|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)|
Amantadine treats parkinsonian dyskinesia as an muscarinic antagonist and acts as a noncompetitive NMDA antagonist. Amantadine was used as an antiviral drug used to treat and prevent influenza A infections. The antiviral mechanism of action is antagonism of the influenza A surface protein M2. M2 inhibition prevents viral shedding. Due to high levels of viral resistance to amantadine and other adamantanes, these drugs are no longer used against influenza A virus.
- 1 Chemical structure
- 2 Medical uses
- 3 Contraindications
- 4 Adverse effects
- 5 Mechanism of action
- 6 Drug to drug interactions
- 7 History
- 8 Veterinary misuse
- 9 See also
- 10 References
Amantadine (trade names Gocovri, Symadine, and Symmetrel) is the organic compound 1-adamantylamine or 1-aminoadamantane (an adamantane backbone with an amino group substituted at one of the four methyne positions). Rimantadine is a closely related derivative of adamantane with similar biological properties (both target the M2 surface protein of influenza A virus).
Amantadine is used to treat Parkinson's disease related dyskinesia 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 or prophylaxis 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 effects
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.
Fatigue in multiple sclerosis
Live attenuated vaccines are contraindicated while taking amantadine. It is possible that amantadine will inhibit viral replication and reduce the efficacy of administered vaccines. The FDA recommends avoiding live vaccination and amantadine for 2 weeks prior to vaccine administration or 48 hours afterwards.
Amantadine has been associated with several central nervous system (CNS) side effects. About 10% or more of patients may experience falls, dizziness, and hallucinations. Other side effects may include constipation or dry mouth.
Serious side effects may include drowsiness (especially while driving), suicidal thoughts, actions, or depression, new or worsened hallucinations, inhibited actions (gambling, sexual activity, spending, other addictions) and diminished control over compulsions, and light headedness, falls, and hypotension (low blood pressure).
Mechanism of action
This section relies too much on references to primary sources. (June 2014) (Learn how and when to remove this template message)
The mechanism of its antiparkinsonian effect is poorly understood. Amantadine appears to be a weak antagonist of the NMDA-type glutamate receptor, increases dopamine release, and blocks dopamine reuptake. Amantadine probably does not inhibit monoamine oxidase (MAO) enzyme. Moreover, the drug has many effects in the brain, including release of dopamine and norepinephrine from nerve endings. It appears to be an anticholinergic antagonist (specifically a nicotinic alpha-7) 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.
The mechanisms for amantadine's antiviral and antiparkinsonian effects are unrelated. Amantadine targets the influenza A M2 ion channel protein. The M2 protein's function is to allow the intracellular virus to replicate (M2 also functions as a proton channel for hydrogen ions to cross into the vesicle), and exocytose newly formed viral proteins to the extracellular space (viral shedding). By blocking the M2 channel, the virus is unable to replicate because of impaired replication, protein synthesis, and exocytosis.
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.
Drug to drug interactions
Amantadine may effect the central nervous system due to dopaminergic and anticholinergic properties. The mechanisms of action are not fully known. Because of the CNS effects, caution is required when prescribing additional CNS stimulants or anticholinergic drugs.
Amantadine was approved by the U.S. Food and Drug Administration in October 1966 as a prophylactic agent against Asian influenza. Amantadine trial experiments exposed volunteer college students to a viral challenge. The group that received amantadine (100 milligrams 18 hours before viral challenge) had less Asia influenza infections than the placebo group. Amantadine received approval for the treatment of influenza virus A in adults in 1976.
An incidental finding in 1969 prompted investigations about amantadine's effectiveness for treating symptoms of Parkinsons disease. A woman with Parkinsons was prescribed amantadine to treat her influenza infection and reported her cogwheel rigidity and tremors improved. Importantly,she also reported her symptoms worsened when she finished the course of amantadine. The published case report was not initially corroborated by any other instances by the medical literature or manufacturer data. A team of researchers looked at a group of ten patients with Parkinsons and gave them amantadine. Seven of the ten patients showed improvement, which was convincing evidence for the need of a clinical trial. The 1969 trial, lead author Robert S. Schwab, MD) included 163 Parkinsons patients and 66% experienced subjective or objective reduction of symptoms. Additional studies from Schwab's team followed patients for greater lengths of time and in different combinations of neurological drugs. The US FDA approved amantadine for use in the treatment of Parkinsons disease.
