Zafirlukast is an orally administered

leukotriene receptor antagonist An antileukotriene, also known as leukotriene modifier and leukotriene receptor antagonist, is a medication which functions as a leukotriene-related enzyme inhibitor ( arachidonate 5-lipoxygenase) or leukotriene receptor antagonist ( cysteinyl leu ...

(LTRA) used for the chronic treatment of

asthma Asthma is a common long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wh ...

. While zafirlukast is generally well tolerated, headaches and stomach upset often occur. Some rare side effects can occur, which can be life-threatening, such as

liver failure Liver failure is the inability of the liver to perform its normal synthetic and metabolic functions as part of normal physiology. Two forms are recognised, acute and chronic (cirrhosis). Recently, a third form of liver failure known as acute- ...

eosinophilic granulomatosis with polyangiitis Eosinophilic granulomatosis with polyangiitis (EGPA), formerly known as allergic granulomatosis, is an extremely rare autoimmune condition that causes inflammation of small and medium-sized blood vessels (vasculitis) in persons with a history of ...

has been associated with zafirlukast, but the relationship is not thought to be causative. Overdoses of zafirlukast tend to be self-limiting. Zafirlukast, like other LTRAs, works by inhibiting the immune system. Through its action on inflammatory cells in the lungs, zafirlukast reduces the production of inflammatory mediators that are implicated in the pathogenesis of

. Zafirlukast is extensively hepatically metabolized by an enzyme called

CYP2C9 Cytochrome P450 family 2 subfamily C member 9 (abbreviated CYP2C9) is an enzyme protein. The enzyme is involved in the metabolism, by oxidation, of both xenobiotics, including drugs, and endogenous compounds, including fatty acids. In humans, t ...

. Zafirlukast inhibits the action of

CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by ''CYP3A4'' gene. It organic redox reaction, oxidizes small foreign organic molecules ( ...

, leading to drug-drug interactions with other drugs that are metabolized by CYP3A4. Genetic differences in LTC4 synthase and

may predict how a person reacts to zafirlukast treatment. Zafirlukast (brand name Accolate) was the first cysteinyl leukotriene receptor antagonist approved in the United States. It is now approved in many other countries under other brand names.

Medical uses

Zafirlukast is

FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

-approved for the prevention and treatment of asthma in adults and children older than 5 years old. Like other leukotriene receptor antagonists, zafirlukast is thought to be useful for the long-term treatment of asthma, but it is generally less effective than inhaled glucocorticoids as monotherapy (which are the standard of care) or long-acting beta-2 agonists in combination therapy. Notably, zafirlukast is ineffective in the event of an acute asthma attack.

Available forms

There are two dosage forms for zafirlukast, notable for their age-adjustments. The 20 mg tablet is for adults and children older than age 12, whereas the 10 mg tablet is for children between the ages of 5 and 12. Tablets should be stored at room temperature, out of direct sunlight, and away from sources of moisture. Tablets are for oral administration only.

Specific populations

Pediatrics

As a general rule, leukotriene receptor antagonists like zafirlukast are more effective in children that are younger and whose asthma is less

atopic Atopy is the tendency to produce an exaggerated immunoglobulin E (IgE) immune response to otherwise harmless substances in the environment. Allergic diseases are clinical manifestations of such inappropriate, atopic responses. Atopy may have a ...

. Atopy refers to a predisposition towards developing allergic conditions, including

hay fever Allergic rhinitis, of which the seasonal type is called hay fever, is a type of rhinitis, inflammation in the nose that occurs when the immune system overreacts to allergens in the air. It is classified as a Allergy, type I hypersensitivity re ...

, and

eczema Dermatitis is a term used for different types of skin inflammation, typically characterized by itchiness, redness and a rash. In cases of short duration, there may be small blisters, while in long-term cases the skin may become thickened ...

