24 Leukotriene Receptor Antagonists
24.1 Most Interesting Information
Leukotrienes mediate many of the unwelcome symptoms of allergy and asthma, such as increased mucus secretion, decreased mucus clearance, and smooth muscle contraction causing bronchoconstriction. Certain drugs have been developed to block leukotriene receptors (i.e., montelukast, zafirlukast) or to inhibit leukotriene synthesis (i.e., zileuton). These drugs have been tested in asthma and allergy, and have shown some benefit. For allergic rhinitis, drugs that block leukotriene receptors are typically not intended as sole therapy. There are certain adverse effects with the leukotriene-modifying agents, so the provider should be educated and be aware before prescribing.
24.2 Serious Stuff
24.2.1 What Are Leukotrienes? (i.e., back to biochemistry class…)
The cys-leukotrienes are produced in leukocytes (especially mast cells and eosinophils), through the arachidonic acid pathway, by the enzyme 5-lipoxygenase. There are various isoforms of cys-leukotrienes, labeled by an alphabet soup (LTA4, LTC4, LTD4, LTE4). The cysLT1 receptor is found in bronchial mucosa and lung fibroblasts, and has a high affinity for LTD4. The cysLT2 receptor, where both LTC4 and LTD4 act, is found on endothelial cells, leukocytes, lung fibroblasts, and smooth muscle cells. LTB4 is a bit different, because it is produced from LTA4 by a hydrolase and acts on receptors BLT1 and BLT2. The BLT receptors are found on polymorphonuclear leukocytes and many tissues. The role of LTB4 and the BLT receptors has been studied less.
24.2.2 Now That the Science Is Over, Why Do We Care About Leukotrienes in Allergy?
Increased mucus secretion, smooth muscle contraction (i.e., bronchoconstriction), and decreased mucociliary clearance are largely initiated by cys-leukotriene release from mast cells in response to allergen. Also, via a positive feedback loop, eosinophils are recruited to target tissues by cys-leukotrienes produced by the eosinophils and mast cells, resulting in increased production of cys-leukotriene. The leukotrienes are, therefore, important mediators of undesirable symptoms in allergy and asthma.
24.2.3 What Are Leukotriene Receptor Antagonists?
Some drugs have been developed that block the cysLT1 receptor, thus reducing the deleterious effects of leukotrienes. These selective cysLT1 receptor antagonists include montelukast and zafirlukast and are taken orally.
In asthma, these drugs demonstrate reduced use of β2-agonist rescue inhalers, reduced nighttime awakenings, some improvement in lung function, decreased health care utilization, and decreased absenteeism. Leukotriene receptor antagonists (LTRAs) are typically recommended as add-on therapy to inhaled corticosteroids in asthma, since the benefit of LTRAs appears to be less than that of inhaled corticosteroids. It is important to remember that all asthma is not the same—the benefit of LTRAs appears to be the best in atopic asthma, pediatric asthma, and exercise-induced bronchospasm.
In allergic rhinitis, level 1 evidence (including at least 13 randomized controlled trials and 6 systematic reviews of randomized controlled trials) demonstrates that LTRAs are superior to placebo for symptom control and improved quality of life (QoL). This effect has been shown in seasonal and perennial allergic rhinitis, as well as in studies-controlled allergen exposure. See later (▶Section 24.2.6) for comparative effectiveness data versus other available allergic rhinitis medications.
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