Marathe P H, Dwersteg J F, Pavlin E G, Haschke R H, Heimbach D M, Slattery J T
Department of Pharmaceutics, University of Washington, Seattle 98195.
Anesthesiology. 1989 May;70(5):752-5. doi: 10.1097/00000542-198905000-00007.
Thermal injury causes resistance to many nondepolarizing muscle relaxants including d-tubocurarine, metocurine, pancuronium, and atracurium. To evaluate the role of pharmacokinetics and pharmacodynamics in this phenomenon, the disposition and effect of atracurium (0.5 mg/kg iv) were studied in thermally injured patients (5 males, 16-43 yr) in comparison with that in nonburned control patients (3 males, 1 female, 24-53 yr). The decline of plasma atracurium concentration with time was biexponential in both groups of patients. There were no significant differences in the mean value of any pharmacokinetic parameter (clearance, V1, V beta, alpha and beta half-lives). The time course of effect was also similar, although the maximum twitch depression was significantly smaller (66.1% vs. 100% maximal twitch depression) and time to recover to 50% of maximal twitch depression was significantly shorter (14.2 vs. 52 min) in thermally injured patients. Patients with thermal injury had an EC50 (plasma concentration of atracurium required for 50% of the maximum possible response) 3.4 times that of control patients. Plasma-free fraction of atracurium in the thermally injured patients was 75% that in controls, and free EC50 (the product of free fraction and EC50) of the thermally injured group was 2.7 times that of controls. The results of this study confirm a pharmacodynamic mechanism for the majority of resistance to atracurium, with a diminished free fraction in plasma also contributing to this effect.
热损伤会导致机体对许多非去极化肌松药产生耐药性，包括右旋筒箭毒碱、美索卡胺、泮库溴铵和阿曲库铵。为了评估药代动力学和药效学在此现象中的作用，研究了阿曲库铵（0.5mg/kg静脉注射）在热损伤患者（5名男性，16 - 43岁）中的处置和效应，并与非烧伤对照患者（3名男性，1名女性，24 - 53岁）进行比较。两组患者血浆阿曲库铵浓度随时间的下降均呈双指数形式。任何药代动力学参数（清除率、V1、Vβ、α和β半衰期）的平均值均无显著差异。效应的时间进程也相似，尽管热损伤患者的最大抽搐抑制明显较小（66.1%对100%最大抽搐抑制），恢复到最大抽搐抑制50%的时间明显较短（14.2对52分钟）。热损伤患者的半数有效浓度（产生最大可能反应50%所需的阿曲库铵血浆浓度）是对照患者的3.4倍。热损伤患者血浆中阿曲库铵的游离分数是对照组的75%，热损伤组的游离半数有效浓度（游离分数与半数有效浓度的乘积）是对照组的2.7倍。本研究结果证实了对阿曲库铵产生耐药性的主要机制是药效学机制，血浆中游离分数的降低也促成了这一效应。
