Zafirlukast

1. Drug Name

• Generic Name: Zafirlukast

• Brand Names: Accolate

2. Drug Classification

• Class: Leukotriene Receptor Antagonist (LTRA)

• Subclass: Anti-inflammatory agent, used primarily in asthma management.

3. Mechanism of Action

• Leukotriene Receptor Blockade: Zafirlukast works by selectively inhibiting the cysteinyl leukotriene (CysLT1) receptor. Leukotrienes, particularly LTC4, LTD4, and LTE4, are mediators that are involved in inflammatory processes in asthma and allergic rhinitis. These leukotrienes bind to the CysLT1 receptor, causing bronchoconstriction, mucous secretion, airway edema, and inflammation. By blocking the CysLT1 receptor, Zafirlukast prevents leukotrienes from exerting their effects, leading to reduced airway inflammation and bronchoconstriction.

• Reduction in Airway Inflammation: In asthma, leukotrienes contribute to bronchoconstriction, mucus production, and airway inflammation. Zafirlukast helps to reduce these effects, thereby improving asthma symptoms, preventing exacerbations, and improving overall lung function.

4. Pharmacokinetics

• Absorption:

  • Bioavailability: Zafirlukast has a bioavailability of approximately 60–70% when taken orally.

  • Tmax (Time to Peak Plasma Concentration): Peak plasma concentrations are reached within 3–5 hours after oral ingestion.

  • Food Effects: The absorption of Zafirlukast is decreased by approximately 40% when taken with food, so it is recommended to take the drug on an empty stomach, at least 1 hour before or 2 hours after meals.

• Distribution:

  • Volume of Distribution (Vd): The volume of distribution of Zafirlukast is approximately 3.1 L/kg.

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

• Metabolism:

  • Zafirlukast is extensively metabolized in the liver by the cytochrome P450 system, primarily through CYP2C9 and CYP3A4 isoenzymes.

  • It has a minor effect on CYP450 enzymes, reducing the likelihood of significant drug interactions, although caution is still recommended when used with strong inhibitors or inducers of these enzymes.

• Excretion:

  • Half-life (t½): The elimination half-life of Zafirlukast is approximately 10 hours.

  • Excretion: Zafirlukast is primarily excreted in the feces (about 90%), with a smaller amount excreted in the urine.

5. Indications

• Primary Indications:

  • Asthma: Zafirlukast is indicated for the prophylaxis and chronic treatment of asthma in adults and children aged 5 years and older.

  • Allergic Rhinitis: Zafirlukast may be used off-label to relieve symptoms of allergic rhinitis.

• Off-Label Uses:

  • Exercise-induced Bronchoconstriction: Zafirlukast is sometimes used off-label to prevent bronchospasm triggered by physical exertion.

  • Chronic Sinusitis: In combination with other treatments, Zafirlukast may be used to help manage chronic sinusitis.

• Special Populations:

  • Pediatrics: Approved for use in children aged 5 years and older for asthma management.

  • Geriatrics: Generally safe in elderly patients, but they may be more prone to side effects and should be monitored for liver dysfunction.

6. Dosage and Administration

• Adult Dosing:

  • Asthma:

    • Oral (Tablet): 20 mg twice daily.

  • Exercise-induced Bronchoconstriction:

    • Oral (Tablet): 20 mg at least 1 hour before exercise.

• Pediatric Dosing:

  • Asthma:

    • Children aged 5 to 11 years: 10 mg twice daily.

    • Children aged 12 years and older: 20 mg twice daily.

• Renal or Hepatic Impairment:

  • Zafirlukast should be used with caution in patients with liver impairment, as it is metabolized in the liver. A dose adjustment may be necessary for patients with hepatic dysfunction.

  • No specific dose adjustments are required for renal dysfunction, but caution is advised in severe cases.

7. Contraindications

• Absolute Contraindications:

  • Hypersensitivity to Zafirlukast or any of its excipients.

• Relative Contraindications:

  • Liver Disease: Zafirlukast is contraindicated in patients with hepatic impairment, including active liver disease, as the drug may exacerbate liver dysfunction.

  • Pregnancy: It should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus.

8. Warnings and Precautions

• Liver Dysfunction: Zafirlukast has been associated with liver enzyme elevations and, in rare cases, hepatotoxicity. Liver function tests should be performed before and periodically during therapy. If liver function deteriorates, the drug should be discontinued.

• Neuropsychiatric Events: Rare neuropsychiatric effects such as agitation, aggression, depression, and suicidal thoughts have been reported. Patients should be monitored for any changes in mood or behavior, particularly in children and adolescents.

