By Dr Milton Maltz MD MPhil, London
Therapy for angina pectoris involves two potential physiological goals: an increase coronary blood supply and reduction of myocardial oxygen consumption. Currently used medication may utilize both mechanisms. However the treatment of stable angina remains incomplete. Many patients remain symptomatic despite full conventional therapy or are intolerant of the various adverse effects from otherwise effective drugs. Calcium antagonists are the most recent addition to the more established therapeutic options of nitrates and beta-blockers.
Nitrates/Nitrites
The nitrates have been the mainstay of treatment of angina pectoris since the use of amyl nitrite was described by Brunton in 1867. Twelve years later Murrel described the use of nitroglycerin for this condition. The major cardiovascular effect of these compounds is dilatation of the venous system. By reducing venous return to the heart, nitrates reduce left ventricular end diastolic volume and myocardial oxygen demand is decreased. This is brought about by a fall in systolic blood pressure due to reduced systemic vascular resistance, reduced left ventricular filling pressure and volume caused peripheral venous pooling. Nitrates are metabolised by hydrolysis to denigrates and mononitrate which are then excreted in the urine. Isosorbide is absorbed via the gut and metabolized on first pass to isosorbide 2-mononitrate and isosorbide 5-mononitrate. The effect of first-pass metabolism varies from patient to patient and this means that the dose of isosorbide denigrate required will also vary from patient to patient. For this reason the isosorbide mononitrate has been introduced which bypasses this first-pass effect. Aso the use of buccal abdominal skin preparations of the nitrate compounds will again bypass the first-pass effects in the liver and provide reliable absorption and blood levels in individual patients. These various preparations fall into two groups: those with a rapid onset of action, used to terminate an acute anginal episode or for immediate prophylaxis, and those with a slower onset and a longer duration of action, these being used for longer-term prophylaxis. Nitrate tolerance is still a controversial subject and much remains to be learned. Nevertheless, there is now sufficient evidence to conclude that it is a real phenomenon that should be considered when selecting regimens for nitrate prophylaxis.
2. Beta-Blockers
The beta adrenergic blocking drugs, colloquially known as “beta-blockers”, are efficacious in the treatment of many patients with stable angina pectoris. By reducing the heart rate, systolic arterial pressure, and left ventricular contractility, these agents reduce myocardial oxygen demand. Beta-blockers may be either selective or non-selective. Selective beta-blockers act predominantly, though not exclusively, on the beta-1-receptor, whilst non-selective beta-blockers act on both beta-1 and beta-2-receptors. Most of the side effects are due to their effect on the beta-2-receptor which will cause peripheral vasoconstriction and bronchoconstriction. The negative inotropic effects of beta-blockers may precipitate heart failure if the function of the left ventricle is significantly impaired. Many would agree that since the beta-2-receptor is irrelevant to the antianginal effect of a drug, a beta-1-receptor agent would depend on the duration of action, convenience of dosing intervals and patient acceptability. Beta-blockers remain the cornerstone of treatment in patients with effort-related angina and their efficacy has been confirmed by numerous clinical trials. However, a significant proportion of patients do not respond adequately to beta-blockers or experience side-effects with them (for example, tiredness, sleep disturbances or bronchospasm). In these patients, calcium antagonists may be used.
3. Calcium antagonists
The term “calcium antagonist” was introduced in the early 1970’s to describe the mode of action of a newly defined group of drugs that inhibit excitation-contraction coupling of cardiac muscle by antagonizing the ionic effects of calcium. A number of synonyms have been introduced for the term calcium antagonists. These incude ‘calcium blockers’, ‘slow channel inhibitors’, ‘slow channel blockers’ and ‘calcium channel blockers’. They are a very heterogeneous group of agents of differing structural specificities for cardiac and peripheral activity (Figure 2). Based on such activity, Singh (1986) constructed a classification of these compounds, into four categories:
(a) Type I agents, typified by verapamil; and its congeners (tiapamil and gallopamil) and diltiazem, prolong AV nodal conduction and refractoriness with little effect on ventricular or atrial refractory period. These actions account for their direct anti arrhythmic properties.
