Amantadine
Encyclopedia
Amantadine is the organic compound
known formally as 1-adamantylamine or 1-aminoadamantane. The molecule consists of adamantane
backbone that has an amino group substituted at one of the four methyne positions. This pharmaceutical is sold under the name Symmetrel for use both as an antiviral
and an antiparkinsonian drug. Rimantadine
is a closely related derivative of adamantane with similar biological properties.
Apart from medical uses, this compound is useful as a building block, allowing the insertion of an adamantyl group.
According to the US Centers for Disease Control and Prevention
, 100% of seasonal H3N2 and 2009 pandemic flu
samples tested have shown resistance to adamantanes, and amantadine is no longer recommended for treatment of influenza. Additionally, its effectiveness as an antiparkinsonian drug is controversial, with a 2003 Cochrane Review concluding that it was ineffective for this purpose.
in October 1966 as a prophylactic agent against Asian influenza and eventually received approval for the treatment of Influenzavirus A
in adults. In 1969, the drug was also discovered by accident to help reduce symptoms of Parkinson's disease
, drug-induced extrapyramidal
syndromes and akathisia
.
movements associated with long-term L-DOPA use, probably related to chronic pulsatile stimulation of dopamine
receptors).
Contrary to its continued use, a 2003 Cochrane review of the scientific literature concluded that there is inadequate evidence to support the use of amantadine for Parkinson's.
For the 2008/2009 flu season, the United States' Centers for Disease Control and Prevention
(CDC) found that 100% of seasonal H3N2 and 2009 pandemic flu samples tested have shown resistance to adamantanes. The CDC issued an alert to doctors to prescribe the neuraminidase inhibitor
s oseltamivir
and zanamivir instead of amantadine and rimantadine for treatment of current circulating flu.
often experienced by patients with multiple sclerosis
. Additionally, there have been anecdotal reports that low-dose amantadine has been successfully used to treat ADHD
. Limited data has shown that amantadine may help to relieve SSRI-induced sexual dysfunction.
(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.
Rare cases of severe skin rashes such as Stevens Johnson Syndrome and suicidal ideation
in patients treated with amantadine have also been reported.
Livedo reticularis is a possible side effect of amantadine use for Parkinson's disease
.
with bromine
or nitric acid
to give the bromide or nitroester at position one. Reaction of either compound with acetonitrile
affords the acetamide, which is hydrolyzed to give 1-adamantylamine:
The mechanisms for amantadine's antiviral and antiparkinsonian effects appear to be unrelated.
Amantadine appears to act through several pharmacological mechanisms, but no dominant mechanism of action has been identified. It is a dopaminergic, noradrenergic and serotonergic substance, blocks monoaminoxidase A and NMDA receptors, and seems to raise beta-endorphin/beta-lipotropin levels.
) 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 the scarcer and costlier oseltamivir
and zanamivir, which work by a different mechanism and are less likely to trigger resistance.
Organic compound
An organic compound is any member of a large class of gaseous, liquid, or solid chemical compounds whose molecules contain carbon. For historical reasons discussed below, a few types of carbon-containing compounds such as carbides, carbonates, simple oxides of carbon, and cyanides, as well as the...
known formally as 1-adamantylamine or 1-aminoadamantane. The molecule consists of adamantane
Adamantane
Adamantane is a colorless, crystalline chemical compound with a camphor-like odor. With a formula C10H16, it is a cycloalkane and also the simplest diamondoid. Adamantane molecules consist of three cyclohexane rings arranged in the "armchair" configuration. It is unique in that it is both rigid...
backbone that has an amino group substituted at one of the four methyne positions. This pharmaceutical is sold under the name Symmetrel for use both as an antiviral
Antiviral drug
Antiviral drugs are a class of medication used specifically for treating viral infections. Like antibiotics for bacteria, specific antivirals are used for specific viruses...
and an antiparkinsonian drug. Rimantadine
Rimantadine
Rimantadine 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 shorten the duration and moderate the severity of influenza. Both rimantadine and the similar drug...
is a closely related derivative of adamantane with similar biological properties.
Apart from medical uses, this compound is useful as a building block, allowing the insertion of an adamantyl group.
According to the US Centers for Disease Control and Prevention
Centers for Disease Control and Prevention
The Centers for Disease Control and Prevention are a United States federal agency under the Department of Health and Human Services headquartered in Druid Hills, unincorporated DeKalb County, Georgia, in Greater Atlanta...
, 100% of seasonal H3N2 and 2009 pandemic flu
2009 flu pandemic
The 2009 flu pandemic was an influenza pandemic, and the second of the two pandemics involving H1N1 influenza virus , albeit in a new version...
samples tested have shown resistance to adamantanes, and amantadine is no longer recommended for treatment of influenza. Additionally, its effectiveness as an antiparkinsonian drug is controversial, with a 2003 Cochrane Review concluding that it was ineffective for this purpose.
