The inflammation also causes an associated increase in the existing hyper-responsiveness to a variety of stimuli. Reversibility of airflow limitation may be incomplete in some patients with asthma. ^[7]

TYPES

Based on clinical grounds and measurement of IgE, there are two major types of bronchial asthma; ‘extrinsic (atopic, allergic) bronchial asthma’ in which symptoms develop only on exposure to a specific allergen, occurs since childhood, due to genetic and external stimuli. In case of ‘intrinsic (non-atopic, idiosyncratic) bronchial asthma’ there is no detectable allergic aetiology, it occurs mostly in middle age. The Table No. 1 helps to easily understand the major difference in extrinsic and intrinsic bronchial asthma.^[8]

Table No.1: Characteristics of extrinsic and intrinsic bronchial asthma.

PARAMETER	EXTRINSIC TYPE	INTRINSIC TYPE
Allergens	Present (dust, pollens, danders etc.)	None
Positive skin test	Yes	No
Serum IgE levels	Elevated	Normal
Age group affected	Children and youth	Older adults
Pattern of bronchial asthma	Intermittent	Continuous
Family history of allergy	Common	Uncommon
Aspirin-sensitivity	None	Present

PATHOGENESIS

Pathogenesis of asthma is complex and it involves inflammation and remodelling of the airways. It mainly consists of two phases: an immediate and a late (delayed) phase.

The immediate phase of the asthmatic attack

Immediate phase involves early reaction which is rapid in onset, reaching maximum in 15-30 min. after challenge and recovering over next 24 hours. Degranulation of mast cells with mediator release is probably an important mechanism involved in early response.^[9]

In susceptible individuals, allergen interacts with dendritic cells and CD4+Tcells, leading to the development of Th0 helper lymphocytes, which give rise to a clone of helper Th2 lymphocytes. Th2 lymphocytes then generate cytokines such as such as interleukin (IL)-5, IL-4 and IL-13.

The Th2 cytokines that are released do the following:

· They attract other inflammatory granulocytes, especially eosinophils, to the mucosal surface. IL-5 and granulocytes-macrophage colony-stimulating factor (GM-CSF) prime eosinophils to produce cysteinyl leukotrienes, and to release granule protein that damage the epithelium. This damage is one cause of bronchial hyper-responsiveness.

· They also promote IgE synthesis and responsiveness in some asthmatics. (IL-4 and IL-13 ‘switch’ B cells to IgE synthesis and cause expression of IgE receptors on mast cells and eosinophils; they also enhance adhesion of eosinophils to endothelium).

Some atopic asthmatics, in addition to these mechanisms; they make allergen-specific IgE that binds to mast cells in the airways. Inhaled allergen cross-links IgE molecules on mast cells, triggering degranulation with release of histamine and leukotriene B4, and prostaglandins (PG)D₂. The first two are powerful bronchoconstrictors to which asthmatics are especially sensitive because of their airways hyper-responsiveness. ^[10]This results in bronchospasm, local vasodilatation, increased capillary permeability and chemotaxis with consequent influx of more inflammatory cells into the walls of the bronchi. ^[9]

Other mediators released during early phase include IL-4, IL-5, IL-13, macrophage inflammatory protein-1α and tumour necrosis factor (TNF)-α. Various chemotaxins and chemokines attract leukocytes- particularly eosinophils and mononuclear cells into the area, setting the stage for the delayed phase.^[10]

The late phase of the asthmatic attack

Late phase bronchoconstriction response begins 4-6 hours after challenge that lasts for upto 24 hours. During this late phase reaction, the airway become non-specifically hyperresponsive to stimuli such as histamine, which may last up to two weeks after a single allergen exposure.^[9]The late phase or delayed response may be nocturnal. It is, in essence, a progressing inflammatory reaction, initiation of which occurred during the first phase, the influx of Th2 lymphocytes being of particular importance. The inflammatory cells include activated eosinophils. These release cysteinyl leukotrienes; interleukins IL-3, IL-5 and IL-8; and the toxic proteins, eosinophil cationic protein, major basic protein and eosinophil-derived neurotoxin. These play an important part in the events of the late phase, the toxic proteins causing damage and loss of epithelium. Other putative mediators of the inflammatory process in the delayed phase are adenosine, induced NO (nitric oxide) and the neuropeptides.^[10]

The acute inflammatory response usually resolves with the repair process restoring normal structure and function. But in chronic asthma, the recovery is incomplete due to ineffective repair. This leads to remodelling of the airway structure. Persistent epithelial damage and the loss of its protective function expose the deeper airway structures to further insults, leading to persistent inflammation and cellular infiltration. Various mediators released cause angiogenesis, smooth muscle proliferation, fibrosis and thickening of airways, leading to persistent obstruction to airflow. Various enzymes and growth factors are important in this remodelling process.^[9]Growth factors released from inflammatory cells act on smooth muscle cells, causing hypertrophy and hyperplasia, and the smooth muscle can itself release proinflammatory mediators and autocrine growth factors.^[10]

DIAGNOSTIC EVALUATION OF BRONCHIAL ASTHMA

Bronchial asthma can often be diagnosed on the basis of a patient’s symptoms and medical history. Presence of any of following mentioned signs and symptoms increase the suspicion of bronchial asthma:

· Wheezing

· Cough, which worse particularly at night

· Recurrent wheeze

· Recurrent difficult breathing

· Recurrent chest tightness

· If above mentioned symptoms occur or worsen at night, awakening the patient.^[11]

· In addition, if these symptoms occur or worsen in the presence of

§ Animals with fur

§ Aerosol chemicals

§ Changes in temperature

§ Domestic dust mites

§ Drugs (aspirin, β blockers)

§ Exercise

§ Pollen

§ Respiratory infections

§ Smoke

§ Strong emotional expression. ^[12]

Bronchial asthma tests may include:

· Allergy testing: It may be helpful to identify allergens in people with persistent asthma. It can be performed by any of following mentioned test.

