Leukotriene modifiers are gaining acceptance for use in patients with mild to moderate asthma.
There have been many changes in our approach to asthma in the 7 years since the 1991 publication of the Expert Panel Report1 of the National Heart, Lung and Blood Institute (NHLBI). One of these changes has been a shift in attention from bronchospasm as the main culprit to inflammation as a prime contributor to asthma’s symptoms and sequelae. Along with this shift has come a better understanding of the role of allergens and other environmental agents in initiating asthma attacks. Researchers also have a better understanding of the body’s response to these irritants and have identified many biochemical intermediaries responsible for this pathophysiologic response. Among those intermediaries are the leukotrienes. Identification of the role of leukotrienes has led to the development of a class of drugs called leukotriene modifiers.
The 1997 NHLBI2 asthma-management guidelines suggest the use of these drugs for the long-term control of asthma (in patients aged 12 or more years) as alternatives to low-dose inhaled glucocorticoids.
The therapeutic management of chronic asthma has changed markedly within the past decade.3 b2-selective adrenergic agonists, once employed exclusively in many cases, have been largely relegated to acute treatment. Similarly, the use of theophylline, once a first-line agent, has been greatly reduced. Inhaled corticosteroids have assumed primary importance, along with the preventive mast-cell stabilizers cromolyn sodium and nedocromil. The impetus for change has been the increasing recognition of inflammation as an essential part of the allergic response. Mainstream asthma research now involves the search for compounds that inhibit the formation or action of inflammatory mediators such as histamine, leukotrienes, prostaglandins, and bradykinins.
Suppression of bronchial inflammation can be accomplished using corticosteroids in most patients; only in a small minority are more potent (and toxic) drugs such as methotrexate required. Even inhaled steroids, however, have side actions that limit their applicability. These side actions include oral candidiasis and hoarseness resulting from a direct local effect on the vocal cords. Antileukotrienes, under investigation for nearly 20 years4 but only recently emerging from experimental status, provide a relatively nontoxic avenue for reducing the inflammatory and hypersecretory elements of asthma.5
Leukotrienes are a group of arachidonic acid derivatives that, similar to prostaglandins and thromboxanes, have 20 carbon atoms; hence, the collective term eicosanoids. Originally, the leukotriene group was identified as the slow-reacting substance of anaphylaxis (SRS-A),6 which extended the allergic response. As the biochemistry of eicosanoids evolved, it was shown that SRS-A comprised a group of compounds derived from arachidonic acid through the activity of the enzyme 5-lipoxygenase (5-LO).
The most bioactive of these, LTC4, LTD4, and LTE4, are conjugated with the amino acid cysteine and are known as the cysteinyl leukotrienes (cysLTs). These were found in 19805 to be potent constrictors of bronchial smooth muscle Subsequently, they were shown to stimulate airway mucus secretion and extravasation of fluids and proteins into the airway tissues.7
In a recent review, Spector8 implicated leukotrienes as causing increased vascular permeability leading to edema formation, increased mucus production with decreased mucociliary transport, contraction of bronchial smooth muscle, and infiltration of inflammatory cells into lung tissues. Two cysLTs, LTC4 and LTD4, are reported to be about 1,000 times more potent than histamine in producing bronchospasm,9 and their effects are also much more prolonged. Emphasis has been placed on the biosynthesis of leukotrienes by mast cells, but eosinophils appear to be involved; another leukotriene, LTB4, has a low eosinophil chemotactic effect.10 The increased presence of leukotrienes in the bronchoalveolar lavage fluid of asthma patients is usually demonstrable, and the measurement of LTE4 in the urine provides a simple estimate that correlates with asthma after exercise and allergen challenge.11 It should be understood that laboratory measurement of leukotrienes is not yet possible in the hospital setting.
Thus, the reduction of leukotriene effects is consonant with clinical improvement of asthma. The two main approaches to this goal have been to inhibit leukotriene formation and to occupy leukotriene receptors. Both of these mechanisms are now represented by compounds that have recently been approved by the US Food and Drug Administration (FDA). Their comparative clinical properties have been revealed only by rather limited reports of their therapeutic uses. Because, in comparison with other anti-asthma drugs, their toxicity is low, more comprehensive studies are in progress and results should soon be forthcoming.
