An Overview Of Clinical Pharmacology Of Montelukast Biology Essay

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Montelukast is a potent and selective antagonist of the cysteinyl leukotriene receptor (cysLT1). It competitively antagonize cysLT1 receptor mediated bronchoconstriction, increased vascular permeability and recruitment of eosinophils. Leukotriene receptor inhibitors are compounds of a new pharmacological class for asthma management and their discovery had made a signi¬cant impact on treatment strategies of asthma management.

Montelukast is available in salt form as montelukast Sodium and described chemically as 1-[({(R)-m-[(E)-2-(7-chloro-2-quinolyl)-vinyl]-α-[o-(1-hydroxy-1-methylethyl)phenethyl]-ben-zyl}thio)methyl] cyclopropaneacetate.

Montelukast was discovered in 1990 and is used in the management of chronic asthma , allergic rhinitis , and as prophylaxis for exercise-induced asthma. It is available as 5mg, 10mg film coated and chewable tablet and 4mg oral granules form.

Cysteinyl Leukotriene receptor mediators:

Leukotrienes were previously called as slow reacting substance of Anaphylaxis' or SRS-A. These are in¬‚ammatory substances released by mast cells during the immediate response to inhaled allergen. Leukotriens are derived from arachidonic acid which is a precursor of prostaglandins (Wasserman 1988;Wenzel 1997). Leukotrienes can be divided into two families. One is leukotriene B4 which acts primarily in conditions in which in¬‚ammation is produced by neutrophils such as in¬‚ammatory bowel disease, cystic ¬brosis, and psoriasis. The other group is of (C4,D4, E4) , called cysteinyl leukotrienes, bind to highly selective leukotriens receptors to induce eosinophil- and mast cell- induced bronchoconstriction and in¬‚ammation that cause asthma (Davis 1997).Leukotrine 4 (LTD 4) was found to be 1000 times more potent than histamine in the contraction of smooth muscles.

Drugs that can interfere with the production of leukotriens and their binding to receptor have been designed. Leukotriene synthesis inhibitors (e.g. zileuton), inhibit the enzyme 5-lipoxygenase and thus block many leukotrienes production (e.g. B4,C4, D4, and E4) (Georgitis 1999). Leukotriene receptor antagonists (e.g. montelukast, za¬rlukast, pranlukast) block leukotriene D4 (LTD4 ) receptors (Georgitis 1999). Both leukotriene modi¬ers types are administered orally as tablets.

Discovery of montelukast:

In late 1930's, Felldberg and Kalaway, two Australian scientist, observed the release of a substance from the lungs of guinea pig, when the treated it with antigen. They found that this substance caused the contraction of smooth muscles and they named it 'slow reacting substance of Anaphylaxis' or SRS-A. The way of contraction was different from histamine as this substance caused slow and sustained contraction (histamine causes a rapid and reversible contraction). It was difficult to describe it structural characteristics, however, it was thought to be produce from mast cells and poly morphonuclear leukocytes. Later studies showed that nasal polyps and human lungs were able to produce this substance and it was the reason of human asthma.

A number of pharmaceutical companies started to investigate SRS-A, to develop a theray for Asthma treatment. In 1970's, researchers working at Merck frosst center of therapeutic research, used SRS-A to screen its lead structure by working on Guinea pig ileum. At that time, workers in England discovered first putative antagonist of SRS-A, which was named FPL-55712.

After a long period research, Bengt Samuelsson of the Karolinska institute in 1979, proposed the structure of SRS-A which he named Leukotriene C. As result of significant work it was proposed that SRS-A was the mixture of Leukotrienes C4, D4 and E4 (LTC4, LTD4 & LTE4), which are different from each other on the basis of cystine containing prptide attached at carbon 6 position.

Biosynthesis of cysteinylleukotriene

Further studied showed that LTD4 was the prominent character present in SRS-A and responsible for bronchoconstriction and changes in vascular permeability. These studies lead to the hypothesis that the blocker of leukotriene 4 might be useful in treatment of asthma. In 1980's, a large number of Leukotriene antagonists were discovered by Lilly and Merck, with better potency than FPL-57712. But still these were not as potent to prescribe for asthma treatment and it led to further research. Majority of the compounds were not safe in respect to liver and kidney profile on treated animals. Researchers were met disappointment many times and at last in 1990 they were successful able to discover a safe drug named Montelukast (MK-0476).