§ Allergy Skin Prick Test- This is the most common allergy test. With this test, small amounts of an allergy trigger are given by pricking or puncturing the skin on the arm or the back with a needle or similar device. If an individual is allergic to that substance, a reaction in the form of a wheal- a red, itchy bump, usually appears within 15 minutes. The bigger the bump, the more sensitive the person is to that specific allergen.

§ Allergy Blood Test-Allergies can also be determined by blood tests, such as the radioallergosorbent test (RAST) and other blood tests that use radioactive or enzyme markers to determine whether IgE antibodies are present.^[13]

· Food allergies and elimination diet test: Food allergies can be diagnosed through an elimination diet in which suspected foods are eliminated from the diet for a period of four to seven days. If the allergic reaction does not cease during the elimination diet, additional foods are withdrawn until symptoms do stop. At that point, new foods are added back into diet until the symptoms reappear. ^[13]

· Arterial blood gas (ABG): An ABG is a blood test that is performed using blood from an artery. This test measures the arterial oxygen tension (PaO₂), carbon dioxide tension (PaCO₂), and acidity (pH). A low PaO₂ indicates that the patient is not oxygenating properly and is hypoxemic. High PaCO₂indicates under-ventilation. ^[14]

· Blood tests: It is done to measure eosinophil count in blood. Presence of peripheral blood eosinophilia is a characteristic of both allergic and non-allergic asthma.^[15]

· Chest X-ray: Chest X-ray is done to rule out any other diseases that may be causing similar symptoms.^[16]

· Lung function tests: Measurements of lung function by spirometer or peak expiratory flow(PEF) measurements provide an assessment of the severity, reversibility and variability of airflow limitation and help confirm the diagnosis of asthma.^[12]

§ Spirometry-

It is lung function test help to measure breathing capacity, assess asthma control and diagnosis. In this test patient have to breathe into a device called a spirometer to measure forced expiratory volume in one second (FEV₁). Measurements taken before and after administration of a short-acting β₂ agonist (SABA) bronchodilator. An increase in FEV₁of ≥12% (or ≥200ml) after administration of a bronchodilator indicates reversible airflow limitation consistent with asthma.

The absence of reversible airflow limitation does not exclude the diagnosis of bronchial asthma. The use of long-acting β₂ agonists (LABAs) or severe inflammation of the airways can prevent a response to the SABA bronchodilator.^[12,
17]

§ Peak Expiratory Flow (PEF) measurement –

When diagnosing asthma, PEF is not a substitute for spirometry. In this test patient forcefully exhale into the device called peak flow meter to measure the force of air patient can expel out of his lung. It can be an important aid in both diagnosis and monitoring of asthma. The diagnosis of bronchial asthma is supported if: PEF varies by at least 20% (or ˃ 60 L/minute) for 3 days in a week over several weeks or PEF increases by at least 20% in response to bronchial asthma treatment. ^[17]

MANAGEMENT OF BRONCHIAL ASTHMA

There is no cure for asthma, but in majority of cases, well controlled asthma can be achieved with proper management. Objectives of management of asthma includes:

· Symptomatic relief in acute attacks

· Preventing future attacks

· Normal pulmonary function between two attacks.

Objectives of management of asthma can be achieved through pharmacological management which includes use of drugs such as bronchodilators, inhaled corticosteroids, anti-allergic, mast cell stabilizers, anti-leukotrienes and monoclonal antibody.^[18]

Pharmacological management:

Because asthma is a chronic condition, it usually requires continuous medical care. The right medications for patient depend on a number of things, including age, symptoms, asthma trigger and what seems to work best to keep asthma under control. The pharmacological agents used to treat asthma are divided into two broad categories:

(i) Quick-relief (rescue) /reliever drugs:

Quick-relief medications can stop bronchial asthma symptoms, but they do not control airway inflammation that causes the symptoms. These are used during attack or at the first sign of any bronchial asthma symptoms for immediate relief. These are mainly bronchodilators which alleviate smooth muscle constriction.

· Short-acting inhaled β2-agonists

· Anti-cholinergics. ^[16,19]

(ii) Controller/ preventer drugs: If bronchial asthma attacks are severe, unpredictable or flare up more than twice a week, then bronchial asthma treatment with a long-term control medication is recommended. These drugs are used to control the underlying airway inflammation and prevent symptoms and attacks in patients with moderate to severe bronchial asthma. These are mainly anti-inflammatory drugs taken every day even if patients do not have symptoms.

· Methyl xanthines

· Inhaled corticosteroids

· Long-acting inhaled β₂-agonists ( never taken alone)

· Leukotriene modifiers

· Immunomodulators. ^{[16, 20]}

Each type is described in more detail below.

BRONCHODILATORS

In health the bronchial calibre is mainly controlled by the balance between the parasympathetic and sympathetic nervous systems. Bronchodilators affect airway smooth muscle tone by acting on ANS and signalling pathways. Sympathetic activation (mediated primarily by β2-adrenergic receptors) results in bronchodilatation, while parasympathetic stimulation (mediated by muscarinic acetylcholine receptors) results in bronchoconstriction.^[21]

Sympathomimetic agents (β-adrenergic drugs):

Sympathomimetics cause rapid relaxation of airway smooth muscle, hence β–adrenergic agents are the most widely used agents for asthma. These differ in their potency, duration of action, mode of elimination and side effects. Sympathomimetics like adrenaline, isoprenaline and ephedrine are agents with mixed β₁ and β₂ agonistic action; have been used for the treatment of asthma and have a prompt effect due to their β₂effects, but due side effects such as palpitation, cardiac arrhythmia, tachycardia, angina, anxiety, sweating and tremors their use has decreased. Hence selective β₂–agonists are the drugs of choice to minimize side effects.^[22]

