zileuton
Summary
Zileuton is a 5-lipoxygenase (5-LOX) inhibitor used in the treatment of chronic asthma. By blocking 5-LOX, it prevents the conversion of arachidonic acid to leukotrienes, reducing bronchoconstriction and inflammation. It is less commonly used than leukotriene receptor antagonists due to hepatotoxicity and dosing frequency.
Detail
Zileuton inhibits 5-lipoxygenase, the enzyme responsible for converting arachidonic acid into 5-HPETE and subsequently leukotrienes (LTB4, LTC4, LTD4, LTE4). This is distinct from leukotriene receptor antagonists (montelukast, zafirlukast), which block the CysLT1 receptor rather than leukotriene synthesis. By decreasing leukotriene production, zileuton reduces bronchoconstriction, mucus secretion, and vascular permeability associated with asthma exacerbations, making it useful for prophylaxis of chronic asthma (not for acute attacks). Clinically, it is used less frequently than montelukast due to: (1) need for more frequent dosing (up to 4 times daily for immediate-release formulation), (2) risk of hepatotoxicity requiring LFT monitoring, and (3) drug interactions via inhibition of CYP1A2 (affecting theophylline, warfarin metabolism). Key boards-relevant associations: leukotrienes are important mediators in asthma, particularly LTC4/D4/E4 causing bronchoconstriction, increased vascular permeability, and mucus production; LTB4 is a neutrophil chemoattractant. Zileuton and leukotriene modifiers are particularly useful in aspirin-exacerbated respiratory disease (AERD, Samter's triad: asthma, aspirin sensitivity, nasal polyps) because aspirin/NSAIDs shunt arachidonic acid metabolism toward the lipoxygenase pathway, increasing leukotriene production.
Sources
- First Aid for the USMLE Step 1
- Katzung's Basic and Clinical Pharmacology
- Goodman & Gilman's The Pharmacological Basis of Therapeutics
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