An update on the utility and safety of cholinesterase inhibitors for the treatment of Alzheimer’s disease

ABSTRACT

Introduction: Alzheimer’s disease (AD) is the most common cause of major neurocognitive disorders with a prevalence in the US of about 5.7 million in 2018. With the disease burden projected to increase dramatically in the coming years, it is imperative to review the current available treatment regimens for their safety and utility. The cholinesterase inhibitors (ChEIs) have continued to play a pivotal role in managing the symptoms and possibly slowing the rate of progression of AD since 1993. Owing to their being a mainstay in the treatment of AD, the safety and efficacy of prescribing these drugs needs to be reviewed often, especially with the approval of new formulations and doses.

Areas covered: The three ChEIs currently approved by the FDA are donepezil, rivastigmine and galantamine. This article will review the safety and tolerability of these ChEIs and analyze the potential disease modifying properties of these drugs. The authors have reviewed all recent literature including review articles, meta-analyzes, clinical trials and more.

Expert opinion: These ChEIs differ subtly in their mechanisms of action, in their tolerability and safety and FDA-approved indications. All are considered first-line, symptomatic treatments of the various phases of AD and may even have potentially disease-modifying effects.

KEYWORDS:

• Alzheimer’s disease treatment
• cholinesterase inhibitors
• safety of cholinesterase inhibitors
• side effects
• adverse effects
• donepezil
• galantamine
• rivastigmine
• symptomatic treatment for Alzheimer’s disease

Article highlights

• The ChEIs are still considered the mainstay of treatment which target the cholinergic hypothesis of AD.

• Among the 3 FDA approved ChEIs, donepezil at a dose of 23mg/day and rivastigmine transdermal patch of 13.3mg/24hr can be used in severe AD.

• GI side effects are the most common adverse events and it can be minimized by slow titration of the dose.

• Introducing the ChEIs early on in the disease stage, helps to minimize the behavioral problems associated with later stages of AD.

• Even though there have been case reports of cardiac side effects with donepezil, the studies done so far have not shown any major arrhythmogenic, hypotensive, or negative chronotropic effects.

• The higher proportion of adverse events due to rivastigmine is due to improper application of the patch, especially applying a new patch without removing the old patch.

• In a large randomized controlled trial, galantamine showed lower mortality rate when compared to placebo, thus establishing its safety.

This box summarizes key points contained in the article.

Declaration of interest

GT Grossberg is a consultant for Acadia, Alkahest, Allergan, Avanir, Axovant, BioXcel, GE, Genentech, Lundbeck, Novartis, Otsuka, Roche and Takeda; has received research support from Janssen, Genentech/Roche and NIA; and has served on a safety monitoring committee for EryDel, Intra-Cellular Therapies, Merck and Newron. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This paper was not funded.