Chelly J E, Hysing E S, Abernethy D R, Doursout M F, Hartley C J, Guerret M, Merin R G
J Pharmacol Exp Ther. 1987 Jun;241(3):899-906.
Nicardipine properties (30 micrograms/kg i.v.) were studied in a group of eight dogs awake and anesthetized with isoflurane 1.6% end-tidal. Awake, nicardipine produced a decrease in mean arterial pressure (-12 +/- 2 mm Hg) associated with an increase in cardiac output (1.63 +/- 0.2 liters/min), heart rate (75 +/- 9 beats/min), dP/dt (741 +/- 202 mm Hg/sec) and carotid (41 +/- 11 ml/min) and coronary blood flows (39 +/- 6 ml/min). During isoflurane, responses to nicardipine injections were less pronounced except for mean arterial pressure (-19 +/- 2 mm Hg) and reversed for dP/dt (-290 +/- 63 mm Hg/sec). In a second group of six conscious dogs, nicardipine (30 micrograms/kg i.v.) injected after ganglionic blockade (chlorisondamine, 2 mg/kg i.v.) elicited changes similar to those recorded during isoflurane anesthesia, data that demonstrated the importance of isoflurane-induced baroreflex blockade as a mechanism of the pharmacodynamic interactions between nicardipine and isoflurane. Isoflurane reduced nicardipine initial volume of distribution (11.6 +/- 1.2 vs. 8.9 +/- 0.8 liters), total clearance (28.5 +/- 2.9 vs. 19.2 +/- 2.1 liters/hr) and volume of distribution at steady state (50.0 +/- 11.3 vs. 29.2 +/- 3.7 liters, P less than .05). Nicardipine-induced hemodynamic changes were linearly correlated with the drug concentrations in plasma. In the presence of isoflurane, the slopes of these relationships were reduced for all hemodynamic variables except for mean arterial pressure, for which the slope was more pronounced, and dP/dt, for which the slope was reversed. In conclusion, isoflurane alters the drug plasma concentration-effect relationship of nicardipine as a result of both pharmacokinetic and pharmacodynamic interactions.
在一组8只清醒和用1.6%呼气末异氟烷麻醉的犬中研究了尼卡地平（静脉注射30微克/千克）的特性。清醒时，尼卡地平使平均动脉压降低（-12±2毫米汞柱），同时心输出量增加（1.63±0.2升/分钟）、心率增加（75±9次/分钟）、dp/dt增加（741±202毫米汞柱/秒）以及颈动脉血流量（41±11毫升/分钟）和冠状动脉血流量增加（39±6毫升/分钟）。在异氟烷麻醉期间，除平均动脉压（-19±2毫米汞柱）外，对尼卡地平注射的反应不太明显，而dp/dt的反应则相反（-290±63毫米汞柱/秒）。在另一组6只清醒犬中，在神经节阻断（静脉注射氯筒箭毒碱，2毫克/千克）后注射尼卡地平（静脉注射30微克/千克）引起的变化与异氟烷麻醉期间记录的变化相似，这些数据证明了异氟烷诱导的压力感受器反射阻断作为尼卡地平和异氟烷之间药效学相互作用机制的重要性。异氟烷降低了尼卡地平的初始分布容积（11.6±1.2对8.9±0.8升）、总清除率（28.5±2.9对19.2±2.1升/小时）和稳态分布容积（50.0±11.3对29.2±3.7升，P<0.05）。尼卡地平引起的血流动力学变化与血浆中的药物浓度呈线性相关。在异氟烷存在的情况下，除平均动脉压（其斜率更明显）和dp/dt（其斜率相反）外，所有血流动力学变量的这些关系的斜率均降低。总之，由于药代动力学和药效学相互作用，异氟烷改变了尼卡地平的药物血浆浓度-效应关系。
