Proarrhythmic Effect of Acetylcholine-Esterase Inhibitors Used in the Treatment of Alzheimer’s Disease: Benefit of Rivastigmine in an Experimental Whole-Heart Model

Ellermann, Christian; Coenen, Alix; Niehues, Philipp; Leitz, Patrick; Kochhäuser, Simon; Dechering, Dirk G.; Fehr, Michael; Eckardt, Lars; Frommeyer, Gerrit

doi:10.1007/s12012-019-09543-8

Cited by 15 publications

(16 citation statements)

References 35 publications

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“… 72 Thus, in this study spatial dispersion of repolarisation but not duration of repolarisation, per se , was associated with proarrhythmic risk with AChEis, leading the authors to suggest that QT interval measurement alone may be insufficient to evaluate proarrhythmic risk with these drugs. 72 Whilst further work is required to elucidate the underlying basis of the differences between the drugs, at least in this comparative setting rivastigmine appears to be safer than either galantamine or donepezil. 72 …”

Section: Discussionmentioning

confidence: 71%

“…A recent study has compared the effects of rivastigmine, with those of galantamine and donepezil on ventricular repolarisation and propensity to generate early after-depolarisations (EADs). 72 Ventricular repolarisation of Langendorff-perfused rabbit hearts was prolonged by donepezil but not galantamine, whereas spatial dispersion of repolarisation was prolonged by both drugs. Susceptibility to EADs and TdP was increased by both drugs.…”

Section: Discussionmentioning

confidence: 94%

“… 72 Whilst further work is required to elucidate the underlying basis of the differences between the drugs, at least in this comparative setting rivastigmine appears to be safer than either galantamine or donepezil. 72 …”

Section: Discussionmentioning

confidence: 99%

“…Preclinical data show a clear repolarisation delay with donepezil, whereas conflicting data have been obtained in respect of galantamine. 70 , 72 hERG data are lacking for rivastigmine, but repolarisation delay in rabbit hearts with rivastigmine was not associated with QT dispersion, EADs or TdP. 72 This may suggest that rivastigmine has greater cardiac safety.…”

Section: Discussionmentioning

confidence: 99%

“… 70 , 72 hERG data are lacking for rivastigmine, but repolarisation delay in rabbit hearts with rivastigmine was not associated with QT dispersion, EADs or TdP. 72 This may suggest that rivastigmine has greater cardiac safety. Further comparative pre-clinical data on rivastigmine, galantamine and donepezil would be valuable, especially in respect of the current lack of information as to whether rivastigmine inhibits hERG channels, as well as comparative data on action potential prolongation by the three drugs under a standardised set of conditions.…”

Section: Discussionmentioning

confidence: 99%

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QT interval prolongation andTorsades de Pointeswith donepezil, rivastigmine and galantamine

Malone

Hancox

2020

Therapeutic Advances in Drug Safety

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Background: Acetylcholinesterase inhibitors (AChEis) including donepezil, galantamine and rivastigmine are used to treat Alzheimer’s disease (AD). This study aimed to evaluate evidence from the case report literature for an association between these agents and risk of QT interval prolongation and Torsades de Pointes (TdP) arrhythmia. Methods: Published literature was mined with predetermined MeSH terms for each of donepezil, galantamine and rivastigmine, to identify cases of QT interval prolongation and TdP. Case reports were analysed using causality scales and a QT interval nomogram. Results: A total of 13 case reports were found (10 for donepezil, 2 for galantamine and 1 for rivastigmine) with rate corrected QT interval (QTc) prolongation. Five cases with donepezil exhibited TdP. TdP was not reported in the cases with galantamine and rivastigmine. The use of a QT heart rate nomogram highlighted risk with donepezil compared with the other two drugs and the application of the Naranjo causality scale suggested probable or possible causation for all donepezil cases. All patients had at least two other risk factors for TdP, including modifiable risk factors such as electrolyte disturbances, bradycardia, co-administration of QT prolonging drugs. A number of recent cases involved recent changes in medication. Conclusion: Our evaluation of the case report literature suggests that there is evidence for a causal association between donepezil and QTc/TdP risk. Attention to risk factors for QTc prolongation/TdP should be exercised when prescribing donepezil and modifiable risk factors corrected. Owing to the low number of cases with galantamine and rivastigmine, further work is needed to establish whether these drugs may be more suitable than donepezil for patients with other risk factors for TdP.

