Montelukast Sodium

Author: chiara brusa
Date: 11/12/2011



Montelukast sodium, the active ingredient in SINGULAIR®, is a selective and orally active leukotriene receptor antagonist that inhibits the cysteinyl leukotriene CysLT1 receptor.
The empirical formula is C35H35ClNNaO3S, and its molecular weight is 608,18.
The structural formula is:


  • Anti-Asthmatic Agents
  • Leukotriene Antagonists

Recent advances in antileukotriene therapy,2010 PubMed


Montelukast sodium is indicated for:
* Prophylaxis and chronic tretement of asthma in adults and pediatric patients 12 months of age and older,
* Prevention of exercise-induced bronchoconstriction in patients 15 years of age and older,
* The relief of symptoms of allergic rhinitis (seasonal allergic rhinitis in adults and pediatric patients 2 years of age and older, and perennial allergic rhinitis in adults and pediatric patients 6 months of age and older).

Montelukast sodium is not indicated for use in the reversal of bronchospasm in acute asthma attacks, including status asthmaticus. Patients should be advised to have appropriate rescue medication available.



Montelukast sodium is rapidly absorbed following oral administration.


Montelukast sodium is more than 99% bound to plasma proteins. The steady state volume of distribution of Montelukast sodium averages 8 to 11 liters.


Montelukast sodium is extensively matabolized. In studies with therapeutic doses, plasma concentrations of metabolities of Montelucast sodium are undetectable at steady state in adults and pediatric patients.
In vitro studies using human liver microsomes indicate that cytochromes P450 3A4 and 2C9 are involved in the metabolism of Montelukast sodium. Clinical studies investigating the effect of known inhibitors of cytochromes P450 3A4 (e.g. ketoconazole, erythromycin) or 2C9 (e.g. fluconazole) on montelukast sodium pharmacokinetic have not been conducted. Based on further in vitro results in human liver microsomes, therapeutic plasma concentrations of Montelukast sodium do not inhibit cytochromes P450 3A4, 2C9, 1A2, 2A6, 2C19, or 2D6. In vitro studies have shown that Montelikast sodium is a potent inhibitor of cytochrome P450 2C8; however, data from a clinical drug-drug interaction study inolving Montelukast sodium and Rosiglitazone (a probe substrate representative of drugs primarily metabolized by CYP2C8) demonstrated that Montelukast sodium does not inhibit CYP2C8 in vivo, and therefore is not anticipated to alter the metabolism of drugs metabolized by this enzyme.


Montelukast sodium and its metabolites are excreted almost exclusively via the bile.


The LTs are lipoxygenase products formed from the metabolism of arachidonic acid (AA), an essential fatty acid found in the membrane of all cells. The LTs are synthesized by the action of key enzyme 5-lipoxygenase on aa in the presence of 5-lipoxygenase-activating protein (FLAP). The biosynthesis of the LTs proceeds as a result of the sequential catalytic actions on AA, forming leukotriene A4 (LTA4), leukotriene B4 (LTB4), leukotriene C4 (LTC4), leukotriene D4 (LTD4), and leukotriene E4 (LTE4). Because LTC4, LTD4 and LTE4 all contain the amino acid cysteine, they are collectively referred to as the cysteinylleukotrienes.
The non-cysteinyl LT, LTB4, binds to the B leukotriene (BLT) receptor, which is responsible for recruitment and activation of leukocytes, in particular neutrophils. Leukotriene B4 does not appear to exert biological effects associated with asthma and acts more as a chemotactic agent.
On the other hand, the cysteinyl LTs, LTC4, LTD4 and LTE4, are potent recruiters foe eosinophils in vivo and in vitro and have been correlated with the pathophysiology of asthma and allergic rhinitis. In asthma, leukotriene-mediated effects include airway edema, smooth muscle contraction and altered cellular activity associated with tha inflammatory process, In allergic rhinitis, CysLTs are released from the nasal mucosa after allerge exposure during both early- and late- phase reactions and are associated with symptoms of allergic rhinitis. The CysLTs exert their biologic actions by binding to two CysLT receptors, CysLT1 and CysLT2. however, most of the actions of the CysLTs relevant to asthma are mediated through CysLT1 receptor stimulation, which is stimulated mostly by LTC4 and LTD4. The CysLT1 receptor is found in the human airway (including airway smooth muscle cells and airway macrophages) and on other pro-inlammatory cells (including eosinophils and certain myeloid stem cells).

Montelukast sodium binds with high affinity and selectivity to the Cys LT1 receptor (in preference to other pharmacologically important airway receptors, such as the prostanoid, cholinergic or beta-adrenergic receptor) and inhibits physiologic actions of LTD4 at the CysLT1 receptor without any agonist activity.


The side effects of Montelukast sodium are usualli mild, and generally did not cause patients to stop taking their medicine.