Now specific β₂ stimulants like salbutamol are available, which produce bronchodilatation with minimal cardiac side effects.Β₂-adrenoceptor activity is mediated by cAMP. The β₂-adrenergic drugs increase adenylcylase activity, which promotes the conversion of ATP to active cyclic adenosine monophosphate (c-AMP), and this in turn decreased intracellular calcium, increased membrane potassium conductance, and decreased myosin light chain kinase activity. The combination of these leads to smooth muscle relaxation and bronchodilatation.^{[23, 24]}Cyclic-AMP also inhibits the secretion of SRS –A (slow reacting substance of anaphylaxis), histamine, and the eosinophil chemotactic factor (ECF-A) from the mast cells. ^[25]

These β₂-agonists can further classified as short-acting and long-acting β2 agonists.

(i) Short-acting β2-agonists:

The short acting selective β2 adrenergic stimulants are the preferred rescue drugs. E.g. Salbutamol,isoetharine, terbutaline, fenoterol, bitolterol. These are very effective for treating acute attacks of bronchial asthma and prevention of exercise-induced asthma. They are less useful when taken regularly and should be used only as needed. They are safe during pregnancy. Salbutamol described as prototype of this class.^[26]

Salbutamol – Salbutamol is the most commonly used drug and can be given orally, IV, IM and by inhalation in meter doses. It is virtually devoid of cardiovascular effects in usual doses. The oral dose is 2-4 mg three times daily. In aerosol, the doses are small and safer. For inhalation 100-200 µg may be repeated 4 hourly with a maximum of 8 inhalations in 24 hours.^[27]It has prominent bronchodilator action of rapid onset (1-5min. after inhalation) and a single inhalation dose (100 µg) lasts for about 4-6 hours. Salbutamol is used in mild intermittent asthma on ‘as needed’ basis. ^[26]

(ii) Long-acting β2 agonist:

Salmeterol and formaterol are long acting β_2-agonists and their onset of action is slow (10-15min.) effect lasts for 12 hours.^[28] Therefore, they are used in chronic bronchial asthma.

Salmeterol –

Salmeterol is about 50 times more selective than salbutamol as a β2-agonist.Its dose 50µg by inhalation bid, may be increased to 100 µg bid in severe cases. Formoterol is similar in indications as salmeterol and administered by inhalation in a dose of 12 µg bid, increased to 24 µg bid in more severe cases. ^[^27]It is used as the drug of choice in the prevention of nocturnal bronchial asthmatic attacks^[29]and those induced by exercise.^[30]In adults, when added to inhaled steroids they improve symptoms. In children this benefit is uncertain.^[31] They should not be used without an accompanying steroid due to an increased risk of severe symptoms, including exacerbation in both children and adults. ^[32-34]

Anti-cholinergics:

E.g. Atropine, Ipratropium bromide, oxitropium bromide, tiotropium bromide. These are competitive antagonists at muscarinic acetylcholine receptors; leading to broncho relaxation and decreased mucus secretion. There are several subtypes of muscarinic receptors, three of these M1, M2, and M3 are predominantly localized in the smooth muscle of the airways, although higher in density in the proximal airways and in the submucoal glands.^[35] However, except for occasional resistant cases, anticholinergics are now not used in the treatment of asthma as they reduce bronchial secretions, whereby residual secretions become viscid and difficult to remove from bronchioles. ^[22]

Atropine-

Because inhaled atropine is highly absorbed across the respiratory epithelium, it causes many systemic anticholinergic effects. Hence because of side effects (tachycardia, xerostomia, blurred vision, constipation, difficulty in urination) and slow onset of action, atropine today has no place in the management of bronchial asthma.^[22,
27]

Ipratropium bromide –

It is a quaternary ammonium salt derived from atropine.Unlike atropine, ipratropium is not significantly absorbed, and appears to have fewer systemic adverse effects.But inhaled ipratropium can cause dry mouth and g.i.t. upset.^{[36, 37]}It is specifically useful in cardiac patients. It is used as an aerosol in dose of 200µg.^[22]Addition of Ipratropium to beta-agonist therapy offers a significant, albeit modest, improvement in pulmonary function, even reduction in the rate of hospital admissions. ^[38]Current guidelines recommend the use of a combination of beta2 agonists and anti-cholinergics, particularly for patients with acute severe or life threatening asthma. ^{[39, 40, 41]}A combination of ipratropium and a β₂ agonist by inhalation produces additive effects because ipratropium acts on large and medium sized bronchi whereas β₂ agonist act on the smaller bronchi. ^[26]

Tiotropium bromide-

Tiotropium bromide is a once-daily, long-acting anticholinergic with high potency as a selective antagonist at the muscarinic acetylcholine receptors and with kinetic selectivity. Tiotropium rapidly dissociates from the auto-inhibitory M2 receptors, but slowly dissociates from M1 and M2 receptors, which mediate acetylcholine-mediated bronchoconstriction and mucus secretion. This increased duration of binding at the M3 receptors results in prolonged bronchodilatation, allowing a once-daily dose compared with the three to four doses per day previously necessary with ipratropium. ^[42]

Methyl xanthines and its derivatives:

E.g. Theophylline, aminophylline, diprophylline, deriphyllin. These are a nonselective phosphodiesterase (PDE) inhibitor. PDE type III and IV break downcyclic adenosine monophosphate (cAMP) into 5-AMP, whereas PDE V break down cyclic guanosine monophosphate (cGMP) into 5-GMP.Inhibition of this enzyme results in accumulation of cGMP and cAMP, which in turn produces bronchodilatation and inhibition of inflammatory cells.^[43]Another mechanism by which xanthines produce bronchodilatation involves blockage of adenosine receptors situated on various organs and prevent adenosine mediated stimulation of these receptors and leads to bronchodilatation. Additionally they improve mucociliary clearance. Improve ventilatory activity in bronchial asthma.^[44]

