Neuraminidase inhibitors

Mechanism of action and rational design

The influenza virus attaches to respiratory tract cells via hemagglutinin, which binds to sialic acids on the epithelial surface. After new viral particles are assembled inside the cell, the enzyme neuraminidase comes into play. It cleaves terminal sialic acids, allowing virions to detach from the membrane, cross the mucous layer, and infect neighboring cells.

Drugs of this group (Oseltamivirum, Zanamivirum) were developed using rational drug design. By studying the structure of the enzyme-sialic acid complex, scientists synthesized its chemical analogs. They bind to the active site of neuraminidase more tightly than the natural substrate and alter its conformation.

As a result, the enzyme's function is blocked:

• The release of new virions from the infected cell is impaired.
• The virus cannot penetrate the mucous barrier.
• The spread of infection through the respiratory tract is halted.

Conclusion: replication is limited to a single cycle, which aborts the development of a full-scale infectious process. At the same time, these drugs exhibit high selectivity — they suppress viral neuraminidase at concentrations 100 times lower than those required to inhibit homologous mammalian enzymes.

Pharmacological profile of zanamivir

Zanamivir (trade name Relenza) is the first representative of the group, active against influenza A and B viruses. It is used for the prevention and treatment in adults and children over 5 years of age.

The main pharmacokinetic feature of the drug is extremely low oral bioavailability (less than 5%). Therefore, it is administered exclusively topically via inhalation. With this route of administration:

• About 80% of the drug substance is deposited in the oral cavity and pharynx.
• Approximately 15% reaches the lower respiratory tract.
• Only 5–20% of the dose is absorbed into the systemic circulation.

Elimination occurs via the kidneys; the drug is excreted unchanged.

Safety profile: Inhalation administration may provoke adverse respiratory effects ranging from dyspnea to the development of bronchospasm. Allergic reactions (urticaria, laryngeal edema) occur extremely rarely. Due to the risk of bronchospasm, zanamivir is not recommended for patients with chronic respiratory diseases, primarily bronchial asthma and COPD.

Pharmacokinetics and clinical use of oseltamivir

Oseltamivir is a second-generation drug with improved pharmacokinetics. It is a prodrug and is well absorbed upon oral administration (bioavailability of the active substance is about 80%).

In the body, under the action of hepatic and intestinal esterases, bioactivation occurs — the drug is converted into the active metabolite (oseltamivir carboxylate). It is excreted by the kidneys unchanged, with a half-life of 6–10 hours.

The drug is indicated for the treatment and prevention of influenza A and B in adults and children over 1 year of age (for children under 12 years, the dosage is calculated based on body weight). A key condition for efficacy is that therapy must be initiated within the first 48 hours after symptom onset.

Adverse effects:

1. Dyspepsia: nausea, vomiting, abdominal pain. These are associated with a local irritant effect on the gastrointestinal mucosa. Symptoms are usually transient and resolve spontaneously within 1–2 days. To reduce their severity, the drug should be taken with food.
2. Neurological disorders: headache, dizziness, and insomnia are possible.

Briefly: answers to topical questions

Class and exam questions

What else to study on this topic

• The role of hemagglutinin in the influenza virus life cycle
• Mechanisms of prodrug bioactivation by liver esterases
• Comparative pharmacokinetics of oseltamivir and zanamivir
• Pathophysiology of bronchospasm during inhalation drug delivery
• Guidelines for calculating pediatric dosages by body weight

Other topics in the "Antivirals" section

Prepared by WhiteCoat Pro faculty in accordance with the medical school curriculum. For educational purposes only.