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| {{drugbox |
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| | image = Memantine.png
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| | image2 = Memantine-3d-sticks.png
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| |width=150
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| |IUPAC_name = 1-amino-3,5-dimethyl-adamantane
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| |CAS_number = 19982-08-2
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| | ATC_prefix= N06
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| | ATC_suffix= DX01
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| | PubChem= 4054
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| | DrugBank= APRD00221
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| | C=12 | H=21 | N=1
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| |molecular_weight = 179.3 g/mol
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| |bioavailability = ~100%
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| |metabolism = [[Hepatic]] (<10%)
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| |elimination_half-life = 60–100 hours
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| |excretion = [[Renal]]
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| |pregnancy_category = B2 <small>([[Australia|Au]])</small>, B <small>([[U.S.]])</small>
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| |legal_status = S4 <small>(Au)</small>, POM <small>([[United Kingdom|UK]])</small>, ℞-only <small>(U.S.)</small>
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| |routes_of_administration = Oral
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| | licence_EU =Axura
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| | licence_US =Namenda
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| }}
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| {{SI}}
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| {{CMG}}
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| ==Overview==
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| '''Memantine''' is the first in a novel class of [[Alzheimer's disease]] medications acting on the [[glutamatergic system]]. Memantine was developed by [[Merz Pharma|Merz]] and licensed to [[Forest Laboratories|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 and '''Ebixa'''® by Lundbeck.
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| ==Pharmacology==
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| ===Glutamatergic (NMDA receptor)===
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| A dysfunction of glutamatergic neurotransmission, manifested as [[Neuron|neuronal]] [[excitotoxicity]], is hypothesized to be involved in the [[etiology]] of [[Alzheimer's disease]]. Targeting the [[glutamic acid|glutamatergic]] system, specifically [[NMDA receptor]]s, offers a novel approach to treatment in view of the limited efficacy of existing drugs targeting the [[Acetylcholine|cholinergic]] system.<ref name="Cacabelos1999">Cacabelos R, Takeda M, Winblad B. The glutamatergic system and neurodegeneration in dementia: preventive strategies in Alzheimer's disease puku. Int J Geriatr Psychiatry 1999;14(1):3-47. PMID 10029935</ref>
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| Memantine is a low-affinity voltage-dependent [[Uncompetitive_inhibitor|uncompetitive]] [[NMDA Receptor Antagonists|antagonist at glutamatergic NMDA receptors]]. <ref name=Rogawski2003 >{{cite journal | last =Rogawski | first =MA | authorlink = | coauthors = Wenk GL| title =The neuropharmacological basis for the use of memantine in the treatment of Alzheimer's disease | journal = CNS Drug Rev | volume =9| issue=3 | pages =275-308 | date= 2003 | url = | doi = | id = PMID 14530799}} </ref> <ref name=Robinson >{{cite journal | last =Robinson | first =DM | authorlink = | coauthors = Keating GM| title =Memantine: a review of its use in Alzheimer's disease | journal = Drugs| volume =66 | issue =11 | pages =1515-1534 | publisher = | date =2006 | url = | doi = | id =PMID 16906789 | accessdate =2007-01-17 }} </ref> By binding to the NMDA receptor with a higher affinity than [[Magnesium|Mg<sup>2+</sup>]] ions, memantine is able to inhibit the prolonged influx of [[Calcium|Ca<sup>2+</sup>]] ions which forms the basis of neuronal excitotoxicity. The low affinity and rapid 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. <ref name=Rogawski2000>{{cite journal |last=Rogawski | first=MA | authorlink = | coauthors = | title= Low affinity channel blocking (uncompetitive) NMDA receptor antagonists as therapeutic agents--toward an understanding of their favorable tolerability | journal = Amino Acids | volume =19 | issue=1 |pages=133-149 | date=2000 |url = | doi = | id=PMID 11026482 }} </ref> Whether the interaction of memantine with NMDA receptors plays a role in the symptomatic improvement the drug produces in Alzheimer's disease is a matter of speculation. 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.
