Elsevier

The Lancet

Volume 353, Issue 9146, 2 January 1999, Pages 57-62
The Lancet

New Drug Classes
Leukotriene-receptor antagonists

https://doi.org/10.1016/S0140-6736(98)09019-9Get rights and content

Summary

Leukotriene-receptor antagonists are the first novel class of antiasthma drugs to become available over the past three decades. They have an unique profile in that they are a hybrid of an anti-inflammatory and bronchodilator drug, and they can be taken as a tablet once or twice daily. The published data with leukotriene-receptor antagonists such as montelukast or zafirlukast show good antiasthmatic activity over a wide spectrum of asthma severity either as monotherapy or with inhaled steroids. Another potential spin-off of leukotriene-receptor antagonists is that they also seem to be effective in treating allergic rhinitis, which commonly coexists in patients with asthma. Here I overview the clinical pharmacology of leukotriene antagonists and appraise the published data from clinical trials, and look at the appropriate position of these agents in asthma management guidelines.

Section snippets

Clinical pharmacology

Zafirlukast and montelukast are potent and highly selective antagonists of type 1 cysteinyl leukotriene receptors, with affinities approximately two-fold greater than the natural ligand (figure 1).3 The cysteinyl leukotrienes (C4, D4, and E4) are generated from the arachidonic acid pathway via 5-lipoxygenase to the intermediate leukotriene A4 and then to leukotriene C4 (by leukotriene C4 synthase), leukotriene D4 (by γ-glutamyl-transpeptidase), and leukotriene E4 (by dipeptidase). The cysteinyl

Clinical efficacy

The position of leukotriene antagonists in asthma management guidelines is unclear, mainly because there was little published data when these guidelines were written.1 The two key clinical questions about the role of leukotriene antagonists are whether they should be used as first-line preventative monotherapy instead of low-dose inhaled corticosteroid for step 2 patients (ie, those with mild persistent asthma), and whether they should be used as an alternative to long-acting bronchodilators as

Adverse effects and drug interactions

There are data from randomised clinical trials in 7186 patients exposed to zafirlukast and 3797 patients with placebo, over up to 20 weeks (data on file at Zeneca Limited UK, and Accolate UK product data sheet, 1998). The frequency of adverse effects for zafirlukast versus placebo was reported: headache, 9·9 versus 9·0%; nausea, 2·6 versus 2·2%; diarrhoea, 2·3 versus 1·8%; and abdominal pain, 1·6 versus 1·2%. Serum alanine transaminase was increased in 1% of patients on zafirlukast and in 0·9%

Allergic rhinitis

The pathophysiology and role of inflammatory mediators in allergic rhinitis, particularly the importance of the cysteinyl leukotrienes, is well established.45 For example, allergen-induced nasal congestion and leukotriene synthesis are attenuated by an orally active inhibitor of 5-lipoxygenase.46 Studies with leukotriene antagonists in patients with allergic rhinitis demonstrate rapid onset of symptomatic relief which is similar to that of oral antihistamines, while the combination of

Conclusions

Leukotriene antagonists represent an important advance in non-steroidal anti-inflammatory therapy in asthma, either as an alternative or adjunctive treatment to inhaled corticosteroids. The leukotriene antagonists are active over a wide spectrum of asthma severity and exhibit both anti-inflammatory and bronchodilator activity, along with a high therapeutic index. They are also effective in aspirin-sensitive asthma as well as helping to reduce nocturnal asthma in which there is a component of

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