The role of leukotrienes in the pathogenesis of bronchospasm
Cysteinyl leukotrienes (including $LTC_4$, $LTD_4$, and $LTE_4$ fractions) play a key role in the development of allergic and inflammatory reactions in the airways. Previously in medical literature, this complex of mediators was known as the "slow-reacting substance of anaphylaxis".
Released in tissues, leukotrienes stimulate specific CysLT receptors located on bronchiolar smooth muscle cells. This interaction triggers a cascade of reactions: potent bronchospasm occurs, vascular permeability increases, exudation is enhanced, and bronchial mucosal edema rapidly develops. Antileukotriene drugs are designed to break this pathological chain.
Classification and mechanisms of action
Pharmacological intervention in leukotriene metabolism is possible at two different stages. Accordingly, two main groups of drugs are distinguished:
- Leukotriene synthesis inhibitors (5-lipoxygenase inhibitors). The main representative of the group is zileuton. The drug acts at the stage of inflammatory mediator formation. It selectively inhibits the enzyme 5-lipoxygenase (5-LOX), thereby completely blocking the biosynthesis of leukotrienes from arachidonic acid.
- Leukotriene receptor blockers. This group includes zafirlukast, montelukast, and pranlukast. Their mechanism of action involves competitive receptor blockade. For example, zafirlukast selectively blocks $LTD_4$ receptors on smooth muscle cells. Drugs of this group do not prevent the formation of leukotrienes, but deprive them of the ability to bind to their target, reliably eliminating the bronchoconstrictor effect.
Pharmacological effects and clinical use
The main purpose of prescribing antileukotriene agents is the long-term treatment and prevention of bronchial asthma attacks, as well as the treatment of allergic rhinitis. It is important to understand that these drugs are not suitable for relieving acute attacks, diagnosis, or rehabilitation. The effect of their administration develops slowly (in the case of zafirlukast, about 24 hours).
In addition to eliminating bronchospasm caused by cysteinyl leukotrienes, receptor blockers exhibit pronounced anti-inflammatory effects. They decrease vascular wall permeability, reduce exudation, and relieve bronchial mucosal edema.
Pharmacokinetic features and safety
The drugs are administered orally, but have significant differences in metabolism:
- Zafirlukast: Absorption from the intestine is slow and incomplete. The presence of food in the stomach further impairs absorption, so the tablets should be taken strictly on an empty stomach (1 hour before meals or 2 hours after). The half-life is about 10 hours, which requires administration twice daily. The drug inhibits microsomal liver enzymes, which may prolong the action of other medications. Adverse effects: dyspepsia, gastritis, pharyngitis, headache.
- Montelukast: It is a selective CysLT receptor antagonist. Although it is also metabolized by microsomal liver enzymes, the drug itself does not inhibit them. This ensures a low potential for drug interactions at the metabolic level—montelukast does not alter the duration of action of other drugs.
- Zileuton: Characterized by rapid absorption from the gastrointestinal tract, but a very short half-life (only 1–2.3 hours). Fever, myalgia (muscle pain), dyspepsia, and dizziness may occur during its administration.
Pathogenesis of aspirin-induced asthma
A specific indication for prescribing zileuton is the prevention of aspirin-induced asthma—a severe bronchospasm triggered by the use of nonsteroidal anti-inflammatory drugs (NSAIDs).
This complication is based on the phenomenon of "substrate shunting". Non-selective cyclooxygenase inhibitors (especially acetylsalicylic acid) completely block the cyclooxygenase pathway of arachidonic acid metabolism. As a result, all accumulating arachidonic acid is "shunted" (redirected) to the alternative lipoxygenase pathway. This leads to excessive, uncontrolled synthesis of leukotrienes and, consequently, to asphyxia. Zileuton, by blocking 5-lipoxygenase, interrupts this pathway and prevents the development of bronchospasm.
To avoid confusion regarding the effect of these drugs on the liver, remember: Montelukast does not affect microsomal enzymes (safe for combination therapy), whereas zafirlukast inhibits them.
Class and exam questions
Why are antileukotriene drugs not used to relieve an acute asthma attack?
Their pharmacological effect develops too slowly (for example, about a day in the case of zafirlukast). These agents are intended exclusively for the long-term prevention of attacks, not for emergency relief.
How does food intake affect the pharmacokinetics of zafirlukast?
Food significantly worsens its already slow and incomplete intestinal absorption. Therefore, the drug must be taken strictly on an empty stomach: one hour before a meal or two hours after.
What is the essence of the "substrate shunting" phenomenon in aspirin-induced asthma?
Upon cyclooxygenase blockade by non-selective NSAIDs, all arachidonic acid is redirected to the lipoxygenase pathway. This causes a sharp, excessive synthesis of leukotrienes, which inevitably leads to bronchospasm.
What else to study on this topic
- Chemical structure of zafirlukast and montelukast
- Anti-inflammatory effects of leukotriene receptor blockers
- Adverse effects of zileuton: fever, myalgia, dizziness
- Use of antileukotriene agents in allergic rhinitis
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