donepezil
Brand: Aricept
Prototype Drug
Drug Class: cholinesterase inhibitor
Drug Family: antidementia
Subclass: reversible acetylcholinesterase inhibitor / piperidine
Organ Systems: cns
Mechanism of Action
Reversibly inhibits acetylcholinesterase in the CNS, increasing synaptic acetylcholine concentrations; preferentially inhibits central over peripheral AChE; does not alter disease progression but modestly improves or stabilizes cognition, behavior, and ADL function in Alzheimer's disease.
acetylcholinesterase (AChE)
Indications
- Alzheimer's disease (mild, moderate, severe)
- dementia associated with Parkinson's disease (off-label)
- vascular dementia (off-label)
Contraindications
- hypersensitivity to donepezil or piperidine derivatives
Adverse Effects
Common
- nausea
- diarrhea
- insomnia
- vivid dreams/nightmares
- muscle cramps
- anorexia
- bradycardia
Serious
- peptic ulcer disease exacerbation/GI bleeding (cholinergic effect)
- bradycardia and syncope (vagotonic effect)
- seizures (cholinergic)
- bladder outflow obstruction worsening
- pulmonary effects in asthma/COPD patients
Pharmacokinetics (ADME)
| Absorption | ~100% bioavailability; not affected by food |
| Distribution | Protein binding ~96%; Vd ~12 L/kg; crosses BBB |
| Metabolism | CYP2D6 and CYP3A4 to active 6-O-desmethyl donepezil and inactive metabolites |
| Excretion | Renal (~57%) and fecal (~15%); hepatic impairment may require monitoring |
| Half-life | 70–80 hours (allows once-daily dosing) |
| Onset | Weeks for measurable effect |
| Peak | 3–4 hours |
| Duration | 24 hours |
| Protein Binding | 96% |
| Vd | ~12 L/kg |
Drug Interactions
| Drug / Agent | Mechanism | Severity |
|---|---|---|
| anticholinergic drugs | pharmacodynamic antagonism — reduces donepezil's cholinergic benefit | moderate |
| NSAIDs | additive GI irritation; cholinergic stimulation already increases GI acid | moderate |
| succinylcholine | AChE inhibition prolongs succinylcholine's neuromuscular blockade | major |
Nursing Considerations
- Administer at bedtime to minimize GI side effects; 23 mg tablet must be taken with food due to higher peak levels and GI irritation
- Monitor heart rate at each visit; donepezil's vagotonic (bradycardic) effect can be clinically significant — hold and notify prescriber if pulse <50 bpm
- Monitor for GI side effects (nausea, diarrhea, anorexia); weight loss in already-thin dementia patients is a significant safety concern
- Counsel caregivers: donepezil does not reverse or halt Alzheimer's disease progression; realistic expectations include modest improvement or slower decline over 6–12 months
Clinical Pearls
- Donepezil has the longest half-life (~72 hours) of the cholinesterase inhibitors (rivastigmine: 1–2 hours; galantamine: 7 hours), enabling once-daily dosing with high adherence rates
- Cholinesterase inhibitors are the only FDA-approved treatments for Alzheimer's disease cognition and are entirely symptomatic — they modestly improve cognitive test scores and delay nursing home placement but do not modify the underlying amyloid/tau pathology
Safety Profile
Pregnancy use-with-caution
Lactation use-with-caution
Renal Adjustment Not required
Hepatic Adjustment Not required
TDM Not required
Concordance Terms
Cross-referenced clinical concepts — click any term to see all content where it appears.