Pathophysiological Role of Leukotrienes
Leukotrienes are potent pro-asthmatic inflammatory mediators. Historically, cysteinyl leukotrienes (designated as LTC₄, LTD₄, LTE₄) were referred to as the "slow-reacting substance of anaphylaxis." In the body, they are released by mast cells and eosinophils.
The primary site of their pathological action is the respiratory tract. By binding to specific receptors, these substances cause a number of adverse effects:
- Bronchoconstriction (narrowing of the bronchial lumen).
- Mucus hypersecretion due to increased activity of bronchial glands.
- Mucosal edema, resulting from increased vascular permeability.
- Inflammatory tissue infiltration due to the accumulation of eosinophils.
Leukotriene Receptor Antagonists
This group includes montelukast and zafirlukast. Their target is the CysLT₁ receptors (cysteinyl leukotriene receptors type 1).
The mechanism of action involves the selective and reversible inhibition of these receptors. These drugs prevent endogenous leukotrienes from binding to airway cells. Consequently, the following pharmacological effects are achieved:
- Bronchospasm is suppressed.
- Mucosal edema is reduced.
- Bronchial gland secretion is decreased.
These drugs are used to prevent bronchial asthma attacks (showing particular efficacy in "aspirin-exacerbated" respiratory disease) and to treat allergic rhinitis.
Frequent side effects include headache and dyspeptic disorders. In rare cases, allergic granulomatous angiitis (Churg-Strauss syndrome) may develop. It is also important to consider that zafirlukast inhibits microsomal liver enzymes (cytochrome P450 family), requiring caution when combining it with other medications.
Leukotriene Synthesis Inhibitors
The sole representative of this group is zileuton. Unlike receptor antagonists, it interferes with the biochemical cascade at an earlier stage.
The drug's target is the enzyme 5-lipoxygenase. Zileuton blocks the activity of this enzyme, interrupting the conversion of arachidonic acid. This leads to the inhibition of the synthesis of all leukotriene groups:
- Cysteinyl leukotrienes (LTC₄, LTD₄, LTE₄), which are responsible for bronchospasm and edema.
- Leukotriene LTB₄, which normally causes chemotaxis (attracting neutrophils and eosinophils to the site of inflammation).
Thus, zileuton prevents the effects of all leukotrienes, including those mediated by CysLT₁ receptors. The drug is administered orally, binds extensively to blood proteins, and is metabolized in the liver. Its duration of action is approximately 5 hours. However, the clinical use of zileuton is strictly limited due to its marked hepatotoxicity.
Arachidonic Acid Cascade
To better understand the sites of action of these drugs, it is necessary to examine the metabolism of arachidonic acid in the cell cytosol:
- Initial stage: Arachidonic acid serves as the substrate. Under the action of the enzyme 5-lipoxygenase, it is converted into leukotriene LTA₄. This specific step is blocked by zileuton.
- Chemotaxis branch: Leukotriene LTB₄ is synthesized from LTA₄. It acts on eosinophils and neutrophils, recruiting them to the site of inflammation.
- Bronchospasm branch: LTA₄ is sequentially converted into cysteinyl leukotrienes: LTC₄ → LTD₄ → LTE₄.
- Receptor level: Cysteinyl leukotrienes exit the cell and activate CysLT₁ receptors, triggering eosinophil migration, edema, mucus secretion, and bronchial spasm. This final step is blocked by montelukast and zafirlukast.