Introduction
Memantine is an N-methyl-D-aspartate (NMDA) receptor antagonist used in the management of Alzheimer's Disease (AD). It is different from many other Alzheimer's Disease medications, as it works by a different mechanism than the cholinesterase enzyme inhibitors normally employed in the management of Alzheimer's disease . Memantine blocks the effects of glutamate, a neurotransmitter in the brain that leads to neuronal excitability and excessive stimulation in Alzheimer's Disease .
Uses
Memantine is an NMDA receptor antagonist used to treat moderate to severe dementia in Alzheimer's.
Memantine is used to manage moderate to severe Alzheimer's dementia .
A more recent systemic review and meta-analysis indicates that memantine is beneficial as a first line drug for the treatment of Alzheimer's dementia. Cholinesterase inhibitors may be added to memantine for further beneficial effects on behavioral symptoms and other symptoms of dementia .
Associated Conditions
Pharmacodynamics
General effects
This drug inhibits calcium influx into cells that is normally caused by chronic NMDA receptor activation by glutamate . This leads to the improvement of Alzheimer's dementia symptoms, demonstrated by increased cognition and other beneficial central nervous system effects .
Effects on neuroplasticity
Like other NMDA receptor antagonists, memantine at high doses can reduce neuronal synaptic plasticity that is involved in learning and memory processes. At lower concentrations, which are normally used in the clinical setting, memantine can enhance neuronal synaptic plasticity in the brain, improve memory, and act as a neuroprotectant against the destruction of neurons caused by excitatory neurotransmitters .
Effect on various receptors
Memantine has demonstrated minimal activity for GABA, benzodiazepine, dopamine, adrenergic, histamine, and glycine receptors, as well as voltage-dependent Ca2+, Na+ or K+ channels. This drug has shown antagonist activity at the 5HT3 receptors. Laboratory studies suggest that memantine does not affect the reversible inhibition of the acetylcholinesterase normally caused by donepezil, galantamine, or tacrine .
Mechanism of Action
Continuous activation of the N-methyl-D-aspartate (NMDA) receptors in the central nervous system caused by glutamate is thought to cause some of the Alzheimer's disease symptoms. This overactivation is thought to contribute to neurotoxicity due to the excitatory properties of glutamate . The pharmacological effect of memantine likely occurs via the drug's behavior as an uncompetitive (open-channel) NMDA receptor antagonist, preventing glutamate action on this receptor. Memantine has a preference for the NMDA receptor-operated cation channels. Despite these antagonist effects, memantine has not been proven to prevent or retard the neurodegeneration seen in patients diagnosed with Alzheimer’s disease .
Absorption
After an oral dose, memantine is well absorbed. Its peak drug concentrations are attained in about 3-7 hours. Memantine shows linear pharmacokinetics when given at normal therapeutic doses. This drug can be taken without regard to food, as there is no effect of food on memantine absorption .
Volume of Distribution
The mean volume of distribution of memantine is 9-11 L/kg .
Protein Binding
The protein binding for memantine is about 45% .
Route of Elimination
This drug is mainly excreted in the urine. Approximately 48% of administered memantine is excreted unchanged in urine .
The remainder of the drug is metabolized to three main metabolites. These metabolites are the N-glucuronide conjugate, 6-hydroxy memantine, and 1-nitroso-deaminated memantine, which show minimal NMDA receptor antagonist activity .
Half Life
Within the range of 60-100 hours .
The terminal elimination half-life was significantly increased in patients with moderate to severe renal impairment, in comparison with patients with normal renal function . Exercise caution when this drug is administered to patients with renal dysfunction.
Clearance
This drug is cleared by active tubular secretion in the kidneys. Tubular reabsorption of this drug is pH dependent .
Toxicity
LD50
Oral LD50, mouse 437-498 mg/kg Oral LD50, rat 328-370 mg/kg
Carcinogenesis, Mutagenesis, Impairment of Fertility
No evidence of carcinogenicity was seen in mouse and rat models administered memantine at doses equivalent to supratherapeutic human doses . Additionally, no genotoxic potential was noted when a battery of assays was performed. No effects on fertility or reproductive performance were noted in rats given to 18 mg/kg/day (equivalent to 9 times the maximum recommended human dose) orally from 14 days preceding mating through gestation and lactation in females, or for 60 preceding mating activity in males animals .
Use in pregnancy
This drug is considered a pregnancy category B drug, meaning no sufficiently controlled and adequate studies of memantine in pregnant women have been performed. This drug should be taken during pregnancy only if the potential benefit justifies the possible fetal risk .
Use in nursing
It is unknown whether memantine is excreted in human milk. Due to that fact that many drugs are found excreted in human milk, caution should be observed when this drug is taken by a nursing mother .
Food Interactions
- Take with a full glass of water.
- Take with or without food. The absorption is unaffected by food.
Dosage
Week 1 (Everyday): Morning- 5 mg (1 tablet), Night- No dose
Week 2 (Everyday): Morning- 5 mg (1 tablet), Night- 5 mg (1 tablet)
Week 3 (Everyday): Morning- 10 mg (2 tablets), Night- 5 mg (1 tablet)
Week 4 and onwards (Everyday): Morning- 10 mg (2 tablets), Night- 10 mg (2 tablets)
Missed Dose: If any dose is missed, just wait and take the next dose at the usual time. Do not double the dose to compensate for the missed dose.
In case renal impairment: In patients with moderate renal impairment (creatinine clearance 30-49 ml/min) daily dose should be 10 mg (1 ml solution, equivalent to two downward strokes). If tolerated well after at least 7 days of treatment, the dose could be increased up to 20 mg/day according to standard titration scheme. In patients with severe renal impairment (creatinine clearance 5-29 ml/min) daily dose should be 10 mg (1 ml solution, equivalent to two downward strokes) per day.
In case of hepatic impairment: In patients with mild or moderate hepatic impaired function, no dosage adjustment is needed. Administration of memantine is not recommended in patients with severe hepatic impairment.
Children under 18 years: Memantine is not recommended for use in children below 18 years due to lack of data on safety and efficacy.
