Mechanism of Action of Donepezil
Donepezil works by reversibly and selectively inhibiting acetylcholinesterase, the enzyme that breaks down acetylcholine, thereby increasing the availability of acetylcholine at cholinergic synapses in the brain. 1, 2
Pharmacological Mechanism
Donepezil is a piperidine-type cholinesterase inhibitor that is highly selective for acetylcholinesterase rather than butyrylcholinesterase, making it more specific in its action compared to other agents. 3, 4
By blocking acetylcholinesterase activity, donepezil decreases acetylcholine hydrolysis, which compensates for the loss of functioning cholinergic neurons in the basal forebrain that occurs in Alzheimer's disease. 1, 5
The drug is a reversible, noncompetitive inhibitor, meaning its effects are temporary and it does not permanently bind to the enzyme. 3
Additional Neuroprotective Effects
Beyond simple cholinesterase inhibition, donepezil may influence Alzheimer's disease pathophysiology through several other mechanisms:
Attenuation of oxidative stress and neuroinflammation, which has been demonstrated in rodent models when co-administered with chemotherapy agents. 1
Enhancement of neurogenesis and activation of neurotrophic mechanisms that may support brain cell survival. 1, 4
Protection against glutamate-induced excitotoxicity and promotion of non-amyloidogenic pathways for amyloid precursor protein (APP) processing. 4
Indirect effects on cerebrovascular function, potentially improving brain perfusion and preserving regional cerebral blood flow. 4
Putative modulation of other neurotransmitter systems beyond the cholinergic system. 4
Recommended Dosing for Alzheimer's Disease
Mild to Moderate Alzheimer's Disease
Start with 5 mg once daily in the evening, just prior to retiring, which can be taken with or without food. 2, 6
Increase to 10 mg once daily after 4 to 6 weeks if the initial dose is well tolerated; do not advance to 10 mg before this time period. 2, 6
The 10 mg dose provides additional cognitive and functional benefit over the 5 mg dose, though it is associated with slightly higher rates of adverse events. 7, 8
Moderate to Severe Alzheimer's Disease
Begin with 5 mg once daily in the evening, just as with mild to moderate disease. 2
Advance to 10 mg once daily after 4 to 6 weeks, then consider further escalation. 2
A 23 mg once-daily dose may be used after patients have been on 10 mg daily for at least 3 months, though benefits on 23 mg are no greater than on 10 mg and adverse events are more frequent. 2, 8
The 23 mg tablet must not be split, crushed, or chewed. 2
Clinical Efficacy Timeline
Beneficial effects on cognition can be observed as early as 3 weeks after starting treatment. 3, 6
Full efficacy assessment requires 6 to 12 months of continuous therapy to adequately evaluate treatment response. 6, 7
Approximately 20 to 35% of patients achieve clinically meaningful improvement, roughly equivalent to delaying cognitive decline by about one year. 6, 3
Common Pitfalls to Avoid
Do not rely solely on brief mental status tests (e.g., MMSE) to assess response; use caregiver reports, functional assessments, and comprehensive cognitive batteries. 6, 7
Do not discontinue prematurely; some patients require up to 12 months to demonstrate benefit, and stabilization or slower deterioration constitutes success. 6, 7
Minimize gastrointestinal side effects by taking donepezil with food and using gradual dose titration over 4 to 6 weeks rather than rapid escalation. 9, 6
Do not expect cure or reversal; donepezil provides modest symptomatic benefit by temporarily stabilizing cognition or slowing the rate of decline. 6, 5