Epistemis

Montelukast, Zafirlukast and Zileutón

  • Leukotriene Receptor Antagonists (LTRA)

LTRAs and 5-lipoxygenase inhibitors modulate the arachidonic acid metabolic pathway, directly interfering in the processes of bronconstriction and inflammation dependent on proinflammatory lipids.

Mechanism

The cysteinyl-leukotriene pathway

In response to immunological or physical stimuli, phospholipase A2 releases arachidonic acid from cell membranes, which is processed by the enzyme 5-lipoxygenase (5-LOX) and 5-lipoxygenase activating protein (FLAP) to produce leukotriene A4 (LTA4). This is converted into LTC4, LTD4 and LTE4 (the cysteinyl-leukotrienes), which are released by mast cells and eosinophils.

Cysteinyl-leukotrienes bind to the CysLT1 receptor located in the bronchial smooth muscle and the capillary endothelium of the mucosa, inducing:

  • Potent bronconstriction (≈ 1000 times more potent than histamine).
  • Hypersecretion of thick mucus and decreased mucociliary clearance.
  • Submucosal edema due to plasma extravasation and increased eosinophil chemotaxis.
🚫 Montelukast / Zafirlukast
  • Mechanism: Competitive and selective antagonists of the CysLT1 receptor.
  • They block the action of LTD4 and LTE4 in the muscle receptor, effectively inhibiting contraction and bronchial edema.
🧪 Zileutón
  • Mechanism: Direct inhibitor of the enzyme 5-lipoxygenase (5-LOX).
  • Blocks the origin of the metabolic pathway, preventing the synthesis of all leukotrienes (including the neutrophil chemotactic LTB4).

Pharmacokinetics

Pharmacokinetics

  • Montelukast: Rapid absorption orally, with a bioavailability of 64%. Highly bound to plasma proteins (>99%). Extensively metabolized in the liver by the isoenzymes CYP3A4, CYP2C8 and CYP2C9. Almost exclusively biliary/fecal excretion. Half-life of 3 - 5.5 hours.
  • Zileutón: Rapid absorption, metabolized in the liver by glucuronidation and CYP1A2. Half-life of 2.5 hours. Requires periodic monitoring of liver transaminases due to risk of hepatotoxicity.

Indicators and dose

Approved clinical indications

  • Bronchial asthma: Alternative to the use of inhaled corticosteroids in mild intermittent asthma, or more commonly, as complementary treatment in patients who do not achieve optimal control with ICS/LABA.
  • Seasonal or perennial allergic rhinitis.
  • Prevention of exercise-induced bronchospasm.
  • Respiratory disease exacerbated by aspirin (AERD / Samter's Triad): (Asthma, nasal polyposis and aspirin intolerance). These patients have a constitutional basal overproduction of leukotrienes, showing high therapeutic sensitivity to LTRAs.

Dosage and Clinical Adjustment

Montelukast (Single daily dose, preferably at night):

  • Adults and adolescents 15 years of age: 10 mg orally in standard tablets.
  • Pediatric patients 6 - 14 years: 5 mg orally in chewable tablets.
  • Pediatric patients 2 - 5 years: 4 mg orally in chewable tablets or oral granules.

Adjustment in Renal and Hepatic Impairment: No dose adjustment is required in renal impairment of any degree or in mild to moderate hepatic impairment (Child-Pugh A/B) for montelukast.

Security

FDA Safety Alert (Black Box): Neuropsychiatric Effects of Montelukast

Montelukast crosses the blood-brain barrier and has been unequivocally associated with the occurrence of serious neuropsychiatric adverse effects, prompting a black box warning by the FDA. These effects include agitation, vivid nightmares, insomnia, major depression, and suicidal behavior (suicide ideation and attempts). Treatment should be stopped immediately if changes in mood or behavior occur in the patient.

Epistemis is educational review material. It is not a medical device, does not diagnose or prescribe treatment, and does not replace formal medical training, current clinical guidelines, or professional clinical judgment.

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Leukotriene Receptor Antagonists (LTRA)
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