Herbette L G, Vecchiarelli M, Sartani A, Leonardi A
Department of Radiology and Medicine, University of Connecticut Health Center, Farmington, USA.
Blood Press Suppl. 1998;2:10-7.
Calcium-channel antagonist drugs of the 1,4-dihydropyridine type have been shown to bind to the L-type calcium channel. These drugs are not only amphiphilic, but new molecular designs have become increasingly lipophilic and can readily transport across cell membranes, accessing both hydrophilic and hydrophobic environments, despite becoming more soluble in the membrane bilayer. This biophysical understanding appears not only to define the molecular pathways for drug binding to the calcium-channel receptor, but also to explain differences in the overall clinical pharmacokinetics observed for different drugs in this class. The pharmacokinetic profile of calcium antagonists, although influenced to some degree by interactions with their target calcium-channel receptor, appears to be largely dictated by their interactions with cell membranes at the molecular level. There appears to be a correlation between the duration of action of such membrane-active drugs and the membrane partition coefficient in conjunction with the washout rate. This class of drugs has evolved from a drug such as amlodipine, with a long duration of action related to prolonged plasma half-life, to lercanidipine, which has the shortest plasma half-life relative to its intrinsically long duration of action. Recently, it was discovered that membrane cholesterol reduces the amount of calcium-channel antagonist that can partition into the membrane. Atherosclerotic disease results in increased levels of membrane cholesterol in smooth muscle cells. Latest generation calcium antagonist, which have a long duration of action, can better overcome this negative effect. Lercanidipine has now been shown to have one of the highest measured tolerances to cholesterol, which may indicate its ability to treat a broad range of hypertensive patients with varying degrees of progressive atherosclerotic disease. On what criteria should the effectiveness of calcium antagonists be evaluated? A good calcium antagonist needs to exhibit a placebo-like side-effect profile, thus ensuring good patient compliance. However, an intrinsically long-lasting, once-a-day dose is also pharmacokinetically desirable. To be a truly optimal calcium antagonist, it should function and be efficacious over a broad range of hypertensive patients. It should be able to control blood pressure in light of other complications such as progressive atherosclerotic disease. Recent studies indicate that during the progression of atherosclerosis, cholesterol levels within cell membranes of the arterial wall increase, a process that can reduce the effective concentration of calcium antagonists in these membranes. What is needed is a calcium antagonist that is slow acting to reduce vasodilatory induced side-effects and intrinsically long lasting to ensure once-a-day dosage, and that possesses a high cholesterol tolerance factor to overcome the molecular and compositional changes taking place in the arterial wall, so that it can treat effectively a broad range of hypertensive patients.
1,4 - 二氢吡啶类钙通道拮抗剂药物已被证明可与L型钙通道结合。这些药物不仅具有两亲性，而且新的分子设计使其亲脂性越来越强，尽管在膜双层中溶解度增加，但仍能轻易穿过细胞膜，进入亲水和疏水环境。这种生物物理学认识似乎不仅确定了药物与钙通道受体结合的分子途径，还解释了该类不同药物在整体临床药代动力学上的差异。钙拮抗剂的药代动力学特征虽然在一定程度上受与其靶钙通道受体相互作用的影响，但似乎在很大程度上取决于它们在分子水平上与细胞膜的相互作用。这类膜活性药物的作用持续时间与膜分配系数以及清除率之间似乎存在相关性。这类药物已从像氨氯地平这样作用持续时间长且与血浆半衰期延长有关的药物，发展到乐卡地平，乐卡地平相对于其固有的长作用持续时间而言血浆半衰期最短。最近发现，膜胆固醇会减少可分配到膜中的钙通道拮抗剂的量。动脉粥样硬化疾病会导致平滑肌细胞膜胆固醇水平升高。最新一代作用持续时间长的钙拮抗剂能够更好地克服这种负面影响。现已证明乐卡地平对胆固醇的耐受性是已测药物中最高的之一，这可能表明它有能力治疗广泛的患有不同程度进行性动脉粥样硬化疾病的高血压患者。应该依据什么标准来评估钙拮抗剂的有效性呢？一种好的钙拮抗剂需要表现出类似安慰剂的副作用特征，从而确保患者有良好的依从性。然而，从药代动力学角度来看，本质上长效且每日一次给药也是理想的。要成为真正最佳的钙拮抗剂，它应该在广泛的高血压患者中发挥作用且有效。它应该能够根据诸如进行性动脉粥样硬化疾病等其他并发症来控制血压。最近的研究表明，在动脉粥样硬化进展过程中，动脉壁细胞膜内的胆固醇水平会升高，这一过程会降低这些膜中钙拮抗剂的有效浓度。需要的是一种作用缓慢以减少血管舒张引起的副作用且本质上长效以确保每日一次给药，并且具有高胆固醇耐受因子以克服动脉壁中发生的分子和成分变化的钙拮抗剂，这样它就能有效治疗广泛的高血压患者。
