Memantine

Memantine is the first in a novel class of Alzheimer's disease medications acting on the glutamatergic system by blocking NMDA glutamate receptors. Memantine is marketed under the brands Axura and Akatinol by Merz, Namenda by Forest, Ebixa and Abixa by Lundbeck and Memox by Unipharm.

Clinical use

Although memantine is approved for treatment of moderate to severe Alzheimer's disease^[1], its usage has been recommended against by the UK's National Institute for Clinical Excellence,^[2] on the grounds that its high cost outweighs the benefits of treatment in most patients.

Memantine has been associated with a moderate decrease in clinical deterioration in Alzheimer's disease.^[3] A systematic review of randomised controlled trials found that memantine has a small positive effect on cognition, mood, behaviour, and the ability to perform daily activities in moderate to severe Alzheimer's disease, but an unknown effect in mild to moderate disease.^[4]

Memantine is also being tested for opioid dependence, systemic lupus erythematosus, depression, obsessive compulsive disorder, problem gambling, attention-deficit hyperactivity disorder (ADHD),^[5] glaucoma, tinnitus, neuropathic pain,^[6] pervasive developmental disorders, HIV associated dementia^[7], nystagmus,^[8] and multiple sclerosis.^[9]

Adverse effects

Memantine is generally well-tolerated.^[4] Common adverse drug reactions include: confusion, dizziness, drowsiness, headache, insomnia, agitation, and/or hallucinations. Less common adverse effects include: vomiting, anxiety, hypertonia, cystitis, and increased libido.^[3][10] On the other hand; it has been reported to induce reversible neurological impairment in multiple sclerosis, that led to stop an ongoing clinical trial.^[9][11]

Pharmacology

Glutamatergic (NMDA receptor)

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 NMDA receptors, offers a novel approach to treatment in view of the limited efficacy of existing drugs targeting the cholinergic system.^[12]

Memantine is a low-affinity voltage-dependent uncompetitive antagonist at glutamatergic NMDA receptors.^[13][14] By binding to the NMDA receptor with a higher affinity than Mg²⁺ ions, memantine is able to inhibit the prolonged influx of Ca²⁺ ions which forms the basis of neuronal excitotoxicity. The low affinity and rapid off-rate kinetics of memantine at the level of the NMDA receptor-channel, however, preserves the physiological function of the receptor as it can still be activated by the relatively high concentrations of glutamate released following depolarization of the presynaptic neuron.^{[15][16][17][18][19][20][21]} The interaction of memantine with NMDA receptors plays a major role in the symptomatic improvement the drug produces in Alzheimer's disease. Moreover, there is no evidence as yet that the ability of memantine to protect against NMDA receptor-mediated excitotoxicity has a disease modifying effect in Alzheimer's, although this has been suggested in animal models.^[16]

Serotonergic (5-HT₃ receptor)

Memantine acts as a non-competitive antagonist at the 5HT₃ receptor, with a potency similar to that for the NMDA receptor.^[22] The clinical significance of this serotonergic activity in the treatment of Alzheimer's disease is unknown.

Cholinergic (Nicotinic acetylcholine receptor)

Memantine acts as a non-competitive antagonist at different neuronal nicotinic acetylcholine receptors (nAChRs) at potencies possibly similar to the NMDA and 5-HT3 receptors, but this is difficult to ascertain with accuracy because of the rapid desensitization of nAChR responses in these experiments.^[20][23][24] 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.^[25]

Dopaminergic (D₂ receptor)

Memantine acts as an agonist at the dopamine D₂ receptor.^[26]

History

Memantine was first synthesized and patented by Eli Lilly and Company in 1968 (as cited in the Merck Index), and then developed by Merz in collaboration with Neurobiological Technologies, Inc. and licensed to Forest for the U.S. and Lundbeck for selected European and international markets.

See also

• Donepezil (Aricept)
• Galantamine
• Exelon
• Dimebon

Notes