Glutamate is a primary excitatory neurotransmitter in the brain, and gluta-mate receptor activity is required for memory, motor function, and perception. Levels of glutamate increase during times of learning and memory and bind to alpha amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors. The binding of glutamate to AMPA receptors triggers NMDA receptors, thus altering membrane permeability and allowing the influx of calcium (Ca2+) into the neurons.
The pathogenesis of AD has been linked to the “glutamate excitotoxicity hypothesis,” which states that an excess of glutaminergic stimulation causes an overactivation of NMDA receptors. This leads to calcium overflow into the neurons, activating catabolic enzymes such as nucleases, proteases, and phospho-lipases. Increased activity of these enzymes promotes cell death, as a result of hypoxia and ischemia, and eventually causes learning and memory recall signals to be disrupted and unrecognized.
Memantine is a noncompetitive, low-to moderate-affinity NMDA receptor antagonist with an apparent dual mechanism of action. At the receptor level, it displays rapid binding properties and a pronounced voltage dependency that modulates the glutaminergic neuro-transmission system. In a state of reduced glutamate release, memantine produces improved neurotransmission and activation of neurons. However, when glutamate release is excessive, memantine inhibits the excitatory action of glutamate by antagonizing NMDA receptors. The drug thus blocks NMDA receptors from excessive gluta-minergic stimulation and prevents an increase in calcium influx; it subsequently results in decreased cell death and alleviates symptoms of AD. The affinity of memantine for cerebellar tissue is thought to be higher than that for frontal lobe brain tissue.
After oral administration, memantine is absorbed rapidly and completely. It has linear pharmacokinetic properties over the therapeutic dose range, and the time to peak concentration is three to seven hours. A therapeutic response in patients with dementia has been observed within 14 days of therapy.
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Memantine is not highly protein-bound; although its protein binding varies greatly (from 10% to 45%), it is widely distributed in the brain, especially in the temporal lobe, hypothalamus, and pons. Memantine is excreted primarily unchanged in the urine. Its terminal elimination half-life is approximately 60 to 80 hours.