Clinical pharmacology of multiple action compounds

There are two principal divisions of the beta adrenoceptor blocking drugs in widespread clinical use, non-selective and selective agents, with or without intrinsic sympathomimetic activity. These properties confer differing pharmacological properties. A beta blocking drug with significant intrinsic sympathomimetic activity can be regarded as a multiple action drug. A third division of beta adrenoceptor blocking drugs is a newer development; these, which beside blocking the beta receptor, have an important peripheral vasodilator activity. Labetalol was the first drug of this group, prizidilol followed, but has been withdrawn because of toxicity. Several other agents are now under evaluation including bucindolol, carvedilol, dilevalol (one of the isomers of labetalol) and medroxalol. Celiprolol is an agent which is beta 1 selective and in addition has peripheral vasodilator activity. There are three mechanisms which have been described as responsible for peripheral vasodilation, 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, to a small degree with medroxalol and carvedilol, and has been suggested with celiprolol. Beta 2 mediated vasodilatation has been shown by celiprolol, dilevalol and medroxalol, and evidence of a vasodilatation independent of alpha or beta receptors has been obtained with celiprolol and carvedilol. More evidence is required to be sure of the exact contribution of each of these mechanisms. Combined action results in important haemodynamic differences from beta blockade, notably, peripheral resistance is reduced and less effect is seen on cardiac output.(ABSTRACT TRUNCATED AT 250 WORDS)