N-methyl-D-aspartate (NMDA) receptor antagonist
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Description
Memantine slows the rate of clinical deterioration in patients with moderate to severe Alzheimer’s disease. This disease causes a progressive dementia leading to a steady decline in cognitive function which adversely affects functional abilities required for activities of daily living. Alzheimer’s disease impacts 15 million people worldwide and there is no cure. Treatment is the only means to slow this devastating disease.[1] Approximately 5% of the population over the age of 65 is affected by Alzheimer’s and the prevalence doubles every 5 years after the age of 65. [2] Memantine is a non-competitive receptor antagonist for the N-methyl-D-asparate (NMDA) receptor. [1] Glutamate is an excitatory neurotransmitter in the brain which stimulates the NMDA receptor. The NMDA receptor is influential for memory, dementia and Alzheimer’s disease. Too much glutamate in the brain leads to neuronal damage via a mechanism which results in excessive calcium in the neurons of the brain. The drug was derived from amantadine. [3] Memantine was approved June 2002 in Europe and October 2003 in the USA.[4]
Memantine is the only NMDA antagonist on the market to date and is approved for moderate to severe Alzheimer’s disease.[3] The drug demonstrates its efficacy by showing less deterioration when compared with placebo. The deterioration was measured by several scales which demonstrated a statistically significant difference, including The Severe Impairment Battery (p< 0.001) and the Functional Assessment Staging Score (p=0.02).[1] Caregivers were noted to spend less time with those patients receiving memantine. The drug is well tolerated, with more patients in the placebo group discontinuing therapy due to adverse effects.[1]
Mechanism of action
Memantine is a non-competitive antagonist which blocks the N-methyl-D-asparate (NMDA) receptor. When blocked, the NMDA receptor prevents excess calcium from entering the neurons, which has been proven to be neuroprotective. [3] Glutamate is the neurotransmitter that physically activates the NMDA receptors. In Alzheimer’s, glutamate causes excitotoxicity, which is thought to be the cause of neuronal cell death. When excitotoxicity occurs, glutamate stimulates the NMDA receptors leading to a rise in intracellular calcium. The excess calcium is toxic to the brain, causing the progressive decline in brain function. Memantine binds at the magnesium binding site in the neurons causing a similar action to that of magnesium, though memantine stays in the channel longer. Memantine blocks calcium in a voltage-dependent manner. At rest, memantine blocks the NMDA receptors and in times of pathological over-activation, there is a “tonic increase” in glutamate levels. The drug allows for normal learning by not compromising the brains synaptic plasticity. Due to the pharmacokinetics of the drug, 15-20% of the channels are consistently unblocked and can be physically activated at any point. Via this mechanism, memantine prevents NMDA and glutamate induced neuronal cell death. [1]
Agents in Class
References WIth Links to PubMed
- Reisberg B, Doody R, Stoffler A, Schmitt F, Ferris S, Mobius HJ. Memantine in moderate-to-severe Alzheimer's disease. N Engl J Med 2003;348(14):1333-41.
- Klafki HW, Staufenbiel M, Kornhuber J, Wiltfang J. Therapeutic approaches to Alzheimer's disease. Brain 2006;129(Pt 11):2840-55.
- Robinson DM, Keating GM. Memantine: a review of its use in Alzheimer's disease. Drugs 2006;66(11):1515-34.
References
- ↑ 1.0 1.1 1.2 1.3 1.4 Reisberg B, Doody R, Stoffler A, Schmitt F, Ferris S, Mobius HJ. Memantine in moderate-to-severe Alzheimer's disease. N Engl J Med 2003;348(14):1333-41.
- ↑ Klafki HW, Staufenbiel M, Kornhuber J, Wiltfang J. Therapeutic approaches to Alzheimer's disease. Brain 2006;129(Pt 11):2840-55.
- ↑ 3.0 3.1 3.2 Robinson DM, Keating GM. Memantine: a review of its use in Alzheimer's disease. Drugs 2006;66(11):1515-34.
- ↑ Memantine(Namenda®)Monograph.Clinical Pharmacology (database on the internet) Available at www.clinicalpharmacolgy.com.