History
Amantadine was approved by the U.S. Food and Drug AdministrationFood and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
in October 1966 as a prophylactic agent against Asian influenza and eventually received approval for the treatment of Influenzavirus A
Influenzavirus A
Influenza A virus causes influenza in birds and some mammals and is the only species of Influenzavirus A. Influenzavirus A is a genus of the Orthomyxoviridae family of viruses. Strains of all subtypes of influenza A virus have been isolated from wild birds, although disease is uncommon...
in adults. In 1969, the drug was also discovered by accident to help reduce symptoms of Parkinson's disease
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
, drug-induced extrapyramidal
Extrapyramidal system
In human anatomy, the extrapyramidal system is a neural network located in the brain that is part of the motor system involved in the coordination of movement. The system is called "extrapyramidal" to distinguish it from the tracts of the motor cortex that reach their targets by traveling through...
syndromes and akathisia
Akathisia
Akathisia, or acathisia, is a syndrome characterized by unpleasant sensations of inner restlessness that manifests itself with an inability to sit still or remain motionless...
.
Parkinson
As an antiparkinsonian it can be used as monotherapy; or together with L-DOPA to treat L-DOPA-related motor fluctuations (i.e., shortening of L-DOPA duration of clinical effect, probably related to progressive neuronal loss) and L-DOPA-related dyskinesias (choreiformChorea (disease)
Choreia is an abnormal involuntary movement disorder, one of a group of neurological disorders called dyskinesias. The term choreia is derived from the Greek word χορεία , see choreia , as the quick movements of the feet or hands are vaguely comparable to dancing or piano playing.The term...
movements associated with long-term L-DOPA use, probably related to chronic pulsatile stimulation of dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
receptors).
Contrary to its continued use, a 2003 Cochrane review of the scientific literature concluded that there is inadequate evidence to support the use of amantadine for Parkinson's.
Influenza
Amantadine is no longer recommended for treatment of influenza B infection.For the 2008/2009 flu season, the United States' Centers for Disease Control and Prevention
Centers for Disease Control and Prevention
The Centers for Disease Control and Prevention are a United States federal agency under the Department of Health and Human Services headquartered in Druid Hills, unincorporated DeKalb County, Georgia, in Greater Atlanta...
(CDC) found that 100% of seasonal H3N2 and 2009 pandemic flu samples tested have shown resistance to adamantanes. The CDC issued an alert to doctors to prescribe the neuraminidase inhibitor
Neuraminidase inhibitor
Neuraminidase inhibitors are a class of antiviral drugs targeted at the influenza virus, which work by blocking the function of the viral neuraminidase protein, thus preventing the virus from reproducing by budding from the host cell....
s oseltamivir
Oseltamivir
Oseltamivir INN , an antiviral drug, slows the spread of influenza virus between cells in the body by stopping the virus from chemically cutting ties with its host cell; median time to symptom alleviation is reduced by 0.5–1 day. The drug is sold under the trade name Tamiflu, and is taken orally...
and zanamivir instead of amantadine and rimantadine for treatment of current circulating flu.
Off-label uses
Amantadine is frequently used to treat the chronic fatigueFatigue
Fatigue may refer to:*Fatigue , structural damage from repeated loading*Fatigue , a state of physical and/or mental weakness*Fatigue , safety implications of tiredness...
often experienced by patients with multiple sclerosis
Multiple sclerosis
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...
. Additionally, there have been anecdotal reports that low-dose amantadine has been successfully used to treat ADHD
Attention-deficit hyperactivity disorder
Attention deficit hyperactivity disorder is a developmental disorder. It is primarily characterized by "the co-existence of attentional problems and hyperactivity, with each behavior occurring infrequently alone" and symptoms starting before seven years of age.ADHD is the most commonly studied and...
. Limited data has shown that amantadine may help to relieve SSRI-induced sexual dysfunction.
Adverse effects
Amantadine has been associated with several central nervous systemCentral nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
(CNS) side effects, likely due to amantadine's dopaminergic
Dopaminergic
Dopaminergic means related to the neurotransmitter dopamine. For example, certain proteins such as the dopamine transporter , vesicular monoamine transporter 2 , and dopamine receptors can be classified as dopaminergic, and neurons which synthesize or contain dopamine and synapses with dopamine...
and adrenergic
Adrenergic
An adrenergic agent is a drug, or other substance, which has effects similar to, or the same as, epinephrine . Thus, it is a kind of sympathomimetic agent...
activity, and to a lesser extent, its activity as an anticholinergic
Anticholinergic
An anticholinergic agent is a substance that blocks the neurotransmitter acetylcholine in the central and the peripheral nervous system. An example of an anticholinergic is dicycloverine, and the classic example is atropine....
. CNS side effects include nervousness, anxiety, agitation, insomnia, difficulty in concentrating, and exacerbations of pre-existing seizure
Seizure
An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...
disorders and psychiatric symptoms in patients with schizophrenia
Schizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
or Parkinson's disease
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
. 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.
Rare cases of severe skin rashes such as Stevens Johnson Syndrome and suicidal ideation
Suicidal ideation
Suicidal ideation is a common medical term for thoughts about suicide, which may be as detailed as a formulated plan, without the suicidal act itself. Although most people who undergo suicidal ideation do not commit suicide, some go on to make suicide attempts...
in patients treated with amantadine have also been reported.
