBNER & DONSCHEDE 1976; LIVESLEY et 01. 1973), though in one study verapamil proved to be superior to practolol (FAGHER et 01. 1977). The aim of drug therapy in angina pectoris is to reduce the oxygen consumption of the myocardium. Since p-blockers and Ca-blockers both reduce oxygen consumption but do so in different ways, it ought, theoretically speaking, to be an advantage to combine /?- and Cablockers. There are studies which support this kind of assumption (EKELUND & O R 6 1976; KENMURE & SCRUTON 1976). Theoretically, of course, this also increases the risk of side-effects, but no serious coniplications occurred in the reported series. Nor have they occurred among the limited number of patients on whom I have tested a combination of pand Ca-blockers. Prinzmetal’s variant angina constitutes a special group of patients where the angina symp-
41 toms in certain cases are induced by a spasm in the coronary vessels. Ca-blockers have also been reported to have a positive effect on these patients, but these findings are based on studies without adequate controls (HOSODA & KIMURA 1976). Arrhythmias
ventricular rate is regularly observed (SCHAMROTH et al. 1972). Similar reductions of ventricular rate occur in patients with auricular flutter. One interesting observation is the more regular R-R interval which occurs in patients with auricular fibrillations after the administration of verapamil (SCHAMROTH 197 I : SCHAMROTH et crl. 1972). This equalization of the R-R interval seems to be less pronounced in elderly persons (SCHAMROTH et 01. 1972). The mechanism is not known. There has been conjecture concerning a stabilizing effect on the various degrees of “concealed conduction” in the AV node which may be at the bottom of the regular ventricufar response in cases of auricular fibrillation. No such equalization of the R-R interval occurs after the administration of a /?-blocker, acebutolol (JOHANSSON, unpublished results) (Fig. 1). There is no difference between digoxin and p-methyl-digoxin in terms of equalizing effect (JOHANSSON et al. 1977).
Ca-blockers have also been used as antiarrhytmic agents. Clinical experience is confined t o experience of verapamil. In animal experiments, verapamil has proved antiarrhythmically efficacious against experimentally induced arrhythmias (SCHMID & HANNA 1967; RODRIGUES-PEREIRA & VIANA 1968; SlNGH & WILLIAMS 1972). Increasingly comprehensive clinical documentation has gradually been accumulated, and verapamil has proved effective above all in the treatment of supraventricular arrhythmias (Symposium on Arrhythmias, Meda AB 1974; KRIKLER 1974). A iiricular fibrillation can sometimes be regularized by verapamil, and a reduction of the -14.5
R-R INTERVALL IN MM
a14.5 1s.5
-13.0
R
ACEBUTOLOL
12.0
-
11.0
10.0
GH 17 01 17
P
11.0 YOI
Daua
ion
9.0 8.0 7.0 6.0 5.0 4.0 x
ac
P
3.0
3 .O
2.0 1.0
REST
Nacl
0.l5~1&~0.23%
o.a-t~&
050%
0 . w 12.%’
Fig. I. R-R intervals in patient with atrial fibrillation after increasing dosages of a @-blockingagent,
acebutolol.
48 From a clinical viewpoint this regularizing effect can sometimes be useful in patients with persistent auricular fibrillation who find the irregularity of their cardiac activity unpleasant and disturbing. Paroxysmal siipraventricular tachycardia can often be stopped by the intravenous administration of verapamil (Symposium on Arrhythmias, Meda AB, 1974; KRIKLER 1974) and the oral administration of verapamil reduces the frequency of relapses into paroxysmal supraventricular tachycardia (MIDTBO 1974). Verapamil has proved to have regularizing effect on several patients with auricular tachycardia with AV-block (STORSTEIN & LANDMARK 1975), an arrhythmia which is by no means invariably a manifestation of digitalis intoxication (STORSTEIN & RASMUSSEN 1974). The tachycardias which occur in connection with the Wolff-Pnrkinson-White-syndrome can often be successfully stopped with verapamil. Verapamil is preferable for WPW patients with auricular fibrillation, because the administration of digitalis to such patients is liable to cause ventricular fibrillation.
