Leukotriene receptor antagonists

Quick revision

Three oral drugs interrupt one inflammatory pathway at two different points, and the reason the class is taught is not its efficacy but its safety labelling.

• Montelukast and zafirlukast are cysteinyl leukotriene receptor antagonists; zileuton is a 5-lipoxygenase inhibitor and therefore acts upstream, blocking synthesis rather than the receptor. (1) (2) (3)
• Montelukast's boxed warning names agitation, aggression, depression, sleep disturbances and suicidal thoughts and behaviour, and states that the underlying mechanisms are not well understood. (1)
• In allergic rhinitis the montelukast label reserves treatment for patients with an inadequate response or intolerance to alternative therapies, because the benefit may not outweigh the neuropsychiatric risk. (1)
• All three are maintenance drugs taken by mouth, and all three labels exclude them from the reversal of bronchospasm in an acute asthma attack. (1) (2) (3)
• Zileuton is contraindicated in active liver disease, and serum ALT is assessed before treatment, monthly for three months, then every two to three months for the rest of the first year. (3)
• Zafirlukast has caused fulminant hepatitis progressing to liver transplantation and death, and its absorption falls by roughly 40% when it is taken with food. (2)
• Zafirlukast prolongs the prothrombin time in patients on warfarin, and both zafirlukast and zileuton raise theophylline exposure. (2) (3)
• Systemic eosinophilia, sometimes with the vasculitic features of Churg-Strauss syndrome, is reported with both receptor antagonists, usually as oral steroid therapy is being reduced. (1) (2)

Overview

Leukotrienes are lipid mediators made from arachidonic acid by the enzyme 5-lipoxygenase. The cysteinyl leukotrienes among them produce, in the words of the zafirlukast label, airway edema, smooth muscle constriction, and altered cellular activity associated with the inflammatory process. Three oral drugs interrupt that pathway and are licensed in asthma. Montelukast and zafirlukast sit at the receptor; zileuton sits at the enzyme. (2) (3) (9)

The dominant fact about this class is a safety one. The montelukast boxed warning opens: "Serious neuropsychiatric (NP) events have been reported with the use of montelukast sodium. The types of events reported were highly variable, and included, but were not limited to, agitation, aggression, depression, sleep disturbances, suicidal thoughts and behavior (including suicide). The mechanisms underlying NP events associated with montelukast sodium use are currently not well understood." The label does not claim to explain the association, and a page about this class should not claim more than the label does. (1)

That warning is followed by a prescribing instruction rather than a caution alone: "Because of the risk of NP events, the benefits of montelukast sodium may not outweigh the risks in some patients, particularly when the symptoms of disease may be mild and adequately treated with alternative therapies. Reserve use of montelukast sodium for patients with allergic rhinitis who have an inadequate response or intolerance to alternative therapies." The benefit-risk judgement therefore depends on the indication, and it is tightest where the disease being treated is the mildest. (1)

The counselling obligation is written into the same warning: "Discuss the benefits and risks of montelukast sodium with patients and caregivers when prescribing montelukast sodium. Advise patients and/or caregivers to be alert for changes in behavior or new NP symptoms when taking montelukast sodium. If changes in behavior are observed, or if new NP symptoms or suicidal thoughts and/or behavior occur, advise patients to discontinue montelukast sodium and contact a healthcare provider immediately." The United Kingdom regulator reaches the same practical conclusion from its own data, having received 1,223 reports of suspected neuropsychiatric adverse reactions since authorisation in 1998. (1) (5)

Clinically these are preventers, not relievers. The NHS medicine page states plainly that montelukast is used alongside inhalers or other asthma medicine and that a reliever inhaler, not montelukast, is what treats an attack. Where this class sits against inhaled corticosteroids is a separate question, dealt with on the inhaled corticosteroids page in this section; the labelling point that belongs here is that a leukotriene modifier is not an abrupt replacement for a steroid a patient is already taking. (6) (1)

Classification and drug examples

The class splits at the point in the leukotriene pathway each drug attacks. That single distinction predicts which mediators are still active during treatment and which monitoring the label demands.

