Leukotriene inhibitors offer effective anti-inflammatory asthma therapy without the safety concerns associated with long-term inhaled corticosteroid administration
Inflammation plays a key role in the pathogenesis of asthma. In susceptible individuals, inflammation causes symptoms usually associated with widespread but variable airflow obstruction. An increased understanding of the role of inflammation in asthma has led to an emphasis on “controller” therapy with anti-inflammatory agents. Furthermore, early treatment of asthma with an effective anti-inflammatory agent may interrupt or limit progression of the inflammatory process and prevent irreversible airway damage.
Inhaled corticosteroids have become a cornerstone of asthma management because of their anti-inflammatory properties. Unfortunately, many patients attain a suboptimal therapeutic benefit from these agents because of failure to properly use metered-dose inhalers and other delivery devices. In addition, there is concern over the potential for systemic effects such as hypothalamic-pituitary-adrenal (HPA) axis suppression and bone demineralization from chronic use of inhaled corticosteroids, particularly in pediatric patients. (Studies evaluating the relationship between long-term inhaled corticosteroid use and systemic adverse effects have varied wildly in design and have yielded conflicting results.) Clearly, there is a need for a safe and effective oral anti-inflammatory asthma medication.
Leukotrienes, a family of lipid mediators derived from arachidonic acid, are produced by leukocytes and many other cells, including those found in the lung. Several leukotrienes have been implicated in the inflammatory cascade leading to asthma.1 Leukotriene modifiers, therefore, represent an important therapeutic advance in the management of chronic asthma. To date, three leukotriene modifiers have become available—zileuton, zafirlukast, and montelukast.
Synthesis
Arachidonic acid is an essential fatty acid that is present in most cells. It is released from membrane phospholipids by the activation of the enzyme phospholipase-A2. Arachidonic acid is then metabolized by one of two metabolic pathways.
It is either converted to various prostaglandins and thromboxanes by the enzyme cyclooxygenase, or it is converted to leukotriene A4 (LTA4) and various other leukotrienes by the enzyme 5-lipoxygenase, which must bind to a membrane-bound protein known as 5-lipoxygenase-activating protein (FLAP) in order to work.2,3 Collectively, the derivatives of the 20-carbon arachidonic acid are sometimes referred to as eicosanoids (“eicos” is from the Greek word eikosi, which means “twenty”).
LTA4 can be converted by different enzymes to either leukotriene B4 (LTB4) or leukotriene C4 (LTC4).2,4 LTC4 can form leukotriene D4 (LTD4) and leukotriene E4 (LTE4) in sequential cascade reactions. Collectively, LTC4, LTD4, and LTE4 are referred to as cysteinyl leukotrienes because they have cysteinyl residues. The cysteinyl leukotrienes can elicit many of the hallmark features of asthma.5 In addition, LTB4 may have a minor role in the pathogenesis of asthma.6
Role of Leukotrienes in asthma
Airflow obstruction is a principal mechanism by which asthma exerts its symptoms. In asthma, airflow obstruction can be caused by four primary mechanisms: bronchoconstriction caused by contraction of smooth muscle lining the airways; mucosal edema caused by vascular leakage; increased secretion of mucus; and the presence of an inflammatory-cell infiltrate that is rich in eosinophils. The cysteinyl leukotrienes have been found to play a role in each of these mechanisms.2
The bronchoconstriction mediated by cysteinyl leukotrienes is perhaps the most significant effect of these agents in asthma. Cysteinyl leukotrienes have been shown to induce bronchoconstriction with a potency 100-1,000 times that of histamine.7 They are among the most powerful bronchoconstrictor agents known. In addition, the bronchoconstriction produced by cysteinyl leukotrienes is more prolonged than that produced by histamine.
LTB4, a noncysteinyl leukotriene, may also play a role in the pathogenesis of asthma. LTB4 is strongly chemoattractive for neutrophils and somewhat chemoattractive for eosinophils.6 Eosinophils are thought to play a major role in asthma, and have been found in increased numbers in bronchoalveolar lavage (BAL) fluid and bronchial biopsies from patients with asthma. Neutrophils have also been identified in increasing numbers in BAL fluid after allergen challenge, but their role in asthma is less clear.
Asthma also exerts its effects through bronchial hyperresponsiveness, and leukotrienes may play a role in mediating this response. In healthy subjects, LTD4 has been shown to produce an increase in the bronchial responsiveness to methacholine that lasts for up to 2 weeks.5,8 In addition, an enhanced airway response to histamine has been demonstrated in asthma patients after inhalation of LTC4, LTD4, or LTE4.7
In asthma, there is increased production of leukotrienes.9 The most important cellular sources of leukotrienes in asthma are probably eosinophils, mast cells, and basophils. Therapy with leukotriene modifiers is aimed at either blocking the formation of leukotrienes at some point along the arachidonic acid cascade, or blocking the action of cysteinyl leukotrienes at the leukotriene receptor.
