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| Trade names | Gocovri, Symadine, Symmetrel, others |
| Other names | 1-Adamantylamine; 1-Adamantanamine; 1-Aminoadamantane; Midantane; Midantan |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a682064 |
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| Routes of administration | By mouth |
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| Pharmacokinetic data | |
| Bioavailability | 86–90%[1] |
| Protein binding | 67%[1] |
| Metabolism | Minimal (mostly to acetyl metabolites)[1] |
| Eliminationhalf-life | 10–31 hours[1] |
| Excretion | Urine[1] |
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| ECHA InfoCard | 100.011.092 |
| Chemical and physical data | |
| Formula | C10H17N |
| Molar mass | 151.253 g·mol−1 |
| 3D model (JSmol) | |
| Melting point | 180 °C (356 °F)[6] |
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Amantadine, sold under the brand nameGocovri among others, is amedication used to treatdyskinesia associated withparkinsonism andinfluenza caused by type A influenzavirus, though its use for the latter is no longer recommended because of widespreaddrug resistance.[7][8] It is also used for a variety of other conditions. The drug is takenby mouth.
Amantadine has a mildside-effect profile. Common neurological side effects includedrowsiness,lightheadedness,dizziness, andconfusion.[9] Because of its effects on thecentral nervous system (CNS), it should be combined cautiously with additional CNSstimulants oranticholinergic drugs. Given that it iscleared by the kidneys, amantadine is contraindicated in persons withend-stage kidney disease.[5] Due to its anticholinergic effects, it should be taken with caution by those withenlarged prostates orglaucoma.[10]
Thepharmacology of amantadine is complex.[11][12] It acts as asigma σ1 receptoragonist,nicotinic acetylcholine receptor negative allosteric modulator,dopaminergic agent, and weakNMDA receptor antagonist, among other actions.[11][12] The precisemechanism of action of its therapeutic effects in the treatment of CNS disorders is unclear.[11][12] Theantiviral mechanism of action is inhibition of the influenza virus AM2 proton channel, which prevents endosomal escape (i.e., the release of viral genetic material into the host cytoplasm).[13][14] Amantadine is anadamantanederivative and is related tomemantine andrimantadine.[15]
Amantadine was first used for the treatment ofinfluenza A.[11] After its antiviral properties were initially reported in 1963, amantadine received approval forprophylaxis against the influenza virus A in 1966.[11][16] In 1968, its antiparkinsonian effects were serendipitously discovered.[11] In 1973, theFood and Drug Administration (FDA) approved amantadine for use in the treatment ofParkinson's disease.[11] In 2020, theextended-release formulation was approved for use in the treatment oflevodopa-induced dyskinesia.[11][17]
Amantadine was initially developed to prevent replication of the influenza A virus.[18] Its main clinical use today is treatment ofParkinson's disease.[18] Other uses include treatment of drug-inducedextrapyramidal side effects, motor fluctuations duringlevodopa therapy in Parkinson's disease,traumatic brain injury, andautistic spectrum disorders.[18]
Amantadine is used to treat Parkinson's disease-relateddyskinesia and drug-induced parkinsonism syndromes.[19] Amantadine may be used alone or in combination with another anti-Parkinson's oranticholinergic drug.[20] The specific symptoms targeted by amantadine therapy are dyskinesia and rigidity.[19] Theextended release amantadine formulation is commonly used to treat dyskinesias in people receivinglevodopa therapy for Parkinson's disease.[19] A 2003Cochrane review had concluded evidence was insufficient to prove the safety or efficacy of amantadine to treat dyskinesia.[21]
In 2008, theWorld Health Organization (WHO) reported amantadine is not effective as a stand-alone parkinsonian therapy, but recommended it could be used in combination therapy with levodopa.[22]
Amantadine is not recommended for treatment orprophylaxis of influenza A in the United States.[7] Amantadine has no effect preventing or treatinginfluenza B infections.[7] The USCenters for Disease Control and Prevention (CDC) found 100% of seasonalH3N2 and 2009pandemic flu samples were resistant to adamantanes (amantadine and rimantadine) during the 2008–2009 flu season.[20][23]
