Calcium channel blockers in hypertension

International Elsevier

Journal of Cardiology,

25 (1989) 1-6

1

IJC 00920

Review

Calcium channel blockers in hypertension Breminand Department

of Experimental

and Clinical Pharmncolo~,

Maharaj Unioersit_y of Natal Mediccrl School, Durban. South Africa

(Received 26 January 1989: revision accepted 3 April 1989)

Key words:

Hypertension;

Treatment;

Calcium

antagonist

Introduction Calcium channel blockers have become established as an important class of drugs for the treatment of angina pectoris. Recently, increasing attention has been paid to their use in hypertension [l]. Since much of the information that is presented is derived from clinical studies involving the first generation calcium channel blockers (verapamil, nifedipine and diltiazem, which are the only calcium channel blockers available in many countries at present) only these drugs will be discussed in this review.

Efficacy in Hypertension Interest in calcium channel blockers as potential anti-hypertensive agents was generated by two observations; firstly, that calcium channel blockers induce vasodilation, and, secondly, that most patients with hypertension have an elevated total peripheral resistance [2]. Since calcium channel blockers reduce total peripheral resistance by inducing vasodilation, they would be expected to reduce the blood pressure in patients with hypertension. This is, indeed, the case. In a large number of controlled randomised clinical studies.

Correspondence to: Dr. B. Maharaj, Dept. of Experimental and Clinical Pharmacology, University of Natal Medical School, P.O. Box 17039, Congella, 4013, South Africa. 0167-5273/89/$03.50

verapamil, diltiazem and nifedipine have been found to be effective in reducing the arterial blood pressure of patients with mild to moderate essential hypertension whether used as monotherapy or in combination with other anti-hypertensive drugs [3,4]. Much of the published information, however, was generated by short-term studies. Clinical trials have been conducted to compare the efficacy of calcium channel blockers with established anti-hypertensive drugs, including diuretics, beta-blockers and methyldopa. The results indicate that, when used as monotherapy, their anti-hypertensive effects are comparable to those of the established drugs [3]. Few studies have compared the antihypertensive effects of nifedipine. verapamil and diltiazem directly. On the basis of those which are available, it appears that there is little difference in their efficacy in reducing blood pressure [5,6]. Posture does not appear to alter the effect of calcium channel blockers. They lower blood pressure in the sitting, standing and supine position, and the reduction in blood pressure is achieved without the development of orthostatic hypotension [3].

Effect on Glucose Tolerance and Lipid Levels Hypertension, diabetes mellitus and hyperlipidaemia are all independent risk factors for the development of coronary artery and other vascular diseases. When they occur together, the risk is

0 1989 Elsevier Science Publishers B.V. (Biomedical

Division)

2

increased even further [7]. In consequence, increasing attention is being paid to the effect of anti-hypertensive drugs on certain biochemical and metabolic parameters, including lipid profile and glucose tolerance, particularly since these may be adversely affected by some regimens prescribed in the management of hypertension [8,9]. Initially, there was concern that calcium channel blockers might have a hyperglycaemic effect [lo]. This has since been shown not to be the case in long-term studies involving both non-diabetic [ll-131 and diabetic patients [14-171. Calcium channel blockers are lipid neutral; thus, they do not produce any adverse changes in serum lipoprotein levels [13,14,18-201. There is evidence from animal studies that calcium channel blockers have an anti-atherogenic effect. Against this background, a number of prospective clinical trials which are designed to determine whether calcium channel blockers retard the progression of atherosclerotic lesions in the coronary and carotid arteries have been initiated. These studies are currently in progress and are important, given that anti-hypertensive therapy has not been shown to protect against coronary arterial disease. Furthermore, although it is likely that they may have this effect, calcium channel blockers have not yet been reported to prevent strokes, a major benefit of established anti-hypertensive drugs (such as betablockers).

Effects on Renal Function Hypertension may complicate primary renal disease or damage the kidney secondarily as a result of morbid vascular changes associated with prolonged or severe elevation of arterial pressure. It is relevant, therefore, to examine the effect of calcium channel blockers on renal function. Calcium channel blockers maintain glomerular filtration rate and renal blood flow, and decrease renal vascular resistance while reducing the peripheral blood pressure [21-241. In a recent paper, it was reported that nifedipine improved glomerular filtration rate, renal blood flow and decreased renal vascular resistance, even in those patients in whom there was no reduction in arterial blood pressure [21].

