The Influence of Verapamil and Nicardipine on the Rate of Metabolism of Midazolam

Certified Registered Nurse Anesthetists administer numerous drugs to surgical patients who may be on a wide and varied pharmacological regimen. It is important that the nurse anesthetist be aware of potential drug-drug interactions. The purpose of this study is to assess the in vitro metabolic reactions of midazolam in the presence of the calcium channel blockers verapamil and nicardipine in hepatic microsomes from three different human livers. Midazolam a widely used premedicant in anesthesia, and the calcium channel blockers verapamil and nicardipine are all metabolized by the cytochrome P450 3A4 subfamily of liver microsomal enzymes. Recent clinical observations and experimental studies suggest that midazolam's effects can be augmented by microsomal inhibition when drugs compete for the same family of metabolizing enzymes. In this study the metabolism of midazolam's major metabolite alpha hydroxymidazolam was measured in the presence of differing concentrations of calcium channel blockers using human liver microsomes. Data were analyzed using regression analysis to determine the percent of inhibition and metabolism and Lineweaver-Burk plots were used to determine the inhibition constant (Ki). The mean Ki for nicardipine was 1.35 and 29.3 for verapamil. Nicardipine was the stronger inhibitor of the two calcium channel blockers. Midazolam's effects in the presence of nicardipine and verapamil may be augmented or prolonged.