Due to narrow therapeutic range these agents are not used as first line agents in bronchial asthma. In refractory cases and in severe attacks xanthines are used by oral or intravenous (i.v.) route. Pulse rate and BP must be watched during intravenous infusion.^{[44, 45]}

During asthma attack:

Aminophylline is a combination of theophylline and ethylenediamine, and is one of the most effective drugs used as a prophylactic and in severe asthma. It is also effective in patients who do not respond to catecholamines. It is used as 250-500mg in 10 ml solution by slow i.v. injection or i.v. infusion as a first line treatment in patients with severe asthmatic attacks.^[22]If treatment with inhaled selective β2 agonists in adequate doses fails to relieve an acute attack in about half to one hour, aminophylline (xanthine derivative) is administered by i.v. infusion in a dose of 5 mg/kg over 15-30 min., followed by 0.5-1 mg/kg/hour for several hours.^[26]

Prevention of acute attacks-Therapeutic range of theophylline is narrow hence slight increase in concentration can increase the magnitude of effects and side effects in large proportion. Slow release preparations of theophylline given in the evening may be useful as adjuncts in preventing nocturnal attacks.^{[44, 46]}

ANTI-INFLAMMATORY

Inhaled corticosteroids (ICS):

With the current paradigm of asthma as a chronic inflammatory disorder of the airways, ICS have become the preferred therapy for all patients (children, teens, and adults) with persistent asthma-mild, moderate, and severe. Inhaled steroids are cost effective in the management of asthma. In general they are part of daily asthma treatment and are used every day. Inhaled corticosteroids help to control narrowing and treat inflammation of airway and only very small amounts of the medicine are absorbed into body. So these medicines don’t tend to cause the serious side effects, such as weakening of the bones; that corticosteroids can cause when taken in liquid, pill, or injection form (systemic corticosteroids).^[47]

Inhaled corticosteroids are the most powerful and most effective medicine for long-term control of asthma in most people. When taken consistently, they improve lung function, improve symptoms, and reduce asthma attacks and admissions to the hospital for asthma. ^[48]

The exact mechanism is not known but they are considered to act by (i) anti-inflammatory property at multiple levels, (ii) preventing the release of some mediators like leukotrienes, cytokines, PGs and (iii) reducing hyper reactivity. They do not have a bronchodilator effect and onset of action is also slow.^[22]Corticosteroids alter the transcription of many genes. In general, corticosteroids increase the transcription of genes coding for the β2-adrenergic receptor and a number of anti-inflammatory proteins such as IL-10, IL-12, and IL-1 receptor antagonist (IL-1ra). Corticosteroids decrease the transcription of genes coding for many pro-inflammatory proteins; examples include IL-2, IL-3, IL-4, IL-5, IL-6, IL-11, IL-13, IL-15, TNF-α, GM-CSF, SCF, endothelial adhesion molecules, chemokines, inducible nitric oxide synthase (iNOS), cyclooxygenase (COX), phospholipase A2, endothelin-1, and NK1-2 receptor. IL-4 is an important in inducing B-cell production of IgE, while IL-5 is an important recruiter of eosinophils. Therefore, inhibition of IL-4 and IL-5 markedly reduces the inflammatory response in asthma.^[45]

ICS monotherapy is recommended as first-line treatment for persistent asthma for all age groups, including children. One study noted that children who use inhaled corticosteroids do not have an increased risk for broken bones (fractures) compared to those who are not using the medicine. ^[49]The full potential of ICS monotherapy should be explored before alternative treatments such as leukotriene modifiers and LABA are attempted. Regular use of ICS can reduce rates of asthma exacerbation and prevent increase in hyperresponsiveness ^[50]and accelerated loss of lung function. ^[51] ICS taken in combination with other agents such as theophylline,^[52]long acting β₂–agonists, and leukotriene antagonists is useful.^[53]

Unwanted effects:

Chronic use of steroids by inhalation can lead to oropharyngeal candidiasis ( T lymphocytes are important in protection against fungal infection), and sore throat and croaky voice, but use of ‘spacing’ devices, which decrease oropharyngeal deposition of the drug and increase airway deposition, reduce these problems. ^[54]

Beclomethasone dipropionate:

Beclomethasone dipropionate HFA inhalation aerosol is indicated in the maintenance treatment of asthma as prophylactic therapy in patients 5 years of age or older. ^[55]The combination of larger particle sizes with poor inhaler technique leads too much of the drug settling in the oropharynx. Beclomethasone dipropionate HFA does not require a spacer and is provided in a liquid solution, resulting in small particle sizes (1.1 mm). Consequently, it has been shown that more of the drug reaches the entire lung, including both large and small airways and reducing oropharyngeal adverse effects, even if the patient exhibits poor technique.^{[56, 57]}

Leukotriene modifiers:

Leukotrienes (LT₄, LTD₄, LTE₄) liberated during inflammation are more potent and longer acting than histamine as bronchoconstrictors. They increase mucus secretion, decrease mucociliary clearance and increase vascular permeability. Leukotrienes modifiers have no bronchodilator effect, but have preventive effect. Their use with corticosteroids may permit a decrease in the dose of corticosteroids.^[22,
26]

Drugs that modify the leukotriene system are:

(i) Competitive antagonist of LT₁ receptor: Montelukast, Zafirlukast, Pranlukast.

(ii) Leukotriene synthesis inhibitor: Zileuton.

