Combined alpha adrenoceptor antagonism and calcium channel blockade in normal subjects

Abstract

Because both verapamil and prazosin act on peripheral vascular smooth muscle and undergo extensive first-pass metabolism, the possibility of dynamic and kinetic interactions with their concurrent use was investigated. The acute hemodynamic effects of oral prazosin (1 mg), oral verapamil (160 mg), and their combination were evaluated in eight men with normotension. The kinetics of both drugs, alone and in combination, were also assessed. Verapamil did not change blood pressure or heart rate, but prazosin induced a fall in blood pressure, particularly on standing (lowest systolic pressure was 98 mm Hg). The combination of prazosin and verapamil had an earlier, longer, and greater hypotensive effect that was maximal 4 hr after dosing, with a standing systolic pressure of 89 mm Hg. Increases in heart rate were less after the combination (maximum of 102 bpm) than after prazosin alone (maximum of 112 bpm), although there were greater falls in blood pressure with the combination than with prazosin alone. Increases in plasma catecholamine and aldosterone levels and plasma renin activity were greatest with the combination. No differences were found in the kinetics of verapamil when combined with prazosin, but the combination affected prazosin kinetics, with increases in peak prazosin concentrations and AUC. Our data suggest that the greater hypotensive activity of the combination results at least in part from a kinetic interaction that enhances the bioavailability of prazosin, but it is possible that a dynamic interaction at the level of vascular smooth muscle or compensatory cardiac activity also plays a role.