Effects of inhalational anesthetics on verapamil pharmacokinetics in dogs

Six dogs were chronically intrumented in order to collect aortic blood samples and record mean arterial pressure, cardiac output and heart rate. Each animal received verapamil 200 μg·kg^-1 by 10-min intravenous infusions on four occasions in random sequence: awake, and during halothane 1.2%, enflurane 2.5%, and isoflurane 1.6% anesthesia. Rate of initial distribution of verapamil was reduced during anesthetic exposure. Verapamil intercompartmental clearance from the central compartment to halothane and isoflurane, and tended to decrease during enflurane exposure as well. Verapamil terminal volume of distribution at steady-state was reduced by halothane, enflurane, and isoflurane exposure as compared with awake: 65 ± 10, 80 ± 9, and 93 ± 19 l, respectively, versus 132 ± 12 l (mean ± SEM; P<0.05). Verapamil total clearance was also reduced by halothane, enflurane, and isoflurane as compared with awake: 37 ± 4, 39 ± 2 and 41 ± 3 l·h^-1, respectively, versus 64 ± 7 l·h^-1 (P<0.05). Verapamil administered to awake animals resulted in a decrease from baseline in mean arterial pressure; 95 ± 8 mmHg versus 108 ± 4 mmHg (P<0.05): and an increase in cardiac output; 2.60 ± 0.33 l·min^-1 versus 1.93 ± 0.22 l·min^-1 (P<0.05). During halothane, enflurane, and isoflurane anesthesia, verapamil administration resulted in a similar decrease in mean arterial pressure; however cardiac output decreased, in contrast to the increase noted in awake animals. This study suggests that the pharmacokinetic drug-drug interactions may contribute to pharmacodynamic interactions between verapamil and inhalational anesthetics. Our data also indicate that increased plasma concentrations after a single verapamil dose may occur due to decreased intercompartmental clearance, and to a lesser extent increased initial volume of distribution and decreased apparent volume of distribution.