(i) Competitive antagonist of LT₁ receptor:

Leukotriene receptor antagonists have a unique profile in that they are a hybrid of an anti-inflammatory and bronchodilator drug, and they can be taken as a tablet once or twice daily. The published data with montelukast or zafirlukast show good anti-asthmatic activity over a wide spectrum of asthma severity either as monotherapy or with inhaled steroids.^[58]

Montelukast

Montelukast sodium is an oral, potent and selective antagonist at cysteinyl leukotriene₁ receptors (CysLT₁Rs), which mediates the bronchoconstrictors and proinflammatory actions of the CysLTs in asthma.^[59]

Montelukast provides significant protection against Exercised-induced bronchoconstriction at 2 hours after a single oral dose. ^[60]In susceptible individuals, montelukast has been shown to inhibit bronchoconstriction provoked by aspirin,^[61]inhaled allergen ^[62] and exercise (both in children and adults).^[63-65]Furthermore maintenance therapy with 10 mg once-daily montelukast for 8 weeks provides greater and more sustained bronchoprotection against EIB than the LABA salmeterol (50 µg twice daily).^[66]

(ii) Leukotriene synthesis inhibitor:

The leukotriene pathway is initiated when arachidonic acid is converted to leukotriene A4 by the enzyme 5-lipooxygense. Inhibition of 5-lipoxygense by the drug zileuton reduces the biosynthesis of the LTA4 and its active derivatives, the cysteinyl leukotrienes.^[67,
68]Long-term use results in improvement in pulmonary function and asthma control, and the anti-inflammatory effects may modulate underlying airway inflammation.^[69] Furthermore, zileuton can prevent exacerbations of asthma that require prednisone treatment.^[70]

Unwanted effects:

Elevated liver transaminases have also been noted in individuals on montelukast, zileuton, and zafirlukast, and the FDA advices that liver function be tested monthly for 3 months, then quarterly for the next year, followed by intermittent testing. ^[71] On rare occasions Churg-Strauss syndrome (CSS) has been reported in patients receiving leukotriene receptor antagonists but the consensus is that this is because of withdrawal of concomitant corticosteroid therapy that had masked this disease. ^{[72, 73]}

Mast cell stabilizers:

E.g. Disodium chromoglycate (cromolyn), nedocromil. These drugs are now hardly used for treatment of asthma. Although these agents have a better safety profile than any other asthma medication, largely due to its low systemic absorption. But they have only weak anti-inflammatory effects and short duration of action. They are not bronchodilators, having no direct effects on smooth muscle, nor do they inhibit the actions of any of the known smooth muscle stimulants. Given prophylactically they reduce both immediate and late-phase asthmatic responses and reduce hyper-reactivity. ^{[45, 54]}They have found a role as a prophylactic therapy in patients with allergic asthma associated with specific triggers. They are especially useful in exercise induced asthma, as they can be taken immediately prior to exercise. They relieve respiratory symptoms and reduce dose of bronchodilators and corticosteroids.^[44]

Mast cell stabilizers act on mast cells and prevent them from releasing substances that cause allergic reactions. They block a calcium channel that is important for degranulation (which occurs after exposure to specific antigens) of sensitized mast cells, and inhibits the release of histamine and slow-reacting substances of anaphylaxis.^[74]Additionally it depresses the exaggerated neuronal reflexes that are triggered by stimulation of the ‘irritant receptors’. ^[54]They make the airways less sensitive to many asthma triggers. Mast cell stabilizers are not rescue medication. They work slowly over time, taking 2-6 weeks to become effective. These drugs come in metered dose inhalers and in a solution for nebulizers. ^[75]

Disodium cromoglycate (DSCG):

Disodium cromoglycate inhibits mast cell degranulation and its primary advantages are its minimal side effects. DSCG is poorly absorbed from G.I.T. after oral administration. Therefore, it is available as an inhalant that can be administered via the nasal or respiratory tract. When given as an inhaled dose, ~8% is absorbed systemically through the bronchial tree. It is rapidly absorbed from lungs and is excreted unchanged in urine and bile. It is given with intermittent beta2 agonists to children having frequent episodic asthma. ^{[45,
76, 77]}

Inhaled DSCG is recognized as an effective prophylactic drug for the treatment of asthma. ^{[78, 79, 80]}It has also been demonstrated to have salutary effects in patients with food allergy ^[81] and seasonal allergic rhinitis. ^{[82, 83]}

Unwanted effects:

Therapeutic doses of DSCG are well tolerated by patients. It has no serious toxic effects, but may cause bronchospasm, wheezing, cough, sneezing, nasal congestion, and pharyngeal irritation which is associated with a direct irritant effect of the powder on the bronchial tree, including. ^[84]

Anti-IgE monoclonal antibody: E.g. Omalizumab.

Omalizumab is a recombinant, humanized monoclonal anti-IgE antibody that binds with high affinity to the FcϵRI receptor-binding site on IgE.^[85]Thus Omalizumab both decreases the quantity of circulating IgE and preventsthe remaining IgE from binding to mast cells-FcϵRI.^[86] In response to the lower levels of circulating IgE, FcϵRI receptor on mast cells, basophils and dendritic cells is down-regulated. Receptor down-regulation reduces stimulation of Th2 lymphocytes and decrease the late-phase asthmatic response.^{[87, 88]}

This agent is administered subcutaneously every 2 to 4 weeks. In clinical trials; it was reported that Omalizumab was associated with a statistically significant reduction in the rate of asthma exacerbations as well as significant improvements in asthma-related quality of life, morning peak expiratory flow rate, and asthma symptoms scores. It also reduce the dose of steroids needed for disease control in atopic asthma.^[89,
90] It has been found to be safe and effective in adult and adolescent patients with allergic asthma. Although it’s high cost and the inconvenience of parental administration have limited the use of Omalizumab to severe cases of asthma. ^{[45, 91, 92]}

CONCLUSION:

Airway inflammation, a prominent feature in asthma, needs to be targeted with effective medication. Inhaled corticosteroids play a pivotal role in combating airway inflammation and control of bronchial asthma. Although additional anti-inflammatory and bronchodilator treatment is needed as per patients conditions and severity of asthma. As we learn more about asthma pathophysiology and the various inflammatory phenotypes may make it possible to target drug therapy to the various pathways of the disease, thereby improving asthma control; even may help in development and implementation of an optimal strategy for its management and prevention.

