Pharmacokinetics of pentobarbital and thiamylal as combined anesthetics in sheep

This study was performed to investigate the possible mechanisms underlying prolongation of anesthesia times in sheep caused by the sequential administration of thiamylal and pentobarbital. Sodium thiamylal was injected as an intravenous bolus dose (13.2 mg/kg) followed in 7 min by sodium pentobarbital (14.3 mg/kg) by the same route to seven sheep. Separate studies were conducted for each of the two drugs administered separately to the same animals at the same doses. Mean anesthesia times (to the return of the palpebral reflex) were 7.89 min (thiamylal), 5.39 min (pentobarbital) and 34.1 min (the sequential combination). The kinetic parameters Vd(area), Vd(ss), t 1/2 beta, and ClB for either drug were not affected by the other when given in combination. The t 1/2 alpha was shorter, and the Vc was smaller, for pentobarbital when administered with thiamylal, while there were no changes in thiamylal disposition for the combination regimen. Computer-generated curves, associated with the two-compartment open model showing the fraction of dose in each compartment as a function of time, illustrated that pentobarbital rapidly achieved higher concentrations in the peripheral compartment after prior thiamylal administration. Protein-binding studies showed that this could not be attributed to displacement of pentobarbital from plasma albumin by thiamylal. Calculation of total and free drug concentrations at the time of awakening showed that, when the drugs were combined, the concentration of each drug was less than half of that observed at awakening when they were studied separately. It can be concluded that the prolonged sleeping times associated with the sequential combination of the two agents were not due to an alteration in kinetic parameters of either drug caused by the other, but rather to an additive effect of the subanesthetic concentrations of the two drugs when combined. The fact that sleeping times were supra-additive is attributed to a shift of awakening time from the distribution (alpha) phase, when given independently, to the elimination (beta) phase when administered in combination.