Montelukast Actions

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Actions of Montelukast in details

The action of the drug on the human body is called Pharmacodynamics in Medical terminology. To produce its effect and to change the pathological process that is happening the body and to reduce the symptom or cure the disease, the medicine has to function in a specific way. The changes it does to the body at cellular level gives the desired result of treating a disease. Drugs act by stimulating or inhibiting a receptor or an enzyme or a protein most of the times. Medications are produced in such a way that the ingredients target the specific site and bring about chemical changes in the body that can stop or reverse the chemical reaction which is causing the disease.
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Pharmacology: Pharmacodynamics: Montelukast is a selective and active leukotriene receptor antagonist. Montelukast inhibits bronchoconstriction due to antigen challenge. Montelukast is a selective leukotriene receptor antagonist of the cysteinyl leukotriene CysLT1 receptor. The cysteinyl leukotrienes (LTC 4, LTD 4, LTE 4) are products of arachidonic acid metabolism that are released from various cells, including mast cells and eosinophils. They bind to cysteinyl leukotriene receptors (CysLT) found in the human airway. Binding of cysteinyl leukotrienes to leukotriene receptors has been correlated with the pathophysiology of asthma, including airway edema, smooth muscle contraction and altered cellular activity associated with the inflammatory process, factors that contribute to the signs and symptoms of asthma.

It binds to CysLT type-1 receptors found in human airway (smooth muscle cells and macrophages), which prevents airway edema, smooth muscle contraction and other respiratory inflammation. The leukotrienes are also released from the nasal mucosa after allergen exposure where Montelukast sodium may inhibit symptoms of allergic rhinitis.

Montelukast binding to the CysLT1 receptor is high-affinity and selective, preferring the CysLT1 receptor to other pharmacologically important airway receptors eg, the prostanoid, cholinergic or β-adrenergic receptor. Montelukast inhibits physiologic actions of LTD4 at the CysLT1 receptors, without any agonist activity.

Montelukast causes bronchodilation within 2 hrs of oral administration; these effects were additive to the bronchodilation caused by a β-agonist.

Pharmacokinetics: Absorption: Montelukast is rapidly and nearly completely absorbed following oral administration. Peak plasma concentrations of Montelukast occur 3-4 hrs after oral doses. The mean oral bioavailability is 64%. The oral bioavailability and peak plasma concentration (Cmax) are not influenced by a standard meal.

Distribution: Montelukast is >99% bound to plasma proteins. The steady-state volume of distribution of Montelukast averages 8-11 L. Studies in rats with radiolabeled Montelukast indicate minimal distribution across the blood-brain barrier.

Metabolism: Montelukast is extensively metabolized in the liver by cytochrome P-450 isoenzymes CYP3A4 and CYP2C9. Therapeutic plasma concentrations of Montelukast do not inhibit cytochromes P-450 3A4, 2C9, 1A2, 2A6, 2C19 or 2D6.

Elimination: The plasma clearance of Montelukast averages 45 mL/min in healthy adults. Montelukast and its metabolites are excreted principally in the faeces via the bile.

Elimination Half-Life: 2.7-5 hrs.

How should I take Montelukast?

Take Montelukast exactly as prescribed by your doctor. Follow all directions on your prescription label. Do not take this medicine in larger or smaller amounts or for longer than recommended.

Montelukast is usually taken once daily in the evening for prevention of asthma or allergy symptoms. For exercise-induced bronchoconstriction, take a single dose at least 2 hours before you exercise, and do not take another dose for at least 24 hours. Follow your doctor's instructions.

Montelukast is not a rescue medicine. It will not work fast enough to treat an asthma attack. Use only a fast acting inhalation medicine for an asthma attack. Tell your doctor if it seems like your asthma medications don't work as well.

Swallow the regular tablet whole, with a glass of water.

The Montelukast chewable tablet must be chewed completely before you swallow it.

The oral granules can be placed directly into the mouth and swallowed, or mixed with a spoonful of applesauce, mashed carrots, rice, or ice cream.

Oral granules can also be mixed with 1 teaspoon of baby formula or breast milk. Do not use any other type of liquid for mixing the granules. Other liquids can be taken before or after taking the medicine.

