Leukotriene Synthesis Inhibitors

Leukotriene synthesis inhibitors block 5-lipoxygenase, the enzyme that forms all leukotrienes. Zileuton is the only agent in clinical use. It is an oral add-on drug for asthma, and its availability is limited to a few markets.

Mechanism. Inhibition of 5-lipoxygenase lowers production of leukotriene B4 and of the cysteinyl leukotrienes LTC4, LTD4 and LTE4. The effect on leukotriene B4 adds anti-inflammatory action that receptor antagonists lack.

Pharmacokinetics. Absorption is rapid, with peak levels at about 1.7 hours and a half life of about 2.5 hours for the immediate release form. Protein binding is about 93 percent. Metabolism is by CYP1A2, CYP2C9, CYP3A4 and glucuronidation.

Pharmacodynamics. FEV1 improves by about 10 to 15 percent in responders within hours, and the effect is similar to receptor antagonists. It reduces the need for reliever and for oral corticosteroid in some patients.

Zileuton immediate release. 600 mg four times daily with meals and at bedtime, from 12 years of age.

Zileuton extended release. 1200 mg (two 600 mg tablets) twice daily within 1 hour after the morning and evening meals, from 12 years of age.

Differences from receptor antagonists. It acts on all leukotrienes, including leukotriene B4, and gives broader inhibition. It needs more frequent dosing, liver monitoring and many interaction checks.

Asthma. Add-on to an inhaled corticosteroid in patients who do not control on a leukotriene receptor antagonist or who cannot take inhaled long acting beta 2 agonists.

Aspirin-exacerbated respiratory disease. Useful, as leukotriene overproduction drives symptoms and bronchospasm.

Not for acute attacks. A short acting beta 2 agonist is kept for rescue.

Region. Zileuton is unavailable in most countries. Montelukast is the usual leukotriene modifier where supply allows.

Hepatotoxicity. Raised alanine aminotransferase occurs in a minority of patients. Check alanine aminotransferase before starting, monthly for the first 3 months, every 2 to 3 months for the rest of the first year, and periodically after that. Stop the drug for jaundice, symptoms of liver injury or alanine aminotransferase over 5 times the upper limit of normal.

Contraindications. Active liver disease, alanine aminotransferase of 3 times the upper limit of normal or more, and hypersensitivity.

Other adverse effects. Dyspepsia, nausea, headache, myalgia, sinusitis and neuropsychiatric events such as sleep disturbance and mood change.

Interactions. Zileuton inhibits CYP1A2, which roughly halves theophylline clearance, so halve the theophylline dose and check levels. It raises the INR in patients on warfarin and raises propranolol levels. Check the interaction before adding any drug cleared by CYP1A2.

Monitoring. Alanine aminotransferase on the schedule given for the first year, asthma control, reliever use, and theophylline level when combined.

Special groups. Pregnancy: avoid unless essential, because data are limited. Breastfeeding: avoid. Children: not used under 12 years. Older adults: no adjustment, watch liver tests. Hepatic impairment: contraindicated. Renal impairment: no adjustment.

Referral and escalation. Rising transaminases, jaundice or persistent poor control needs stopping the drug and specialist review.