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Section: Discussionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 3 more Smart Citations

QT interval prolongation andTorsades de Pointeswith donepezil, rivastigmine and galantamine

Malone

Hancox

2020

Therapeutic Advances in Drug Safety

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Recent Advancements of Nanomedicine in Neurodegenerative Disorders Theranostics

Mukherjee

Madamsetty

Bhattacharya

et al. 2020

Adv Funct Materials

100

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Recent times have witnessed an upsurge in the incidence of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Prion disease, and amyotrophic lateral sclerosis. The treatment of the same remains a daunting challenge due to the limited access of therapeutic moieties across the blood–brain barrier. Engineered nanoparticles with a size less than 100 nm provide multifunctional abilities for solving these biomedical and pharmacological issues due to their unique physico‐chemical properties along with capability to cross the blood–brain barrier. Needless to mention, there is a scarcity of review articles summarizing recent developments of various nanomaterials including liposomes, polymeric nanoparticles, metal nanoparticles, and bio‐nanoparticles toward the therapeutic and theranostics applications for various neurodegenerative disorders. Here, a broad spectrum of nanomedicinal approaches to eradicate neurodegenerative disorders is provided, along with a brief account of neuroprotection and neuronal tissue regeneration, current clinical status, issues related to safety, toxicity, challenges, and future outlook.

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Comparative risk of cardiac arrhythmias associated with acetylcholinesterase inhibitors used in treatment of dementias – A narrative review

Huang

Alsabbagh

2020

Pharmacology Res & Perspec

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Donepezil, galantamine, and rivastigmine are the three acetylcholinesterase inhibitors (AChEIs), out of a total of only four medications prescribed in the treatment of Alzheimer's Disease (AD) and related dementias. These medications are known to be associated with bradycardia given their mechanism of action of increasing acetylcholine (ACh). However, in March 2015, donepezil was added to the CredibleMeds “known‐risk” category, a list where medications have a documented risk for acquired long‐QT syndrome (ALQTS) and torsades de pointes (TdP) – a malignant ventricular arrhythmia that is a different adverse event than bradycardia (and is not necessarily associated with ACh action). The purpose of this article is to review the three AChEIs, especially with regards to mechanistic differences that may explain why only donepezil poses this risk; several pharmacological mechanisms may explain why. However, from an empirical point‐of‐view, aside from some case‐reports, only a limited number of studies have generated relevant information regarding AChEIs' and electrocardiogram findings; none have specifically compared donepezil against galantamine or rivastigmine for malignant arrhythmias such as TdP. Currently, the choice of one of the three AChEIs for treatment of AD symptoms is primarily dependent upon clinician and patient preference. However, clinicians should be aware of the potential increased risk associated with donepezil. There is a need to examine the comparative risk of malignant arrhythmias among AChEIs users in real‐world practice; this may have important implications with regards to changes in AChEI prescribing patterns.

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Proarrhythmic Effect of Acetylcholine-Esterase Inhibitors Used in the Treatment of Alzheimer’s Disease: Benefit of Rivastigmine in an Experimental Whole-Heart Model

Cited by 15 publications

References 35 publications

QT interval prolongation andTorsades de Pointeswith donepezil, rivastigmine and galantamine

QT interval prolongation andTorsades de Pointeswith donepezil, rivastigmine and galantamine

Recent Advancements of Nanomedicine in Neurodegenerative Disorders Theranostics

Comparative risk of cardiac arrhythmias associated with acetylcholinesterase inhibitors used in treatment of dementias – A narrative review

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