Donepezil

Mechanism

Chemical and Commercial Profile

Common trade names: Aricept, Donepezil Normon, Limerik.
Group: Reversible acetylcholinesterase inhibitor, derived from piperidine.

Mechanism of Action

Donepezil acts by increasing the synaptic availability of acetylcholine in cerebral cortical and hippocampal cholinergic pathways:

Cholinergic Potentiation Mechanism \text{Donepezilo} \longrightarrow \text{Selective and reversible inhibition of Acetylcholinesterase (AChE)} \longrightarrow \text{Increase of Acetylcholine in Synaptic Cleft}

By binding reversibly and selectively to the enzyme Acetylcholinesterase (AChE), it prevents the hydrolysis of the neurotransmitter acetylcholine. This symptomatically compensates for the depletion of cholinergic neurons in the nucleus basalis of Meynert observed in Alzheimer's disease, optimizing the function of the network of nicotinic and muscarinic receptors involved in memory consolidation and learning.

It has 1200 times greater binding selectivity for acetylcholinesterase (AChE) compared to butyrylcholinesterase (BuChE), substantially minimizing cholinergic peripheral autonomic adverse effects.

Pharmacokinetics

Pharmacokinetics

• Absorption: Excellent oral absorption without interference from food intake; 100% bioavailability. C_max 3-4 hours after taking.
• Distribution: Large volume of distribution (12 L/kg). Plasma protein binding of 96%.
• Metabolism: Hepatic oxidative catalyzed mainly by the isoenzymes CYP3A4 and CYP2D6, also undergoing secondary glucuronidation. It generates multiple metabolites, of which the metabolite 6-O-desmethyldonepezil retains an activity equivalent to the parent molecule.
• Excretion: Renal (57%) and fecal (14%) mainly as inactive conjugated metabolites.
• Half-life (t_1/2): Prolonged: ~70 hours in adults. It allows a convenient dosage in a single daily dose and facilitates a state of constant plasma balance.

Indicators and dose

Indications

• Symptomatic treatment of mild, moderate and severe Alzheimer's dementia.
• Off-label: Idiopathic vascular dementia, mixed dementia, mild cognitive impairment associated with Parkinson's disease.

Dosage and Settings

• Initial Dose: 5 mg per day orally (administered in a single nightly dose immediately before bedtime to minimize daytime cholinergic gastrointestinal effects).
• Maintenance phase: Maintain the dose of 5 mg/day for at least a full month to ensure biological tolerance of the compound; subsequently increase to the dose of 10 mg/day if clinically required. Maximum authorized dose: 10 mg/day.
• Kidney Failure: Does not require special dose adjustments.
• Liver Failure: Mild to moderate liver cirrhosis: Titrate slowly and consider spacing dose increases at minimum intervals of 6-8 weeks.

Security

Contraindications

• Hypersensitivity to the active ingredient or to piperidine derivatives.
• Pregnancy and breastfeeding period.

Adverse Effects (ADR)

Cholinergic Cardiac Safety Alert

Due to its vagotonic cholinergic action, donepezil can induce marked sinus bradycardia and prolongation of atrioventricular conduction in the myocardium. Its use is associated with an increased risk of high-grade atrioventricular blocks, repeated syncope and secondary accidental falls in predisposed geriatric patients. Careful monitoring and an electrocardiogram are advised prior to starting your therapeutic regimen.

• Gastrointestinal (direct cholinergic effects): Frequent liquid diarrhea (10%), nausea, repetitive vomiting and acid dyspepsia due to increased motility and gastric secretion. It is mitigated by nightly administration of the drug.
• Musculoskeletal: Transient painful muscle cramps, diffuse myalgias.
• CNS: Sleep insomnia, tension headache, vivid nightmares and mild paradoxical agitation.

Clinical Interactions

• Anticholinergics: Direct antagonistic interaction of therapeutic efficacy. Drugs such as amitriptyline, benzatropine or oxybutynin nullify the cognitive effect of donepezil.
• Enzyme inhibitors or inducers: Strong CYP3A4 inhibitors (such as ketoconazole or erythromycin) increase the plasma levels of donepezil, while inducers such as carbamazepine or rifampin strongly decrease its clinical efficacy.

Pregnancy and Breastfeeding

FDA Category: C. Its prescription in pregnant women is not recommended due to the absence of robust clinical safety data in humans. Breastfeeding: Not recommended. It is unknown whether it passes into breast milk and due to its systemic procholinergic effect there is a high risk of gastrointestinal hypermotility, diarrhea and bradycardia in the infant.