Memantine

Memantine is a medication used to treat moderate to severe Alzheimer's disease.[2][3] It is less preferred than acetylcholinesterase inhibitors such as donepezil.[3] Treatment should only be continued if beneficial effects are seen.[3] It is taken by mouth.[2]

Memantine
Clinical data
Trade namesAxura, Ebixa, Namenda, others[1]
AHFS/Drugs.comMonograph
MedlinePlusa604006
License data
Pregnancy
category
  • AU: B2
  • US: B (No risk in non-human studies)
    Routes of
    administration    		By mouth
    ATC code
    Legal status
    Legal status
    • AU: S4 (Prescription only)
    • UK: POM (Prescription only)
    • US: ℞-only
    Pharmacokinetic data
    Bioavailability~100%
    MetabolismLiver (<10%)
    Elimination half-life60–100 hours
    ExcretionKidney
    Identifiers
    CAS Number
    PubChem CID
    IUPHAR/BPS
    DrugBank
    ChemSpider
    UNII
    KEGG
    ChEMBL
    CompTox Dashboard (EPA)
    ECHA InfoCard100.217.937
    Chemical and physical data
    FormulaC12H21N
    Molar mass179.3 g/mol g·mol−1
    3D model (JSmol)
      (verify)

    Common side effects include headache, constipation, sleepiness, and dizziness.[2][3] Severe side effects may include blood clots, psychosis, and heart failure.[3] It is believed to work by blocking NMDA receptors.[2]

    Memantine was approved for medical use in the United States in 2003.[2] It is available as a generic medication.[3] A month supply in the United Kingdom costs the NHS about 1.60 GBP as of 2019.[3] In the United States the wholesale cost of this amount is about US$5.50.[4] In 2016 it was the 147th most prescribed medication in the United States with more than 4 million prescriptions.[5]

    Medical use

    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.[6][7] One guideline recommends memantine or an AChE inhibitor be considered in people in the early to mid stage of dementia.[8]

    Memantine has been associated with a modest improvement;[9] with small positive effects on cognition, mood, behavior, and the ability to perform daily activities in moderate to severe Alzheimer's disease.[10][11] There does not appear to be any benefit in mild disease.[12]

    While memantine can be used in combination with donepezil in those with dementia, the benefit of this is questionable and such dual use is not recommended by the National Institute of Clinical Excellence (NICE).[13] Memantine when added to donepezil in those with moderate to severe dementia resulted in "limited improvements" per a 2017 review.[14] Effects in autism are unclear.[15]

    Adverse effects

    Memantine is, in general, well-tolerated.[9] 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.[9][16]

    Like many other NMDA antagonists, memantine behaves as a dissociative anesthetic at supratherapeutic doses.[17] Despite isolated reports, recreational use of memantine is rare due to the drug's long duration and limited availability.[17] Also memantine seems to lack most of the psychoactive effects recreational users are usually looking for, such as euphoria or hallucinations.[18]

    Memantine appears to be generally well-tolerated by children with autism spectrum disorder.[19]

    Pharmacology

    Glutamate

    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.[20]

    Memantine is a low-affinity voltage-dependent uncompetitive antagonist at glutamatergic NMDA receptors.[21][22] By binding to the NMDA receptor with a higher affinity than Mg2+ ions, 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, preserves the function of the receptor at synapses, as it can still be activated by physiological release of glutamate following depolarization of the postsynaptic neuron.[23][24][25] 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 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.[24]

    Serotonin

    Memantine acts as a non-competitive antagonist at the 5-HT3 receptor, with a potency similar to that for the NMDA receptor.[26] Many 5-HT3 antagonists function as antiemetics, however the clinical significance of this serotonergic activity in the treatment of Alzheimer's disease is unknown.