The U.S. CDC guidelines recommend onlyneuraminidase inhibitors for influenza treatment and prophylaxis.[medical citation needed] The CDC recommends against amantadine and rimantadine to treat influenza A infections.[7]
Similarly, the 2011 WHO virology report showed all tested H1N1 influenza A viruses were resistant to amantadine.[8] WHO guidelines recommend against use of M2 inhibitors for influenza A.[medical citation needed] The continued high rate of resistance observed in laboratory testing of influenza A has reduced the priority of M2 resistance testing.[medical citation needed]
A 2014 Cochrane review did not find evidence for efficacy or safety of amantadine used for the prevention or treatment of influenza A.[24]
An extended-releaseformulation of amantadine is used to treatlevodopa-induced dyskinesia in patients with Parkinson's disease.[4] The WHO recommends the use of amantadine as a combination therapy to reduce levodopa side effects.[22]
A 2007 Cochrane literature review concluded that no overall evidence supports the use of amantadine in treating fatigue in patients with multiple sclerosis (MS).[25] A follow-up 2012 Cochrane review stated that some amantadine-induced improvement in fatigue may occur in some people with MS.[26] Despite multiple control trials that have also demonstrated improvements in subjective and objective ratings of fatigue, no final conclusion has been drawn regarding its effectiveness.[27]
Consensus guidelines from the German Multiple Sclerosis Society (GMSS) in 2006 state that amantadine produces moderate improvement in subjective fatigue, problem solving, memory, and concentration. Thus, in 2006, GMSS guidelines recommended the use of amantadine in MS-related fatigue.[28]
In the UK, NICE recommends considering amantadine for MS fatigue.[29]
Disorders of consciousness (DoC) includecoma,vegetative state (VS), and minimally conscious state (MCS). Amantadine has been shown to increase the rate of emergence from a MCS, defined by consistent demonstration of interactive communication and functional objective use. Intraumatic brain injury patients in theintensive care unit, amantadine has also been shown in various randomized control trials to increase the rate of functional recovery and arousal, particularly in the time period immediately following an injury.[30] Also, significantly improved consciousness has been reported in patients treated for nontraumatic cases of DoC, such as in the case of asubarachnoid hemorrhage,cerebral hemorrhage, andhypoxic encephalopathy.[31] In 2018, theAmerican Academy of Neurology updated treatment guidelines on the use of amantadine for patients with prolonged DoC, recommending the use of amantadine (100–200 mg b.i.d.) for adults with DoC 4 to 16 weeks after injury to support early functional recovery and reduce disability.[32]
In various studies, amantadine andmemantine have been shown to accelerate the rate of recovery from a brain injury.[33][34] The time-limited window following a brain injury is characterized byneuroplasticity, or the capacity ofneurons in the brain to adapt and compensate after injury. Thus,physiatrists often start patients on amantadine as soon as impairments are recognized. Some case reports also show improved functional recovery with amantadine treatment occurring years after the initial brain injury.[30] Evidence is insufficient to determine if the functional gains are a result of effects through thedopamine ornorepinephrine pathways. Some patients may benefit from direct dopamine stimulation with amantadine, while others may benefit more from other stimulants that act more on the norepinephrine pathway, such asmethylphenidate.[30] If treatment with amantadine improves long-term outcomes or simply accelerates recovery is unclear.[33] Nonetheless, amantadine-induced acceleration of recovery reduces the burden of disability, lessens health-care costs, and minimizespsychosocial stressors in patients.[citation needed]
Amantadine is contraindicated in persons with end-stage kidney disease,[4] as the drug is renally cleared.[1][10][35]
Amantadine may haveanticholinergic side effects. Thus, patients with an enlarged prostate or glaucoma should use with caution.[9]
Live attenuated vaccines are contraindicated while taking amantadine.[4] Amantadine might inhibit viral replication and reduce the efficacy of administered vaccines. The U.S.Food and Drug Administration recommends avoiding amantadine for two weeks prior to vaccine administration and 48 hours afterward.[10]
