Neuraminidase inhibitors

I. Introduction

Neuraminidase inhibitors (NAIs) are a class of antiviral agents specifically used in the treatment and prophylaxis of influenza virus infections. These drugs act by blocking the activity of neuraminidase, a surface glycoprotein enzyme found on influenza viruses. Neuraminidase facilitates the release of newly formed viral particles from infected host cells. By inhibiting this enzyme, NAIs effectively limit viral replication and spread, making them essential in the early stages of infection or for preventive use during seasonal influenza outbreaks and pandemics.

NAIs are active against both influenza A and B viruses and have been a critical component in global antiviral stockpiles for pandemic preparedness, especially in light of viruses like H1N1, H5N1 (avian flu), and H7N9.

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II. Mechanism of Action

Influenza viruses replicate inside host respiratory epithelial cells and produce new virions. These virions must be released from the host cell to infect neighboring cells. The viral neuraminidase enzyme:

• Cleaves terminal sialic acid residues from glycoproteins and glycolipids on the surface of the host cell and the virus

• Facilitates the budding and release of new virions

• Prevents virus aggregation

NAIs mimic the natural sialic acid substrate and bind to the active site of the neuraminidase enzyme, thereby:

• Preventing the release of virions from infected cells

• Limiting the spread of infection within the respiratory tract

• Reducing viral load and disease severity

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III. Approved Neuraminidase Inhibitors

1. Oseltamivir phosphate (Tamiflu®)

• Route: Oral capsule or suspension

• Approval: FDA-approved in 1999

• Indications:

  • Treatment of acute uncomplicated influenza A and B in individuals ≥2 weeks of age

  • Post-exposure and seasonal prophylaxis

• Dose:

  • Adults: 75 mg twice daily for 5 days (treatment); once daily for 10 days (prophylaxis)

  • Pediatric: Weight-based

• Metabolism: Prodrug; converted to active oseltamivir carboxylate in liver

• Adverse Effects: Nausea, vomiting, headache, neuropsychiatric events (especially in adolescents)

• Resistance: H274Y mutation in H1N1 can confer resistance

2. Zanamivir (Relenza®)

• Route: Inhaled powder via Diskhaler

• Approval: FDA-approved in 1999

• Indications:

  • Treatment and prophylaxis of influenza A and B in individuals ≥7 years (treatment), ≥5 years (prophylaxis)

• Dose: 10 mg (2 inhalations) twice daily for 5 days

• Contraindications: Individuals with reactive airway diseases (asthma, COPD)

• Adverse Effects: Bronchospasm, throat irritation, cough

• Resistance: Rare; minimal cross-resistance with oseltamivir

3. Peramivir (Rapivab®)

• Route: Intravenous

• Approval: FDA-approved in 2014

• Indications:

  • Treatment of acute uncomplicated influenza in individuals ≥2 years of age

• Dose: Single IV infusion of 600 mg over 15–30 minutes

• Use: Particularly in hospitalized patients who cannot take oral/inhaled medications

• Adverse Effects: Diarrhea, elevated transaminases, skin reactions

4. Laninamivir octanoate (Inavir®)

• Route: Inhaled

• Approval: Approved in Japan in 2010 (not FDA-approved)

• Indications:

  • Single-dose inhaled treatment of influenza A and B

  • Long-acting prophylaxis

• Mechanism: Similar to zanamivir but with extended action

• Use: More common in Asian countries

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IV. Pharmacokinetic Comparison

Drug	Route	Bioavailability	Half-life	Elimination
Oseltamivir	Oral	~80% (prodrug)	6–10 hours	Renal (active metabolite)
Zanamivir	Inhaled	~15% (local)	2.5–5 hours	Renal
Peramivir	Intravenous	100%	~20 hours	Renal
Laninamivir	Inhaled	Local tissue retention	>70 hours	Pulmonary metabolism, renal

