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Indo American Journal of Pharmaceutical Research, 2014

ISSN NO: 2231-6876

CURRENT STATUS OF LEUKOTRIENE ANTAGONISTS IN BRONCHIAL ASTHMA


Priyanka Joshi , Dr. Rajesh Pandey , Dr. Jasbir Singh , Dr. Kuldip Singh Sodhi
Department of Biochemistry, Maharishi Markandeshwar Institute of Medical Science and Research (MMIMSR), Mullana, Ambala,
Haryana, India. Pin- 133207.
ARTICLE INFO
Article history
Received 09/12/2014
Available online
19/12/2014

Keywords
Bronchial Asthma,
Leukotrienes,
Antagonists,
Montelukast,
Zafirlukast.

ABSTRACT
Leukotrienes are released by several cell types and can cause bronchoconstriction and
inflammation. Leukotrienes play an important role in the pathogenesis of bronchial asthma.
The cysteinyl-leukotrienes (C4, D4 and E4) are able to induce all components of the
asthmatic reaction. Leukotriene antagonists competitively block leukotrienes receptors on
bronchial smooth muscle. The synthesis of adequate receptor antagonists stimulated
expectations to develop new and especially effective anti-asthmatic drugs. The results of the
first generation compounds were not encouraging. Newer compounds (e.g. montelukast,
zafirlukast) are able to protect from bronchoconstriction inducing noxes (especially in
analgesic intolerance), to improve chronic asthma (symptoms scores, long-time respiratory
rescue medications). Especially remarkable are recent data which prove anti-inflammatory
activities. Studies are underway to define the position of these drugs in generally accepted
recommendations on asthma therapy, singly or in combination with conventional antiasthmatics.

Copy right 2014 This is an Open Access article distributed under the terms of the Indo American journal of Pharmaceutical
Research, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Please cite this article in press as Priyanka Joshi et al. Current Status of Leukotriene Antagonists In Bronchial Asthma. Indo
American Journal of Pharm Research.2014:4(12).

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Corresponding author
Priyanka Joshi
(M.Sc. MLT, Intern),
Department of Biochemistry,
Maharishi Markandeshwar Institute of Medical Sciences and Research (MMIMSR),
Mullana, Ambala, Haryana, India. Pin- 133207
07206403648
priyankaj725@gmail.com

Vol 4, Issue 12, 2014.

Priyanka Joshi et al.

ISSN NO: 2231-6876

INTRODUCTION
Bronchial asthma or simply asthma is a syndrome characterized by airflow obstruction that varies markedly, both
spontaneously and with treatment. Asthma is one of the most common diseases globally and currently affects approximately 300
million people worldwide. The prevalence of asthma has risen in affluent countries over the last 30 years but now appears to have
stabilized, with approximately 10-12% of adults and 15% of children affected by the disease. [1] As per National Family Health Survey
of India, 2468 persons per 100,000 population are reported to be suffering from asthma, which is considerably higher in rural areas
(2649 per 100,000 population) than in urban areas (1966 per 100,000 population). [2] According to the Global Burden of Asthma
Report (GINA), over 50 million suffer from asthma in Central and Southern Asia and an absolute 2% increase in the prevalence of
asthma in India would result in an additional 20 million people with this disease. [2] The epidemiologic observation suggests that there
is a maximum number of individuals in the community, who are likely to be affected by asthma, most likely by genetic predisposition.
In childhood, twice as many males as females are asthmatic, but by adulthood the sex ratio has equalized.
RISK FACTORS AND TRIGGERS
Asthma is a heterogeneous disease with interplay between genetic and environmental factors. Several risk factors have been
implicated (Table 1)[1].
Table 1: Risk factors and triggers involved in asthma.
Endogenous factors
Genetic predisposition
Atopy
Airway hyper responsiveness
Gender
Ethnicity
Obesity
Early viral infections

Environmental factors
Indoor allergens
Outdoor allergens
Occupational
sensitizers
Passive smoking
Respiratory infections

Triggers
Allergens
Upper respiratory tract viral infections.
Exercise and hyperventilation.
Cold air
Sulfur dioxide and irritant gases
Drugs (-blockers, aspirin)
Stress
Irritants (household sprays, paint fumes)

