From the Guidelines
Memantine works by partially blocking the N-methyl-d-aspartic acid receptor, preventing excess stimulation of the glutamate system, which influences memory and learning. As an uncompetitive NMDA receptor antagonist, memantine binds to the receptor channel when it's open, preventing excessive calcium influx while still allowing normal physiological activation 1. This mechanism is particularly important in Alzheimer's disease, where glutamate dysregulation leads to excitotoxicity and neuronal damage.
Key Points
- Memantine is typically prescribed at a starting dose of 5 mg once daily, gradually increasing to a target dose of 10 mg twice daily (20 mg total) over several weeks to minimize side effects.
- The medication has a moderate affinity for the receptor and rapid unblocking kinetics, which allows it to reduce pathological activation while preserving normal function.
- This selective action differentiates memantine from other NMDA antagonists and explains why it's generally well-tolerated, with common side effects including dizziness, headache, confusion, and constipation 1.
Clinical Considerations
- While memantine doesn't cure Alzheimer's disease, it can temporarily improve cognitive function and slow symptom progression by protecting neurons from excitotoxic damage.
- Treatment of dementia with cholinesterase inhibitors and memantine can result in statistically significant but clinically marginal improvement in measures of cognition and global assessment of dementia 1.
- The effectiveness of memantine is supported by studies that show small effect sizes in improving cognitive function and behavior, although the evidence is limited by short study durations and inconsistent effects on quality of life 1.
From the FDA Drug Label
Memantine is postulated to exert its therapeutic effect through its action as a low to moderate affinity uncompetitive (open-channel) NMDA receptor antagonist which binds preferentially to the NMDA receptor-operated cation channels.
- Mechanism of Action: Memantine works as an NMDA receptor antagonist.
- Key Points:
- Binds to NMDA receptor-operated cation channels
- Low to moderate affinity uncompetitive (open-channel) antagonist
- Preferential binding to NMDA receptor-operated cation channels Memantine's therapeutic effect is postulated to be through this mechanism of action 2
From the Research
Mechanism of Action
- N-methyl-D-aspartate (NMDA) receptor antagonists, such as memantine, work by blocking the NMDA glutamate receptors to normalize the glutamatergic system and ameliorate cognitive and memory deficits 3, 4, 5.
- Memantine is an uncompetitive (channel blocking) NMDA receptor antagonist, which means it binds to the NMDA receptor and blocks the flow of ions through the channel 3, 5.
- The key to memantine's therapeutic action lies in its uncompetitive binding to the NMDAR, which preserves the physiological function of the receptor and underpins memantine's tolerability and low adverse event profile 4.
Therapeutic Effects
- Memantine has been demonstrated to be safe and effective in the symptomatic treatment of Alzheimer's disease (AD) 3, 6, 7.
- Memantine can protect against the excitotoxic destruction of cholinergic neurons and promote synaptic plasticity, which can preserve or enhance memory in animal models of AD 3.
- Memantine may also be useful in the treatment of vascular dementia and Parkinson's disease, as it has been shown to have neuroprotective effects in various animal models 4, 7.
Pharmacological Properties
- Memantine has fast channel-blocking kinetics and strong voltage-dependence, which allows it to block channel activity induced by low, tonic levels of glutamate while sparing synaptic responses required for normal behavioral functioning, cognition, and memory 3, 7.
- Memantine has a low potential for interaction with other drugs, making it suitable for use in combination with acetylcholinesterase inhibitors and in elderly patients receiving multiple drug therapy 7.
- The extended-release formulation of memantine provides a more convenient dosage regimen and lower pill burden, which may improve adherence to therapy 6.