Donepezil-Induced Adverse Side Effects of Cardiac Rhythm: 2 Cases Report of Atrioventricular Block and Torsade de Pointes

Tanaka, Atsushi; Koga, Shoichi; Hiramatsu, Yoshihiro

doi:10.2169/internalmedicine.48.2181

Cited by 54 publications

(46 citation statements)

References 18 publications

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“…However, none of these studies gave detailed information on the adverse effects of donepezil on the cardiac conduction system, such as QT prolongation (19)(20)(21)(22)(23)(24). Moreover, it was also reported that bradycardia, complete atrioventricular block and QT prolongation were seen in patients taking donepezil (24)(25)(26)(27)(28). Therefore, there has been significant anxiety among prescribers regarding the potential for cardiac adverse effects associated with ChEIs, such as donepezil in elderly patients with AD (29).…”

Section: Discussionmentioning

confidence: 99%

Cardiac Safety of Donepezil in Elderly Patients with Alzheimer Disease

et al. 2012

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Objective Donepezil is a widely used cholinesterase inhibitor for the treatment of Alzheimer's disease (AD), however its cholinergic adverse side effects on the cardiovascular system are still unclear. In this study, we aimed to examine the adverse side effects caused by donepezil on cardiac rhythm and postural blood pressure changes in elderly patients with Alzheimer Disease. Methods The ECG parameters including heart rate, PR, QT, QTc interval and QRS duration and postural blood pressure changes were recorded at the baseline and at each donepezil dose level (5 and 10 mg/d). Patients Seventy-one consecutive patients who were referred by primary care centers to a Geriatric Clinic were enrolled and underwent comprehensive geriatric assessment. Results Fifty-two subjects completed the study. There were no significant changes relative to the baseline in any of the ECG parameters or arterial blood pressure at any of the investigated dosages of donepezil. Conclusion It was demonstrated that donepezil was not associated with increased negative chronotropic, arrhythmogenic or hypotensive effects for elderly patients with Alzheimer's disease.

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Section: Discussionmentioning

confidence: 99%

Cardiac Safety of Donepezil in Elderly Patients with Alzheimer Disease

et al. 2012

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“…This drug is effective and well tolerated with less adverse effects than other inhibitors of acetylcholinesterase, such as physostigmine and tacrine (Sugimoto et al, 2000). However, several case reports have stated that donepezil induces adverse side effects of cardiac rhythm, such as prolonged QT interval and Torsade de Pointes arrhythmias (Takaya et al, 2009;Tanaka et al, 2009). One of the mechanisms of QT prolongation and Torsade de Pointes includes the blockage of the human ethera-go-go-related gene (hERG) current, which underlies the rapidly activating delayed rectifier voltage-gated K þ (Kv) currents in human cardiomyocytes (Thomas et al, 2002;Witchel et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Effects of donepezil on hERG potassium channels

et al. 2015

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“…In the present study, we focused on the interaction of donepezil and cilostazol at efflux transporters as a potential explanation of the clinically reported cardiotoxicity of donepezil when coadministered with cilostazol (Tanaka et al, 2009;Shinozaki, 2012;Igeta et al, 2013). This is an important issue because simultaneous use of donepezil and cilostazol has been proposed to improve the pharmacologic outcome (Lee et al, 2007;Ihara et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, it has been reported that donepezil may cause cardiac toxicity, such as QT prolongation (Takaya et al, 2009). There are also case reports of cardiac toxicity of donepezil in patients concurrently receiving cilostazol, benidipine, or memantine (Tanaka et al, 2009;Shinozaki, 2012;Igeta et al, 2013). However, the mechanism of the putative drug-drug interaction (DDI) has not yet been clarified, even though donepezil is often administered with other drugs, as it is frequently prescribed for elderly people.…”

Section: Introductionmentioning

confidence: 99%

Local Drug-Drug Interaction of Donepezil with Cilostazol at Breast Cancer Resistance Protein (ABCG2) Increases Drug Accumulation in Heart

Takeuchi

Shinozaki

Nakanishi

et al. 2015

Drug Metabolism and Disposition

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Clinical reports indicate that cardiotoxicity due to donepezil can occur after coadministration with cilostazol. We speculated that the concentration of donepezil in heart tissue might be increased as a result of interaction with cilostazol at efflux transporters such as P-glycoprotein (P-gp, ABCB1) and breast cancer resistance protein (BCRP, ABCG2), which are expressed in many tissues including the heart, and our study tested this hypothesis. First, donepezil was confirmed to be a substrate of both BCRP and P-glycoprotein in transporter-transfected cells in vitro. Cilostazol inhibited BCRP and P-glycoprotein with half-inhibitory concentrations of 130 nM and 12.7 mM, respectively. Considering the clinically achievable unbound plasma concentration of cilostazol (about 200 nM), it is plausible that BCRP-mediated transport of donepezil would be affected by cilostazol in vivo. Indeed, in an in vivo rat study, we found that coadministration of cilostazol significantly increased the concentrations of donepezil in the heart and brain, where BCRP functions as a part of the blood-tissue barrier, whereas the plasma concentration of donepezil was unaffected. In addition, in vitro accumulation of donepezil in heart tissue slices of rats was significantly increased in the presence of cilostazol. These results indicate that donepezil-cilostazol interaction at BCRP may be clinically relevant in heart and brain tissues. In other words, the tissue distribution of drugs can be influenced by drug-drug interaction (DDI) at efflux transporters in certain tissues (local DDI) without any apparent change in plasma concentration (systemic DDI).

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Donepezil-Induced Adverse Side Effects of Cardiac Rhythm: 2 Cases Report of Atrioventricular Block and Torsade de Pointes

Abstract: Acetylcholinesterase inhibitors (AChIs)

Cited by 54 publications

References 18 publications

Cardiac Safety of Donepezil in Elderly Patients with Alzheimer Disease

Cardiac Safety of Donepezil in Elderly Patients with Alzheimer Disease

Effects of donepezil on hERG potassium channels

Local Drug-Drug Interaction of Donepezil with Cilostazol at Breast Cancer Resistance Protein (ABCG2) Increases Drug Accumulation in Heart

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