Abstract
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.
Similar content being viewed by others
References
Chae YJ, Lee HJ, Jeon JH, Kim IB, Choi JS, Sung KW, Hahn SI (2015) Effects of donepezil on hERG potassium channels. Brain Res 1597:77–85
Farlow M, Veloso F, Moline M, Yardley J, Brand-Schieber E, Bibbiani F, Zou H, Hsu T, Satlin A (2011) Safety and tolerability of donepezil 23 mg in moderate to severe Alzheimer's disease. BMC Neurol 11:57
Fridericia LS (1920) Die Systolendauer im Elektrokardiogramm bei normalen Menschen und bei Herzkranken (in German). Acta Med Scand 53:469–486
Harvey RD, Grant AO (2018) Agents used in cardiac arrhythmias. In: Katzung BG (ed) Basic & clinical pharmacology, 14th edn. McGraw-Hill Education, New York, pp 228–253
Johannesen L, Vicente J, Mason JW, Sanabria C, Waite-Labott K, Hong M, Guo P, Lin J, Sørensen JS, Galeotti L, Florian J, Ugander M, Stockbridge N, Strauss DG (2014) Differentiating drug-induced multichannel block on the electrocardiogram: randomized study of dofetilide, quinidine, ranolazine, and verapamil. Clin Pharmacol Ther 96:549–558
Katzung BG (2018) Special aspects of geriatric pharmacology. In: Katzung BG (ed) Basic & clinical pharmacology, 14th edn. McGraw-Hill Education, New York, pp 1058–1067
Kilkenny C, Browne W, Cuthill IC, Emerson M, Altman DG (2010) Animal research: reporting in vivo experiments: the ARRIVE guidelines. Br J Pharmacol 160:1577–1579
Kitt J, Irons R, Al-Obaidi M, Missouris C (2015) A case of donepezil-related torsades de pointes. BMJ Case Rep. https://casereports.bmj.com/content/2015/bcr-2015-211900
Kosasa T, Kuriya Y, Matsui K, Yamanishi Y (1999a) Effect of donepezil hydrochloride (E2020) on basal concentration of extracellular acetylcholine in the hippocampus of rats. Eur J Pharmacol 380:101–107
Kosasa T, Kuriya Y, Yamanishi Y (1999b) Effect of donepezil hydrochloride (E2020) on extracellular acetylcholine concentration in the cerebral cortex of rats. Jpn J Pharmacol 81:216–222
Matsui K, Mishima M, Nagai Y, Yuzuriha T, Yoshimura T (1999) Absorption, distribution, metabolism, and excretion of donepezil (Aricept) after a single oral administration to rat. Drug Metab Dispos 27:1406–1414
McGrath J, Drummond G, McLachlan E, Kilkenny C, Wainwright C (2010) Guidelines for reporting experiments involving animals: the ARRIVE guidelines. Br J Pharmacol 160:1573–1576
McLaren AT, Allen J, Murray A, Ballard CG, Kenny RA (2003) Cardiovascular effects of donepezil in patients with dementia. Dement Geriatr Cogn Disord 15:183–188
Nagueh SF, Sun H, Kopelen HA, Middleton KJ, Khoury DS (2001) Hemodynamic determinants of the mitral annulus diastolic velocities by tissue Doppler. J Am Coll Cardiol 37:278–285
Pappano AJ (2018) Cholinoceptor-activating & cholinesterase-inhibiting drug. In: Katzung BG (ed) Basic & clinical pharmacology, 14th edn. McGraw-Hill Education, New York, pp 107–123
Satoh T, Zipes DP (1996) Rapid rates during bradycardia prolong ventricular refractoriness and facilitate ventricular tachycardia induction with cesium in dogs. Circulation 94:217–227
Sugiyama A (2008) Sensitive and reliable proarrhythmia in vivo animal models for predicting drug-induced torsades de pointes in patients with remodelled hearts. Br J Pharmacol 154:1528–1537
Sugiyama A, Hashimoto K (1998) Effects of gastrointestinal prokinetic agents, TKS159 and cisapride, on the in situ canine heart assessed by cardiohemodynamic and electrophysiological monitoring. Toxicol Appl Pharmacol 152:261–269
Sugiyama A, Ishida Y, Satoh Y, Aoki S, Hori M, Akie Y, Kobayashi Y, Hashimoto K (2002a) Electrophysiological, anatomical and histological remodeling of the heart to AV block enhances susceptibility to arrhythmogenic effects of QT-prolonging drugs. Jpn J Pharmacol 88:341–350
Sugiyama A, Satoh Y, Ishida Y, Yoneyama M, Yoshida H, Hashimoto K (2002b) Pharmacological and electrophysiological characterization of junctional rhythm during radiofrequency catheter ablation of the atrioventricular node: possible involvement of neurotransmitters from autonomic nervous system. Circ J 66:696–701
Takahara A, Sugiyama A, Ishida Y, Satoh Y, Wang K, Nakamura Y, Hashimoto K (2006) Long-term bradycardia caused by atrioventricular block can remodel the canine heart to detect the histamine H1 blocker terfenadine-induced torsades de pointes arrhythmias. Br J Pharmacol 147:634–641
Takaya T, Okamoto M, Yodai K, Hata K, Kijima Y, Nakajima H, Nishikawa Y, Kita T, Ito M, Seo T, Kawashima S (2009) Torsades de pointes with QT prolongation related to donepezil use. J Cardiol 54:507–511
Umegaki H, Khookhor O (2013) The response of the autonomic nervous system to the cholinesterase inhibitor, donepezil. Neuroendocrinol Lett 34:383–387
Van de Water A, Verheyen J, Xhonneux R, Reneman RS (1989) An improved method to correct the QT interval of the electrocardiogram for changes in heart rate. J Pharmacol Methods 22:207–217
Acknowledgments
The authors thank Dr. Yuji Nakamura (deceased on March 26, 2018) for his technical assistance during operation of experiment and Mrs. Yuri Ichikawa for her technical assistance during preparation of the manuscript.
Funding
This study was supported in part by research grants from Japan Society for the Promotion of Science (JSPS KAKENHI) grant number 19K16505 (to M.H-N.) and 20K16136 (to R.K.), and the Project Research Grant of Toho University School of Medicine grant number 17-11 (to M.H-N.) and 19-07 (to R.K.).
Author information
Authors and Affiliations
Contributions
M.H-N. and A.S. conceived the experiments, M.H-N., A.G., H.I-N., K.C., and T.W. conducted the experiments; M.H-N., R.K., Y.N., Y.T., A.M., and A.S. analyzed the results. All authors reviewed the manuscript. All data were generated in-house and that no paper mill was used.
Corresponding author
Ethics declarations
All experiments were approved by the Toho University Animal Care and User Committee (approval number: 16-51-323, 16-51-324, 17-52-323, and 17-52-324) and performed according to the Guideline for the Care and Use of Laboratory Animals of Toho University and ARRIVE guidelines (Kilkenny et al. 2010; McGrath et al. 2010).
Conflicts of interest
The authors declare that they have no conflict of interest.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
ESM 1
(XLSX 45 kb)
Rights and permissions
About this article
Cite this article
Hagiwara-Nagasawa, M., Kambayashi, R., Goto, A. et al. Analysis of electropharmacological and proarrhythmic effects of donepezil using the halothane-anesthetized intact dogs and the conscious chronic atrioventricular block ones. Naunyn-Schmiedeberg's Arch Pharmacol 394, 581–589 (2021). https://doi.org/10.1007/s00210-020-01997-w
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00210-020-01997-w