(b) Type II agents include nifedipine and other dihypropyridines. In vivo, these agents are devoid of electrophysiologic effects in usual doses. They are potent peripheral vasodilators with some selectivity of action for different vascular beds; their overall haemodynamic effects are dominated by this peripheral vasodilatation and augmentation of sympathetic reflexes.
(c) Type III agents include flunarizine and cinnarizine (piperazine derivatives), which, in vivo and in vitro, are potent dilators of peripheral vessels, with no corresponding calcium-blocking in the heart.
(d) Type IV agents are agents with a broader pharmacological profile (perhexiline, lidoflazine and bepridil); they block calcium fluxes in the heart, in the peripheral vessels, or both. They may inhibit the fast channel in the heart and have other electrophysiologic actions. The overall haemodynamic properties of the calcium antagonist make them potentially useful in clinical syndromes resulting from altered myocardial supply and demand relationship. Nifedipine, verapamil and diltiazem have all been found efficacious in classic exertion angina. They have been studied using various endpoints, alone and in combination with other antianginal drugs and occasionally compared to each other.
Nifedipine: Extensie studies demonstrate consistent efficacy of the drug over short and long term follow-up. A single sublingual dose of 10 or 20 mg will generally increase exercise tolerance by 20 to 70%, as judged by grade stress testing against of placebo control (Ekelund and Atterhog 1975). The data from four double-blind controlled studies, using a single dose of nifedipine, demonstrated an average reduction in exercise-induced ischemic ST depression of 32% (Stone et al 1980). The acute improvement in exercise -induced ST segment depression in patients with chronic stable angine appeared to persist for at least six weeks when therapy was continued with 20mg of nifedipine t.i.d. In a haemodynamic study in patients with coronary artery disease, the sublingual administrator of 20mg of nifedipine shortened the duration of pain and reduced ST segment depression (Majid and DeJong 1982). In addition to nifedipine’s peripheral vasodilator properties in patients with classical angina, there is evidence that the drug may also block abnormal coronary vasoconstriction (Gunther et al 1981). Several studies have stressed the enhanced benefits to be derived from combination of nifedipine and a beta-blocker (Lynch et al 1980; Ekelund and Oro 1979). Clinically, the combination of nifedipine (10mg three times daily) with propanolol (40m t.i.d) or metropolol, leads to a greater decrease in anginal frequency and nitroglycerin consumption (Kenmure and Scruto 1979; Ekelund and Oro 1979; Fox et al 1981).
Thus nifedipine alone, or especially in combination with a beta-blocker is an an effective drug for the treatment of patients with classical angina pectoris.
Verapamil: Verapamil has also been demonstrated to be effective as first line, single therapy in chronic table angina. A number of controlled double -blind clinical trials have demonstrated a significant reduction in frequency of anginal episodes and nitroglycerine consumption while improving exercise tolerance. Verapamil was given at varying doses (Livesley et al 1973, Bala-Subramanian 1980). The drugs causes a 10% reduction in rate-pressure product at rest and a 12% reduction at sub-maximal exercise compared to over 30% by beta-blockers (Jesephson et al 1982). In addition, at peak exercise and at a rate-pressure product, similar to that obtained on placebo, there appears to be less marked ST-segment depression, suggesting a favourable redistribution of coronary blood flow to ischemic zones (Brodsky et al 1982), or possibly other as yet undefined cellular mechanisms mediating the antianginal effects of the drugs. Higher dose regimens of verapamil (e.g. 120mg, t.i.d) significantly decrease anginal frequency and prolong exercise tolerance (Livesley et al 1973).
Diltiazem: Diltiazem has a similar, but not identical, spectrum of effect to that o verapamil, affecting sinoatrial automaticity and conduction through the atrioventricular node. As with verapamil, the dose of diltiazem is an importante determinant of the therapeutic response. Following oral administration, over 90 percent is absorbed, but bioavailability is about 45 percent (first-pass hepatic metabolism). Unlike verapamil and nifedipine, only 35 percent of diltiazem is excreted by the kidneys. The major advantages of diltiazem are the relatively few side effects and the modest negative inotropic effect. Like all the other calcium antagonists, diltiazem must be given several times a day for optimal therapy. Tiapamil is a new compound in the group.