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

Posted on: Wednesday, 9 March 2005, 03:00 CST

There are currently three leukotriene modifiers approved for use in the pediatrie population. This paper will review the pathophysiology of asthma and allergic rhinitis and the associated family burden. The use of leukotriene modifiers for step-up management of asthma and allergic rhinitis as recommended by the National Heart, Lung, and Blood Institute's (NHLBl) National Asthma Education and Prevention Program (NAEPP), their action, dosing, side effects, and nursing implications will be reviewed.

Case Examples

E.B. is a 6-year-old female who presented to the clinic for a well child examination. Past medical history includes mild persistent asthma controlled on Flovent 44 meg 2 puffs BID and albuteral prn. Upon further questioning, the mother states her child continues to have nighttime coughing greater than two times a week in addition to daytime symptoms three times a week. As the primary care provider you decide to step up her therapy and add Singulair 5 mg daily in the evening.

A.C. is a 17-year-old male presenting at your office with a history of seasonal allergies. His symptoms include clear rhinorrhea, watery itchy eyes, and sneezing. He continues to cough, especially at night, despite taking Claritin 10 mg daily. As his health care provider you decide to start him on Accolate 20 mg BID.

Epidemiology and Family Burden of Asthma and Allergic Rhinitis

Asthma is one of the most prevalent chronic illnesses in the united States, affecting 9 million children (12.7%) (Center for Disease Control [CDC], 2003). The CDC's National Center for Health Statistics has recently published alarming statistics showing an increase in morbidity and mortality related to pediatrie asthma (CDC, 2003). Between 1980-1999, there were an estimated 3,537,000 office visits for asthma in children between 0-14 years of age. During this same period, there were 658,000 emergency department visits and 190,000 hospitalizations for exacerbation of asthma in children. In 1999, 176 children age 14 years and younger died from asthma. Furthermore, parent loss of work and school absence related to asthma increased greater than 50% from approximately 6.2 million missed days to 14 million missed days of work for parents and 6.6 million days absent from school to 14 million absent days from school for children due to asthma (CDC, 2003; Mannino et al., 2002).

Seasonal allergic rhinitis is also becoming more common, affecting 20-40 million people yearly, with an estimated 40% being children (Qonyeau & Partisano, 2003). It has been estimated that between 60%-78% of people with asthma also suffer from allergic rhinitis (Gonyeau & Partisano, 2003). An emerging theory is that asthma and allergic rhinitis are two conditions along the same continuum of inflammatory processes involving a common airway instead of two distinct diseases of the upper and lower airway (Qonyeau & Partisano, 2003). In fact, researchers have labeled the two conditions the "united airway disease" (Passalacqua, Ciprandi, & Canonica, 2001) and "asthma-rhinitis disorder" (Passalacqua, Ciprandi, Pasquali, Guerra, & Canonica, 2004).

Both asthma and seasonal allergic rhinitis are associated with significant costs and morbidity. Together, these two illnesses have had a great impact on health care economics within the United States. Approximately $3 billion yearly is spent on asthma-related costs including direct costs, such as medical costs, and indirect costs related to caregiver missed work days (Lasley, 2003). The costs associated with seasonal allergic rhinitis are similar (Skoner, 2001). It is estimated that approximately $2.7 billion in direct and indirect costs are associated with seasonal allergic rhinitis (Gonyeau & Partisano, 2003; Skoner, 2001).

The Role of Leukotrienes in the Pathophysiology of Asthma and Allergic Rhinitis

Asthma is a chronic inflammatory condition affecting the airways involving the production and activity of inflammatory cells (i.e., mast cells, eosinphils, T lymphocytes, macrophages, neutrophils, and epithelial cells) and several chemical mediators including leukotrienes, histamine, platelet-activating factor, and bradykinin (Lasley, 2003; National Asthma Education and Prevention Program [NAEPP], 2003). In response to allergens, irritants, viral infections, and exercise, hyper-responsiveness of the airways occurs leading to constriction. Airway obstruction, edema, and increased mucous production result in the symptoms of asthma allergies. Chronic inflammation of the airway results in airway remodeling and may lead to irreversible changes in lung function.

Leukotrienes are 20-carbon unsaturated fatty acids and are released during the inflammatory process. Leukotrienes LTA4, LTB4, LTC4, LTD4 and LTE4 are metabolized at different levels via the 5- lipoxygenase pathway in response to certain antigens causing bronchoconstriction, increased mucous production, and inflammation (Bisgaard, 2001; Coffey & Peters-Golden, 2003; Krawiec & Wenzel, 1999; Lasley, 2003). In laboratory-controlled trials, leukotrienes caused prolonged airway constriction when administered in low doses, and the effect was reversed after the administration of leukotriene receptor agonists (Drazen, Israel, & O'Byrne, 1999).

Table 1. Zafirlukast

Table 2. Montelukast

Leukotrienes have also demonstrated a significant role in the pathophysiology of allergic rhinitis. During an allergic response, leukotrienes are released from the cells. Leukotrienes are inflammatory mediators that cause vasodilatation and mucosal swelling, which results in the congestion associated with seasonal allergic rhinitis. Leukotriene receptor antagonists inhibit leukotrienes, thereby decreasing congestion associated with seasonal allergic rhinitis (Gonyeau & Partisano, 2003).

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 (NHLBl) 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. Qonyeau and Partisane (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).

Table 3. Zileuton

Zafirlukast. 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). Mausea, 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. 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. 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, & Qaudiosi, 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.

