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Montelukast and Zafirlukast are leukotriene D4 receptors antagonists that are used prophylactically for the management of asthma, antigen, exercise, or drug-induced asthma.

Montelukast is used as add-on therapy in adults and children (6 years and over) with mild to moderate persistent asthma which is inadequately controlled by inhaled corticosteroids and 'as needed' short-acting ß-agonists.

It is also used for the prophylaxis of asthma in which the predominant component is exercise-induced bronchoconstriction.

Zafirlukast has recently been introduced for the treatment of asthma" in adults and children (over 12 years of age).

Classification

Leukotriene Esterase Inhibitors are classified into two classes.

  1. 5-Lipoxygenase inhibitor such as Zileuton
  2. Cysteinyl Leukotriene Receptor antagonists: Montelukast and Zafirlukast.

For an easier understanding of these Leukotriene antagonist medications, it is important that we have a basic understanding of what are leukotrienes.

What are leukotrienes?

Leukotrienes are fatty acid-derived mediators that contain a conjugated triene structure. Leukotrienes are products of arachidonic acid metabolism and are formed when arachidonic acid is liberated from the cell membrane of cells, as a result of cell activation by an allergen.

They are generated by 5-Lipoxygenase and converts arachidonic into 5-HPETE, which in turn is converted into LTB4 which is a potent mediator of inflammation and Cysteinyl-LTs (LTC4, LTD4, LTE4 that mediate asthmatic responses.

LTB4 is a potent pro-inflammatory chemo-attractant.

LTC4 is activated to an active metabolite (LTD4) by the removal of the terminal amino acid in the peptide side-chain.

Removal of a second amino acid results in a less active metabolite known as LTE4. LTC4, LTD4 and LTE4, the ‘cysteinyl leukotrienes’, account for ‘slow-reacting substance of anaphylaxis’ (SRS-A).

These active metabolites all bind to the Cysteinyl Leukotriene Receptor 1 to cause bronchoconstriction, increase in vascular permeability producing edema and chemoattraction of eosinophil.

Leukotriene B4 is a powerful chemo-attractant and increases vascular permeability producing mucosal edema.

Cysteinyl leukotrienes are potent spasmogens and pro-inflammatory substances.

Clinically used agents that modulate leukotrienes are the leukotriene antagonists that antagonize cysteinyl leukotrienes at the Cysteinyl leukotriene 1 receptor.

These medications are effective as oral maintenance therapy in chronic persistent asthma.

Montelukast has anti-inflammatory properties and is a mild, slow-onset bronchodilator.

Cysteinyl Leukotriene (Cyst LTs)

They are mediated by a shared receptor for LTC4, LTD4, and LTE4.

They cause a longer contraction of bronchial muscles when compared to histamine.

It also causes Peripheral vasodilation and coronary vasoconstriction.

Cyst LTs are found in the sputum of chronic bronchitis, asthmatic lung; lavage of allergic rhinitis.

Montelukast

Montelukast blocks leukotriene receptors but has no effect on the synthesis of leukotriene

Chemical Class: Leukotriene receptor antagonist

Therapeutic class: Antiasthmatic

Pregnancy category: B

Pharmacological effects of Montelukast:

Decreases airway edema, smooth muscle contraction, and altered cellular activity associated with the inflammatory process.

In allergic rhinitis, decrease symptoms of nasal obstruction.

Montelukast is effective in aspirin-sensitive asthma that is associated with a diversion of arachidonic acid from the cyclooxygenase pathway to the formation of leukotriene via lipoxygenase. This diversion results from the blockage by aspirin.

Pharmacokinetics

This drug is rapidly absorbed from the gastrointestinal tract.

The mean plasma half-life is 2.7–5.5 hours.

The drug is 60-70% metabolized in the liver by cytochrome 3A and 2C9 and is mainly excreted in the bile.

It has a half-life of 10 hours.

When Montelukast is administered, it binds the cysteine leukotriene 1 receptor.

