Amantadine, sold under the brand name Gocovri among others, is a
medication
A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy (pharmacotherapy) is an important part of the medical field and re ...
used to treat
dyskinesia
Dyskinesia refers to a category of movement disorders that are characterized by involuntary muscle movements, including movements similar to tics or chorea and diminished voluntary movements. Dyskinesia can be anything from a slight tremor of t ...
associated with
parkinsonism
Parkinsonism is a clinical syndrome characterized by tremor, bradykinesia (slowed movements), rigidity, and postural instability. These are the four motor symptoms found in Parkinson's disease (PD), after which it is named, dementia with Lewy bo ...
and
influenza caused by type A influenzavirus, though its use for the latter is no longer recommended due to widespread
drug resistance
Drug resistance is the reduction in effectiveness of a medication such as an antimicrobial or an antineoplastic in treating a disease or condition. The term is used in the context of resistance that pathogens or cancers have "acquired", that is, ...
.
It acts as a
nicotinic antagonist
A nicotinic antagonist is a type of anticholinergic drug that inhibits the action of acetylcholine (ACh) at nicotinic acetylcholine receptors. These compounds are mainly used for peripheral muscle paralysis in surgery, the classical agent of this t ...
,
dopamine agonist
A dopamine agonist (DA) is a compound that activates dopamine receptors. There are two families of dopamine receptors, D2-like and D1-like, and they are all G protein-coupled receptors. D1- and D5-receptors belong to the D1-like family and the ...
, and noncompetitive
NMDA antagonist
NMDA receptor antagonists are a class of drugs that work to antagonize, or inhibit the action of, the ''N''-Methyl-D-aspartate receptor (NMDAR). They are commonly used as anesthetics for animals and humans; the state of anesthesia they induce ...
.
The antiviral
mechanism of action
In pharmacology, the term mechanism of action (MOA) refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect. A mechanism of action usually includes mention of the specific molecular targe ...
is antagonism of the influenzavirus A
M2 proton channel
The Matrix-2 (M2) protein is a proton-selective viroporin, integral in the viral envelope of the influenza A virus. The channel itself is a homotetramer (consists of four identical M2 units), where the units are helices stabilized by two disulfide ...
, which prevents endosomal escape (i.e. the release of viral genetic material into the host cytoplasm).
Amantadine was first used for the treatment of
influenza A
'' A virus'' (''IAV'') causes influenza in birds and some mammals, and is the only species of the genus ''Alphainfluenzavirus'' of the virus family '' Orthomyxoviridae''. Strains of all subtypes of influenza A virus have been isolated from wi ...
. After antiviral properties were initially reported in 1963, amantadine received approval for
prophylaxis
Preventive healthcare, or prophylaxis, consists of measures taken for the purposes of disease prevention.Hugh R. Leavell and E. Gurney Clark as "the science and art of preventing disease, prolonging life, and promoting physical and mental hea ...
against the influenza virus A in 1976.
However, amantadine-resistant influenza viruses were first reported during the 1980 influenza A epidemic and resistance frequency continued to rise into the early 2000s. Currently, amantadine is no longer recommended for the treatment of influenza A due to a high level of amantadine resistance among circulating influenza A viruses.
In 1973, the
Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
(FDA) approved amantadine for use in the treatment of
Parkinson's disease
Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...
. In 2017, the extended release formulation was approved for use in the treatment of levodopa-induced
dyskinesia
Dyskinesia refers to a category of movement disorders that are characterized by involuntary muscle movements, including movements similar to tics or chorea and diminished voluntary movements. Dyskinesia can be anything from a slight tremor of t ...
.
