Donepezil - Drug Monograph

Introduction

Donepezil hydrochloride is a centrally acting, reversible acetylcholinesterase inhibitor approved for the treatment of dementia associated with Alzheimer's disease. As a second-generation cholinesterase inhibitor, it represents a cornerstone in the pharmacological management of cognitive symptoms in mild to moderate Alzheimer's disease.

Mechanism of Action

Donepezil exerts its therapeutic effects through reversible inhibition of acetylcholinesterase in the central nervous system. By inhibiting the breakdown of acetylcholine, it increases the concentration of this neurotransmitter in synaptic clefts, thereby enhancing cholinergic neurotransmission. This mechanism is particularly relevant in Alzheimer's disease, which is characterized by degeneration of cholinergic neurons and decreased acetylcholine levels in cortical and hippocampal regions.

Indications

• Treatment of mild to moderate dementia of the Alzheimer's type
• Treatment of severe dementia of the Alzheimer's type (higher dose formulation)
• Off-label uses may include other forms of dementia, though evidence is limited

Dosage and Administration

• Initial dose: 5 mg orally once daily, preferably at bedtime
• May increase to 10 mg daily after 4-6 weeks if tolerated
• Maximum dose: 23 mg daily (for severe Alzheimer's disease after至少 3 months at 10 mg daily)

• Hepatic impairment: Use with caution; consider lower starting dose
• Renal impairment: No dosage adjustment typically needed
• Geriatric patients: No dosage adjustment typically needed
• Pediatric patients: Not recommended

Pharmacokinetics

Contraindications

• Known hypersensitivity to donepezil, piperidine derivatives, or any component of the formulation
• Patients with history of serious skin reactions to donepezil

Warnings and Precautions

• Cholinergic crisis: May occur with overdose; symptoms include severe nausea, vomiting, salivation, sweating, bradycardia, hypotension, and convulsions
• Peptic ulcer disease: Use with caution in patients at risk for gastrointestinal bleeding
• Seizure disorder: May potentially lower seizure threshold
• Cardiac conduction abnormalities: May cause bradycardia and syncope
• Asthma/COPD: May increase bronchial secretions and cause bronchoconstriction
• Bladder outflow obstruction: May worsen symptoms

Drug Interactions

• Anticholinergic agents (e.g., oxybutynin, tolterodine): May decrease efficacy of donepezil
• Cholinergic agents (e.g., bethanechol): Additive effects; increased risk of adverse reactions
• CYP2D6 and CYP3A4 inhibitors (e.g., ketoconazole, quinidine): May increase donepezil levels
• CYP2D6 and CYP3A4 inducers (e.g., rifampin, carbamazepine): May decrease donepezil levels
• Beta-blockers: May potentiate bradycardia
• Succinylcholine: May prolong neuromuscular blockade

Adverse Effects

• Nausea (11%)
• Diarrhea (10%)
• Insomnia (9%)
• Muscle cramps (8%)
• Fatigue (5%)

• Gastrointestinal bleeding
• Significant bradycardia and syncope
• Seizures
• Extrapyramidal symptoms
• Bladder outflow obstruction

Monitoring Parameters

• Cognitive function assessment (MMSE, ADAS-cog) at baseline and periodically
• Weight monitoring (especially during initiation)
• Gastrointestinal symptoms
• Heart rate and rhythm (particularly in patients with cardiac history)
• Renal and hepatic function (baseline and as clinically indicated)
• Signs of cholinergic excess

Patient Education

• Take medication at bedtime to minimize daytime side effects
• Do not abruptly discontinue without medical supervision
• Report any signs of gastrointestinal bleeding (black stools, abdominal pain)
• Report significant nausea, vomiting, or diarrhea
• Inform all healthcare providers about donepezil use before any surgical procedures
• Be aware of potential for dizziness or syncope, especially when standing quickly
• Notify physician if experiencing slow heart rate or fainting episodes
• Keep all follow-up appointments for monitoring

References

1. Birks JS. Cholinesterase inhibitors for Alzheimer's disease. Cochrane Database Syst Rev. 2006;(1):CD005593. 2. Rogers SL, Farlow MR, Doody RS, et al. A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer's disease. Neurology. 1998;50(1):136-145. 3. Donepezil prescribing information. FDA-approved labeling. Revised 2022. 4. Tiseo PJ, Perdomo CA, Friedhoff LT. Metabolism and elimination of 14C-donepezil in healthy volunteers: a single-dose study. Br J Clin Pharmacol. 1998;46 Suppl 1:19-24. 5. Seltzer B. Donepezil: a review. Expert Opin Drug Metab Toxicol. 2005;1(3):527-536. 6. National Institute for Health and Care Excellence (NICE). Donepezil, galantamine, rivastigmine and memantine for the treatment of Alzheimer's disease. NICE guideline [TA217]. 2011.