Mechanism of action:

Montelukast is a selective, reversible leukotriene receptor antagonist. Leukotrienes were first

discovered in the 1930's as potent mediators of inflammation and given the name slow-reacting

substance of anaphylaxis. Bronchoconstriction, increased mucous formation, and increased

vascular permeability with edema formation are all possible mechanisms of airflow obstruction

secondary to leukotrienes. The cysteinyl leukotriene (LTC4, LTD4, and LTE4) are products of arachadonic acid metabolism which are released by mast cells, monocytes, eosinophils, and basophils. Studies have shown LTD4 to be 140 to 6,000 times more potent than histamine as a bronchoconstrictor. Montelukast binds with high affinity to the LTD4 receptor, inhibiting bronchoconstriction. In clinical trials, montelukast has been found to inhibit bronchoconstriction at doses ranging from 5 to 250 mg, when administered four hours prior to a nebulized LTD4 challenge. ,, ,,

Clinical Pharmacology of montelukast:

Montelukast has rapid onset of action, and produce improvement even after the first day of treatment. Montelukast also produces good effects as if given with inhaled corticosteroids.


Montelukast is rapidly absorbed following oral administration, reaching peak levels 2 to 2.5 hours after administration of the 5 mg tablet and 2 to 4 hours after administration of the 10 mg tablet.,, . Bioavailability varies between the two tablet strengths. The 10 mg tablet is approximately 64% bioavailable, regardless of whether it is administered with food. The 5 mg tablet is 73% bioavailable in the fasting state, but bioavailability declines to 63% when it is taken with food. Montelukast is 100% protein bound.,,

Montelukast undergoes extensive metabolism in the liver by the cytochrome P450 enzyme system, specifically CYP3A4 and CYP2C9, and is excreted into the bile.,, The mean plasma half-life of the drug is 2.7 to 5.5 hours. Patients with mild to moderate hepatic dysfunction and evidence of cirrhosis have been shown to have a decrease in metabolism and a resulting increase in AUC of 40% with a prolonged elimination half-life. Despite these effects, dosage adjustment has not been required for patients with liver disease. Dosage adjustments are also not necessary for patients with renal dysfunction.

Dosing recommendations:

Montelukast is currently available as Singulair , manufactured by Merck. It is available as a 5 mg chewable tablet and a 10 mg film-coated tablet. Currently, there is no parenteral form of the drug. The recommended dosage for children 6 to 14 years of age is one 5 mg chewable tablet daily in the evening. For patients > 15 years of age, the usual dosage is 10 mg daily in the evening. The maximum daily dose of montelukast is 10 mg, although doses as high as 250 mg have been found to be safe in clinical trials. Higher doses, however, have not been found to improve efficacy.,

Patients should be advised to take montelukast even if they are asymptomatic and not to change the dose without the recommendation of a physician. Patients should also be reminded that this agent is not to be used for an acute asthma attack. Although montelukast functions as an anti- inflammatory, it should not be abruptly substituted for inhaled corticosteroids. Phenylketonurics should not receive the 5 mg chewable tablets, as that dosage form contains phenylalanine.

Therapeutic Applications:

Montelukast is indicated for the prophylaxis and chronic treatment of asthma in patients greater

than six years of age. Unlike the other leukotriene antagonists, zafirlukast and zileuton,

montelukast is approved by the Food and Drug Administration (FDA) for use in young children.

Approval for exercise-induced asthma has not yet been established., . Montelukast can be administered orally once a day and increase the compliance of asthmatic patients. It has efficient effect against allergens, brochoconstrition and exercise induced asthma. No serious adverse and side effects of montelukast have been reported yet. It is the only leukotriene receptor anatagonist which is approved by the Food and drug administration to be administered in children of 2 to 12 years of age.

