What is the classification, indication, and mechanism of action of Amantadine?

Amantadine: Classification, Indication, and Mechanism of Action

Drug Classification

Amantadine is classified as an adamantane antiviral agent and an antiparkinsonian medication. 1, 2 It belongs to a class of chemically related antiviral drugs known as adamantanes, which also includes rimantadine. 1

FDA-Approved Indications

Amantadine has two distinct therapeutic categories:

Antiviral Indications

• Prophylaxis against influenza A virus infection 2
• Treatment of uncomplicated respiratory tract illness caused by influenza A virus strains, particularly when administered early in the course of illness 2
• Active only against influenza A (H1N1, H2N2, H3N2 subtypes); has very little or no activity against influenza B 2

Neurological Indications

• Treatment of idiopathic Parkinson's disease (Paralysis Agitans) 2
• Treatment of postencephalitic parkinsonism 2
• Treatment of symptomatic parkinsonism following carbon monoxide intoxication or nervous system injury 2
• Treatment of drug-induced extrapyramidal reactions 2

Mechanism of Action

Antiviral Mechanism

Amantadine prevents the release of infectious viral nucleic acid into host cells by interfering with the transmembrane domain of the viral M2 protein. 2 This M2 protein, though a minor surface constituent of influenza virus particles, is essential for virus replication. 1

• The drug blocks the ion-channel function of the influenza virus M2 protein 1, 2
• In certain cases, amantadine also prevents virus assembly during virus replication 2
• It does not interfere with the immunogenicity of inactivated influenza A virus vaccine 2
• The drug allows subclinical infection to occur while preventing clinical illness, enabling development of protective immune responses 3

Antiparkinsonian Mechanism

The precise mechanism in Parkinson's disease remains incompletely understood, but involves multiple pathways. 2

• NMDA receptor antagonism: Amantadine is a weak, non-competitive NMDA receptor antagonist (Ki = 10µM) 2, 4
• Dopaminergic effects: Earlier animal studies suggest direct and indirect effects on dopamine neurons 2
• Anticholinergic-like activity: Although not possessing direct anticholinergic activity in animal studies, it exhibits anticholinergic-like side effects clinically (dry mouth, urinary retention, constipation) 2
• Anti-inflammatory effects: Inhibits microglial activation and neuroinflammation, which may contribute to neuroprotection 5
• Acetylcholine modulation: Inhibits NMDA receptor-mediated stimulation of acetylcholine release from neostriatum in therapeutic concentrations 4

Critical Clinical Limitations

For Influenza Treatment

Amantadine is clinically obsolete for influenza treatment due to widespread resistance. 1, 3, 6

• The CDC no longer recommends adamantanes for influenza due to high resistance rates among circulating H3N2 and H1N1 strains 7, 6
• Influenza A variants with reduced sensitivity to amantadine have been isolated and are transmissible 2
• H5 avian influenza viruses in Southeast Asia are resistant to amantadine 1
• Neuraminidase inhibitors (oseltamivir, zanamivir) are now the first-line agents for influenza A treatment 7, 6

Pharmacokinetic Considerations

• Well absorbed orally with maximum plasma concentrations directly related to dose up to 200 mg/day 2, 8
• Primarily excreted unchanged in urine by glomerular filtration and tubular secretion 2, 8
• Dose reduction required for patients ≥65 years and those with renal insufficiency (creatinine clearance <30 mL/min) 3, 6
• Accumulates in patients with renal dysfunction, necessitating dose adjustments to avoid toxicity 8

Common Adverse Effects

• CNS reactions occur in 5-33% of recipients and are more severe in elderly patients 3
• Side effects include headache, nausea, vomiting, dizziness, and confusion 1
• Anticholinergic-like effects: dry mouth, urinary retention, constipation 2

Historical Context

Amantadine was originally approved in 1966 for chemoprophylaxis of influenza A (H2N2) infection and later in 1976 for treatment and chemoprophylaxis of influenza type A virus infections. 1 Its antiparkinsonian properties were discovered serendipitously when a single patient noticed relief in her Parkinson's disease symptoms after taking amantadine for a flu infection. 9