Effect on Left Ventricular Hypertrophy Hypertension may also be complicated by the development of left ventricular hypertrophy, which is known to be associated with an increased risk of sudden death [25], possibly due to arrhythmias [26,27]. It has been shown that calcium channel blockers reduce left ventricular mass concomitantly with a decrease in arterial pressure [24,28, 291. There is evidence to suggest that the regression of left ventricular hypertrophy is accompanied by a reduction in premature ventricular contractions; this may have important clinical implications [29].

Adverse Effects Information on the adverse effects of calcium channel blockers in hypertension is fairly limited. Available information indicates that they are generally safe and well-tolerated drugs. The adverse effects that have been noted are similar to those that have been associated with their use in other conditions. These include adverse effects related to the pharmacological actions of calcium channel blockade (vasodilation, interference with atrioventricular conduction, and deterioration in cardiac function). Effects due to uasodilation such as headache, facial flushing, dizziness and ankle oedema (in the absence of congestive cardiac failure) have been noted to be most frequent with nifedipine, which is the most powerful vasodilator in the group, and least with diltiazem [30]. The reflex tachycardia that may result from administration of nifedipine can be obtunded by co-administration of a beta-blocker. Interference with atrioventricular conduction may occur when either verapamil or diltiazem is used; nifedipine has no effect on atrioventricular conduction in therapeutic doses [31]. This characteristic of verapamil and diltiazem may produce problems, especially in patients who have preexisting atrioventricular node disease, and those who are also given other drugs which are known to impair atrioventricular conduction, such as beta-blockers. Therefore, if one has to prescribe a calcium channel blocker for such patients, nifedipine would be the preferred choice [31]. Deterioration in cardiac function may complicate the use of all calcium channel blockers

3

because calcium influx is important in myocardial contractility; calcium channel blockers decrease calcium influx and, therefore, have the potential to produce a negative inotropic effect. In consequence, they may impair left ventricular function, especially in patients with underlying left ventricular dysfunction [31]. If a calcium channel blocker is indicated in a patient in whom there is concern about left ventricular function, nifedipine should be used because its afterload-reducing properties tend to counter-balance its negative inotropic effect [31]; this is, however, not always the case [32]. Other adverse effects include constipation, gynaecomastia, and cutaneous reactions. Constipation has been noted, particularly with verapamil, and also with diltiazem [30]. It has been recognised recently that all calcium channel blockers can produce gynaecomastia, although the precise mechanism is not yet known [33]. Cutaneous reactions include various types of skin rashes which are noted in 1 to 2% of patients given verapamil and diltiazem, and in some cases may necessitate stopping the drug [34].

Role of Calcium Channel Blockers in Hypertension Hypertensive

crises

Nifedipine is well established as a very useful drug in the treatment of hypertensive crises, because the reduction in blood pressure it produces occurs very rapidly; the onset of action is within 5 to 10 minutes, and the effect may last for 3 to 4 hours. It is safe; adverse effects are infrequent and usually minor in nature, such as palpitations [35]. A further advantage is that nifedipine is very easily administered, unlike most drugs used in the treatment of hypertensive crises which must be given intravenously. The patient should be instructed to bite the capsule and swallow the contents. This method is preferable to sublingual administration because absorption of the drug through the buccal mucosa is negligible [36,37]. Mild to moderate essential hypertension Calcium as effective

channel blockers are now recognised drugs in the therapy of mild to mod-

erate essential hypertension. The Joint National Committee on the Detection, Evaluation and Treatment of High Blood Pressure (in the United States of America) modified the step-care therapy for hypertension to include calcium channel blockers as possible initial monotherapy along with thiazide diuretics, beta-blockers, and angiotensin converting enzyme inhibitors, and as possible second- or third-line drugs in the treatment of hypertension [38]; calcium antagonists had been considered as alternatives to recommended step 2 or 3 drugs in an earlier report [39]. There are certain patient groups that are more likely to respond to and benefit from monotherapy with calcium channel blockers; these include patients with concomitant disease, and black or elderly hypertensives. Patients