Mechanism of action

One pathway, two points of attack. Arachidonic acid is converted by 5-lipoxygenase to leukotriene A4 and onward to the cysteinyl leukotrienes, which act at the CysLT1 receptor to produce airway oedema, bronchoconstriction and inflammatory cell activity. Montelukast and zafirlukast occupy that receptor; zileuton disables the enzyme that starts the sequence.

Molecular target

The CysLT1 receptor, and the enzyme 5-lipoxygenase upstream of it

Pharmacodynamic effect

Anti-inflammatory and preventive rather than bronchodilator

Effect kinetics

Effect depends on continued daily dosing; no immediate relief of bronchospasm

1. 5-lipoxygenase generates leukotriene A4 from arachidonic acid

   LiverTox describes 5-lipoxygenase as the enzyme responsible for the conversion of arachidonic acid into leukotriene A4. Everything else in the pathway, cysteinyl and non-cysteinyl alike, descends from that single step. (8)

2. Cysteinyl leukotrienes act at CysLT1 to produce the asthmatic phenotype

   The zafirlukast label ties leukotriene D4 and E4, components of slow-reacting substance of anaphylaxis, to airway edema, smooth muscle constriction, and altered cellular activity associated with the inflammatory process. LiverTox adds that in allergic rhinitis these mediators are released into nasal tissue after allergen exposure. (2) (9)

3. Receptor antagonism: montelukast and zafirlukast occupy CysLT1

   Montelukast binds with high affinity and selectivity to the CysLT1 receptor rather than to prostanoid, cholinergic or beta-adrenergic receptors, which is why it has no bronchodilator action of its own. Zafirlukast is a selective and competitive antagonist at the same cysteinyl arm of the pathway. (1) (2)

4. Synthesis inhibition: zileuton acts one step earlier

   Zileuton is an inhibitor of 5-lipoxygenase and thus inhibits LTB4, LTC4, LTD4 and LTE4 formation. Because a CysLT1 antagonist only occupies a receptor, LTB4 continues to be produced and to signal during treatment with montelukast or zafirlukast; under zileuton it is not made in the first place. (3) (1)

5. The consequence is prevention, not rescue

   Interrupting a mediator pathway reduces the inflammatory background over days of regular dosing but does nothing to relax a smooth muscle already in spasm. Each of the three labels therefore states that the drug is not indicated for reversal of bronchospasm in an acute asthma attack, and the zafirlukast label adds that it is not a bronchodilator. (1) (2) (3)

Major clinical uses

Pharmacokinetics

• This page gives no dose regimens. Choice of agent, formulation and monitoring interval belongs to the treating clinician working from a current prescribing reference, because they depend on age, indication, liver function and the rest of the patient's asthma treatment.
• All three are more than 90% protein bound, montelukast and zafirlukast at more than 99% and zileuton at 93%, which matters chiefly when interpreting displacement interactions. (1) (2) (3)

Adverse effects

Common

• Headache: The commonest complaint across the class. Headache was reported in 12.9% of zafirlukast-treated patients in clinical trials, and headache appears among the adverse reactions listed at 5% or more with montelukast. (2) (1)
• Gastrointestinal upset: Nausea, diarrhoea and abdominal pain were each reported in a small percentage of zafirlukast recipients, and abdominal pain and diarrhoea appear in the montelukast adverse reaction list. (2) (1)
• Respiratory tract and ear, nose and throat events: Montelukast's adverse reactions occurring in at least 5% of patients and more often than with placebo include upper respiratory infection, pharyngitis, cough, rhinorrhoea, sinusitis, influenza and otitis media, reflecting the paediatric and adult populations studied. (1)
• Sleep disturbance and mood change at low frequency: The UK regulator quantifies these: sleep disturbances, depression and agitation including aggressive behaviour may affect up to 1 in 100 people, and disturbances of attention or memory up to 1 in 1,000. (4)