Geriatrics

The hepatic clearance of zafirlukast is impaired in adults 65 years of age and older, resulting in a 2–3 fold increase in the maximum plasma concentration and the total area under the curve. Zafirlukast may increase the risk for infections (7.0% vs 2.9%, zafirlukast vs. placebo incidence respectively), especially lower respiratory tract infections, in older adults, though the infections noted were not severe.

Pregnancy

Zafirlukast is considered to be "

pregnancy category The pregnancy category of a medication is an assessment of the risk of fetal injury due to the pharmaceutical, if it is used as directed by the mother during pregnancy. It does ''not'' include any risks conferred by pharmaceutical agents or their ...

B." This is due, in part, to the wide safety margin of zafirlukast in animal studies investigating teratogenicity. No teratogenicity has been observed in doses up to 2000 mg/kg/day in cynomolgus monkeys, representing an equivalent 20x exposure of the maximum recommended daily oral dose in human adults. However, spontaneous abortions occurred in cynomolgus monkeys at 2000 mg/kg/day, though the dose itself was maternally toxic.

Lactation

There is limited research on the use of zafirlukast in women whom are breastfeeding. Based on data from the manufacturer, it is expected that 0.6% of the maternal weight-adjusted dose would reach a breastfed infant, though the effects in the infant are unknown.

Renal impairment

Renal impairment does not appear to affect the pharmacokinetic profile of zafirlukast.

Hepatic impairment

The hepatic clearance of zafirlukast is impaired by significant hepatic impairment. Cirrhosis of the liver can increase the maximum plasma concentration and the total area under the curve (a measure of drug exposure) by 50–60%.

Contraindications

Zafirlukast is contraindicated in people who are hypersensitive or allergic to it.

Adverse effects

Zafirlukast is generally well tolerated, though headache and gastrointestinal (GI) upset can occur. The incidence of headaches is between 12 and 20%, which is similar to the incidence of headaches found in patients taking

placebos A placebo ( ) can be roughly defined as a sham medical treatment. Common placebos include inert tablets (like sugar pills), inert injections (like saline), sham surgery, and other procedures. Placebos are used in randomized clinical trials to ...

in the studies that led to zafirlukast's approval. GI upset may include nausea, stomach discomfort/pain, and diarrhea. GI complaints can be lessened by taking zafirlukast with food, though this can dramatically impair the amount of drug that gets absorbed into the body (see the section on drug-food interactions below). Other common side effects include flu-like symptoms, sleep disturbances (abnormal dreams, insomnia), hallucinations, and daytime drowsiness.

Neuropsychiatric effects

Neuropsychiatric side effects have been reported with the use of zafirlukast and other LTRAs. While some side effects are less severe (e.g. abnormal dreams), others are more serious (e.g. hallucinations, tremors, suicidality). These effects were discovered through post-marketing reports, as the initial trials were not designed to monitor for neuropsychiatric side effects.

Hepatotoxicity

Zafirlukast can also cause rare but serious side effects like acute liver injury. Zafirlukast-induced hepatotoxicity generally occurs within the first 2–6 months of initiating therapy, though cases have been reported up to 13 months after starting zafirlukast. Zafirlukast-induced hepatotoxicity is characterized by a spectrum of liver damage symptoms, including fatigue, nausea, and right upper quadrant pain followed by dark urine, jaundice and pruritus. Liver enzyme elevations are common, and the pattern usually reflects hepatocellular damage, resembling acute viral hepatitis. It is unclear how the hepatotoxicity occurs, but it may be due to a metabolic intermediate of zafirlukast since it is metabolized in the liver through the enzyme

. When it does occur it can be fatal, and reexposure with zafirlukast may result in a worse injury. Switching zafirlukast to another medication in the same class (e.g.

montelukast Montelukast, sold under the brand name Singulair among others, is a medication used in the maintenance treatment of asthma. It is generally less preferred for this use than inhaled corticosteroids. It is not useful for acute asthma attacks. ...

) or in the related class of 5-lipoxygenase inhibitors can be attempted, but caution should be employed. According to the "Dear Health Care Provider" letter from AstraZeneca, zafirlukast-induced hepatotoxicity has occurred predominantly in females.

