The educational role for RCPs has expanded as the number of pharmacologic agents available to treat asthma has increased
The respiratory community’s concept of asthma was simple and straightforward 20 years ago. Asthma was a disease characterized by reversible airflow obstruction primarily involving the bronchial smooth muscle. In response to antigenic triggers, a small number of bronchoconstrictive agents were produced, the most important of which were histamine and what was then called slow-reacting substance of anaphylaxis. In 1980, it was identified as an arachidonic acid metabolite.1,2 When metabolized in the airway, the end products of arachidonic acid were cysteinyl leukotrienes, bronchoconstrictors up to 1,000 times more potent than histamine. Several years after this discovery, bronchoscopic studies3 determined that even the airways of patients with very mild asthma were inflamed, exhibiting an infiltrate dominated by eosinophils. Subsequent investigations over the past 15 years have identified an extremely complex inflammatory infiltrate involving a large number of cytokines, chemokines, inflammatory cells, and adhesion molecules.
As a result of such studies, the pharmacological management of asthma has changed dramatically. Instead of relying on b-agonist bronchodilators for the relief of bronchospasm, clinicians now place primary emphasis on the use of anti-inflammatory agents. Inhaled corticosteroids provide anti-inflammatory action similar to that of oral corticosteroids, and they are considered the most effective agents, but have a theoretically safer therapeutic index. In recent years, more potent inhaled corticosteroid formulations have been developed that have further improved their efficacy as long-term asthma-control agents. Less potent anti-inflammatory agents such as the cromolyns have also been used, especially in the treatment of allergic asthma in childhood. Because of their narrow therapeutic index, the use of theophyllines as first-line therapy has decreased significantly.
Despite their broad anti-inflammatory effects, inhaled corticosteroids do not suppress the inflammatory effects of the cysteinyl leukotrienes. A report by Drazen et al4 in 1992 clearly demonstrated that leukotrienes are present in the asthma patient’s airway and may play a significant role in the inflammatory lesion. Elevated levels of leukotrienes can be measured in the blood of asthma patients5 and are also found in bronchoalveolar lavage fluid6 and airway-biopsy specimens.7 Studies by Taylor et al,8 Reiss et al,9 and Christie et al10 confirmed their presence in acute asthma exacerbations, exercise-induced bronchospasm, and aspirin-induced asthma.
The precise role of the leukotriene-receptor antagonists in the therapeutic management of asthma is not fully established,11,12 despite the variety of inflammatory effects attributed to the cysteinyl leukotrienes and the current availability of a number of leukotriene-receptor antagonists. Even though the leukotriene-receptor antagonists are oral tablets rather than inhaled medications, they have become significant agents in asthma management.
Identifying Airway Leukotrienes
Human slow-reacting substance of anaphylaxis is made up of two specific leukotrienes, LTC4 and LTD4. Studies have shown leukotrienes to be more active than histamine as smooth-muscle bronchoconstrictors, and to have a more sustained action, as well.13 In addition to their bronchoconstrictive effects, leukotrienes are capable of producing airway microvascular leakage, mucus secretion, and increasing eosinophilic infiltration into the inflammatory lesion. These effects are particularly noteworthy during exercise-induced bronchospasm and aspirin-induced asthma, but have also been seen in allergic asthma.
An increase in the urinary level of LTE4 was found in acutely ill asthma patients who had responded to repeated b-agonist therapy.4 LTC4, LTD4, and LTE4 were also found to be released from mast cells after allergen challenge.14 Most recently, the cysteinyl leukotriene 1 receptor, one of two cysteinyl leukotriene receptors, has been identified and cloned and has had its amino-acid sequence determined.15 In the normal human lung, it was found in tissue macrophages and in smooth muscle, particularly in peribronchial and peribronchiolar smooth-muscle cells. All the known leukotriene-receptor antagonists target the cysteinyl leukotriene 1 receptor. As a result of these and many more published studies, it is clear that leukotrienes may play an important role in the airway inflammatory lesions of many asthma patients, and that this is a role not inhibited by inhaled corticosteroids.
Clinical Studies
In the past several years, a number of reports have demonstrated that leukotriene activity within the airway may be inhibited either by blocking arachidonic acid metabolism or inhibiting leukotriene receptor activity. In 1991, Taylor et al16 demonstrated that an orally administered leukotriene-receptor antagonist caused bronchodilation during both early- and late-phase allergen-induced bronchoconstriction. It was also demonstrated that an LTD4 receptor antagonist significantly inhibited the fall in forced expiratory volume in 1 second (FEV1) that occurred during exercise-induced bronchospasm.14 This drop in FEV1 was subsequently shown to be reduced 47% after 2 weeks of treatment with montelukast.17 A similar beneficial effect of montelukast was also reported in children with exercise-induced bronchospasm.18 Most recently, two studies19,20 involving more than 300 patients confirmed the effectiveness of montelukast in ameliorating the effects of exercise-induced bronchospasm.
