A patient with moderate persistent asthma inadequately controlled on inhaled corticosteroids is considered for zileuton. Compared with montelukast, zileuton differs mechanistically because it:

• A Blocks the cysteinyl leukotriene receptor type 1
• B Antagonizes thromboxane A2 receptors on airway smooth muscle
• C Inhibits phospholipase A2, blocking arachidonic acid release
• D Inhibits 5-lipoxygenase, preventing leukotriene synthesis itself ✓

Explanation

Zileuton is the only marketed direct inhibitor of 5-lipoxygenase, the enzyme that converts arachidonic acid to leukotriene A4, thereby reducing formation of all leukotrienes including LTB4 and the cysteinyl leukotrienes. Montelukast and zafirlukast act downstream as competitive antagonists at the CysLT1 receptor. Zileuton does not touch phospholipase A2 or thromboxane receptors. Its clinically important baggage is hepatotoxicity, mandating liver enzyme monitoring during therapy.

Reference: Katzung Basic and Clinical Pharmacology, 15th ed.

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