Antivirals for Influenza

Antiviral agents against influenza are important in preventing and treating influenza infection. Influenza is often self-limited, but high-risk populations suffer significant morbidity and mortality from the illness. Different classes of drugs act on the influenza virus. Neuraminidase inhibitors include oseltamivir (oral), zanamivir (inhalation) and peramivir (IV); these drugs act by inhibiting neuraminidase, the enzyme that cleaves off the new virus particle. By blocking the enzymatic effect, further release of progeny virus to nearby respiratory cells is reduced. Baloxavir, a selective inhibitor of influenza cap-dependent endonuclease, inhibits viral mRNA synthesis. Both neuraminidase inhibitors and baloxavir have activity against influenzas A and B. Adamantanes, or M2 inhibitors, include amantadine and rimantadine, which are active against influenza A but are not often used owing to resistance.

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  • Virus strains are classified by the core proteins (A, B, C).
  • Seasonal influenza is an illness caused by influenza A or B virus.
  • Influenza is often a self-limited infection, but those at risk for complications can have significant morbidity and mortality.
  • Antiviral drugs are available for prevention and treatment of influenza.

Mechanism of invasion

  • A viral particle attaches its hemagglutinin (HA) spikes to sialic acid–containing receptors on the surface of respiratory epithelial cells.
    • The viral particle is internalized via receptor-mediated endocytosis. 
    • The virus uncoats via the action of M2 protein, allowing an influx of hydrogen particles. 
    • The viral RNA then moves into the nucleus of the cell → replication → messenger RNA → translation into new viral proteins.
  • Viral particles are brought to the surface of the cell and assembled into virions. 
  • Hemagglutinin again binds to the sialic acid–containing receptors. 
  • Neuraminidase then cleaves the new viral particle off of the respiratory epithelial cell → infection of nearby cells.

Classes of antiinfluenza agents

  • Active against influenza A and B:
    • Neuraminidase inhibitors:
      • Oseltamivir
      • Peramivir
      • Zanamivir
    • Selective inhibitor of influenza cap-dependent endonuclease: baloxavir
  • Active against influenza A: adamantanes (amantadine, rimantadine)

Neuraminidase Inhibitors

Chemistry and pharmacodynamics

  • Analogues of sialic acid 
  • Mechanism of action: 
    • Inhibits influenza neuraminidase by causing a conformational change in the enzyme
    • Neuraminidase cleaves off the virion from the sialic acid–containing receptor: 
      • This act is important to release the virion from the infected cells.
      • Without the enzymatic step, viral aggregation occurs at the cell surface.
    • Inhibition of neuraminidase → ↓ viral spread in the respiratory tract
  • Mechanism of resistance:
    • Mutations in neuraminidase
    • Mutations in hemagglutinin


Table: Pharmacokinetics of neuraminidase inhibitors
  • Oral
  • Absorbed rapidly
  • Bioavailability not decreased by food
  • IV
  • Single 600-mg dose
  • Low plasma protein binding
  • Half-life: 6–10 hours
  • 30% protein-bound
  • Half-life: 20 hours
  • On inhalation, drug reaches oropharynx and lungs
  • Half-life: 2–3 hours
MetabolismNo significant metabolism
  • Renal
  • Unchanged in urine
  • Requires dose adjustment in renal insufficiency
  • Renal
  • Unchanged in urine
  • Requires dose adjustment in renal insufficiency
Up to 15% absorbed and excreted in the urine


  • Prophylaxis against seasonal influenza: oseltamivir, zanamivir
  • Treatment of influenza (≤ 48 hours after symptom onset)

Adverse effects and contraindications

Table: Adverse effects and contraindications of neuraminidase inhibitors
Adverse effects
  • Nausea, vomiting
  • Headache
  • Hallucination, delirium, confusion
  • Hypersensitivity reactions (SJS, EM)
  • Renal and hepatic function abnormalities
  • Diarrhea
  • Hypersensitivity reactions (SJS, EM)
  • Hallucinations, delirium
  • Sore throat
  • Cough, bronchospasm
  • Hypersensitivity to oseltamivir
  • Precaution with cardiovascular, hepatic and renal diseases
  • Hypersensitivity to peramivir
  • Precautions with renal disease
  • Hypersensitivity to zanamivir
  • Precautions with COPD and asthma
COPD: chronic obstructive pulmonary disease
EM: erythema multiforme
SJS: Stevens-Johnson syndrome