The most common side effects with Montelukast sodium include:
* Stomach pain
* Stomach or intestinal upset
* Heartburn
* Tiredness
* Fever
* Stuffy nose
* Cough
* Flu
* Upper respiratory infection
* Dizziness
* Headache
* Rush

Less common side effects that have happened with montelukast sodium include:
* Increased bleeding tendency
* Allergic reactions [including swelling of the face, lips, tongue and/or throat (which may cause trouble breathing or swallowing), hives and itching]
* Drowsiness, pins and needles/numbness, seizures
* Palpitations
* Nose bleed
* Diarrhea, indigestion, inflammation of the pancreas, nausea, vomiting
* Hepatitis
* Bruising
* Joint pain, muscle aches and muscle cramps
* Swelling

Behavior and mood-related changes have been reported: agitation including aggressive behavior or hostility, bad/vivid dreams, depression, feeling anxious, hallucinations, irritability, restlessness, sleep walking, suicidal thoughts and actions (including suicide), tremor, trouble sleeping.

In rare cases, patients with asthma on therapy with Montelukast sodium may present with systemic eosinophilia, sometimes presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition which is often treated with systemic corticosteroid therapy. These events usually, but not always, have been associated with the reduction of oral corticosteroid therapy. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. A causal association between Montelukast sodium and these underlying conditions has not been established.

Churg-Strauss syndrome (CSS) has long been considered as a rare disease, but there has been a recent increase in case reports in association with asthma therapies. This has raised the question of how rare this disease truly is and whether incidence has indeed increased in association with asthma therapy.
In particular CSS in association with asthma therapy was first reported by Wechsler et al in 1998 in patients receiving Zafirlukast, an antagonist of the CysLT1 receptor, following reduction in the dose of oral corticosteroids.

Pulmonary infiltrates, eosinophilia, and cardiomyopathy following corticosteroid withdrawal in patients wiyh asthma receiving zafirlukast, 1998 PubMed

Further reports described a clinical syndrome resembling CSS in association with the other CysLT1 receptor antagonists (Montelukast, Pranlukast).

The possible link between use of antileukotrienes and development of Churg-Strauss syndrome (CSS) remains controversial.

A recent retrospective analysis of the FDA Adverse Event Reporting Database found leukotriene receptor antagonist drugs to be implicated in 163 of 181 cases of suspected drug-induced CSS.
LTRA therapy was a suspect medication in 90% of confirmed cases of CSS in the FDA AERS database. Among the cases of CSS associated with LTRA use in which there was adequate documentation, about two-thirds were not related to a reduction in oral or inhaled corticosteroid therapy, pre-existing or possible prodromal CSS. The authors recognised that it was not possible to determine in individual cases whether the association between CSS and LTRA therapy is causal, coincidental or directly related to other patterns of disease presentation or medication use. However, they cautiously suggested that, in a majority of cases, LTRA therapy may have a role in the pathogenesis of this disorder.
The pathophysiological mechanisms by which CSS may develop as a result of LTRA therapy are not clear and have yet to be demonstrated: links have not been identified in prospective studies. Indeed, the mechanisms underlying all cases of CSS are not well understood.

Association between leukotriene receptor antagonist therapy and Churg-Strauss syndrome: an analysis of the FDA AERS database, 2010 PubMed


One proposed theory to explain the association between the LTRAs and CSS is that a patient may have an underlying subclinical form of CSS, or formes frustes, and instituting therapy with LTRAs allows the tapering of GCS and thus the development of full-blown CSS (Churg et al 1995).

Interestingly, a second theory is that CSS is an allergic response to therapy with LTRAs, as CSS has been shown to be a hypersensitivity reaction to different antibiotics (eg, erythromycin, azithromycin, roxithromycin) (Dietz et al 1998; Katz and Papernik 1998). However, in the reported cases through the year 2000 in patients on LTRA, development of CSS happened from 2 days to 8 months after the initiation of treatment with LTRAs, with most patients being on the LTRA for at least 2 months, which is an unusually long time for drug hypersensitivity to develop (Jamaleddine et al 2002).

A third theory is based on the imbalance in leukotriene receptor stimulation (Katz and Papernik 1998). It has been postulated that the use of LTRAs may lead to imbalances between blockade of the actions of cysteinyl-leukotriene (cysLT) (LTC4, LTD4, and LTE4) on the cysteinyl-leukotriene receptor 1 (cysLT1) and the actions of other mediators such as leukotriene B4 (LTB4) and 5-oxo 6,8,11,14-eicosatetraenoic acid (Conen et al 2004, Guilpain et al 2002, Solans et al 2002, Stirling et al 1999).
LTB4 has been shown to have biological effects on proinflammatory cells including neutrophils, eosinophils, macrophages, basophils, mast cell precursors and lymphocytes (Dahlen et al 2006, Iikura et al 2005, Rubin et al 2007, Evans et al 2008, Harrizi et al 2008).
The unopposed actions of cysLT through the cysteinyl-leukotriene receptor 2 (cysLT2) or through other uncharacterised receptors cannot be discounted (Lee et al 2009)

The linkage between Churg-Strauss syndrome and leukotriene receptor antagonists: fact or fiction?, 2005 PubMed

More information is required to support any postulated pathophysiological mechanisms underlying the association of LTRAs and CSS.


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