After opening or mixing the oral granules, you must use them within 15 minutes. Do not save an open packet or mixed medicine for later use.

It may take up to several weeks before your symptoms improve. Keep using Montelukast as directed and tell your doctor if your symptoms do not improve after several weeks of treatment.

If you also take a steroid asthma medicine, do not stop using it suddenly without first talking to your doctor. You may need to use less and less before you stop the medication completely.

Asthma is usually treated with a combination of drugs. Use all medications as directed by your doctor. Read the medication guide or patient instructions provided with each medication. Do not change your doses or medication schedule without your doctor's advice, even if you have no asthma symptoms.

Store Montelukast at room temperature away from moisture and heat. Do not open a packet of oral granules until you are ready to use the medicine.

Montelukast administration

Administration of drug is important to know because the drug absorption and action varies depending on the route and time of administration of the drug. A medicine is prescribed before meals or after meals or along with meals. The specific timing of the drug intake about food is to increase its absorption and thus its efficacy. Few work well when taken in empty stomach and few medications need to be taken 1 or 2 hrs after the meal. A drug can be in the form of a tablet, a capsule which is the oral route of administration and the same can be in IV form which is used in specific cases. Other forms of drug administration can be a suppository in anal route or an inhalation route.
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Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

Montelukast is usually taken once daily in the evening for prevention of asthma or allergy symptoms. For exercise-induced bronchoconstriction, take a single dose at least 2 hours before you exercise, and do not take another dose for at least 24 hours. Follow your doctor's instructions.

If you already take this medication to prevent asthma or allergy symptoms, do not use it for exercise-induced bronchoconstriction.

Swallow the regular tablet whole, with a glass of water.

The chewable tablet must be chewed completely before you swallow it.

The oral granules can be placed directly into the mouth and swallowed, or mixed with a spoonful of applesauce, mashed carrots, rice, or ice cream.

Oral granules can also be mixed with 1 teaspoon of baby formula or breast milk. Do not use any other type of liquid for mixing the granules. Other liquids can be taken before or after taking the medicine.

After opening or mixing the oral granules, you must use them within 15 minutes. Do not save an open packet or mixed medicine for later use.

Montelukast will not work fast enough to treat an asthma attack that has already begun. Use only a fast-acting inhalation medicine to treat an asthma attack. Talk with your doctor if any of your asthma medications do not seem to work as well in treating or preventing attacks.

It may take up to several weeks before your symptoms improve. Keep using the medication as directed and tell your doctor if your symptoms do not improve after several weeks of treatment.

Asthma is usually treated with a combination of drugs. Use all medications as directed by your doctor. Read the medication guide or patient instructions provided with each medication. Do not change your doses or medication schedule without your doctor's advice, even if you have no asthma symptoms.

If you also take a steroid asthma medicine, do not stop using it suddenly without first talking to your doctor. You may need to use less and less before you stop the medication completely.

Call your doctor right away if you feel that this medicine is not working as well as usual, or if it makes your condition worse. If it seems like you need to use more of any of your medications in a 24-hour period, talk with your doctor.

Store at room temperature away from moisture and heat. Do not open a packet of oral granules until you are ready to use the medicine.

Montelukast pharmacology

Pharmacokinetics of a drug can be defined as what body does to the drug after it is taken. The therapeutic result of the medicine depends upon the Pharmacokinetics of the drug. It deals with the time taken for the drug to be absorbed, metabolized, the process and chemical reactions involved in metabolism and about the excretion of the drug. All these factors are essential to deciding on the efficacy of the drug. Based on these pharmacokinetic principles, the ingredients, the Pharmaceutical company decides dose and route of administration. The concentration of the drug at the site of action which is proportional to therapeutic result inside the body depends on various pharmacokinetic reactions that occur in the body.
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Mechanism of Action

The cysteinyl leukotrienes (LTC4, LTD4, LTE4) are products of arachidonic acid metabolism and are released from various cells, including mast cells and eosinophils. These eicosanoids bind to cysteinyl leukotriene (CysLT) receptors. The CysLT type-1 (CysLT1) receptor is found in the human airway (including airway smooth muscle cells and airway macrophages) and on other pro-inflammatory cells (including eosinophils and certain myeloid stem cells). CysLTs 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 the inflammatory process. In allergic rhinitis, CysLTs are released from the nasal mucosa after allergen exposure during both early- and late-phase reactions and are associated with symptoms of allergic rhinitis.

