Torsadegenic action of the antipsychotic drug sulpiride assessed using in vivo canine models.
A patient had QT prolongation and syncope after starting sulpiride therapy. The present experiments were performed to clarify the causal link among the sulpiride administration, QT prolongation, and the onset of torsade de pointes. Two in vivo models were used: halothane-anesthetized dogs and chronic atrioventricular (AV) block dogs. In the halothane-anesthetized animals (n = 6), sulpiride (2 and 20 mg/kg intravenously) decreased total peripheral resistance and increased heart rate, cardiac output, and ventricular contractility concomitantly. A transient attenuation of these effects occurred soon after the high-dose administration. No significant change was detected in left ventricle preload and depolarization, but repolarization and effective refractory period were significantly prolonged after high-dose administration. The extent of changes was greater in repolarization than in refractoriness, indicating prolongation of the final repolarization phase (electrically vulnerable period). In the chronic AV block animals (n = 4), onset of torsades de pointes with marked QT prolongation was demonstrated after the administration of 60 and 120 mg/kg orally of sulpiride. These results suggest that the QT prolongation and the change in the final repolarization phase with increased sympathetic tone may be the mechanisms responsible for the arrhythmogenic effect of sulpiride. Thus, caution should be paid with the use of sulpiride in patients at risk for elevated plasma concentrations and having preexisting susceptibility to QT prolongation.
Department of Pharmacology, Yamanashi Medical University Tamaho-cho, Nakakoma-gun, Yamanashi 409-3898, Japan. atsushis@res.yamanashi-med.ac.jp
Atsushi
A
Sugiyama
Yoshioki
Y
Satoh
Hiroyuki
H
Shiina
Satoshi
S
Takeda
Keitaro
K
Hashimoto
D000200:Action Potentials / Q000187:drug effects; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D014150:Antipsychotic Agents / Q000009:adverse effects* / Q000097:blood; D004285:Dogs; D018492:Dopamine Antagonists / Q000009:adverse effects* / Q000097:blood; D004562:Electrocardiography / Q000187:drug effects; D004594:Electrophysiology; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D008133:Long QT Syndrome / Q000097:blood / Q000139:chemically induced*; D013469:Sulpiride / Q000009:adverse effects* / Q000097:blood; D016171:Torsades de Pointes / Q000139:chemically induced*
D014150:Antipsychotic Agents; D018492:Dopamine Antagonists; D013469:Sulpiride