Role of Leukotrienes in the Pathogenesis of Bronchospasm
Cysteinyl leukotrienes (specifically fractions $LTC_4$, $LTD_4$, and $LTE_4$) play a key role in the development of allergic and inflammatory reactions in the airways. Historically, this complex of mediators was known as the "slow-reacting substance of anaphylaxis" (SRS-A).
When released in tissues, leukotrienes stimulate specific CysLT receptors located on bronchiolar smooth muscle cells. This interaction triggers a cascade of reactions: severe bronchospasm develops, vascular permeability increases, exudation rises, and bronchial mucosal edema rapidly progresses. 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, drugs are divided into two main groups:
- Leukotriene synthesis inhibitors (5-lipoxygenase inhibitors). The primary representative is zileuton. This 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 antagonists. This group includes zafirlukast, montelukast, and pranlukast. Their mechanism of action relies on competitive receptor blockade. For instance, zafirlukast selectively blocks $LTD_4$ receptors on smooth muscle cells. These drugs do not prevent leukotriene formation, but they deny them access to their targets, reliably eliminating bronchoconstrictor effects.
Pharmacological Effects and Clinical Indications
The primary goal of prescribing antileukotriene agents is the long-term treatment and prophylaxis of bronchial asthma, as well as the management of allergic rhinitis. It is essential to understand that these drugs are not suitable for relieving acute attacks, diagnosis, or emergency rescue. The therapeutic effect develops slowly (taking approximately 24 hours in the case of zafirlukast).
In addition to relieving leukotriene-mediated bronchospasm, receptor antagonists exert marked anti-inflammatory effects. They decrease vascular permeability, reduce exudation, and relieve bronchial mucosal edema.
Pharmacokinetics and Safety Profiles
These drugs are administered orally, but they exhibit significant pharmacokinetic differences:
- Zafirlukast: Intestinal absorption is slow and incomplete. The presence of food in the stomach further impairs absorption, so tablets must be taken strictly on an empty stomach (1 hour before or 2 hours after meals). The half-life is approximately 10 hours, requiring twice-daily administration. The drug inhibits hepatic microsomal enzymes, which can prolong the action of other medications. Adverse effects include dyspepsia, gastritis, pharyngitis, and headache.
- Montelukast: A selective CysLT receptor antagonist. Although it is also metabolized by hepatic microsomal enzymes, it does not inhibit them. This results in a low potential for metabolic drug interactions—montelukast does not alter the duration of action of other drugs.
- Zileuton: Rapidly absorbed from the gastrointestinal tract, but has a very short half-life (only 1–2.3 hours). Adverse effects may include fever, myalgia, dyspepsia, and dizziness.
Pathogenesis of Aspirin-Exacerbated Respiratory Disease
A specific indication for zileuton is the prevention of aspirin-exacerbated respiratory disease (AERD), also known as "aspirin-induced asthma"—a severe bronchospasm triggered by nonsteroidal anti-inflammatory drugs (NSAIDs).
This complication is driven by the phenomenon of "substrate shunting." Non-selective cyclooxygenase (COX) inhibitors (especially acetylsalicylic acid) completely block the cyclooxygenase pathway of arachidonic acid metabolism. As a result, all accumulating arachidonic acid is shunted (redirected) into the alternative lipoxygenase pathway. This leads to excessive, uncontrolled leukotriene synthesis and subsequent severe bronchospasm. By inhibiting 5-lipoxygenase, zileuton interrupts this pathway and prevents bronchospasm.