Donepezil, an inhibitor for
acetylcholinesterase used for patients with
Alzheimer's disease, has been shown to inhibit IKr, occasionally inducing
torsade de pointes. In order to analyze the causal relationship between
donepezil treatment and onset of lethal arrhythmias, we initially assessed electropharmacological effects of
donepezil hydrochloride of 0.01, 0.1, and 1 mg/kg, i.v. over 10 min using the
halothane-anesthetized intact dogs (n = 4), possibly providing subtherapeutic to supratherapeutic plasma concentrations. Although the low or middle dose did not exert any effect, the high dose transiently increased the ventricular refractoriness along with modest prolongation of the late repolarization period, indicating potential IKr inhibitory action in vivo. Moreover, the high dose induced the positive chronotropic, inotropic, and dromotropic actions along with the pressor effect and prolongation of early repolarization period, suggesting sympathicotonic condition in the central nervous system. Next, we examined proarrhythmic effects of
donepezil hydrochloride of 0.1 and 1 mg/kg, i.v. over 10 min using the conscious chronic
atrioventricular block dogs (n = 4). Although the low dose hardly affected the cardiovascular variables, the high dose increased the atrial and ventricular rate without significantly altering the repolarization period, possibly reflecting sympathicotonic condition. Importantly, the high dose induced non-sustained
ventricular tachycardia in half of the animals. Thus,
donepezil by itself did not induce
torsade de pointes in vivo, which suggests that
donepezil-induced sympathicotonic condition may induce Ca2+ overload, triggering the ventricular arrhythmias, but might indirectly attenuate its IKr inhibitory action, preventing excessive repolarization delay.