Anti‑Influenza Drugs

Introduction / Overview

Influenza viruses constitute a significant cause of acute respiratory illness worldwide, contributing to considerable morbidity, mortality, and economic burden each year. Seasonal epidemics and occasional pandemics emphasize the need for effective pharmacologic interventions to reduce disease severity, shorten duration of symptoms, and prevent complications such as pneumonia, exacerbation of chronic diseases, and secondary bacterial infections. The development of antiviral agents targeting specific viral replication steps has transformed the management of influenza, offering therapeutic options beyond supportive care. This chapter presents a comprehensive review of anti‑influenza drugs, emphasizing their pharmacological properties, clinical applications, and considerations for specific patient populations.

Learning Objectives

• Identify the principal classes of anti‑influenza agents and their chemical features.
• Describe the molecular mechanisms by which these agents inhibit viral replication.
• Summarize key pharmacokinetic attributes that influence dosing regimens.
• Recognize approved indications, off‑label uses, and the evidence base supporting each therapy.
• Understand common and serious adverse effect profiles, drug interactions, and special population considerations.

Classification

Direct‑Acting Antivirals

Direct‑acting agents are divided into two major subclasses: neuraminidase inhibitors and M2 ion‑channel blockers. Neuraminidase inhibitors target the viral surface sialidase enzyme, impeding release of progeny virions from infected epithelial cells. M2 blockers bind to the viral M2 proton channel, preventing acidification of the viral interior required for uncoating. Within each subclass, agents differ by molecular structure and pharmacokinetic properties.

Neuraminidase Inhibitors

• Oseltamivir – a prodrug converted to its active 4‑oxobutyl derivative; chemically a fluorinated carbamate ester.
• Zanamivir – a non‑prodrug, a guanidino‑sugar analog containing a sulfonamide moiety.
• Peramivir – an intravenous guanidino derivative, structurally related to zanamivir but lacking a sulfonamide group.
• Baloxavir marboxil – a prodrug of baloxavir acid, a cyclopropyl‑aryl carboxylate that inhibits cap‑dependent endonuclease activity.

M2 Ion‑Channel Blockers

• Amantadine – a cyclic amine, originally derived from a 1,4‑diazepine scaffold.
• Rimantadine – a structural isomer of amantadine differing in the position of the methyl group.

Indirect‑Acting Antivirals (Immune Modulators)

Although not directly inhibiting viral replication, immunomodulatory agents such as interferons have been employed, particularly in severe or refractory cases. Their use is limited by side‑effect profiles and lack of robust evidence for routine clinical practice.

Mechanism of Action

Neuraminidase Inhibitors

Neuraminidase inhibitors competitively bind the catalytic pocket of the viral neuraminidase enzyme, mimicking the transition state of sialic acid cleavage. This inhibition prevents cleavage of terminal sialic acid residues from glycoproteins on the cell surface, thereby blocking the release of new virions and limiting cell‑to‑cell spread. The potency of these inhibitors varies among influenza A and B strains; however, most circulating strains retain susceptibility to oseltamivir and zanamivir, with occasional reduced susceptibility in some oseltamivir‑resistant H1N1 isolates.

Cap‑Dependent Endonuclease Inhibition (Baloxavir)

Baloxavir acid targets the cap‑dependent endonuclease subunit of the viral polymerase complex (PA). By binding to the active site metal ions (Mg²⁺/Mn²⁺), it prevents cleavage of the host mRNA cap, a prerequisite for viral mRNA synthesis. This inhibition leads to a rapid decline in viral RNA production. Baloxavir’s single‑dose regimen reflects the prolonged post‑exposure inhibitory effect observed in preclinical models.

M2 Ion‑Channel Blockers

M2 blockers bind to the transmembrane segment of the M2 proton channel, stabilizing the closed conformation and preventing acidification of the viral interior. This acidification is necessary for the conformational changes that release the viral ribonucleoprotein complex into the host cytoplasm. By halting this step, M2 blockers effectively inhibit the early phase of viral replication.

Pharmacokinetics

Absorption

Oseltamivir is formulated as a prodrug and exhibits good oral bioavailability (~80 %) after ingestion of the capsule or tablet. Absorption is pH‑dependent; higher gastric acidity enhances conversion to the active carboxylate. Zanamivir, administered via inhalation, achieves high concentrations in the respiratory tract but poor systemic absorption, limiting systemic exposure. Peramivir is delivered intravenously, bypassing gastrointestinal variability. Baloxavir marboxil is orally administered; its prodrug undergoes rapid hydrolysis to baloxavir acid, with absorption largely independent of gastric pH. M2 blockers exhibit moderate oral absorption, with amantadine reaching peak plasma concentrations within 1–2 h and rimantadine peaking at 3–4 h.