Livedo reticularis is a possible side effect of amantadine use for Parkinson's disease
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
.
Synthesis
Amantadine may be prepared by reacting adamantaneAdamantane
Adamantane is a colorless, crystalline chemical compound with a camphor-like odor. With a formula C10H16, it is a cycloalkane and also the simplest diamondoid. Adamantane molecules consist of three cyclohexane rings arranged in the "armchair" configuration. It is unique in that it is both rigid...
with bromine
Bromine
Bromine ") is a chemical element with the symbol Br, an atomic number of 35, and an atomic mass of 79.904. It is in the halogen element group. The element was isolated independently by two chemists, Carl Jacob Löwig and Antoine Jerome Balard, in 1825–1826...
or nitric acid
Nitric acid
Nitric acid , also known as aqua fortis and spirit of nitre, is a highly corrosive and toxic strong acid.Colorless when pure, older samples tend to acquire a yellow cast due to the accumulation of oxides of nitrogen. If the solution contains more than 86% nitric acid, it is referred to as fuming...
to give the bromide or nitroester at position one. Reaction of either compound with acetonitrile
Acetonitrile
Acetonitrile is the chemical compound with formula . This colourless liquid is the simplest organic nitrile. It is produced mainly as a byproduct of acrylonitrile manufacture...
affords the acetamide, which is hydrolyzed to give 1-adamantylamine:
Dosage and mechanism of action
A starting dose is often 100 mg once daily. All influenza B strains, many influenza A strains (and virtually all H1N1 "swine flu" strains) are resistant to amantadine, so a failure at this dose is likely due to resistance and not underdosing. For its anti-Parkinsonian effects, a starting dose of 300 mg once daily is normal, but can be increased to a limit of about 400 mg.The mechanisms for amantadine's antiviral and antiparkinsonian effects appear to be unrelated.
- The mechanism of Amantadine's antiviral activity involves interference with a viral protein, M2M2 proteinThe M2 protein is a proton-selective ion channel protein, integral in the viral envelope of the influenza A virus. The channel itself is a homotetramer , where the units are helices stabilized by two disulfide bonds...
(an ion channelIon channelIon channels are pore-forming proteins that help establish and control the small voltage gradient across the plasma membrane of cells by allowing the flow of ions down their electrochemical gradient. They are present in the membranes that surround all biological cells...
), which is required for the viral particle to become "uncoated" once taken inside a cell by endocytosisEndocytosisEndocytosis is a process by which cells absorb molecules by engulfing them. It is used by all cells of the body because most substances important to them are large polar molecules that cannot pass through the hydrophobic plasma or cell membrane...
.
- The mechanism of its antiparkinsonian effect is poorly understood. The drug has many effects in the brain, including release of dopamineDopamineDopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
and norepinephrineNorepinephrineNorepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
from nerveNerveA peripheral nerve, or simply nerve, is an enclosed, cable-like bundle of peripheral axons . A nerve provides a common pathway for the electrochemical nerve impulses that are transmitted along each of the axons. Nerves are found only in the peripheral nervous system...
endings. It appears to be a weak NMDA receptor antagonistNMDA receptor antagonistNMDA receptor antagonists are a class of anesthetics that work to antagonize, or inhibit the action of, the N-methyl d-aspartate receptor . They are used as anesthesia for animals and, less commonly, for humans; the state of anesthesia they induce is referred to as dissociative anesthesia...
as well as an anticholinergicAnticholinergicAn anticholinergic agent is a substance that blocks the neurotransmitter acetylcholine in the central and the peripheral nervous system. An example of an anticholinergic is dicycloverine, and the classic example is atropine....
.
Amantadine appears to act through several pharmacological mechanisms, but no dominant mechanism of action has been identified. It is a dopaminergic, noradrenergic and serotonergic substance, blocks monoaminoxidase A and NMDA receptors, and seems to raise beta-endorphin/beta-lipotropin levels.
Veterinary misuse
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 (H5N1H5N1
Influenza A virus subtype H5N1, also known as "bird flu", A or simply H5N1, is a subtype of the influenza A virus which can cause illness in humans and many other animal species...
) 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 the scarcer and costlier oseltamivir
Oseltamivir
Oseltamivir INN , an antiviral drug, slows the spread of influenza virus between cells in the body by stopping the virus from chemically cutting ties with its host cell; median time to symptom alleviation is reduced by 0.5–1 day. The drug is sold under the trade name Tamiflu, and is taken orally...
and zanamivir, which work by a different mechanism and are less likely to trigger resistance.
See also
- RimantadineRimantadineRimantadine 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 shorten the duration and moderate the severity of influenza. Both rimantadine and the similar drug...
- TromantadineTromantadineTromantadine is an antiviral medicine used to treat herpes simplex virus. It is available in a topical gel under trade name Viru-Merz. Its performance is similar to aciclovir.Like rimantadine and amantadine, tromantadine is a derivative of adamantane....