Montelukast and Zafirlukast are Cysteinyl Leukotriene Receptor Antagonists (LTRAs) used in the prophylactic treatment of asthma , particularly when triggered by antigens, exercise, or drugs (e.g., aspirin) .
Classification of Leukotriene Modulators
| Class | Example | Mechanism |
|---|---|---|
| 5-Lipoxygenase Inhibitor | Zileuton | Inhibits leukotriene synthesis |
| Cysteinyl Leukotriene Receptor Antagonists (CysLT1) | Montelukast, Zafirlukast | Blocks receptor binding of LTC4, LTD4, and LTE4 |
What Are Leukotrienes?
- Fatty acid-derived eicosanoids formed from arachidonic acid via the 5-lipoxygenase enzyme pathway.
- Released by mast cells, eosinophils , and basophils upon allergen exposure.
- Mediate bronchoconstriction, vascular permeability (edema) , and eosinophil recruitment .
Types
- LTB4 : Strong chemoattractant , promotes neutrophil migration.
- LTC4, LTD4, LTE4 (Cysteinyl leukotrienes): Mediate bronchospasm , mucosal edema , and eosinophilic inflammation .
Montelukast
- Chemical Class : Leukotriene Receptor Antagonist
- Therapeutic Class : Antiasthmatic
- Pregnancy Category : B
- Bioavailability : >90%
- Protein Binding : ~99%
- Half-life : ~2.7–5.5 hours
- Metabolism : Liver (CYP3A4, CYP2C9)
- Excretion : Biliary
Mechanism of Action
Blocks CysLT1 receptors → prevents actions of LTC4, LTD4, LTE4 → reduces bronchoconstriction, inflammation, and edema .
Indications
| Condition | Dose |
|---|---|
| Asthma prophylaxis | 10 mg once daily (evening) |
| Exercise-induced bronchoconstriction | 10 mg, 2 hrs before activity |
| Allergic rhinitis | 10 mg once daily |
| Pediatric dosing | 12–24 mo: 4 mg granules 2–5 yrs: 4 mg chewable 6–14 yrs: 5 mg chewable >15 yrs: Adult dose |
Zafirlukast
- Use : Maintenance treatment of asthma
- Dose : 20 mg twice daily (adults), 10 mg twice daily (ages 5–12)
- Administration : Take 1 hour before or 2 hours after meals for optimal absorption.
Clinical Pharmacology
- Not a bronchodilator for acute asthma attacks.
- Used as add-on therapy in patients not controlled on inhaled corticosteroids and short-acting β2-agonists.
Adverse Effects
Montelukast & Zafirlukast
- Common : Headache, abdominal pain, fatigue, fever
- Neuropsychiatric : Agitation, depression, insomnia, suicidal ideation, hallucinations (especially Montelukast – black box warning)
- Respiratory : Cough, pharyngitis, sinusitis
- GI : Diarrhea, liver enzyme elevation (esp. Zafirlukast)
- Rare : Churg-Strauss syndrome (eosinophilic vasculitis), hypersensitivity reactions, hepatotoxicity, Stevens-Johnson syndrome
Drug Interactions
| Drug | Effect |
|---|---|
| Phenobarbital | ↓ Montelukast levels (enzyme inducer) |
| Warfarin | ↑ Prothrombin time (Zafirlukast) |
| Erythromycin | ↓ Zafirlukast absorption |
| Theophylline | ↑ Plasma levels (Zafirlukast) |
Warnings and Precautions
- Not for acute asthma or status asthmaticus .
- Do not substitute abruptly for corticosteroids .
- Monitor closely during steroid tapering for signs of vasculitis (Churg-Strauss) .
- Monitor for neuropsychiatric symptoms during therapy initiation and dose changes.
- Avoid NSAIDs in aspirin-sensitive patients; Montelukast may not prevent reactions.
- Zafirlukast is contraindicated in pregnancy and breastfeeding .
- Caution in phenylketonuria patients: Chewable forms contain phenylalanine.
Clinical Pearls
- Montelukast is especially beneficial in:
- Aspirin-sensitive asthma
- Exercise-induced bronchospasm
- Children with persistent asthma
- Evening administration preferred for maximum symptom control.
- Monitor liver function periodically, especially with Zafirlukast.
