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Antihypertensive Drugs: Clinical Pharmacology and Therapeutic Use

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Summary

Although there is an ever increasing number of antihypertensive agents available, they can be classified into four major categories according to their mode of action: (1) the diuretics; (2) sympathetic inhibiting drugs; (3) the vasodilators; and (4) the angiotensin II analogues and converting enzyme inhibitors.

Regardless of their biochemical structure or site of action on the renal tubule, the diuretics act in a similar fashion and produce their antihypertensive effect by depleting plasma and extracellular fluid volume. The sympathetic inhibiting agents lower blood pressure by producing adrenergic blockade at various levels within the sympathetic nervous system, and each agent has a fairly specific site of action. The ganglionic blockers inhibit neural transmission at the level of the paravertebral autonomic ganglia; however, because they interfere with parasympathetic as well as sympathetic function, they are associated with many irritating side-effects and have been largely replaced by newer agents. Reserpine and guanethidine act at the level of the neuroeffector junction by interfering with the release of noradrenaline. Whether or not reserpine has a central component to its antihypertensive effect remains controversial.

Clonidine acts within the central nervous system by inhibiting sympathetic outflow to the cardiovascular system. The major site of action of methyldopa also resides in the central nervous system and its antihypertensive effect is dependent upon the central conversion of α-methyldopa to α-methyl-noradrenaline; however, it also has a peripheral component to its action. Prazosin was originally classified as a direct-acting vasodilating agent but recent evidence suggests that its primary mode of action resides in post-synaptic α-adrenoreceptor blockade.

When used by themselves, the β-adrenoreceptor blocking agents lower pressure in approximately 30% of patients. The reduction in pressure is closely related to the fall in total peripheral resistance, and appears to be dissociated from suppression of renin release. When employed in combination with diuretics and vasodilators, the therapeutic effectiveness of the β-blockers is greatly enhanced and a significant antihypertensive effect is obtained in up to 90% of patients. The β-blockers are often classified according to whether they are relatively ‘cardioselective’ or ‘non-selective’ in their pharmacological effect. However, differences in cardioselectivity are probably of little significance in regard to the antihypertensive potency of the various agents. The antihypertensive action of the MAO inhibitors is not well understood, but because of their potentially lethal side-effects, the use of these agents should be discouraged.

The pharmacological effect of the direct-acting vasodilators hydrallazine, diazoxide and minoxidil is confined to the arterial circulation and the reduction in blood pressure is accompanied by a reflex increase in heart rate and cardiac output, which limits their antihypertensive effect. The increase in cardiac output can, however, be effectively prevented or blunted by β-blockers and other sympatholytic agents. The co-administration of a vasodilator with a β-blocker and a diuretic is an effective antihypertensive combination with relatively few side-effects. Sodium nitroprusside produces vasodilatation of both the arterial and venous circulation and because it reduces cardiac preload as well as afterload, it does not induce an increase in cardiac output.

The angiotensin II antagonists and converting enzyme inhibitors are currently under investigation. They may prove valuable in selecting patients with renovascular hypertension who may benefit from surgical treatment, and may play an important role in the future management of angiotensin-dependent hypertension.

Antihypertensive therapy continues to remain, of necessity, largely empirical. However, we are slowly emerging from an era of ‘blind empiricism’ to one of ‘enlightened empiricism’.

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  1. Research Division and the Department of Hypertension and Nephrology, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio, 44106, USA

    Gary L. Wollam,  Ray W. Gifford Jr. &  Robert C. Tarazi

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Wollam, G.L., Gifford, R.W. & Tarazi, R.C. Antihypertensive Drugs: Clinical Pharmacology and Therapeutic Use. Drugs 14, 420–460 (1977). https://doi.org/10.2165/00003495-197714060-00002

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