title: Spectral analysis of heart rate variability as a quantitative measure of parasympatholytic effect--integrated pharmacokinetics and pharmacodynamics of three anticholinergic drugs.
abstract: The time course and concentration-effect relationship of parasympatholytic effects of three anticholinergic drugs were investigated using spectral analysis of heart rate (HR) variability. Single intravenous (i.v.) doses of atropine (10 microg/kg), glycopyrrolate (5 microg/kg), scopolamine (5 microg/kg), and placebo were given to eight healthy volunteers in a double-blind, randomized 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 drug 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 series of R-R intervals (RRI) free from ectopic beats. To perform pharmacokinetic-pharmacodynamic (PK-PD) modeling, venous plasma drug concentrations were measured. Atropine and glycopyrrolate, and, to a lesser extent, scopolamine induced decreases in HF power and increases in LF/HF ratio of HR variability, 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 parasympathomimetic effect was dominant. Interindividual variability was least for the Hayano index of HF power (square root (RRI HF-power)/RRI*100), and profound and consistent decreases were seen after atropine and glycopyrrolate. Pharmacokinetics were best fitted to a two-compartment open model, and effect compartment link modeling using the Hayano index was performed with the atropine and glycopyrrolate data. The best description of the PK-PD relationship for both drugs was achieved using the sigmoidal Emax model. Mean (+/-SD) EC50, sigmoidicity 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) l/h for atropine and 1.35 (+/-0.49) ng/mL, 4.34 (+/-1.55) and 2.26 (+/-0.81) l/h for glycopyrrolate. Spectral analysis of HR variability appears to be a powerful tool in monitoring parasympatholytic drug activity. A sigmoidal Emax model with an extremely steep concentration-response relationship was revealed for atropine and glycopyrrolate. The effects of scopolamine were more incongruous.
authors.affiliation: Department of Clinical Pharmacology, Turku University Hospital, Finland.
authors.forename: H
authors.initials: H
authors.lastname: Scheinin
authors.forename: A
authors.initials: A
authors.lastname: Helminen
authors.forename: S
authors.initials: S
authors.lastname: Huhtala
authors.forename: P
authors.initials: P
authors.lastname: Grönroos
authors.forename: J A
authors.initials: JA
authors.lastname: Bosch
authors.forename: T
authors.initials: T
authors.lastname: Kuusela
authors.forename: J
authors.initials: J
authors.lastname: Kanto
authors.forename: T
authors.initials: T
authors.lastname: Kaila
mesh_terms: D000328:Adult; D001285:Atropine / Q000493:pharmacokinetics / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D018680:Cholinergic Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004562:Electrocardiography; D006024:Glycopyrrolate / Q000493:pharmacokinetics / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008954:Models, Biological; D010275:Parasympathetic Nervous System / Q000187:drug effects*; D010276:Parasympatholytics / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D012016:Reference Values; D012119:Respiration / Q000187:drug effects; D012601:Scopolamine / Q000493:pharmacokinetics / Q000494:pharmacology; D013997:Time Factors
chemical_list: D018680:Cholinergic Antagonists; D010276:Parasympatholytics; D001285:Atropine; D012601:Scopolamine; D006024:Glycopyrrolate