Other Indications for Leukotriene Modifiers

Leukotrienes have been used to treat a variety of conditions other than asthma. In a single-blind, placebo-controlled, crossover study, montelukast was shown to be an effective agent in refractory chronic idiopathic urticaria (Erbagci, 2002). Leukotriene modifiers have been used for the treatment of eosinophilic conditions not related to asthma such as eosinophilic esophagitis (Attwood et al., 2003) and eosinophilic gastroenteritis (Schwartz, Pardi, & Murray, 2001). Montelukast has also been used successfully in the treatment of interstitial cystitis, resulting in significant improvement in urinary frequency and pain (Bouchelouche, Nordling, HaId, & Bouchelouche, 2001).

Conclusion

Leukotrienes are not recommended for acute exacerbations of asthma but should be continued during acute episodes. In order to achieve full therapeutic effect, leukotrienes should be taken on a regular schedule. All patients should have a short acting beta2- agonist bronchodilator for acute symptoms. Nurses must take these recommendations into consideration when deciding a treatment plan for individuals with asthma and/or seasonal allergic rhinitis.

The Primary Care Approaches section focuses on physical and developmental assessment and other topics specific to children and their families, If you are interested in author guidelines and/or assistance, contact Patricia L. Jackson Alien at pat.jacksonallen@yale.edu.

References

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AstraZeneca Pharmaceuticals LR (2004). Product information: Accolate. Wilmington, DE: Author.

Attwood, S., Lewis, C., Bronder, C., Morris, C., Armstrong, G., & Whittam, J. (2003). Eosinophilic esophagitis: A novel treatment using Montelukast. Gut 52,181-185.

Balzano, G., Fuschillo, S., & Gaudiosi, C. (2002). Leukotriene receptor antagonists in the treatment of asthma: An update. Allergy, 57(Suppl. 72), 16-19.

Bisgaard, H. (2001). Leukotriene modifiers in pediatrie asthma management. Pediatrics, 707(2), 381-390.

Bouchelouche, K., Nordling, J., HaId, T., & Bouchelouche, R (2001). The cysteinyl leukotriene D4 receptor antagonist montelukast for the treatment of interstitial cystitis. Journal of Urology, 166, 1734-1737.

Center for Disease Control (CDC). (2003). Summary health statistics for U.S. children: National health interview survey, 2001. Vital and Health Statistics, 70(216), 1-62.

Coffey, M., & Peters-Golden, M. (2003). Extending the understanding of leukotrienes in asthma. Current Opinion in Allergy & Clinical Immunology, 3(1), 57-63.

Critical Therapeutics. (2004). Zileuton. Retrieved November 3, 2004, from www.criticaltherapeutics.com/zileuton.html

Drazen, J.M., Israel, E., & O'Byrne, P.M. (1999) Drug therapy: Treatment of asthma with drugs modifying the leukotriene pathway. The New England Journal of Medicine, 340(3), 197206.

Ducharme, F. (2003). Inhaled glucocorticoids versus leukotriene receptor antagonists as single agent asthma treatment: Systematic review of current evidence. British Medical Journal, 326, 621-626.

Erbagci, Z. (2002). The leukotriene receptor antagonist montelukast in the treatment of chronic idiopathic urticaria. Journal of Allergy & Clinical Immunology, 11, 484-488.

Gonyeau, M., & Partisano, A. (2003). A clinical review of montelukast in the treatment of seasonal allergic rhinitis. Formulary, 38, 368-378.

Katial, R.K., Stelzle, R.C., Bonner, M.W., Marino, M., Cantilena, L.R., & Smith, LJ. (1998). A drug interaction between zafirlukast and theophylline. Achieves of Internal Medicine, 758(15), 1713- 1715.

Knorr, B., Matz, J., Bernstein, J., Nguyen, H., Seidenberg, B., Reiss, T., et al. (1998). Montelukast for chronic asthma in 6- to 14- year-old children: A randomized, double-blind trial. Journal of the American Medical Association, 279(15), 1181-1186.

Krawiec, M.E., & Wenzel, S.E. (1999). Use of leukotriene antagonists in childhood asthma. Current Opinion in Pediatrics, 77(6), 540-554.

Lasley, M. (2003). New treatments for asthma. Pediatrics in Review, 24(1), 222-232.

Mannino, D.M., Homa, D.M., Akinbami, L.J., Moorman, J.E., Gwynn, C., & Redd, S.C. (2002). Surveillance for asthma B United States, 1980-1999. Morbidity & Mortality Weekly Report, 57(SSOD, 1-13.

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National Asthma Education and Prevention Program (NAEPP). (2003). Expert panel report 2: Guidelines of the diagnosis and management of asthma update on selected topics 2002. National Institutes of Health Publication - No. 02-5074. Bethesda, MD: NAEPP.

Passalacqua G, Ciprandi G, & Canonica GW. (2001). The nose-lung interaction: United airways disease. Current Opinion in Allergy and Clinical Immunology, 7, 7-14.

Passalacqua, G., Ciprandi, G., Pasquali, M., Guerra, L., & Canonica, G. (2004). An update on the asthma-rhinitis link. Current Opinion in Allergy and Clinical Immunology, 4(3), 177-183.

Schwartz, D., Pardi, D., & Murray, J. (2001). Use of montelukast as steroid-sparing agent for recurrent eosinophilic gastroenteritis. Digestive Diseases & Sciences, 46, 1787-1790.

Skoner, D. (2001). Allergic rhinitis: Definition, epidemiology, pathophysiology, detection, and diagnosis. Journal of Allergy and Clinical Immunology, 708(1Suppl.), S2-S8.

Nancy Cantey Bana\siak, MSN, PNP, APRN, BC, is Assistant Professor Pediatrie Nurse Practitioner Specialty, Yale university School of Nursing, New Haven, CT.

Mikki Meadows-Oliver, MSN, MPH, CPNP, APRN, is Lecturer, Yale university School of Nursing, New Haven, CT.

Copyright Anthony J. Jannetti, Inc. Jan/Feb 2005

Source: Pediatric Nursing

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