Serious adverse effects

• Neuropsychiatric events with montelukast, the subject of a boxed warning: The warning names agitation, aggression, depression, sleep disturbances and suicidal thoughts and behaviour including suicide, describes the reported events as highly variable, and states that the mechanisms are currently not well understood. The UK regulator places hallucinations and suicidal thinking and behaviour at up to 1 in 10,000 people, and concluded in April 2024 that the benefits of montelukast continue to outweigh the risks for most patients in asthma while the risk needed to be communicated better. Monitoring for behavioural change, and the decision to continue or discontinue, rest with the treating clinician; the label directs that treatment be stopped and a healthcare provider contacted immediately if such symptoms appear. (1) (4) (5)
• Hepatic injury with zafirlukast: Cases of life-threatening hepatic failure have been reported, and in rare cases patients have either presented with fulminant hepatitis or progressed to hepatic failure, liver transplantation and death. The label directs that treatment be discontinued and liver function tests, in particular serum ALT, measured immediately if liver dysfunction is suspected from signs such as right upper quadrant pain, nausea, lethargy, pruritus or jaundice. (2)
• Transaminase elevation and idiosyncratic liver injury with zileuton: ALT elevations above three times the upper limit of normal occurred in 1.9% of patients treated for at least one year against 0.2% of placebo recipients, with onset typically within four to eight weeks. LiverTox grades zileuton as a possible rare cause of clinically apparent liver injury. Treatment is stopped and hepatic enzymes followed until normal if transaminases reach five times the upper limit of normal or symptoms of liver dysfunction appear. (8) (3)
• Eosinophilic conditions, including features of Churg-Strauss syndrome: Patients on montelukast may present with systemic eosinophilia, sometimes with clinical features of vasculitis consistent with Churg-Strauss syndrome. The zafirlukast label reports systemic eosinophilia, eosinophilic pneumonia or the same vasculitic picture, usually though not always in association with reduction of oral steroid therapy. Because the timing follows steroid withdrawal, any change to concurrent corticosteroid treatment is a clinician decision that requires the patient to be watched for these features. (1) (2)

Drug-specific effects

• Montelukast: Patients with known aspirin sensitivity should continue avoidance of aspirin or non-steroidal anti-inflammatory agents while taking montelukast: the drug does not confer protection in aspirin-exacerbated respiratory disease. (1)
• Zafirlukast: Accumulation in the elderly and in cirrhosis. Apparent oral clearance falls with age, giving roughly two- to three-fold higher Cmax and AUC in patients aged 65 and over, and Cmax and AUC are about 50-60% greater in stable alcoholic cirrhosis. (2)
• Zafirlukast: Neuropsychiatric events have been reported in adult, adolescent and paediatric patients, with post-marketing reports including insomnia and depression. This is a warning rather than a boxed warning. (2)
• Zileuton: Post-marketing neuropsychiatric reports for zileuton include sleep disorders and behaviour changes, so the pattern is not unique to the receptor antagonists. (3)

Contraindications, precautions and interactions

Contraindications

• Zileuton is contraindicated in active liver disease, and in persistent hepatic function enzyme elevations greater than or equal to three times the upper limit of normal. (3)
• None of the three may be used to reverse bronchospasm in an acute asthma attack, including status asthmaticus; a reliever is required for that purpose. (1) (2) (3)

Precautions

• Before montelukast is prescribed, its benefits and risks are to be discussed with the patient and any caregiver, and both advised to be alert for changes in behaviour or new neuropsychiatric symptoms during treatment. (1)
• The UK regulator advises that families be told what to watch for, since a patient may not recognise a change in their own mood, sleep or behaviour, and that the leaflet's list of neuropsychiatric reactions be read carefully. (4)
• Montelukast must not be abruptly substituted for inhaled or oral corticosteroids, although the dose of an inhaled corticosteroid may be reduced gradually under medical supervision. (1)
• Zileuton requires serum ALT before treatment begins, monthly for the first three months, every two to three months for the remainder of the first year, and periodically thereafter during long-term use. (3)
• For zafirlukast, periodic transaminase testing has not been shown to prevent serious injury, and the label rests instead on prompt withdrawal once clinical signs of hepatic dysfunction appear. (2)
• Higher zafirlukast exposure in older patients and in cirrhosis makes those groups the ones in whom hepatic adverse effects are most likely to matter. (2)