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LEUKOTRIENES
Leukotrienes (LTs) are unsaturated fatty acids generated by action of the 5-lipoxygenase (5-LO) enzyme on the cell
membrane-bound arachidonic acid (AA). Two classes of LTs are derived from the 5-LO pathway, the nonpeptide LTs LTA4 and
LTB4, and the cysteinyl-LTs LTC4, LTD4 and LTE4. Once secreted extracellularly, LTs act on specic receptors, after which they
are rapidly degraded, with a very short half-life. In particular, the activation of the recently cloned Cys-LT1 receptor, whose
expression has been demonstrated on bronchial smooth muscle cells and various inammatory cell types in the lung, is responsible for
the bronchoconstrictive and proinammatory actions, including increased microvascular permeability with oedema and increased
mucus secretion, possessed by cysteinyl-LTs.[3]
Pharmacological research for the identication and development of anti-LT drugs started towards the end of the 1970s and
the beginning of the 1980s, soon after the discovery by Samuelson and his group at the Karolinska Institute in Sweden of the chemical
nature and potent activity of LTs. Since 1987, clinical studies on various compounds with anti-LT properties were initiated, and just
10 years later the rst anti-LT drugs zileuton, pranlukast, zarlukast, and montelukast were almost contemporarily commercialized.
Zileuton blocks the synthesis of LTs by inhibiting the 5-LO enzyme, whereas pranlukast, zarlukast, and montelukast are all orally
active cysteinyl-LT receptor antagonists (LTRA).
Recommended adult doses are 2040 mg twice daily for zarlukast and 10 mg once daily for montelukast. Only montelukast
is licensed for use in children, with a 5-mg dose for children 612 years of age and a 4-mg dose (only in USA) for children 25 years
of age. A number of studies have demonstrated that LTRAs show bronchodilating and anti-inammatory properties, that make these
drugs ideal candidates for the treatment of asthma. [4]
In fact, they are capable of blunting both the early and late bronchoconstrictive response and the cellular inammatory
response to inhaled allergen, and to prevent the exercise induced and the aspirin induced bronchoconstriction, without evidence of
tolerance with prolonged use.[2] Finally, long-term treatments with LTRAs are able to reduce both the blood and sputum eosinophilia
in both adults and children with asthma.[4]
Cysteinyl leukotrienes are important pro-inflammatory and bronchoconstrictor mediators in the pathogenesis of asthma,
while leukotriene receptor antagonists (LTRAs) demonstrate hybrid anti-inflammatory and bronchodilatory properties.[5] Current
international guidelines [6] recommend using an LTRA as first-line therapy in patients with mild, persistent asthma, or as second-line
therapy in conjunction with inhaled corticosteroids, as an alternative to increasing the dose of inhaled corticosteroids. Cells that do not
express 5-LO, including platelets, erythrocytes, endothelial cells and epithelial cells, also have the capacity to produce cysteinyl-LTs
and/or LTB4 through the transcellular metabolism of LTA4 synthesized by activated neutrophils.[7] After their intracellular formation,

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The allergens that lead to sensitization are usually proteins that have protease activity, and the most common allergens are
derived from house dust mites, cat and dog fur, cockroaches, grass and tree pollens, and rodents. Atopy is genetically determined
production of specific IgE antibody, with many patients showing a family history of allergic diseases.

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Priyanka Joshi et al.

ISSN NO: 2231-6876

cysteinyl-LTs and LTB4 are released to the extracellular space through specific carrier-proteins that are potential targets for future
antileukotriene drugs.[8]
Cysteinyl-LTs are functionally involved in airway remodeling that includes eosinophil cell inflammatory response, airway
smooth muscle cell hyperplasia, mucus gland hyperplasia, mucus hypersecretion, and collagen deposition beneath the epithelial layer
and in the lung interstitium at sites of leukocytes infiltration. [9, 10]
LEUKOTRIENE RECEPTOR ANTAGONISTS
Selective CysLT1 receptor antagonists that have been approved for clinical use in asthma include montelukast, zafirlukast
and pranlukast (Table 2).[11] Zileuton, a 5-LO inhibitor, has been approved for the prevention and chronic treatment of asthma in
adults and children 12 years of age and older in the United Kingdom and USA. Montelukast is the most prescribed CysLT1 receptor
antagonist in Europe and the USA, whereas pranlukast is only marketed in Japan and other Asian countries. Zafirlukast was the first
anti-LT that was approved in Europe, but it is not frequently prescribed due to possible food and drug interactions, and its twice daily
administration regimen.[11, 8] The fact that selective CysLT1 receptor antagonists and 5-LO inhibitors have similar efficacy in shortterm treatment studies and challenge models indicates that most of the antiasthmatic effects of anti-LTs are due to CysLT1
antagonism.[8] The use of zileuton is limited because of a small, but distinct, incidence of hepatic enzyme elevation, which is not
observed with montelukast, and the short half-life, requiring four daily administrations.[8] A twice-daily controlled-release formulation
of zileuton has been approved by the U.S. Food and Drug Administration (FDA). [12]
At least two aspects of selective 5-LO inhibitors concerning the inhibition of LTB4 synthesis deserve further investigation:
their effects on airway hyper responsiveness (AHR) in patients with asthma [13, 14], that is slightly affected by CysLT 1 antagonists [15];
the potential efficacy of 5-LO inhibitors in rhinitis and rhinopolyposis as these drugs are very effective in reducing nasal symptoms in
patients with aspirin-sensitive asthma (ASA).[13]
Table 2: Salient pharmacological characteristics of antileukotrienes [11].
S.
No.
1.

Drug

2.

Pranlukast

CysLT1
receptor
antagonism

3.

