Leukotrienes: Their Role in the Treatment of Asthma and Seasonal Allergic Rhinitis

Nancy Cantey Banasiak; Mikki Meadows-Oliver


Pediatr Nurs. 2005;31(1):35-38. 

In This Article

Leukotriene Modifiers

Leukotriene modifiers are the most recent class of medications approved for use in the treatment of asthma and allergic rhinitis since the introduction of inhaled corticosteroids in 1972. According to the National Heart, Lung, and Blood Institute's (NHLBI) NAEPP, leukotriene modifiers are an alternative medication for use in children with mild persistent asthma especially children unable to comply with inhaled steroids (NAEPP, 2003). They are also considered to be an additional medication for the step-up approach, or combination therapy, recommended by the NAEPP for moderate and severe persistent asthma not controlled with inhaled corticosteroids alone (NAEPP, 2003).

The leukotriene modifiers are the first classification of drugs that are mediator-specific therapy for asthma (Krawiec & Wenzel, 1999). The Food and Drug Administration (FDA) approved three leukotriene modifiers divided into two classes. The first class leukotriene-receptor antagonists prevent leukotriene binding and includes zafirlukast (Accolate®) and montelukast (Singulair®). The second classification is leukotriene-receptor inhibitors, which focus on synthesis inhibition and include zileuton (Zyflo®).

Leukotriene modifiers appear to have a beneficial role in the treatment of both asthma and allergic rhinitis and are currently recommended as alternative therapy to inhaled corticosteroids or in combination depending on severity of symptoms. The use of leukotrienes as monotherapy for asthma or allergic rhinitis is being debated. In a systematic review comparing the use of inhaled glucocorticoids with leukotriene antagonists as monotherapy in the treatment of asthma, Ducharme (2003) concluded that leukotriene antagonists are less effective than inhaled glucocorticoids when used as a single agent in the treatment of asthma. Gonyeau and Partisano (2003), in their review of leukotriene antagonists as a treatment for seasonal allergic rhinitis, also concluded that leukotriene antagonists appear to have a primary role, not as a single treatment agent, but as an adjunct to intranasal steroids and antihistamines.

Leukotriene modifiers are well tolerated with few side effects. Case studies have suggested zafirlukast and zileuton affect theophylline and warfarin levels requiring frequent monitoring of theophylline level and prothrombin time in those individuals taking these medications (Abbott Laboratories, 2003; Katial et al., 1998; Krawiec & Wenzel, 1999). Elevated liver transaminases have also been noted in individuals on montelukast, zileuton, and zafirlukast, and the FDA advises that liver function be tested monthly for 3 months, then quarterly for the next year, followed by intermittent testing (Krawiec & Wenzel, 1999).


Zafirlukast (Accolate®) (see Table 1 ) is a synthetic peptide leukotriene-receptor antagonist recommended for children 7 years of age and older. It is used for the management of mild, persistent asthma; step-up therapy for moderate persistent asthma; exercise-induced asthma; and management of allergic rhinitis. It inhibits the binding of three leukotrienes (LTC4, LTD4 and LTE4) that are responsible for smooth muscle constriction and hyperresponsiveness after contact with an allergen challenge including exercise (Krawiec & Wenzel, 1999). The dose for 7-11 years of age is 10 mg BID. For children 12 years of age and older, the recommended dose is 20 mg BID. Food reduces the mean bioavailability by about 40%, therefore zafirlukast should be taken on an empty stomach either 1 hour before meals or 2 hour post prandial (Krawiec & Wenzel, 1999). Side effect of zafirlukast include headache, which was reported by 4.5 % of 7-11-year-olds and 12.9% of children 12 years and older (AstraZeneca Pharmaceuticals LP, 2004). Nausea, abdominal pain, diarrhea, rash, and elevated liver functions tests have occurred in clinical trials (AstraZeneca Pharmaceuticals LP, 2004). Zafirlukast is contraindicated for individuals who are hypersensitive to zafirlukast or any active ingredient in the medication and nursing mothers. Zafirlukast is a category B drug for pregnant women, and they should use the medication only if clearly needed. There have been no clinical trials on pregnant women and no teratogency noted in animals with doses 160 times the maximum dose for adults. With doses of 2000 mg/kg/day an increase in spontaneous abortions was noted in animal studies (AstraZeneca Pharmaceuticals LP, 2004). Individuals on warfarin therapy should have close monitoring of their prothrombin time since the zafirlukast can significantly affect warfarin levels resulting in prolonged prothrombin times (Krawiec & Wenzel, 1999). Elevated theophylline levels have been documented in the literature with patients on theophylline and zafirlukast (AstraZeneca Pharmaceuticals LP, 2004; Katial et al., 1998). It is recommended that theophylline levels be monitored closely.


Montelukast (Singulair®) (see Table 2 ) is also a leukotriene-receptor antagonist. It is used for the long-term management of children with asthma over the age of 2 years. Montelukast is recommended as an alternative medication to inhaled corticosteroids or as adjunctive therapy for the treatment of mild and moderate persistent asthma. In January 2003, the FDA approved montelukast for use as monotherapy in the treatment of allergic rhinitis (Gonyeau & Partisano, 2003).

Montelukast is not recommended for acute exacerbations but should be continued during an acute attack, and all children on montelukast should have beta2-agonist prescribed for additional therapy during acute symptoms. Children with seasonal allergies, exercise and aspirin induced asthma, nocturnal asthma, and allergic rhinitis have benefited from leukotriene modifiers (Merck & Co., 2004). The advantages of montelukast are the rapid onset of action, ease of administration, safety in children as young as 2 years of age, chewable tablets, and the benefit of a once daily medication. The recommended dosage for children 2-5 years of age is a 4 mg chewable tablet once daily. For children 6-14 years of age, the recommended dose is a 5 mg chewable tablet daily, and for adolescents, the dose is 10 mg daily. It is recommended that the medication be taken at night to alleviate the common morning symptoms associated with allergies, but this has not been studied (Merck & Co., 2004). The most frequently reported side effect is headache occurring in about 18%-19% of treated individuals (Knorr et al., 1998). Other side effects were reported in less than 4.2% of treated individuals and included abdominal pain, cough, increased liver function tests (LFTs,) diarrhea, and rash (Merck & Co., 2004). Patients on phenobarbital and rifampin should be monitored closely along with monitoring LFTs on a regular basis ( Merck & Co.).


Zileuton (Zyflo®) (see Table 3 ) is a 5-lipoxygenase inhibitor. It limits 5-lipoxygenase pathway activation limiting the production of LTA4, LTC4, and the derivatives of cysteinyl LT, LTD4, and LTE4, which are potent vasoconstrictors (Balzano, Fuschillo, & Gaudiosi, 2002). Zyflo is indicated for children greater than 12 years of age for the treatment of chronic asthma. The recommended dose is 600 mg four times a day. Zileuton is contraindicated for children with liver disease or elevated LFTs, and allergy to zileuton (Abbott Laboratories, 2003). The most serious side effect is elevated liver enzymes, and LFTs should be monitored on a regular basis (Krawiec & Wenzel, 1999). Headache is a side effect experienced by 25% of patients taking zileutin. Additional reported side effects include unspecified pain, dyspepsia, nausea, and abdominal pain (Abbott Laboratories, 2003). Patients taking theophylline, warfarin, and propranolol should be monitored closely and have their medications adjusted accordingly (Abbott Laboratories, 2003). Critical Therapeutics obtained licensing rights for Zyflo from Abbot in 2004 and is currently in the process of obtaining FDA approval for selling the product (Critical Therapeutics, 2004). Zyflo is expected to be back on the market in 2005.


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