Drug interactions

• Warfarin: Coadministration of zafirlukast with warfarin produces a clinically significant increase in prothrombin time, and the label requires close prothrombin time monitoring with anticoagulant adjustment. Zileuton likewise increases warfarin levels and its label requires prothrombin time monitoring. (2) (3)
• Theophylline: Zileuton increases theophylline levels, and the label directs that the theophylline dose be reduced and levels monitored. Rare cases of raised theophylline levels, with or without signs of toxicity, have been reported when zafirlukast was added to an existing theophylline regimen. (3) (2)
• Propranolol and other beta-blockers: Zileuton increases propranolol levels and beta-blocker activity, so the combination is monitored. (3)
• Erythromycin: Erythromycin decreased mean plasma concentrations of zafirlukast by approximately 40% through reduced bioavailability, an interaction in the opposite direction to the one students usually expect from a macrolide. (2)
• Aspirin: Coadministration of aspirin increased mean plasma concentrations of zafirlukast by approximately 45%. (2)
• Food: A high-fat or high-protein meal reduced mean zafirlukast bioavailability by about 40%, which is why the label separates administration from meals. Montelukast is unaffected in this respect, its bioavailability and Cmax being uninfluenced by a standard meal. (2) (1)

Comparison tables

High-yield exam pearls

• Only montelukast carries the boxed warning, and only montelukast has the allergic rhinitis restriction attached to it. (1) (2) (3) Examiners test whether a candidate applies a warning to a whole class by reflex. Zafirlukast and zileuton do report neuropsychiatric events, but as ordinary warnings.
• Zileuton is not a leukotriene receptor antagonist at all, despite sitting in the same teaching class. (3) (8) It inhibits the synthesising enzyme, so LTB4 as well as the cysteinyl leukotrienes falls. A question that contrasts synthesis inhibition with receptor blockade is asking about exactly this.
• Zafirlukast is the one that must be separated from food; montelukast is not. (2) (1) A high-fat or high-protein meal cuts zafirlukast bioavailability by around 40%, whereas a standard meal changes neither montelukast's bioavailability nor its Cmax.
• Eosinophilic conditions in this class cluster around corticosteroid reduction. (1) (2) Both receptor antagonists report systemic eosinophilia and Churg-Strauss features usually associated with a fall in oral steroid dose, which is a temporal association rather than proof of causation.
• Two of the three interact with warfarin and with theophylline in the same direction: more effect, more risk. (2) (3) Zafirlukast raises prothrombin time and can raise theophylline levels; zileuton raises both warfarin and theophylline exposure and also propranolol levels.

Common exam traps

• Trap: Treating a leukotriene modifier as something that can relieve an attack because it improves breathing over time. Actually: Zafirlukast's label states it is not a bronchodilator, and each of the three excludes reversal of bronchospasm in acute asthma. The NHS page tells patients to use the reliever inhaler for an attack. (2) (1) (6)
• Trap: Assuming the montelukast boxed warning explains a mechanism for the neuropsychiatric events. Actually: It says the opposite: the mechanisms are currently not well understood, and a causal association with underlying conditions has not been established. A page that offers a mechanism is claiming more than the label does. (1)
• Trap: Starting a leukotriene modifier and stopping an inhaled corticosteroid on the same day. Actually: The label allows gradual reduction of inhaled corticosteroid under medical supervision, but forbids abrupt substitution. Eosinophilic complications reported in this class cluster around exactly that manoeuvre. (1) (2)
• Trap: Expecting erythromycin to raise zafirlukast levels because macrolides usually inhibit metabolism. Actually: Erythromycin reduced mean zafirlukast concentrations by about 40% by decreasing its bioavailability, while aspirin raised them by about 45%. (2)
• Trap: Answering that a leukotriene modifier is licensed for allergic rhinitis as a class. Actually: Only montelukast holds that indication, and its own label reserves it for patients with an inadequate response or intolerance to alternative therapies. (1) (2)

Self-test questions

Answers are hidden until you open them. These questions are written from this page's cited content and are for study only — they are not clinical guidance.