Off-label use
Off-label use is the use of pharmaceutical drugs for an unapproved indication (medicine), indication or in an unapproved age group, dose (biochemistry), dosage, or route of administration. Both prescription drugs and over-the-counter drugs (OTCs) ...
s include improvement of
fatigue
Fatigue describes a state of tiredness that does not resolve with rest or sleep. In general usage, fatigue is synonymous with extreme tiredness or exhaustion that normally follows prolonged physical or mental activity. When it does not resolve ...
in
multiple sclerosis
Multiple (cerebral) sclerosis (MS), also known as encephalomyelitis disseminata or disseminated sclerosis, is the most common demyelinating disease, in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This d ...
and accelerating the rate of functional recovery and arousal following a
brain injury
An injury is any physiological damage to living tissue caused by immediate physical stress. An injury can occur intentionally or unintentionally and may be caused by blunt trauma, penetrating trauma, burning, toxic exposure, asphyxiation, or o ...
.
Amantadine has a mild side effect profile. Common neurological side effects include drowsiness, light headedness, dizziness, and confusion.
Due to its effects on the central nervous system, it should not be combined with additional
CNS stimulants or
anticholinergic
Anticholinergics (anticholinergic agents) are substances that block the action of the neurotransmitter called acetylcholine (ACh) at synapses in the central and peripheral nervous system.
These agents inhibit the parasympathetic nervous system ...
drugs. Amantadine is contraindicated in persons with
end stage kidney disease
Chronic kidney disease (CKD) is a type of kidney disease in which a gradual loss of kidney function occurs over a period of months to years. Initially generally no symptoms are seen, but later symptoms may include leg swelling, feeling tired, vo ...
, given that the drug is cleared by the kidneys.
It should also be taken with caution in those with enlarged prostates or
glaucoma
Glaucoma is a group of eye diseases that result in damage to the optic nerve (or retina) and cause vision loss. The most common type is open-angle (wide angle, chronic simple) glaucoma, in which the drainage angle for fluid within the eye rem ...
, due to its anticholinergic effects.
Live attenuated vaccines are contraindicated while taking amantadine, as it may limit the efficacy of the administered vaccine.
Chemical structure
Amantadine (brand names Gocovri, Symadine, and Symmetrel
) is the
organic compound
In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen or carbon-carbon bonds. Due to carbon's ability to catenate (form chains with other carbon atoms), millions of organic compounds are known. The ...
1-adamantylamine or 1-aminoadamantane, which consists of an
adamantane
Adamantane is an organic compound with a formula C10H16 or, more descriptively, (CH)4(CH2)6. Adamantane molecules can be described as the fusion of three cyclohexane rings. The molecule is both rigid and virtually stress-free. Adamantane is the m ...
backbone with an
amino
In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituent ...
group substituted at one of the four
methyne
In organic chemistry, a methine group or methine bridge is a trivalent functional group , derived formally from methane. It consists of a carbon atom bound by two single bonds and one double bond, where one of the single bonds is to a hydrogen. T ...
positions.
Rimantadine
Rimantadine ( INN, sold under the trade name 'Flumadine'') is an orally administered antiviral drug used to treat, and in rare cases prevent, influenzavirus A infection. When taken within one to two days of developing symptoms, rimantadine can s ...
is a closely related adamantane derivative with similar biological properties; both target the
M2 proton channel
The Matrix-2 (M2) protein is a proton-selective viroporin, integral in the viral envelope of the influenza A virus. The channel itself is a homotetramer (consists of four identical M2 units), where the units are helices stabilized by two disulfide ...
of
influenza A virus
''Influenza A virus'' (''IAV'') causes influenza in birds and some mammals, and is the only species of the genus ''Alphainfluenzavirus'' of the virus family ''Orthomyxoviridae''. Strain (biology)#Microbiology or virology, Strains of all subtypes ...
.
Mechanism of action
Parkinson's disease
The mechanism of its antiparkinsonian effect is poorly understood. Amantadine is 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
Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...
and
norepinephrine
Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad'', ...
from nerve endings. It appears to be an
anticholinergic
Anticholinergics (anticholinergic agents) are substances that block the action of the neurotransmitter called acetylcholine (ACh) at synapses in the central and peripheral nervous system.
These agents inhibit the parasympathetic nervous system ...