V. Clinical Indications and Efficacy

1. Treatment of Influenza

• Must be initiated within 48 hours of symptom onset

• Benefits:

  • Reduces duration of illness by ~1–1.5 days

  • Decreases severity and viral shedding

  • Prevents complications such as otitis media, pneumonia, hospitalization

2. Prophylaxis

• Effective in household and institutional settings

• Reduces transmission rates during outbreaks

• Recommended for:

  • High-risk individuals

  • Nursing home residents

  • Immunocompromised patients

3. Pandemic Preparedness

• Stockpiled by governments (e.g., oseltamivir) for potential pandemics (e.g., H5N1, H1N1, H7N9)

• Limited data for new strains; susceptibility testing essential

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VI. Resistance Mechanisms

Influenza viruses can develop resistance to NAIs, primarily through mutations in the neuraminidase (NA) gene:

• Oseltamivir: Most prone to resistance via mutations like H274Y (H1N1), R292K (H3N2)

• Zanamivir and Peramivir: Lower resistance rates; mutations impact fitness

• Surveillance by WHO and CDC helps guide treatment recommendations

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VII. Adverse Effects and Safety Profile

Drug	Common Side Effects	Serious Reactions
Oseltamivir	Nausea, vomiting, abdominal pain	Neuropsychiatric events (rare)
Zanamivir	Cough, bronchospasm, headache	Worsening asthma, allergic reactions
Peramivir	Diarrhea, elevated liver enzymes	Anaphylaxis, Stevens-Johnson Syndrome
Laninamivir	Cough, sore throat, headache	Rare hypersensitivity

Precautions:

• Oseltamivir should be dose-adjusted in renal impairment

• Zanamivir not recommended in respiratory disease

• Neuropsychiatric events should prompt discontinuation, especially in children and adolescents

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VIII. Contraindications

Drug	Contraindications
Oseltamivir	Hypersensitivity, caution in severe renal disease
Zanamivir	Reactive airway disease (asthma, COPD)
Peramivir	Severe allergy to peramivir or other NAI
Laninamivir	Hypersensitivity, not for children <10 years

IX. Drug Interactions

NAIs generally have low potential for drug–drug interactions due to:

• Minimal cytochrome P450 involvement

• Limited protein binding

However:

• Probenecid may increase oseltamivir levels by reducing renal clearance

• Combination with live attenuated influenza vaccine (LAIV) may reduce vaccine efficacy (avoid NAI use 2 weeks before and 48 hours after LAIV administration)

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X. Comparison with Other Antivirals

Class	Example	Target	Notes
Neuraminidase Inhibitors	Oseltamivir	Viral NA	Active against influenza A & B
Endonuclease Inhibitors	Baloxavir marboxil	Cap-dependent endonuclease	Single-dose, faster symptom relief
M2 Inhibitors (obsolete)	Amantadine, Rimantadine	M2 proton channel	Active only against influenza A; high resistance

XI. Emerging Therapies and Research

1. Baloxavir marboxil (Xofluza)

   • Inhibits viral replication earlier in the life cycle

   • FDA-approved for influenza A & B

   • Single oral dose; shorter time to symptom alleviation

   • Not a neuraminidase inhibitor but under consideration in NAI-resistant cases

2. Combination Therapy

   • NAI + endonuclease inhibitors

   • NAI + monoclonal antibodies (investigational)

3. Universal Flu Drugs

   • Targeting conserved viral proteins across all strains

   • Still in preclinical or early clinical stages

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XII. Summary of Key Differences

Drug	Route	Frequency	Use in Prophylaxis	Use in Treatment	Resistance Rate
Oseltamivir	Oral	BID × 5 days	Yes	Yes	Moderate
Zanamivir	Inhaled	BID × 5 days	Yes	Yes	Low
Peramivir	IV	Single dose	No	Yes	Low
Laninamivir	Inhaled	Single dose	Yes (Japan)	Yes	Very low