Leukotriene modifiers in the treatment of asthma

Leukotriene modifiers are an entirely new class of asthma treatment, which have entered clinical practice in 1996-7 in several countries including Britain, Japan, and the United States. Their development is an example of rational drug design following the elucidation of leukotriene structures in 1979-80 and the subsequent confirmation of their pathophysiological role as inflammatory mediators in asthma.¹

There are two types of leukotriene modifier: leukotriene synthesis inhibitors and cysteinyl leukotriene receptor antagonists.² Both are used to block the bronchoconstrictor and pro-inflammatory activity of cysteinyl leukotrienes within the asthmatic airway. Cysteinyl leukotrienes (LTC₄, LTD₄, and LTE₄) were originally identified as long lasting smooth muscle spasmogens and collectively termed “slow reacting substance of anaphylaxis” (SRS-A). They are now known to be metabolites of arachidonic acid formed by the 5-lipoxygenase pathway¹ and are produced almost exclusively by inflammatory leucocytes, especially mast cells, basophils, and eosinophils. The leukotriene receptor antagonists block the activity of cysteinyl leukotrienes at their receptors (CysLT₁) on bronchial smooth muscle and elsewhere, while the leukotriene synthesis inhibitors block the synthesis of all leukotrienes by interrupting the 5-lipoxygenase pathway.²

Cysteinyl leukotrienes are among the most potent constrictors of human bronchial smooth muscle known, being 10-5000 times more potent in vitro than other bronchoconstrictor agents such as histamine, prostanoids, or platelet activating factor.³,⁴ When inhaled by normal or asthmatic subjects, they cause sustained bronchoconstriction lasting 30-45 minutes. Asthmatic patients are hyperresponsive to the bronchoconstrictor effects of cysteinyl leukotrienes, especially LTE₄. Their ability to impair airflow is augmented by airway oedema, mucus hypersecretion, and reduced mucociliary clearance. After a single dose, inhaled cysteinyl leukotrienes induce non-specific bronchial hyperresponsiveness for up to one week.³ They have been detected in the fluid from bronchoalveolar lavage and urine of asthmatic subjects after inhaled allergen challenge and in the urine after acute spontaneous exacerbations.⁵,⁶ Cysteinyl leukotrienes are potent and selective chemoattractants for human eosinophils⁴,⁷ and may also be involved in airway remodelling in asthma, causing hyperplasia of bronchial smooth muscle and airway epithelium.⁴

The important contributions of cysteinyl leukotrienes to airway dysfunction and eosinophilia in asthma have been confirmed by clinical trials of leukotriene modifying agents.²,⁸,⁹ Although first generation compounds such as FPL 55712 lacked potency and were toxic, the second generation antagonists such as montelukast, pranlukast, and zafirlukast show much greater potency against inhaled leukotrienes, while the synthesis inhibitors such as zileuton and BAYx1005 can reduce leukotriene synthesis to negligible levels.

Most early clinical trials of leukotriene modifiers in asthmatic subjects have used the inhaled allergen challenge model to assess their effect on the early bronchoconstrictor response and on the late bronchoconstrictor response, which is associated with leucocyte influx and increased bronchial responsiveness.¹⁰ Both types of leukotriene modifier block the early response by 70-80%, showing that cysteinyl leukotrienes released from mast cells are the most important mediators of acute allergic bronchoconstriction.²,⁸,⁹ More surprisingly, they also consistently block up to 70% of the late response, showing that late bronchoconstriction is mostly due to cysteinyl leukotriene release, probably from infiltrating eosinophils. The eosinophilia itself is inhibited by leukotriene modifiers, suggesting that eosinophil influx is partly induced by the chemoattractant activity of leukotrienes released during the early response.

In patients with asthma, leukotriene modifiers improve baseline lung function and reduce bronchial hyperresponsiveness for several months.^11–14 Treatment with oral montelukast, zafirlukast, or zileuton significantly improves many clinical outcome measures, including night time awakenings, daytime symptom scores, and use of β₂ agonists.^11–13 The size of these effects is similar to that seen in patients treated with 400-500 μg of inhaled beclomethasone daily. An anti-inflammatory effect is also suggested by significant reductions in eosinophil counts in the sputum and blood of asthmatic patients treated with montelukast or zileuton, and by significant reductions in the use of corticosteroids.⁹,¹¹

Present evidence suggests that these drugs may be especially useful in defined patient populations.⁸ They are effective in blocking bronchoconstriction after challenge of susceptible asthmatic patients with exercise or cold, dry air, with a particularly dramatic effect on shortening recovery time. They are also effective in blocking adverse reactions to aspirin and other non-steroidal anti-inflammatory drugs in susceptible asthmatic patients.¹⁵ Even in the absence of exposure to non-steroidal anti-inflammatory drugs, persistent severe asthma in patients sensitive to aspirin is associated with chronic overproduction of cysteinyl leukotrienes, which may be caused by a genetic anomaly in the luekotriene synthetic pathway.¹⁶,¹⁷ Conversely, a subgroup of patients in whom leukotrienes may play relatively little role in asthma pathophysiology has been identified, reinforcing the need to target leukotriene modifiers to appropriate patient groups for maximal benefit.¹⁸

Although most trials have been performed in patients with mild or moderate asthma, some evidence suggests that leukotriene modifiers may also be useful in more severe asthma, as their effects are additive to those achieved with moderate or high doses of inhaled corticosteroids.⁸ The corticosteroid sparing effects of these drugs may prove to be important in reducing the side effects of chronic treatment with oral corticosteroids. Although their anti-inflammatory effects are likely to be less pronounced than those of high dose corticosteroids, their excellent side effect profile and their availability as oral drugs are likely to ensure that compliance with treatment is substantially better than for inhaled corticosteroids.

While interrupting the leukotriene pathway offers a new opportunity for treating asthma, the position of such drugs in the asthma armamentarium has not yet been firmly established. Further effectiveness studies are needed to determine the true value of this oral anti-asthma treatment. From the available data, leukotriene modifiers seem to act across the whole spectrum of asthma severity, although it will be important to distinguish responders from non-responders.