Spectral analysis of heart rate variability as a quantitative measure of parasympatholytic effect - Integrated pharmacokinetics and pharmacodynamics of three anticholinergic drugs

The time course and concentration-effect relationship of parasympatholytic effects of three anticholinergic drugs were investigated using spectral ana lysis of heart rate (HR) variability. Single intravenous (TV) doses of atro pine (10 mu g/kg), glycopyrrolate (5 mu g/kg), scopolamine (5 mu g/kg), and placebo were given to eight healthy volunteers in a double-blind, randomiz ed cross-over study. Electrocardiogram (ECG) was recorded at baseline and 2 .5, 5, 10, 20, and 30 minutes, and 1, 1.5, 2, 3, 4, 5, and 6 hours after dr ug administration, while the subjects breathed at a fixed 0.25 Hz frequency . The powers of two frequency bands (low frequency [LF] = 0.07-0.15 Hz and high frequency [HF] = 0.15-0.40 Hz) were calculated using stationary time s eries of R-R intervals (RRI) free from ectopic beats. To perform pharmacoki netic-pharmacodynamic (PK-PD) modeling, venous plasma drug concentrations w ere measured. Atropine and glycopyrrolate, and, to a lesser extent, scopola mine induced decreases in HF power and increases in LF/HF ratio of HR varia bility, indicating parasympatholytic activity and corresponding changes in sympathovagal balance. Maximal average decreases in HF power were 99%, 94%, and 82%, respectively, but in two scopolamine subjects, a parasympathomime tic effect was dominant. Interindividual variability was least for the Haya no index of HF power (root (RRI HF-power)/RRI*100), and profound and consis tent decreases were seen after atropine and glycopyrrolate. Pharmacokinetic s were best fitted to a two-compartment open model, and effect compartment link modeling using the Hayano index was performed with the atropine and gl ycopyrrolate data. The best description of the PK-PD relationship for both drugs was achieved using the sigmoidal E-max model. Mean (+/-SD) EC50, sigm oidicity factor (gamma), and equilibration rate constant (k(e0)) estimates were 1.35 (+/-0.27) ng/mL, 6.07 (+/-1.98) and 11.0 (+/-5.28) 1/h for atropi ne and 1.35 (+/-0.49) ng/mL, 4.34 (+/-1.55) and 2.26 (+/-0.81) 1/h for glyc opyrrolate. Spectral analysis of HR variability appears to be a powerful to ol in monitoring parasympatholytic drug activity. A sigmoidal E-max model w ith an extremely steep concentration-response relationship was revealed for atropine and glycopyrrolate. The effects of scopolamine were more incongru ous.