Cholinesterase Inhibitors for Dementia

Cholinesterase inhibitors block acetylcholinesterase (and butyrylcholinesterase for rivastigmine), raising acetylcholine in the synapse and compensating for cholinergic neuronal loss. They are first-line for mild to moderate Alzheimer disease and for Parkinson disease dementia and dementia with Lewy bodies.

Pharmacokinetics. Donepezil has a half life of about 70 hours and is metabolised by CYP2D6 and CYP3A4. Rivastigmine is metabolised by esterases with few interactions. Galantamine is metabolised by CYP2D6 and CYP3A4.

• Donepezil 5 mg once daily, increased to 10 mg after 4 to 6 weeks. In moderate to severe disease, 23 mg daily where licensed.
• Rivastigmine 1.5 mg twice daily with food, increased every 2 weeks by 1.5 mg twice daily to 3 to 6 mg twice daily; maximum 12 mg daily. Patch 4.6 mg/24 h, increased after 4 weeks to 9.5 mg/24 h, then 13.3 mg/24 h.
• Galantamine prolonged release 8 mg daily, increased at 4-week intervals to 16 to 24 mg daily.

Differences. The rivastigmine patch causes less nausea. Donepezil is once daily. Rivastigmine is the preferred drug in Parkinson disease dementia.

• Start low and increase slowly to the highest tolerated dose, as benefit increases with dose.
• If donepezil causes vivid dreams or insomnia, move the dose to the morning.
• Do not stop abruptly.

Selection. Switch to another cholinesterase inhibitor if the first is not tolerated; benefit is usually modest.

Contraindications. Sick sinus syndrome, atrioventricular block, severe bradycardia. Caution in asthma and chronic obstructive pulmonary disease, peptic ulcer, epilepsy, and recent myocardial infarction.

Adverse effects. Nausea, vomiting, diarrhoea, anorexia, weight loss, bradycardia, syncope, muscle cramps, vivid dreams, urinary incontinence, bronchospasm, gastrointestinal bleeding. Overdose causes a cholinergic crisis, treated with atropine 1 to 2 mg intravenously.

Interactions. Anticholinergic drugs oppose the effect. Beta blockers, digoxin and amiodarone add bradycardia. Donepezil and galantamine levels rise with paroxetine, fluoxetine and ketoconazole, and fall with rifampicin. Cholinesterase inhibitors prolong the effect of suxamethonium.

Special groups.

• Pregnancy and breastfeeding: not indicated.
• Older adults: check pulse and ECG; falls and syncope.
• Kidney impairment: no adjustment.
• Liver impairment: galantamine maximum 16 mg daily in moderate impairment, avoid in severe; lower doses of rivastigmine and donepezil.

Monitoring. Pulse, weight, nausea, falls, and cognitive and functional scores every 6 months.

Referral and escalation. Syncope, heart rate under 50 beats/min, unexplained weight loss, or gastrointestinal bleeding.