The main therapeutic applications of montelukast are as follows:


Bronchiolitis due to RSV infection often change to post bronchiolitic reactive airways disease, which produce asthma-like wheeze and some other symptoms of asthma. In a pilot study, montelukast 5 mg orally was given daily for 4 weeks to infants who were admitted in hospital for moderate to severe bronchiolitis. It was observed that the symptoms of asthma and daytime cough was reduced, and more compliance was seen compared with placebo.

The beneficial effects of montelukast over placebo were apparent after 2 weeks of treatment. Although the safety and efficacy of such treatment should be to be properly established.

Efficacy in Asthma:

Asthma is the most frequent admitting diagnosis for children and a leading cause of chronic

illness. For many years, bronchoconstriction was thought to be the primary mechanism of this

disease. However, chronic inflammation has now been recognized as the major cause of asthma exacerbations.,. Current recommendations for the treatment of chronic asthma now include

consistent treatment of inflammation as a primary goal. Research is being focused on developing

drugs to inhibit inflammatory mediators. Montelukast is among the new agents targeted at

reducing inflammation in hopes of alleviating asthma symptoms.

Montelukast produced improvements in comparison to placebo in chronic and exercise-induced asthma in both adults , and children., , . In a systematic studies of montelukast in adults and children comparing leukotriene receptor antagonists with inhaled corticosteroids for the treatment of mild to moderate asthma. In half of the studies, montelukast was used, found to be less effective in managing asthma control. A more recent study in children produced a similar conclusion, but another study of 12 months in children with mild persistent asthma, showed that montelukast was not inferior to an inhaled corticosteroid (fluticasone).

It was observed that treatment with leukotriene receptor antagonist like Montelukast led to 10-15% improvement in baseline lung function of asthma patients even after the first dose administered. The efficacious results of montelukast were varied with treatment regimen and the impairment in lung function of patient. However, montelukast caused 10-15% improvement in lung function even in presence and absence of additive therapy of inhaled corticosteroids. It was also observed in 6-13 week trial that no tolerance against montelukast was developed in the patient. Addition of montelukast to an inhaled corticosteroid has significantly improved asthma control in children, and adults with mild to moderate asthma.

Improvement in a variety of symptoms like total asthma symptoms also involving night time awakening and morning time asthma symptoms were seen as well as inhaled β2 antagonist use was decreased. In 3 months studies of montelukast, symptoms improvement was also seen. A peorocol was designed to study montelukast in combination with inhaled steroids. In the beginning high dose of steroids was given and reduction in the dose of steroids with montelukast or placebo was observed. The reduction in the dose with montelukast was higher than with placebo. In 2003, a 16 week randomized, double blind, controlled study was designed and conducted on 639 patients to study the effect of montelukast in concomitant therapy of inhaled budesonide. It was concluded that the patients with persistant asthma symptoms and mild airway obstruction in spite of budesonide treatment, concomitant treatment with montelukast was more significant in improving asthma. Montelukast is not recommended in acute asthma, however an intravenous form of montelukast is under investigation for the treatment of severe acute asthma.,


Montelukast has been used, with some success, in systemic mastocytosis treatment in infants.


Other important uses of montelukast involves its use in seasonal allergy rhinitis. Other important uses of montelukast involves its use in seasonal allergy rhinitis. Allergic rhinitis is a worldwide health problem that generates an important healthcare burden in terms of outpatient visits by adults, children and adolescents. According to the recent Alergológica 2005 study, conducted by 300 allergologists in a total of 4500 new patients, rhinitis or rhinoconjunctivitis represents the main cause of consultation among 55.5% of all patients seen in Spanish allergology clinics. Placebo-controlled studies have shown that it is effective in the cure of symptoms in both seasonal allergic rhinitis,, and perennial allergic rhinitis. A meta-analysis of leukotriene antagonists mainly montelukast was done for the management of allergic rhinitis. It was concluded that leukotriene antagonists were more effective modestly than placebo and produced similar efficacy to antihistamines, and led to reducie nasal symptoms and improved rhinoconjunctivitis. However, even in combination with antihistamines, they are less effective than corticodteroids. A later systematic review, in which different studies of allergic rhinitis using a combination of montelukast and an antihistamine were done. The results were comparable with intranasal corticosteroids. Also, use of montelukast in some patients with both allergic rhinitis and asthma, resulted in significant improvements as compared with placebo.

