Wu Zhufeng, Wang Sheng, Peng Xuemei, Lu Chunying, Ye Xiaodong, Wu Baojian
Division of Pharmaceutics, College of Pharmacy, Jinan University, Guangzhou, China (Z.W., B.W.); Department of Anesthesiology, Guangdong Cardiovascular Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China (S.W., X.Y.); and Department of Anesthesiology, First Affiliated Hospital of Jinan University, Guangzhou, China (X.P., C.L.).
Division of Pharmaceutics, College of Pharmacy, Jinan University, Guangzhou, China (Z.W., B.W.); Department of Anesthesiology, Guangdong Cardiovascular Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China (S.W., X.Y.); and Department of Anesthesiology, First Affiliated Hospital of Jinan University, Guangzhou, China (X.P., C.L.)
Drug Metab Dispos. 2016 Jan;44(1):75-82. doi: 10.1124/dmd.115.067405. Epub 2015 Oct 15.
The neuromuscular blocking agent cisatracurium is frequently used adjunctively in anesthesia to facilitate endotracheal intubation and to provide muscle relaxation during surgery. We aimed to determine the pharmacokinetics (PK)/pharmacodynamics (PD) of cisatracurium in patients with congenital heart defects (CHDs), such as ventricular septal defects and atrial septal defects, and to assess the effects of CHDs on the PK/PD profiles of cisatracurium. A modified two-compartment model with drug clearance from both compartments was best fitted to the PK data to determine the PK parameters. The model suggested that septal defects significantly lowered the rate of cisatracurium distribution from the central to peripheral compartment. The intercompartment rate constants k12 and k21 were significantly reduced (35%-60%, P < 0.05) in patients with ventricular septal defects and in patients with atrial septal defects compared with control patients. Consistently, septal defects caused a marked increase (160%-175%, P < 0.001) in the distribution half-life. Furthermore, significantly delayed pharmacodynamic responses to cisatracurium were observed in patients with septal defects. The onset time (i.e., the time to maximal neuromuscular block) was prolonged from 2.2 minutes to 5.0 minutes. PK/PD modeling suggested that reduced concentrations of cisatracurium in the effect compartment due to poorer distribution were the main cause of lagged pharmacodynamic responses. In conclusion, cisatracurium PK/PD were significantly altered in patients with septal defects. Our study should be of use in clinical practice for the administration of cisatracurium to patients with CHDs.
神经肌肉阻滞剂顺式阿曲库铵常用于麻醉辅助，以利于气管插管并在手术期间提供肌肉松弛。我们旨在确定顺式阿曲库铵在患有先天性心脏病（CHD）（如室间隔缺损和房间隔缺损）患者中的药代动力学（PK）/药效动力学（PD），并评估CHD对顺式阿曲库铵PK/PD曲线的影响。采用一个两室模型，两个室均有药物清除，对PK数据进行最佳拟合以确定PK参数。该模型表明，间隔缺损显著降低了顺式阿曲库铵从中央室向周边室的分布速率。与对照患者相比，室间隔缺损患者和房间隔缺损患者的室间速率常数k12和k21显著降低（35%-60%，P<0.05）。一致地，间隔缺损导致分布半衰期显著延长（160%-175%，P<0.001）。此外，在间隔缺损患者中观察到对顺式阿曲库铵的药效学反应明显延迟。起效时间（即达到最大神经肌肉阻滞的时间）从2.2分钟延长至5.0分钟。PK/PD建模表明，由于分布较差导致效应室中顺式阿曲库铵浓度降低是药效学反应滞后的主要原因。总之，间隔缺损患者的顺式阿曲库铵PK/PD发生了显著改变。我们的研究应有助于临床实践中对CHD患者使用顺式阿曲库铵。
