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 (CYP3A) 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 coronary artery bypass grafting were randomly assigned to receive either diltiazem (60 mg orally 2 h before induction of anesthesia and an infusion of 0.1 mg.kg-1.h-1 started at induction and continued for 23 h) or placebo in a double-blind study. Anesthesia was induced with 0.1 mg/kg midazolam, 50 micrograms/kg alfentanil, and 20 to 80 mg propofol and maintained with infusions of 1 microgram.kg-1.min-1 of both midazolam and alfentanil supplemented with isoflurane. Plasma midazolam and alfentanil concentrations and areas under the plasma concentration-time curves were determined. The terminal half-life and the time for the drug plasma level to decrease 50% after cessation of the infusion (t50) were calculated for midazolam and alfentanil. Separation from mechanical ventilation and tracheal extubation were performed according to the study protocol.


RESULTS
Diltiazem increased the mean concentration-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 half-life of midazolam was 43% (P < 0.05) and that of alfentanil was 50% (P < 0.05) longer in patients receiving diltiazem. The mean t50 of alfentanil was 40% longer (P < 0.05) in patients receiving diltiazem, but the change in the mean t50 of midazolam (25%) was not statistically significant. In patients receiving diltiazem, tracheal extubation was performed on average 2.5 h later (P = 0.054) than in those receiving placebo.


CONCLUSIONS
Diltiazem slows elimination of midazolam and alfentanil and may delay tracheal extubation after large doses of these anesthetic adjuncts. CYP3A-mediated drug interactions should be considered as confounders when recovery from anesthesia with midazolam and alfentanil infusions is assessed.
Ahonen
J
J
University Central Hospital, Helsinki, Finland.
Olkkola
K T
KT
Salmenperä
M
M
Hynynen
M
M
Neuvonen
P J
PJ
D000759:Adjuvants, Anesthesia / Q000097:blood / Q000493:pharmacokinetics*; D015760:Alfentanil / Q000097:blood / Q000493:pharmacokinetics*; D000762:Anesthesia Recovery Period; D018686:Anesthetics, Intravenous / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D001026:Coronary Artery Bypass; D004110:Diltiazem / Q000494:pharmacology*; D004311:Double-Blind Method; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008297:Male; D008874:Midazolam / Q000097:blood / Q000493:pharmacokinetics*; D008875:Middle Aged
D000759:Adjuvants, Anesthesia; D018686:Anesthetics, Intravenous; D002121:Calcium Channel Blockers; D015760:Alfentanil; D004110:Diltiazem; D008874:Midazolam