Administration in children.

Asthma generally begins and has its greatest prevalence in children younger than 5 years old. This age group often presents with intermittent symptoms (i.e., long asymptomatic periods inter-

rupted by episodes of asthma generally in association with the common cold). The episodic nature of this type of asthma may be due to greater variability of asthma in young children, under- reporting of symptoms because of reliance on second-hand care-giver report, increased susceptibility of respiratory infections, or decreased effectiveness of current controller treatment in the younger age group. A study was conducted on 2-5 tears of age children to see effectiveness of montelukast in this age group. It was observed Montelukast effectively reduced asthma exacerbations in 2- to 5-year-old patients with intermittent asthma over 12 months of treatment and was generally well tolerated.

Even with the recent approval of montelukast by the FDA, clinical experience is still very limited. Only one large-scale study has been published to date in children with chronic asthma. Montelukast sodium is available as oral granules and chewable tablets for use in children. Oral granules are mostly used and suitable for infants as they can be given direct orally or mixed with a small amount of soft food including juices. Oral doses are licensed for the management of chronic asthma and as well as prophylaxis for exercise-induced asthma, are as follows:

• 6 months to 5 years, 4 mg daily taken in the evening

• 6 to 14 years, 5 mg daily taken in the evening

• 15 years and over, use the adult dose, 10mg of montelukast in evening.

Montelukast is also licensed for use in allergic rhinitis and the above doses can be given in seasonal allergic rhinitis and perennial allergic rhinitis.

Cystic fibrosis.

In cystic fibrosis, patient experience bronchial hyper responsiveness similar to that seen in asthma. Aspergillus as an antigen in body stimulate leukotriens synthesis and T helper cell inflammation and lead to cystic fibrosis. Leukotrienes receptor antagonists are proved to be good in treatment of cystic fibrosis.

In 2002, a small study was conducted in children suffering from cystic fibrosis and it was found that montelukast play an important role in reduction of eosinophilic inflammation. Another study, reported that lung function was improved, coughing and wheezing also reduced. It was concluded that montelukast may produce measurable anti-inflammatory activity in patients with cystic fibrosis. In a small group study of adult patients with cystic fibrosis, montelukast showed to improve symptoms, in particular exercise tolerance and peak expiratory flow rates. A study on pharmacokinetics of montelukast in cystic fibrosis showed that there is no need of dose adjustment in patients with cystic fibrosis to achive same plasma concentration as is achieved in asthma. However, rhe effectiveness of this concentration in both patients (suffering from asthma and cystic fibrosis) is unknown.

Sleep-disordered breathing.

Montelukast administered with an intranasal corticosteroid is been reported to be beneficial in a study conducted in children with residual sleep-disordered breathing after adenoidectomy and tonsillectomy.

Graft-versus-host disease.

A pilot study was conducted in chronic graft-versus-host disease (GVHD) after allogeneic haematopoietic stem cell transplantation, in 15 of 19 persons improvement was observed by adding montelukast in their standard immunosuppressive regimens. It was also seen that in 4 patients signs of chronic GVHD were cured, 2 patients showed significant improvement, and 9 patients showed moderate improvement.


One of the suspected adverse effect of montelukast use is urticaria. A study was conduceted to investigate use of montelukast in the treatment of urticaria and it produced variable results. In another study, montelukast was used with antihistamine desloratadine for the treatment of delayed pressure urticaria. It was reported to be more effective than placebo when used in combinition.


From early clinical studies it was reported that montelukast can be indicated for the treatment of eczema,, however there is need of more work on it as more recent studies are failed to show any improvement in montelukast therapy compared with placebo.,

Allergic conjunctivitis:

Recent study on montelukast have done for its use in allergic conjunctivitis and it was concluded that topical ocular montelukast can be a potential therapeutic drug with a new route of administration that can be used for treatment of allergic conjunctivitis.