(specifically at
alpha-7 nicotinic receptor
The alpha-7 nicotinic receptor, also known as the α7 receptor, is a type of nicotinic acetylcholine receptor implicated in long-term memory, consisting entirely of α7 subunits.Pharmacology, (Rang, Dale, Ritter & Moore, , 5th ed., Churchill Liv ...
s) like the similar pharmaceutical
memantine
Memantine is a medication used to slow the progression of moderate-to-severe Alzheimer's disease. It is taken by mouth.
Common side effects include headache, constipation, sleepiness, and dizziness. Severe side effects may include blood clots ...
.
In 2004, it was discovered that amantadine and memantine bind to and act as
agonist
An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...
s of the
σ1 receptor (K
i = 7.44 μM and 2.60 μM, respectively), and that activation of the σ
1 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
Rimantadine ( INN, sold under the trade name 'Flumadine'') is an orally administered antiviral drug used to treat, and in rare cases prevent, influenzavirus A infection. When taken within one to two days of developing symptoms, rimantadine can s ...
, and
bromantane
Bromantane, sold under the brand name Ladasten, is an atypical psychostimulant and anxiolytic drug of the adamantane family related to amantadine and memantine which is used in Russia in the treatment of neurasthenia. Although the effects of t ...
, and could explain the psychostimulant-like effects of this family of compounds.
Influenza
![Virus Replication](https://upload.wikimedia.org/wikipedia/commons/3/3a/Virus_Replication.svg)
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.
Amantadine and
rimantadine
Rimantadine ( INN, sold under the trade name 'Flumadine'') is an orally administered antiviral drug used to treat, and in rare cases prevent, influenzavirus A infection. When taken within one to two days of developing symptoms, rimantadine can s ...
function in a mechanistically identical fashion, entering the barrel of the tetrameric M
2 channel and blocking pore function—i.e., proton translocation.
Resistance to the drug class is a consequence of mutations to the pore-lining
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
residues of the channel, preventing both amantadine and rimantadine from binding and inhibiting the channel in their usual way.
Pharmacokinetics
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, there is a greater risk for toxicity.
Half-life elimination averages eight days in patients with
end-stage kidney disease
Chronic kidney disease (CKD) is a type of kidney disease in which a gradual loss of kidney function occurs over a period of months to years. Initially generally no symptoms are seen, but later symptoms may include leg swelling, feeling tired, vo ...
. Amantadine is only minimally removed by
hemodialysis
Hemodialysis, also spelled haemodialysis, or simply dialysis, is a process of purifying the blood of a person whose kidneys are not working normally. This type of dialysis achieves the extracorporeal removal of waste products such as creatinin ...
.
Amantadine is metabolized to a small extent (5-15%) by
acetylation
:
In organic chemistry, acetylation is an organic esterification reaction with acetic acid. It introduces an acetyl group into a chemical compound. Such compounds are termed ''acetate esters'' or simply '' acetates''. Deacetylation is the oppo ...
. It is mainly excreted (90%) unchanged in urine by
kidney
The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blood ...
excretion.
Medical uses
Parkinson's disease
Amantadine is used to treat
Parkinson's disease
Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...
-related
dyskinesia
Dyskinesia refers to a category of movement disorders that are characterized by involuntary muscle movements, including movements similar to tics or chorea and diminished voluntary movements. Dyskinesia can be anything from a slight tremor of t ...
and drug-induced
parkinsonism
Parkinsonism is a clinical syndrome characterized by tremor, bradykinesia (slowed movements), rigidity, and postural instability. These are the four motor symptoms found in Parkinson's disease (PD), after which it is named, dementia with Lewy bo ...
syndromes.
Amantadine may be used alone or in combination with another anti-Parkinson's or
anticholinergic
Anticholinergics (anticholinergic agents) are substances that block the action of the neurotransmitter called acetylcholine (ACh) at synapses in the central and peripheral nervous system.
These agents inhibit the parasympathetic nervous system ...
drug.
The specific symptoms targeted by amantadine therapy are dyskinesia and rigidity.