with concomitant

disease

Patients with coronary arterial disease are likely to benefit from calcium channel blockade [31]. Therefore, when hypertension and coronary arterial disease co-exist, calcium channel blockers can be given. They are likely to ameliorate both conditions [40]. Also, they can be used in hypertensive patients with other serious concomitant disease because they do not cause deterioration in asthma [41], chronic obstuctive pulmonary disease, peripheral vascular disease, hyperlipidaemia, gout, diabetes mellitus and renal disease, and may improve some of these conditions [42]. The elderly hypertensive

patient

Calcium channel blockers have been shown to be effective when used as monotherapy in elderly hypertensives [43-451. They are considered to be “physiologically appropriate” [28]; hypertension in the elderly is characterised by an elevated total peripheral resistance, a low cardiac output, reduced intravascular volume, and low plasma renin activity. Calcium channel blockers produce favourable changes in all these pathophysiological alterations [28]. Furthermore, calcium channel blockers are suited to elderly hypertensives because the reduction in blood pressure occurs without the development of orthostatic hypotension, renal and cerebral blood flow are maintained, and this group of

4

drugs has a favourable effect on some concomitant illnesses which are likely to be present in the elderly patient [46]. The black hvpertensioe

patient

Epidemiological surveys in the United States of America indicate that hypertension in blacks is more frequent, develops at an earlier age, is more severe, and is more likely to be associated with morbidity and mortality, which develop at an earlier age than in whites [38,50]. Calcium channel blockers are effective in black hypertensive patients [14,43,45,47-491, and are also considered to be physiologically appropriate in black patients given that the haemodynamic profile of black and elderly hypertensive patients is essentially similar, except for their plasma volume status - black patients tend to be volume-expanded while the elderly hypertensives tend to be volume-depleted [46,50]. There is an increasing tendency to individualise therapy in hypertension [46], an approach recommended by the Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure [38]. Other workers [43] have proposed a pathophysiologically-orientated and individualised anti-hypertensive treatment regimen which is based upon patient age and plasma renin activity; antihypertensive monotherapy with beta-blockers or angiotensin-converting enzyme inhibitors. is recommended in younger patients and those with high plasma renin activity, calcium channel blockers or diuretics are recommended for older patients and those with low renin levels, while combinations of beta-blockers with nifedipine or diuretics, or angiotensin-converting enzyme inhibitors with diuretics or calcium channel blockers are the preferred combination therapies. This approach is based on the observations that calcium channel blockers were more effective in elderly and low-renin patients [43]. In contrast, other workers have not found any correlation between response and age or renin status [49,51]. Current It is important for hypertension

Limitations

to determine if new therapies fulfil the criteria for an ideal

antihypertensive agent [8]. Although there is no ideal antihypertensive drug as yet, calcium channel blockers do possess many of the qualities needed. They are efficacious, although not uniformly so: there is evidence which suggests that their efficacy correlates positively with age. They are vasodilators. In consequence, they improve the basic haemodynamic fault in most patients with hypertension, namely an elevated total peripheral resistance. Calcium channel blockers are safe; serious adverse effects and biochemical alterations are rare. They meet some of the criteria for convenience. Side effects such as impaired cognitive or sexual function are rare; therefore, they are not detrimental to the patient’s well-being (quality of life). Furthermore, drug interactions are few, and they treat concomitant disease. Currently available calcium channel blockers, however, have a very short half-life, which necessitates frequent administration - at least two or three times a day [3]; this may affect patient compliance. If current research efforts prove successful, once-daily formulations of all three drugs should become available in the near future. Another limitation is cost; as with most new anti-hypertensive drugs, cost becomes an important consideration. Conclusion Calcium channel blockers are effective antihypertensive agents. They can be used as monotherapy, or in combination with other drugs. They have a favourable effect on various circulatory parameters and on target organ function, and do not cause adverse metabolic or biochemical changes. Acknowledgements I thank Professor W.P. Leary for his critical review of this paper and Mrs. Odette French for typing the manuscript. References 1 Massie BM. Hirsch AT. Inouye IK. Tubau JF. Calcium channel blockers as antihypertensive agents. Am J Med 1984;77(suppl 4A):135-142.

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