Donepezil

Indications

• FDA-approved for dementia of the Alzheimer type across mild, moderate, and severe stages, making it the broadest cholinesterase inhibitor label.
• The 23 mg tablet is approved only for moderate to severe disease after at least 3 months on 10 mg daily, with more gastrointestinal adverse effects.
• Adlarity transdermal system delivers 5 or 10 mg daily through a weekly patch for patients who cannot reliably swallow tablets.
• Used off-label for dementia with Lewy bodies and Parkinson disease dementia, where cholinergic deficits are prominent and often responsive.
• Used off-label for vascular and mixed dementia, where the effect size is smaller and guidelines do not routinely recommend it.
• Expected benefit is stabilization or modest improvement in cognition and function for months, not reversal or prevention of progression.

Mechanism of action

• Reversibly and noncompetitively inhibits acetylcholinesterase, raising synaptic acetylcholine in cortex and hippocampus.
• It is relatively selective for acetylcholinesterase over butyrylcholinesterase, which differs from rivastigmine and may affect tolerability.
• Increased cholinergic tone partly compensates for the loss of basal forebrain cholinergic neurons that occurs early in Alzheimer disease.
• The effect is symptomatic and neurochemical, with no impact on amyloid, tau, or the underlying rate of neurodegeneration.
• Peripheral cholinergic stimulation from the same mechanism causes nausea, diarrhea, bradycardia, and increased gastric acid secretion.

Pharmacokinetics

• Well absorbed with a Tmax of 3-4 hours and bioavailability near 100 percent; food does not meaningfully change absorption.
• Elimination half-life is about 70 hours, so steady state takes 2-3 weeks and a missed dose rarely causes abrupt worsening.
• Metabolized by CYP2D6 and CYP3A4 with subsequent glucuronidation, and roughly 17 percent is excreted unchanged in urine.
• Protein binding is about 96 percent, mainly to albumin, and the drug distributes widely including into the central nervous system.
• No dose adjustment is required for mild to moderate renal or hepatic impairment, though severe impairment has not been well studied.

Dosing

• Start 5 mg PO once daily at bedtime and hold that dose for at least 4 to 6 weeks before considering an increase.
• Increase to 10 mg PO daily, the usual maintenance dose for all severities and the best balance of benefit and tolerability.
• Consider 23 mg daily only in moderate to severe disease after 3 months at 10 mg, accepting substantially more nausea and vomiting.
• If nausea or vivid dreams interfere, move dosing to morning with food or use the weekly transdermal patch instead of oral tablets.
• After an interruption of more than several days, restart at 5 mg and retitrate to avoid a recurrence of gastrointestinal effects.
• No renal or hepatic dose adjustment is specified, but titrate more slowly in frail patients and those with low body weight.

Adverse effects

• Nausea, diarrhea, vomiting, anorexia, and weight loss are the dominant effects and are dose dependent, especially at 23 mg.
• Insomnia, vivid or disturbing dreams, and muscle cramps are common; switching to morning dosing usually resolves sleep complaints.
• Bradycardia, heart block, and syncope occur through vagotonic effects and matter most in patients with sick sinus syndrome or on rate-control drugs.
• Increased gastric acid secretion raises ulcer and gastrointestinal bleeding risk, particularly with concurrent NSAIDs or anticoagulants.
• Urinary incontinence, worsening bladder outlet symptoms, and increased bronchial secretions in asthma or COPD can emerge with treatment.
• Rare reports include seizures, rhabdomyolysis, and neuroleptic malignant syndrome, chiefly after rapid dose escalation.

Monitoring

• Baseline pulse and an ECG when there is syncope, bradycardia, conduction disease, or concurrent rate-slowing medication.
• Track weight at each visit, since anorexia and weight loss are common and consequential in older adults with dementia.
• Measure cognition and function with MMSE or MoCA plus a functional scale at baseline and about every 6 months.
• Reassess benefit deliberately at 3 to 6 months and discuss discontinuation when there is clear ongoing decline without functional benefit.
• Ask about falls, dizziness, gastrointestinal symptoms, and sleep disruption, the effects most likely to reduce quality of life.

Interactions

• Anticholinergic drugs such as oxybutynin, diphenhydramine, and tricyclic antidepressants directly oppose the mechanism and should be deprescribed.
• Beta-blockers, digoxin, diltiazem, verapamil, and amiodarone add to bradycardia and increase the risk of syncope and falls.
• CYP2D6 and CYP3A4 inhibitors such as paroxetine, fluoxetine, and ketoconazole raise donepezil levels and worsen cholinergic effects.
• Enzyme inducers including carbamazepine, phenytoin, rifampin, and dexamethasone can lower donepezil concentrations and reduce efficacy.
• Cholinesterase inhibition exaggerates succinylcholine-type neuromuscular blockade, so anesthesia teams should be told the patient takes it.

Special populations

• Geriatric: this is the primary population, and the key concerns are bradycardia, falls, weight loss, and anticholinergic co-prescribing.
• Pregnancy and lactation: essentially no relevant human data, and the indication rarely arises in patients of reproductive age.
• Pediatric: safety and effectiveness have not been established, and use for autism or ADHD is not supported by evidence.
• Renal or hepatic impairment: no formal adjustment is required, but clearance is slower in cirrhosis and titration should be cautious.
• Low body weight, typically under 55 kg, predicts more nausea, vomiting, and weight loss and argues for staying at 5-10 mg.

Clinical pearls

• Do not stop and restart casually; after several missed days retitrate from 5 mg to avoid vomiting.
• Vivid nightmares at bedtime dosing usually disappear when the dose is moved to the morning.
• The 23 mg tablet buys little and costs a lot in nausea; most patients belong at 10 mg.