J. Ahonen et al., EFFECT OF DILTIAZEM ON MIDAZOLAM AND ALFENTANIL DISPOSITION IN PATIENTS UNDERGOING CORONARY-ARTERY BYPASS-GRAFTING, Anesthesiology, 85(6), 1996, pp. 1246-1252
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.