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 localization of their pathological effect is the respiratory tract. By binding to specific receptors, these substances induce a series of adverse effects:
- Bronchoconstriction (narrowing of the bronchial lumen).
- Mucus hypersecretion due to increased activity of bronchial glands.
- Mucosal edema resulting from increased vascular wall permeability.
- Inflammatory infiltration of tissues due to the accumulation of eosinophils.
Leukotriene receptor blockers
This group includes montelukast and zafirlukast. Their target is the CysLT₁ receptors (cysteinyl leukotriene type 1 receptors).
The mechanism of action involves the selective and reversible inhibition of these receptors. The drugs prevent endogenous leukotrienes from binding to airway cells. As a result, the following pharmacological effects are achieved:
- Bronchospasm is suppressed.
- Mucosal edema is reduced.
- The production of secretion by bronchial glands is decreased.
These medications are used to prevent asthma attacks (showing particular efficacy in the "aspirin-induced" form of the disease) and to treat allergic rhinitis.
Common 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), so it must be combined with other medications with caution.
Leukotriene synthesis inhibitors
The sole representative of this group is zileuton. Unlike receptor blockers, 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 induces 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, actively binds 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 pronounced hepatotoxicity.
Arachidonic acid biochemical cascade
To better understand the sites of drug action, it is necessary to examine the logic of arachidonic acid metabolism 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 inflammation zone.
- Bronchospasm branch: LTA₄ is sequentially converted into cysteinyl leukotrienes: LTC₄ → LTD₄ → LTE₄.
- Receptor link: Cysteinyl leukotrienes exit the cell and activate CysLT₁ receptors, triggering eosinophil migration, edema, mucus secretion, and bronchial spasm. This final stage is blocked by montelukast and zafirlukast.
Briefly: answers to topical questions
What are the precise pharmacokinetic parameters of zileuton?
The precise pharmacokinetic parameters of zileuton include the characteristics of its absorption, distribution, metabolism, and elimination.
- Route of administration — oral.
- Absorption — rapid from the gastrointestinal tract.
- Plasma protein binding — high.
- Metabolism — occurs in the liver.
- Half-life — short, approximately 1–2.3 hours.
- Duration of action — about 5 hours.
Class and exam questions
What is the difference between the mechanisms of action of zileuton and montelukast?
Zileuton blocks the enzyme 5-lipoxygenase, halting the synthesis of all types of leukotrienes from arachidonic acid. Montelukast acts at the level of target cells, selectively blocking CysLT₁ receptors from already synthesized cysteinyl leukotrienes.
Why is zileuton rarely used?
Its use is severely restricted due to pronounced hepatotoxicity—the ability to exert damaging effects on the liver.
In which form of asthma are receptor blockers particularly effective?
Drugs of this group (montelukast, zafirlukast) demonstrate special efficacy in the prevention of "aspirin-induced" asthma attacks.
What is the "slow-reacting substance of anaphylaxis"?
This is the historical name for cysteinyl leukotrienes (LTC₄, LTD₄, LTE₄). They are released by mast cells and eosinophils, acting as potent pro-asthmatic mediators.
What else to study on this topic
- The role of 5-lipoxygenase in the arachidonic acid cascade.
- The pathogenesis of "aspirin-induced" bronchial asthma.
- Churg-Strauss syndrome: etiology and relationship with pharmacotherapy.
- The effect of zafirlukast on microsomal liver enzymes (cytochrome P450).
- Mechanisms of leukocyte chemotaxis mediated by leukotriene B₄.
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