Memry Mechanism of Action





United Lab
Full Prescribing Info
Pharmacology: Evidence suggests that malfunctioning of glutamatergic neurotransmission, particularly the N-methyl-D-aspartate (NMDA)-receptors, contributes to both expression of symptoms and disease progression in neurodegenerative dementia.
Memantine hydrochloride is a rapid, strongly voltage-dependent, low to moderate affinity uncompetitive (open-channel) NMDA-receptor antagonist which binds preferentially to the NMDA receptor-operated cation channels. Prolonged increased levels of glutamate in the brain of demented patients are sufficient to counter the Mg2+ ions voltage-dependent block of NMDA receptors and allow continuous influx of Ca2+ ions into cells which lead to neuronal degeneration. Studies showed that memantine hydrochloride binds more effectively than Mg2+ at the NMDA receptor, and thereby effectively blocks this prolonged influx of Ca2+ ions through the NMDA channels while preserving the transient physiological activation of the channels by higher concentrations of synaptically released glutamate. Thus, memantine hydrochloride modulates the effects of pathologically elevated tonic levels of glutamate that may lead to neuronal dysfunction.
There is no evidence that memantine hydrochloride prevents or slows neurodegeneration in patients with Alzheimer's disease. However, studies show that memantine hydrochloride produced statistically significant effects in preventing worsening in three endpoints (e.g., cognitive, global and functional) in patients with moderate to severe Alzheimer's disease (MMSE total score <20).
Memantine hydrochloride showed low to negligible affinity for GABA, benzodiazepine, dopamine, adrenergic, histamine, and glycine receptors and for voltage-­dependent Ca2+, Na+, K+ channels. Memantine hydrochloride also showed antagonistic effects at the 5HT3 receptors with a potency similar to that for the NMDA receptors and blocked nicotinic acetylcholine receptors with one-sixth to one-tenth the potency. In vitro studies have shown that memantine hydrochloride does not affect the reversible inhibition of acetylcholinesterase by donepezil, galantamine or tacrine.
Pharmacokinetics: Memantine hydrochloride is completely absorbed after oral administration; absolute bioavailability is approximately 100%. It has linear pharmacokinetics over the therapeutic dose range of 10 to 40 mg. Maximum plasma concentration is achieved in 3 to 8 hours. Food tended to slow the rate but not the extent of memantine hydrochloride absorption.
Daily doses of 20 mg lead to steady-state plasma concentrations ranging from 70 to 150 ng/mL (0.5-1 µM) with large in interindividual variations. A mean cerebrospinal fluid (CSF)/serum ratio of 0.52 was obtained when daily doses of 5 to 30 mg were administered. The volume of distribution is approximately 10 L/kg. Protein binding varied from 42 to 54% and no relationship was observed between plasma memantine hydrochloride concentration and protein binding.
Memantine hydrochloride undergoes partial hepatic metabolism. It is excreted mainly (60 to 80%) in its unchanged form in urine. Human metabolites are 1-amino-3-hydroxymethyl-5-methyl-adamantane, 3-amino-1-hyrdoxy-5,7-dimethyl-amantane and various secondary hydroxylated not yet definitively identified memantine hydrochloride derivatives; phase II metabolism amounts for up to 10%. The known metabolites do not have any NMDA-antagonistic activity. In vitro studies have shown that memantine hydrochloride is not metabolized by cytochrome P450 (CYP) isoenzymes 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, and 3A4.
Memantine hydrochloride is eliminated predominantly by the kidneys in a mono-exponential manner with a terminal half-life of 60 to 100 hours. In volunteers the normal kidney function, systemic clearance amounts to 170 mL/min. In a study on the absorption, metabolism and excretion of orally administered 14C-memantine, a mean of 84% of the dose was recovered within 20 days, the majority being excreted unchanged renally.
Renal clearance has been shown to depend on the pH of the urine. Under alkaline conditions, the renal clearance of unchanged memantine hydrochloride is markedly reduced compared to neutral or acidic urine conditions due to tubular reabsorption of memantine hydrochloride under alkaline conditions.
Special Population: Hepatic Impairment: After single oral dose administration of 20 mg memantine hydrochloride in subjects with moderate hepatic impairment (Child-Pugh Class B, score 7 to 9) and subjects who were age-, gender- and weight-matched to the hepatically-impaired subjects, no change in memantine hydrochloride exposure (based on Cmax and AUC) was seen in subjects with moderate hepatic impairment as compared with healthy subjects. However, the terminal elimination half-life increased by about 16% in subjects with moderate hepatic impairment as compared with healthy subjects.
Renal Impairment: After single oral dose administration of 20 mg memantine hydrochloride in subjects with mild renal impairment (creatinine clearance, CLcr, >50 to 80 mL), moderate renal impairment (Clcr 30 to 49 mL/min), severe renal impairment (CLcr 5 to 29 mL/min), or in healthy subjects (Clcr 80 mL/min) matched as closely as possible by age, weight and gender to the subjects with renal impairment, the mean AUC0-∞ increased by 4%, 60% or 115% in subjects with mild, moderate or severe renal impairment respectively, compared to healthy subjects. The terminal half-life increased by 18%, 41% or 95% in subjects with mild, moderate or severe renal impairment, respectively, compared to healthy subjects.
In the elderly with impaired renal function [creatinine clearance (CLcr): 50 mL/min], a significant correlation was observed between CLcr and total renal clearance (CLtot) of memantine hydrochloride. Total renal clearance substantially exceeded renal clearance by filtration, thus indicating that a significant part of renal clearance is due to tubular secretion processes.
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