Pharmacokinetic interactions between midazolam and propofol: an infusion study

We have tested the hypothesis that the synergistic interactionwhich occurs when midazolam and propofol are combined for i.v. sedation is caused by an increase in the free plasma concentrationof one of the drugs. Six patients undergoing general anaesthesiareceived an infusion of propofol with the addition of an infusionof midazolam commenced 30 min later. Another six patients receivedan infusion of midazolam with the addition of an infusion ofpropofol 30 min later. All infusions were administered via pharmacokineticmodel-controlled syringe pumps programmed to maintain a constantplasma concentration. Venous blood samples were taken beforeand after introduction of the second infusion for later analysis.Free plasma concentration of midazolam increased from 2.0 (SD1.5) ng mt^–1 to 2.2 (1.9) ng ml^–1 after introductionof the propofol infusion (P = 0.32). Free propofol plasma concentrationwas unchanged at 18.5 (5.3) ng ml^–1 before and 18.7 (7.8)ng ml^–1 after introduction of the midazolam infusion (P= 0.94). It was concluded that the observed synergism with thiscombination cannot be explained solely by alteration in freeplasma concentration of either of these drugs when they areadministered together. (Br. J. Anaesth. 1994; 72: 62–65)