Nordlander Margareta, Sjöquist Per-Ove, Ericsson Hans, Rydén Lars
Department of Integrative Pharmacology, AstraZeneca R and D Mölndal, SE 431 83 Mölndal, Sweden.
Cardiovasc Drug Rev. 2004 Fall;22(3):227-50. doi: 10.1111/j.1527-3466.2004.tb00143.x.
Clevidipine is an ultrashort-acting vasoselective calcium antagonist under development for short-term intravenous control of blood pressure. Studies in animals, healthy volunteers and patients have demonstrated the vascular selectivity and rapid onset and offset of antihypertensive action of clevidipine, a synthetic 1,4-dihydropyridine that inhibits L-type calcium channels. Clevidipine has a high clearance (0.05 L/min/kg) and is rapidly hydrolyzed to inactive metabolites by esterases in arterial blood. Its half-life in patients undergoing cardiac surgery is less than one min. Unlike sodium nitroprusside, a drug commonly used for the short-term control of blood pressure, which dilates both arterioles and veins, clevidipine reduces blood pressure through a selective effect on arterioles. As documented in animals and in cardiac surgical patients, clevidipine reduces peripheral resistance without any undesirable effect on cardiac filling pressure. It increases stroke volume and cardiac output. In anesthetized patients undergoing cardiac surgery clevidipine, unlike sodium nitroprusside, does not increase heart rate. In addition of having a favorable hemodynamic profile, suitable for rapid control of blood pressure, clevidipine protects against ischemia/reperfusion injuries, which are not uncommon during major surgery. In anesthetized pigs, clevidipine reduced infarct size after 45 min-long myocardial ischemia by 40%. In rats, renal function and splanchnic blood flow were better maintained when blood pressure was reduced with clevidipine than with sodium nitroprusside. Clevidipine was well tolerated in Phases I and II of clinical trials that included more than 300 individuals/patients. Since there are no known compounds with similar pharmacodynamic and pharmacokinetic properties in clinical development, it is anticipated that clevidipine, a compound tailored to the needs of anesthesiologists, has the potential to become a drug of choice for controlling blood pressure during surgical procedures.
氯维地平是一种超短效的血管选择性钙拮抗剂，正在研发用于短期静脉控制血压。在动物、健康志愿者和患者身上进行的研究表明，氯维地平具有血管选择性，其降压作用起效迅速且作用消失快。氯维地平是一种合成的1,4 -二氢吡啶，可抑制L型钙通道。氯维地平清除率高（0.05 L/min/kg），在动脉血中被酯酶迅速水解为无活性的代谢产物。其在心脏手术患者中的半衰期小于1分钟。与常用于短期控制血压的硝普钠不同，硝普钠可同时扩张小动脉和静脉，而氯维地平通过对小动脉的选择性作用来降低血压。如在动物和心脏手术患者中所证实的，氯维地平可降低外周阻力，而对心脏充盈压无不良影响。它可增加每搏输出量和心输出量。在接受心脏手术的麻醉患者中，氯维地平与硝普钠不同，不会增加心率。除了具有有利于快速控制血压的血流动力学特征外，氯维地平还可预防缺血/再灌注损伤，这种损伤在大手术中并不少见。在麻醉猪中，氯维地平可使45分钟长时间心肌缺血后的梗死面积减少40%。在大鼠中，用氯维地平降低血压时，肾功能和内脏血流比用硝普钠时能得到更好的维持。在包括300多名个体/患者的临床试验的I期和II期研究中，氯维地平耐受性良好。由于在临床研发中没有已知的具有类似药效学和药代动力学特性的化合物，预计氯维地平这种针对麻醉医生需求定制的化合物，有可能成为手术过程中控制血压的首选药物。
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