Hypertension The Ca-blockers have a vasodilatory effect and their acute administration brings about a drop in blood pressure coupled with a rise in the pulse rate. It is therefore natural to discuss the possible role of these drugs in the treatment of hypertension, perhaps not as a single drug, but, on account of the tachycardia, together with p-blockers, i.e. analogously to a combination of p-blockers and hydralazin. Tt is to be hoped that the complication entailed by hydralazin treatment which can be seen in the form of SLE will then be eliminated. Parenterally administered verapamil has proved effective in the treatment of hypertensive crisis (ESSER ef al. 1969). The reduction of blood pressure which was discovered more or less by chance when verapamil was administered orally to slightly hypertensive patients with ischaemic heart disease (LIVESLEY et al. 1973; TSCHIRDEWAHN & KLEPZIG 1963; HOFFMAN 1964) led to further studies of its anti-hypertensive effect. Although preliminary data point to a pressure
reduction following oral administration of verapamil (BENDER 1970; LEVY 1973) further studies are needed. Nifedipine also reduces blood pressure when administered acutely. In a preliminary study of 30 hypertensive patients, nifedipine and placebo double-blind cross-over, respectively, were added in addition to various forms of anti-hypertensive treatment. No further reduction of blood pressure was found to result from nifedipine in a dose of 10 mg t.i.d. for 3 weeks (LAASER et al. 1975).
Reduction of myocardial infarction size In recent years there have been exhaustive discussions of the possibilities of reducing oxygen consumption in a heart affected by an acute infarction and thereby reducing the extent of the infarction (MAROKO & BRAUNWALD 1976). Several interventions in the form of intra-aortic balloon counterpulsation and the administration of several drugs in experimental studies have proved capable of reducing the extent of the infarct. The efficacy of drugs in clinical practice is less apparent. One reason for this may be that drugs are often administered too late in the infarction process, by which time irreversible ischaemic damage has already occurred. Another reason may be that the amount of myocardium salvaged is only marginal. Yet another reason may be that the myocardium thus salvaged becomes a site for arrhythmias or gives rise to other complications, so that the net gain is slight. In view of the reduction of oxygen consumption that is brought about by the Ca-blockers, one is tempted to suppose that they would have a protective influence on an ischaemic myocardium. FLECKENSTEIN et 01. (1974) have shown that isoprenaline-induced myocardial necrosis can be prevented by the simultaneous administration of Ca-blockers. Experiments in dogs have shown that both nifedipine (HENRY 1976) and verapamil (SMITH et 01. 1975) have a cardioprotective effect in experimentally induced cardiac infarction. No convincing clinical series exist as yet. Cardiomyopathies Hereditary cardiomyopathy in hamster is manifested in the form of multifocal degenerative
49 changes, above all myocytolysis and myofibrillary calcinosis, which develop without morphological signs of deteriorated microcirculation. The calcium increase occurring in the myocardium during the prenecrotic stage has been ascribed to a primary defect in the cell organelles, which govern calcium homeostasis, but it may also be the result of changing enzymatic activity in the plasma membranes controlling calcium transport. JASMIN and SOLYMOSS (1975) were able to show that verapamil and prenylamine, and also - to a lesser extent - cinnarizine, were capable of preventing this development or of reducing the gravity of the cardiac lesions in hamsters with cardiomyopathy. FLECKENSTEIN et al. (1974) showed that calcium uptake in the myocardium of these hamsters had risen a great deal higher than the level for normal hamsters. Cardiomyopathy in man constitutes a heterogeneous group which doubtless has a number of different etiologies. Some of these may possibly be of the same nature as the hereditary hamster cardiomyopathies, so that a Ca-blocker might be therapeutically useful.
* * * The muscle-relaxing effect of nifedipine has been used, with a certain measure of success, in the treatment of patients with complaints of the urinary tract. Renal calculus pains are said to be relieved and patients with prostate adenoma are reported to be less inconvenienced by pollakisuria and nycturia. Similarly, there were improvements in patients suffering from neurogenic disturbances of the bladder; these were also reflected by an increase in bladder capacity (BODEKER et al. 1976). Incipient miscarriages are tending more and more frequently to be treated with sympathicomimetics. This quite often produces cardiovascular side-effects, which have been treated with verapamil with a certain degree of success (GUMMERUS 1975). MC MURTRY et (11. (1976) established that the pulmonary vasoconstriction occurring in hypoxia was due to a transmembranic influx of extracellular calcium. It is therefore open to question whether Ca-blockers can have a pressure-reducing effect in the narrow circle of patients with pulmonary hypertension.
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