Amantadine

Amantadine, sold under the brand name Gocovri among others, is a medication used to treat dyskinesia associated with parkinsonism and influenza caused by type A influenzavirus, though its use for the latter is no longer recommended because of widespread drug resistance. Because of its effects on the central nervous system (CNS), it should be combined cautiously with additional CNS stimulants or anticholinergic drugs. Given that it is cleared by the kidneys, amantadine is contraindicated in persons with end-stage kidney disease. Due to its anticholinergic effects, it should be taken with caution by those with enlarged prostates or glaucoma.

The pharmacology of amantadine is complex. Amantadine is an adamantane derivative and is related to memantine and rimantadine.

Amantadine was first used for the treatment of influenza A. In 1968, its antiparkinsonian effects were serendipitously discovered.

Medical uses

Amantadine was initially developed to prevent replication of the influenza A virus. Amantadine may be used alone or in combination with another anti-Parkinson's or anticholinergic drug. The specific symptoms targeted by amantadine therapy are dyskinesia and rigidity.

In 2008, the World 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.

Influenza A

Amantadine is not recommended for treatment or prophylaxis of influenza A in the United States. Amantadine has no effect preventing or treating influenza B infections.

The U.S. CDC guidelines recommend only neuraminidase inhibitors for influenza treatment and prophylaxis. The CDC recommends against amantadine and rimantadine to treat influenza A infections. 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.

Extrapyramidal symptoms

An extended-release formulation of amantadine 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. A follow-up 2012 Cochrane review stated that some amantadine-induced improvement in fatigue may occur in some people with MS. 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.

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.

In the UK, NICE recommends considering amantadine for MS fatigue.

Disorders of consciousness

Disorders of consciousness (DoC) include coma, 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. In traumatic brain injury patients in the intensive 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. Also, significantly improved consciousness has been reported in patients treated for nontraumatic cases of DoC, such as in the case of a subarachnoid hemorrhage, cerebral hemorrhage, and hypoxic encephalopathy. In 2018, the American Academy of Neurology  updated treatment guidelines on the use of amantadine for patients with prolonged DoC, recommending the use of amantadine (100–200mg b.i.d.) for adults with DoC 4 to 16 weeks after injury to support early functional recovery and reduce disability.

Brain injury recovery

In various studies, amantadine and memantine 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, or the capacity of neurons 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.

Amantadine may have anticholinergic side effects. Thus, patients with an enlarged prostate or glaucoma should use with caution.

Neurological

Side effects include drowsiness (especially while driving), lightheadedness, falls, and dizziness.

Cardiovascular

Amantadine may cause orthostatic hypotension, syncope, and peripheral edema.

Kidney

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.

Pregnancy and lactation

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 in breast 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. In addition, antidopaminergic drugs such as metoclopramide and typical antipsychotics should be avoided. These interactions are likely related to opposing dopaminergic mechanisms of action, which inhibits amantadine's anti-Parkinson effects.

Pharmacology

Mechanism of action

Central nervous system disorders

The mechanism of action of the antiparkinsonian effects of amantadine is poorly understood. The effects of amantadine in Parkinson's disease were originally assumed to be anticholinergic or dopaminergic, but the situation soon proved more complicated than this. It is a negative allosteric modulator of the nicotinic acetylcholine receptors, specifically the α4β2 and α7 nicotinic acetylcholine receptors. In 2004, it was discovered that amantadine and memantine bind to and act as agonists of the sigma σ1 receptor (Ki = 7.44μM and 2.60μM, respectively) and that activation of the σ1 receptor is potentially involved in the dopaminergic effects of amantadine at therapeutically relevant concentrations. σ1 receptor activation is one of amantadine's more potent actions.

Amantadine shows amphetamine-like psychostimulant effects (e.g., stimulation of locomotor activity) in animals at sufficiently high doses. It has been found to inhibit the reuptake of serotonin, norepinephrine, and dopamine and to induce the release of serotonin, norepinephrine, and dopamine. The concentrations needed for these effects, though, are very high and may not be therapeutically relevant.

Amantadine is a phosphodiesterase inhibitor, for example of PDE1.]]

thumb|class=skin-invert-image|Model of viral replication.

The mechanisms for amantadine's antiviral and antiparkinsonian effects are unrelated.

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.

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, the risk for toxicity increases.

Half-life elimination averages eight days in patients with end-stage kidney disease. Amantadine is only minimally removed by hemodialysis.

Amantadine is metabolized to a small extent (5–15%) by acetylation. It is mainly excreted (90%) unchanged in urine by kidney excretion. Rimantadine is a closely related adamantane derivative with similar biological properties; both target the M2 proton channel of influenza A virus. in adults 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) 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 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. Currently, adamantane 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. 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 or anticholinergic drugs.

Society and culture

Names

Brand names of amantadine include Gocovri, Symadine, and Symmetrel.

Recreational use

Recreational use of amantadine at supratherapeutic doses has been reported. Recreational use of the related drug memantine has similarly been reported. 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.

In September 2015, the U.S. FDA announced the recall of Dingo Chip Twists "Chicken in the Middle" dog treats because the product has the potential to be contaminated with amantadine.

Research

Depression

Interest in and study of amantadine in the treatment of depression has arisen. A 2017 systematic review of off-label augmentation for treatment of unipolar depression found two open-label studies of amantadine for augmenting imipramine and found that it was effective. However, the quality of evidence was very low and no conclusions could be drawn about its effectiveness. A 2010 randomized clinical trial showed similar improvements in ADHD symptoms in children treated with amantadine as in those treated with methylphenidate, with less frequent side effects. 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-generation antipsychotics.

COVID-19

Amantadine has been studied in the treatment of COVID-19.