Montelukast

1. Drug Name

• Generic Name: Montelukast

• Brand Names: Singulair, Montair, Similuk

2. Drug Classification

• Class: Leukotriene Receptor Antagonist (LTRA)

• Subclass: Anti-inflammatory agent used in the management of asthma and allergic rhinitis.

3. Mechanism of Action

• Leukotriene Receptor Blockade: Montelukast acts by selectively binding to and inhibiting the cysteinyl leukotriene 1 (CysLT1) receptor. Leukotrienes are inflammatory mediators produced during allergic reactions and asthma exacerbations. By blocking the CysLT1 receptor, montelukast prevents leukotrienes from exerting their effects on airway inflammation, bronchoconstriction, mucus secretion, and vascular permeability.

• Reduction of Inflammatory Response: Leukotrienes, which include LTC4, LTD4, and LTE4, are involved in the pathophysiology of asthma and allergic rhinitis. These mediators promote bronchoconstriction, increased vascular permeability, and eosinophilic inflammation. By inhibiting these leukotrienes, montelukast helps to reduce airway inflammation and prevent bronchospasm in asthma, as well as nasal congestion in allergic rhinitis.

4. Pharmacokinetics

• Absorption:

  • Bioavailability: Montelukast is well absorbed after oral administration, with a bioavailability of approximately 64%.

  • Tmax (Time to Peak Plasma Concentration): Peak plasma concentrations are reached within 2–4 hours after oral ingestion.

  • Food Effects: Food does not significantly affect the absorption of montelukast.

• Distribution:

  • Volume of Distribution (Vd): The volume of distribution is approximately 8–11 L in healthy adults.

  • Protein Binding: Montelukast is highly protein-bound (approximately 99%).

• Metabolism:

  • Montelukast is extensively metabolized by the liver via cytochrome P450 enzymes, primarily CYP3A4 and CYP2C9.

  • It has a relatively minor effect on CYP enzymes, and thus it is unlikely to cause significant interactions with drugs metabolized by these pathways.

• Excretion:

  • Half-life (t½): The elimination half-life of montelukast is approximately 2.7 to 5.5 hours in healthy adults.

  • Excretion: It is primarily excreted in the feces (86%), with a minor amount excreted in the urine (0.2% of the dose).

5. Indications

• Primary Indications:

  • Asthma: Montelukast is used for the prophylaxis and chronic treatment of asthma, including the prevention of exercise-induced bronchoconstriction (EIB).

  • Allergic Rhinitis: It is also indicated for the relief of symptoms associated with seasonal and perennial allergic rhinitis, such as sneezing, itching, and nasal congestion.

• Off-Label Uses:

  • Chronic Urticaria: Montelukast has been used off-label to manage chronic idiopathic urticaria, though it is not a first-line treatment.

  • Allergic Asthma: In patients with allergic asthma, montelukast may be used as an adjunct to other asthma therapies.

  • Sinusitis: Sometimes used in combination with other treatments for chronic sinusitis, especially in cases where allergic rhinitis is contributing to the symptoms.

• Special Populations:

  • Pediatrics: Approved for use in children aged 2 years and older for asthma and allergic rhinitis.

  • Geriatrics: Generally safe for use in elderly patients, but should be used with caution if there are any liver function concerns.

6. Dosage and Administration

• Adult Dosing:

  • Asthma:

    • Oral (Tablet): 10 mg once daily in the evening.

  • Allergic Rhinitis:

    • Oral (Tablet): 10 mg once daily, preferably in the evening.

  • Exercise-induced Bronchoconstriction (EIB): 10 mg taken at least 2 hours before exercise.

• Pediatric Dosing:

  • Asthma:

    • Children aged 6 to 14 years: 5 mg once daily (chewable tablet).

    • Children aged 2 to 5 years: 4 mg once daily (chewable tablet).

  • Allergic Rhinitis:

    • Children aged 6 to 14 years: 5 mg once daily.

    • Children aged 2 to 5 years: 4 mg once daily.

• Renal or Hepatic Impairment:

  • No dose adjustment is required for mild to moderate hepatic or renal impairment, but montelukast should be used with caution in patients with severe hepatic impairment due to limited data.

7. Contraindications

• Absolute Contraindications:

  • Hypersensitivity to montelukast or any of its excipients.

• Relative Contraindications:

  • Active Liver Disease: Patients with active hepatic disease or cirrhosis should use montelukast with caution.

  • Severe Allergic Reactions: Though rare, anaphylaxis and other serious allergic reactions can occur. Discontinue use if these occur.