Montelukast is an orally active compound that binds with high affinity and selectivity to the CysLT1 receptor (in preference to other pharmacologically important airway receptors, such as the prostanoid, cholinergic, or β-adrenergic receptor). Montelukast inhibits physiologic actions of LTD4 at the CysLT1 receptor without any agonist activity.

Pharmacodynamics

Montelukast causes inhibition of airway cysteinyl leukotriene receptors as demonstrated by the ability to inhibit bronchoconstriction due to inhaled LTD4 in asthmatics. Doses as low as 5 mg cause substantial blockage of LTD4-induced bronchoconstriction. In a placebo-controlled, crossover study (n=12), Montelukast inhibited early- and late-phase bronchoconstriction due to antigen challenge by 75% and 57%, respectively.

The effect of Montelukast on eosinophils in the peripheral blood was examined in clinical trials. In patients with asthma aged 2 years and older who received Montelukast, a decrease in mean peripheral blood eosinophil counts ranging from 9% to 15% was noted, compared with placebo, over the double-blind treatment periods. In patients with seasonal allergic rhinitis aged 15 years and older who received Montelukast, a mean increase of 0.2% in peripheral blood eosinophil counts was noted, compared with a mean increase of 12.5% in placebo-treated patients, over the double-blind treatment periods; this reflects a mean difference of 12.3% in favor of Montelukast. The relationship between these observations and the clinical benefits of Montelukast noted in the clinical trials is not known.

Pharmacokinetics

Absorption

Montelukast is rapidly absorbed following oral administration. After administration of the 10-mg film-coated tablet to fasted adults, the mean peak Montelukast plasma concentration (Cmax) is achieved in 3 to 4 hours (Tmax). The mean oral bioavailability is 64%. The oral bioavailability and Cmax are not influenced by a standard meal in the morning.

For the 5-mg chewable tablet, the mean Cmax is achieved in 2 to 2.5 hours after administration to adults in the fasted state. The mean oral bioavailability is 73% in the fasted state versus 63% when administered with a standard meal in the morning.

For the 4-mg chewable tablet, the mean Cmax is achieved 2 hours after administration in pediatric patients 2 to 5 years of age in the fasted state.

The 4-mg oral granule formulation is bioequivalent to the 4-mg chewable tablet when administered to adults in the fasted state. The co-administration of the oral granule formulation with applesauce did not have a clinically significant effect on the pharmacokinetics of Montelukast. A high fat meal in the morning did not affect the AUC of Montelukast oral granules; however, the meal decreased Cmax by 35% and prolonged Tmax from 2.3 ± 1.0 hours to 6.4 ± 2.9 hours.

The safety and efficacy of Montelukast in patients with asthma were demonstrated in clinical trials in which the 10-mg film-coated tablet and 5-mg chewable tablet formulations were administered in the evening without regard to the time of food ingestion. The safety of Montelukast in patients with asthma was also demonstrated in clinical trials in which the 4-mg chewable tablet and 4-mg oral granule formulations were administered in the evening without regard to the time of food ingestion. The safety and efficacy of Montelukast in patients with seasonal allergic rhinitis were demonstrated in clinical trials in which the 10-mg film-coated tablet was administered in the morning or evening without regard to the time of food ingestion.

The comparative pharmacokinetics of Montelukast when administered as two 5-mg chewable tablets versus one 10-mg film-coated tablet have not been evaluated.

Distribution

Montelukast is more than 99% bound to plasma proteins. The steady state volume of distribution of Montelukast averages 8 to 11 liters. Studies in rats with radiolabeled Montelukast indicate minimal distribution across the blood-brain barrier. In addition, concentrations of radiolabeled material at 24 hours postdose were minimal in all other tissues.

Metabolism

Montelukast is extensively metabolized. In studies with therapeutic doses, plasma concentrations of metabolites of Montelukast are undetectable at steady state in adults and pediatric patients.

