Beta adrenergic blocking drugs

Abstract

Although the beta-adrenoceptor blocking drugs were initially used in the treatment of angina pectoris, arrhythmias and phaeochromocytoma, other uses have been found which were not originally predicted from an understanding of the pharmacology of these agents. The major and first such use has been to lower blood pressure in hypertension, which now represents a major indication for the use of these drugs. Their use has subsequently been explored in thyrotoxicosis, anxiety states, schizophrenia, drug addiction withdrawal syndromes, migraine, obstruction of the outflow tract of the heart and glaucoma. The widest experience has been gained with propranolol and clinical responses that have been demonstrated for this drug usually also occur with the newer beta-adrenoceptor blocking drugs. Beta adrenergic blocking drugs may possess other properties namely intrinsic sympathomimetic action, membrane stabilizing action and cardioselectivity (Frishman, 1979). These properties have been used as a basis for classification of the agents (Table 1) (Fitzgerald, 1972, Prichard, 1978). There is usually little change in blood pressure after acute administration of beta blocking agents at rest, but the rise of blood pressure on exercise (Shinebourne, Fleming and Hamer, 1967; Thadani et al., 1973) or the overshoot after the Valsalva manoeuvre (Prichard and Gillam, 1966), is markedly reduced. The initial report of the hypotensive effect of beta adrenoceptor blocking drugs appeared in 1964 (Prichard, 1964) and the use of propranolol in hypertension was described later the same year (Prichard and Gilliam, 1964). After some initial delay the value of beta adrenoceptor blocking drugs in hypertension has become widely accepted (Simpson, 1974). The slow acceptance of beta blocking drugs may have been because beta receptor antagonists inhibit the force of cardiac contraction which was considered undesirable and was also associated with untoward reactions in acutely ill patients. The increase in peripheral resistance, also seemed disadvantageous. Moreover the anti-hypertensive effect had not been described in animals and the mechanism of this action was unknown. A further reason was the use of inadequate doses and the full hypotensive effect was often delayed. Early investigators tended to fix doses at sub-optimal levels despite original reports (Prichard and Gillam, 1964, 1966) emphasizing the importance of variable dosage regimes. The misgivings about dosage arose from erroneous concepts of complete betaadrenoceptor blockade where a relatively small dose, of propranolol had been observed to block the effect of a dose of isoprenaline which had previously given a maximal tachycardia. Considerably larger doses were needed to produce maximum inhibition of exercise induced tachycardia or even the supine or standing resting heart rate (Boakes et al., 1973). It is these larger doses that are often needed to give an adequate antihypertensive effect. It was also believed that large doses had a 'direct depressing action' ('quinidine-like effect', 'membrane action' local anaesthetic effect) on the heart. A membrane action is