Cholinesterase Inhibitors for Alzheimer's Disease
The four cholinesterase inhibitors available for treating Alzheimer's disease are donepezil (Aricept), rivastigmine (Exelon), galantamine (Reminyl), and tacrine (Cognex). 1
Currently Available Agents
First-Line Cholinesterase Inhibitors
- Donepezil (Aricept) - FDA-approved acetylcholinesterase inhibitor for mild, moderate, and severe Alzheimer's disease 2
- Galantamine (Reminyl) - FDA-approved cholinesterase inhibitor for mild to moderate dementia of the Alzheimer's type 3
- Rivastigmine (Exelon) - Approved for mild to moderate Alzheimer's disease 1
Historical Agent (Rarely Used)
- Tacrine (Cognex) - The first cholinesterase inhibitor approved, but rarely used today due to hepatotoxicity requiring liver function monitoring 1, 4
Mechanism of Action
- All four agents work by raising acetylcholine levels in the brain through inhibition of acetylcholinesterase 1
- Tacrine, donepezil, galantamine, and physostigmine are reversible inhibitors of both acetylcholinesterase and butyrylcholinesterase 4
- Rivastigmine is a pseudoirreversible inhibitor 4
Clinical Indications by Disease Severity
- Mild to moderate Alzheimer's disease: Donepezil, galantamine, or rivastigmine are first-line agents 5, 6
- Moderate to severe Alzheimer's disease: Donepezil can be used, as it is approved for severe disease 2
- Vascular dementia: Donepezil 10 mg and galantamine 16-24 mg probably improve cognition slightly 7
Key Pharmacologic Differences
Donepezil
- Dosing: Once daily (5 mg initially, increase to 10 mg after 4 weeks) 1, 6
- Half-life: 70-80 hours (longest of all cholinesterase inhibitors) 4
- Bioavailability: 40-100% 4
- Hepatotoxicity: Not hepatotoxic, no liver monitoring required 1, 8
- Metabolism: Via cytochrome P450 enzymes 4
Rivastigmine
- Dosing: Twice daily (start 1.5 mg twice daily, titrate by 3 mg/day every 4 weeks to maximum 6-12 mg/day) 1
- Half-life: 0.3-12 hours 4
- Bioavailability: 40-100% 4
- Metabolism: Via esterases (not CYP450), excreted in urine 4
- Food interaction: Taking with food reduces adverse effects 1, 4
Galantamine
- Dosing: Twice daily with meals (start 4 mg twice daily, increase to 8 mg twice daily after 4 weeks) 1
- Half-life: 0.3-12 hours 4
- Bioavailability: 40-100% 4
- Metabolism: Via cytochrome P450 enzymes with active metabolites 4
Tacrine
- Dosing: Four times daily 4
- Bioavailability: 17-37% (lowest of all agents) 4
- Hepatotoxicity: Associated with elevated liver enzymes in 49% of patients 4
- Current use: Rarely prescribed due to hepatotoxicity and frequent dosing 1
Common Pitfalls and Practical Considerations
- No head-to-head superiority: No studies demonstrate that one cholinesterase inhibitor is more effective than another 1, 9
- Main differences are tolerability and dosing convenience: Donepezil's once-daily dosing and lack of hepatotoxicity make it the most straightforward choice 1, 9
- Modest benefits: Approximately 20-35% of patients show a 7-point improvement on neuropsychological tests, equivalent to reversing one year's cognitive decline 1, 6
- Disease progression continues: These drugs do not prevent disease progression; the illness advances even during treatment 6, 10