Extended Link Model to Describe the Impact of Chronic Antiepileptic Therapy on the Effects of Neuromuscular Blocking Agents.
Elba Romero E1, Juan Fernández-Candil2, Pedro L. Gambús2, Ricardo Valero2, Enrique Carrero2, Lorea Bueno1, Neus Fábregas2, Iñaki F. Trocóniz1
1Department of Pharmacy and Pharmaceutical Technology, University of Navarra, Spain; 2,Department of Anesthesiology, Hospital Clinic, Barcelona, Spain.
Objectives: Antiepileptic drugs decrease the intensity of the effect of most neuromuscular blocking agents (NMBA). Wright et al., 2004, found that CL and C50 of vecuronium were increased in those patients receiving chronic phenytoin therapy (CPT). Fernández-Candil et al., 2008, found, for the less potent drug rocuronium, a similar increase in CL in patients under CPT, however the estimate of C50 remained unchanged with respect to the group of subjects in absence of CPT. The aim of this work was to propose a mechanism-based model to conciliate the discrepancies found in C50 between vecuronium and rocuronium in patients under CPT. The estimates of C50 for vecuronium, and rocuronium show that vecuronium is a much more potent drug (95 vs 836 ng·mL-1). It might be possible that the effect of more potent drugs are more sensitive to changes in the total concentration of receptors in the biophase (Rtot).
Methods: The twitch height response vs time profiles were simulated for vecuronium and rocuronium using the published population PK parameters corresponding to CPT patients and the PD parameters of the non CPT patients,[1,2] for five different Rtot values: 0.28 (control) 0.42, 0.56, 0.7, and 0.84 mM. The Pharmacodynamic (PD) model used through simulations was an extension of the Link model, in which it is not assumed that the concentration of drug bound to the receptors is negligible.
Results: The effect vs time curves in the case of vecuronium are displaced to the right as in the case of an increase in C50, however for the case of rocuronium the profiles are independent of Rtot in the range studied.
Conclusions: The results suggest that CPT has an effect at the PD level, which will be reflected as increase in the empirical PD parameter C50 mainly in the case of highly potent NMBA drugs.
 Wright et al. Anesthesiol 2004; 100: 626-33
 Fernández-Candil et al. Eur J Clin Pharmacol (in press)
 De Haes et al. Anesth Analg. 2002; 95: 588-96
 Sheiner et al. Clin Pharmacol Ther 1979; 25: 358-71