Verapamil pharmacodynamics and disposition in obese hypertensive patients

Verapamil (0.15 mg/kg) was administered by 10-min intravenous infusion to 12 obese (127 +/- 8 kg) and 11 normal weight (74 +/- 4 kg) hypertensive patients. All subjects were of similar age and without clinical or laboratory evidence of cardiac or renal dysfunction. Verapamil plasma concentrations were determined and pharmacokinetic parameters derived. Electrocardiographic P-R interval, used as a measure of A-V nodal conduction, mean blood pressure, and heart rate were determined simultaneously with blood sampling for 24 h following the dose. Elimination half-life was prolonged in obese patients (10.1 +/- 1.8 vs. 3.6 +/- 0.4 h; p less than 0.005) due to a marked increase in volume of distribution at steady-state (713 +/- 99 vs. 301 +/- 33 L; p less than 0.005) with no change in total verapamil clearance [1,339 +/- 180 obese vs. 1,250 +/- 147 ml/min; not significant (NS)]. Verapamil plasma protein binding was similar between groups (percent unbound, 4.8 +/- 0.5 obese vs. 5.1 +/- 0.5%; NS). Using a sigmoid Emax pharmacodynamic model, Emax (maximal prolongation in P-R interval) was unchanged in obesity (53.7 +/- 12.5 obese vs. 45.9 +/- 12.0 ms; NS). However, EC50 (verapamil concentration required to achieve 50% of Emax prolongation in P-R interval) was greater in obese patients (45.9 +/- 6.7 vs. 22.6 +/- 2.0 ng/ml; p less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)