Verapamil Pharmacodynamics and Disposition in Obese Hypertensive Patients

Abstract

Summary: 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 < 0.005) due to a marked increase in volume of distribution at steady-state (713 ± 99 vs. 301 ± 33 L; p < 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 < 0.005). Reflex increase in heart rate after verapamil was less in obese (4 ± 2 vs. 11 ± 2 beats/min; p < 0.01) than control patients, although the maximum hypotensive effect was similar for both groups (−15 ± 3 vs. −10 ± 1 mm Hg; NS). The pharmacodynamic findings are consistent with either decreased direct verapamil effect and/or impaired baroreflex sensitivity, sympathetic, and parasympathetic reflex responses due to verapamil-induced hypotension in obese as compared to normal-weight hypertensive patients. The pharmacokinetic findings (increased volume of distribution, no change in clearance) in the context of the pharmacodynamic findings indicate that for similar clinical verapamil effect after single intravenous doses, verapamil dose should be increased as a function of total body weight in obese hypertensive patients, and even with this adjustment some drug effects may be attenuated.