Donepezil
Donepezil is a reversible acetylcholinesterase inhibitor used for the symptomatic treatment of Alzheimer's dementia from mild to severe stages. Originally launched by Eisai as Aricept, it is now widely available as a generic in tablets and orally disintegrating tablets.
- Chemical formula
- C24H29NO3
- CAS number
- 120014-06-4
- ATC code
- N06DA02
- Molecular weight
- 379.49 g/mol
- Drug class
- Acetylcholinesterase inhibitor
- Also known as
- Aricept, Donepezilo, Donepezilum, E2020
What is it?
Donepezil is a piperidine-class acetylcholinesterase inhibitor discovered by Eisai under the code E2020 and approved by the FDA in 1996 as Aricept, which Eisai co-marketed with Pfizer for many years. It was the second cholinesterase inhibitor to reach the market after tacrine, but the first that was well tolerated enough for routine use, and it quickly became the standard first-line symptomatic treatment for Alzheimer's disease. Authorised generics have been available since 2010, and donepezil is now the most prescribed anti-dementia drug worldwide. It treats symptoms only; it does not slow the underlying neurodegeneration.
Mechanism of action
Donepezil reversibly inhibits acetylcholinesterase, the enzyme that hydrolyses acetylcholine in the synaptic cleft. By slowing that breakdown it raises the concentration and prolongs the action of acetylcholine at remaining cholinergic synapses, partly compensating for the loss of basal forebrain cholinergic neurons that characterises Alzheimer's disease. It is roughly a thousand times more selective for acetylcholinesterase than for butyrylcholinesterase, which limits peripheral effects. Clinical benefit on cognition and daily function is modest, develops over 6 to 12 weeks and is dose-related between 5mg and 10mg; the 23mg dose adds a small further effect at the cost of more gastrointestinal side effects.
Pharmacokinetics
Donepezil is almost completely absorbed after oral dosing, with bioavailability approaching 100% and peak plasma levels at 3 to 4 hours; food has no effect. It is about 96% bound to plasma proteins, mainly albumin and alpha-1 acid glycoprotein. Hepatic metabolism proceeds via CYP2D6 and CYP3A4 followed by glucuronidation, yielding several metabolites of which 6-O-desmethyldonepezil is active. The elimination half-life is approximately 70 hours, so steady state takes about 15 days and once-daily dosing is sufficient. Clearance is somewhat reduced in the elderly and in hepatic impairment, but no routine dose adjustment is required for mild to moderate renal or hepatic disease.
Indications
Donepezil is approved for the symptomatic treatment of dementia of the Alzheimer's type: mild, moderate and severe stages in the United States, and mild to moderately severe in the European Union. In Japan it is also approved for dementia with Lewy bodies. Off-label uses include vascular and mixed dementia, Parkinson's disease dementia and cognitive impairment in Down syndrome, with variable evidence. It is usually combined with memantine as the disease progresses. Treatment should be started and reviewed by a clinician experienced in dementia care, with reassessment every 6 to 12 months and discontinuation considered when no meaningful benefit persists.
Safety profile
The most common adverse effects are cholinergic and dose-related: nausea, diarrhoea, vomiting, anorexia, weight loss, muscle cramps, fatigue, insomnia and vivid dreams. Bradycardia, sinoatrial and atrioventricular block and syncope are the most important serious effects, particularly in patients with conduction disease or on beta blockers; falls and fainting warrant cardiac review. Donepezil may increase gastric acid secretion and the risk of ulcer bleeding with NSAIDs, aggravate asthma or COPD, lower the seizure threshold and worsen urinary outflow obstruction. It prolongs succinylcholine-type muscle relaxation during anaesthesia. Anticholinergic drugs antagonise its effect, while strong CYP2D6 or CYP3A4 inhibitors raise its plasma levels.
Products containing this ingredient
Frequently asked questions
How does donepezil compare with rivastigmine and galantamine? ▾
All three are cholinesterase inhibitors with similar modest efficacy on cognition in Alzheimer's disease. Donepezil has the longest half-life (about 70 hours), allowing once-daily dosing with no food restriction, and the simplest titration, which is why it is usually tried first. Rivastigmine also inhibits butyrylcholinesterase and is available as a patch that reduces gastrointestinal effects; it is licensed for Parkinson's disease dementia. Galantamine additionally modulates nicotinic receptors and requires twice-daily or extended-release dosing. According to clinical guidelines, the choice is driven by tolerability, formulation and comorbidity rather than by differences in efficacy.
Should donepezil be taken in the morning or at night? ▾
The prescribing information recommends taking donepezil once daily in the evening, just before bedtime, so that the peak of nausea coincides with sleep. However, a meaningful minority of patients develop insomnia, vivid dreams or nightmares, and for them a morning dose is equally effective. Because the half-life is about 70 hours, the time of day has little effect on plasma levels; consistency matters more than the clock. Patients should ask their doctor or pharmacist before changing the schedule, and the orally disintegrating tablet should be allowed to dissolve on the tongue before swallowing with water.
What should I do if a dose of donepezil is missed? ▾
A single missed dose should simply be skipped, with the next dose taken at the usual time; doubling up increases nausea and the risk of a slow heart rate without any benefit, since the long half-life smooths over a one-day gap. According to the prescribing information, if treatment has been interrupted for more than a few days, it should be restarted at 5mg and titrated upwards again, because tolerance to the gastrointestinal effects is lost within about a week. Carers often use a pill organiser or a set evening routine to reduce missed doses.
Can donepezil be taken with alcohol? ▾
There is no direct pharmacokinetic interaction between donepezil and alcohol, but the combination is not advisable. Alcohol impairs memory and attention, counteracting the purpose of treatment, increases the risk of falls in a population already prone to them, and can worsen nausea and dizziness. In Alzheimer's disease, alcohol may also precipitate confusion or agitation. According to clinical guidelines, patients and carers should discuss any regular alcohol use with the treating doctor, who will usually advise avoiding it or limiting it to very small amounts.
How long should donepezil be continued? ▾
Donepezil is generally continued for as long as it provides a worthwhile benefit, which may be years. The DOMINO-AD trial showed that stopping donepezil in moderate to severe disease led to faster cognitive and functional decline than continuing, so routine discontinuation at a fixed stage is no longer recommended. According to clinical guidelines, benefit should be reassessed every 6 to 12 months; stopping may be appropriate when the patient no longer responds, develops intolerable side effects, or reaches a stage where symptomatic treatment no longer serves their goals of care. Any withdrawal should be a shared decision with the doctor.
Does donepezil interact with other medicines? ▾
Yes, several interactions matter. Anticholinergic drugs such as oxybutynin, tricyclic antidepressants and some antihistamines directly oppose its effect and should be avoided. Beta blockers, calcium channel blockers, digoxin and amiodarone add to its heart-rate-slowing effect. Strong CYP2D6 or CYP3A4 inhibitors such as paroxetine, fluoxetine, ketoconazole and itraconazole raise donepezil levels, while inducers such as rifampicin, carbamazepine and phenytoin lower them. NSAIDs increase the risk of gastrointestinal bleeding. Anaesthetists should be told about donepezil before surgery. A pharmacist or doctor can review the full medication list.
Sources
This page is compiled from the official prescribing information for Donepezil. The links below open a search for that active ingredient in each register, so you always reach the current version of the label rather than a cached copy.
The information on this website is provided for reference and educational purposes only. It does not replace consultation with a qualified healthcare professional.