Bhatt Shashi B, Amann Anton, Nigrovic Vladimir
Department of Anesthesiology, Medical University of Ohio, Toledo, USA.
J Pharmacokinet Pharmacodyn. 2006 Aug;33(4):461-83. doi: 10.1007/s10928-006-9017-1. Epub 2006 Jun 3.
Nondepolarizing muscle relaxants (MRs) diminish the indirectly evoked single twitch due to their binding to the postsynaptic receptors. Additionally, the MRs produce progressive diminution of successive twitches upon repetitive stimulation (fade). Our study addresses the generation of fade as observed under clinical situation. The study was conducted in two phases. In the clinical part, we have evaluated the time course of twitch depression and fade following the administration of several doses of three MRs (rocuronium, pancuronium, and cisatracurium). In the second part, we have modified our model of neuromuscular transmission to simulate the time course of twitch depression and fade. The MR was assumed to bind to a single site on the presynaptic receptor to produce fade. The rates of interaction with the presynaptic receptors were characterized in terms of the arbitrarily assigned equilibrium dissociation constant and the half-life for dissociation of the presynaptic complex. A method was developed to relate the release of acetylcholine to the occupancy of the presynaptic receptors. The strength of the first and the fourth twitch was calculated from the peak concentration of the activated postsynaptic receptors, i.e., of those receptors with both sites occupied by acetylcholine. Our results indicate that, while the affinity of the MR for the presynaptic receptor plays little role in the time course of fade, the rate of dissociation of the complex between the presynaptic receptors and the muscle relaxant may be critical in determining the time course of fade. Tentative estimates of this parameter are offered.
非去极化肌松药（MRs）由于与突触后受体结合而减弱间接诱发的单收缩。此外，MRs在重复刺激时会使连续的收缩逐渐减弱（衰减）。我们的研究探讨了临床情况下观察到的衰减的产生机制。该研究分两个阶段进行。在临床部分，我们评估了给予三种MRs（罗库溴铵、泮库溴铵和顺式阿曲库铵）不同剂量后单收缩抑制和衰减的时间进程。在第二部分，我们修改了神经肌肉传递模型以模拟单收缩抑制和衰减的时间进程。假设MR与突触前受体上的单个位点结合以产生衰减。根据任意设定的平衡解离常数和突触前复合物解离的半衰期来表征与突触前受体的相互作用速率。开发了一种方法来关联乙酰胆碱的释放与突触前受体的占有率。根据活化的突触后受体（即两个位点都被乙酰胆碱占据的那些受体）的峰值浓度计算第一次和第四次收缩的强度。我们的结果表明，虽然MR对突触前受体的亲和力在衰减的时间进程中作用不大，但突触前受体与肌松药之间复合物的解离速率可能对确定衰减的时间进程至关重要。本文提供了该参数的初步估计值。
