A New Molecule with Vasodilating and Beta-adrenoceptor Blocking Properties

Carvedilol is a new substance displaying beta-sympatholytic and vasodilating activities in the same dose range. Data obtained from a considerable number of animal experiments show that the beta-blocking properties of carvedilol resemble those of propranolol. However, in contrast to propranolol the arterial blood pressure decreases dose dependently after single doses of carvedilol due to a reduced total peripheral resistance. The vasodilating activity of carvedilol can be demonstrated in a variety of experimental models. According to the present state of knowledge neither alpha-blockade, nor Ca antagonism, serotonin antagonism, prostaglandin-mediated vasorelaxation, or endothelial-derived relaxing factor (EDRF)-dependent activity are responsible for the antihypertensive effect. Thus, although the mechanism of vasodilation has still not been completely clarified, a postreceptor mechanism seems likely. The acute vasodilating properties in humans have been shown as a dose-dependent increase of the finger pulse amplitude in healthy subjects after both intravenous and oral administration, and as a decrease of the regional resistances and an increase of regional blood flow. The pharmacokinetics of carvedilol are dose linear and peak concentrations are reached within 1-1.5 h after oral administration. The elimination half-life after single oral doses varies from 6-7 h. The renal clearance of 4 ml/min is negligible in comparison with the total body clearance of 590 ml/min. Therefore, the absolute bioavailability of 24% indicates some degree of first-pass extraction. The highly lipophilic drug is extensively distributed to the tissues, as shown by the distribution volume of 132 l. In patients with hypertension, single doses of carvedilol (25-50 mg) decrease systolic and diastolic blood pressure for more than 10 h, whereas heart rate is only slightly decreased. In hypertensive patients treated from 7 days up to 1 year, carvedilol proved to be an effective and safe antihypertensive drug. In contrast to conventional beta-blockers, the reduced vascular resistance, in particular of the renal circulation, observed after both acute and chronic administration of carvedilol, indicated the useful hemodynamic profile of this compound. In addition, patients not sufficiently controlled with conventional beta-blockers responded promptly to carvedilol. At the same time left ventricular performance is not depressed. In a 1-year open clinical trial with hypertensives WHO I and II, the responder rate was about 85% with carvedilol as monotherapy.(ABSTRACT TRUNCATED AT 400 WORDS)