Introduction - leukotriene antagonists
Introduction - leukotriene
How it works
Uses
Off-label indications
Adverse reactions
Contraindications
Drug interactions
Leukotriene antagonists, also known as antileukotrienes, are drugs that inhibit the inflammatory mediators, leukotrienes. They include:
Leukotrienes (LTs) are potent, biological, proinflammatory mediators. They are produced in the body from arachidonic acid by the enzyme 5-lipoxygenase and are divided into groups according to their chemical structure.
Eosinophils, basophils and mast cells are important sources of cysteinyl-LTs (LTC4, LTD4 and LTE4). Cysteinyl-LTs play a role promoting and maintaining chronic inflammatory responses in allergic respiratory and skin disease through their effects on chemotaxis (attracting immune cells), vasodilation (widening blood vessels) and oedema (swelling as fluid leaks through the blood vessels).
Leukotrienes exert their actions by binding to two receptors, cysteinyl-LT1 receptor and cysteinyl-LT2 receptor, which are found in smooth muscle cells and macrophages in the airway and on other pro-inflammatory cells (including eosinophils).
Antileukotriene drugs block the actions of cysteinyl-LTs.
Inhibiting leukotriene activity reduces symptoms of asthma, allergic rhinitis, and certain dermatological conditions by decreasing secretion of mucus, eosinophil recruitment after allergen exposure, bronchoconstriction, oedema, pruritus, and vascular permeability.
Leukotriene antagonists are mainly used to treat asthma.
Montelukast is registered in some countries for the:
Zafirlukast (marketed as Accolate® by Astra Zeneca), pranlukast (marketed as Ultair® by SmithKline Beecham), and aileuton (marketed as Zylflo® by Abbott Laboratories in USA) are available in some countries (eg, US and some European countries) to treat asthma
Leukotriene antagonists have also been of some benefit in a variety of inflammatory skin disorders. However, their role in the treatment of dermatological disease is not yet clear and evidence is limited.
To date, montelukast, zafirlukast, and pranlukast have been reported to be effective in at least some cases of the following skin conditions:
Atopic dermatitis is associated with an increased number of activated mast cells that release leukotrienes. Montelukast, zafirlukast, and zileuton have been reported to reduce the severity of atopic dermatitis in some patients. However, available trial data have not demonstrated consistent benefit to suggest routine off-label montelukast use in patients with atopic dermatitis.
Several case reports and clinical trials of montelukast and zafirlukast in urticaria have reported limited benefit alone or with antihistamines (standard treatment for urticaria). Although evidence is limited, adjunct use of leukotriene receptor antagonists may be considered in select patients with chronic spontaneous urticaria, particularly when symptoms are associated with non-steroidal antiinflammatories (NSAID) sensitivity.
Leukotriene antagonists have been tried in several types of urticaria:
Large-scale, prospective, controlled trials are required to determine which patients with urticaria may benefit from treatment with leukotriene receptor antagonists.
Mastocytosis is a group of disorders in which there are excessive mast cells in the skin, causing itch and in affected babies, blistering. Montelukast has been reported to be useful for at least two babies with severe mastocytosis.
Sjögren-Larsson syndrome is an inborn error of lipid metabolism, characterised by ichthyosis, severe itch, intellectual disability, and spasticity, and in which the degradation of LTB4 is defective. The itch was reported to be significantly reduced in several cases treated with zileuton.
Leukotriene antagonists have been tried in several other skin conditions in which leukotrienes are released such as blistering skin diseases and psoriasis, but there are few published reports of their effectiveness.
Typical adult dosing of leukotriene antagonists:
The most common adverse reactions (incidence ≥ 5% and greater than placebo in clinical trials) listed in descending order of frequency below:
Montelukast carries a boxed warning regarding serious neuropsychiatric adverse effects which includes insomnia, mood disturbance, and increased suicidal ideation; patients should be counselled on this. If any of these occur, patients should notify their physician promptly.
Life-threatening liver failure has been reported in patients treated with recommended doses of zafirlukast and zileuton.
Current safety information is based on treatment for asthma and may not be applicable when leukotriene receptor antagonists are used for other disorders.
No dose adjustment is needed when montelukast is co-administered with theophylline, prednisone, prednisolone, oral contraceptives, terfenadine, digoxin, warfarin, thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, decongestants, and hepatic cytochrome P450 (CYP) enzyme inducers [a large superfamily of enzymes with catalyse the oxidation of organic substances].
Coadministration of zafirlukast with warfarin results in a clinically significant increase in prothrombin time and could result in bleeding. Prothrombin times should be monitored closely, and anticoagulant therapy adjusted accordingly.
Zileuton is metabolised principally by hepatic cytochrome P450 enzymes and dose adjustment may be necessary with cytochrome enzyme inducers.
Approved datasheets are the official source of information for medicines, including approved uses, doses, and safety information. Check the individual datasheet in your country for information about medicines.
We suggest you refer to your national drug approval agency such as the Australian Therapeutic Goods Administration (TGA), US Food and Drug Administration (FDA), UK Medicines and Healthcare products regulatory agency (MHRA) / emc, and NZ Medsafe, or a national or state-approved formulary eg, the New Zealand Formulary (NZF) and New Zealand Formulary for Children (NZFC) and the British National Formulary (BNF) and British National Formulary for Children (BNFC).