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| ===Serotonergic (5-HT<sub>3</sub> receptor)===
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| Memantine acts as an uncompetitive antagonist at the [[5-HT receptor|5HT<sub>3</sub>]] receptor, with a potency similar to that for the NMDA receptor.<ref name="Rammes2001">Rammes G, Rupprecht R, Ferrari U, Zieglgansberger W, Parsons CG. 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 2001;306(1-2):81-4. PMID 11403963</ref> The clinical significance of this [[serotonin|serotonergic]] activity in the treatment of Alzheimer's disease is unknown.
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| ===Cholinergic (Nicotinic acetylcholine receptor)===
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| Memantine acts as an uncompetetive antagonist at different neuronal [[Nicotinic acetylcholine receptor|nicotinic neuronal receptors (nAChRs)]] at potencies similar to the NMDA receptor.<ref name="Buisson1998">Buisson B, Bertrand D. Open-channel blockers at the human α<sub>4</sub>β<sub>2</sub> neuronal nicotinic acetylcholine receptor. Mol Pharmacol 1998;53:555–63. PMID 9495824</ref><ref name="Aracava2005">Aracava Y, Pereira EF, Maelicke A, Albuquerque EX. Memantine blocks α<sub>7</sub>* nicotinic acetylcholine receptors more potently than ''N''-methyl-D-aspartate receptors in rat hippocampal neurons. J Pharmacol Exp Ther 2005;312:1195–205. PMID 15522999</ref> 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.<ref name="Gotti2004">Gotti C, Clementi F. Neuronal nicotinic receptors: from structure to pathology. Prog Neurobiol 2004;74:363–96. PMID 15649582</ref>
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| ==Clinical use==
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| ===Indications===
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| Although memantine is approved for treatment of moderate to severe Alzheimer's Disease<ref name="MountC2006">Mount C, Downton C. Alzheimer's Disease: Progress or Profit?. Nature Medicine 2006 (12) 3: 1280-1284. PMID 16829947</ref>
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| its usage has been recommended against by the UK's [[National Institute for Clinical Excellence]].<ref name="NICE Guidelines"> NICE technology appraisal [http://guidance.nice.org.uk/TA111 guidance 111] Donepezil, galantamine, rivastigmine (review) and memantine for the treatment of Alzheimer’s disease </ref>
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| Memantine has been associated with a moderate decrease in clinical deterioration in Alzheimer's disease.<ref name="AMH2006" /> A systematic review of [[randomised controlled trial]]s 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.<ref name="Areosa2005">Areosa SA, Sherriff F, McShane R. Memantine for dementia. [[Cochrane Collaboration|Cochrane Database Syst Rev]] 2005;(3):CD003154. PMID 16034889</ref>
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| Memantine is also being tested for [[Opioid dependency|Opioid dependence]], [[systemic lupus erythematosus]], [[clinical depression|depression]], [[obsessive compulsive disorder]], [[glaucoma]], [[tinnitus]], [[neuropathy|neuropathic pain]], and [[pervasive developmental disorder]]s.
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| ===Adverse drug reactions===
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| Memantine is generally well-tolerated.<ref name="Areosa2005" /> Common [[adverse drug reaction]]s (≥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]].<ref name="BNF47">Joint Formulary Committee. [[British National Formulary]]. 47th ed. London: British Medical Association and the Royal Pharmaceutical Society of Great Britain; 2004. ISBN 0-85369-584-9</ref><ref name="AMH2006">Rossi S, editor. [[Australian Medicines Handbook]] 2006. Adelaide: Australian Medicines Handbook; 2006.</ref>
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| ==See also==
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| *[[Alzheimer's disease]]
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| *[[Donepezil]]
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| *[[Galantamine]]
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| *[[Rivastigmine]]
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| ==References==
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| {{reflist|2}}
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| {{Anti-dementia drugs}}
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| {{Dissociative_hallucinogens}}
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| [[Category:Antidementia agents]]
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| [[Category:NMDA receptor antagonists]]
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| [[Category:Drugs]]
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| [[Category:Psychiatry]]
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| [[Category:Neurology]]
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