• Eosinophilic Conditions: There is a risk of eosinophilic conditions, such as Churg-Strauss syndrome, especially in patients who are tapering or discontinuing corticosteroid therapy.

• Drug Interactions: Zafirlukast should be used with caution when co-administered with medications that affect the CYP2C9 or CYP3A4 pathways, such as warfarin and certain antifungals or antibiotics.

9. Adverse Effects

• Common Adverse Effects:

  • Headache: A frequent side effect of Zafirlukast.

  • Gastrointestinal: Diarrhea, nausea, abdominal pain.

• Less Common but Clinically Significant:

  • Liver Enzyme Elevations: Elevated liver enzymes, which can be a sign of hepatotoxicity.

  • Neuropsychiatric: Symptoms such as anxiety, irritability, and depression may occur.

• Rare/Serious:

  • Hepatitis: Severe liver injury is rare but possible.

  • Churg-Strauss Syndrome: In patients with asthma who are reducing oral corticosteroids, eosinophilic conditions, including Churg-Strauss syndrome, can develop.

  • Anaphylaxis: Severe allergic reactions may occur.

10. Drug Interactions

• CYP450 Enzyme Interactions: Zafirlukast is metabolized by the liver, particularly by the CYP2C9 and CYP3A4 enzymes. Drugs that inhibit these enzymes may increase Zafirlukast levels, while drugs that induce these enzymes (e.g., rifampin) may reduce its effectiveness.

• Warfarin: Zafirlukast may interact with warfarin, increasing the anticoagulant effect and thus increasing the risk of bleeding. Regular INR monitoring is recommended.

• Other Respiratory Drugs: Zafirlukast can be used in combination with other asthma medications (e.g., inhaled corticosteroids or beta-agonists) without significant pharmacodynamic interactions.

11. Clinical Pharmacology

• Pharmacodynamics: Zafirlukast selectively inhibits the CysLT1 receptor, reducing the effects of leukotrienes. This results in improved asthma control by decreasing bronchoconstriction and airway inflammation. Zafirlukast also helps manage the symptoms of allergic rhinitis by decreasing nasal congestion and inflammation.

• Additional Effects: In addition to its anti-inflammatory properties, Zafirlukast also has bronchoprotective effects, preventing exercise-induced bronchoconstriction.

12. Special Populations

• Pregnancy: Category C. Although animal studies have not shown significant harm, there are insufficient human studies to assess safety in pregnancy. It should only be used if the potential benefits outweigh the risks.

• Lactation: Zafirlukast is excreted in breast milk in small amounts. The decision to use Zafirlukast during breastfeeding should be made after evaluating the potential risks and benefits.

• Pediatrics: Approved for use in children aged 5 years and older. Growth and neuropsychiatric development should be monitored during treatment.

• Geriatrics: No specific dose adjustments are needed for elderly patients, but caution is warranted, especially regarding potential liver dysfunction.

13. Therapeutic Uses

• Asthma: Zafirlukast is used as a long-term prophylactic treatment in asthma, especially in patients whose asthma is not well controlled with inhaled corticosteroids alone.

• Allergic Rhinitis: It may be used as an adjunct to other treatments for allergic rhinitis.

• Exercise-Induced Bronchoconstriction: Zafirlukast can be used to prevent exercise-induced bronchospasm in patients with asthma.

14. Monitoring and Follow-Up

• Liver Function: Monitor liver function tests periodically during therapy.

• Asthma Control: Regular assessment of asthma symptoms, lung function, and the need for additional bronchodilators.

• Neuropsychiatric Symptoms: Monitor for any mood changes, particularly in pediatric and adolescent patients.

15. Overdose Management

• Symptoms of Overdose: Overdose is unlikely to result in significant toxicity. Symptoms may include drowsiness, nausea, and headache.

• Management: Treatment is symptomatic, with no specific antidote available. Gastric lavage or activated charcoal may be administered in cases of recent overdose.

16. Patient Counseling Information

• Administration: Instruct patients to take Zafirlukast on an empty stomach, at least 1 hour before or 2 hours after meals.

• Liver Health: Patients should be informed about the signs of liver dysfunction (e.g., jaundice, dark urine, abdominal pain) and report them immediately.

• Neuropsychiatric Symptoms: Patients should be advised to report any changes in mood, behavior, or mental health, especially in children and adolescents.

• Importance of Adherence: Stress the importance of adhering to prescribed dosages and maintaining continuous asthma control, even when symptoms are not present.