Bioavailability is greater than 90%.

Peak plasma binding about 99%.

Indications and Dosages

Zafirlukast and Montelukast are administered orally, 1–2 times per day usually in the evening.

Montelukast

For asthma prophylaxis the dosage of Montelukast is10mg oral single dose

Exercise-induced bronchoconstriction- 10mg orally two hours before exercise.

For allergic rhinitis, the dose is 10mg orally once daily

In children between 12 to 24 months, the dose is mg granules once daily

2-6 years, give them a chewable tablet of 4 mg

6-15 years use a chewable tablet of 5 mg and more than 15 years use the adult dose.

Zafirlukast

Asthma the dose is 20 mg orally twice daily at least one hour before or two hours after meals in adults.

In pediatric patients between 5-12 years it is 10 mg orally twice daily and more than 12 years it is 20 mg orally twice a day.

Mechanism of Action

Antagonizes receptors for Cysteinyl leukotriene, produced by arachidonic acid metabolism and released from mast cells, eosinophil, and other cells.

When Cysteinyl leukotriene bind to receptors in bronchial airways, they increase endothelial membrane permeability, which leads to airway edema, smooth muscle contraction, and altered activity of cells in asthma’s inflammatory process.

Montelukast exerts its effect by blocking these effects.

Drug Interaction

Phenobarbital decreased amount of circulating Montelukast

Zafirlukast has drug interaction with warfarin sodium, leading to increased prothrombin time, thus dose has to be monitored.

Increase in theophylline levels, which is itself bronchodilator

Erythromycin reduces the absorption of Zafirlukast, potentially reducing the effects of Zafirlukast.

Adverse Reactions

Montelukast and Zafirlukast are generally well-tolerated, but side effects include:

Inflammation at the site in lungs

Rarely hypersensitivity reaction

Churg-Strauss Syndrome due to drugs but due to preexisting underlying disease, eosinophilia and vasculitis are seen.

Adverse effects of Zafirlukast include headache and elevation in liver enzymes: serum transaminases.

Hepatotoxicity.

CNS: Aggression, agitation, anxiousness, asthenia,  depression, disorientation, dizziness, dream abnormalities, fever, hallucinations, headache, hostility, hypoesthesia, insomnia, irritability, memory impairment, paresthesia, restlessness, seizures, sleepwalking, somnolence, suicidal ideation, tremor

CV: Palpitations, edema

EENT: Dental, epistaxis, nasal congestion, otitis media, pharyngitis, sinusitis

GI: Abdominal pain, cholestatic hepatitis, hepatotoxicity, indigestion, infectious gastroenteritis; diarrhea, pancreatitis,

GU: Pyuria

HEME: Increased bleeding tendency, systemic eosinophilia, thrombocytopenia

MS: Arthralgia, muscle cramps, myalgia

RESP: Cough, upper respiratory tract infection, pulmonary eosinophilia

SKIN: Erythema multiforme, erythema nodosum, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria

Other: Anaphylaxis, angioedema (in all patients); flulike syndrome, viral infection (in children)

Warning

Montelukast and Zafirlukast should not be used for an acute asthma attack or in status asthmaticus.

It shouldn’t be abruptly substituted for inhaled or oral corticosteroids; taper corticosteroid dosage gradually.

The patient should be monitored for adverse reactions, such as cardiac and pulmonary symptoms, eosinophilia, and vasculitis, in patients undergoing corticosteroid withdrawal.

Also, it is recommended that you watch the patient closely for suicidal tendencies during Montelukast therapy, especially when therapy starts or dosage changes.

Caution patient with aspirin sensitivity to avoid aspirin and NSAIDs during Montelukast therapy because it may not effectively reduce bronchospasm in such a patient.

A Indicated in age only 12 and over.

Contraindicated during pregnancy and breast-feeding. Avoid its use in the patient with phenylketonuria that chewable tablet contains phenylalanine.


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