Leukotriene receptor antagonists are represented by zafirlukast and several congeners, most having the -lukast suffix (Figure 1).8 Leukotriene synthesis inhibitors include zileuton12 and others listed in the same figure. There are two groups of these compounds: those that inhibit 5-LO directly and those that inhibit a membrane-bound enzyme essential to the activation of 5-LO. This enzyme, 5-LO activating protein (referred to as FLAP), catalyzes the formation of leukotrienes from the parent substances arachidonic acid. It is inhibited by the compound now known as BAY x1005.13
Zafirlukast was the first antileukotriene drug to be approved by the FDA for the treatment of asthma. Definite limitations were imposed on its clinical indications; it was to be used for oral maintenance therapy of chronic asthma, not for acute asthma episodes. Its effects on bronchoconstriction and inflammatory cell infiltration, however, were confirmed, and resulted in its being heavily promoted.15 The drug is supplied in 20-mg tablets to be taken twice daily. Peak blood concentrations are obtained in about 3 hours, but taking the drug with food decreases its bioavailability by 40 percent. It is metabolized in the liver and excreted mostly in feces; its half-life is about 10 hours, but may be longer in elderly patients.15
A recent clinical report16 indicates that zafirlukast reduces daytime symptoms and nighttime awakenings, and also diminishes the need for rescue drugs. Its effectiveness in producing these responses, however, was stated to be only slightly greater than placebo in a subsequent study.17 A comparison with cromolyn sodium (two puffs taken four times daily) indicated that a similar result was obtainable with zafirlukast.18 Patients with aspirin-induced asthma may especially benefit from the drug.19
The adverse effects of zafirlukast are reportedly mild (headache and gastrointestinal disturbances), but increased liver enzyme concentrations may occur. Because the drug inhibits cytochrome P450 isoenzymes (CYP2C9 and CYP3A4), it may interfere with the biotransformation of other drugs, notably warfarin and corticosteroids. If warfarin biotransformation is inhibited, increased prothrombin time results, with the possibility of bleeding episodes. A list of several compounds metabolized by these enzymes indicates that interactions may limit zafirlukast’s applicability and that caution should be exercised when it is prescribed for patients already receiving other medications.
Montelukast sodium, a newly marketed leukotriene receptor antagonist, has the advantage of once-a-day dosing. In an 8-week double-blind trial20 of 336 asthma patients aged 6 to 12 years, montelukast was demonstrated to be of modest benefit in decreasing b-agonist use and episodes of worsening asthma. Daytime symptoms, nocturnal awakenings, days of school lost, and the need for oral steroid use did not change. Another study21 comparing the protective effects of montelukast with those of placebo in treadmill-exercise-induced bronchoconstriction in 27 nonsmoking, stable asthma patients concluded that montelukast provided dose-related protection even at the end of a once-daily dosing interval.
Zileuton, which received FDA approval soon after zafirlukast, is the first 5-LO inhibitor to become available in the United States. Like zafirlukast, it is not recommended for the treatment of acute asthma. It is rapidly absorbed when taken orally, whether with or without food, and it becomes therapeutically effective in 1 to 2 hours. Its plasma half-life is about 2.5 hours.22
In clinical trials23,24 of zileuton administered in doses of 600 mg four times daily, increases in forced expiratory volume in 1 second were significantly greater than with placebo. Asthma symptoms were also controlled more effectively, and exacerbations that required treatment with oral corticosteroids were prevented. Rescue use of b-agonist inhalers was also reduced, although a similar result was obtained with placebo.24 A later study25 confirmed these findings with even more statistical significance. Prevention of hyperreactivity to cold and exercise and reduction of aspirin-induced bronchospasm in zileuton users have been recently reported.26,27
Aminotransferase activity is increased by zileuton, as by zafirlukast. Symptomatic hepatitis with jaundice (resolved when the drug’s use was stopped) has been suspected; the manufacturer now recommends frequent measurement of liver enzymes. Zileuton is metabolized by cytochrome isoenzymes, which may increase serum concentrations of warfarin, theophylline, and propranolol. The risk of hepatic toxicity and the occurrence of dyspepsia limit its use for maintenance treatment of chronic asthma.
Antileukotrienes have attained legitimacy for use in patients with moderate asthma. Whether they can be used alone or must be accompanied by other agents has yet to be established.28 Because leukotrienes are not the only proinflammatory agents involved in asthma, it is likely that corticosteroids, which are generally inhibitory to protein biosynthesis, will remain the primary drugs of choice. It is probable that individual differences in therapeutic response will be clarified as clinical studies are continued. Approval of antileukotriene therapy for children under 12 years of age has not been obtained, and the possible effects of these compounds on the liver will require that further investigations be carried out to establish their safety.
Judith A. Mathewson, MS, RRT, is assistant professor and director of clinical education, Respiratory Care Education, University of Kansas Medical Center, Kansas City, Kan. Hugh S. Mathewson, MD, is professor emeritus, and anesthesiology medical director, Respiratory Care Education, at the medical center. Paul J. Mathews, PhD, RRT, FCCM, is associate professor, Respiratory Care Education, at the medical center.
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