Clinically significant interactions with cholinesterase inhibitors and other antidementia agents

Abstract

Cholinesterase inhibitors (ChEIs) and the NMDA receptor antagonist memantine are the currently approved treatment options for patients diagnosed with Alzheimer’s disease (AD). Due largely to the lack of alternatives, these same medications are consequently used off-label to treat the many other forms of dementia, too. Future treatments for AD may include disease-modifying agents targeting amyloid beta production or aggregation including several immunotherapies. Potential drug interactions with these medications are limited since neither the ChEIs nor memantine is known for strong inhibition or induction of the cytochrome P450 (CYP) enzymes. Inhibitors of CYP3A4 or CYP2D6 may increase the concentrations of donepezil or galantamine leading to increased or reappearance of adverse events, typically GI related. Clinically significant interactions due to protein binding, glucuronidation, and p-glycoprotein are unlikely. Pharmacodynamic interactions may occur with ChEIs when other drugs affecting the cholinergic system are administered concomitantly. Similar pharmacodynamic interactions with memantine are unlikely. The clinical consequences of drug interactions with any of the ChEIs or memantine would most likely present as increased adverse events typical for these medications. Clinicians should monitor for increased cholinergic effects and potentially adjust dosage of ChEIs when drugs with potential pharmacokinetic or pharmacodynamic interactions are added to patient therapy for dementia.