Leukotriene-receptor antagonists
Role in asthma management
Anthony D. D’Urzo, MD, MSC, CCFP Kenneth R. Chapman, MD, MSC, FRCPC, FACP
O B J E C T I V ETo examine the role of leukotriene-receptor antagonists (LTRAs) in management of asthma.
QUALITY OF EVIDENCEMost data were derived from randomized, double-blind, controlled trials.
MAIN MESSAGELeukotrienes appear to have an important role in the pathophysiology of asthma, including airway inflammation. Leukotriene-receptor antagonists are effective in improving asthma control end points, such as allergen, ASA, and exercise challenge, in clinical models of asthma. In chronic asthma, LTRA administration reduces asthma symptoms and rescue β2-agonist use, changes that are paralleled by improvements in lung function. Both zafirlukast and montelukast decrease circulating levels of eosinophils and could have other useful anti-inflammatory properties. Administration of LTRAs allows doses of inhaled corticosteroids to be reduced.
Currently available LTRAs are free of serious side effects and are available as oral formulations.
CONCLUSIONSLeukotriene-receptor antagonists belong to a new class of asthma medication.
While inhaled corticosteroids remain first-line therapy for managing chronic asthma, LTRAs should be considered for patients with ASA-sensitive asthma; as adjunct therapy when low to moderate doses of inhaled steroid alone provide incomplete control; or as adjunct therapy to allow reduction in doses of inhaled corticosteroids.
OBJECTIFExaminer le rôle des antagonistes des récepteurs des leucotriènes (ARLT) dans la prise en charge de l’asthme.
QUALITÉ DES DONNÉESLa majorité des données sont tirées d’essais aléatoires contrôlés à double insu.
P R I N C I PA L M E S S A G ELes leucotriènes semblent exercer une influence importante dans la pathophysiologie de l’asthme, notamment l’inflammation des voies aériennes. Les antagonistes des récepteurs des leucotriènes sont efficaces dans les modèles cliniques de l’asthme pour améliorer la maîtrise des éléments déclencheurs de l’asthme, comme les allergènes, l’AAS et l’effort. Dans l’asthme chronique, l’administration d’ARLT réduit les symptômes de l’asthme et le recours aux agonistes β2électifs pour un soulagement rapide. Ces changements s’accompagnent d’améliorations dans la fonction pulmonaire. Autant le zafirlukast que le montelukast réduisent les niveaux de circulation des éosinophiles et pour raient avoir d’autres propriétés anti- inflammatoires favorables. L’administration d’ARLT per met de réduire les doses de glucocorticostéroïdes inhalés. Les ARLT actuellement sur le marché ne comportent pas d’effets secondaires sérieux et sont disponibles pour administration par voie orale.
CONCLUSIONSLes antagonistes des récepteurs des leucotriènes appartiennent à une nouvelle classe de médication anti-asthmatique. Même si les glucocorticostéroïdes inhalés demeurent la thérapie privilégiée pour maîtriser l’asthme chronique, les ARLT devraient être considérés chez les patients asthmatiques réagissant à l’AAS: comme thérapie d’appoint lorsque des doses de faibles à modérées ne suffisent pas à elles seules à procurer une bonne maîtrise; ou comme thérapie d’appoint pour permettre de réduire les doses de glucocorticostéroïdes inhalés.
This article has been peer reviewed.
Cet article a fait l’objet d’une évaluation externe.
Can Fam Physician2000;46:872-879.
résumé abstract
sthma represents a large and increasing burden of illness in primar y care.1 Once managed through crises, asthma is now managed more effectively with early and regular use of inhaled corticosteroids and intermit- tent use of bronchodilators when needed.2As suc- cessful as this approach has been, both patients and physicians continue to look for improvements and alternatives.
While asthma mortality is small and decreasing, many of our patients continue to suffer needless mor- bidity, such as days lost from work or school.
Moreover, our growing experience with inhaled steroids has shown a small but very real potential for systemic side ef fects, such as osteoporosis3 and cataract formation.4The recent introduction of a new class of asthma medication, leukotriene-receptor antagonists (LTRAs), offers family physicians new treatment options that improve asthma control and are easily administered.