In addition to their beneficial effects on exercise-induced bronchospasm, leukotriene-receptor antagonists have been shown to play a role in the management of chronic stable asthma. In a study of more than 300 children aged 6 to 14 years, Knorr et al21 reported a significant increase in morning FEV1 during an 8-week study of montelukast (delivered as a 5-mg chewable tablet). Montelukast’s onset of action occurred within 1 day, as indicated by a reduction in as-needed b-agonist use. Similar results were reported using zafirlukast (20 mg twice daily) in more than 700 adults.22 Daytime asthma symptoms, nighttime awakenings, and b-agonist use were all decreased during the 13-week study. Both morning peak expiratory flows and FEV1 were significantly increased within 2 days of starting zafirlukast, and the increases were maintained throughout the study period. Pharyngitis was the most common adverse effect, occurring at the same rate seen in the placebo group. Montelukast produced similar results in a multicenter study23 that used a 10-mg daily dose. The onset of action occurred within 1 day, as indicated by improved morning peak expiratory flows. In addition, asthma exacerbations were decreased, and asthma-control days were increased. The adverse effects were no different from those noted in the placebo group.
Two recent reports have added to the list of possible beneficial effects of leukotriene-receptor antagonists in asthma management. In the first study,24 the 642 enrolled patients had asthma that was incompletely controlled by 200 mg of beclomethasone administered twice daily. The addition of 10 mg of montelukast to the inhaled steroid improved pulmonary function and asthma control; FEV1 increased, and both nighttime awakenings and daytime asthma-symptom scores decreased. The second study25 provided evidence of a steroid-sparing effect of montelukast. In patients receiving high doses of inhaled steroids, it was possible to achieve lower daily steroid dosages while maintaining asthma control when montelukast was added, compared with placebo.
In summary, a large number of published studies with leukotriene-receptor antagonists have demonstrated their beneficial effects in asthma management and their excellent safety profiles. Although these beneficial effects have been significant in patients with moderate and severe asthma patients, they have generally not been as great as those obtained using inhaled corticosteroids. In patients with mild asthma, however, the improvements in pulmonary function and asthma control were similar.26
The Role of Leukotriene-Receptor Antagonists
In 1991, the National Asthma Education and Prevention Program (NAEPP) of the National Institutes of Health published its first set of guidelines for asthma management. In 1997, at about the same time that leukotriene-receptor antagonists became available, these guidelines were revised to include at least a brief mention of their potential role in asthma management.11 At that time, unfortunately, few studies of leukotriene-receptor antagonists were available, their clinical use was limited, and their roles as anti-inflammatory agents and as bronchodilators were not established. Since then, a number of reports have demonstrated that leukotriene-receptor antagonists do inhibit the influx of inflammatory cells (principally eosinophils) into the inflammatory airway lesion.27 Among the four levels of disease severity outlined in published consensus asthma guidelines, inhaled corticosteroids are the first-line therapy for both moderate and severe persistent asthma. When symptoms are not completely controlled by inhaled steroids alone, they are often combined with a long-acting b-agonist. When control is still not achieved, the addition of a leukotriene-receptor antagonist is more efficacious than increasing the dose of the inhaled steroid.28 In this setting, leukotriene-receptor antagonists are either second-line or third-line therapy.
For mild intermittent asthma, a level of disease in which symptoms occur only once or twice each week and pulmonary function is normal, short-acting b-agonists are used alone. When symptoms are more frequent, but still do not occur on a daily basis (mild persistent asthma), the current NAEPP guidelines suggest the use of low doses of inhaled corticosteroids as first-line therapy. There has been recent interest in the use of leukotriene-receptor antagonists as a first-line controller agent in this setting. One 4-week study26 comparing the effectiveness of these two alternatives indicates that, at least for the short term, the magnitude of improvement produced by fluticasone propionate, budesonide, and montelukast was similar in patients with mild asthma.26
Because of their excellent safety profile and ease of administration, leukotriene-receptor antagonists have been employed in the management of childhood asthma, both as an alternative to the cromolyns and as an add-on therapy with low-dose inhaled steroids. A recent report has shown montelukast to be safe in children as young as 2 to 5 years of age.29 Pediatric studies in children aged 6 to 14 years have shown excellent therapeutic benefit with the use of a 5-mg chewable tablet of montelukast.21 More recently, a 4-mg chewable tablet of montelukast has been approved for use in children 2 to 5 years of age. Especially in the treatment of young children, the availability of a chewable tablet containing a single daily dose may be a significant advance.