In vitro studies using human liver microsomes indicate that CYP3A4, 2C8, and 2C9 are involved in the metabolism of Montelukast. At clinically relevant concentrations, 2C8 appears to play a major role in the metabolism of Montelukast.

Elimination

The plasma clearance of Montelukast averages 45 mL/min in healthy adults. Following an oral dose of radiolabeled Montelukast, 86% of the radioactivity was recovered in 5-day fecal collections and <0.2% was recovered in urine. Coupled with estimates of Montelukast oral bioavailability, this indicates that Montelukast and its metabolites are excreted almost exclusively via the bile.

In several studies, the mean plasma half-life of Montelukast ranged from 2.7 to 5.5 hours in healthy young adults. The pharmacokinetics of Montelukast are nearly linear for oral doses up to 50 mg. During once-daily dosing with 10-mg Montelukast, there is little accumulation of the parent drug in plasma (14%).

Special Populations

Hepatic Insufficiency: Patients with mild-to-moderate hepatic insufficiency and clinical evidence of cirrhosis had evidence of decreased metabolism of Montelukast resulting in 41% (90% CI=7%, 85%) higher mean Montelukast AUC following a single 10-mg dose. The elimination of Montelukast was slightly prolonged compared with that in healthy subjects (mean half-life, 7.4 hours). No dosage adjustment is required in patients with mild-to-moderate hepatic insufficiency. The pharmacokinetics of Montelukast in patients with more severe hepatic impairment or with hepatitis have not been evaluated.

Renal Insufficiency: Since Montelukast and its metabolites are not excreted in the urine, the pharmacokinetics of Montelukast were not evaluated in patients with renal insufficiency. No dosage adjustment is recommended in these patients.

Gender: The pharmacokinetics of Montelukast are similar in males and females.

Race: Pharmacokinetic differences due to race have not been studied.

Adolescents and Pediatric Patients: Pharmacokinetic studies evaluated the systemic exposure of the 4-mg oral granule formulation in pediatric patients 6 to 23 months of age, the 4-mg chewable tablets in pediatric patients 2 to 5 years of age, the 5-mg chewable tablets in pediatric patients 6 to 14 years of age, and the 10-mg film-coated tablets in young adults and adolescents ≥15 years of age.

The plasma concentration profile of Montelukast following administration of the 10-mg film-coated tablet is similar in adolescents ≥15 years of age and young adults. The 10-mg film-coated tablet is recommended for use in patients ≥15 years of age.

The mean systemic exposure of the 4-mg chewable tablet in pediatric patients 2 to 5 years of age and the 5-mg chewable tablets in pediatric patients 6 to 14 years of age is similar to the mean systemic exposure of the 10-mg film-coated tablet in adults. The 5-mg chewable tablet should be used in pediatric patients 6 to 14 years of age and the 4-mg chewable tablet should be used in pediatric patients 2 to 5 years of age.

In children 6 to 11 months of age, the systemic exposure to Montelukast and the variability of plasma Montelukast concentrations were higher than those observed in adults. Based on population analyses, the mean AUC (4296 ng•hr/mL [range 1200 to 7153]) was 60% higher and the mean Cmax (667 ng/mL [range 201 to 1058]) was 89% higher than those observed in adults (mean AUC 2689 ng•hr/mL [range 1521 to 4595]) and mean Cmax (353 ng/mL [range 180 to 548]). The systemic exposure in children 12 to 23 months of age was less variable, but was still higher than that observed in adults. The mean AUC (3574 ng•hr/mL [range 2229 to 5408]) was 33% higher and the mean Cmax (562 ng/mL [range 296 to 814]) was 60% higher than those observed in adults. Safety and tolerability of Montelukast in a single-dose pharmacokinetic study in 26 children 6 to 23 months of age were similar to that of patients two years and above. The 4-mg oral granule formulation should be used for pediatric patients 12 to 23 months of age for the treatment of asthma, or for pediatric patients 6 to 23 months of age for the treatment of perennial allergic rhinitis. Since the 4-mg oral granule formulation is bioequivalent to the 4-mg chewable tablet, it can also be used as an alternative formulation to the 4-mg chewable tablet in pediatric patients 2 to 5 years of age.