This ar ticle discusses the physiology of leukotrienes, their role in asthma management, and the consequences of blocking leukotriene receptors in patients with asthma. Discussion will focus on LTRAs that are available for clinical use in Canada.
Quality of evidence
We searched MEDLINE using such key words as asthma, leukotriene-receptor antagonists, pathophysi- ology, pharmacology, primar y care, and asthma guidelines. Most data were derived from randomized double-blind, placebo-controlled trials, some of which involved small samples. Recommendations for using LTRAs in family medicine are outlined and consistent with current guidelines on asthma management in Canada.
Evidence relating to the ef ficacy and safety of LTRAs involves data derived from studies using vari- ous clinical models of asthma (allergen-induced asth- ma, ASA-induced asthma, and exercise-induced bronchospasm) and studies involving patients with chronic asthma. Most studies dealing with chronic asthma included patients who would typically be encountered in primary care.
Leukotriene synthesis
Leukotrienes are formed from the metabolism of arachidonic acid (Figure 1), which is derived from the action of phospholipase A2 acting on the cell membrane of virtually any cell. Arachidonic acid is metabolized by two major pathways, the cyclooxy- genase pathway (forming prostaglandins and thromboxanes) and the 5-lipoxygenase pathway (producing leukotrienes). Several stimuli, including IgE-receptor activation, antigen-antibody interac- tion, and microorganisms, can activate phospholi- pase A2to speed the formation of arachidonic acid.5 In the late 1970s, it became evident that the cys- teinyl leukotrienes, leukotriene C4, leukotriene D4
and leukotriene E4 (Figure 1) represented the component molecules of the slow-reacting sub- stance of anaphylaxis.6 Cysteinyl leukotrienes are found to:
• produce smooth muscle spasm,7
• increase vascular permeability,8
• enhance mucus production,9
• decrease mucocillary transport,10and
• attract eosinophils into the airway.10
Inhaled leukotrienes C4and D4are up to 1 000 times more potent than histamine in causing air way obstruction in healthy people, and their effect lasts longer.11Inhaled leukotrienes C4 and D4also appear to increase bronchial hyperresponsiveness to both histamine and methacholine.12Leukotriene-receptor antagonists currently available for clinical use exert their biological effects by selectively binding to the cysteinyl leukotriene receptor type 1.10
Clinical models of asthma
Allergen-induced asthma.In sensitized patients, inhalation of a specific allergen results in acute bron- choconstriction that usually subsides spontaneously within 2 hours; this phenomenon is known as the early asthmatic response. In many asthma patients, the early response resolves only to be followed by a second episode of air way narrowing that begins 3 to 4 hours after allergen challenge. This late response can last as long as 24 hours.13Cysteinyl leukotrienes are produced during the early asthmatic response,14and the degree of leukotriene production correlates directly with the magnitude of the early asthmatic response.15 Several studies involving LTRAs have shown that most of the bronchospasm associated with the early asthmatic response is atten- uated and that the late asthmatic response is partially attenuated by these agents.16-18
A
Dr D’Urzo is a Lecturer in the Department of Family and Community Medicine at the University of Toronto and is Director of the Primary Care Asthma Clinic in Toronto, Ont. Dr Chapman is a Professor of Medicine at the University of Toronto and is Director of the Asthma Centre at The Toronto Hospital.
It is less clear that the LTRAs now available can suppress the air way inflammation seen during the late asthmatic response. In a recent placebo-con- trolled, double-blind crossover trial, Calhoun and col- leagues19 challenged air ways directly by using a bronchoscope to instill a dilute solution of allergen in segmental air ways. They subsequently lavaged the same airways to assess the cellular response. They reported that zafirlukast administration (20 mg bid for 7 days) reduced several indices of the inflamma- tor y allergic response, but the reduction in eosinophil count was not statistically significant. This lack of statistical significance might be due to large intersubject variation and the small sample size (n = 11) of the study. Similarly, a shor t course of montelukast (10 mg daily) has been shown20to pro- tect against allergen-induced air way narrowing but does not significantly suppress sputum eosinophil counts or eosinophil cationic protein levels in asthma patients (n = 9).