Although the safety profile of the leukotriene-receptor antagonists has been extremely positive, a number of reports of pulmonary vasculitis (Churg-Strauss syndrome) appeared following the introduction of zafirlukast.30-32 Subsequently, a few additional cases were noted with montelukast.33-34 In almost all instances, the Churg-Strauss syndrome occurred while systemic steroid doses were being lowered. More recently, sporadic reports of the same syndrome in association with inhaled corticosteroids appeared.35 By November 1998, 33 cases of Churg-Strauss vasculitis had been documented among the estimated 1.3 million patients exposed to zafirlukast.34,36 Wechsler et al34,46 recently reviewed and reported on cases of this syndrome in asthma patients; they concluded that its appearance is probably unrelated to leukotriene-receptor antagonist therapy.
Conclusion
With the addition, almost every year, of both new asthma medications and alternative delivery devices for older drugs, asthma management has become more effective, but more complex. The role of the RCP has also become more important. In addition to their traditional roles in caring for patients with acute disease in the ED or hospital, RCPs must also be patient educators. In this context, it is imperative that they be well informed concerning the increasingly broad spectrum of therapeutic alternatives that exist not only for acute disease, but for the management of chronic disease as well. The leukotriene-receptor antagonists are only the latest of a rapidly expanding variety of pharmacological alternatives for asthma care with which the RCP must be familiar.
 Robert Barbee, MD, is professor emeritus, Department of Medicine, Pulmonary/Critical Care, University of Arizona Health Sciences Center, Tucson, Ariz. |
References
1. Morris HR, Taylor GW, Piper PJ, Tippins JR. Structure of slow-reacting substance of anaphylaxis from guinea-pig lung. Nature. 1980;285:104-106.
2. Lewis RA, Austen KF, Drazen JM, Clark DA, Marfat A, Corey EJ. Slow reacting substances of anaphylaxis: identification of leukotrienes C-1 and D from human and rat sources. Proc Natl Acad Sci USA. 1980;77:3710-3714.
3. Bousquet J, Chanez P, Lacoste JY, et al. Eosinophilic inflammation in asthma. N Engl J Med. 1990;323:1033-1039.
4. Drazen JM, O’Brien J, Sparrow D, et al. Recovery of leukotriene E4 from the urine of patients with airway obstruction. Am Rev Respir Dis. 1992;146:104-108.
5. Shindo K, Fukumura M, Miyakawa K. Plasma levels of leukotriene E4 during clinical course of bronchial asthma and the effect of oral prednisolone. Chest. 1994;105:1038-1041.
6. Wenzel SE, Larsen GL, Johnston K, Voelkel NF, Westcott JY. Elevated levels of leukotriene C4 in bronchoalveolar lavage fluid from atopic asthmatics after endobronchial allergen challenge. Am Rev Respir Dis. 1990;142:112-119.
7. Bradding P, Redington AE, Djukanovic R, Conrad DJ, Holgate ST. 15-Lipoxygenase immunoreactivity in normal and in asthmatic airways. Am J Respir Crit Care Med. 1995;151:1201-1204.
8. Taylor GW, Taylor I, Black P, et al. Urinary leukotriene E4 after antigen challenge and in acute asthma and allergic rhinitis. Lancet. 1989;I:584-588.
9. Reiss TF, Hill JB, Harman E, et al. Increased urinary excretion of LTE4 after exercise and attenuation of exercise-induced bronchospasm by montelukast, a cysteinyl leukotriene receptor antagonist. Thorax. 1997;52:1030-1035.
10. Christie PE, Tagari P, Ford-Hutchinson AW, et al. Urinary leukotriene E4 concentrations increase after aspirin challenge in aspirin-sensitive asthmatic subjects. Am Rev Respir Dis. 1991;143:1025-1029.
11. National Asthma Education and Prevention Program. Expert Panel Report 2: Clinical Practice Guidelines for the Diagnosis and Management of Asthma. Rockville, Md: National Heart, Lung, and Blood Institute; 1997.
12. Global Initiative for Asthma. Asthma management and prevention. GINA guidelines. Available at: http://www.ginasthma.com. Accessed August 25, 2000.
13. Barnes NC, Piper PJ, Costello JF. Comparative effects of inhaled leukotriene C4, leukotriene D4, and histamine in normal human subjects. Thorax. 1984;39:500-504.
14. Finnerty J, Wood-Baker R, Thomson H, Holgate S. Role of leukotrienes in exercise-induced asthma. Inhibitory effect of ICI 204,219, a potent leukotriene D4 receptor antagonist. Am Rev Respir Dis. 1992;145:746-749.
15. Lynch KR, O’Neill GP, Liu Q, et al. Characterization of the human cysteinyl leukotriene CysLT1 receptor. Nature. 1999;399:789-793.