Eosinophilic granulomatosis with polyangiitis

Several cases of

have been reported with the use of zafirlukast,

, pranlukast, and other asthma medications. When eosinophilic granulomatosis with polyangiitis occurs, it tends to occur in people with long-standing asthma and sinus inflammation, chronic oral

corticosteroid Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are invo ...

use, and the recent initiation of a new anti-asthma therapy (like zafirlukast) in conjunction with tapering the corticosteroids. While the exact etiology of the development of eosinophilic granulomatosis with polyangiitis symptoms in proximity to initiating zafirlukast is unknown, it is thought that withdrawal of chronic corticosteroids "unmasks" the previously undetected disease. Because corticosteroid withdrawal often happens while starting a new anti-asthma medication (like zafirlukast), this explains the rare but notable association. These cases may represent misdiagnosed asthma, as eosinophilic granulomatosis with polyangiitis can induce symptoms of airway obstruction that are akin to an acute asthma exacerbation. The highest overdose reported with zafirlukast is 200 mg. All overdose patients have survived. Symptoms reported included rash and upset stomach.

Interactions

Drug–drug interactions

Zafirlukast is an inhibitor of the hepatic drug-metabolizing enzyme cytochrome P450 family 3 subfamily A member 4 (CYP3A4). Zafirlukast may increase the concentration of drugs that are metabolized through CYP3A4, such as the anticoagulant medication

warfarin Warfarin, sold under the brand name Coumadin among others. It is used as an anticoagulant, anticoagulant medication. It is commonly used to prevent deep vein thrombosis and pulmonary embolism, and to protect against stroke in people who ha ...

and the antiepileptic drugs

phenytoin Phenytoin (PHT), sold under the brand name Dilantin among others, is an anticonvulsant, anti-seizure medication. It is useful for the prevention of tonic-clonic seizures (also known as grand mal seizures) and focal seizures, but not absence se ...

and

carbamazepine Carbamazepine, sold under the brand name Tegretol among others, is an anticonvulsant medication used in the treatment of epilepsy and neuropathic pain. It is used as an adjunctive treatment in schizophrenia along with other medications and as ...

Drug-food interactions

The oral absorption (bioavailability) of zafirlukast is decreased by 40% when it is taken with high fat or high protein meals. To avoid this interaction, zafirlukast should be taken on an empty stomach. An empty stomach is classified as an hour before, or two hours after, consuming a meal.

Pharmacology

Pharmacodynamics

Zafirlukast is an antagonist of cysteinyl leukotriene receptor 1 (CysLT1), a receptor found throughout the smooth muscle of the

lungs The lungs are the primary organs of the respiratory system in many animals, including humans. In mammals and most other tetrapods, two lungs are located near the backbone on either side of the heart. Their function in the respiratory syste ...

, within interstitial lung

macrophages Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...

(white blood cells that operate in the interstitial space of the lungs), and rarely in epithelial cells. CystLT1 is a receptor for a specific class of

leukotrienes Leukotrienes are a family of eicosanoid inflammation, inflammatory mediators produced in leukocytes by the redox, oxidation of arachidonic acid (AA) and the essential fatty acid eicosapentaenoic acid (EPA) by the enzyme arachidonate 5-lipoxyg ...

that contain the amino acid

cysteine Cysteine (; symbol Cys or C) is a semiessential proteinogenic amino acid with the chemical formula, formula . The thiol side chain in cysteine enables the formation of Disulfide, disulfide bonds, and often participates in enzymatic reactions as ...

. These cysteinyl leukotrienes include

leukotriene C4 Leukotriene C4 (LTC4) is a leukotriene. LTC4 has been extensively studied in the context of allergy and asthma. In cells of myeloid origin such as mast cells, its biosynthesis is orchestrated by translocation to the nuclear envelope along with co ...

leukotriene D4 Leukotriene D4 (LTD4) is one of the leukotrienes. Its main function in the body is to induce the contraction of smooth muscle, resulting in bronchoconstriction and vasoconstriction. It also increases vascular permeability. LTD4 is released b ...

