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Leukotriene antagonists

Author: Anoma Ranaweera, Staff writer, 2011.


What are leukotriene antagonists?

Leukotriene antagonists, also known as antileukotrienes, are drugs that inhibit leukotrienes. They include:

  • Leukotriene receptor antagonists: montelukast, zafirlukast, and pranlukast
  • Leukotriene synthesis inhibitors: zileuton.

What are leukotrienes?

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 (attrating 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).

How do leukotriene antagonists work?

Antileukotriene drugs block the actions of cysteinyl-LTs.

  • Leukotriene receptor antagonists bind strongly to the cysteinyl-LT1 receptors on target cells.
  • Leukotriene synthesis inhibitors block the enzyme 5-lipoxygenase to prevent the production of leukotrienes.

What are leukotriene antagonists used for?

Leukotriene antagonists are mainly used to treat asthma.

Montelukast is marketed as Singulair® Merck Sharp and Dhome (NZ Ltd.) and is registered by Medsafe in New Zealand for:

  • Prevention and treatment of asthma in children and adults
  • Treatment of seasonal allergies (hay fever) triggered by outdoor allergens such as pollen from trees, grasses and weeds
  • Treatment of year-round allergies generally triggered by indoor allergens such as dust mites, animal dander and/or mould spores.

Zafirlukast (marketed as Accolate® by Astra Zeneca), pranlukast (marketed as Ultair® by SmithKline Beecham), and Zileuton (marketed as Zylflo® by Abbott Laboratories in USA) are available in the US and Europe to treat asthma.

Off-label indications for leukotriene antagonists in dermatology

Leukotriene antagonists have also been found to be useful in a variety of inflammatory skin disorders. However, their role in the treatment of dermatological disease is not yet clear.

To date, montelukast, zafirlukast, and pranlukast have been reported to be effective in at least some cases with the following skin conditions:

Leukotriene antagonists in atopic dermatitis

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 but more trials are required to confirm the results.

Leukotriene antagonists in urticaria

Several case reports and clinical trials of montelukast and zafirlukast in urticaria have reported limited benefit alone or with antihistamines (the standard treatment for urticaria). 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.

Leukotriene antagonists in mastocytosis

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.

Leukotriene antagonists in Sjögren-Larsson syndrome

Sjögren-Larsson syndrome is an inborn error of lipid metabolism, characterised by ichthyosis (dry skin), 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 in other skin diseases

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.

Adverse reactions to leukotriene antagonists

The most common adverse reactions (incidence ≥ 5% and greater than placebo listed in descending order of frequency) reported from clinical trials are listed below in descending order of frequency:

  • Upper respiratory infection
  • Fever
  • Headache
  • Pharyngitis
  • Cough
  • Abdominal pain
  • Diarrhoea
  • Otitis media
  • Influenza
  • Rhinorrhoea
  • Sinusitis
  • Nausea.

Life-threatening liver failure has been reported in patients treated with recommended doses of zafirlukast and zileuton.

The dose of zafirlukast may need to be reduced in patients > 65 years of age due to reduced clearance in urine. No dosage adjustment is necessary in patients with renal insufficiency with montelukast and zileuton.

There are no adequate and well-controlled studies in pregnant women. Montelukst and zafirlukast should be avoided during pregnancy unless the potential benefit justifies the potential risk to the fetus (Pregnancy Risk Category C). Breastfeeding mothers should be advised to discontinue nursing until circulating blood levels are no longer detectable.

Current safety information is based on treatment for asthma and may not be applicable when leukotriene receptor antagonists are used for other disorders.

Contraindications to leukotriene antagonists

Patients with known aspirin sensitivity should be advised to continue to avoid aspirin and non-steroidal anti-inflammatory agents while taking leukotriene antagonists.

Drug interactions

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.

New Zealand approved datasheets are the official source of information for these prescription medicines, including approved uses and risk information. Check the individual New Zealand datasheet on the Medsafe website.



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