REFERENCES:

1. The Global Strategy for Asthma Management and Prevention. Global Initiative for asthma (GINA) 2012. Available from: http://www.ginasthma.org/.

2. Buist AS. Similarities and differences between asthma and chronic obstructive pulmonary disease: treatment and early outcomes. European Respiratory Journal. 21(39) suppl; 2003: 30-35.

3. Greenwood Genetic Centre. Asthma: A multifactorial condition. Available from: http://ggc.org/education/media/index-journal-columns.html?itemid=156&id=375

4. World Health Organization Fact Sheet. Fact sheet No 307: asthma. 2011. Available from: http://web.archive.org/web/ 20110629035454/http://www.who.int/mediacentre/factsheets/fs307/en/

5. GINA (Global Initiative for Asthma) 2012. pp. 3.

6. Blanc PD et al. The association between occupation and asthma in general medical practice. Chest. 115(5); 1999: 1259-1264.

7. Expert Panel Report: Guidelines for the Diagnosis and Management of asthma. National Heart, Lung, and Blood Institute; National asthma education and prevention program. 2003; NIH Publication No. 02-5074.

8. Harsh Mohan. Textbook of pathology. Jaypee brothers medical publishers. New Delhi. 2010; 4th ed: pp. 454-455.

9. Satoskar RS, Bhandarkar SD and Rege NN. Pharmacology and pharmacotherapeutics. Popular prakashan. Mumbai. 2009; 21st ed: pp. 353.

10. Rang HP, Dale MM and Ritter JM. Rang & Dale’s Pharmacology. Churchill Livingstone Elsevier. China. 2007; 6th ed: pp. 358-359.

11. GINA (Global Initiative for Asthma) 2012. pp. 16.

12. Tarek S. Towards a deep understanding of bronchial asthma. Egyptian Journal of Bronchology. 1(1);2007: 120-124.

13. Allergy testing for asthma: Diagnosing asthma. 2011. Available from: http://asthma.about.com/lw/Health-Medicine/Conditions-and-diseases/Allergy-testing-and-asthma.htm

14. Arterial blood gas. Wikipedia, the free encyclopaedia. Available from:http://en.wikipedia.org/wiki/Arterial_blood-gas

15. Milos F and Snezana C. The role of eosinophils in asthma. Medicine and Biology. 8 (1); 2001: 6-10.

16. A.D.A.M. Multimediaencyclopaedia. 2012. Available from:http://pennstatehershey.adam.com/content.aspx?productId=117&pid=1&gid=000141

17. National Asthma Council Australia. Detection and diagnosis. Available from:http://www.nationalasthma.org.au/handbook/diagnosis-in-adults/detection-and-diagnosis#Diagnostictesting

18. Bele V. Pharmacology. Career publications. Nashik. 2008; 1sted: pp. 226.

19. Proper use of asthma medication. ACAAI (American college of allergy, asthma & immunology). Available from:http://www.acaai.org/allergist/asthma/asthma-treatment/proper-use-asthmaedication/Pages/default.aspx

20. Asthma treatment options. ACAAI (American college of allergy, asthma & immunology). Available from:http://www.acaai.org/allergist/asthma/asthma-treatment/Pages/default.aspx

21. TripathiKD. Essentials of medical pharmacology. Jaypee brothers publisher. New Delhi. 2008; 6thed: pp. 93-116.

22. Budhiraja RD. Elementary pharmacology and toxicology. Popular prakashan. Mumbai. 2009; 4thed: pp. 221-227.

23. Johnson M. Beta₂-adrenoceptors: mechanisms of action of beta₂-agonist. Paediatric Respiratory Reviews. 2 (1); 2001: 57-62.

24. Johnson M. Molecular mechanisms of beta2-adrenergic receptor function, response, and regulation. Journal of Allergy and Clinical Immunology. 117(1); 2006: 18-24.

25. Lewis RA et al. Formation of slow-reacting substance of anaphylaxis in human lung tissue and cells before release. The Journal of Experimental Medicine. 140(5); 1974: 1133-1146.

26. Satoskar RS, Bhandarkar SD and Rege NN. Pharmacology and pharmacotherapeutics. Popular prakashan. Mumbai. 2009; 21st ed: pp. 355-363.

27. Barar FSK. Essentials of Pharmacotherapeutics. S. Chand & company. New Delhi. 2011; 6th ed: pp. 544-547.

28. Ullman A and Svedmyr N. Salmeterol, a new long acting inhaled beta₂adrenoreceptor agonist: comparison with salbutamol in adult asthmatic patients. Thorax. 43(9); 1988: 674-678.

29. Fitzpatrick MF et al. Salmeterol in nocturnal asthma: a double blind, placebo controlled trial of a long acting inhaled beta 2 agonist. British Medical Journal. 301(6765); 1990: 1365-1368.

30. Green CP and Price JF. Prevention of exercise induced asthma by inhaled salmeterol xinofoate. Achives of Disease in Childhood. 67(8); 1992: 1014-1017.

31. Ducharme FM et al. Addition of long-acting beta2-agonists to inhaled corticosteroids versus same dose inhaled corticosteroids for chronic asthma in adults and children. Cochrane Database of Systematic Reviews. 12(5); 2010: CD005535.