    Cholinergic

    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. It can be noted that memantine is an antagonist at Alpha-7 nAChR, which may contribute to initial worsening of cognitive function during early memantine treatment. Alpha-7 nAChR upregulates quickly in response to antagonism, which could explain the cognitive-enhancing effects of chronic memantine treatment.[27][28] 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.[29]

    Dopamine

    Memantine acts as an agonist at the dopamine D2 receptor with equal or slightly higher affinity than to the NMDA receptors.[30]

    Sigmaergic

    It acts as an agonist at the σ1 receptor with a low Ki of 2.6 μM (2600 nM).[31] The consequences of this activity are unclear (as the role of sigma receptors in general is not yet that well understood). Due to this low affinity, therapeutic concentrations of memantine likely are too low to have any sigmaergic effect. However, excessive doses of memantine for recreational purposes may indeed activate this receptor.[32]

    History
    Main article: Discovery and development of memantine and related compounds

    Memantine was first synthesized and patented by Eli Lilly and Company in 1968 as an anti-diabetic agent, but it was ineffective at lowering blood sugar. Later it was discovered to have CNS activity, and was developed by Merz for dementia in Germany; the NMDA activity was discovered after trials had already begun. Memantine was first marketed for dementia in Germany in 1989 under the name Axura.[33]

    In the US, some CNS activities were discovered at Children's Hospital of Boston in 1990, and Children's licensed patents covering uses of memantine outside the field of ophthalmology to Neurobiological Technologies (NTI) in 1995.[34] In 1998 NTI amended its agreement with Children's to allow Merz to take over development.[35]

    In 2000 Merz partnered with Forest to develop the drug for Alzheimer's disease in the U.S. under the name Namenda.[33]

    In 2000 Merz partnered with Suntory for the Japanese market and with Lundbeck for other markets including Europe;[36] the drug was originally marketed by Lundbeck under the name Ebixa.[33]

    Sales of the drug reached $1.8 billion for 2014.[37] The cost of Namenda was $269 to $489 a month in 2012.[38]

    In February 2014 as the July 2015 patent expiration for memantine neared, Actavis, which had acquired Forest, announced that it was launching an extended release (XR) form of memantine that could be taken once a day instead of twice a day as needed with the then-current "immediate release" (IR) version, and that it intended to stop selling the IR version in August 2014 and withdraw the marketing authorization. This is a tactic to thwart generic competition called "product hopping". However the supply of the XR version ran short, so Actavis extended the deadline until the fall. In September 2014 the attorney general of New York, Eric Schneiderman, filed a lawsuit to compel Actavis to keep selling the IR version on the basis of antitrust law.[39][40]

    In December 2014, a judge granted New York State its request and issued an injunction, preventing Actavis from withdrawing the IR version until generic versions could launch. Actavis appealed and in May a panel of the Second Circuit Court of Appeals upheld the injunction, and in June Actavis asked that its case be heard by the full Second Circuit panel.[41][42] In August 2015 Actavis' request was denied.[43]

    Brand names

    As of August 2017 memantine was marketed under many brand names worldwide including Abixa, Adaxor, Admed, Akatinol, Alceba, Alios, Almenta, Alois, Alzant, Alzer, Alzia, Alzinex, Alzixa, Alzmenda, Alzmex, Axura, Biomentin, Carrier, Cogito, Cognomem, Conexine, Cordure, Dantex, Demantin, Demax, Dementa, Dementexa, Ebitex, Ebixa, Emantin, Emaxin, Esmirtal, Eutebrol, Evy, Ezemantis, Fentina, Korint, Lemix, Lindex, Lindex, Lucidex, Manotin, Mantine, Mantomed, Marbodin, Mardewel, Marixino, Maruxa, Maxiram, Melanda, Memabix, Memamed, Memando, Memantin, Memantina, Memantine, Mémantine, Memantinol, Memantyn, Memanvitae, Memanxa, Memanzaks, Memary, Memax, Memexa, Memigmin, Memikare, Memogen, Memolan, Memorel, Memorix, Memotec, Memox, Memxa, Mentikline, Mentium, Mentixa, Merandex, Merital, Mexia, Mimetix, Mirvedol, Modualz, Morysa, Namenda, Nemdatine, Nemdatine, Nemedan, Neumantine, Neuro-K, Neuroplus, Noojerone, Polmatine, Prilben, Pronervon, Ravemantine, Talentum, Timantila, Tingreks, Tonibral, Tormoro, Valcoxia, Vilimen, Vivimex, Witgen, Xapimant, Xapimant, Ymana, Zalatine, Zemertinex, Zenmem, Zenmen, and Zimerz.[1]

    It was also marketed in some countries as a combination drug with donepezil under the brands Namzaric, Neuroplus Dual, and Tonibral MD.[1]

    Research

    In ADHD evidence is not sufficient to make any conclusions.[44] It has also been studied in migraines.[45]

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    Further reading
    • Lipton SA (April 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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