, and

leukotriene E4 Leukotriene E4 (LTE4) is a cysteinyl leukotriene involved in inflammation. It is known to be produced by several types of white blood cells, including eosinophils, mast cells, tissue macrophages, and basophils, and recently was also found to b ...

, all of which are produced by inflammatory cells like

eosinophils Eosinophils, sometimes called eosinophiles or, less commonly, acidophils, are a variety of white blood cells and one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates. Along wi ...

, basophils, and

in the lungs. Through their action on CysLT1 these leukotrienes can trigger

bronchoconstriction Bronchoconstriction is the constriction of the airways in the lungs due to the tightening of surrounding smooth muscle, with consequent coughing, wheezing, and shortness of breath. Causes The condition has a number of causes, the most common bei ...

, a state in which the bronchial passages of the lungs constrict, leading to the characteristic, reactive airway symptoms associated with bronchial

. The other pro-inflammatory effects of leukotrienes, such as their inhibition of mucus clearance and their stimulation of mucus secretion and edema, are thought to play a role in the characteristic symptoms of

allergic rhinitis Allergic rhinitis, of which the seasonal type is called hay fever, is a type of inflammation in the nose that occurs when the immune system overreacts to allergens in the air. It is classified as a type I hypersensitivity reaction. Signs a ...

(also called hay fever). By inhibiting the action of these specific leukotrienes, zafirlukast is thought to exert an anti-inflammatory effect against leukotriene-mediated inflammatory conditions.

Pharmacokinetics

Absorption

Zafirlukast is rapidly absorbed into the bloodstream following oral administration, reaching peak plasma levels within 3 hours of taking the dose. The peak plasma level is the maximum concentration of zafirlukast in the blood.

Distribution

Zafirlukast is moderately distributed into the body's tissues, with an apparent

steady state In systems theory, a system or a process is in a steady state if the variables (called state variables) which define the behavior of the system or the process are unchanging in time. In continuous time, this means that for those properties ''p' ...

volume of distribution In pharmacology, the volume of distribution (VD, also known as apparent volume of distribution, literally, ''volume of dilution'') is the theoretical volume that would be necessary to contain the total amount of an administered drug at the same c ...

of 70 liters. Zafirlukast is highly plasma protein bound, 99% bound to

albumin Albumin is a family of globular proteins, the most common of which are the serum albumins. All of the proteins of the albumin family are water- soluble, moderately soluble in concentrated salt solutions, and experience heat denaturation. Alb ...

. Albumin is the most abundant protein found in human plasma and is capable of carrying and transporting drugs (like zafirlukast) throughout the body. ''In vivo'' research indicates that zafirlukast has low

blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that regulates the transfer of solutes and chemicals between the circulatory system and the central nervous system ...

penetration. The blood–brain barrier is a protective system that prevents many chemicals from entering the brain.

Metabolism

Zafirlukast undergoes extensive hepatic metabolism into inactive metabolites. Zafirlukast is primarily metabolized by the enzyme

to a

hydroxylated In chemistry, hydroxylation refers to the installation of a hydroxyl group () into an organic compound. Hydroxylations generate alcohols and phenols, which are very common functional groups. Hydroxylation confers some degree of water-solubility ...

metabolite.

Elimination

Zafirlukast is primarily cleared through biliary excretion at a rate of 20 liters/hour. Zafirlukast is undetectable in urine. The mean terminal half-life ranges 8–16 hours, following linear kinetics up to doses of 80 mg.

Pharmacogenomics

LTC4 synthase

Genetic polymorphisms in the LTC4 synthase promoter may predict response to zafirlukast. The

single-nucleotide polymorphism In genetics and bioinformatics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in a ...

