Combination of sotalol and quinidine in a canine model of torsades de pointes: no increase in the QT-related proarrhythmic action of sotalol.
BACKGROUND
Clinical treatment with a combination of Class IA and III antiarrhythmic drugs is not recommended, as they both favor bradycardia-dependent proarrhythmic events such as torsades de pointes (TdP). However, this theoretical additive effect on ventricular repolarization has never been demonstrated and could be questioned as other Class I drugs, such as mexiletine, a Class IB drug, limit the number of sotalol-induced TdP in dogs with AV block, suggesting the possibility of an antagonistic action of Class I properties against Class III effects.


RESULTS
We compared the electrophysiologic and proarrhythmic effects of sotalol (Class III) alone and combined with quinidine (Class IA) in a canine model of acquired long QT syndrome. Seven hypokalemic (K+: 3 +/- 0.1 mEq/L) dogs with chronic AV block had a demand pacemaker implanted and set at a rate of 25 beats/min. They were submitted to two (sotalol-alone and sotalol-plus-quinidine) experiments 48 hours apart using a randomized cross-over protocol. They were pretreated with quinidine (10 mg/kg + 1.8 mg/kg per hour) or saline infused throughout the experiment, and given sotalol (4.5 mg/kg + 1.5 mg/kg per hour) for 2 hours, 30 minutes after the beginning of the pretreatment infusion during both experiments. Ventricular and atrial cycle lengths were similarly increased by sotalol after quinidine or saline. The sotalol-induced prolongation of the QT interval was significantly shorter in quinidine-pretreated dogs (24 +/- 7 msec after quinidine vs 40 +/- 8 msec after saline). Fewer dogs developed TdP: significantly during the first hour of infusion (1/7 sotalol-plus-quinidine vs 6/7 sotalol-alone dogs, P < 0.05) but nonsignificantly during the second hour (3/7 vs 6/7).


CONCLUSIONS
In this model, the sotalol-plus-quinidine combination is at least no more arrhythmogenic than either of the drugs given alone.
Chézalviel-Guilbert
F
F
Laboratoire de Pharmacologie, Faculté de Médecine Saint Antoine, Paris, France.
Deplanne
V
V
Davy
J M
JM
Poirier
J M
JM
Xia
Y Z
YZ
Cheymol
G
G
Weissenburger
J
J
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000503:physiopathology; D004195:Disease Models, Animal; D004285:Dogs; D004359:Drug Therapy, Combination; D004594:Electrophysiology; D007262:Infusions, Intravenous; D011802:Quinidine / Q000009:adverse effects / Q000494:pharmacology*; D012965:Sodium Chloride / Q000494:pharmacology; D013015:Sotalol / Q000009:adverse effects / Q000494:pharmacology*; D016171:Torsades de Pointes / Q000188:drug therapy / Q000503:physiopathology*
D000889:Anti-Arrhythmia Agents; D012965:Sodium Chloride; D013015:Sotalol; D011802:Quinidine