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Memantine

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Memantine
Clinical data
License data
Pregnancy
category
Routes of
administration		Oral
ATC code
Legal status
Legal status
  • S4 (Au), POM (UK), ℞-only (U.S.)
Pharmacokinetic data
Bioavailability~100%
MetabolismHepatic (<10%)
Elimination half-life60–100 hours
ExcretionRenal
Identifiers
  • 3,5-dimethyl-tricyclo[3.3.1.13,7]decyl amine
    3,5-dimethyladamantan-1-amine
CAS Number
PubChem CID
DrugBank
ChemSpider
CompTox Dashboard (EPA)
ECHA InfoCard100.217.937 Edit this at Wikidata
Chemical and physical data
FormulaC12H21N
Molar mass179.3 g/mol g·mol−1
3D model (JSmol)
  • CC12CC3CC(C)(C1)CC(N)(C3)C2

Memantine is the first in a novel class of Alzheimer's disease medications acting on the glutamatergic system by blocking NMDA glutamate receptors. 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. 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 (≥1% of patients) include: confusion, dizziness, drowsiness, headache, insomnia, agitation, and/or hallucinations. Less common adverse effects include: vomiting, anxiety, hypertonia, cystitis, and increased libido.[10][3] 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]

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.[11]

Memantine is a low-affinity voltage-dependent uncompetitive antagonist at glutamatergic NMDA receptors.[12][13] 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.[14][15][16][17][18][19][20] 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.[15]

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.[21] 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.[22][23][19] 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.[24]

Dopaminergic (D2 receptor)

Memantine contains a dopaminergic component.[25]