Drug-Drug Interactions

Theophylline, Prednisone, and Prednisolone: Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of Montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, and prednisolone.

Montelukast at a dose of 10 mg once daily dosed to pharmacokinetic steady state, did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline [predominantly a cytochrome P450 (CYP) 1A2 substrate]. Montelukast at doses of ≥100 mg daily dosed to pharmacokinetic steady state, did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone.

Oral Contraceptives, Terfenadine, Digoxin, and Warfarin: In drug interaction studies, the recommended clinical dose of Montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Montelukast at doses of ≥100 mg daily dosed to pharmacokinetic steady state did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. Montelukast at a dose of 10 mg once daily dosed to pharmacokinetic steady state did not change the plasma concentration profile of terfenadine (a substrate of CYP3A4) or fexofenadine, the carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily; did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin; did not change the pharmacokinetic profile of warfarin (primarily a substrate of CYP2C9, 3A4 and 1A2) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the International Normalized Ratio (INR).

Thyroid Hormones, Sedative Hypnotics, Non-Steroidal Anti-Inflammatory Agents, Benzodiazepines, and Decongestants: Although additional specific interaction studies were not performed, Montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants.

Cytochrome P450 (CYP) Enzyme Inducers: Phenobarbital, which induces hepatic metabolism, decreased the area under the plasma concentration curve (AUC) of Montelukast approximately 40% following a single 10-mg dose of Montelukast. No dosage adjustment for Montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent CYP enzyme inducers, such as phenobarbital or rifampin, are co-administered with Montelukast.

Effect of Montelukast on Cytochrome P450 (CYP) Enzymes: Montelukast is a potent inhibitor of CYP2C8 in vitro. However, data from a clinical drug-drug interaction study involving Montelukast and rosiglitazone (a probe substrate representative of drugs primarily metabolized by CYP2C8) in 12 healthy individuals demonstrated that the pharmacokinetics of rosiglitazone are not altered when the drugs are coadministered, indicating that Montelukast does not inhibit CYP2C8 in vivo. Therefore, Montelukast is not anticipated to alter the metabolism of drugs metabolized by this enzyme (e.g., paclitaxel, rosiglitazone, and repaglinide). Based on further in vitro results in human liver microsomes, therapeutic plasma concentrations of Montelukast do not inhibit CYP 3A4, 2C9, 1A2, 2A6, 2C19, or 2D6.

Cytochrome P450 (CYP) Enzyme Inhibitors: In vitro studies have shown that Montelukast is a substrate of CYP 2C8, 2C9, and 3A4. Co-administration of Montelukast with itraconazole, a strong CYP 3A4 inhibitor, resulted in no significant increase in the systemic exposure of Montelukast. Data from a clinical drug-drug interaction study involving Montelukast and gemfibrozil (an inhibitor of both CYP 2C8 and 2C9) demonstrated that gemfibrozil, at a therapeutic dose, increased the systemic exposure of Montelukast by 4.4-fold. Co-administration of itraconazole, gemfibrozil, and Montelukast did not further increase the systemic exposure of Montelukast. Based on available clinical experience, no dosage adjustment of Montelukast is required upon co-administration with gemfibrozil.



References

  1. EPA DSStox. "Montelukast: DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology.". https://comptox.epa.gov/dashboard/ds... (accessed September 17, 2018).

Reviews

The results of a survey conducted on ndrugs.com for Montelukast are given in detail below. The results of the survey conducted are based on the impressions and views of the website users and consumers taking Montelukast. We implore you to kindly base your medical condition or therapeutic choices on the result or test conducted by a physician or licensed medical practitioners.

User reports

1 consumer reported administration

When best can I take Montelukast, on an empty stomach, before or after food?
ndrugs.com website users have also released a report stating that Montelukast should be taken After food. In any case, this may not be the right description on how you ought to take this Montelukast. Kindly visit your doctor for more medical advice in this regard. Click here to see other users view on when best the Montelukast can be taken.
Users%
After food1
100.0%


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Information checked by Dr. Sachin Kumar, MD Pharmacology

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