The pharmacology of carvedilol

Abstract

Carvedilol is a potent antihypertensive agent with a dual mechanism of action. At relatively low concentrations it is a competitive β-adrenoceptor antagonist and a vasodilator, whereas at higher concentrations it is also a calcium channel antagonist. The antihypertensive activity of carvedilol is characterized by a decrease in peripheral vascular resistance, resulting from the vasodilator activity of the compound, with no reflex tachycardia, as a result of β-adrenoceptor blockade. The antihypertensive activity of carvedilol is associated with an apparent “renal sparing” effect in that the reduction in mean arterial blood pressure does not compromise renal blood flow or urinary sodium excretion. Studies on the mechanism of action of carvedilol indicate that the compound is a potent competitive antagonist of β₁- and β₂-adrenoceptors with a dissociation constant (K_B) of 0.9 nM at both β-adrenoceptor subtypes. Carvedilol is also a potent α₁-adrenoceptor antagonist (K_B = 11 nM), which accounts for most, if not all, of the vasodilating response produced by the compound. At concentrations above 1 μM, carvedilol is a calcium channel antagonist. This activity can be demonstrated in vivo at doses that represent the higher end of the anti-hypertensive dose-response curve. Although the calcium-channel blocking activity of carvedilol may not contribute to the antihypertensive activity of the compound, it may play a prominent role in certain peripheral vascular beds, such as the cutaneous circulation, where marked increases in blood flow are observed. The data indicate that carvedilol is an antihypertensive agent that is both a β-adrenoceptor antagonist and a vasodilator. The vasodilating activity of carvedilol results largely from α₁-adrenoceptor blockade, and its β-adrenoceptor blocking activity prevents reflex tachycardia. In some regional vascular beds, such as the cutaneous circulation, the calcium-channel blocking activity of carvedilol may be responsible for increasing the blood flow.