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Sunday, July 27, 2025

Donepezil


Donepezil is a centrally acting, reversible acetylcholinesterase inhibitor used primarily in the symptomatic treatment of Alzheimer’s disease (AD) and other forms of dementia. It does not alter the progression of neurodegeneration, but by enhancing cholinergic neurotransmission in the brain, it may temporarily improve cognitive function, memory, and global functioning in affected individuals.

It is one of the most widely prescribed medications for mild, moderate, and severe Alzheimer’s disease and is often used either as monotherapy or in combination with other agents like memantine.

Pharmacological Classification

  • Therapeutic class: Anti-dementia agent

  • Pharmacologic class: Acetylcholinesterase inhibitor

  • ATC code: N06DA02

  • Legal classification: Prescription-only medicine (Rx)

Chemical and Formulation Information

  • Generic name: Donepezil hydrochloride

  • Brand names: Aricept®, Aricept ODT®, Yasnal®, Donecta®, Donecept®

  • Formulations:

    • Film-coated tablets: 5 mg, 10 mg

    • Orally disintegrating tablets (ODT): 5 mg, 10 mg

    • Donepezil + Memantine fixed-dose combinations (e.g., Namzaric® in the US)

Mechanism of Action

Donepezil exerts its therapeutic effects by reversibly inhibiting acetylcholinesterase, the enzyme responsible for degrading acetylcholine (ACh) at synaptic clefts in the central nervous system. In Alzheimer’s disease, where cholinergic neurons are progressively lost, this inhibition helps:

  • Increase ACh concentration at synapses

  • Enhance cholinergic transmission in remaining neurons

  • Improve neurotransmission in brain areas responsible for memory, attention, and learning

It is selective for central (brain) acetylcholinesterase and has minimal effect on butyrylcholinesterase or peripheral cholinesterases at therapeutic doses.

Indications

Approved Uses

  • Mild to moderate Alzheimer's disease

  • Moderate to severe Alzheimer's disease (higher dose of 10 mg/day used)

Off-label Uses

  • Lewy body dementia

  • Parkinson’s disease dementia

  • Vascular dementia (efficacy controversial)

  • Mild cognitive impairment (MCI) – not routinely recommended

  • Cognitive symptoms in Down syndrome or traumatic brain injury (under study)

Dosage and Administration

Standard Adult Dosing

  • Initial dose: 5 mg once daily, preferably in the evening before bedtime

  • After 4–6 weeks, if well-tolerated, increase to 10 mg once daily

  • For severe Alzheimer’s, 23 mg daily tablet (extended-release) is available in some regions (e.g., US)

Oral Disintegrating Tablet (ODT)

  • Can be used in patients with difficulty swallowing

  • Placed on the tongue to dissolve without water

Administration Notes

  • May be taken with or without food

  • Once-daily dosing is maintained due to long half-life (~70 hours)

  • Titrate slowly to minimize side effects

Pharmacokinetics

  • Absorption: Well absorbed orally; peak plasma concentration in 3–4 hours

  • Bioavailability: ~100%

  • Plasma protein binding: ~96%

  • Metabolism: Hepatic via CYP2D6 and CYP3A4 (to inactive metabolites)

  • Elimination half-life: 70 hours

  • Excretion: Urine (57%); feces (15%)

Contraindications

  • Hypersensitivity to donepezil or any component of the formulation

  • Known cholinergic hypersensitivity reactions

  • Severe hepatic impairment (caution advised; limited data)

Warnings and Precautions

  • Bradycardia and heart block: Use with caution in patients with sick sinus syndrome, SA or AV node dysfunction, or on beta-blockers

  • Peptic ulcers/GI bleeding: Risk increased due to cholinergic stimulation; caution in patients with history of ulcers or those on NSAIDs

  • Bladder outflow obstruction: May worsen due to parasympathomimetic effects

  • Asthma or COPD: Cholinergic effects may worsen bronchoconstriction

  • Seizure threshold: Lowered; use with caution in epileptic patients

  • Extrapyramidal symptoms: Rarely may exacerbate Parkinsonism

  • Weight loss and anorexia: Monitor especially in elderly and frail patients

  • Surgery: May interfere with neuromuscular blockade during anesthesia

Adverse Effects

Common (≥1%)