Amantadine is generallywell tolerated and has a mild side effect profile.[36]
Side effects include drowsiness (especially while driving), lightheadedness, falls, and dizziness.[4] Patients on amantadine should avoid combination with other CNS-depressing agents, such as alcohol. Excessive alcohol usage may increase the potential for CNS effects such as dizziness, confusion, and light-headedness.[9]
Rare severe adverse effects includeneuroleptic malignant syndrome, depression, convulsions,psychosis, and suicidal ideation.[9] It has also been associated with disinhibited actions (gambling, sexual activity, spending, other addictions) and diminished control over compulsions.[4]
Amantadine may causeanxiety, feeling overexcited, hallucinations, and nightmares.[37]
Amantadine may cause orthostatic hypotension, syncope, and peripheral edema.[4]
Amantadine has also been associated with dry mouth and constipation.[4]
Rare cases of skin rashes, such asStevens–Johnson syndrome andlivedo reticularis have also been reported in patients treated with amantadine.[38][39]
Amantadine inhibits the kidney's active-transport removal and transfer of creatinine from blood to urine, which normally occurs in the proximal tubules of the nephrons. The active-transport removal mechanism accounts for about 15% of creatinine clearance, so amantadine may increase serum creatinine concentrations 15% above normal levels and give the false impression of mild kidney disease in patients whose kidneys are actually undamaged (because kidney function is often assessed by measuring the concentration of creatinine in blood.) Also, if the patient does have kidney disease, amantadine may cause it to appear as much as 15% worse than it actually is.[40]
Amantadine is USFDA category C for pregnancy.Teratogenic effects have been observed in humans (case reports) and animal reproduction studies. Amantadine may also be present inbreast milk and negatively alter breast milk production or excretion. The decision to breastfeed during amantadine therapy should consider the risk of infant exposure, the benefits of breastfeeding, and the benefits of the drug to the mother.[9]
Amantadine may affect the CNS because of its 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.[10] Thus, concurrent use of alcohol with amantadine is not recommended because of enhanced CNS depressant effects.[41] In addition, antidopaminergic drugs such asmetoclopramide andtypical antipsychotics should be avoided.[42][43] These interactions are likely related to opposing dopaminergic mechanisms of action, which inhibits amantadine's anti-Parkinson effects.[medical citation needed]
Themechanism of action of the antiparkinsonian effects of amantadine is poorly understood.[44] The effects of amantadine in Parkinson's disease were originally assumed to beanticholinergic ordopaminergic, but the situation soon proved more complicated than this.[11][12] Thepharmacodynamics of amantadine are complex, and it interacts with many differentbiological targets at a variety of concentrations and hencepotencies.[11][12]
The drug is a weakantagonist of the NMDA-type glutamate receptor,increases dopamine release, andblocks dopamine reuptake.[11][12][45][46][47] It is anegative allosteric modulator of thenicotinic acetylcholine receptors, specifically theα4β2 andα7 nicotinic acetylcholine receptors.[11]
In 1993, amantadine was found to bind to thesigma σ1 receptor with relatively highaffinity (Ki = 20.25 μM).[11][48] In 2004, it was discovered that amantadine and memantine bind to and act asagonists of thesigma σ1 receptor (Ki = 7.44 μM and 2.60 μM, respectively) and that activation of the σ1 receptor is potentially involved in the dopaminergic effects of amantadine at therapeutically relevant concentrations.[49] σ1 receptor activation is one of amantadine's more potent actions.[11][49] σ1 receptor agonists enhancetyrosine hydroxylase activity, modulateNMDA-stimulated dopamine release, increase dopamine release in thestriatumin vivo, and decrease dopaminereuptake.[11] As such, σ1 receptor activation may be involved in the antiparkinsonian and other central nervous system effects of amantadine.[11][49]
