Memantine

Mechanism of action

Memantine exerts its action through uncompetitive NMDA receptor antagonism, binding preferentially to the NMDA receptor-operated cation channels. Prolonged increased levels of glutamate in the brain of demented patients are sufficient to counter the voltage-dependent block of NMDA receptors by Mg2+ ions and allow continuous influx of Ca2+ ions into cells, ultimately resulting in neuronal degeneration. Studies suggest that memantine binds more effectively than Mg2+ ions at the NMDA receptor, and thereby effectively blocks this prolonged influx of Ca2+ ions through the NMDA channel whilst preserving the transient physiological activation of the channels by higher concentrations of synaptically released glutamate. Thus memantine protects against chronically elevated concentrations of glutamate. Memantine also has antagonistic activity at the type 3 serotonergic (5-HT3) receptor with a potency that is similar to that at the NMDA receptor, and lower antagonistic activity at the nicotinic acetylcholine receptor. This drug has no affinity for γ-aminobutyric acid (GABA), benzodiazepine, dopamine, adrenergic, histamine, or glycine receptors or for voltage-dependent calcium, sodium, or potassium channel.

Reference: Tripathi K.D., “Essentials of Medical Pharmacology”, Jaypee brothers medical publishers, Seventh edition, New Delhi, page no. 489,490.