Introduction
Montelukast is a widely used leukotriene receptor antagonist (LTRA) indicated for the management of asthma, allergic rhinitis, and exercise-induced bronchoconstriction. Since its approval by the U.S. Food and Drug Administration (FDA) in 1998, Montelukast has become a cornerstone in the treatment of respiratory conditions, especially for patients who cannot tolerate or require adjunctive therapy to inhaled corticosteroids.
This article provides a comprehensive overview of Montelukast, including its structure, pharmacological actions, medicinal chemistry, mechanism of action, clinical uses, side effects, contraindications, dosages, and practical considerations.
Structure of Montelukast
- IUPAC Name: 2-[1-({[(1R)-1-{3-[(E)-2-(7-chloroquinolin-2-yl)ethenyl]phenyl}-3-[2-(2-hydroxypropan-2-yl)phenyl]propyl]sulfanyl}methyl)cyclopropyl]acetic acid
- Molecular Formula: Cโโ HโโClNOโS
- Molecular Weight: ~586.2 g/mol
- Drug Class: Leukotriene receptor antagonist (LTRA)
- Structure Type: Synthetic small molecule
Montelukastโs structure consists of a quinoline core, a cyclopropyl acetic acid side chain, and various lipophilic substituents that enhance binding to leukotriene receptors in the airway smooth muscle.
Pharmacological Actions of Montelukast
Montelukast selectively inhibits cysteinyl leukotriene receptor type 1 (CysLT1). This receptor mediates airway inflammation and bronchoconstriction in asthma and allergic rhinitis.
- Anti-inflammatory action: Reduces leukotriene-mediated recruitment of eosinophils and other inflammatory cells.
- Bronchoprotective action: Prevents bronchospasm induced by allergens, cold air, or exercise.
- Anti-allergic effects: Reduces nasal congestion, rhinorrhea, sneezing, and itching in allergic rhinitis.
- Steroid-sparing effect: Provides additional control in patients who require inhaled corticosteroids.
Medicinal Chemistry of Montelukast
Montelukast was developed using structure-based drug design to mimic the activity of endogenous leukotrienes (LTCโ, LTDโ, and LTEโ), which are key mediators of airway inflammation.
- Key functional groups:
- Carboxylic acid group โ essential for receptor binding.
- Sulfanyl group โ enhances lipophilicity and receptor affinity.
- Quinoline moiety โ provides selectivity for CysLT1 over other leukotriene receptors.
- Lipophilicity (logP ~8.5): Allows effective penetration into airway tissues.
- Oral bioavailability (~64%): Enhanced by its lipophilic properties.
Mechanism of Action
Montelukast competitively binds to CysLT1 receptors in the airway smooth muscle and other pro-inflammatory cells.
- In normal physiology: Cysteinyl leukotrienes (LTCโ, LTDโ, LTEโ) bind to CysLT1 receptors โ causing bronchoconstriction, mucus secretion, vascular permeability, and eosinophil recruitment.
- With Montelukast:
- Blocks leukotriene binding to CysLT1 receptors.
- Prevents airway narrowing and hyperresponsiveness.
- Reduces airway inflammation and edema.
- Improves lung function and asthma control.
Clinical Uses of Montelukast
Montelukast has several FDA-approved and off-label uses:
1. Asthma
- Prophylactic and chronic treatment of asthma in adults and children โฅ12 months.
- Effective in patients with mild persistent asthma.
- Used as an add-on therapy in patients with moderate to severe asthma on inhaled corticosteroids.
2. Exercise-Induced Bronchoconstriction (EIB)
- Prevents bronchospasm when taken at least 2 hours before exercise.
- Useful for patients intolerant to ฮฒโ-agonists.
3. Allergic Rhinitis
- Effective in seasonal and perennial allergic rhinitis.
- Relieves nasal congestion, sneezing, itching, and rhinorrhea.
