Dose of midazolam should be reduced during diltiazem and verapamil treatments.

Abstract

1. The effects of diltiazem and verapamil on the pharmacokinetics and pharmacodynamics of midazolam were investigated in a double‐blind randomized cross‐over study of three phases. 2. Nine healthy volunteers were given orally diltiazem (60 mg), verapamil (80 mg) or placebo three times daily for 2 days. On the second day they received a 15 mg oral dose of midazolam, after which plasma samples were collected and performance tests carried out for 17 h. 3. The area under the midazolam concentration‐time curve was increased from 12 +/‐ 1 microgram ml‐1 min to 45 +/‐ 5 micrograms ml‐1 min by diltiazem (P < 0.001) and to 35 +/‐ 5 micrograms ml‐1 min by verapamil (P < 0.001). The peak midazolam concentration was doubled (P < 0.01) and the elimination half‐life of midazolam prolonged (P < 0.05) by both diltiazem and verapamil treatments. 4. These changes in the pharmacokinetics of midazolam were also associated with profound and prolonged sedative effects. 5. If the administration of midazolam cannot be avoided, the dose of midazolam should be reduced during concomitant treatment with diltiazem and verapamil.

Analysis of omeprazole, midazolam and hydroxy-metabolites in plasma using liquid chromatography coupled to tandem mass spectrometry

“…Thummel et al [7] demonstrated an excellent correlation (r = 0.93, p < 0.001) between in vivo total midazolam clearance and hepatic CYP3A content measured ex vivo in liver transplant patients. Midazolam has met most of the putative criteria as a selective and sensitive probe for CYP3A activity [1,[6][7][8], has demonstrated a small degree of intraindividual variability over 3 months, and is not affected by gender or menstrual cycle phase [9]. Midazolam has the advantages of intravenous administration to avoid pre-systemic metabolism, and low cost.…”

Drug–Drug Interactions in Cardiovascular Catheterizations and Interventions

“…McDonnell et al (68) demonstrated that co-administration of atorvastatin in patients receiving intravenous midazolam undergoing general anesthesia resulted in an increase in the area-under-the-curve (AUC) and a decrease in the clearance of midazolam. Although atorvastatin in particular was examined in this trial, most CYP3A4-metabolized statins In addition, studies of diltiazem and verapamil have also demonstrated increases in the peak concentration, AUC, and a decrease in the clearance of intravenous midazolam (69). A combination of non-dihydropyridine (DHP) CCBs and midazolam has also been shown to result in more profound and prolonged sedation than non-exposure to the interaction (70).…”

The Effect of Diltiazem and Nifedipine on the Rate of Metabolism of Midazolam

“…Knowledge of adverse drug interactions is imperative in the practice of anesthesia. In 1994, it was reported that oral administration of CCB diltiazem or verapamil with midazolam prolonged the sedative and hypnotic effects of midazolam in nine healthy volunteers (Backman et al, 1994). Investigation into the effect of CCB on the metabolism of midazolam was warranted because these drugs are frequently administered in the practice of anesthesia.…”

“…Prolonged and profound sedative effects were also observed. The study concluded that if the administration of midazolam could not be avoided than the dose of midazolam should be reduced if given with diltiazem or verapamil (Backman et al, 1994). In another study published in 1996, 30 patients having coronary artery bypass grafting, were randomly assigned to receive either diltiazem two hours before induction of anesthesia with midazolam or a placebo in a double-blind study.…”

“…One in vivo study reported the prolongation of hypnotic effect of midazolam when coadministered with the calcium channel blocker diltiazem (Backman et al, 1994).…”