Adamantane antivirals

Introduction

Adamantane antivirals are a group of synthetic antiviral drugs structurally based on the adamantane ring system. The two classic members are amantadine and rimantadine. They were once widely used in the prevention and treatment of influenza A infections, particularly during seasonal outbreaks.

Their mechanism involves inhibition of the M2 ion channel of influenza A virus, preventing viral uncoating and replication within host cells. However, due to widespread resistance among circulating influenza A strains, adamantanes are no longer recommended for routine use in influenza management.

In addition to influenza, amantadine has therapeutic roles in neurology (Parkinson’s disease, drug-induced extrapyramidal symptoms) due to dopaminergic and NMDA-receptor–modulating properties.

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Mechanism of Action

• Influenza A virus requires the M2 protein ion channel to acidify the viral interior after endocytosis.

• Amantadine and rimantadine block the M2 ion channel, inhibiting uncoating of the viral RNA genome.

• This halts viral replication at an early stage.

• They are not active against influenza B or C, since these viruses lack the M2 protein.

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Agents

1. Amantadine

• Indications:

  • Previously for prophylaxis and treatment of influenza A (not recommended now due to resistance).

  • Parkinson’s disease and drug-induced extrapyramidal symptoms (therapeutic repurposing).

• Typical Dose:

  • Influenza A (historical): 100 mg orally twice daily (adjusted for renal impairment and elderly).

  • Parkinson’s disease: Start 100 mg once daily, increase to 100 mg twice daily; max 400 mg/day depending on tolerance and indication.

• Adverse Effects: Insomnia, dizziness, hallucinations, livedo reticularis, peripheral edema, orthostatic hypotension.

2. Rimantadine

• Indications:

  • Influenza A prophylaxis and treatment (historical, not recommended due to resistance).

• Typical Dose:

  • Adults: 100 mg orally twice daily.

  • Elderly or hepatic impairment: 100 mg once daily.

• Adverse Effects: Better tolerated than amantadine; side effects include GI upset, dizziness, insomnia.

• Advantages: Less CNS penetration than amantadine → fewer neuropsychiatric effects.

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Resistance

• Widespread resistance to amantadine and rimantadine emerged rapidly due to point mutations in the M2 protein of influenza A.

• Current global influenza A strains are largely resistant, making adamantanes obsolete in standard influenza therapy.

• Modern treatment relies on neuraminidase inhibitors (oseltamivir, zanamivir, peramivir) and cap-dependent endonuclease inhibitor (baloxavir marboxil).

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Contraindications and Precautions

• History of seizures (amantadine may lower seizure threshold).

• Severe renal impairment (requires dose adjustment).

• Psychiatric disorders (risk of hallucinations and confusion).

• Pregnancy and breastfeeding (use only if benefits outweigh risks).

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Drug Interactions

• CNS stimulants: Increased risk of insomnia, agitation.

• Anticholinergic drugs: Additive effects (dry mouth, constipation, urinary retention).

• Other dopaminergic agents (levodopa, dopamine agonists): Potentially synergistic effects in Parkinson’s disease.

• Alcohol: Increases CNS adverse effects.

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Clinical Considerations

• Adamantanes have limited role in current antiviral therapy due to resistance.

• Their main modern relevance lies in neurology, especially Parkinson’s disease, where amantadine is used as an adjunct therapy for tremor and dyskinesias.

• In rare situations, such as pandemic preparedness, they might be reconsidered if circulating strains are susceptible.