- May be used as monotherapy or combined with antihistamines.
4. Aspirin-Exacerbated Respiratory Disease (AERD)
- Beneficial in patients with asthma worsened by aspirin/NSAIDs.
5. Off-label Uses
- Atopic dermatitis (limited benefit).
- Chronic urticaria (in combination with antihistamines).
- Sleep apnea and other inflammatory airway conditions (experimental).
Side Effects of Montelukast
Montelukast is generally well-tolerated, but some serious adverse effects have been highlighted by regulatory bodies.
Common Side Effects
- Headache
- Abdominal pain, dyspepsia
- Fatigue
- Fever in pediatric patients
- Upper respiratory tract infections
Rare but Serious Side Effects
- Neuropsychiatric events: agitation, aggression, depression, anxiety, hallucinations, suicidal thoughts (boxed warning by FDA, 2020).
- Churg-Strauss Syndrome (Eosinophilic granulomatosis with polyangiitis) โ very rare, often associated with tapering corticosteroids.
- Hepatotoxicity (rare).
Contraindications
- Hypersensitivity to Montelukast or excipients.
- Caution in patients with:
- Pre-existing psychiatric disorders.
- Hepatic impairment.
- History of eosinophilic vasculitis.
Dosage and Administration
Asthma and Allergic Rhinitis
- Adults and adolescents (โฅ15 years): 10 mg once daily in the evening.
- Children (6โ14 years): 5 mg chewable tablet once daily.
- Children (2โ5 years): 4 mg chewable tablet once daily.
- Infants (6โ23 months): 4 mg oral granules once daily.
Exercise-Induced Bronchoconstriction
- Adults and adolescents (โฅ15 years): 10 mg at least 2 hours before exercise.
- Not recommended for children under 6 years.
Note: Montelukast is not meant for the relief of acute asthma attacks. A short-acting ฮฒโ-agonist (SABA) should always be available.
Drug Interactions
- CYP3A4 and CYP2C9 inducers (e.g., rifampin, phenytoin, carbamazepine) may reduce Montelukast plasma levels.
- No significant interaction with theophylline, warfarin, digoxin, or oral contraceptives.
Clinical Considerations
- Montelukast should be used as add-on therapy rather than first-line in persistent asthma.
- Monitor patients for neuropsychiatric symptoms, especially children and adolescents.
- Evaluate liver function in patients with long-term therapy.
- Patient education is crucial: this drug is for prevention, not for acute attacks.
Conclusion
Montelukast remains a valuable therapeutic option for managing asthma, allergic rhinitis, and exercise-induced bronchospasm, particularly in patients who require an oral alternative or adjunctive therapy to inhaled corticosteroids. Despite its favorable safety profile, healthcare professionals must remain vigilant about rare but serious neuropsychiatric side effects. Proper patient selection, counseling, and monitoring are key to maximizing the benefits of Montelukast therapy.
FAQs
Q1. What is Montelukast used for?
Montelukast is primarily used for the prevention and long-term treatment of asthma, allergic rhinitis, and exercise-induced bronchospasm. It is not intended for acute asthma attacks.
Q2. How does Montelukast work in asthma?
Montelukast works by blocking cysteinyl leukotriene receptors (CysLT1) in the airways, preventing bronchoconstriction, inflammation, and mucus production, thus improving lung function.
Q3. What are the major side effects of Montelukast?
Common side effects include headache, abdominal pain, and fatigue. Rare but serious side effects include neuropsychiatric events such as mood changes, depression, and suicidal thoughts.
Q4. Can Montelukast be used in children?
Yes, Montelukast is approved for use in children as young as 6 months, with age-appropriate dosing forms such as oral granules and chewable tablets.
Q5. Why did the FDA issue a warning on Montelukast?
In 2020, the FDA added a boxed warning about the risk of serious neuropsychiatric side effects, including suicidal thoughts and behavior, particularly in pediatric patients.
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