title: Dual rate-dependent cardiac electrophysiologic effects of haloperidol: slowing of intraventricular conduction and lengthening of repolarization.
abstract: Treatment with the neuroleptic agent haloperidol is sometimes associated with serious cardiac arrhythmias. The proarrhythmic potential of haloperidol may be linked to the drug's rate-dependent modulation of cardiac impulse conduction and repolarization. Herein these heart rate-dependent electrophysiologic actions of haloperidol are investigated in vivo. In anesthetized guinea pigs, haloperidol (0.02 mg/kg/min intravenously) produced significant rate-dependent slowing of intraventricular conduction. On abruptly changing the driving cycle length from 500 ms to 300 ms, conduction slowing rapidly reached a new steady state with a rate constant of 0.80 per beat +/- 0.07. The time course of recovery from conduction slowing on interruption of rapid pacing at a cycle length of 250 ms was well described by two time constants, tau(rec1) = 18.9 ms +/- 8.0 and tau(rec2) = 141.8 ms +/- 87.1, suggesting rapid dissociation of the drug from the Na+ channel. During prolonged stimulation, conduction slowing had a biphasic dependence on heart rate: for each 10-bpm increment in heart rate, conduction slowing increased by 7.9% at rates <220 bpm and by 17% at rates >220 bpm. At all tested cycle lengths, haloperidol caused a significant lengthening of Q(T) intervals, which was inversely dependent on heart rate. Numeric analysis suggested that the excessive increase in conduction slowing at rates >220 bpm was due to the drug's Q(T)-prolonging effect, indicating that, at short cycle lengths, the impulses encroached on the refractory period. Thus, in vivo, haloperidol slows intracardiac conduction with rapid on/off kinetics, comparable to the class I antiarrhythmic agent lidocaine. The Q(T) prolongation by haloperidol may lead to an excessive conduction slowing at high heart rates.
authors.affiliation: Department of Cardiology, Institute of Pharmacology, University of Vienna, Austria.
authors.forename: Deddo
authors.initials: D
authors.lastname: Mörtl
authors.forename: Ernst
authors.initials: E
authors.lastname: Agneter
authors.forename: Peter
authors.initials: P
authors.lastname: Krivanek
authors.forename: Karl
authors.initials: K
authors.lastname: Koppatz
authors.forename: Hannes
authors.initials: H
authors.lastname: Todt
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood; D002036:Bundle of His / Q000187:drug effects / Q000502:physiology; D051668:Delayed Rectifier Potassium Channels; D005260:Female; D006168:Guinea Pigs; D006220:Haloperidol / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood; D006329:Heart Conduction System / Q000187:drug effects* / Q000502:physiology; D006352:Heart Ventricles / Q000187:drug effects; D007262:Infusions, Intravenous; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000503:physiopathology; D015221:Potassium Channels / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated; D016276:Ventricular Function
chemical_list: D014150:Antipsychotic Agents; D051668:Delayed Rectifier Potassium Channels; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D006220:Haloperidol