Acetylsalicylic acid–induced asthma.As many as 10% of asthmatic adults have ASA-induced asthma.11 In some susceptible people, severe, life-threatening
asthma can follow ingestion of ASA or other nons- teroidal anti-inflammatory drugs (NSAIDs).21At pre- sent, the most ef fective therapy for ASA-induced asthma is avoidance of ASA or other NSAIDs. There is, however, good reason to speculate that LTRAs might have a useful role in treatment of ASA-sensitive asthma.
Research suggests that ASA triggers attacks of wheezing in susceptible individuals by blocking cyclooxygenase metabolic degradation of arachidonic acid and directing larger amounts of this substrate down the lipoxygenase (leukotriene-producing) path- way. Leukotriene-receptor antagonists have been shown to protect against bronchospasm associated with oral ASA challenge,22,23protection that ranges from moderate to complete. Montelukast has also been reported to improve the symptom control and pulmonary function of patients with severe ASA-sensi- tive asthma when it was added to their maintenance regimen of inhaled and, in some cases, oral steroids.24
Exercise-induced bronchospasm. Cysteinyl leukotrienes appear to have an important role in causing exercise-induced bronchoconstriction. In eight asth- ma patients with documented exercise-induced
M e m b r a n e p h o s p h o l i p i d s ( p l a s m a o r n u c l e a r )
P h o s p h o l i p a s e A2
Arachidonic acid
C y c l o o x y g e n a s e
P r o s t a g l a n d i n s T h r o m b o x a n e s
L e u k o t r i e n e - r e c e p t o r a n t a g o n i s t s
L e u k o t r i e n e r e c e p t o r ( a i r w a y ) : z a fir l u k a s t a n d m o n t e l u k a s t
R e d u c e d s m o o t h m u s c l e c o n s t r i c t i o n R e d u c e d e o s i n o p h i l c o u n t
R e d u c e d e d e m a
5 - L i p o x y g e n a s e ( z i l e u t o n — i n h i b i t s 5 - l i p o x y g e n a s e )
a n d 5 - l i p o x y g e n a s e - a c t i v a t i n g p r o t e i n
L e u k o t r i e n e E4
L e u k o t r i e n e A4
L e u k o t r i e n e B4
L e u k o t r i e n e C4
L e u k o t r i e n e D4
F i g u re 1.Leukotriene pathway
bronchospasm, administration of 20 mg of zafirlukast as a single dose 2 hours before exercise reduced the mean maximum decrease in forced expiratory volume in 1 second (FEV1) after exercise to 22%, compared with a 36% decrease after placebo.25
In a recent report,26montelukast (10 mg daily for 12 weeks) was associated with significant inhibition (47.4%) of the exercise-induced fall in FEV1 when described in terms of improvement in the area under the FEV1curve. This protective effect was well sus- tained, and there was no evidence of tolerance or rebound worsening of lung function after 3 months of continuous montelukast therapy.26The same cannot be said of long-acting β2-agonists, which lose some effectiveness over time when given continuously to prevent exercise-induced symptoms.27
Role of LTRAs in chronic asthma. While the efficacy of LTRAs in various clinical models of asth- ma has been well documented,19-21studies of LTRAs in asthma management that are most clinically rele- vant to family physicians involve patients with chron- ic asthma. Currently, zafirlukast and montelukast are available in Canada for managing asthma. Both of these drugs are selective and competitive receptor antagonists of leukotriene D4and leukotriene E4. No studies have compared montelukast and zafirlukast with each other. Before instituting new therapy in patients with suboptimal asthma control, physicians should evaluate medication compliance, inhaler technique, and environmental control measures.
Montelukast. Reiss et al28 conducted a 12-week double-blind, placebo-controlled trial involving 681 patients with intermittent or persistent asthma and found that a single 10-mg daily dose of montelukast given at night increased morning FEV1 by 13% as compared with 4% in the placebo group. Montelukast also decreased nocturnal awakenings due to asthma and need for short-acting β2-agonists.