Distribution

Oseltamivir carboxylate distributes widely, achieving concentrations in epithelial lining fluid comparable to plasma levels. Zanamivir’s distribution is largely confined to the lungs due to its hydrophilic nature. Peramivir demonstrates a large volume of distribution (~600 mL/kg) in the pulmonary compartment. Baloxavir acid penetrates tissues, including the respiratory tract, with a moderate protein binding (~20 %). M2 blockers are highly protein‑bound (~70–80 % for amantadine, ~60 % for rimantadine), and amantadine shows limited central nervous system penetration, whereas rimantadine crosses the blood‑brain barrier more readily.

Metabolism

Oseltamivir undergoes hydrolysis by intestinal esterases to the active carboxylate; hepatic metabolism is minimal. Zanamivir is not metabolized significantly. Peramivir is primarily excreted unchanged; minor hepatic metabolism via cytochrome P450 enzymes has been noted. Baloxavir marboxil is converted to baloxavir acid by hepatic esterases and systemic carboxylesterases; subsequent glucuronidation constitutes the major elimination pathway. M2 blockers are metabolized via hepatic glucuronidation (amantadine) and hepatic oxidation (rimantadine). Renal excretion dominates for oseltamivir carboxylate, peramivir, and baloxavir acid, whereas significant hepatic clearance occurs for amantadine and rimantadine at higher doses.

Excretion

Oseltamivir carboxylate is eliminated unchanged by glomerular filtration and tubular secretion (~90 % renal clearance). Zanamivir is primarily excreted by the kidneys but due to low plasma exposure, systemic toxicity is rare. Peramivir is almost entirely eliminated unchanged by the kidneys, with a terminal half‑life of ~5 h in healthy subjects. Baloxavir acid is excreted via both renal and biliary routes, with a terminal half‑life of 2–3 days. M2 blockers have a renal clearance, with amantadine’s half‑life extending to 20–30 h in patients with renal impairment.

Half‑Life and Dosing Considerations

Oseltamivir’s half‑life is ~6 h, necessitating twice‑daily dosing for 5 days (standard) or once‑daily for 10 days in prophylaxis. Zanamivir’s short plasma half‑life (~0.8 h) does not necessitate multiple daily doses due to sustained airway exposure. Peramivir, with a ~5 h half‑life, is administered as a single dose. Baloxavir acid’s long half‑life (~2–3 days) permits a single‑dose regimen for treatment. M2 blockers require twice‑daily dosing (am and pm) for a 5‑day course in treatment or 7‑day prophylaxis. Renal function adjustments are critical for oseltamivir and peramivir; dose reductions or extended dosing intervals are warranted in creatinine clearance <30 mL/min. Baloxavir acid requires dosage modifications for mild to moderate renal impairment but remains safe in severe renal disease. Amantadine dosing is reduced in patients with creatinine clearance <30 mL/min, whereas rimantadine is contraindicated in severe renal dysfunction due to accumulation.

Therapeutic Uses / Clinical Applications

Approved Indications

• Oseltamivir – Treatment of uncomplicated influenza in patients ≥1 year of age and prophylaxis in individuals exposed to influenza virus.
• Zanamivir – Treatment and prophylaxis of influenza in patients ≥6 months of age who can tolerate inhalation.
• Peramivir – Treatment of severe influenza in patients ≥2 years of age requiring intravenous therapy.
• Baloxavir marboxil – Treatment of uncomplicated influenza in patients ≥12 months of age.
• Amantadine / Rimantadine – Treatment and prophylaxis of influenza A in patients ≥2 years of age, though use is limited by widespread resistance.

Off‑Label and Emerging Uses

Oseltamivir and zanamivir have been employed experimentally for influenza B in children and for prophylaxis in pregnant patients, with limited data supporting efficacy. Baloxavir’s single‑dose regimen has been explored for compassionate use in immunocompromised patients with prolonged viral shedding. Amantadine remains in use for neurodegenerative indications (Parkinson disease), though this is unrelated to antiviral activity.

Adverse Effects

Common Side Effects

• Oseltamivir – Nausea, vomiting, diarrhea, headache.
• Zanamivir – Cough, throat irritation, bronchospasm; cough may be triggered by inhalation delivery.
• Peramivir – Injection site pain, headache, nausea.
• Baloxavir marboxil – Nausea, vomiting, diarrhea, nasopharyngitis.
• Amantadine / Rimantadine – Headache, dizziness, insomnia, nausea, neuropsychiatric disturbances (e.g., confusion, hallucinations).