(SNP) A444C (the wild-type DNA base

adenine Adenine (, ) (nucleoside#List of nucleosides and corresponding nucleobases, symbol A or Ade) is a purine nucleotide base that is found in DNA, RNA, and Adenosine triphosphate, ATP. Usually a white crystalline subtance. The shape of adenine is ...

, at the 444th position on the gene, is mutated;

cytosine Cytosine () (symbol C or Cyt) is one of the four nucleotide bases found in DNA and RNA, along with adenine, guanine, and thymine ( uracil in RNA). It is a pyrimidine derivative, with a heterocyclic aromatic ring and two substituents attac ...

is there instead), which is associated with a severe asthma phenotype, has been shown to decrease the clinical response to zafirlukast (both when the genetic alteration was heterozygous or homozygous).

CYP2C9

Zafirlukast is metabolized through the hepatic enzyme

. SNPs that decrease the function of CYP2C9 (such as CYP2C9*3 and CYP2C9*13) may decrease the hepatic clearance of zafirlukast, leading to increased exposure of zafirlukast. Notably, the CYP2C9*3 polymorphism is more commonly encountered in people of south/central Asian ancestry (10.165%) compared to people of Caucasian (7.083%), African American (1.170%), African (1.033%), middle eastern (9.312%), and east Asian (3.365%) ancestry.

Chemistry

Synthesis

Zafirlukast can be synthesized by the following method: Zafirlukast synthesis

Physiochemical properties

Pure zafirlukast is described as a fine, white to pale yellow, amorphous powder. It is practically insoluble in water, slightly soluble in

methanol Methanol (also called methyl alcohol and wood spirit, amongst other names) is an organic chemical compound and the simplest aliphatic Alcohol (chemistry), alcohol, with the chemical formula (a methyl group linked to a hydroxyl group, often ab ...

, and freely soluble in

tetrahydrofuran Tetrahydrofuran (THF), or oxolane, is an organic compound with the formula (CH2)4O. The compound is classified as heterocyclic compound, specifically a cyclic ether. It is a colorless, water- miscible organic liquid with low viscosity. It is ...

dimethylsulfoxide Dimethyl sulfoxide (DMSO) is an organosulfur compound with the formula . This colorless liquid is the sulfoxide most widely used commercially. It is an important polar aprotic solvent that dissolves both polar and nonpolar compounds and is mis ...

, and

acetone Acetone (2-propanone or dimethyl ketone) is an organic compound with the chemical formula, formula . It is the simplest and smallest ketone (). It is a colorless, highly Volatile organic compound, volatile, and flammable liquid with a charact ...

History

Zafirlukast was the first cysteinyl leukotriene receptor antagonist approved in the United States. Zafirlukast was approved in 1996.

Society and culture

Economics

While preliminary evidence suggests that zafirlukast may reduce healthcare costs, the cost-effectiveness of using zafirlukast has not been established.

Brand names

Research

Mechanism of action

There is some research to suggest that zafirlukast actually acts as a partial inverse agonist at the CysLT1 receptor, though zafirlukast is still classified as an antagonist at this receptor. The possible clinical significance of this effect, if true, is unknown.

Other indications

There is some evidence that suggests that zafirlukast may be beneficial in the treatment of chronic urticaria (hives), whether due to a known cause such as cold-exposure or due to an unknown cause (idiopathic). A pilot study indicated that zafirlukast may be of some benefit in

cystic fibrosis Cystic fibrosis (CF) is a genetic disorder inherited in an autosomal recessive manner that impairs the normal clearance of Sputum, mucus from the lungs, which facilitates the colonization and infection of the lungs by bacteria, notably ''Staphy ...

. In the setting of chronic obstructive pulmonary disorder (COPD), a disease characterized by chronic inflammation of the lungs, zafirlukast has been shown to improve lung function.

Veterinary use

Zafirlukast is sometimes used for the treatment of bronchial asthma in cats.

References

External links

* {{Portal bar , Medicine Drugs developed by AstraZeneca Leukotriene antagonists Acylsulfonamides Carbamates Cyclopentanes Indoles Phenol ethers