In a shor t study (1.5 weeks), montelukast was compared with placebo in a crossover trial, and treatment with montelukast was associated with a 16% improvement in FEV1.29In an 8-week trial of 336 children 6 to 14 years old with intermittent or per- sistent asthma, Knorr et al30found that 5 mg of mon- telukast nightly increased mean mor ning FEV1
significantly more than placebo (approximately 8%
vs 4%). Shor t-acting β2-agonist use decreased by 0 . 5 7 p u f f s d a i l y a m o n g m o n t e l u k a s t - t r e a t e d children and increased by 0.22 puffs daily among placebo-treated children.
Noonan et al31 studied patients with mild to moderate asthma and concluded that montelukast administration was associated with dose-related improvements in asthma control end points.
Improvements were seen in FEV1and peak expirato- ry flow rate and in daytime symptom scores, use of as-needed inhaled β2-agonists, and asthma-specific quality of life. In a recent report (n = 226), Lofdahl et al32reported that montelukast permitted a 47% reduc- tion in inhaled corticosteroid dosage compared with a 30% reduction with placebo in a group of asthma patients previously well controlled on inhaled corti- costeroids. Near maximal effects on several asthma control end points have been shown to occur within the first day of treatment with montelukast.
In another double-blind, placebo-controlled trial (n = 40), Leff et al33showed that montelukast (10 mg daily) resulted in significant decreases in both spu- tum and blood eosinophils compared with placebo.
Peak flow rate, symptoms, and β2-agonist use all improved significantly with montelukast use.
Malmstrom et al34 have repor ted that both mon- telukast and beclomethasone (200 µg bid) provide important clinical improvements in need for rescue medication, symptom scores, and lung function as compared with placebo.
Zafirlukast. In a 6-week double-blind, placebo-con- trolled trial, Spector et al35 randomly assigned 255 patients with moderate asthma to receive one of three daily dosages of zafirlukast (10, 20, or 40 mg in divided doses) or placebo. These investigators reported significant improvements in both subjective (asthma symptom score) and objective (FEV1, num- ber of nocturnal awakenings, and use of rescue β2-adrenergic agonist drugs) measures of asthma control. Improvement was dose dependent, with the 10-, 20-, and 40-mg groups exhibiting a 7%, 6%, and 11% increase in FEV1, respectively (P < .05 for the 40-mg group vs placebo). In the placebo group, FEV1
increased by just 1%.
In a 13-week double-blind, placebo-controlled trial36involving 672 asthmatic adults, zafirlukast administration at a dose of 20 mg bid was associated with significant reductions in daytime asthma scores (27%), in mor nings with asthma (29%), and in β2-agonist use (22%). Morning peak expiratory flow rate and FEV1 increased significantly, by 6.9% and 6.3%, respectively, compared with placebo. Changes in symptoms, β2-agonist use, and pulmonary function occurred within 2 days of zafirlukast treatment and continued throughout the trial.
Micheletto et al37indicate that zafirlukast given as a single 20-mg dose is associated with reduced need for (inhaled) steroids as demonstrated by a decrease (-256.3 ± 120.7) in the angular coef ficient for this trend compared with placebo (+12.4 ± 17, P < 0.025, n = 9). These investigators37also reported significant reductions in nighttime awakenings and asthma symptoms. In a double-blind, placebo-controlled trial of 13 weeks’ duration, Kylstra et al38studied the effect of zafirlukast (20 mg bid) on quality of life, event-free days, and peripheral eosinophils in 231 patients and found that zafirlukast significantly increased the number of symptom- and problem-free days, improved quality of life scores, and decreased the number of peripheral eosinophils.
Pharmacologic considerations
Pharmacokinetics of montelukast.Montelukast is rapidly and nearly completely absorbed following oral administration. Peak plasma concentrations are reached in 2 to 3 hours for the 5- and 10-mg formula- tions. Mean plasma half-life is 2.7 to 5.5 hours.
