What are Leukotriene Receptor Antagonists (LTRAs)?
Leukotriene receptor antagonists (LTRAs) are oral anti-inflammatory medications that block leukotriene mediators released from mast cells, eosinophils, and basophils, providing both bronchodilator and anti-inflammatory effects for asthma management. 1
Mechanism of Action
LTRAs interfere with the leukotriene pathway by blocking cysteinyl leukotriene receptors (CysLT1 and CysLT2 subtypes). This unique mechanism creates a hybrid effect—combining anti-inflammatory properties with bronchodilation—distinguishing them from other asthma medications 2, 3.
Available Agents
The two widely available LTRAs are:
- Montelukast (Singulair): Approved for patients older than 1 year, taken once daily 4
- Zafirlukast (Accolate): Approved for patients 7 years and older, taken twice daily 4
A third agent, zileuton, is a 5-lipoxygenase inhibitor (not technically an LTRA but part of the leukotriene modifier class) that requires liver function monitoring 1.
Clinical Role in Asthma Management
Mild Persistent Asthma (Step 2 Care)
LTRAs serve as alternative, but not preferred, therapy for mild persistent asthma. 1 Inhaled corticosteroids (ICS) remain superior—they improve asthma control more effectively than LTRAs in both children and adults 1. However, LTRAs offer advantages in ease of use, high compliance rates, and oral administration for patients unable or unwilling to use ICS 4.
Moderate to Severe Persistent Asthma (Step 3+ Care)
LTRAs can be added as adjunctive therapy with ICS, but for patients 12 years and older, they are not the preferred add-on compared to long-acting beta-agonists (LABAs). 1 The combination of ICS plus LABA consistently outperforms ICS plus LTRA 4, 5.
Special Indications
LTRAs are particularly useful for:
- Exercise-induced bronchoconstriction (EIB): They can attenuate EIB effectively 1
- Aspirin-sensitive asthma: LTRAs may provide specific benefit in this population 6
- Allergic rhinitis: They show efficacy in treating coexisting allergic rhinitis 7, 2
Key Clinical Advantages
- Oral formulation: Once or twice daily dosing improves adherence 2, 8
- No device technique required: Unlike inhalers, eliminating technique-related failures
- Anti-inflammatory effects: Reduce blood eosinophils and airway inflammation 8, 6
- Corticosteroid-sparing: May allow reduction in ICS doses when used as add-on therapy 8, 6
Important Safety Considerations
The FDA issued a Boxed Warning for montelukast in March 2020 regarding neuropsychiatric adverse events. 9 These include agitation, depression, sleep disturbances, and suicidal thoughts. While overall adverse events with LTRAs are generally mild, clinicians must weigh this serious risk, particularly for long-term use 4, 3.
Clinical Pitfalls to Avoid
- Never use LTRAs as monotherapy for moderate-to-severe asthma: They are less effective than ICS 1, 10
- Don't add LTRAs as a third controller: In severe persistent asthma already on high-dose ICS plus LABA, adding an LTRA provides no additional benefit 5
- Monitor for neuropsychiatric effects: Particularly important given the FDA Boxed Warning for montelukast 9
- Zileuton requires liver monitoring: Essential for safe use 1
Comparative Effectiveness
When compared head-to-head with other therapies:
- Less effective than ICS for asthma control in all age groups 1, 10
- Similar to oral antihistamines for allergic rhinitis in seasonal allergic rhinitis, but oral antihistamines may be slightly better for perennial allergic rhinitis 7
- Less preferred than LABA as add-on therapy to ICS in patients ≥12 years 1