Leukotriene Pathway Inhibitors

• Background
  • Leukotriene production:
    • action to 5-lipoxygenase on arachidonic acid
    • synthesized by inflammatory cells found in the airway, including:
      •  eosinophils
      •  macrophages
      •  mast cells
      •  basophils
    • Leukotriene B₄ (neutrophil chemoattractant), leukotriene C₄, and leukotriene D₄ provoke symptoms consistent with those seen in asthma:
      •  bronchoconstriction
      •  mucosal edema
      •  mucus hypersecretion
      •  increase bronchial reactivity

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• Interruption of leukotriene pathways:
  • Inhibition of 5-lipoxygenase-- zileuton
    • Rationale: prevents leukotriene synthesis
    • effective for maintenance treatment of asthma
    • requires monitoring for hepatic toxicity
    • metabolized by cytochrome P450 1A2, 2C9, 3A4:
      • can decrease clearance; increasing concentration of:
        •  theophylline
        •  warfarin (Coumadin)
        •  propranolol (Inderal)

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  • Inhibition of leukotriene D₄ receptor binding -- zafirlukast (Accolate), montelukast (Singulair)
    • Zafirlukast (Accolate):
      • modestly effective for maintenance treatment in mild to moderate asthmatics
      • less effective than inhaled beclomethasone
      •  bioavailability decreases significantly with food
      • theophylline may also decrease its effect
      • zafirlukast: increases serum concentration of oral anticoagulants (made provoke bleeding)
    • Montelukast (Singulair):
      • leukotriene D₄ receptor antagonist
      • modestly effective for maintenance treatment of adults and children with intermittent/persistent asthma
      • less effective than inhaled corticosteroids (addition to montelukast may reduce corticosteroid dosage requirement)
      • montelukast, added to oral/inhaled corticosteroids, improves asthma patients with aspirin-intolerant asthma
      • only leukotriene drug FDA approved for use in children 6 to 12 years old

• Orally effective;may be especially effective in reducing response to aspirin in those asthmatics very sensitive to aspirin

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• Other drug groups possibly beneficial in asthma management:
  • calcium channel blockers
  • nitric oxide donors
  • potassium channel activators
  • Anti-IgE Monoclonal Antibodies