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Pulmonary - Leukotriene inhibitors

montelukast -Singulair ® zafirlukast (Accolate ®)
zileuton (Zyflo ®)  

montelukast Singulair ®  top of page icon

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. Intranasal challenge with CysLTs has been shown to increase nasal airway resistance and symptoms of nasal obstruction. SINGULAIR has not been assessed in intranasal challenge studies. The clinical relevance of intranasal challenge studies is unknown.

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 beta-adrenergic receptor). Montelukast inhibits physiologic actions of LTD4 at the CysLT1 receptor without any agonist activity.

INDICATIONS AND USAGE
SINGULAIR is indicated for the prophylaxis and chronic treatment of asthma in adults and pediatric patients 12 months of age and older.

SINGULAIR is indicated for prevention of exercise-induced bronchoconstriction in patients 15 years of age and older.

SSINGULAIR is indicated for 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).
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Dosing:
Oral:
Children:
12-23 months: Asthma: 4 mg (oral granules) once daily, taken in the evening

2-5 years: Asthma or seasonal allergic rhinitis: 4 mg (chewable tablet or oral granules) once daily, taken in the evening

6-14 years: Asthma or seasonal allergic rhinitis: Chew one 5 mg chewable tablet/day, taken in the evening

Children >/= 15 years and Adults:
Asthma or seasonal allergic rhinitis: 10 mg/day, taken in the evening
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Supplied:
Granules: 4 mg/packet
TTablet: 10 mg

Tablet, chewable: 4 mg [contains phenylalanine 0.674 mg; cherry flavor]; 5 mg [contains phenylalanine 0.842 mg; cherry flavor]

zafirlukast  (Accolate ®) top of page icon

Mechanism of Action:
Zafirlukast is a selective and competitive receptor antagonist of leukotriene D4 and E4 (LTD4 and LTE4), components of slow-reacting substance of anaphylaxis (SRSA). Cysteinyl leukotriene production and receptor occupation have been correlated with the pathophysiology of asthma, including airway edema, smooth muscle constriction, and altered cellular activity associated with the inflammatory process, which contribute to the signs and symptoms of asthma. Patients with asthma were found in one study to be 25-100 times more sensitive to the bronchoconstricting activity of inhaled LTD4 than nonasthmatic subjects.

In vitro studies demonstrated that zafirlukast antagonized the contractile activity of three leukotrienes (LTC4, LTD4 and LTE4) in conducting airway smooth muscle from laboratory animals and humans. Zafirlukast prevented intradermal LTD4-induced increases in cutaneous vascular permeability and inhibited inhaled LTD4-induced influx of eosinophils into animal lungs. Inhalational challenge studies in sensitized sheep showed that zafirlukast suppressed the airway responses to antigen; this included both the early- and late-phase response and the nonspecific hyperresponsiveness.

In humans, zafirlukast inhibited bronchoconstriction caused by several kinds of inhalational challenges. Pretreatment with single oral doses of zafirlukast inhibited the bronchoconstriction caused by sulfur dioxide and cold air in patients with asthma. Pretreatment with single doses of zafirlukast attenuated the early- and late-phase reaction caused by inhalation of various antigens such as grass, cat dander, ragweed, and mixed antigens in patients with asthma. Zafirlukast also attenuated the increase in bronchial hyperresponsiveness to inhaled histamine that followed inhaled allergen challenge.

INDICATIONS AND USAGE
ACCOLATE is indicated for the prophylaxis and chronic treatment of asthma in adults and children 5 years of age and older.

CONTRAINDICATIONS
ACCOLATE is contraindicated in patients who are hypersensitive to zafirlukast or any of its inactive ingredients.

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Dosing:
Children 5-11 years: 10 mg twice daily

Children >/= 12 years and Adults: 20 mg twice daily

Elderly: The mean dose (mg/kg) normalized AUC and Cmax increase and plasma clearance decreases with increasing age. In patients >65 years of age, there is a two- to threefold greater Cmax and AUC compared to younger adults.

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Supplied:
Tablet: 10 mg, 20 mg

zileuton  (Zyflo ®) top of page icon

CLINICAL PHARMACOLOGY
Mechanism of Action:
Zileuton is a specific inhibitor of 5-lipoxygenase and thus inhibits leukotriene (LTB4, LTC4, LTD4, and LTE4) formation. Both the R(+) and S(-) enantiomers are pharmacologically active as 5-lipoxygenase inhibitors in in vitro systems. Leukotrienes are substances that induce numerous biological effects including augmentation of neutrophil and eosinophil migration, neutrophil and monocyte aggregation, leukocyte adhesion, increased capillary permeability, and smooth muscle contraction. These effects contribute to inflammation, edema, mucus secretion, and bronchoconstriction in the airways of asthmatic patients. Sulfido-peptide leukotrienes (LTC4, LTD4, LTE4, also known as the slow-releasing substances of anaphylaxis) and LTB4, a chemoattractant for neutrophils and eosinophils, can be measured in a number of biological fluids including bronchoalveolar lavage fluid (BALF) from asthmatic patients.

Zileuton is an orally active inhibitor of ex vivo LTB4 formation in several species, including dogs, monkeys, rats, sheep, and rabbits. Zileuton inhibits arachidonic acid-induced ear edema in mice, neutrophil migration in mice in response to polyacrylamide gel, and eosinophil migration into the lungs of antigen-challenged sheep.

Zileuton inhibits leukotriene-dependent smooth muscle contractions in vitro in guinea pig and human airways. The compound inhibits leukotriene-dependent bronchospasm in antigen and arachidonic acid-challenged guinea pigs. In antigen-challenged sheep, zileuton inhibits late-phase bronchoconstriction and airway hyperreactivity. In humans, pretreatment with zileuton attenuated bronchoconstriction caused by cold air challenge in patients with asthma.

INDICATIONS AND USAGE
ZYFLO is indicated for the prophylaxis and chronic treatment of asthma in adults and children 12 years of age and older.


CONTRAINDICATIONS
ZYFLO tablets are contraindicated in patients with:

Active liver disease or transaminase elevations greater than or equal to three times the upper limit of normal (greater than or equal3xULN) (see package insert: PRECAUTIONS, Hepatic).
Hypersensitivity to zileuton or any of its inactive ingredients.

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Dosing:
Children >/= 12 years of age and Adults: 600 mg 4 times/day with meals and at bedtime

Elderly: Zileuton pharmacokinetics were similar in healthy elderly subjects (>65 years) compared with healthy younger adults (18-40 years)

Dosing adjustment in hepatic impairment: Contraindicated in patients with active liver disease

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Supplied:
Tablet: 600 mg
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Reference(s)

National Institutes of Health, U.S. National Library of Medicine, DailyMed Database.
Provides access to the latest drug monographs submitted to the Food and Drug Administration (FDA). Please review the latest applicable package insert for additional information and possible updates.  A local search option of this data can be found here.

Disclaimer

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David F. McAuley, Pharm.D., R.Ph.  GlobalRPh Inc.
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