Montelukast is metabolized in the liver by CYP-450 enzymes 3A4 and 2C9 and is excreted mainly in the bile. There have been no reported pharmacokinetic differences between dosing in the morning or in the evening. Dosage adjustments are not required for patients with mild to moderate hepatic insufficiency.39 Montelukast does not appear to interact with any drugs, including oral contraceptives. Bioavailability of montelukast is not influenced by food ingestion.39 Currently there is no information on other potent CYP-450 enzyme inducers, such as rifampin, or inhibitors, such as ketoconazole. The safety of mon- telukast in human pregnancy has not been estab- lished. The overall incidence of side effects reported with montelukast is not significantly different from placebo; the more common adverse events are headache and abdominal pain.39
Dosing for montelukast. Montelukast is avail- able in 10-mg tablets and 5-mg chewable tablets.
Recommended dosage is 5 mg for children 6 to 14 years old and 10 mg for adults, taken daily in the evening. Cost of therapy in Canada is $1.40 and $2.06 for the 5-mg and the 10-mg tablets, respectively.
Pharmacokinetics of zafirlukast. Zafirlukast is rapidly absorbed following oral administration. Peak plasma concentrations are achieved 3 hours after dos- ing. Taking zafirlukast with food reduces its bioavail- ablity.40 The elimination half-life of zafirlukast is
approximately 10 hours. Zafirlukast is metabolized in the liver by the CYP-450 enzyme 2C9 enzyme path- way. Zafirlukast is not recommended for patients with hepatic impairment, including liver cirrhosis.40
Coadministration of zafirlukast with er y- thromycin, theophylline, and terfenadine will result in decreased plasma levels of zafirlukast, but coad- ministration with ASA can increase levels of zafir- lukast. Coadministration with terfenadine does not result in changes in plasma terfenadine levels or in electrocardiographic parameters. Zafirlukast inges- tion increases plasma levels of warfarin, so adjust- ments in anticoagulant therapy might be needed.
Oral contraceptives can be administered with zafir- lukast without adverse interaction. The safety of zafirlukast during human pregnancy has not been established. Overall incidence of side effects report- ed with zafirlukast is not significantly different from that with placebo. The most common adverse events repor ted after long-term therapy with zafirlukast were headache and pharyngitis.40
Dosing for zafirlukast. The recommended dosage of zafirlukast is 20 mg twice daily taken at least 1 hour before or 2 hours after meals. Zafirlukast is approved for adults and children 12 years or older. In Canada, the daily cost of zafirlukast (20 mg twice daily) is $1.40.
In rare cases of patients using zafirlukast and mon- telukast, a reduction in oral steroid therapy has been associated with systemic eosinophilic vasculitis. No causal relationship with zafirlukast or montelukast has been established, and it seems most likely that withdrawal of oral steroids from asthma patients treated successfully with zafirlukast and montelukast has unmasked an existing vasculitis rather than caused one.
Leukotriene-receptor antagonists in asthma management
Can LTRAs be first-line maintenance therapy for per- sistent asthma? Many studies have tested LTRAs in this role, most commonly comparing them with placebo. Clearly, LTRAs are superior to placebo.
When LTRAs are added to inhaled corticosteroids in a combination maintenance regimen, they improve symptoms and lung function fur ther or allow a reduction in steroid dosage.
In the latest Canadian consensus guidelines for management of asthma, LTRAs are regarded as use- ful adjunct therapy, best used with inhaled cortico- steroids. For this revision of the guidelines, there was
insufficient evidence and experience to recommend LTRAs as sole maintenance therapy. For patients who choose not to use inhaled corticosteroids or those who find using inhaled cor ticosteroids dif ficult, LTRAs should be considered the anti-inflammator y therapy of choice. Interestingly, the response to LTRAs among asthma patients varies. Some patients demonstrate marked improvements in both objective and subjective parameters; others experience much less benefit. This observation in some studies likely contributes to the small yet statistically significant improvement in various primary end points. At pre- sent, it is impossible to identify which patients are most likely to respond to LTRA therapy.
