Zafirlukast

Mechanism of action

The pathogenesis of allergic airway inflammation is based on arachidonic acid metabolism. In the cytosol, under the action of the enzyme 5-lipoxygenase, it is synthesized into an unstable precursor, leukotriene A₄ (LTA₄). The pathway then branches: part goes to the formation of LTB₄ (responsible for chemotaxis), while another part is converted into cysteinyl leukotrienes: LTC₄, LTD₄, LTE₄.

These potent pro-asthmatic mediators are released by mast cells and eosinophils. Historically, this pool of substances was called the "slow-reacting substance of anaphylaxis". Upon exiting the cell, they bind to specific CysLT₁ receptors on the membranes of bronchial smooth muscle cells.

Zafirlukast is a selective and reversible antagonist. It competitively occupies CysLT₁ receptors, preventing endogenous leukotrienes from binding to them and interrupting the pathological cascade at the final receptor stage.

Pharmacological effects

By blocking the receptor link, the drug eliminates the effects normally caused by CysLT₁ receptor activation. Key pharmacodynamic effects include:

• Reversal of bronchoconstriction: prevention and relief of bronchiolar smooth muscle spasm induced by leukotrienes.
• Anti-inflammatory action: reduction of microvascular wall permeability, leading to decreased plasma exudation and subsidence of airway mucosal edema.
• Reduction of secretion: inhibition of mucus hypersecretion by bronchial glands, which improves bronchial patency.
• Inhibition of cellular infiltration: reduction of eosinophil migration into the inflammation site.

Indications for use

The drug is intended for baseline therapy; its effect develops slowly (within 24 hours). It is not suitable for relieving acute status asthmaticus. In clinical practice, it is used for:

• Long-term prophylaxis and prevention of bronchial asthma attacks.
• Treatment of patients with "aspirin-induced" asthma, where antileukotriene drugs show particular pathogenetic efficacy.
• Symptomatic treatment of allergic rhinitis.

Side effects

The drug is generally well tolerated, but the following adverse reactions may occur:

• Common: dyspeptic disorders (including gastritis), headache, pharyngitis.
• Rare: development of Churg–Strauss syndrome (allergic granulomatous angiitis), a severe systemic vascular disorder.

Pharmacokinetic features and prescription

Absorption of zafirlukast from the intestine is slow and incomplete. The presence of food in the gastrointestinal tract significantly reduces its absorption. Therefore, the golden rule of administration is strictly on an empty stomach (1 hour before or 2 hours after a meal). The half-life ($t_{1/2}$) is about 10 hours, which dictates the need to take the drug twice daily.

Drug interactions: Unlike montelukast, zafirlukast is an inhibitor of hepatic microsomal enzymes (cytochrome P450 family). This requires high clinical vigilance: during combination therapy, zafirlukast can slow down the metabolism and prolong the action of other drugs.

Prescription example: Available in 0.02–0.04 g tablets.

Rp.: Tab. Zafirlukasti 0.02 D.t.d. N. 28 S. Oral, 1 tablet 2 times a day (strictly on an empty stomach).

Briefly: answers to topical questions

Class and exam questions

What else to study on this topic

• Arachidonic acid cascade and the role of 5-lipoxygenase
• Differences between leukotriene receptor antagonists and leukotriene synthesis inhibitors (zileuton)
• Pathogenesis of "aspirin-induced" bronchial asthma
• Churg–Strauss syndrome: etiology and clinical presentation
• Hepatic microsomal enzymes and cytochrome P450 isoenzymes

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