Donepezil

Donepezil is a reversible acetylcholinesterase inhibitor used for symptomatic treatment of mild to moderate Alzheimer disease and, in some labels, severe disease. It is also used off-label in dementia with Lewy bodies and Parkinson disease dementia. Benefit is modest and symptomatic, and the main risks are gastrointestinal effects, bradycardia, syncope and weight loss.

Mechanism. Inhibits acetylcholinesterase in the brain, raising acetylcholine available at cholinergic synapses.

Pharmacokinetics. Bioavailability near 100% and protein binding about 96%. Half-life is about 70 hours and steady state takes about 15 days. It is metabolised by cytochrome P450 2D6 and 3A4.

First-line use. Mild to moderate Alzheimer disease. Treatment continues while there is clear benefit.

• Oral donepezil: 5 mg once daily, taken at bedtime (or in the morning if vivid dreams or insomnia occur), for at least 4 to 6 weeks. Then 10 mg once daily if tolerated. Maximum 10 mg daily in most labels; a 23 mg daily dose is licensed in some regions for moderate to severe disease after at least 3 months at 10 mg.

• Review benefit and tolerability at 3 months, then about every 6 months. Stop if there is no benefit or if side effects persist.

Alternative use. Dementia with Lewy bodies and Parkinson disease dementia (off-label), at the same doses.

Kidney, liver, weight and age.

• Kidney: no adjustment.

• Liver: mild to moderate impairment, titrate to tolerance. Severe impairment is not studied.

• Older adults and low body weight: higher risk of nausea, weight loss and bradycardia.

Contraindications. Hypersensitivity to donepezil or piperidine derivatives.

Serious adverse effects. Bradycardia, sinoatrial and atrioventricular block, syncope, QT prolongation and torsades de pointes, gastrointestinal bleeding, seizures, urinary outflow obstruction, worsening of asthma or chronic obstructive lung disease, and neuroleptic malignant syndrome (rare).

Common adverse effects. Nausea, vomiting, diarrhoea, anorexia, weight loss, insomnia, vivid dreams, muscle cramps and fatigue.

Interactions. Anticholinergics oppose its effect. Beta blockers, digoxin, verapamil, diltiazem and amiodarone add bradycardia. Non-steroidal anti-inflammatory drugs add gastrointestinal bleeding risk. Cytochrome P450 2D6 and 3A4 inhibitors (fluoxetine, quinidine, ketoconazole) raise levels. Rifampicin, carbamazepine and phenytoin lower levels. Succinylcholine-type muscle relaxants are prolonged.

Common prescribing errors. Starting at 10 mg. Missing bradycardia and syncope. Co-prescribing anticholinergic bladder drugs. Continuing without a benefit review.

Special groups.

• Pregnancy: not indicated.

• Breastfeeding: not indicated.

• Anaesthesia: tell the anaesthetist, because neuromuscular blockade may be prolonged.

Formulations. Tablets 5, 10 and 23 mg. Orally disintegrating tablets 5 and 10 mg. Take with or without food.

Monitoring.

• Baseline pulse and ECG if there is cardiac disease, syncope or interacting drugs.

• Weight, pulse, gastrointestinal symptoms and cognition (for example a brief cognitive score) every 3 to 6 months. Carer-reported function.

Stopping. Reduce gradually, since abrupt withdrawal can worsen cognition and behaviour. Stop for bradycardia, syncope or intolerable effects.

Referral and escalation. Refer for behavioural symptoms, rapid decline, syncope, or when considering stopping in advanced disease.