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.
- "SYMMETREL® (amantadine hydrochloride)" (PDF). TGA eBusiness Services. NOVARTIS Pharmaceuticals Australia Pty Limited. 29 June 2011. Retrieved 24 February 2014.
- Golan DE, Armstrong EJ, Armstrong AW (2017). Principles of pharmacology: the pathophysiologic basis of drug therapy (4th ed.). Philadelphia: Wolters Kluwer. pp. 142, 199, 205t, 224t, 608, 698–700. ISBN 9781451191004. OCLC 914593652.
- "Australian Product Information – Symmetrel (Amantadine Hydrochloride) Capsules". Australian Department of Health Therapeutic Goods Administration. Retrieved 13 July 2019.
- "Influenza Antiviral Medications: Summary for Clinicians | CDC". www.cdc.gov. 17 April 2019. Retrieved 14 July 2019.
- "WHO | Summary of influenza antiviral susceptibility surveillance findings, September 2010 - March 2011". WHO. Retrieved 19 July 2019.
- "Amantadine: MedlinePlus Drug Information". medlineplus.gov. Retrieved 22 July 2019.
- "Amantadine". www.drugbank.ca. Retrieved 13 July 2019.
- "Amantadine - an overview | ScienceDirect Topics". www.sciencedirect.com. Retrieved 13 July 2019.
- "Rimantadine hydrochloride (CHEBI:8865)". www.ebi.ac.uk. Retrieved 13 July 2019.
- Crosby NJ, Deane KH, Clarke CE, et al. (Cochrane Movement Disorders Group) (22 April 2003). "Amantadine for dyskinesia in Parkinson's disease". The Cochrane Database of Systematic Reviews (2): CD003467. doi:10.1002/14651858.CD003467. PMID 12804468.
- Stuart M, Kouimtzi M, Hill S (eds.). "World Health Organization Model Formulary 2008" (PDF). World Health Organization. Retrieved 19 July 2019.
- CDC weekly influenza report – week 35, cdc.gov
- Alves Galvão MG, Rocha Crispino Santos MA, Alves da Cunha AJ, et al. (Cochrane Acute Respiratory Infections Group) (November 2014). "Amantadine and rimantadine for influenza A in children and the elderly". The Cochrane Database of Systematic Reviews (11): CD002745. doi:10.1002/14651858.CD002745.pub4. PMID 25415374.
- "Highlights of Prescribing Information Gocovri (Amantadine)" (PDF). US FDA. August 2017. 4143492. Retrieved 14 July 2019.
- Braley TJ, Chervin RD (August 2010). "Fatigue in multiple sclerosis: mechanisms, evaluation, and treatment". Sleep. 33 (8): 1061–7. doi:10.1093/sleep/33.8.1061. PMC 2910465. PMID 20815187.
- "SYMMETREL® (Amantadine Hydrochloride, USP) fact sheet" (PDF). U.S. Food and Drug Administration Access Data. Retrieved 28 July 2019.
- "Symmetrel (Amantadine) Prescribing Information" (PDF). Endo Pharmaceuticals. May 2003. Retrieved 2 August 2007.
- Singhal KC, Rahman SZ (2002). "Stevens Johnson Syndrome Induced by Amantadine". Rational Drug Bulletin. 12 (1): 6.
- Cook PE, Dermer SW, McGurk T (November 1986). "Fatal overdose with amantadine". Canadian Journal of Psychiatry. 31 (8): 757–8. doi:10.1177/070674378603100814. PMID 3791133.
- Vollum DI, Parkes JD, Doyle D (June 1971). "Livedo reticularis during amantadine treatment". British Medical Journal. 2 (5762): 627–8. doi:10.1136/bmj.2.5762.627. PMC 1796527. PMID 5580722.
- "Amantadine - MeSH - NCBI".
- Jasek, W, ed. (2007). Austria-Codex (in German) (62nd ed.). Vienna: Österreichischer Apothekerverlag. p. 3962. ISBN 978-3-85200-181-4.
