Asthma represents a large and increasing burden of illness in primary care. Once managed through crises, asthma is now managed more effectively with early and regular use of inhaled corticosteroids and intermittent use of bronchodilators when needed. As successful 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 morbidity, 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 effects, such as osteoporosis and cataract formation. The 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 article 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 and USA.
Quality of evidence
We searched MEDLINE using such key words as asthma, leukotriene-receptor antagonists, pathophysiology, pharmacology, primary care, and asthma guidelines. Most data were derived from randomized double-blind, placebo-controlled trials, some of which involved small samples. Recommendations for using leukotriene-receptor antagonists in family medicine are outlined and consistent with current guidelines on asthma management in Canada and USA.
Evidence relating to the efficacy and safety of LTRAs involves data derived from studies using various clinical models of asthma (allergen-induced asthma, 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.
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 cyclooxygenase pathway (forming prostaglandins and thromboxanes) and the 5-lipoxygenase pathway (producing leukotrienes).
Several stimuli, including IgE-receptor activation, antigen-antibody interaction, and microorganisms, can activate phospholipase A2 to speed the formation of arachidonic acid. In the late 1970s, it became evident that the cysteinyl leukotrienes, leukotriene C4, leukotriene D4 and leukotriene E4 (Figure 1) represented the component molecules of the slow-reacting substance of anaphylaxis. Cysteinyl leukotrienes are found to:
- produce smooth muscle spasm,
- increase vascular permeability,
- enhance mucus production,
- decrease mucocillary transport, and
- attract eosinophils into the airway.
Inhaled leukotrienes C4 and D4 are up to 1000 times more potent than histamine in causing airway obstruction in healthy people, and their effect lasts longer. Inhaled leukotrienes C4 and D4 also appear to increase bronchial hyperresponsiveness to both histamine and methacholine. Leukotriene-receptor antagonists currently available for clinical use exert their biological effects by selectively binding to the cysteinyl leukotriene receptor type 1.
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