Serious and Rare Adverse Reactions

Oseltamivir’s neuropsychiatric events (agitation, delirium) are rare but reported, particularly in pediatric populations. Zanamivir may precipitate bronchospasm in patients with pre‑existing airway disease, necessitating pre‑medication with bronchodilators. Peramivir has been associated with rare cases of hemolysis in patients with glucose‑6‑phosphate dehydrogenase deficiency. Baloxavir’s safety profile is generally favorable; the most common severe reaction is a transient increase in liver enzymes, typically resolving without intervention. Amantadine and rimantadine carry a higher risk of CNS toxicity, especially in elderly patients or those with renal dysfunction.

Black Box Warnings

Oseltamivir carries a boxed warning for the potential of neuropsychiatric events in children and adolescents. Amantadine and rimantadine have boxed warnings for neuropsychiatric adverse reactions, including confusion, hallucinations, and suicidal ideation. These warnings underscore the importance of monitoring and dose adjustment in vulnerable populations.

Drug Interactions

Oseltamivir and zanamivir have minimal drug‑drug interaction potential due to negligible cytochrome P450 metabolism. Peramivir may interfere with drugs cleared by the kidneys, necessitating dose adjustment. Baloxavir acid is a substrate of CYP3A4 and may be affected by strong inhibitors or inducers; however, clinically significant interactions have not been extensively documented. Amantadine is a substrate of organic cation transporters; concomitant use with drugs that inhibit these transporters (e.g., cimetidine) may increase amantadine exposure. Rimantadine’s pharmacokinetics can be affected by agents that alter the gastric pH, impacting absorption.

Special Considerations

Pregnancy and Lactation

Oseltamivir and zanamivir are considered pregnancy category C; limited data suggest no teratogenicity but careful risk‑benefit assessment is advised. Peramivir’s safety profile in pregnancy is insufficiently characterized. Baloxavir is category B; no definitive evidence of fetal harm. Amantadine is category C; lactation data indicate minimal drug transfer into breast milk, yet potential neuropsychiatric effects in the infant remain theoretical. Routine prophylactic use during pregnancy is generally avoided unless exposure risk is high.

Pediatric Considerations

In infants and young children, oseltamivir dosing is weight‑based, with lower doses for those <5 kg. Zanamivir requires inhalation technique proficiency; nebulization may be employed in younger children. Peramivir is suitable for patients ≥2 years of age, with weight‑based dosing. Baloxavir’s approval extends to children ≥12 months; dosing is weight‑based, with a maximum daily dose. Amantadine and rimantadine are rarely used in pediatrics due to resistance concerns and safety profiles.

Geriatric Considerations

Older adults may exhibit altered pharmacokinetics, particularly decreased renal clearance, necessitating dose adjustments for oseltamivir and peramivir. Neuropsychiatric side effects of amantadine and rimantadine are more pronounced in this population. Vigilant monitoring for confusion and delirium is recommended.

Renal and Hepatic Impairment

Renal impairment necessitates dose reduction for oseltamivir (creatinine clearance 30–50 mL/min: 150 mg BID; <30 mL/min: 75 mg BID) and peramivir (creatinine clearance 30–50 mL/min: 300 mg IV; <30 mL/min: 150 mg IV). Baloxavir requires dose adjustment for mild to moderate renal impairment but remains safe in severe renal disease due to minimal renal elimination of the active metabolite. Hepatic impairment has limited impact on oseltamivir and peramivir; however, amantadine and rimantadine dosing should be reduced or avoided in severe hepatic dysfunction.

Summary / Key Points

• Neuraminidase inhibitors (oseltamivir, zanamivir, peramivir, baloxavir) remain first‑line therapies for uncomplicated influenza, with each agent offering distinct pharmacokinetic advantages.
• M2 ion‑channel blockers (amantadine, rimantadine) are now largely obsolete due to widespread resistance and safety concerns.
• Early initiation of antiviral therapy (ideally within 48 h of symptom onset) is associated with reduced symptom duration and lower complication rates.
• Oseltamivir and zanamivir exhibit minimal systemic drug interactions, whereas baloxavir’s metabolism may be affected by CYP3A4 modulators.
• Special populations (pregnant women, children, elderly, renal/hepatic impairment) require dose adjustments or alternative agents based on pharmacokinetic profiles and safety data.
• Adverse effect monitoring should focus on neuropsychiatric events with oseltamivir, CNS toxicity with amantadine/rimantadine, and bronchospasm with inhaled zanamivir.
• Resistance testing, when available, can guide therapy selection, particularly in severe or refractory cases.

References

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