[ The ]extended release
Modified-release dosage is a mechanism that (in contrast to immediate-release dosage) delivers a drug with a delay after its administration (delayed-release dosage) or for a prolonged period of time (extended-release R, XR, XLdosage) or to a sp ...
amantadine formulation is commonly used to treat dyskinesias in people receiving levodopa
-DOPA, also known as levodopa and -3,4-dihydroxyphenylalanine, is an amino acid that is made and used as part of the normal biology of some plants and animals, including humans. Humans, as well as a portion of the other animals that utilize -DOPA ...
therapy for Parkinson's disease.[ A 2003 ]Cochrane review
Cochrane (previously known as the Cochrane Collaboration) is a British international charitable organisation formed to organise medical research findings to facilitate evidence-based choices about health interventions involving health professi ...
had concluded there was insufficient evidence to prove the safety or efficacy of amantadine to treat dyskinesia.
In 2008, the World Health Organization
The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. The WHO Constitution states its main objective as "the attainment by all peoples of the highest possible level of h ...
reported amantadine is not effective as a stand-alone parkinsonian therapy, but recommended it could be used in combination therapy with levodopa.
Influenza A
Amantadine is not recommended for treatment or prophylaxis
Preventive healthcare, or prophylaxis, consists of measures taken for the purposes of disease prevention.Hugh R. Leavell and E. Gurney Clark as "the science and art of preventing disease, prolonging life, and promoting physical and mental hea ...
of influenza A
'' A virus'' (''IAV'') causes influenza in birds and some mammals, and is the only species of the genus ''Alphainfluenzavirus'' of the virus family '' Orthomyxoviridae''. Strains of all subtypes of influenza A virus have been isolated from wi ...
in the United States. Amantadine has no effect preventing or treating influenza B
''Influenza B virus'' is the Monotypic taxon, only species in the genus ''Betainfluenzavirus'' in the virus family ''Orthomyxoviridae''.
Influenza B virus is known only to infect humans and Pinniped, seals. This limited host range is apparently ...
infections. The US Centers for Disease Control and Prevention
The Centers for Disease Control and Prevention (CDC) is the national public health agency of the United States. It is a United States federal agency, under the Department of Health and Human Services, and is headquartered in Atlanta, Georgi ...
found 100% of seasonal H3N2
Influenza A virus subtype H3N2 (A/H3N2) is a subtype of viruses that causes influenza (flu). H3N2 viruses can infect birds and mammals. In birds, humans, and pigs, the virus has mutated into many strains. In years in which H3N2 is the predomina ...
and 2009 pandemic
A pandemic () is an epidemic of an infectious disease that has spread across a large region, for instance multiple continents or worldwide, affecting a substantial number of individuals. A widespread endemic (epidemiology), endemic disease wi ...
flu samples were resistant to adamantanes (amantadine and rimantadine) during the 2008–2009 flu season.
The U.S. Centers for Disease Control and Prevention
The Centers for Disease Control and Prevention (CDC) is the national public health agency of the United States. It is a United States federal agency, under the Department of Health and Human Services, and is headquartered in Atlanta, Georgi ...
(CDC) guidelines recommend only neuraminidase inhibitors for influenza treatment and prophylaxis. The CDC recommends against amantadine and rimantadine to treat influenza A infections.
Similarly, the 2011 World Health Organization (WHO) virology report showed all tested H1N1 influenza A viruses were resistant to amantadine. 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.
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 levodopa-induced dyskinesia in patients with Parkinson's disease. The WHO recommends the use of amantadine as a combination therapy to reduce levodopa side effects.
Off-label uses
Fatigue in multiple sclerosis
Amantadine, along with modafinil
Modafinil, sold under the brand name Provigil among others, is a central nervous system (CNS) stimulant medication used to treat sleepiness due to narcolepsy, shift work sleep disorder, and obstructive sleep apnea. While it has seen off-label ...
and methylphenidate
Methylphenidate, sold under the brand names Ritalin and Concerta among others, is the most widely prescribed central nervous system (CNS) stimulant medication used to treat attention deficit hyperactivity disorder (ADHD) and, to a lesser extent, ...