Zafirlukast

CysLT1
receptor
antagonism

Particularly
effective
in
exercise-induced
asthma,
ASA,
allergen- induced asthma; as
add-on therapy with ICS

Zileuton

LO
inhibition

Particularly
effective
in
exercise-induced asthma and
ASA

Montelukast

Mechanism
of action
CysLT1
receptor
antagonism

Benefits

Side effects

Dose

Comments

As monotherapy in children
with mild persistent asthma;
particularly
effective
in
exercise-induced
asthma,
ASA,
allergen-induced
asthma; as add-on therapy
with ICS
Particularly
effective
in
exercise-induced
asthma,
ASA,
allergen-induced
asthma; as add-on therapy
with ICS.

Headache,
abdominal
pain;
possible association
with Churg- Strauss
syndrome.

Adults: 10 mg
o.d., Children 6 to
14 years of age: 5
mg o.d., children
2 to 5 years of
age: 4 mg o.d.

Most
widely
prescribed
CysLT1 receptor
antagonist.

Abdominal
pain,
liver
enzymes
elevations; possible
association
with
ChurgStrauss
syndrome
Headache,
abdominal
pain,
liver
enzymes
elevations; possible
association
with
Churg-syndrome
Headache,
abdominal
pain;
liver
enzymes
elevations (5%)

Adults: 225 mg
b.i.d.

Only marketed in
Asia.

Children 12
years of age and
adults: 20 mg
b.i.d. Children 5
to 11 years of age:
10 mg b.i.d.
Adults
and
children 12 years
of age and older:
600 mg q.i.d.

First
CysLT1
receptor
antagonist to be
approved;
food
and
drug
interactions
Virtually
abandoned
because of poor
compliance
and
hepatic toxicity.

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COMPARATIVE ASPECTS
CysLT1 receptor antagonists are less effective than inhaled glucocorticoids as first-line agents in both adults [16] and children
with asthma.[17] In patients with asthma who are not sufficiently controlled with a constant dose of inhaled budesonide alone, add-on
therapy with montelukast improves asthma control[18] to a level comparable to that achieved by doubling the dose of budesonide. [19]
The advantage of this therapeutic strategy would be the reduced risk of side effects due to long-term administration of high-dose
inhaled glucocorticoids.[19] In patients whose symptoms remain uncontrolled with inhaled fluticasone alone, the addition of
montelukast is a therapeutic option [20], although the addition of a long-acting 2-agonist is generally more effective than a CysLT1

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Abbreviations:
ASA = aspirin-sensitive asthma; CysLT = cysteinyl-leukotrienes; ICS = inhaled corticosteroids.

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receptor antagonist for preventing exacerbations requiring systemic steroids, and for improving lung function, symptoms and the use
of rescue 2 agonists.[21, 22] In patients with well-controlled asthma based on symptoms and lung function testing, the addition of
pranlukast to the combination of inhaled glucocorticoids and long-acting 2-agoinst gives better control of airway inflammation
compared with therapy with the combination of inhaled glucocorticoid/long-acting 2-agoinst alone.[23, 24]
LTRAs show some anti-inammatory activity and, in this context, montelukast is able to prevent in asthmatic patients both
the early and late asthmatic response to inhaled allergen [25] and to reduce with long-term treatments the eosinophil levels both in the
blood [26] and in the airways.[27] Oral montelukast, 10 mg once a day, with inhaled beclomethasone, 200 mg twice a day, for 12 weeks
has demonstrated inhaled beclomethasone to be slightly superior to montelukast in improving clinical and functional indexes in
patients with mild to moderate asthma.[28]
There are limited prospective, comparative studies examining the safety of CysLT 1 receptor antagonists in pregnancy.[29]
Montelukast does not appear to increase the baseline rate of major malformations. [29, 30] The lower birth weight observed in infants
born to women treated with montelukast could be attributed to severity/control of the maternal asthma. [29, 30]
Treatment with inhaled fluticasone (100 g b.i.d. for four weeks) reduces LTE 4 concentrations in EBC by 18% in children
with intermittent and mild persistent asthma. The therapeutic response to CysLT 1 receptor antagonists as well as to inhaled
glucocorticoids in both adults and children with asthma is variable. In children with mild persistent asthma, montelukast withdrawal
can result in enhanced airway inflammation, as reflected by increased fractional exhaled nitric oxide concentrations (F ENO) and
worsening of lung function.[31]

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CONCLUSIONS AND FUTURE PERSPECTIVES


Bronchial asthma is a multifaceted disease with respect to its etiology as well as its treatment. [32] Most of our knowledge of
the pathophysiological role of LTs in asthma is currently limited to CysLT1 receptor-mediated effects, whereas the role of the CysLT2
receptor is largely unknown. The identification of responders to CysLT1 receptor antagonists might be relevant for a more rational
therapy of patients with asthma. The bottom line is that regular treatment with LTRAs have proved to be benecial in asthmatic
patients by improving airway function, asthma symptoms, as-needed use of rescue medications, and quality of life. At present,
international guidelines for asthma management recommend that LTRAs should be used for regular treatment in patients with
moderate asthma not completely controlled by inhaled corticosteroids in order to improve the asthma control, in patients with
moderate asthma well controlled by inhaled corticosteroids in order to try to reduce the dose of inhaled corticosteroids, and, as
monotherapy, in patients with mild persistent asthma in order to reduce airway inammation and minimize symptoms and use of
rescue medications.[33]

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