Gastrointestinal disorders.

Eosinophilic oesophagitis is rare condition and involve eaosinophilic infiltration of oesophagus and also cause intermittent painful dysphagia. Brnifits of montelukast are reported by the patients suffering from with eosinophilic oesophagitis. In a systemic review of drugs recommended for diagnosis and treatment of eosinophilic oesophagitis it was seen that Leukotiens receptor antagonists at high doses induce sympothomeic relief. However, no improvement in histology was observed and current literature do not support its use in eosinophilic oesophagitis treatment.

Adverse effects & Precautions:

Montelukast appears to be well tolerated. In clinical trials, the most common adverse effect

reported was headache, occurring in approximately 18% of patients. Rash, dyspepsia, dizziness,

and abdominal pain were all reported in less than 2% of patients. Elevated liver transaminases

have been reported with montelukast use, but not at a greater incidence than with placebo. A

small percentage of pediatric patients have experienced diarrhea, sinusitis, and otitis media

during montelukast clinical trials. , .FDA (Food and drug administration) investigated mood/ behavior changing associated with montelukast in March 2008, other post marketing adverse reactions were also reported in some patients involving depression, tremors, anxiousness and suicidality.

Other adverse drug reactions associated with montelukast involve

Hepatic impairment.

Montelukast is eliminated by hepatic metabolism. Although adverse effects on the liver of patients receiving montelukast are observed but still is not considered to be contraindicated in hepatic impairment, and no dose adjustment is required in hepatic impairment.

Clinical trials on Leukotrienes receptor antagonists involving Zafrilukast and ziluton,, showed that they induce hepatitis and hepatic failure within 13 months or more, while trials on montelukast showed that it not cause liver toxicity. Discontinuing montelukast use lead to normalization of liver functions. It is recommend that liver function should be tested within 4 weeks of initiation of therapy with any leukotriene modi¬er and that testing must be repeated at regular intervals of at 3, 6, and 12 months.

Churg-Strauss syndrome.

It is a systemic small vessel vasculitis involving skin, lungs, heart, gastrointestinal tract and peripheral nerves. The aetiology of Churg-Strauss syndrome is unknown. However, it is reported that in rare cases it is associated with the use of leukotriene receptor antagonists (LRA) such as montelukast.,,,,,. Relapse was observed in a patient with Churg syndrome who was in complete remission when montelukast therapy was started.

Pregnancy and Lactation

Montelukast is classified as pregnancy category B. The drug has been shown to cross the placenta of pregnant rats and rabbits, but there have been no reports of its use in pregnant women. Montelukast is also known to be excreted into breastmilk, but only limited information is available on the significance of this finding. Caution should be used prior to initiating montelukast therapy in nursing mothers.,


Cytochrome P450 inducers: Caution are recommended when montelukast is administerd with potent inducers of the cytochrome P450 isoenzyme CYP3A4 such as Phenobarbital, phenytoin, valproate or rifampicin.

Corticosteroids. When montelukast and prednisone was administered concomitantly, they produced peripheral oedema in a patient.

Phenobarbital. Changes in pharmacokinetic parameters were observed in 14 healthy subjecrs taking phenobarbital 100 mg daily for 14 days, after administering single oral dose of montelukast 10mg. Peak serum concentrations were reduced by 20% and area under the serum concentration-time curve was also reduced by 38%. However, these results did not lead to dose adjustment of montelukast when given with phenobarbital.


The treatment of chronic asthma has seen many changes in the past 15 years. The National

Institute of Health's current guidelines for the diagnosis and management of asthma recommend

daily anti-inflammatory therapy as the most effective method to control chronic asthma.

Leukotrienes have been shown to be mediators in the inflammatory process and excellent targets

for therapy aimed at reducing chronic symptoms. Montelukast is safe to administer in children from six months to onwards, however, dose adjustment is necessary. Montelukast can prevent or modify more persistent asthma that has been associated with RSV. It also proved to me most effective in concomitant therapy with cortico steroids. Overall, it is a safest drug with good tolerance and wide spectrum of indications.