, are the most commonly used medications for the treatment of multiple sclerosis
Multiple (cerebral) sclerosis (MS), also known as encephalomyelitis disseminata or disseminated sclerosis, is the most common demyelinating disease, in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This d ...
(MS) related fatigue in clinical practice. A 2007 Cochrane literature review concluded that there was no overall evidence supporting the use of amantadine in treating fatigue in patients with MS. A follow up 2012 Cochrane review stated that there may be some amantadine-induced improvement in fatigue in some people with MS. Despite multiple control trials that have also demonstrated improvements in subjective and objective ratings of fatigue, there is no final conclusion regarding its effectiveness.
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, GMSS guidelines strongly recommend the use of amantadine in MS-related fatigue.
In the UK NICE recommends considering amantadine for MS fatigue.
Awareness in patients with disorders of consciousness
Disorders of consciousness
Disorders of consciousness are medical conditions that inhibit consciousness. Some define disorders of consciousness as any change from complete self-awareness to inhibited or absent self-awareness and arousal. This category generally includes min ...
(DoC) include coma
A coma is a deep state of prolonged unconsciousness in which a person cannot be awakened, fails to respond normally to painful stimuli, light, or sound, lacks a normal wake-sleep cycle and does not initiate voluntary actions. Coma patients exhi ...
, vegetative state
A persistent vegetative state (PVS) or post-coma unresponsiveness (PCU) is a disorder of consciousness in which patients with severe brain damage are in a state of partial arousal rather than true awareness. After four weeks in a vegetative stat ...
(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. In traumatic brain injury
A traumatic brain injury (TBI), also known as an intracranial injury, is an injury to the brain caused by an external force. TBI can be classified based on severity (ranging from mild traumatic brain injury TBI/concussionto severe traumatic b ...
patients in the intensive care unit
220px, Intensive care unit
An intensive care unit (ICU), also known as an intensive therapy unit or intensive treatment unit (ITU) or critical care unit (CCU), is a special department of a hospital or health care facility that provides intensiv ...
, 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. There are also reports of significantly improved consciousness in patients treated for non-traumatic cases of DoC, such as in the case of a subarachnoid hemorrhage
Subarachnoid hemorrhage (SAH) is bleeding into the subarachnoid space—the area between the arachnoid membrane and the pia mater surrounding the brain. Symptoms may include a severe headache of rapid onset, vomiting, decreased level of consci ...
, cerebral hemorrhage
Intracerebral hemorrhage (ICH), also known as cerebral bleed, intraparenchymal bleed, and hemorrhagic stroke, or haemorrhagic stroke, is a sudden bleeding into the tissues of the brain, into its ventricles, or into both. It is one kind of bleed ...
, and hypoxic encephalopathy. In 2018 the American Academy of Neurology
The American Academy of Neurology (AAN) is a professional society representing over 38,000 neurologists and neuroscientists. As a medical specialty society it was established in 1948 by A.B. Baker of the University of Minnesota to advance the ar ...
(AAN) updated treatment guidelines on the use of amantadine for patients with prolonged DoC, recommending the use of amantadine (100–200 mg bid) for adults with DoC 4–16 weeks post injury to support early functional recovery and reduce disability.
Neuroplasticity and overall functional recovery in patients with brain injury
In various studies, amantadine and memantine
Memantine is a medication used to slow the progression of moderate-to-severe Alzheimer's disease. It is taken by mouth.
Common side effects include headache, constipation, sleepiness, and dizziness. Severe side effects may include blood clots ...
have been shown to accelerate the rate of recovery from a brain injury. The time-limited window following a brain injury is characterized by neuroplasticity
Neuroplasticity, also known as neural plasticity, or brain plasticity, is the ability of Neural circuit, neural networks in the brain to change through growth and reorganization. It is when the brain is rewired to function in some way that diffe ...
, or the capacity of neuron
A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. N ...
s in the brain to adapt and compensate after injury. Thus, physiatrists will often start patients on amantadine as soon as impairments are recognized. There are also case reports showing improved functional recovery with amantadine treatment occurring years after the initial brain injury. There is insufficient evidence to determine if the functional gains are a result of effects through the dopamine
Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...
or norepinephrine
Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad'', ...