1. Which statement best describes how zileuton differs mechanistically from montelukast?

   • Zileuton inhibits 5-lipoxygenase and so reduces formation of the leukotrienes, whereas montelukast blocks the CysLT1 receptor
   • Zileuton blocks the CysLT1 receptor more selectively than montelukast does
   • Zileuton is a bronchodilator acting at beta-2 adrenoceptors
   • Zileuton inhibits cyclo-oxygenase and reduces prostaglandin formation
   Show answer

   Answer: Zileuton inhibits 5-lipoxygenase and so reduces formation of the leukotrienes, whereas montelukast blocks the CysLT1 receptor

   The zileuton label describes it as an inhibitor of 5-lipoxygenase that thus inhibits LTB4, LTC4, LTD4 and LTE4 formation, while montelukast binds with high affinity and selectivity to the CysLT1 receptor rather than to prostanoid, cholinergic or beta-adrenergic receptors. (3) (1)

2. A prescriber is considering montelukast purely for seasonal allergic rhinitis in a patient whose symptoms are mild and who has not tried anything else. What does the labelling require?

   • Use is reserved for patients with an inadequate response or intolerance to alternative therapies
   • Montelukast is the preferred first choice for all allergic rhinitis
   • Montelukast may be used first provided liver enzymes are checked monthly
   • Allergic rhinitis is not an indication for montelukast at any point
   Show answer

   Answer: Use is reserved for patients with an inadequate response or intolerance to alternative therapies

   The boxed warning states that the benefits may not outweigh the risks in some patients, particularly where symptoms are mild and adequately treated with alternatives, and reserves allergic rhinitis use for inadequate response or intolerance to alternative therapies. Liver enzyme monitoring belongs to zileuton, not montelukast. (1)

3. Which monitoring requirement belongs specifically to zileuton?

   • Serum ALT before treatment, monthly for the first three months, then every two to three months for the rest of the first year
   • Prothrombin time measured before every dose
   • Annual eosinophil count in all patients
   • Serum potassium at each review
   Show answer

   Answer: Serum ALT before treatment, monthly for the first three months, then every two to three months for the rest of the first year

   That schedule is set out in the zileuton label, which also contraindicates the drug in active liver disease or persistent enzyme elevations at or above three times the upper limit of normal. Prothrombin time is monitored only where warfarin is co-prescribed. (3)

4. Which of these interactions is documented for zafirlukast?

   • A clinically significant increase in prothrombin time when given with warfarin
   • Loss of oral contraceptive efficacy through enzyme induction
   • A doubling of digoxin clearance
   • Precipitation of serotonin syndrome with selective serotonin reuptake inhibitors
   Show answer

   Answer: A clinically significant increase in prothrombin time when given with warfarin

   The zafirlukast label records a clinically significant increase in prothrombin time on coadministration with warfarin and requires close monitoring with anticoagulant dose adjustment. The other three options are not described in that label. (2)

Frequently asked questions

References

1. MONTELUKAST SODIUM tablet, film coated - prescribing information, including the boxed warning DailyMed, U.S. National Library of Medicine
2. ACCOLATE (zafirlukast) tablet, film coated - prescribing information DailyMed, U.S. National Library of Medicine
3. ZILEUTON tablet, multilayer, extended release - prescribing information DailyMed, U.S. National Library of Medicine
4. Drug Safety Update: Montelukast - reminder of the risk of neuropsychiatric reactions Medicines and Healthcare products Regulatory Agency
5. Outcome of MHRA review of neuropsychiatric reactions with montelukast Medicines and Healthcare products Regulatory Agency
6. About montelukast National Health Service, United Kingdom
7. Montelukast - MedlinePlus drug information MedlinePlus, U.S. National Library of Medicine
8. Zileuton - LiverTox: Clinical and Research Information on Drug-Induced Liver Injury NIDDK, NCBI Bookshelf
9. Leukotriene Receptor Antagonists - LiverTox: Clinical and Research Information on Drug-Induced Liver Injury NIDDK, NCBI Bookshelf

Related drug classes

• Inhaled and intranasal corticosteroids
• Beta-2 agonist bronchodilators
• Antihistamines
• Methylxanthines

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