Donepezil induces ventricular arrhythmias by delayed repolarisation
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Donepezil induces ventricular arrhythmias by delayed repolarisation Jason Kho 1
&
Adam Ioannou 2 & Amit K J Mandal 1 & Constantinos G Missouris 1,3
Received: 16 November 2020 / Accepted: 17 November 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Acetylcholinesterase inhibitors such as donepezil delay the progression of Alzheimer’s dementia by increasing acetylcholine concentrations in the central nervous system. However, it is becoming apparent that cholinesterase inhibition by donepezil is not confined to the brain. This is supported by previous case reports of peripheral cholinergic side effects and adverse cardiac arrhythmias such as Torsades de Pointes which are reversible upon cessation of donepezil. The augmented acetylcholine concentrations and IKr inhibition in cardiomyocytes caused by donepezil are believed to mediate this effect. Keywords Donepezil . Electrocardiography . Cardiac arrhythmias . Cholinesterase inhibitors
To the Editor: The early phase of Alzheimer’s dementia is presumed to be secondary to progressive cholinergic neurodegeneration. Acetylcholinesterase inhibitors, such as donepezil, delay the progression of this phase by increasing the acetylcholine concentration in the central nervous system. It is becoming apparent, however, that cholinesterase inhibition by donepezil is not only isolated to the brain. This is supported by case reports of peripheral cholinergic side effects including nausea, vomiting and diarrhoea and adverse cardiac arrhythmias such as Torsades de Pointes (TdP), which are reversible upon cessation of donepezil (Kitt et al. 2015; Takaya et al. 2009; Mandal et al. 2019). The augmented acetylcholine concentrations and IKr inhibition in cardiomyocytes caused by donepezil are believed to mediate this effect. We read with interest the study performed by HagiwaraNagasawa et al. (2020) which analysed the electropharmacological and proarrhythmic effects of donepezil involving two groups of four beagle dogs; the second group had a complete
* Jason Kho [email protected] 1
Department of Cardiology and Internal Medicine, Frimley Health NHS Foundation Trust, Wexham Park Hospital, Wexham Street, Slough, UK
2
Royal Free London NHS Foundation Trust, Royal Free Hospital, London, UK
3
University of Cyprus Medical School, Nicosia, Cyprus
atrioventricular block induced by catheter ablation of atrioventricular node while the first did not. The first group demonstrated an increased ventricular refractory period and modest prolongation of late repolarisation at high doses of donepezil, indicating possible IKr inhibitory effect. In the second group, high doses of donepezil increased sympathetic drive to the heart manifested by increased atrial and ventricular rate and the induction of non-sustained ventricular tachycardia in two specimens. No TdP was demonstrated. We would like to highlight our recent study involving 59 patients on long-term treatment with donepezil (more than 1 year) which demonstrated significant prolongation in the
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