Leukotriene Modifiers

Intro & MOA - Pathway Power

• Leukotrienes (LTs): Pro-inflammatory lipid mediators. Synthesized from Arachidonic Acid (AA) via the 5-Lipoxygenase (5-LOX) pathway.
  • Key enzyme: 5-LOX.
  • Main types: LTB$_4$ (chemotaxis) and Cysteinyl LTs (CysLTs: LTC$_4$, LTD$_4$, LTE$_4$).

• LT Pathophysiological Roles:

  • LTB$_4$: Powerful chemoattractant for neutrophils & eosinophils.
  • CysLTs: Induce bronchoconstriction (many times > histamine), ↑vascular permeability, ↑mucus secretion, and airway inflammation. 📌 "L"eukotrienes = "L"ung inflammation.

• General MOA of Leukotriene Modifiers:

  • Synthesis Inhibition: Block 5-LOX enzyme (e.g., Zileuton).
  • Receptor Antagonism: Block CysLT$_1$ receptors (e.g., Montelukast, Zafirlukast).

⭐ CysLTs, particularly LTD$_4$, are key mediators in asthma pathophysiology, causing prolonged bronchoconstriction.

Classification & Drugs - The Modulator Squad

Leukotriene modifiers target the inflammatory pathway. Two main classes:

• 5-Lipoxygenase (5-LOX) Inhibitors: Directly block leukotriene synthesis.
• Cysteinyl Leukotriene Receptor Antagonists (LTRAs): Block leukotriene action at CysLT1 receptors. 📌 LUKASTs block Leukotriene receptors.

PK & Clinical Uses - Action Stations

• Pharmacokinetics (PK)
  • Zileuton (5-LOX Inhibitor)
    • Metabolism: CYP1A2, 2C9, 3A4.
    • Interactions: ↑ Theophylline, Warfarin levels. Requires LFT monitoring.
  • Zafirlukast (CysLT1 Antagonist)
    • Metabolism: CYP2C9 (major), CYP3A4 (minor).
    • Interactions: ↑ Warfarin. Food ↓ bioavailability.
  • Montelukast (CysLT1 Antagonist)
    • Metabolism: CYP3A4, 2C9.
    • Minimal drug interactions; generally well-tolerated. No LFT monitoring needed.
• Clinical Uses
  • Prophylaxis: Mild-moderate persistent asthma.
  • Aspirin-Exacerbated Respiratory Disease (AERD).
  • Exercise-Induced Bronchoconstriction (EIB): Dose 2 hours pre-exercise.
  • Allergic Rhinitis (especially Montelukast).
  • ⚠️ Key Point: NOT effective for acute asthma attacks.
• ⭐ Exam Favourite Fact

  Churg-Strauss syndrome (allergic granulomatosis with angiitis) has been rarely reported in patients with asthma being treated with Zafirlukast or Montelukast, often after steroid withdrawal.

AEs & Interactions - Safety Signals

*   Hypersensitivity
*   Acute asthma attacks
*   Liver disease (for Zileuton)

⭐ Montelukast carries an FDA warning for serious neuropsychiatric events, including suicidal ideation and behavioral changes.

High‑Yield Points - ⚡ Biggest Takeaways

• Leukotriene modifiers block the leukotriene pathway; not for acute asthma attacks.
• Montelukast & Zafirlukast are LTD4 receptor antagonists; Zileuton inhibits 5-lipoxygenase.
• Used for prophylaxis of mild-moderate asthma (esp. aspirin-induced) & allergic rhinitis.
• All are orally administered for chronic therapy.
• Zileuton: Major risk of hepatotoxicity (monitor LFTs).
• Zafirlukast & Zileuton: CYP450 enzyme inhibitors (e.g., ↑warfarin).
• Rare: Neuropsychiatric events (montelukast/zafirlukast); Churg-Strauss syndrome.