Leukotriene Receptor Antagonists

Leukotriene receptor antagonists (montelukast and zafirlukast) block the cysteinyl leukotriene 1 receptor and reduce bronchoconstriction, airway oedema and mucus secretion. They are oral drugs used as add-on or alternative controller therapy in asthma and in allergic rhinitis, and they are less effective than inhaled corticosteroids.

Mechanism. Cysteinyl leukotrienes (LTC4, LTD4 and LTE4) from mast cells and eosinophils act at the CysLT1 receptor to cause smooth muscle contraction, vascular leak, mucus secretion and eosinophil recruitment. Receptor blockade opposes each of these effects. Pranlukast is a third agent with limited availability.

Pharmacokinetics. Montelukast bioavailability is about 64 percent, with peak levels at 3 to 4 hours and a half life of 2.7 to 5.5 hours. CYP2C8 is the main route, with CYP3A4 and CYP2C9 as minor routes. Zafirlukast is metabolised by CYP2C9, has a half life of about 10 hours and loses absorption when taken with food.

Pharmacodynamics. Benefit starts within a day and builds over days to weeks. Response is modest and varies, and is better in allergic disease, exercise-induced bronchoconstriction and aspirin-exacerbated respiratory disease.

Differences. Montelukast is preferred because it is given once daily, can be used from young childhood and has fewer interactions. Zafirlukast needs dosing apart from food and carries a risk of hepatotoxicity.

Formulations. Montelukast comes as 10 mg tablets, chewable tablets and granules. The chewable tablets contain phenylalanine, which matters in phenylketonuria.

Asthma. Used as add-on to an inhaled corticosteroid when a long acting beta 2 agonist is not tolerated or not wanted, or as an alternative controller in mild asthma when inhaled corticosteroid is refused or not tolerated. As add-on it is less effective than a long acting beta 2 agonist. It does not treat acute attacks.

Exercise-induced bronchoconstriction. Montelukast 10 mg at least 2 hours before exercise, with no repeat dose within 24 hours. Do not use it for this purpose in patients already taking daily montelukast.

Aspirin-exacerbated respiratory disease. Useful add-on, because cysteinyl leukotriene overproduction drives the disease.

Preschool wheeze. Montelukast 4 mg nightly for a short course during viral episodes has modest benefit in some children. It does not help bronchiolitis.

Allergic rhinitis. Montelukast 10 mg once daily, alone or with an antihistamine, when intranasal corticosteroid is not tolerated.

Practical point. Oral dosing helps when inhaler technique is poor. Availability and cost vary, so confirm local supply.

Neuropsychiatric events. Montelukast carries a boxed-warning level risk of agitation, aggression, nightmares, sleep disturbance, depression and suicidal thinking. Ask about mood and sleep at initiation and at review, and stop the drug if events occur. Reserve use for patients with no suitable alternative when treating allergic rhinitis alone.

Hepatotoxicity. Zafirlukast can cause liver injury. Stop it for jaundice, right upper quadrant pain, dark urine or raised transaminases.

Eosinophilic granulomatosis with polyangiitis. Tapering oral corticosteroids while on a leukotriene receptor antagonist can unmask the disease. Suspect it with rash, neuropathy, sinus disease and rising eosinophils.

Other adverse effects. Headache, abdominal pain, dyspepsia, upper respiratory infection and rash.

Interactions. Zafirlukast raises the INR in patients on warfarin, so monitor closely. Aspirin raises zafirlukast levels, and erythromycin lowers them. Rifampicin, phenobarbital and phenytoin lower montelukast exposure, and gemfibrozil raises it. No routine montelukast dose change is needed.

Monitoring. Control of asthma, reliever use, mood and sleep, and liver tests with zafirlukast if symptoms arise. Assess response at 4 to 6 weeks and stop if there is no benefit.

Special groups. Pregnancy: montelukast may be continued if it controls asthma. Breastfeeding: small amounts in milk, acceptable. Children: monitor behaviour and sleep. Hepatic impairment: montelukast needs no adjustment in mild to moderate disease, and zafirlukast is contraindicated in hepatic impairment. Renal impairment: no adjustment.

Referral and escalation. Persistent poor control on an inhaled corticosteroid with a leukotriene receptor antagonist needs a switch to a long acting beta 2 agonist, adherence and technique review, and specialist assessment. New suicidal thoughts need urgent assessment and withdrawal of the drug.