Leukotriene modifiers

Leukotriene modifiers

Leukotriene modifiers are used for the prevention and long-termcontrol of mild asthma.

Leukotriene receptor antagonists include:

·                 Montelukast

·                 zafirlukast.

Leukotriene formation inhibitors include:

·                 zileuton.

Pharmacokinetics

Montelukast is rapidly absorbed. Zafirlukast’s absorption is de-creased by food, so it should be given 1 hour before or 2 hours af-ter meals.

All of the leukotriene modifiers are highly protein-bound (more than 90%).

Metabolism and excretion

Zafirlukast is extensively metabolized in the liver by the cy-tochrome P450 2C9 (CYP2C9) enzyme into inactive metabolites and excreted primarily in stool. In general, this class of drugs is metabolized, induced, or inhibited by the cytochrome P450 en-zyme system, which is important for establishing drug interac-tions.

Caution required

Zileuton is contraindicated in the patient with active liver disease. Closely monitor the patient with liver impairment who’s taking zafirlukast for adverse reactions; he may require a dosage adjust-ment. This doesn’t apply for montelukast.

Pharmacodynamics

Leukotrienes are substances released from mast cells, eosino-phils, and basophils that can cause smooth-muscle contraction of the airways, increased permeability of the vasculature, increased secretions, and activation of other inflammatory mediators.

Leukotrienes may be inhibited by two different mechanisms. The leukotriene receptor antagonists zafirlukast and montelukast prevent the D4 and E4 leukotrienes from interacting with their re-ceptors, thereby blocking their action. The leukotriene formation inhibitor zileuton inhibits the production of 5-lipoxygenase, there-by preventing the formation of leukotrienes.

Pharmacotherapeutics

Leukotriene modifiers are primarily used to prevent and control asthma attacks in the patient with mild to moderate disease. Mon-telukast is also indicated for the treatment of allergic rhinitis.

Drug interactions

·                 Zafirlukast inhibits CYP2C9 and thus could increase the risk of toxicity if used with phenytoin or warfarin.

·                 Zafirlukast and zileuton inhibit CYP3A4 and thus could increase the risk of toxicity if used with amlodipine, atorvastatin, carba-mazepine, clarithromycin, cyclosporine, erythromycin, hormonal contraceptives, itraconazole, ketoconazole, lovastatin, nelfinavir, nifedipine, ritonavir, sertraline, simvastatin, or warfarin.

·                 Zileuton inhibits CYP1A2 and thus could increase the risk of toxicity if used with amitriptyline, clozapine, desipramine, fluvox-amine, imipramine, theophylline, or warfarin.

Talkin’ toxicity

·                 Zafirlukast, zileuton, and montelukast are metabolized by CYP2C9 and thus could increase the risk of toxicity if used with amiodarone, cimetidine, fluconazole, fluoxetine, fluvoxamine, iso-niazid, metronidazole, or voriconazole. If carbamazepine, pheno-barbital, phenytoin, primidone, or rifampin is used with leuko-trienes, the effectiveness of the leukotrienes could be reduced.

·                 Zileuton and montelukast are metabolized by CYP3A4 and thus could increase the risk of toxicity if used with amiodarone, cimeti-dine, clarithromycin, cyclosporine, erythromycin, fluoxetine, flu-voxamine, grapefruit juice, itraconazole, ketoconazole, metronida-zole, or voriconazole and could result in decreased effectiveness if used with carbamazepine, efavirenz, garlic supplements, modafi-nil, nevirapine, oxcarbazepine, phenobarbital, phenytoin, primi-done, rifabutin, rifampin, or St. John’s wort.

·                 Zileuton is metabolized by CYP1A2 and thus could increase the risk of toxicity if used with cimetidine, clarithromycin, erythro-mycin, fluvoxamine, or isoniazid and could result in decreased ef-fectiveness if used with carbamazepine, phenobarbital, phenytoin, primidone, rifampin, ritonavir, or St. John’s wort or if used by a smoker. (See Adverse reactions to leukotriene modifiers.)