Amantadine

[uh-man-tuh-deen]

Amantadine is the organic compound known formally as 1-aminoadamantane. The molecule consists of adamantane backbone that is substituted at one of the four methyne positions with an amino group. This compound 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.

Uses

Approved

It was approved by the U.S. Food and Drug Administration 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 and drug-induced extrapyramidal syndromes.

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 (choreiform movements associated with long-term L-DOPA use, probably related to chronic pulsatile stimulation of dopamine receptors).

Off-label uses

There have been anecdotal reports, based on research by Dr. William Singer of Harvard University, that low-dose amantadine has been successfully used to treat ADHD. Amantadine has been shown to relieve SSRI-induced anorgasmia in some people, though not in all people.

Side effects

Amantadine has been associated with several central nervous system 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 agent is thus limited by the need to screen patients for a history of seizures and psychiatric symptoms. In Parkinson's patients who show such symptoms, the risks of amantadine may well outweigh the benefits. Vomiting has been recorded in pigeons fed amantadine.

Cases of suicidal ideation in patients treated with amantadine have been described, although this psychiatric adverse event is relatively rare. Nonetheless, clinical surveillance of suicidal ideation in patients on amantadine is warranted at the clinician's discretion, as amantadine has been implicated as the major fatal (biologically toxic) factor in completed patient suicides.

Another potential side effect is livedo reticularis, a dermatological reaction that results in skin mottling and purpurish mesh network of blood vessels.

Mechanism of action

The mechanism for its antiviral and antiparkinsonian effects seems to be unrelated. The mechanism of its antiparkinsonian effect is poorly understood. The drug appears to induce release of dopamine from the nerve endings of the brain cells, together with stimulation of norepinephrine response. Furthermore, it appears to be a weak NMDA receptor antagonist and an anticholinergic. In terms of the mechanism of its antiviral properties, amantadine interferes with a viral protein, M2 (an ion channel), which is required for the viral particle to become "uncoated" once it is taken inside the cell by endocytosis.

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 (H5N1) strains in China and southeast Asia are resistant to amantadine, but strains circulating elsewhere seem to be sensitive. If amantadine resistant strains of the virus spread, the drug of choice in an avian flu outbreak will likely be restricted to one of the scarcer and costlier oseltamivir or zanamivir, which work by a different mechanism and are less likely to trigger resistance.

Declining effectiveness

Early in the 2005/2006 flu season, the United States' Center for Disease Control [CDC] found rates of amantadine resistance to be much higher than in previous seasons. Looking at samples from 26 states yielded the following findings:

A total of 193 (92.3%) of 209 influenza A(H3N2) and 2 (25%) of 8 influenza A(H1N1) viruses analyzed contained point mutations resulting in a serine-to-asparagine change at amino acid 31 (S31N) of the M2 protein that conferred amantadine resistance.

A resistance rate of 92% for the major flu strain was called "alarmingly high". The CDC issued an alert to doctors not to prescribe amantadine any more for the season. Among some Asian countries, A/H3N2 and A/H1N1 resistance has reached 100%.

In Popular Culture

Amantadine was referenced in an episode of House entitled 'Wilson's Heart'. A character was taking it for a flu she had contracted. A bus she was traveling in was hit by a garbage truck resulting in renal failure. Because her body could no longer filter the amantadine from her system, she eventually died of amantadine poisoning.