Selective Inhibitor of Cap-Dependent Endonuclease

Chemistry and pharmacodynamics

  • Baloxavir marboxil (BXM): prodrug that undergoes hydrolysis to become baloxavir acid (BXA), the active form.
  • Mechanism of action: 
    • Activity against an earlier part of viral replication (compared to neuraminidase inhibitors)
    • Inhibits the enzyme, virus cap-dependent endonuclease (CEN):
      • An enzyme in the influenza virus polymerase, CEN facilitates the cap-snatching process during viral mRNA synthesis.
      • Inhibiting CEN → ↓ transcription
    • Hence, inhibits viral replication 


  • Absorption: 
    • Available in oral form 
    • Avoid intake with dairy products, calcium-fortified beverages, and antacids.
  • Distribution: 
    • Protein binding: 94%
    • Long half-life: 80 hours
  • Metabolism: metabolized by UGT1A3 and CYP3A4 
  • Excretion: biliary excretion


  • Acute uncomplicated influenza (≤ 48 hours after symptom onset)
  • Postexposure prophylaxis for influenza 

Adverse effects and contraindications

  • Adverse effects:
    • Diarrhea
    • Rash
    • Hypersensitivity reactions
    • Delirium, hallucination
  • Contraindications: hypersensitivity to baloxavir


Chemistry and pharmacodynamics

  • Amantadine (1-aminoadamantane hydrochloride) and rimantadine (amantadine derivative): tricyclic amines
  • Mechanism of action (M2 inhibitor): 
    • Targets M2 ion channel protein, which allows for hydrogen ion influx, and facilitates viral uncoating
    • In effect, prevents viral replication
  • Mechanism of resistance: mutation involving RNA sequence that encodes for the M2 protein (transmembrane domain)


Table: Pharmacokinetics of adamantanes
AbsorptionGood oral bioavailabilityGood oral bioavailability
  • Half-life: 12–18 hours
  • 67% protein-bound
  • Half-life: 24–36 hours
  • 40% protein-bound
MetabolismNo significant metabolismUndergoes hepatic metabolism
ExcretionRenal (excreted unchanged)Renal


  • Influenza A (but role limited owing to widespread resistance)
  • Drug-induced parkinsonism syndromes
  • Parkinson disease

Adverse effects and contraindications

  • Adverse effects:
    • Neuropsychiatric:
      • Anxiety
      • Insomnia
      • Confusion
      • Hallucination
      • Seizure
    • Amantadine: anticholinergic effect (dry mouth, mydriasis)
  • Contraindications:
    • Hypersensitivity to adamantanes
    • Amantadine is contraindicated in angle closure glaucoma (anticholinergic effect).
  • Precautions in psychosis, seizures, hepatic and renal impairment

Comparison of Antiviral Agents for Influenza

Table: Comparison of antiviral agents for influenza
Neuraminidase inhibitorsBaloxavirAmantadine
Mechanism of actionInhibits neuraminidase, preventing spread to uninfected cellsEndonuclease inhibitor, preventing mRNA synthesisPrevents M2 channel activity, inhibiting viral uncoating
  • Oral
  • IV
  • Inhalation
EliminationRenalBiliary excretionRenal
IndicationsPrevention and treatment of influenzas A and BPrevention and treatment of influenzas A and BTreatment and prophylaxis of influenza A (use limited owing to resistance)
Notable adverse effects
  • Oseltamivir: nausea, vomiting
  • Zanamivir: sore throat, cough
  • Peramivir: diarrhea
DiarrheaCNS side effects


  1. Acosta, E.P. (2017). Antiviral agents (nonretroviral). Chapter 62 of Brunton, L.L., Hilal-Dandan, R., Knollmann, B.C. (Eds.), Goodman & Gilman’s: The Pharmacological Basis of Therapeutics, 13th ed. McGraw-Hill.
  2. ​​Safrin, S. (2021). Antiviral agents. Chapter 49 of Katzung, B.G., & Vanderah, T.W. (Eds.), Basic & Clinical Pharmacology, 15th ed. McGraw-Hill.
  3. Zachary, K.C. (2020). Pharmacology of antiviral drugs for influenza. UpToDate. Retrieved September 1, 2021, from 
  4. Zachary, K.C. (2021). Treatment of seasonal influenza. UpToDate. Retrieved September 1, 2021, from

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