van Zwieten P A, Pfaffendorf M
Department of Pharmacotherapy, University of Amsterdam, The Netherlands.
J Hypertens Suppl. 1993 Dec;11(6):S3-8.
Importance of L-channels for calcium: Calcium L-channels, the specific target of calcium antagonists, appear to be the receptors for these therapeutic agents. Therefore, the accessibility of these channels/receptors to calcium antagonists is a major determinant of the response to these drugs in cardiovascular disorders, including essential hypertension. As with numerous other drugs, the concentration at the receptor level and its time-course largely determine not only the intensity but also the rate of onset and the duration of the drug's effect. Disadvantages of nifedipine: Within the series of dihydropyridine calcium antagonists, the first compound introduced was nifedipine, a relatively hydrophilic drug. Owing to its hydrophilic character the drug rapidly reaches the receptor, thus explaining the rapid onset of its vasodilator action. Accordingly, reflex tachycardia develops, which is not only triggered by the degree of vasodilation but also by the rapidity of its onset. In addition, nifedipine has a short duration of action, requiring the use of special galenic formulations to allow one dose a day. New dihydropyridine calcium antagonists: In view of the disadvantages of the hydrophilic calcium antagonists, attempts have been made to develop dihydropyridines with a slower onset and a longer duration of action. This may be achieved by drugs which are largely in the ionized state at a physiological pH (e.g. amlodipine) and therefore combine slowly with the receptor and bind firmly to various tissue compartments. Another logical approach is the use of highly lipophilic drugs such as lacidipine. Because of its physicochemical properties, the effect in equilibrium is reached very slowly, after up to 5 h in isolated tissues and after more than 2 h after intravenous administration. Lacidipine appears to slowly enter a lipid compartment surrounding the dihydropyridine binding site, which has to be saturated before an equilibrium effect is reached. In addition, the persistence of the drug in this lipid compartment contributes to its long-lasting vasodilator effect.
L型钙通道对钙的重要性：钙L型通道是钙拮抗剂的特定靶点，似乎是这些治疗药物的受体。因此，这些通道/受体对钙拮抗剂的可及性是心血管疾病（包括原发性高血压）对这些药物反应的主要决定因素。与许多其他药物一样，受体水平的浓度及其时间进程不仅在很大程度上决定了药物作用的强度，还决定了起效速度和持续时间。硝苯地平的缺点：在二氢吡啶类钙拮抗剂系列中，首个引入的化合物是硝苯地平，一种相对亲水的药物。由于其亲水特性，该药物迅速到达受体，从而解释了其血管舒张作用起效迅速的原因。相应地，会出现反射性心动过速，这不仅由血管舒张程度引发，还由其起效速度导致。此外，硝苯地平作用持续时间短，需要使用特殊的药剂配方才能实现每日一剂。新型二氢吡啶类钙拮抗剂：鉴于亲水钙拮抗剂的缺点，人们尝试开发起效较慢、作用持续时间较长的二氢吡啶类药物。这可以通过在生理pH值下主要处于离子化状态的药物（如氨氯地平）来实现，因此这类药物与受体结合缓慢，并能牢固地结合到各种组织区室。另一种合理的方法是使用高度亲脂性的药物，如拉西地平。由于其物理化学性质，在离体组织中平衡效应要在长达5小时后才能非常缓慢地达到，静脉给药后则要在2小时以上。拉西地平似乎会缓慢进入围绕二氢吡啶结合位点的脂质区室，在达到平衡效应之前该脂质区室必须饱和。此外，药物在这个脂质区室中的持久性有助于其持久的血管舒张作用。