Binding of amantadine to the NMDA receptor was first reported in 1989, and antagonism of the receptor was first reported in 1991.[11] Despite some reports, the NMDA receptor antagonism of amantadine is probably not its primary mechanism of action.[11][12] It occurs at relatively high concentrations and many of the effects of amantadine are different from those of NMDA receptor antagonists.[11] Some of its effects, such as enhancement of dopamine release in the striatum, are even reversed by NMDA receptor antagonists,[11] but NMDA receptor antagonism could still contribute to the effects of amantadine.[11]
Although some publications have reported that amantadine inhibitsmonoamine oxidase, the drug probably does not actually inhibit thisenzyme.[11][12][50]
Amantadine showsamphetamine-likepsychostimulant effects (e.g.,stimulation of locomotor activity) in animals at sufficiently high doses.[12][51] It has been found toinhibit the reuptake of serotonin, norepinephrine, and dopamine and toinduce the release of serotonin, norepinephrine, and dopamine.[12][11][52][53] The concentrations needed for these effects, though, are very high and may not be therapeutically relevant.[12][11] It is about 1/25th to 1/50th as potent as amphetamines.[12] Amantadine has been found to increase dopamine levels in the striatum.[12][11] It does not act as amonoaminergic activity enhancer.[51][54][55]
Amantadine is aphosphodiesterase inhibitor, for example ofPDE1.[11]
Amantadine has been found to increasearomatic amino acid decarboxylaseexpression.[11] This enzyme is responsible for thesynthesis of dopamine fromL-DOPA.[11] An imaging study in humans found that amantadine increased AADC activity in the striatum by up to 27%.[11]
Various additional actions of amantadine have been described.[11]
The mechanisms for amantadine's antiviral and antiparkinsonian effects are unrelated.[1][10] 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), andexocytose 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.[57]
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.[20]
Resistance to the drug class is a consequence of mutations to the pore-liningamino acid residues of the channel, preventing both amantadine and rimantadine from binding and inhibiting the channel in their usual way.[58]
Amantadine is well-absorbed orally. The onset of action is usually within 48 hours when used for parkinsonian syndromes, including dyskinesia. As plasma concentrations of amantadine increase, the risk for toxicity increases.[59][60]
Half-life elimination averages eight days in patients with end-stage kidney disease. Amantadine is only minimally removed byhemodialysis.[60][61]
Amantadine is metabolized to a small extent (5–15%) byacetylation. It is mainly excreted (90%) unchanged in urine by kidney excretion.[59]
Amantadine is theorganic compound 1-adamantylamine or 1-aminoadamantane, which consists of anadamantane backbone with anamino group substituted at one of the fourtertiary carbons.[62]Rimantadine is a closely related adamantane derivative with similar biological properties;[63] both target theM2 proton channel ofinfluenza A virus.[20]
Amantadine (1-aminoadamantane) isstructurally related to other adamantanes includingadapromine (1-(adamantan-1-yl)propan-1-amine),bromantane (N-(4-bromophenyl)adamantan-2-amine),memantine (1-amino-3,5-dimethyladamantane), andrimantadine (1-(1-aminoethyl)adamantane), among others.[citation needed]
Antiviral properties were first reported in 1963 at the University of Illinois Hospital in Chicago. In this amantadine trial study, volunteer college students were exposed to a viral challenge. The group who received amantadine (100 milligrams 18 hours before viral challenge) had less Asia influenza infections than theplacebo group.[16] Amantadine received approval for the treatment ofinfluenza virus A[64][65][66][67] in adults in 1976.[16] It was first used inWest Germany in 1966. Amantadine was approved by the U.S. Food and Drug Administration in October 1968, as aprophylactic agent against Asian (H2N2) influenza and received approval for prophylactic use for influenza A in 1976.[16][5][68]
During the 1980 influenza A epidemic, the first amantadine-resistance influenza viruses were reported. The frequency of amantadine resistance among influenza A (H3N2) viruses from 1991 and 1995 was as low as 0.8%. In 2004, the resistance frequency increased to 12.3%. A year later, resistance increase significantly to 96%, 72%, and 14.5% in China, South Korea, and the United States, respectively. By 2006, 90.6% of H3N2 strains and 15.6% ofH1N1 were amantadine resistant. A majority of the amantadine-resistant H3N2 isolates (98.2%) was found to contain an S31N mutation in the M2 transmembrane domain that confers resistance to amantadine.[69] Currently,adamantane resistance is high among circulating influenza A viruses. Thus, they are no longer recommended for treatment of influenza A.[70]
