Abshagen U
Boehringer Mannheim GmbH, Pharmaceuticals Research, F.R.G.
J Cardiovasc Pharmacol. 1987;10 Suppl 11:S23-32.
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)
卡维地洛是一种在相同剂量范围内具有β-交感神经阻滞和血管舒张活性的新型物质。大量动物实验获得的数据表明，卡维地洛的β-阻滞特性与普萘洛尔相似。然而，与普萘洛尔不同的是，单次给予卡维地洛后，由于总外周阻力降低，动脉血压呈剂量依赖性下降。卡维地洛的血管舒张活性可在多种实验模型中得到证实。根据目前的知识水平，α-阻滞、钙拮抗、5-羟色胺拮抗、前列腺素介导的血管舒张或内皮衍生舒张因子（EDRF）依赖性活性均与降压作用无关。因此，尽管血管舒张机制尚未完全阐明，但似乎可能是一种受体后机制。在健康受试者中，静脉内和口服给药后，卡维地洛的急性血管舒张特性表现为手指脉搏振幅呈剂量依赖性增加，以及局部阻力降低和局部血流量增加。卡维地洛的药代动力学呈剂量线性，口服给药后1-1.5小时内达到峰值浓度。单次口服给药后的消除半衰期为6-7小时。与590 ml/min的全身清除率相比，4 ml/min的肾清除率可忽略不计。因此，24%的绝对生物利用度表明存在一定程度的首过提取。如132 l的分布容积所示，这种高度亲脂性药物广泛分布于组织中。在高血压患者中，单次给予卡维地洛（25-50 mg）可使收缩压和舒张压降低超过10小时，而心率仅略有下降。在接受治疗7天至1年的高血压患者中，卡维地洛被证明是一种有效且安全的抗高血压药物。与传统的β-阻滞剂不同，急性和慢性给予卡维地洛后观察到的血管阻力降低，尤其是肾循环阻力降低，表明该化合物具有有益的血流动力学特征。此外，对传统β-阻滞剂控制不佳的患者对卡维地洛反应迅速。同时左心室功能未受抑制。在一项针对WHO I级和II级高血压患者的为期1年的开放临床试验中，卡维地洛作为单一疗法的有效率约为85%。（摘要截短至400字）
