Aging alters verapamil elimination and dynamics: single dose and steady-state responses

Verapamil elimination kinetics and pharmacodynamic effects were studied in 29 healthy individuals (23-81 years of age) after single i.v. doses (0.15-0.22 mg/kg) and during infusions to reach stable plasma verapamil concentrations of 28 +/- 11, 57 +/- 19 and 112 +/- 26 ng/ml (mean +/- S.D.). Aging prolonged verapamil elimination (P less than .008): elimination half-life of 218 +/- 91 min in young (ages 20-39), 280 +/- 78 min in middle-aged (40-59) and 288 +/- 73 min in elderly (greater than 60). After single verapamil doses. 1) heart rate increased with lesser increases in elderly subjects; 2) blood pressure decreased (P = .006) with greater decreases in elderly subjects; 3) spontaneous P-R intervals increased with lesser increases in elderly subjects but, 4) atrioventricular conduction times increased during transesophageal pacing without detectable age differences in responses. During steady-state infusions, 1) heart rate during sinus rhythm was unchanged but atrioventricular dissociation with junctional rhythms developed in elderly subjects (3/9); 2) blood pressure decreased with greater decreases in the elderly; 3) spontaneous P-R intervals increased with lesser increases in the elderly but no age differences in paced P-R interval changes were detected at equivalent verapamil concentrations; 4) heart rate variation (during sinus rhythm) decreased in an age-independent manner as measured by decreases in the S.D. of R-R intervals and decreased power spectral content with greatest changes seen in high frequency (respiratory) content; and 5) heart rate and blood pressure responses to cold pressor and handgrip testing were not attenuated by verapamil. In conclusion, aging prolongs verapamil elimination and alters dynamic responses to verapamil with greater sinus node depression and hypotensive effects in elderly vs. younger subjects. Although less spontaneous P-R interval prolongation was seen on ECG of the elderly vs. young, underlying atrioventricular conduction was prolonged by verapamil independent of age as shown by results when pacing was used to eliminate frequency-dependent effects caused by differing heart rate responses.