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 as methylphenidate
Methylphenidate, sold under the brand names Ritalin and Concerta among others, is the most widely prescribed central nervous system (CNS) stimulant medication used to treat attention deficit hyperactivity disorder (ADHD) and, to a lesser extent, ...
. It is unclear if treatment with amantadine improves long-term outcomes or simply accelerates recovery. Nonetheless, amantadine-induced acceleration of recovery reduces the burden of disability, lessens health care costs, and minimizes psychosocial
The psychosocial approach looks at individuals in the context of the combined influence that psychological factors and the surrounding social environment have on their physical and mental wellness and their ability to function. This approach is ...
stressors in patients.
Attention deficit hyperactivity disorder
A 2010 randomized clinical trial showed similar improvements in ADHD
Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by excessive amounts of inattention, hyperactivity, and impulsivity that are pervasive, impairing in multiple contexts, and otherwise age-inapp ...
symptoms in children treated with amantadine as in those treated with methylphenidate
Methylphenidate, sold under the brand names Ritalin and Concerta among others, is the most widely prescribed central nervous system (CNS) stimulant medication used to treat attention deficit hyperactivity disorder (ADHD) and, to a lesser extent, ...
, with less frequent side effects. A 2021 retrospective study showed 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-generation antipsychotics.
Adverse effects
Amantadine is generally well tolerated and has a mild side-effect profile.
Neurological
Side effects include drowsiness (especially while driving), lightheadedness, falls, and dizziness. Patients on amantadine should avoid combination with other central nervous system
The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all par ...
(CNS) depressing agents, such as alcohol. Excessive alcohol usage may increase the potential for CNS effects such as dizziness, confusion, and light headedness.
Rare severe adverse effects include neuroleptic malignant syndrome
Neuroleptic malignant syndrome (NMS) is a rare but life-threatening reaction that can occur in response to neuroleptic or antipsychotic medication. Symptoms include high fever, confusion, rigid muscles, variable blood pressure, sweating, and fas ...
, depression, convulsions, psychosis
Psychosis is a condition of the mind that results in difficulties determining what is real and what is not real. Symptoms may include delusions and hallucinations, among other features. Additional symptoms are incoherent speech and behavior ...
, and suicidal ideation. It has also been associated with disinhibited actions (gambling, sexual activity, spending, other addictions) and diminished control over compulsions.
Cardiovascular
Amantadine may cause orthostatic hypotension, syncope, and peripheral edema.
Gastrointestinal
Amantadine has also been associated with dry mouth and constipation.
Skin
Rare cases of skin rashes, such as Stevens–Johnson syndrome
Stevens–Johnson syndrome (SJS) is a type of severe skin reaction. Together with toxic epidermal necrolysis (TEN) and Stevens–Johnson/toxic epidermal necrolysis (SJS/TEN), it forms a spectrum of disease, with SJS being less severe. Erythema ...
and livedo reticularis
Livedo reticularis is a common skin finding consisting of a mottled reticulated vascular pattern that appears as a lace-like purplish discoloration of the skin. The discoloration is caused by reduction in blood flow through the arterioles that supp ...
have also been reported in patients treated with amantadine.
Pregnancy and lactation
Amantadine is Food and Drug Administration category C for pregnancy. Teratogenic
Teratology is the study of abnormalities of physiological development in organisms during their life span. It is a sub-discipline in medical genetics which focuses on the classification of congenital abnormalities in dysmorphology. The related t ...
effects have been observed in humans (case reports) and animal reproduction studies. Amantadine may also be present in breast milk
Breast milk (sometimes spelled as breastmilk) or mother's milk is milk produced by mammary glands located in the breast of a human female. Breast milk is the primary source of nutrition for newborns, containing fat, protein, carbohydrates ( lacto ...
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.