If LTRAs are to be added to a patient’s therapy, what steps should be taken? First, patients anxious to tr y out the “new pills for asthma” must be informed that the new medication is not intended to replace their cur rent inhalers. Shor t-acting β2-agonists, such as salbutamol, will still be needed for relief of episodic wheezing. As noted above, the agents are generally recommended as adjuncts to inhaled corticosteroid therapy. If patients are using moderate doses (400-1000 µg/d) of beclomethasone dipropionate or equivalent and still experience regular symptoms, an LTRA can be considered as add-on therapy.
Second, it is helpful to identify one or more end points of asthma control to follow during a therapeu- tic trial of the new agent. If patients receive a 2-week sample of medication, they should have sufficient time to see improvement in need for β2-agonists, noc- turnal awakenings, peak flow records, or spirometry results.
Third, if patients benefit from LTRAs and begin to use them regularly, they must have an action plan to guide them through any future exacerbations. The role of LTRAs in exacerbations has not been studied, but there is no reason to believe that doubling or tripling the usual clinical dose will be helpful. Patients must be given useful self-treatment alternatives. For most, this would be an increase in dose of inhaled corticosteroids or addition of a short “burst” of pred- nisone. The role of LTRAs in asthma management continues to evolve. Further studies are required to evaluate:
• the role of LTRAs as first-line therapy,
• the steroid-sparing potential of these agents,
• the potential of adding LTRAs as an alternative to increasing the dose of inhaled cor ticosteroids,
• how to choose between long-acting β2-agonists and LTRAs as adjuncts,
• the anti-inflammatory potential of LTRAs, and
• the role of these drugs for severe asthma.
Conclusion
Convincing evidence suggests that cysteinyl leukotrienes have an important role as inflammato- r y mediators in the pathophysiology of asthma.
Asthma symptoms triggered by physiologic, envi- ronmental, and allergic stimuli are alleviated by LTRAs. Clinical experience with zafirlukast and
Key points
• Leukotriene-receptor antagonists are a new class of asthma medication that are an adjunct to steroids and bronchodilators.
• Leukotriene-receptor antagonists are particu- larly useful in allergy-, ASA-, and exercise- induced asthma.
• In Canada, montelukast and zafirlukast are available and have been shown to be effective, with few side effects. No direct comparisons between the two have been made.
• Leukotriene-receptor antagonists appear to help reduce dependence on steroids and res- cue bronchodilator use, but do not replace these drugs as first-line treatment.
Points de repère
• Les antagonistes des récepteurs des leu- cotriènes appartiennent à une nouvelle classe de médication contre l’asthme qui sert d’ap- point aux glucocorticostéroïdes et aux bron- chodilatateurs.
• Les antagonistes des récepteurs des leu- cotriènes sont particulièrement utiles dans les cas d’asthme déclenché par une allergie, l’AAS ou l’effort.
• Au Canada, le montelukast et le zafirlukast sont disponibles sur le marché, leur efficacité a été démontrée et ils ont peu d’effets secondaires.
Aucune comparaison directe n’a été faite entre les deux.
• Les antagonistes des récepteurs des leu- cotriènes semblent aider à réduire la dépen- dance à l’égard des glucocorticostéroïdes et le recours aux bronchodilatateurs pour un soulagement rapide, mais ne remplacent pas ces médicaments comme thérapies de premier choix.
montelukast indicate that both medications are safe and well tolerated in a spectrum of disease severity.
At present, inhaled corticosteroids remain first-line therapy for control of air way inflammation.
Leukotriene-receptor antagonists appear to have a role as steroid-sparing agents and as treatment for exercise-induced and ASA-sensitive asthma. This new class of medication will prove useful to family physicians managing asthma patients.
Acknowledgment
We thank Deborah K. D’Urzo, David Renwick, and Kim Lunn for their assistance in preparing this manuscript.
Correspondence to: Dr Anthony D. D’Urzo, Director, Primary Care Asthma Clinic, 1670 Duf ferin St, Suite 107, Toronto, ON M6H 3M2
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