- Kornhuber J, Bormann J, Hübers M, Rusche K, Riederer P (April 1991). "Effects of the 1-amino-adamantanes at the MK-801-binding site of the NMDA-receptor-gated ion channel: a human postmortem brain study". European Journal of Pharmacology. 206 (4): 297–300. doi:10.1016/0922-4106(91)90113-v. PMID 1717296.
- Blanpied TA, Clarke RJ, Johnson JW (March 2005). "Amantadine inhibits NMDA receptors by accelerating channel closure during channel block". The Journal of Neuroscience. 25 (13): 3312–22. doi:10.1523/JNEUROSCI.4262-04.2005. PMID 15800186.
- Strömberg U, Svensson TH (November 1971). "Further studies on the mode of action of amantadine". Acta Pharmacologica et Toxicologica. 30 (3): 161–71. doi:10.1111/j.1600-0773.1971.tb00646.x. PMID 5171936.
- Peeters M, Romieu P, Maurice T, Su TP, Maloteaux JM, Hermans E (April 2004). "Involvement of the sigma 1 receptor in the modulation of dopaminergic transmission by amantadine". The European Journal of Neuroscience. 19 (8): 2212–20. doi:10.1111/j.0953-816X.2004.03297.x. PMID 15090047.
- Thomaston JL, Alfonso-Prieto M, Woldeyes RA, Fraser JS, Klein ML, Fiorin G, DeGrado WF (November 2015). "High-resolution structures of the M2 channel from influenza A virus reveal dynamic pathways for proton stabilization and transduction". Proceedings of the National Academy of Sciences of the United States of America. 112 (46): 14260–5. doi:10.1073/pnas.1518493112. PMC 4655559. PMID 26578770.
- PubChem. "Amantadine". pubchem.ncbi.nlm.nih.gov. Retrieved 29 July 2019.
- Okun, M. S.; Haider, M.; Hubsher, G. (3 April 2012). "Amantadine: The journey from fighting flu to treating Parkinson disease". Neurology. 78 (14): 1096–1099. doi:10.1212/WNL.0b013e31824e8f0d. ISSN 0028-3878. PMID 22474298.
- Hounshell DA, Kenly Smith J (1988). Science and Corporate Strategy: Du Pont R&D, 1902–1980. Cambridge University Press. p. 469. ISBN 9780521327671.
- "Sales of flu drug by du Pont unit a 'disappointment'". The New York Times. Wilmington, Delaware. 5 October 1982. Retrieved 19 May 2008.
- Maugh TH (November 1979). "Panel urges wide use of antiviral drug". Science. 206 (4422): 1058–60. doi:10.1126/science.386515. PMID 386515.
- Maugh TH (April 1976). "Amantadine: an alternative for prevention of influenza". Science. 192 (4235): 130–1. doi:10.1126/science.192.4235.130. PMID 17792438.
- Schwab, Robert S. (19 May 1969). "Amantadine in the Treatment of Parkinson's Disease". JAMA: The Journal of the American Medical Association. 208 (7): 1168. doi:10.1001/jama.1969.03160070046011. ISSN 0098-7484.
- Schwab, R. S. (13 November 1972). "Amantadine in Parkinson's disease. Review of more than two years' experience". JAMA: The Journal of the American Medical Association. 222 (7): 792–795. doi:10.1001/jama.222.7.792. ISSN 0098-7484.
- Bastings E. "NDA 208944 Approval Letter" (PDF).
- Sipress A (18 June 2005). "Bird Flu Drug Rendered Useless". Washington Post. pp. A01. Retrieved 2 August 2007.
- Kumar B, Asha K, Khanna M, Ronsard L, Meseko CA, Sanicas M (April 2018). "The emerging influenza virus threat: status and new prospects for its therapy and control". Archives of Virology. 163 (4): 831–844. doi:10.1007/s00705-018-3708-y. PMID 29322273.
- Aoki FY, Boivin G, Roberts N (2007). "Influenza virus susceptibility and resistance to oseltamivir". Antiviral Therapy. 12 (4 Pt B): 603–16. PMID 17944268.
- "Enforcement Report – Week of September 23, 2015". FDA.gov. US Food and Drug Administration, US Department of Health & Human Services.