Donepezil

Mechanism

Mechanism of Action

Highly selective non-competitive reversible inhibitor of the enzyme acetylcholinesterase at the level of the central nervous system, with low affinity for peripheral butyrylcholinesterase. By selectively binding to brain cholinesterase, it increases the concentration of the neurotransmitter acetylcholine in the synaptic clefts of the cortical cholinergic pathways and the basal forebrain, which undergo progressive degeneration in patients with dementia. This temporarily enhances the cognitive and behavioral transmission preserved in Alzheimer's disease.

Pharmacokinetics

Key Pharmacokinetics

• Routes: Oral (coated and orodispersible tablets). It is preferably administered at night, before going to bed, to mitigate initial cholinergic dizziness and nausea.
• Absorption: Excellent oral absorption, reaching maximum concentrations in about 3 to 4 hours.
• Metabolism: Extensive liver through cellular oxidation by the isoenzymes CYP2D6 and CYP3A4, also undergoing subsequent glucuronidation. It has two active metabolites of lesser potency.
• Half-life: Exceptionally long, approximately 70 hours. This allows only one dose per day and requires weeks of treatment to achieve stable steady-state concentrations.
• Excretion: Mixed, urine (57%) and feces (15%) in the form of metabolites and free active ingredient.

Indicators and dose

Approved and Off-label Indications

Approved: Symptomatic treatment of mild, moderate and severe dementia of the Alzheimer type.

Off-label: Mild cognitive impairment associated with vascular dementia, diffuse Lewy body dementia, cognitive impairment in multiple sclerosis.

Dosage and Adjustments

Alzheimer's Dementia (Oral): Starting dose of 5 mg orally once daily in the evening. After a minimum period of 4-6 weeks of demonstrated tolerance, increase the dose to the usual maintenance dose of 10 mg once daily. In moderate-severe dementia it can be increased to 23 mg/day after several months of a 10 mg dose.

Renal/hepatic adjustment: Does not require systematic initial reduction guidelines in moderate renal or hepatic insufficiency. Caution is advised in decompensated cirrhosis.

Security

Contraindications

Absolute: Demonstrated hypersensitivity to donepezil or piperidine derivatives for pharmaceutical use.

Relative: Pre-existing cardiac conduction disorders (sinus node disease, atrioventricular block of any degree without pacemaker), severe underlying bronchial asthma, active peptic ulcer or history of gastrointestinal bleeding.

Adverse Effects (ADR)

Common: Moderate watery diarrhea, nocturnal muscle cramps, daytime fatigue, post-dose nausea, initial insomnia, vivid and unusual dreams, moderate anorexia with mild weight loss.

Serious: Severe sinus bradycardia, syncope of vagal origin (which can cause falls and bone fractures in the elderly), advanced heart block, gastrointestinal bleeding of ulcerative origin, transient generalized epileptic seizures.

Interactions

Anticholinergic drugs (e.g., trihexyphenidyl, benztropine): Direct pharmacodynamic antagonism of the cognitive benefit of therapy.

CYP3A4 or CYP2D6 inducers (e.g., rifampicin, phenytoin, carbamazepine): They accelerate hepatic clearance, markedly decreasing plasma levels of donepezil.

Pregnancy and Breastfeeding

FDA Classification: Category C. No controlled or conclusive clinical data available on gestational safety or milk excretion; Its use is discouraged.