Mechanism of Action
The pathogenesis of allergic airway inflammation begins with arachidonic acid metabolism. In the cytosol, the enzyme 5-lipoxygenase converts it into an unstable precursor—leukotriene A₄ (LTA₄). The pathway then branches: part forms LTB₄ (responsible for chemotaxis), while another part converts into cysteinyl leukotrienes: LTC₄, LTD₄, and LTE₄.
These potent pro-asthmatic mediators are released by mast cells and eosinophils. Historically, this pool of substances was known as the "slow-reacting substance of anaphylaxis" (SRS-A). Upon release, they bind to specific CysLT₁ receptors on the membranes of bronchial smooth muscle cells.
Zafirlukast is a selective and reversible antagonist. It competitively binds to CysLT₁ receptors, preventing endogenous leukotrienes from binding and interrupting the pathological cascade at the final receptor level.
Pharmacological Effects
By blocking the receptor link, the drug eliminates the effects normally caused by CysLT₁ receptor activation. Key pharmacodynamic effects include:
- Relief of bronchoconstriction: Prevention and suppression of bronchiolar smooth muscle spasms induced by leukotrienes.
- Anti-inflammatory action: Reduction of microvascular permeability, leading to decreased plasma exudation and resolution of airway mucosal edema.
- Reduction of secretion: Inhibition of bronchial gland hypersecretion, improving airway patency.
- Inhibition of cellular infiltration: Suppression of eosinophil migration to the site of inflammation.
Indications
The drug is intended for baseline (maintenance) therapy; its effect develops slowly (over 24 hours). It is unsuitable for terminating acute asthma attacks. In clinical practice, it is used for:
- Long-term prophylaxis and prevention of bronchial asthma attacks.
- Management of patients with aspirin-exacerbated respiratory disease ("aspirin" asthma), where antileukotriene drugs show specific pathogenetic efficacy.
- Symptomatic treatment of allergic rhinitis.
Adverse Effects
The drug is generally well tolerated, but the following adverse reactions may occur:
- Common: Dyspeptic disorders (including gastritis), headache, pharyngitis.
- Rare: Churg–Strauss syndrome (eosinophilic granulomatosis with polyangiitis), a severe systemic vasculitis.
Pharmacokinetics and Prescription
Zafirlukast absorption from the gastrointestinal tract is slow and incomplete. The presence of food in the GI tract significantly decreases its absorption. Therefore, the golden rule of administration is strictly on an empty stomach (1 hour before or 2 hours after a meal). The elimination half-life ($t_{1/2}$) is approximately 10 hours, necessitating twice-daily administration.
Drug Interactions: Unlike montelukast, zafirlukast is an inhibitor of hepatic microsomal enzymes (cytochrome P450 system). This requires high clinical vigilance: combination therapy with zafirlukast may slow the metabolism and prolong the effects of other medications.
Prescription Example: Available in 20–40 mg tablets.
Rp.: Tab. Zafirlukasti 0.02 D.t.d. N. 28 S. Oral, 1 tablet twice daily (strictly on an empty stomach).