Servonex Mechanism of Action

Pharmacotherapeutic group: Antidementia drugs; anticholinesterase. ATC Code: N06DA02.
Pharmacology: Pharmacodynamics: Mechanism of action: Donepezil hydrochloride is a specific and reversible inhibitor of acetyl-cholinesterase, the predominant cholinesterase in the brain.
Donepezil hydrochloride is in vitro over 1000 times more potent an inhibitor of this enzyme than of butyrylcholinesterase, an enzyme that is present mainly outside the central nervous system.
Pharmacokinetics: Absorption: Maximum plasma levels are reached approximately 3 to 4 hours after oral administration. Plasma concentrations and area under the curve rise in proportion to the dose. The terminal disposition half-life is approximately 70 hours, thus, administration of multiple single daily doses results in gradual approach to steady state. Approximate steady state is achieved within 3 weeks after initiation of therapy.
Once at steady state, plasma donepezil hydrochloride concentrations and the related pharmacodynamic activity show little variability over the course of the day.
Food did not affect the absorption of donepezil hydrochloride.
Distribution: Donepezil hydrochloride is approximately 95% bound to human plasma proteins. The plasma protein binding of the active metabolite 6-O-desmethyldonepezil is not known. The distribution of donepezil hydrochloride in various body tissues has not been definitively studied. Donepezil hydrochloride and/or its metabolites may persist in the body for more than 10 days.
Biotransformation/Elimination: Donepezil hydrochloride is both excreted in the urine intact and metabolised by the cytochrome P450 system to multiple metabolites, not all of which have been identified. Following administration of a single 5 mg dose of 14C-labelled donepezil hydrochloride, plasma radioactivity, expressed as a percent of the administered dose, was present primarily as intact donepezil hydrochloride (30%), 6-Odesmethyl donepezil (11% only metabolite that exhibits activity similar to donepezil hydrochloride), donepezil-cis-N-oxide (9%), 5-Odesmethyl donepezil (7%) and the glucuronide conjugate of 5-Odesmethyl donepezil (3%). Approximately 57% of the total administered radioactivity was recovered from the urine (17% as unchanged donepezil), and 14.5% was recovered from the faeces, suggesting biotransformation and urinary excretion as the primary routes of elimination. There is no evidence to suggest enterohepatic recirculation of donepezil hydrochloride and/or any of its metabolites. Plasma donepezil concentrations decline with a half-life of approximately 70 hours. Sex, race and smoking history have no clinically significant influence on plasma concentrations of donepezil hydrochloride. The pharmacokinetics of donepezil has not been formally studied in healthy elderly subjects or in Alzheimer's or vascular dementia patients. However mean plasma levels in patients closely agreed with those of young healthy volunteers.
Patients with mild to moderate hepatic impairment had increased donepezil steady state concentrations; mean AUC by 48% and mean Cmax by 39%.