16. Taylor IK, O’Shaughnessy KM, Fuller RW, Dollery CT. Effect of cysteinyl-leukotriene receptor antagonist ICI 204.219 on allergen-induced bronchoconstriction and airway hyperreactivity in atopic subjects. Lancet. 1991;337:690-694.
17. Leff JA, Busse WW, Pearlman D, et al. Montelukast, a leukotriene-receptor antagonist, for the treatment of mild asthma and exercise-induced bronchoconstriction. N Engl J Med. 1998;339:147-152.
18. Kemp JP, Dockhorn RJ, Shapiro GG, et al. Montelukast once daily inhibits exercise-induced bronchoconstriction in 6- to 14-year-old children with asthma. J Pediatr. 1998;133:424-428.
19. Villaran C, O’Neill SJ, Helbling A, et al. Montelukast versus salmeterol in patients with asthma and exercise-induced bronchoconstriction. J Allergy Clin Immunol. 1999;104:547-553.
20. Edelman JM, Turpin JA, Bronsky EA, et al. Oral montelukast compared with inhaled salmeterol to prevent exercise-induced bronchoconstriction. A randomized, double-blind trial. Ann Intern Med. 2000;132:97-104.
21. Knorr B, Matz J, Bernstein JA, et al. Montelukast for chronic asthma in 6- to 14-year-old children: a randomized, double-blind trial. JAMA. 1998;279:1181-1186.
22. Fish JE, Kemp JP, Lockey RF, Glass M, Hanby LA, Bonuccelli CM. Zafirlukast for symptomatic mild-to-moderate asthma: a 13-week multicenter study. Clin Ther. 1997;19:675-690.
23. Reiss TF, Chervinsky P, Dockhorn RJ, Shingo S, Seidenberg B, Edwards TB. Montelukast, a once-daily leukotriene receptor antagonist, in the treatment of chronic asthma: a multicenter, randomized, double-blind trial. Arch Intern Med. 1998;158:1213-1220.
24. Laviolette M, Malmstrom K, Lu S, et al. Montelukast added to inhaled beclomethasone in treatment of asthma. Am J Respir Crit Care Med. 1999;160:1862-1868.
25. Lofdahl C-G, Reiss TF, Leff JA, et al. Randomised, placebo controlled trial of effect of a leukotriene receptor antagonist, montelukast, on tapering inhaled corticosteroids in asthmatic patients. BMJ. 1999;319:87-90.
26. Hughes GL, Edelman JM, Turpin JA, et al. Randomized, open-label pilot study comparing the effects of montelukast sodium tablets, fluticasone aerosol inhaler and budesonide dry powder inhaler on asthma control in mild asthmatics. Am J Respir Crit Care Med. 1999;159:A641.
27. Ramsay C, Li D, Wang D, Ansari T, Barnes N, Jeffery P. Bronchial biopsy specimen variability: requirement for large sample size and repeated measurements to improve reliability. Am J Respir Crit Care Med. 1999;159:A655.
28. Ringdal N, White M, Harris A. Addition of zafirlukast (Accolate™) compared with a double-dose of inhaled corticosteroids in patients with reversible airways obstruction symptomatic on inhaled corticosteroids. Am J Respir Crit Care Med. 1999;159:A639.
29. Knorr B, Noonan G, Nguyen H, et al. Evaluation of the safety profile of montelukast (MK-0476) in pediatric patients aged 2 to 5 years [abstract]. J Allergy Clin Immunol. 2000;105. In press.
30. Wechsler ME, Garpestad E, Flier SR, et al. Pulmonary infiltrates, eosinophilia, and cardiomyopathy following corticosteroid withdrawal in patients with asthma receiving zafirlukast. JAMA. 1998;279:455-457.
31. Holloway J, Ferriss J, Groff J, Craig TJ, Klinek M, Klinik M. Churg-Strauss syndrome associated with zafirlukast [published erratum appears in J Am Osteopath Assoc. 1998;98:676]. J Am Osteopath Assoc. 1998;98:275-278.
32. Knoell DL, Lucas J, Allen JN. Churg-Strauss syndrome associated with zafirlukast. Chest. 1998;114:332-334.
33. Wechsler ME, Finn D, Jordan M, Gunawardena D, Drazen JM. Montelukast and the Churg-Strauss syndrome. Am J Respir Crit Care Med. 1999;159:A641.
34. Wechsler ME, Finn D, Gunawardena D, et al. Churg-strauss syndrome in patients receiving montelukast as treatment for asthma. Chest. 2000;117:708-713.
35. Flovent (fluticasone propionate). Physician’s Desk Reference. 54th ed. Montvale, NJ: Medical Economics; 2000:1186-1192.
36. Wechsler ME, Pauwels R, Drazen JM. Leukotriene modifiers and Churg-Strauss syndrome: adverse effect or response to corticosteroid withdrawal? Drug Saf. 1999;21:241-251.