An incidental finding in 1969 prompted investigations about amantadine's effectiveness for treating symptoms of Parkinson's disease.[16] A woman with Parkinson's disease was prescribed amantadine to treat her influenza infection and reported hercogwheel rigidity and tremors improved. She also reported that her symptoms worsened after she finished the course of amantadine.[16] 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 10 patients with Parkinson's disease and gave them amantadine. Seven of them showed improvement, which was convincing evidence for the need of a clinical trial, which included 163 patients with Parkinson's disease; 66% experienced subjective or objective reduction of symptoms with a maximum daily dose of 200 mg.[16][71] Additional studies followed patients for greater lengths of time and in different combinations of neurological drugs.[72] It was found to be a safe drug that could be used over long periods of time with few side effects as monotherapy or in combination with L-dopa or anticholinergic drugs.[16] By April 1973, the U.S. FDA approved amantadine for use in the treatment of Parkinson's disease.[10][16]
In 2017, the U.S. FDA approved the use of amantadine in an extended-release formulation for the treatment of dyskinesia, an adverse effect of levodopa in people with Parkinson's disease.[73][74]
Brand names of amantadine include Gocovri, Symadine, and Symmetrel.[75][1][76]
Recreational use of amantadine at supratherapeutic doses has been reported.[77] It is a weakNMDA receptor antagonist and is reported to producedissociative andphencyclidine-like effects in animals and humans at sufficiently high doses.[77][78][79] However, the very longduration of action of amantadine (>40 hours) has likely limited itsmisuse potential.[77] Recreational use of the related drugmemantine has similarly been reported.[77]
In 2005, Chinese poultry farmers were reported to have used amantadine to protect birds againstavian influenza.[80] 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.[80] 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 toneuraminidase inhibitorsoseltamivir andzanamivir, which block the action ofviral neuraminidase enzyme on the surface of influenza virus particles.[69] Increasing incidence of oseltamivir resistance in circulating influenza strains (e.g.,H1N1) exists, highlighting the need for new anti-influenza therapies.[81]
In September 2015, the U.S. FDA announced the recall ofDingo Chip Twists "Chicken in the Middle" dog treats because the product has the potential to be contaminated with amantadine.[82]
Interest in and study of amantadine in the treatment ofdepression has arisen.[12][83][18][11][84] A 2017systematic review ofoff-labelaugmentation for treatment ofunipolar depression found twoopen-label studies of amantadine for augmentingimipramine and found that it was effective.[85] However, thequality of evidence was very low and no conclusions could be drawn about its effectiveness.[85] A 2022 systematic review ofrandomized controlled trials of glutamatergic agents fortreatment-resistant depression identified oneclinical trial of amantadine for this use.[84] Amantadine was found to be effective in treating depressive symptoms in the trial.[84] The mechanism of action of amantadine in the treatment of depression is unclear, but various mechanisms have been postulated.[18][83] These includedopaminergic actions like indirect enhancement ofdopaminerelease,dopamine reuptake inhibition, andD2 receptor interactions,noradrenergic actions,glutamatergic actions such asNMDA receptor antagonism, andimmunomodulation, among many others.[18][83][12]
Amantadine has been studied in the treatment ofattention-deficit hyperactivity disorder (ADHD).[86] A 2010 randomized clinical trial showed similar improvements in ADHD symptoms in children treated with amantadine as in those treated withmethylphenidate, with less frequent side effects.[87] A 2021 retrospective study showed that amantadine may serve as an effective adjunct to stimulants for ADHD-related symptoms and appears to be a safer alternative to second- or third-generationantipsychotics.[88]
Amantadine has been studied in the treatment ofCOVID-19.[89][90]
