Simultaneous Modeling of In Vivo and In Vitro Effects of Nondepolarizing Neuromuscular Blocking Drugs

Abstract

Nondepolarizing neuromuscular blocking drugs (NDNBs) are clinically used to produce muscle relaxation during general anesthesia. This study explored a suitable model structure to simultaneously describe in vivo and in vitro effects of three clinically used NDNBs; cisatracurium, vecuronium, and rocuronium. In particular, we examined how to reconcile an apparent discrepancy that rocuronium is less potent at inducing muscle relaxation in vivo than predicted from in vitro experiments. We developed a framework for estimating model parameters from published in vivo and in vitro data, and thereby compared the descriptive abilities of several candidate models. Modeling of the dynamic effect of activation of acetylcholine receptors (AChRs) was essential for describing in vivo experimental results, and a cyclic gating scheme of AChRs appeared to be appropriate. Furthermore, the above discrepancy in experimental results can be explained as follows: the in vivo concentration of acetylcholine is relatively low and can activate only a part of AChRs, whereas more than 95% of AChRs are activated during in vitro experiments. Furthermore, rocuronium has smaller site-selectivity than cisatracurium and vecuronium.