What is amantadine used for and what is its mechanism of action (MOA)?

Amantadine: Uses and Mechanism of Action

Amantadine is primarily used for influenza A prophylaxis/treatment and Parkinson's disease management, working through viral M2 protein inhibition for influenza and NMDA receptor antagonism plus dopaminergic effects for Parkinson's disease.

Uses of Amantadine

1. Influenza A Management

• Antiviral Activity: Effective only against influenza A viruses (all subtypes: H1N1, H2N2, H3N2); has no activity against influenza B 1

• Prophylaxis:

  • 70-90% effective in preventing illness when taken before and throughout influenza A outbreaks 2
  • Indicated for high-risk individuals vaccinated after influenza A activity has begun 2
  • For unvaccinated persons caring for high-risk individuals 2
  • For immunodeficient persons with expected poor antibody response to vaccination 2
  • For persons with contraindications to influenza vaccine 2

• Treatment:

  • Reduces severity and duration of influenza A symptoms when started within 48 hours of symptom onset 2
  • Effectiveness diminishes if started later than 48 hours after symptoms begin 2

⚠️ Important Note: Since 2006, amantadine is no longer recommended for influenza treatment or prophylaxis in the United States due to widespread resistance. The CDC found that 92% of influenza A (H3N2) viruses demonstrated resistance to adamantanes 2.

2. Parkinson's Disease Management

• Symptomatic treatment of Parkinson's disease 1, 3
• Management of levodopa-induced dyskinesias 4
• Treatment of drug-induced extrapyramidal reactions 1

Mechanism of Action

1. Antiviral Mechanism

• M2 Protein Inhibition: Blocks the ion channel formed by viral M2 protein, preventing the release of viral nucleic acid into the host cell 1
• Viral Assembly Interference: In some cases, prevents virus assembly during replication 1
• Specificity: Active only against influenza A viruses that contain the M2 protein; ineffective against influenza B 1, 2

2. Mechanism in Parkinson's Disease

• NMDA Receptor Antagonism: Acts as a weak, non-competitive NMDA receptor antagonist (K₁ = 10μM) 1
• Dopaminergic Effects: Has both direct and indirect effects on dopamine neurons 1
• Anticholinergic-like Effects: Though not shown to have direct anticholinergic activity in animal studies, clinically exhibits anticholinergic-like side effects (dry mouth, urinary retention, constipation) 1

Pharmacokinetics

• Absorption: Well absorbed orally 1, 5
• Distribution: Widely distributed throughout the body with little drug present in circulation 5
• Metabolism: Eight metabolites identified; one N-acetylated compound accounts for 5-15% of the administered dose 1
• Elimination: Primarily excreted unchanged in urine through glomerular filtration and tubular secretion 1, 6
• Half-life:
  • Normal renal function: 11.8 ± 2.1 hours 6
  • Impaired renal function: 18.5 hours to 33.8 days (depending on severity) 6
  • Hemodialysis patients: Mean 8.3 days 6

Side Effects and Precautions

• CNS Side Effects: Nervousness, anxiety, insomnia, difficulty concentrating, lightheadedness (5-10% of patients) 2
• Gastrointestinal Effects: Anorexia, nausea 2
• More Serious CNS Effects: Seizures and confusion, particularly in elderly, those with renal disease, or seizure disorders 2
• Dose Adjustment: Required for elderly patients and those with impaired renal function 2, 6

Clinical Pearls

• Amantadine was discovered serendipitously for Parkinson's disease when a patient noticed relief in her symptoms after taking it for influenza 3
• Intravenous amantadine has shown immediate improvement in motor scores in Parkinson's patients and progressive reduction of involuntary movements in those with dyskinesias 7
• Resistance develops rapidly when used for influenza treatment, with resistant strains emerging in approximately one-third of treated patients 2