How Leukotriene Modifiers Work
There are four pharmacotherapeutic classes of leukotriene modifiers currently in some stage of development. Each is defined by its mechanism of action. The classes are: (1) inhibitors of 5-lipoxygenase; (2) inhibitors of FLAP; (3) cysteinyl leukotriene–receptor antagonists; and (4) LTB4-receptor antagonists. Currently available leukotriene modifiers work either by blocking the enzyme 5-lipoxygenase, thereby inhibiting the lipoxygenase pathway of arachidonic acid metabolism (zileuton), or by preventing leukotrienes from binding to their receptors (montelukast and zafirlukast).
Inhibitors of 5-lipoxygenase directly block this enzyme, thereby preventing the metabolism of arachidonic acid to LTA4. Zileuton is an orally active 5-lipoxygenase inhibitor. It has been shown to improve pulmonary function and reduce symptoms in subjects with asthma. FLAP inhibitors bind to FLAP, making it unavailable to bind to 5-lipoxygenase, thus preventing the metabolism of arachidonic acid to LTA4. These agents are still at an early stage of development.
Extensive research has been done on cysteinyl leukotriene–receptor antagonists, particularly LTD4-receptor antagonists. These agents block the actions of cysteinyl leukotrienes on target cells such as smooth muscle and mucus cells. Montelukast and zafirlukast, which are orally active cysteinyl leukotriene–receptor antagonists, have been shown to improve pulmonary function and reduce symptoms in subjects with asthma.10
Asthma Management
In 1997, the National Asthma Education Program (NAEP) of the National Heart, Lung, and Blood Institute (NHLBI) issued new guidelines for the diagnosis and management of asthma.11 First and foremost of these guidelines is that antiasthma therapy should not merely alleviate symptoms but also prevent exacerbations and control chronic symptoms by reducing inflammation. According to the NAEP, first-line therapy should focus on preventing or reversing airway inflammation.11 Leukotriene modifiers, therefore, may have a role in the first-line management of selected asthma patients.
The NAEP guidelines also define the step-care approach to asthma management, in which treatment progresses along a continuum according to the severity of disease.
Leukotriene Modifiers
Three leukotriene modifiers have been approved in the United States for maintenance therapy of persistent asthma: zileuton, zafirlukast, and montelukast. These agents have different mechanisms of action: zileuton blocks a critical step in leukotriene production, whereas zafirlukast and montelukast prevent leukotrienes from binding to their receptors.
Zileuton
Zileuton is approved for use as 600-mg tablets four times a day, for a total daily dose of 2,400 mg. It may be taken with meals or at bedtime. Zileuton may react with several commonly used medications. It can cause increased serum levels of theophylline, and may increase the beta-blocking action of propranolol. In patients taking the anticlotting drug warfarin, zileuton may increase the prothrombin time (PT). Zileuton may increase serum levels of liver enzymes; therefore, the agent is contraindicated in patients with acute liver disease or serum transaminase levels greater than or equal to three times the upper limit of normal. The manufacturer also recommends monitoring liver enzymes before treatment begins, once a month for the first 3 months of treatment, every 2 to 3 months for the remainder of the first year, and periodically thereafter for patients receiving long-term zileuton therapy.
Zafirlukast
Zafirlukast is given at a dose of 20 mg twice a day, for a total daily dose of 40 mg. It should be given on an empty stomach; otherwise, serum drug levels may be reduced. At the recommended dose of zafirlukast, the risk of liver function abnormalities is low, and routine monitoring is unnecessary. However, it is important to recognize that liver function abnormalities may arise at higher-than-recommended doses.
There have been rare cases of eosinophilic conditions, including Churg-Strauss syndrome, reported among patients treated with zafirlukast.12-14 Churg-Strauss syndrome is a granulomatous, necrotizing vasculitis that is usually associated with corticosteroid tapering in patients with severe asthma. Because of recent case reports, there has been some concern among clinicians regarding the possible association between zafirlukast administration and vasculitis. The reported cases of Churg-Strauss syndrome among patients treated with zafirlukast are probably a result of corticosteroid tapering.
Like zileuton, zafirlukast may increase the PT in patients taking warfarin. In addition, care should be taken with concomitant therapy with phenytoin, carbamazepine, and erythromycin.
Montelukast
Montelukast is dosed once a day. The dosage for adolescents and adults 15 years of age and older is one 10-mg tablet every evening. The dosage for pediatric patients 6 to 14 years of age is one 5-mg chewable tablet every evening. For pediatric patients 2 to 5 years of age, the dose is one 4-mg chewable tablet every evening.
Montelukast does not appear to affect hepatic function. No significant drug interactions have been noted in patients taking montelukast.
Conclusion
Leukotriene inhibitors represent a major advance in the pharmacologic management of patients with asthma. These agents offer effective anti-inflammatory asthma therapy without the safety concerns associated with long-term inhaled corticosteroid administration.
Three agents, zileuton, zafirlukast, and montelukast, are currently available, and several others are in various stages of development. It is important to understand the metabolism of arachidonic acid in order to understand how different leukotriene inhibitors work. Leukotriene inhibitors appear to be most useful in patients with mild-to-moderate persistent disease.
John D. Zoidis, MD, is a contributing writer for RT Magazine.
References
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