|Metabolism||Minimal (mostly to acetyl metabolites)|
|Elimination half-life||10–31 hours|
|CompTox Dashboard (EPA)|
|Chemical and physical data|
|Molar mass||151.249 g/mol g·mol−1|
|3D model (JSmol)|
The antiviral mechanism of action is antagonism of influenza A surface protein M2. M2 inhibition prevents viral shedding. The drug treats parkinsonian tremors as an muscarinic antagonist and acts as a noncompetitive NMDA antagonist.
Amantadine (trade name Symmetrel in Australia ) is the organic compound 1-adamantylamine or 1-aminoadamantane (an adamantane backbone with an amino group substituted at one of the four methyne positions).
Amantadine is used to treat Parkinson's disease and drug-induced parkinsonism syndromes. Amantadine may be used alone or combined with another anti-parkison or anticholinergic drug. The specific symptoms targeted by amatadine therapy are dyskinesia and rigidity. Levodopa and amantadine is a common combination.
Amantadine is no longer recommended for treatment orprophylaxis of influenza A in the United States. Amantadine has no effect preventing or treating influenza B infections. The Centers for Disease Control found 100% of seasonal H3N2 and 2009 pandemic flu samples were resistant to adamantanes (amantadine and rimantidine) during the 2008-2009 flu season.
The CDC guidelines updated to recommend only neuraminidase inhibitors for influenza treatment and prophylaxis. The CDC currently recommends against amantadine and rimantadine to treat influenza A infections.
Similarly, the 2011 World Health Organization virology report showed all tested H1N1 influenza A viruses were resistant to amantadine.  Current WHO guidelines recommend against use of M2 inhibitors for influenza A. The continued high rate of resistance observed in laboratory testing of influenza A has reduced the priority of M2 resistance testing until further notice.
A 2014 Cochrane review did not find evidence for efficacy or safety of amantadine used for the prevention or treatment of influenza A.
Extra-pyramidal Side EffectsEdit
An extended release formulation is used to treat dyskinesia, a side effect of levodopa which is taken by people who have Parkinsons. WHO recommendations are currently for amantadine as a combination therapy to reduce levadopa side effects.
Off Label UsesEdit
Fatigue in multiple sclerosisEdit
Amantadine has been associated with several central nervous system (CNS) side effects, likely due to amantadine's dopaminergic and adrenergic activity, and to a lesser extent, its activity as an anticholinergic. CNS side effects include nervousness, anxiety, agitation, insomnia, difficulty in concentrating, and exacerbations of pre-existing seizure disorders and psychiatric symptoms in patients with schizophrenia or Parkinson's disease. The usefulness of amantadine as an anti-parkinsonian drug is somewhat limited by the need to screen patients for a history of seizures and psychiatric symptoms.
Mechanism of actionEdit
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The mechanisms for amantadine's antiviral and antiparkinsonian effects are unrelated. The mechanism of amantadine's antiviral activity involves interference with the viral protein, M2, a proton channel. After entry of the virus into cells via endocytosis, it is localized in acidic vacuoles; the M2 channel functions in transporting protons with the gradient from the vacuolar space into the interior of the virion. Acidification of the interior results in disassociation of ribonucleoproteins, and the initiation of viral replication. Amantadine and rimantadine function in a mechanistically-identical fashion, entering the barrel of the tetrameric M2 channel and blocking pore function—i.e., proton translocation. Resistance to the drug class is a consequence of mutations to the pore-lining residues of the channel, preventing both amantadine and rimantadine from inhibiting the channel in their usual way.
Influenza B strains possess a structurally distinct M2 channel with channel-facing side chains that fully obstruct the channel vis-à-vis binding of adamantine-class channel inhibitors, while still allowing proton flow and channel function to occur; this constriction in the channels is responsible for the ineffectiveness of this drug and rimantadine towards all circulating Influenza B strains.
Amantadine is a weak antagonist of the NMDA-type glutamate receptor, increases dopamine release, and blocks dopamine reuptake. Amantadine probably does not inhibit MAO enzyme. Moreover, the mechanism of its antiparkinsonian effect is poorly understood. The drug has many effects in the brain, including release of dopamine and norepinephrine from nerve endings. It appears to be a weak NMDA receptor antagonist as well as an anticholinergic, specifically a nicotinic alpha-7 antagonist like the similar pharmaceutical memantine.
In 2004, it was discovered that amantadine and memantine bind to and act as agonists of the σ1 receptor (Ki = 7.44 µM and 2.60 µM, respectively), and that activation of the σ1 receptor is involved in the dopaminergic effects of amantadine at therapeutically relevant concentrations. These findings may also extend to the other adamantanes such as adapromine, rimantadine, and bromantane, and could explain the psychostimulant-like effects of this family of compounds.
Amantadine was approved by the U.S. Food and Drug Administration in October 1966 as a prophylactic agent against Asian influenza, and eventually received approval for the treatment of influenza virus A in adults. In 1969, the drug was also discovered by accident upon trying to help reduce symptoms of Parkinson's disease, drug-induced extrapyramidal syndromes, and akathisia.
In 2017, the U.S. Food and Drug Administration approved the use of amantadine in an extended release formulation developed by Adamas Pharma for the treatment of dyskinesia, an adverse effect of levodopa, that people with Parkinson's experience.
In 2005, Chinese poultry farmers were reported to have used amantadine to protect birds against avian influenza. In Western countries and according to international livestock regulations, amantadine is approved only for use in humans. Chickens in China have received an estimated 2.6 billion doses of amantadine. Avian flu (H5N1) strains in China and southeast Asia are now resistant to amantadine, although strains circulating elsewhere still seem to be sensitive. If amantadine-resistant strains of the virus spread, the drugs of choice in an avian flu outbreak will probably be restricted to neuraminidase inhibitors oseltamivir and zanamivir which block the action of viral neuraminidase enzyme on the surface of influenza virus particles. However, there is an increasing incidence of oseltamivir resistance in circulating influenza strains (e.g., H1N1), highlighting the serious need for the development of new anti-influenza therapies.
On September 23, 2015, the US Food and Drug Administration announced the recall of Dingo Chip Twists "Chicken in the Middle" dog treats because the product has the potential to be contaminated with amantadine.
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