8. Warnings and Precautions

• Neuropsychiatric Events: Montelukast has been associated with mood and behavioral changes, including agitation, aggression, depression, anxiety, and suicidal thoughts. Monitor patients, especially children and adolescents, for any new or worsening psychiatric symptoms.

• Eosinophilic Conditions: In rare cases, patients on montelukast may experience eosinophilic conditions such as Churg-Strauss syndrome, which can present with symptoms of vasculitis and worsening asthma. Monitoring should be conducted in patients who are withdrawn from oral corticosteroids.

• Hepatic Dysfunction: Caution is recommended in patients with liver dysfunction as montelukast is metabolized by the liver.

9. Adverse Effects

• Common Adverse Effects:

  • Respiratory: Cough, sore throat.

  • Gastrointestinal: Diarrhea, abdominal pain.

  • Central Nervous System: Headache, dizziness.

• Less Common but Clinically Significant:

  • Neuropsychiatric: Anxiety, depression, irritability, insomnia, and in rare cases, suicidal ideation.

• Rare/Serious:

  • Anaphylaxis: Severe allergic reactions, though uncommon, can include symptoms like swelling, rash, and difficulty breathing.

  • Eosinophilic Conditions: Churg-Strauss syndrome with eosinophilia leading to vasculitis and other systemic symptoms.

10. Drug Interactions

• CYP450 Enzyme Interactions: Montelukast is minimally metabolized by the CYP450 system, and is not significantly affected by inhibitors or inducers of CYP enzymes. However, caution is still needed when co-administered with medications that impact the CYP3A4 enzyme (e.g., ketoconazole).

• Warfarin: Caution is advised when montelukast is used with warfarin, as montelukast may slightly alter the anticoagulant effect.

• Other Respiratory Medications: Combination with other asthma medications (e.g., corticosteroids, beta-agonists) is common, but no significant pharmacodynamic interactions are reported.

11. Clinical Pharmacology

• Pharmacodynamics: Montelukast effectively blocks the actions of cysteinyl leukotrienes at the CysLT1 receptor, leading to a reduction in bronchoconstriction, inflammatory cell recruitment, and mucus production in the airways.

• Additional Effects: It improves airway function by reducing inflammation, preventing bronchospasm, and limiting allergic reactions in the upper and lower respiratory tracts.

12. Special Populations

• Pregnancy: Category B. Montelukast is considered safe for use during pregnancy based on animal studies. However, it should only be used during pregnancy if the potential benefit outweighs the risk.

• Lactation: Montelukast is excreted in breast milk in small amounts. It is generally considered safe during breastfeeding, but it should be used cautiously.

• Pediatrics: Approved for use in children aged 2 years and older for both asthma and allergic rhinitis.

• Geriatrics: No dose adjustment is necessary for elderly patients, but caution should be exercised in patients with comorbid conditions.

13. Therapeutic Uses

• Asthma: Montelukast is a key part of long-term asthma management, particularly in patients who experience frequent exacerbations or in those who are not adequately controlled with inhaled corticosteroids alone.

• Allergic Rhinitis: Used for seasonal and perennial allergic rhinitis, often in combination with antihistamines for optimal symptom control.

• Exercise-induced Bronchoconstriction (EIB): Often used as a preventive measure before physical activity.

• Adjunct Therapy: May be used as adjunct therapy in patients requiring additional asthma control alongside inhaled corticosteroids or long-acting beta-agonists.

14. Monitoring and Follow-Up

• Pulmonary Function: Monitor asthma control using spirometry or peak flow measurements.

• Psychiatric Symptoms: Regular monitoring for new or worsening neuropsychiatric symptoms, especially in children and adolescents.

• Liver Function: Consider routine liver function tests if there is concern for hepatic dysfunction.

15. Overdose Management

• Symptoms of Overdose: Overdose may present with symptoms such as drowsiness, thirst, abdominal pain, and headache.

• Management: Treatment is symptomatic and supportive. There is no specific antidote for montelukast overdose. Gastric lavage or activated charcoal may be considered in cases of recent ingestion.

16. Patient Counseling Information

• Administration: Advise patients to take montelukast in the evening, even when symptoms are not present, to ensure consistent therapy.

• Neuropsychiatric Effects: Inform patients and caregivers about the potential for mood changes, anxiety, or depression, and to report any new or unusual behavioral changes.

• Importance of Adherence: Emphasize the importance of taking the medication as prescribed and not stopping it abruptly, even if symptoms improve.