  • Nausea, vomiting, diarrhea, anorexia, abdominal pain

  • Insomnia, vivid dreams, headache, fatigue, somnolence

  • Muscle cramps, dizziness

  • Bradycardia, syncope, fall-related injuries

  • Weight loss

  • Rash, pruritus

Uncommon/Rare (<1%)

  • Seizures, hallucinations, aggression, depression

  • Gastrointestinal bleeding, hepatitis

  • Rhabdomyolysis (rare reports)

  • QT prolongation and torsades de pointes (very rare)

Drug Interactions

  • CYP3A4 and CYP2D6 inhibitors (e.g., ketoconazole, paroxetine): May increase donepezil levels

  • CYP inducers (e.g., rifampin, carbamazepine, phenytoin): May decrease efficacy

  • Anticholinergic drugs (e.g., atropine, oxybutynin): Antagonize donepezil’s effects

  • Cholinergic drugs (e.g., bethanechol, rivastigmine): Additive cholinergic activity and side effects

  • Beta-blockers (e.g., atenolol): Additive bradycardia risk

  • Muscle relaxants (e.g., succinylcholine): Prolonged neuromuscular blockade due to acetylcholinesterase inhibition

  • NSAIDs: Increased risk of peptic ulceration

Use in Special Populations

Elderly

  • Main population of use

  • Adverse effects (e.g., bradycardia, syncope) more prominent in frail elderly

Pediatric Use

  • Not indicated or approved for pediatric patients

Hepatic Impairment

  • Mild to moderate: No dose adjustment

  • Severe: Use with caution; limited data

Renal Impairment

  • No dose adjustment necessary

  • Metabolism is hepatic, not renal

Pregnancy and Lactation

Pregnancy (Category C – US FDA)

  • No adequate human studies

  • Animal studies suggest potential fetal harm at high doses

  • Use only if potential benefit justifies potential risk

Lactation

  • Unknown if excreted in breast milk

  • Caution advised; breastfeeding is not recommended during therapy

Comparative Notes (No Tables)

Donepezil vs. Rivastigmine

  • Both are acetylcholinesterase inhibitors

  • Donepezil is once-daily and selective for acetylcholinesterase

  • Rivastigmine also inhibits butyrylcholinesterase and is available as a transdermal patch, which may be better tolerated

Donepezil vs. Galantamine

  • Galantamine has dual mechanisms: acetylcholinesterase inhibition and nicotinic modulation

  • Donepezil has a longer half-life and once-daily dosing

  • Galantamine may have more GI side effects initially

Donepezil vs. Memantine

  • Memantine is an NMDA receptor antagonist used in moderate to severe AD

  • Often combined with donepezil for additive benefits

  • Memantine has fewer cholinergic side effects

Overdose and Management

Symptoms

  • Cholinergic crisis: Nausea, vomiting, drooling, sweating, bradycardia, hypotension, collapse, seizures, respiratory depression

Management

  • Supportive care

  • Atropine IV: Antidote of choice (2–4 mg IV, repeated as needed)

  • Monitor ECG, vital signs, and respiratory status

Patient Counseling Points

  • Take at the same time each day, preferably in the evening

  • If gastrointestinal upset occurs, try switching to morning administration

  • Do not abruptly discontinue the drug

  • Report any signs of fainting, irregular heartbeat, or severe nausea

  • Continue treatment even if symptoms seem stable—donepezil delays progression, not cures dementia

  • Keep out of reach of children due to overdose risk

  • Encourage routine cognitive assessments to monitor effectiveness

Regulatory and Clinical Guidelines

  • NICE (UK): Recommends donepezil for mild-to-moderate Alzheimer's disease

  • American Academy of Neurology (AAN): Supports use in early-stage AD

  • WHO Essential Medicines List: Included as a core medicine for dementia treatment

  • Long-term studies suggest modest benefit, with improvement seen in global functioning, activities of daily living, and cognition




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