32. Fanta CH. Asthma. New England Journal of Medicine. 360(10); 2009: 1002-14.

33. Cates CJ and Cate MJ. Regular treatment with salmeterol for chronic asthma: serious adverse events. Cochrane Database of Systematic Reviews. 16(3); 2008: CD006363.

34. FDA Drug Safety Communication: New safety requirements for long-acting inhaled asthma medications called Long-acting beta-agonists (LABAs). FDA. Feb 2010. http://www.fda.gov/ Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm213836.htm

35. Barnes PJ. Muscarinic receptor subtypes in airways. Life Sciences. 52(5-6); 1993: 521-527.

36. Chapman KR. History of anticholinergic treatment in airways disease. In Gross NJ, ed. London. Franklin Scientific Publications Ltd. 1993. pp. 9-17.

37. Scullion JE. The development of anticholinergics in the management of COPD. International Journal of Chronic Obstructive Pulmonary Disease. 2(1); 2007: 33-40.

38. Rodrigo G, Rodrigo and Burschtin O. A meta-analysis of ipratropium bromide in adults with acute asthma. The American Journalof Medicine. 107(4); 1999: 363-370.

39. GINA (Global Initiative for Asthma) 2012. pp. 37.

40. Stoodley RG, Aaron SD and Dales RE. The role of ipratropium bromide in the emergency management of acute asthma exacerbation: a meta-analysis of randomized clinical trials. Annals of Emergence Medicine. 34(1); 1999: 8-18.

41. Plotnick LH and Ducharme FM. Combined inhaled anti-cholinergics and beta2-agonists for initial treatment of acute asthma in children. Cochrane Database of Systematic Reviews. 4; 2000. CD000060.

42. Barnes PJ. The pharmacological properties of tiotropium. Chest. 117(2 suppl); 2000: 63-66.

43. Barnes PJ and Pauwels RA. The theophylline in the management of asthma: time for reappraisal? European Respiratory Journal. 7(30); 1994: 579-591.

44. Bele V. Pharmacology. Career publications. Nashik. 2008; 1st ed: pp. 223.

45. Golan DE, Tashjian AH, Armstrong EJ and Armstrong AW. Principles of pharmacology: the pathophysiologic basis of drug therapy. Lippincott Williams & Wilkins. Philadelphia. 2008. 2^nded: pp. 830-836.

46. Barnes PJ, Greening AP, Neville L, Timmers J, Poole GW. Single dose slow-release aminophylline at night prevents nocturnal asthma. Lancet. 1(8267); 1982: 299-301.

47. WebMd. Asthma Health centre. Inhaled corticosteroids for long-term control of asthma. March 2011. Available from:http://www.webmd.com/asthma/inhaled-corticosteroids-for-long-term-control-of-asthma

48. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. National Institutes of Health (2007). National Asthma Education and Prevention Program.NIH Publication No. 08-5846. pp. 216-220. Available from:http:/www.nhlbi.nih.gov/guidelines/asthma/index.htm.

49. Schlienger RG et al. Inhaled corticosteroids and the risk of adult fractures in children and adolescents. Pediatrics. 114(2); 2004: 469-473.

50. Juniper EF et al. Effect of long-term treatment with an inhaled corticosteroid (budesonide) on airway responsiveness and clinical asthma in nonsteroid dependent asthmatics. The American Review of Respiratory Disease. 142(2); 1990: 832-836.

51. Haahtela T et al. Comparison of a β₂-agonist, terbutaline, with an inhaled corticosteroid, budesonide, in newly detected asthma.The New England Journal of Medicine. 325; 1991: 388-392.

52. Evans DJ et al. A comparison of low-dose inhaled budesonide plus theophylline and high-dose inhaled budesonide for moderate asthma. The New England Journal of Medicine. 337; 1997: 1412-1418.

53. Laviolette M et al. Montelukast added to inhaled beclomethasone in treatment of asthma. American Journal of Respiratory and Critical Care Medicine. 160; 1999: 1862-1868.

54. Rang HP, Dale MM and Ritter JM. Rang & Dale’s Pharmacology. Churchill Livingstone Elsevier. China. 2007; 6th ed: pp. 364.

55. Spangler DL. The role of inhaled corticosteroids in asthma treatment: a health economic perspective. The American Journal of Managed Care.18(2 Suppl); 2012: 35-39.

56. Beam DS. Value of inhaled corticosteroid therapy in long term asthma management. Pharmacy& Therapeutics. 35(7); 2010: 377-416.

57. Leach CL et al. Influence of particle size and patient dosing technique on lung deposition of HFA-beclomethasone from a metered dose inhaler. Journal of Aerosol Medicine. 18(4); 2005: 379-385.

58. Lipworth BJ. Leukotriene-receptor antagonists. Lancet. 353(9146); 1999: 57-62.

59. Zuzana D, Eva M and Leif B. Montelukast in the treatment of asthma and beyond. Expert Review of Clinical Immunology. 5(6); 2009: 639-658.

60. Philip G et al. Protection against exercise-induced bronchoconstriction two hours after a single oral dose of montelukast. Journal of Asthma. 44 (3); 2007: 213-217.

61. Dahlen SE et al. Improvement of aspirin-intolerant asthma by Montelukast, a leukotriene antagonist: a randomized, double-blind, placebo-controlled trial. American Journal of Respiratory and Critical Care Medicine. 165(1); 2002: 9-14.

62. Diamant Z et al. the effect of montelukast (MK-0476), a cysteinyl leukotriene receptor antagonist, on allergen-induced airway responses and sputum cell counts in asthma. Clinical & Experimental Allergy. 29(1); 1999: 42-51.

