Pharmacokinetic interactions between midazolam and propofol: an infusion study.

We have tested the hypothesis that the synergistic interaction which occurs when midazolam and propofol are combined for i.v. sedation is caused by an increase in the free plasma concentration of one of the drugs. Six patients undergoing general anaesthesia received an infusion of propofol with the addition of an infusion of midazolam commenced 30 min later. Another six patients received an infusion of midazolam with the addition of an infusion of propofol 30 min later. All infusions were administered via pharmacokinetic model-controlled syringe pumps programmed to maintain a constant plasma concentration. Venous blood samples were taken before and after introduction of the second infusion for later analysis. Free plasma concentration of midazolam increased from 2.0 (SD 1.5) ng ml-1 to 2.2 (1.9) ng ml-1 after introduction of the propofol infusion (P = 0.32). Free propofol plasma concentration was 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 this combination cannot be explained solely by alteration in free plasma concentration of either of these drugs when they are administered together.