Memantine, sold under the brand name Namenda among others, is a medication used to slow the progression of moderate-to-severe Alzheimer's disease. It is taken by mouth. Common side effects include headache, constipation, sleepiness, and dizziness. Severe side effects may include blood clots, psychosis, and heart failure. It is believed to work by acting on NMDA receptors, working as a pore blocker of these ion channels. Memantine was first discovered in 1963. It was approved for medical use in Germany in 1989, in the European Union in 2002, and in the United States in 2003. It is available as a generic medication. In 2023, it was the 145th most commonly prescribed medication in the United States, with more than 3 million prescriptions.
Medical uses
Alzheimer's disease and dementia Memantine is used to treat moderate-to-severe Alzheimer's disease, especially for people who are intolerant of or have a contraindication to AChE (acetylcholinesterase) inhibitors. One guideline recommends memantine or an AChE inhibitor be considered in people in the early-to-mid stage of dementia. Memantine has been associated with a modest improvement; with small positive effects on cognition, mood, behavior, and the ability to perform daily activities in moderate-to-severe Alzheimer's disease. There does not appear to be any benefit in mild disease. Memantine when added to donepezil in those with moderate-to-severe dementia resulted in "limited improvements" in a 2017 review. The UK National Institute for Clinical Excellence (NICE) issued guidance in 2018 recommending consideration of the combination of memantine with donepezil in those with moderate-to-severe dementia.
Radiation therapy Memantine has been recommended for use by professional organization consensus to prevent neurocognitive decline after whole brain radiotherapy.
Adverse effects Memantine is, in general, well tolerated. Common adverse drug reactions (≥1% of people) include confusion, dizziness, drowsiness, headache, insomnia, agitation, and/or hallucinations. Less common adverse effects include vomiting, anxiety, hypertonia, cystitis, and increased libido. Like many other NMDA receptor antagonists, memantine behaves as a dissociative anesthetic at supratherapeutic doses. Despite isolated reports, recreational use of memantine is rare due to the drug's long duration and limited availability. Additionally, memantine seems to lack effects such as euphoria or hallucinations. Memantine appears to be generally well tolerated by children with autism spectrum disorder.
Pharmacology
Pharmacodynamics Memantine is an uncompetitive NMDA receptor antagonist, with an IC50 binding affinity of ~500-1,000 nM (0.5-1 μM), but displays higher potency at extrasynaptic NMDA receptors (IC50 = ~22 nM), suggesting preferential inhibition of pathological glutamatergic signaling. Memantine also exhibits activity at several other receptors:
Dopamine D2High receptor agonist (IC50 affinity = ~137-917 nM); increases dopaminergic activity in the prefrontal cortex and striatum. Memantine may inhibit the release of prolactin through D2 agonism, based on studies from isolated anterior pituitary cells. Alpha 7 nicotinic acetylcholine receptor antagonist (IC50 affinity = 340nM-5,000 nM or 0.34-5 μM). 5-HT3 receptor receptor antagonist (IC50 affinity = ~1,000 nM). Believed to block NMDA overactivation and restore cognitive dysfunction without significantly impairing normal synaptic transmission. No meaningful acetylcholinesterase (AChE) inhibition.
Glutamatergic A dysfunction of glutamatergic neurotransmission, manifested as neuronal excitotoxicity, is hypothesized to be involved in the etiology of Alzheimer's disease. Targeting the glutamatergic system, specifically ionotropic glutamate NMDA receptors, offers a novel approach to treatment in view of the limited efficacy of existing drugs targeting the cholinergic system. Memantine is a low-affinity voltage-dependent uncompetitive antagonist at glutamatergic NMDA receptors with an IC50 binding affinity of ~500-1,000 nM (0.5-1 μM), but displays higher potency at extrasynaptic NMDA receptors (~22 nM). Magnesium (Mg2+), the natural NMDA channel blocker, has an apparent dissociation constant (Ka/Ki) of roughly 2-3 mM (2,000,000-3,000,000 nM), making memantine ~1000x stronger at NMDA than Mg2+. By binding to the NMDA receptor with a higher affinity than Mg2+, memantine is able to inhibit the prolonged influx of Ca2+ ions, particularly from extrasynaptic receptors, which forms the basis of neuronal excitotoxicity. The low affinity, uncompetitive nature, and rapid off-rate kinetics of memantine at the level of the NMDA receptor channel, however, preserve the function of the receptor at synapses, as it can still be activated by physiological release of glutamate following depolarization of the postsynaptic neuron. The interaction of memantine with NMDA receptors plays a major role in the symptomatic improvement that the drug produces in Alzheimer's disease. However, there is no evidence yet that memantine's ability to protect against extrasynaptic NMDA receptor-mediated excitotoxicity has a disease-modifying effect in Alzheimer's disease, although this has been suggested in animal models.
Serotonergic Memantine acts as a non-competitive antagonist of the serotonin 5-HT3 receptor, with a potency similar to that for the NMDA receptor. Many 5-HT3 receptor antagonists function as antiemetics, however the clinical significance of this anti-serotonergic activity of memantine in Alzheimer's disease is unknown.
Cholinergic Memantine acts as a non-competitive antagonist at the α7 nicotinic acetycholine receptor (IC50 affinity = 340nM-5,000nM or 0.34-5 μM). Several studies have observed that Memantine's antagonism at nAChRs is higher than both its affinity to NMDA and 5-HT3 receptors, but this may be difficult to ascertain with accuracy due to rapid desensitization of nAChRs. Antagonism of α7 nAChRs may contribute to the initial worsening of cognitive function during early Memantine treatment. Nicotinic acetylcholine receptor, specifically α7 nAChR, upregulate quickly in response to antagonism, which could explain the possible cognitive-enhancing effects of Memantine. It has been shown that the number of nicotinic receptors in the brain are reduced in Alzheimer's disease, even in the absence of a general decrease in the number of neurons, and nicotinic receptor agonists are viewed as interesting targets for anti-Alzheimer drugs.
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