63. Leff JA et al. Montelukast, a leukotriene-receptor antagonist, for the treatment of mild asthma and exercise-induced bronchoconstriction. The New England Journal of Medicine. 339 (3); 1998: 147-152.

64. Villaran C et al. Montelukast versus salmeterol in patients with asthma and exercise-induced bronchoconstriction. TheJournal of Allergy and Clinical Immunology. 104(3.1); 1999: 547-553.

65. Edelman JM et al. Oral montelukast compared with inhaled salmeterol to prevent exercise-induced bronchoconstriction. Annals of Internal Medicine. 132(2); 2000: 97-104.

66. Storms W et al. A comparison of the effects of oral montelukast and inhaled salmeterol on response to rescue bronchodilatation after challenge. Respiratory Medicine. 98(11); 2004: 1051-1062.

67. Bell RL et al. The discovery and development of zileuton: an orally active 5-lipoxygenase inhibitor. International Journal of Immunopharmacology. 14(3); 1992: 505-510.

68. Israel E et al. The effect of inhibition of 5-lipoxygenase by zileuton in mild to moderate asthma. Annals of Internal Medicine. 119(11); 1993: 1059-1066.

69. Wenzel SE et al. Effect of 5-lipoxygenase inhibition on bronchoconstriction and airway inflammation in nocturnal asthma. American Journal of Respiratory and Critical Care Medicine. 152(3); 1995: 897-905.

70. Israel E et al. Effect of treatment with zileuton, a 5-lipoxygenase inhibitor, in patients with asthma. The Journal of the American Medical Association. 275(12); 1996: 931-936.

71. Krawiec ME and Wenzel SE. Use of leukotriene antagonist in childhood asthma. Current Opinion in Pediatrics. 11(6); 1999: 540-554.

72. Jamaleddine G et al. Leukotriene antagonists and the Churg-Strauss syndrome. Seminars in Arthritis and Rheumatism. 31(4); 2002: 218-227.

73. Wechsler ME et al. Churg-Strauss syndrome in patients receiving montelukast as treatment for asthma. Chest. 117(3); 2000: 708-713.

74. Drug information online. Drugs.com. Respiratory inhalant products: Mast cell stabilizers. Available from:http://www.drugs.com/drug-class/mast-cell-stabilizers.html

75. Palo Alto Medical Foundation. Sutter Health. Inhaled medications: Mass cell Stabilizers. Available from: http://www.pamf.org/asthma/medications/inhaled/mastcell.html

76. Tasche MJ et al. Inhaled disodium cromoglycate (DSCG) as maintenance therapy in children with asthma: a systemic review. Thorax. 55(11); 2000: 913-920.

77. Moss GF et al. Plasma levels and urinary excretion of disodium cromoglycate after inhalation by human volunteers. Toxicology and Applied Pharmacology. 20(2); 1971:147-156.

78. Bernstein IL et al. A controlled study of cromolyn sodium sponsored by the Drug Committee of the American Academy of Allery. The Journal of Allergy and Clinical Immunology. 50(4); 1972: 235-245.

79. Howarth PH et al. Influence of albuterol, cromolyn sodium and ipratropium bromide on the airway and circulating mediator responses to allergen bronchial provocation in asthma. The American Review of Respiratory Disease. 132(5); 1985: 986-992.

80. Hughes D, Mindorff C and Levison H. The immediate effect of sodium cromoglycate on the airway. Annals of Allergy. 48(1); 1982: 6-8.

81. Businco L et al. Effectiveness of oral sodium cromoglycate (SCG) in preventing food allergy in children. Annals of Allergy. 51(1.1); 1983: 47-50.

82. Sorri M, Jokinen K and Palva A. Disodium cromoglycate therapy in perennial rhinitis. ActaOto-laryngologica. 86(360Suppl); 1978: 30-32.

83. Pelikan Z. The effects of disodium cromoglycate and beclomethasone diproprionate on the late nasal mucosa response to allergen challenge. Annals of Allergy.49(4); 1982: 200-212.

84. Douglas W. Histamine and serotonin and their antagonists. In: Goodman L, Gilman A, Rall T, Murad F, ed. The pharmacologic basis of therapeutics. Macmillan. New York. 7thed: 1985: 605-638.

85. Shields RL et al. Inhibition of allergic reactions with antibodies to IgE. International Archives of Allergy and Immunology. 107(1-3); 1995: 308-312.

86. Liu J et al. Characterization of complex formation by humanized anti-IgE monoclonal antibody and monoclonal human IgE. Biochemistry. 34(33); 1995: 10474-10482.

87. MacGlashan DW et al. Down-regulationof FcϵRI expression on human basophils during in vivo treatment of atopic patients with anti-IgE antibody. TheJournal of Immunology. 158(3); 1997: 1438-1445.

88. Fahy JV et al. The effect of an anti-IgE monoclonal antibody on the early –and late-phase responses to allergen inhalation in asthmatic subjects. American Journal of Respiratory and Critical Care Medicine. 155; 1997: 1828-1834.

89. Mazer B. Omalizumab reduced inhaled corticosteroid use and exacerbations in childhood allergic asthma. ACP Journal Club. 136 (1); 2002: 16.

90. Milgrom H et al. Treatment of allergic asthma with monoclonal anti-IgE antibody. The New England Journal of Medicine 341(26); 1999: 1966-1973.

91. Humbert M et al. Benefits of Omalizumab as add on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4 treatment): INNOVATE. Allergy. 60; 2005: 306-316.

92. Soler M et al. The anti-IgE antibody Omalizumab reduces exacerbations and steroid requirement in allergic asthmatics. The European Respiratory Journal. 18 (2); 2001: 254-261.

Received on 23.03.2013

Modified on 10.04.2013

Accepted on 14.04.2013

Research J. Pharmacology and Pharmacodynamics. 5(4): July–August 2013, 257-265