See also

Notes

  1. ^ Mount C, Downton C (2006). "Alzheimer disease: progress or profit?". Nat Med. 12 (7): 780–4. doi:10.1038/nm0706-780. PMID 16829947. {{cite journal}}: Unknown parameter |month= ignored (help)
  2. ^ NICE technology appraisal guidance 111 Donepezil, galantamine, rivastigmine (review) and memantine for the treatment of Alzheimer’s disease
  3. ^ a b Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006.
  4. ^ a b Areosa SA, Sherriff F, McShane R (2005). "Memantine for dementia". Cochrane Database Syst Rev (3): CD003154. doi:10.1002/14651858.CD003154.pub4. PMID 16034889.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  5. ^ Open-Label Pilot Study of Namenda in Adult Subjects With ADHD and ADHD NOS [1]
  6. ^ Dan Ziegler. "New drugs to prevent or treat diabetic polyneuropathy" (pdf). Retrieved 2008-01-07. {{cite web}}: line feed character in |title= at position 39 (help)
  7. ^ Schifitto G, Navia BA, Yiannoutsos CT; et al. (2007). "Memantine and HIV-associated cognitive impairment: a neuropsychological and proton magnetic resonance spectroscopy study". AIDS. 21 (14): 1877–86. doi:10.1097/QAD.0b013e32813384e8. PMID 17721095. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  8. ^ Corbett J (2007). "Memantine/Gabapentin for the treatment of congenital nystagmus". Curr Neurol Neurosci Rep. 7 (5): 395–6. doi:10.1007/s11910-007-0061-z. PMID 17764629. {{cite journal}}: Unknown parameter |month= ignored (help)
  9. ^ a b Villoslada P, Arrondo G, Sepulcre J, Alegre M, Artieda J (2008). "Memantine induces reversible neurologic impairment in patients with MS". Neurology. doi:10.1212/01.wnl.0000342388.73185.80. PMID 19092106. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  10. ^ Joint Formulary Committee (2004). British National Formulary (47th ed. ed.). London: BMA and the Royal Pharmaceutical Society of Great Britain. ISBN 0-85369-584-9. {{cite book}}: |edition= has extra text (help)
  11. ^ Cacabelos R, Takeda M, Winblad B (1999). "The glutamatergic system and neurodegeneration in dementia: preventive strategies in Alzheimer's disease". Int J Geriatr Psychiatry. 14 (1): 3–47. doi:10.1002/(SICI)1099-1166(199901)14:1<3::AID-GPS897>3.0.CO;2-7. PMID 10029935. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  12. ^ Rogawski, MA (2003). "The neuropharmacological basis for the use of memantine in the treatment of Alzheimer's disease". CNS Drug Rev. 9 (3): 275–308. PMID 14530799. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  13. ^ Robinson, DM (2006). "Memantine: a review of its use in Alzheimer's disease". Drugs. 66 (11): 1515–34. doi:10.2165/00003495-200666110-00015. PMID 16906789. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  14. ^ Rogawski, MA (2000). "Low affinity channel blocking (uncompetitive) NMDA receptor antagonists as therapeutic agents—toward an understanding of their favorable tolerability". Amino Acids. 19 (1): 133–49. doi:10.1007/s007260070042. PMID 11026482. {{cite journal}}: Cite has empty unknown parameter: |coauthors= (help)
  15. ^ a b Parsons CG, Stöffler A, Danysz W (2007). "Memantine: a NMDA receptor antagonist that improves memory by restoration of homeostasis in the glutamatergic system—too little activation is bad, too much is even worse". Neuropharmacology. 53 (6): 699–723. doi:10.1016/j.neuropharm.2007.07.013. PMID 17904591. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  16. ^ Chen HS, Pellegrini JW, Aggarwal SK; et al. (1992). "Open-channel block of N-methyl-D-aspartate (NMDA) responses by memantine: therapeutic advantage against NMDA receptor-mediated neurotoxicity". J Neurosci. 12 (11): 4427–36. PMID 1432103. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |day= ignored (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  17. ^ Chen HS, Lipton SA (1997). "Mechanism of memantine block of NMDA-activated channels in rat retinal ganglion cells: uncompetitive antagonism". J Physiol. (Lond.). 499 (Pt 1): 27–46. PMC 1159335. PMID 9061638. {{cite journal}}: Unknown parameter |day= ignored (help); Unknown parameter |month= ignored (help)
  18. ^ Lipton SA (2006). "Paradigm shift in neuroprotection by NMDA receptor blockade: memantine and beyond". Nat Rev Drug Discov. 5 (2): 160–70. doi:10.1038/nrd1958. PMID 16424917. {{cite journal}}: Unknown parameter |month= ignored (help)
  19. ^ a b Chen HS, Lipton SA (2006). "The chemical biology of clinically tolerated NMDA receptor antagonists". J Neurochem. 97 (6): 1611–26. doi:10.1111/j.1471-4159.2006.03991.x. PMID 16805772. {{cite journal}}: Unknown parameter |month= ignored (help)
  20. ^ Lipton SA (2007). "Pathologically activated therapeutics for neuroprotection". Nat Rev Neurosci. 8 (10): 803–8. doi:10.1038/nrn2229. PMID 17882256. {{cite journal}}: Unknown parameter |month= ignored (help)
  21. ^ Rammes G, Rupprecht R, Ferrari U, Zieglgänsberger W, Parsons CG (2001). "The N-methyl-D-aspartate receptor channel blockers memantine, MRZ 2/579 and other amino-alkyl-cyclohexanes antagonise 5-HT(3) receptor currents in cultured HEK-293 and N1E-115 cell systems in a non-competitive manner". Neurosci Lett. 306 (1–2): 81–4. doi:10.1016/S0304-3940(01)01872-9. PMID 11403963. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  22. ^ Buisson B, Bertrand D (1998). "Open-channel blockers at the human alpha4beta2 neuronal nicotinic acetylcholine receptor". Mol Pharmacol. 53 (3): 555–63. PMID 9495824. {{cite journal}}: Unknown parameter |day= ignored (help); Unknown parameter |month= ignored (help)
  23. ^ Aracava Y, Pereira EF, Maelicke A, Albuquerque EX (2005). "Memantine blocks alpha7* nicotinic acetylcholine receptors more potently than n-methyl-D-aspartate receptors in rat hippocampal neurons". J Pharmacol Exp Ther. 312 (3): 1195–205. doi:10.1124/jpet.104.077172. PMID 15522999. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  24. ^ Gotti C, Clementi F (2004). "Neuronal nicotinic receptors: from structure to pathology". Prog Neurobiol. 74 (6): 363–96. doi:10.1016/j.pneurobio.2004.09.006. PMID 15649582. {{cite journal}}: Unknown parameter |month= ignored (help)
  25. ^ Seeman P, Caruso C, Lasaga M (2008). "Memantine agonist action at dopamine D2High receptors". Synapse. 62 (2): 149–53. doi:10.1002/syn.20472. PMID 18000814. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)

Further reading

  • Lipton SA (2005). "The molecular basis of memantine action in Alzheimer's disease and other neurologic disorders: low-affinity, uncompetitive antagonism". Current Alzheimer research. 2 (2): 155–65. doi:10.2174/1567205053585846. PMID 15974913.
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