What is the mechanism of action of leukotriene inhibitors, such as montelukast (singulair)?

Mechanism of Action of Leukotriene Inhibitors

Leukotriene inhibitors like montelukast work by selectively blocking the cysteinyl leukotriene type-1 (CysLT1) receptor, thereby preventing proinflammatory lipid mediators from promoting airway smooth muscle contraction, mucus production, and inflammatory cell recruitment. 1, 2

Biochemical Pathway

Cysteinyl leukotrienes (LTC4, LTD4, LTE4) are products of arachidonic acid metabolism that are released from inflammatory cells including mast cells, eosinophils, and macrophages in the respiratory mucosa when exposed to asthma triggers. 1, 2, 3

These eicosanoids bind to CysLT receptors found throughout the human airway, including:

• Airway smooth muscle cells 2
• Airway macrophages 2
• Eosinophils and myeloid stem cells 2
• Epithelial cells 1

Specific Receptor Antagonism

Montelukast is an orally active compound that binds with high affinity and selectivity to the CysLT1 receptor, inhibiting the physiologic actions of LTD4 without any agonist activity. 2

The drug demonstrates preferential binding to CysLT1 receptors over other pharmacologically important airway receptors such as:

• Prostanoid receptors 2
• Cholinergic receptors 2
• β-adrenergic receptors 2

Dual Mechanism: Anti-Inflammatory and Bronchodilatory Effects

By blocking the leukotriene pathway, montelukast exhibits both modest anti-inflammatory and bronchodilating activity. 1

Anti-Inflammatory Actions:

• Reduces airway edema by decreasing venopermeability 3
• Inhibits eosinophil migration into airway mucosa 3
• Decreases mucus secretion and hypersecretion 3
• Reduces release of RANTES (CCL5), an eosinophil chemoattractant, from dendritic cells 4
• Lowers leukotriene concentrations in respiratory tract secretions, with documented reductions in LTC4 from 5.03 ng/mL to 1.42 ng/mL after 4 weeks of treatment 5

Bronchodilatory Actions:

• Prevents smooth muscle contraction induced by cysteinyl leukotrienes 1
• Blocks bronchoconstriction from various triggers including exercise, cold air, allergen exposure, and aspirin challenge 3, 6
• Provides prolonged, potent antagonism of LTD4-induced bronchoconstriction lasting at least 20 hours after a single dose 6

Clinical Pharmacology

Montelukast acts within 1 to 2 hours of oral administration and maintains bronchoprotective activity for 24 hours. 1

The drug demonstrates:

• Rapid absorption with peak plasma concentration (Cmax) achieved in 2-4 hours depending on formulation 2
• High oral bioavailability of 64-73% 2
• Extensive plasma protein binding (>99%) 2
• Minimal blood-brain barrier penetration 2

Variability in Response

There is significant inter-patient variability in response to leukotriene inhibitors, with approximately 50% of patients being responders showing 30-80% attenuation of exercise-induced bronchoconstriction. 1

This variability reflects the fact that multiple mediators (including prostaglandin D2 and histamine) contribute to airway inflammation and bronchoconstriction, not just leukotrienes. 1 The incomplete protection observed in some patients confirms that leukotrienes are important but not the sole mediators in asthma pathophysiology. 1

Key Advantage: No Tolerance Development

Unlike long-acting beta-agonists, tolerance does not develop with long-term use of leukotriene receptor antagonists. 1 This makes montelukast particularly valuable for daily maintenance therapy and intermittent prophylaxis of exercise-induced bronchoconstriction. 1