Progress in antihypertensive therapy with a multiple-action drug.

The beta-blockers in clinical use have been classified into 2 major divisions, nonselective or selective agents, and those with or without intrinsic sympathomimetic activity (ISA). These properties confer differing pharmacological properties with some relevance to the treatment of hypertension. A beta-blocker with significant beta 2-ISA can be regarded as a multiple-action drug. A third division of beta-blockers is a newer development; these agents, besides blocking the beta-receptor, possess important peripheral vasodilator activity. Labetalol was the first drug of this group and prizidolol followed, but has been withdrawn because of toxicity. Several other agents now under evaluation include bucindolol and medroxolol, and carvedilol and dilevalol (1 of the isomers of labetalol), which have been the most widely studied in hypertension. Combined action results in important haemodynamic differences compared with pure beta-blockade. Notably, peripheral resistance is reduced, and there is less reduction in, or no effect on, cardiac output. The 3 following mechanisms have been described as responsible for peripheral vasodilatation: alpha-receptor blockade, beta 2-agonism, and a dilator action independent of either the alpha- or beta-receptors. Evidence for these various mechanisms is more readily obtainable from animal experiments, but some confirmatory evidence has been obtained in man. Inhibition of alpha-stimulation has been found with labetalol and to a small degree with medroxalol and carvedilol. beta 2-Mediated vasodilatation has been shown by dilevalol and medroxolol, and evidence of vasodilatation independent of alpha- or beta-receptors has been obtained with carvedilol. More evidence is required to confirm the exact contribution of each of these mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)