Leukotriene modifiers

Drug Class: Leukotriene receptor antagonists and 5-lipoxygenase inhibitors
Examples of Generic Names:
Montelukast
Zafirlukast
Zileuton

Brand Names:
Montelukast – Singulair
Zafirlukast – Accolate
Zileuton – Zyflo

Formulation:
Oral tablets
Oral granules (montelukast)
Chewable tablets (montelukast)
Extended-release tablets (zileuton)

Available Presentation:
Montelukast – 4 mg, 5 mg (chewable); 10 mg tablet; 4 mg oral granules
Zafirlukast – 10 mg, 20 mg tablets
Zileuton – 600 mg extended-release tablets

Route of Administration:
Oral

Mechanism of Action:
Leukotriene modifiers interfere with the leukotriene pathway, which plays a central role in inflammation, bronchoconstriction, and mucus production in asthma and allergic rhinitis.
Montelukast and zafirlukast are leukotriene receptor antagonists. They selectively block cysteinyl leukotriene receptors (CysLT1) on airway smooth muscle and other cells, inhibiting the action of leukotrienes LTC4, LTD4, and LTE4. This reduces airway edema, bronchoconstriction, and inflammation.
Zileuton is a 5-lipoxygenase inhibitor. It blocks the enzyme responsible for leukotriene synthesis, reducing all leukotriene formation, including LTB4 (a potent chemotactic agent) and the cysteinyl leukotrienes.

Therapeutic Use / Indications:
– Chronic asthma (mild to moderate persistent asthma)
– Exercise-induced bronchoconstriction (EIB)
– Allergic rhinitis (seasonal and perennial)
– Aspirin-exacerbated respiratory disease (AERD)
– Chronic urticaria (off-label, montelukast)
– Atopic dermatitis (limited evidence, off-label)

Common Side Effects:
– Headache
– Abdominal pain
– Diarrhea
– Fatigue
– Cough
– Flu-like symptoms
– Neuropsychiatric effects (e.g., sleep disturbance, agitation with montelukast)

Serious Adverse Effects:
– Hepatotoxicity (zileuton > zafirlukast; requires monitoring)
– Eosinophilic conditions (e.g., Churg-Strauss syndrome)
– Neuropsychiatric events (boxed warning for montelukast: agitation, depression, suicidal thoughts)
– Allergic reactions (rare: rash, anaphylaxis)

Precautions:
– Montelukast should not be used as monotherapy for acute asthma attacks
– Monitor liver function with zileuton and zafirlukast
– Monitor neuropsychiatric status, especially in children and adolescents
– Avoid alcohol with zileuton (increased risk of liver toxicity)
– Discontinue if signs of systemic eosinophilia or vasculitis appear

Contraindications:
– Known hypersensitivity to the drug or its components
– Active liver disease or elevated liver enzymes (zileuton)
– Use of zileuton with drugs extensively metabolized by CYP1A2 (e.g., theophylline) without monitoring

Drug Interactions:
– Zileuton: inhibits CYP1A2 and may increase levels of theophylline, propranolol, warfarin
– Zafirlukast: metabolized via CYP2C9, may increase INR with warfarin
– Montelukast: fewer interactions; metabolized by CYP3A4 and CYP2C9, but clinically significant interactions are rare
– Rifampin and phenobarbital may reduce the effectiveness of leukotriene modifiers by inducing CYP enzymes

Monitoring Parameters:
– Liver function tests (zileuton and zafirlukast, especially during first 3 months)
– Mental health status for behavior changes or suicidal thoughts
– Symptom control in asthma or allergic rhinitis
– Frequency of use of rescue inhalers (should decrease with effective therapy)

Special Populations:
Children – Montelukast is approved for use in children as young as 6 months (oral granules), with careful monitoring of behavior
Elderly – No specific dosage adjustment required, but monitor liver function
Pregnancy – Montelukast and zafirlukast are generally considered safe (Category B)
Liver Impairment – Avoid zileuton and zafirlukast in significant hepatic dysfunction

Storage:
Store all forms at room temperature
Protect oral granules from moisture
Do not freeze or refrigerate liquid formulations

Examples of Commonly Used Agents and Doses:
Montelukast 10 mg once daily (adults)
Montelukast 5 mg once daily (children 6–14 years)
Montelukast 4 mg once daily (children 2–5 years)
Zafirlukast 20 mg twice daily (adults)
Zileuton 600 mg four times daily (immediate-release) or twice daily (extended-release)