Interactions
Amantadine may affect 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. Thus, concurrent use of alcohol with Amantadine is not recommended due to enhanced CNS depressant effects. In addition, anti-dopaminergic drugs such as metoclopramide
Metoclopramide is a medication used for stomach and esophageal problems. It is commonly used to treat and prevent nausea and vomiting, to help with emptying of the stomach in people with delayed stomach emptying, and to help with gastroesoph ...
and typical anti-psychotics should be avoided. These interactions are likely related to opposing dopaminergic mechanisms of action, which inhibits amantadine's anti-Parkinson effects.
Contraindications
Amantadine is contraindicated
In medicine, a contraindication is a condition that serves as a reason not to take a certain medical treatment due to the harm that it would cause the patient. Contraindication is the opposite of indication, which is a reason to use a certain tre ...
in persons with end stage kidney disease
Chronic kidney disease (CKD) is a type of kidney disease in which a gradual loss of kidney function occurs over a period of months to years. Initially generally no symptoms are seen, but later symptoms may include leg swelling, feeling tired, vo ...
. The drug is renally cleared.
Amantadine may have anticholinergic
Anticholinergics (anticholinergic agents) are substances that block the action of the neurotransmitter called acetylcholine (ACh) at synapses in the central and peripheral nervous system.
These agents inhibit the parasympathetic nervous system ...
side effects. Thus, patients with an enlarged prostate or glaucoma
Glaucoma is a group of eye diseases that result in damage to the optic nerve (or retina) and cause vision loss. The most common type is open-angle (wide angle, chronic simple) glaucoma, in which the drainage angle for fluid within the eye rem ...
should use with caution.
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 U.S. Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
recommends avoiding amantadine for two weeks prior to vaccine administration and 48 hours afterward.
History
Influenza A
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 that received amantadine (100 milligrams 18 hours before viral challenge) had less Asia influenza infections than the placebo
A placebo ( ) is a substance or treatment which is designed to have no therapeutic value. Common placebos include inert tablets (like sugar pills), inert injections (like Saline (medicine), saline), sham surgery, and other procedures.
In general ...
group. Amantadine received approval for the treatment of influenza virus A
'' A virus'' (''IAV'') causes influenza in birds and some mammals, and is the only species of the genus ''Alphainfluenzavirus'' of the virus family '' Orthomyxoviridae''. Strains of all subtypes of influenza A virus have been isolated from wi ...
in adults in 1976. It was first used in West Germany
West Germany is the colloquial term used to indicate the Federal Republic of Germany (FRG; german: Bundesrepublik Deutschland , BRD) between its formation on 23 May 1949 and the German reunification through the accession of East Germany on 3 O ...
in 1966. Amantadine was approved by the U.S. Food and Drug Administration in October 1968, as a prophylactic
Preventive healthcare, or prophylaxis, consists of measures taken for the purposes of disease prevention.Hugh R. Leavell and E. Gurney Clark as "the science and art of preventing disease, prolonging life, and promoting physical and mental hea ...
agent against Asian (H2N2) influenza and received approval for prophylactic use for influenza A in 1976.
During the 1980 influenza A epidemic, the first amantadine-resistance influenza viruses were reported. The frequency of amantadine resistance among influenza A (H3N2
Influenza A virus subtype H3N2 (A/H3N2) is a subtype of viruses that causes influenza (flu). H3N2 viruses can infect birds and mammals. In birds, humans, and pigs, the virus has mutated into many strains. In years in which H3N2 is the predomina ...
) 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% of H1N1
In virology, influenza A virus subtype H1N1 (A/H1N1) is a subtype of influenza A virus. Major outbreaks of H1N1 strains in humans include the Spanish flu, the 1977 Russian flu pandemic and the 2009 swine flu pandemic. It is an orthomyxovirus ...
were amantadine-resistant. A majority of the amantadine-resistant H3N2 isolates (98.2%) were found to contain an S31N mutation in the M2 transmembrane domain that confers resistance to amantadine. Currently, adamantane
Adamantane is an organic compound with a formula C10H16 or, more descriptively, (CH)4(CH2)6. Adamantane molecules can be described as the fusion of three cyclohexane rings. The molecule is both rigid and virtually stress-free. Adamantane is the m ...
resistance is high among circulating influenza A viruses. Thus, they are no longer recommended for treatment of influenza A.
