Prisant L Michael
Hypertension and Clinical Pharmacology, Medical College of Georgia, 1467 Harper Street, HB 2010, Augusta, GA 30912, USA.
J Clin Pharmacol. 2008 Feb;48(2):225-39. doi: 10.1177/0091270007310378. Epub 2007 Dec 14.
Beta-blockers are well-established therapeutic agents in the treatment of hypertension and cardiovascular disease. However, these agents are highly heterogeneous. Beta-blockers differ in their ancillary pharmacologic properties, which are clinically important. Nebivolol is a highly selective beta(1)-adrenergic receptor blocker that induces vasodilation through stimulation of the endothelial nitric oxide/L-arginine pathway. As a racemic mixture of d- and l-enantiomers, nebivolol is highly lipophilic and rapidly absorbed. Nebivolol undergoes extensive hepatic metabolism through the cytochrome P450 2D6 (CYP2D6) system. As a result of genetic polymorphisms, CYP2D6 has variable activity, manifested by extensive and poor metabolizers of nebivolol. Time to maximum concentration is 0.5 to 2 hours, and half-life is 11 hours in extensive metabolizers; these values are about 3 times longer in poor metabolizers. Urinary and fecal excretion of unchanged nebivolol is less than 0.5% of the dose. Nebivolol has a unique hemodynamic profile of reduced systemic vascular resistance and increased left ventricular function. These properties are attributed to its vasodilating action and contrast with the hemodynamic effects of conventional beta-blockers. Nebivolol is thus a novel beta-blocker with several important pharmacologic properties that distinguish it from traditional beta-blockers. These unique properties may confer clinical benefits beyond simple blood pressure lowering.
β受体阻滞剂是治疗高血压和心血管疾病的成熟治疗药物。然而，这些药物具有高度异质性。β受体阻滞剂在其辅助药理特性方面存在差异，而这些特性在临床上很重要。奈必洛尔是一种高度选择性的β₁肾上腺素能受体阻滞剂，通过刺激内皮型一氧化氮/L-精氨酸途径诱导血管舒张。作为d-和l-对映体的外消旋混合物，奈必洛尔具有高度脂溶性且吸收迅速。奈必洛尔通过细胞色素P450 2D6（CYP2D6）系统进行广泛的肝脏代谢。由于基因多态性，CYP2D6具有可变活性，表现为奈必洛尔的广泛代谢者和代谢不良者。在广泛代谢者中，达峰时间为0.5至2小时，半衰期为11小时；在代谢不良者中，这些值约长3倍。未改变的奈必洛尔经尿液和粪便排泄量不到给药剂量的0.5%。奈必洛尔具有独特的血流动力学特征，即全身血管阻力降低和左心室功能增强。这些特性归因于其血管舒张作用，与传统β受体阻滞剂的血流动力学效应形成对比。因此，奈必洛尔是一种新型β受体阻滞剂，具有多种重要的药理特性，使其有别于传统β受体阻滞剂。这些独特的特性可能带来超出单纯降低血压的临床益处。
