EFFECT OF DILTIAZEM ON MIDAZOLAM AND ALFENTANIL DISPOSITION IN PATIENTS UNDERGOING CORONARY-ARTERY BYPASS-GRAFTING

Background Midazolam and alfentanil are desirable anesthetic adjuncts for cardiac anesthesia. They are metabolized by cytochrome P450 3A (CY P3A) enzymes, These isozymes are inhibited by concurrent medications, including the calcium channel antagonist diltiazem, which may have an effect on recovery from anesthesia. Methods: Thirty patients having co ronary artery bypass grafting mere randomly assigned to receive either diltiazem (60 mg orally 2 h before induction of anesthesia and an inf usion of 0.1 mg . kg(-1) . h(-1) started at induction and continued fo r 23 h) or placebo in a double-blind study, Anesthesia was induced wit h 0.1 mg/kg midazolam, 50 mu g/kg alfentanil, and 20 to 80 mg propofol and maintained with infusions of 1 mu g . kg(-1) . min(-1) of both mi dazolam and alfentanil supplemented with isoflurane. Plasma midazolam and alfentanil concentrations and areas under the plasma concentration -time curves mere determined. The terminal half-life and the time for the drug plasma level to decrease 50% after cessation of the infusion (t(50)) were calculated for midazolam and alfentanil. Separation from mechanical ventilation and tracheal extubation mere performed accordin g to the study protocol. Results: Diltiazem increased the mean concent ration-time curves (from end of anesthesia until 23 h) of midazolam by 24% (P < 0.05) and that of alfentanil by 40% (P < 0.05), The mean hal f-life of midazolam was 43% (P < 0.05) and that of alfentanil was 50% (P < 0.05) longer in patients receiving diltiazem. The mean t(50) of a lfentanil was 40% longer (P < 0.05) in patients receiving diltiazem, b ut the change in the mean t(50) of midazolam (25%) was not statistical ly significant. In patients receiving diltiazem, tracheal extubation w as performed on average 2.5 h later (P = 0.054) than in those receivin g placebo, Conclusions: Diltiazem slows elimination of midazolam and a lfentanil and may delay tracheal extubation after large doses of these anesthetic adjuncts. CYP3A-mediated drug interactions should be consi dered as confounders when recovery from anesthesia with midazolam and alfentanil infusions is assessed.