Parkinson's disease
An incidental finding in 1969 prompted investigations about amantadine's effectiveness for treating symptoms of Parkinson's disease
Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...
. A woman with Parkinson's disease was prescribed amantadine to treat her influenza infection and reported her cogwheel rigidity and tremors improved. She also reported that her symptoms worsened after 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 Parkinson's disease and gave them amantadine. Seven of the ten patients showed improvement, which was convincing evidence for the need of a clinical trial, which included 163 patients with Parkinson's disease and 66% experienced subjective or objective reduction of symptoms with a maximum daily dose of 200 mg. Additional studies followed patients for greater lengths of time and in different combinations of neurological drugs. 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
-DOPA, also known as levodopa and -3,4-dihydroxyphenylalanine, is an amino acid that is made and used as part of the normal biology of some plants and animals, including humans. Humans, as well as a portion of the other animals that utilize -DOPA ...
or anti-cholinergic drugs. By April 1973, the U.S. Food and Drug Administration approved amantadine for use in the treatment of Parkinson's disease.
In 2017, the U.S. Food and Drug Administration approved the use of amantadine in an extended release formulation for the treatment of dyskinesia
Dyskinesia refers to a category of movement disorders that are characterized by involuntary muscle movements, including movements similar to tics or chorea and diminished voluntary movements. Dyskinesia can be anything from a slight tremor of t ...
, an adverse effect of levodopa
-DOPA, also known as levodopa and -3,4-dihydroxyphenylalanine, is an amino acid that is made and used as part of the normal biology of some plants and animals, including humans. Humans, as well as a portion of the other animals that utilize -DOPA ...
in people with Parkinson's disease.
Veterinary misuse
In 2005, Chinese poultry farmers were reported to have used amantadine to protect birds against avian influenza
Avian influenza, known informally as avian flu or bird flu, is a variety of influenza caused by viruses adapted to birds. . 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
Influenza A virus subtype H5N1 (A/H5N1) is a subtype of the influenza A virus which can cause illness in humans and many other animal species. A bird-adapted strain of H5N1, called HPAI A(H5N1) for highly pathogenic avian influenza virus of typ ...
) 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
Oseltamivir, sold under the brand name Tamiflu, is an antiviral medication used to treat and prevent influenza A and influenza B, viruses that cause the flu. Many medical organizations recommend it in people who have complications or are at hig ...
and zanamivir
Zanamivir is a medication used to treat and prevent influenza caused by influenza A and influenza B viruses. It is a neuraminidase inhibitor and was developed by the Australian biotech firm Biota Holdings. It was licensed to Glaxo in 1990 and ap ...
which block the action of viral neuraminidase
Viral neuraminidase is a type of neuraminidase found on the surface of influenza viruses that enables the virus to be released from the host cell. Neuraminidases are enzymes that cleave sialic acid (also called neuraminic acid) groups from ...
enzyme on the surface of influenza virus particles.[ However, there is an increasing incidence of oseltamivir resistance in circulating influenza strains (e.g., ]H1N1
In virology, influenza A virus subtype H1N1 (A/H1N1) is a subtype of influenza A virus. Major outbreaks of H1N1 strains in humans include the Spanish flu, the 1977 Russian flu pandemic and the 2009 swine flu pandemic. It is an orthomyxovirus ...
), highlighting the need for new anti-influenza therapies.
In September 2015, the U.S. Food and Drug Administration announced the recall of Dingo
The dingo (''Canis familiaris'', ''Canis familiaris dingo'', ''Canis dingo'', or ''Canis lupus dingo'') is an ancient (Basal (phylogenetics), basal) lineage of dog found in Australia (continent), Australia. Its taxonomic classification is de ...
Chip Twists "Chicken in the Middle" dog treats because the product has the potential to be contaminated with amantadine.
References
External links
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