Memry Mechanism of Action

Pharmacology: Tablet: 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.
Pharmacodynamics: Oral soln: The effects of glutamate, the primary excitatory neurotransmitter in the central nervous system (CNS), are mediated by various receptor types, including N-methyl-D-aspartate (NMDA) receptors, which play a role in physiologic processes such as learning and memory formation. The persistent activation of NMDA receptors by glutamate has been considered as a possible cause of neurodegeneration in different types of dementia, including dementia of the Alzheimer's type (Alzheimer's disease), and is thought to contribute to the symptomatology of Alzheimer's disease.
Memantine hydrochloride is a noncompetitive NMDA receptor antagonist. With low to moderate affinity, it preferentially binds to NMDA receptors-operated cation channels. Though not fully understood, memantine acts by effectively blocking glutamate under conditions of excessive stimulation. In addition, memantine exhibits antagonism at the type 3 serotonergic (5-HT) receptor with a potency that is similar to that at the 3NMDA receptor. Memantine also blocks the nicotinic acetylcholine receptor with a potency of about one-sixth to one-tenth to that at the NMDA receptor. Memantine has low to negligible affinity for gamma-aminobutyric acid (GABA), benzodiazepine, dopamine, adrenergic, histamine, or glycine receptors, or for voltage dependent calcium, sodium, or potassium channels. In humans, memantine has not been shown to prevent or slow down the neurodegenerative processes, or alter the course of the underlying dementia process in patients with Alzheimer's disease.
Pharmacokinetics: Tablet: 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 C_max 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, CL_cr, >50 to 80 mL), moderate renal impairment (Cl_cr 30 to 49 mL/min), severe renal impairment (CL_cr 5 to 29 mL/min), or in healthy subjects (Cl_cr 80 mL/min) matched as closely as possible by age, weight and gender to the subjects with renal impairment, the mean AUC_0-∞ 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 (CL_cr): 50 mL/min], a significant correlation was observed between CL_cr and total renal clearance (CL_tot) 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.
Oral soln: After oral administration, memantine is highly absorbed, with an absolute bioavailability of approximately 100%. Peak plasma concentrations (C_max) following single oral doses of the therapeutic range (i.e., 10 to 40 mg) of memantine were reached in about 3 to 8 hours after drug intake. Memantine has linear pharmacokinetics over the therapeutic dose range. Food tends to slow that rate of memantine absorption but not the extent of absorption. The administration of memantine 20 mg daily resulted to steady-state plasma concentrations ranging from 70 to 150 ng/mL with large interindividual variations.
The apparent volume of distribution of memantine is 9 to 11 L/kg, and the plasma protein binding is about 45%. Memantine rapidly crosses the blood-brain barrier, and a mean cerebrospinal fluid/serum ratio of 0.52 was attained with the daily administration of memantine 5 to 30 mg.
Memantine undergoes partial hepatic metabolism. In man, about 80% of the circulating memantine-related substance is present as the parent compound. The main metabolites of memantine in humans are N-3,5-dimethyl-gludantan, the isomeric mixture of 4- and 6-hydroxy-memantine, and 1-nitroso-3,5-dimethyl-adamantane. None of these metabolites demonstrate antagonism towards NMDA activity. The hepatic microsomal CYP450 enzyme is not significantly involved in the metabolism of memantine.
About 60% to 80% of the administered dose of memantine is excreted in the urine, predominantly in the unchanged form. Memantine is eliminated in a monoexponential manner, with a terminal elimination half-life of about 60 to 100 hours. Seventy-four percent (74%) of the administered dose is excreted as the sum of the parent drug and N-glucuronide conjugate. In subjects with normal kidney function, the total clearance of memantine is 170 mL/min/1.73 m. Renal clearance has been shown to involve the active tubular secretion regulated by pH-dependent tubular reabsorption and probably mediated by cation transport protein.
Special Populations: Renal impairment: The mean AUC from zero to infinity (AUC) increased by 4%, 60%, and 115% in patients with mild, moderate, and severe renal impairment, respectively. Compared to healthy subjects, the terminal elimination half-life increased by 18%, 41%, and 95% in patients with mild, moderate, and severe renal impairment, respectively.
A significant correlation between the creatinine clearance (CrCl) and total renal clearance of memantine was observed in elderly volunteers with impaired renal function (CrCl of 50 to ≤80 mL/min/1.73 m). After a single 20 mg oral dose of memantine, the systemic exposure in elderly patients with mild to moderate renal impairment were greater than elderly patients with normal renal functions by 14% and 39%, respectively. Total renal clearance was substantially higher than renal clearance by filtration, indicating that a significant part of renal clearance is due to tubular secretion.
Hepatic impairment: Memantine is metabolized to a minor extent into metabolites which do not possess NMDA antagonistic activity. The terminal elimination half-life of patients with moderate hepatic impairment (Child-Pugh B) was increased by about 16% compared to healthy subjects; memantine exposure was similar in healthy subjects, as measured by the C_max and AUC. The administration of memantine is not recommended in patients with severe hepatic impairment, as the pharmacokinetics of memantine have not been evaluated in this population.
Gender: After multiple dose administration of memantine 20 mg daily, females had about 45% higher exposure compared to males. However, there was no difference in exposure when body weight was considered.
Elderly: The pharmacokinetics of memantine in young and elderly patients are similar.