Dual rate-dependent cardiac electrophysiologic effects of haloperidol: slowing of intraventricular conduction and lengthening of repolarization.
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.
Mörtl
Deddo
D
Department of Cardiology, Institute of Pharmacology, University of Vienna, Austria.
Agneter
Ernst
E
Krivanek
Peter
P
Koppatz
Karl
K
Todt
Hannes
H
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
D014150:Antipsychotic Agents; D051668:Delayed Rectifier Potassium Channels; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D006220:Haloperidol