Memotin Mechanism of Action

Pharmacology: The main active ingredient of Memotin tablet is memantine HCl, an N-methyl-D-aspartate (NMDA) receptor antagonist used for the palliative treatment of moderate to severe dementia of the Alzheimer's disease.
Pharmacodynamics: Persistent activation of central nervous system N-methyl-D-aspartate (NMDA) receptors by the excitatory amino acid glutamate has been hypothesized to contribute to the symptomatology of Alzheimer's disease. Memantine is postulated to exert its therapeutic effect through its action as a low to moderate affinity uncompetitive (open-channel) NMDA receptor antagonist, that binds preferentially to the NMDA receptor-operated cation channels. There is no evidence that memantine prevents or slows neurodegeneration in patients with Alzheimer's disease.
Pharmacokinetics: Absorption: Memantine hydrochloride is well absorbed following oral administration, with peak plasma concentrations achieved in about 3-7 hours and has linear pharmacokinetics over the therapeutic dose range. There is no difference in memantine exposure whether the drug is taken with food or on empty stomach. However, C_max is achieved about 18 hours after administration with food compared with 25 hours after administration on an empty stomach. Memantine may be taken without regard to food.
Distribution: The mean volume of distribution of memantine is 9 to 11 L/kg, and the plasma protein binding is low (45%).
Metabolism/Excretion: Memantine undergoes partial hepatic metabolism; about 48% of administered drug is excreted unchanged in urine. The remainder is converted primarily to 3 polar metabolites, which pose minimal NMDA receptor antagonist activity: N-glucuronide conjugate, 6-hydroxy memantine, and 1-nitroso-deaminated memantine. A total of 74% of the administered dose is excreted as the sum of the parent drug and the N-glucoronide conjugate. The hepatic microsomal cytochrome P450 (CYP-450) enzyme system does not play a significant role in the metabolism of memantine. Renal clearance involves active tubular secretion moderated by pH-dependent tubular reabsorption. Memantine has a terminal elimination half-life of about 60 to 80 hours.
Special populations: Renal function impairment: Mean AUC_0-∞ increased 4%, 60%, and 115% in subjects with mild, moderate, and severe renal impairment, respectively, compared with healthy subjects. The terminal elimination half-life increased 18%, 41%, and 95% in subjects with mild, moderate, and severe renal impairment, respectively, compared with healthy subjects.
Hepatic function impairment: Terminal elimination half-life increased by approximately 16% in subjects with moderate hepatic impairment when compared with healthy subjects. The pharmacokinetics of memantine have not been evaluated in patients with severe hepatic impairment.
Gender: Following multiple-dose administration of memantine 20 mg twice daily, women has an approximately 45% higher exposure than men but there was no difference in exposure when body weight was taken into account.