donepezil
Summary
Donepezil is a centrally acting acetylcholinesterase (AChE) inhibitor used as first-line symptomatic treatment for mild to moderate Alzheimer's disease. It increases synaptic acetylcholine levels in the brain to improve cognition, though it does not alter disease progression. Common side effects relate to cholinergic excess (GI upset, bradycardia).
Detail
Mechanism: Donepezil selectively and reversibly inhibits acetylcholinesterase in the CNS, preventing breakdown of acetylcholine and thereby enhancing cholinergic neurotransmission, which is deficient in Alzheimer's disease due to degeneration of basal forebrain cholinergic neurons (nucleus basalis of Meynert). Unlike some other AChE inhibitors, it has minimal peripheral AChE inhibition, contributing to a somewhat better side effect profile, though GI and cardiac cholinergic effects still occur.
Clinical use: Approved for mild, moderate, and severe Alzheimer's disease. Often used alongside memantine (NMDA receptor antagonist) in moderate-severe disease. Other AChE inhibitors used similarly include rivastigmine and galantamine.
Adverse effects: Cholinergic toxicity symptoms—nausea, vomiting, diarrhea, anorexia, weight loss, muscle cramps, vivid dreams/insomnia. Bradycardia and syncope can occur due to increased vagal tone, so caution in patients with sick sinus syndrome or conduction abnormalities. Can exacerbate COPD/asthma due to bronchoconstriction and peptic ulcer disease due to increased gastric acid secretion.
Contraindications/cautions: Use cautiously with other drugs that slow heart rate (beta-blockers), in patients with GI bleeding risk, or bladder outlet obstruction.
Pharmacokinetics: Long half-life (~70 hours) allowing once-daily dosing; hepatically metabolized via CYP2D6 and CYP3A4.
Board relevance: Frequently tested as part of Alzheimer's pharmacotherapy along with memantine, and as an example of a reversible AChE inhibitor (contrast with irreversible organophosphates and physostigmine's use in anticholinergic toxicity). Also relevant for muscarinic side effect recognition (SLUDGE symptoms, bradycardia).
Sources
- First Aid for the USMLE Step 1
- Katzung's Basic and Clinical Pharmacology
- UpToDate: Treatment of Alzheimer disease
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