Asthma Management

Asthma
Asthma literally means panting Asthma is a chronic inflammatory disorder of the airways These airways are hypersensitive to certain triggers in the environment Asthma cannot be cured but its symptoms can be controlled with proper environmental changes and medications

Conceptual model for the immunopathogenesis of asthma

Phase 1. First exposure to allergens Exposure to an allergen Production of allergic antibodies (IgEs) by immune system Phase 2. Subsequent exposures to allergens Allergen + antibody (IgE) reaction on the surface of mast cells Immune cells rupture

Histamine

(LTC4, LTD4, LTE4)

Leukotriene

Basic granular protein

o Hyperreactivity

o o o o

Bronchoconstriction Vasodilation Inflammation Edema

o Bronchoconstriction o Vasodilation o Inflammation

Epidemiology
o More common in urban areas o Prevalence of asthma in adult population is 5.3% o Children suffer the most o About 7 million people including 4 million children are
suffering from asthma in Bangladesh

Ref: International Journal of Epidemiology. 2002; Vol. 31, No. 2: 483 - 488

Aetiology
The specific abnormality of asthma is hyperreactivity of lungs to one or more stimuli. There are a no. of possible trigger factors-

o Allergens (pollens, moulds, house-dust mite, animals) o Viral respiratory tract infections o Cold and dry air o Chemical irritants (industrial, household) o Drugs (aspirin, adrenergic receptor blocker etc.) o Exercise o Psychological stimuli (emotion, stress, laughter)

Pathophysiology
Asthma is a reversible airway disease with the following pathophysiological characteristics-

o Airway hyperreactivity o Airway inflammation o Airflow obstruction

Figure: Asthmatic airway

Clinical manifestations

Recurrent coughing Wheezing Chest tightness Shortness of breath Difficulty in sleeping Difficulty in breathing (dyspnea) Wake up at night because of coughing & chest tightness

Investigation
The two most common tools to measure lung function are: Spirometer Peak flow meter Forced Vital Capacity (FVC): This is the total amount of air that can be forcibly blow out after full inspiration. It measures in liters. Forced Expiratory Volume in 1 Second (FEV1): This is the amount of air that can be forcibly blow out in one second, measured in litres. FEV1/FVC: This is the ratio of FEV1 to FVC. In healthy adults this should be approximately 75 - 80%. Any reduction indicates deterioration in lungs performance. Peak Expiratory Flow (PEF): This is the speed of the air moving out from the lungs at the beginning of the expiration, measured in liters per second.

Treatment
There are basically three kinds of medicines:

Quick relievers Short-acting 2agonist Anticholinergics Short-acting theophylline Systemic corticosteroids Protectors Long-acting 2agonist Sustained release theophylline Sustained release salbutamol

Controllers
Corticosteroids Sodium cromoglycates Leukotriene antagonists Anti-IgE therapy

Classification
1. Mild intermittent: o Mild symptoms occurs in less than two times a week o Nighttime symptoms occur less than two times a month o Do not have problems in-between flare-ups o The variation in PEF is less than 20% 2. Mild persistent: o More than two times a week, but no more than one time per day o Nighttime symptoms occur greater than two times a month o Activity levels affected by the flare-ups o FEV1 or PEF is less than 80% of the predicted value, & the variation in PEF is 20-30%

Classification
3. Moderate persistent: o Asthma symptoms occurs once a day o Nocturnal symptoms occur more than once a week o Have to use inhaled short-acting 2-agonists every day o FEV1 and PEF values are 60-80% of the predicted values, and PEF varies by more than 30% 4. Severe persistent: o Have continuous or frequent symptoms o Frequent nocturnal symptoms o Limited physical activity o FEV1 and PEF values are less than 60% of the predicted values, and PEF varies by more than 30%

Step care management

Treatment of chronic asthma can be given in a stepwise progression, according to the severity of the patients asthma symptoms. Step 1: Inhaled short acting 2-agonist as needed Step 2: Standard dose inhaled corticosteroids + Step 1 Step 3: Increase dose of inhaled corticosteroids + Step 1 OR, Step 2 + Inhaled long acting 2-agonist Step 4: High dose of inhaled corticosteroid + Inhaled long acting 2agonist + Step 1 Step 5: Step 4 + Oral therapy (oral steroids, and others)

Short-acting 2agonist
Selective inhaled 2 adrenoreceptor agonists (Salbutamol, Terbutalin) are the mainstay of the management of asthma.

Mode of action

Relax airway smooth muscle Modulate mediator release from inflammatory cells Enhance mucociliary clearance Decrease vascular permeability

Long-acting 2agonist
Long-acting inhaled 2agonist (Salmeterol, Formoterol) used when Standard introductory doses of inhaled glucocorticoids fail to achieve the control of asthma before raising the dose of inhaled glucocorticoids Protection required against asthma attack specially during night (nocturnal asthma) and exercise Same as short-acting 2agonist Effects persists for at least 12 hours

Mode of action

Fig: 2-Adrenoreceptor agonist signaling pathways

Methylxanthines
Only theophylline is clinically used as second-line bronchodilator. It is given with -agonists for severe airflow obstruction.

Mode of action

The bronchodilator effect may be related to phosphodiesterase (PDE) inhibition Excites the phrenic nerve which increase the activity of diaphragm, as well as, acts as anti-inflammatory Adenosine receptor antagonism (inhibit mediator release from mast cells)

Agonist

Agonist

Receptor

Theophylline

Receptor

Adenyl cyclase

PDE3,4

PDE5

Guanylyl cyclase

ATP

cAMP

AMP

GMP

cGMP

GTP

PKA

PKG

Inflammatory cell inhibition

Bronchodilatation

Fig: Role of theophylline in Asthma

Anticholinergics
Prevent the action of acetylcholine. Commonly used anticholinergics are Ipratropium bromide and Oxitropium bromide

Mode of action

Inhibit the action of acetylcholine at muscarinic receptors Block the increase of GMP which causes constriction Block reflex bronchoconstriction caused by inhaled irritants

CNS
Vagus nerve Parasympathetic nerve ACh Parasympathetic ganglion

Anticholinergics

ACh Irritant receptors Airway epithelium

ACh Submucosal gland

Inflammatory cell

Airway irritants, mediators

Fig: Role of anticholinergics in Asthma

Fig: Role of sympathomimetic agents in Asthma

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Anti-Inflammatory medications
Anti-inflammatory medicines (Beclomethasone, Budesonide, Fluticasone) reduce airway inflammation.

Mode of action

Modulate cytokine and chemokine production Inhibit eicosanoid synthesis Markedly inhibit the accumulation of leucocytes in lung tissue Decrease vascular permeability

Sodium Cromoglycates
Commonly used Sodium Cromoglycates are Cromolyn Sodium and Nedocromil Sodium They are used as prophylaxis in-

o Allergic asthma in children o Exercise induced asthma

Mode of action

Stabilizes mast cells

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Leukotriene antagonists
Leukotriene is a powerful bronchoconstrictor and vasodilator. Leukotriene antagonists are of two types-

Leukotriene-Receptor antagonists: Zafirlucast, Montelucast Mode of action: Selective competitive antagonist for
leukotriene-receptor

Leukotriene-Synthesis inhibitors: Zileuton Mode of action: Zileuton is a potent and selective inhibitor of 5lipoxygenase activity and thus inhibit the formation of leukotriene

Anti-IgE therapy
Omalizumab is the first biological drug approved for the treatment of asthma.

Mode of action:

Omalizumab binds tightly to free IgE in the circulation to form Omalizumab-IgE complexes o Omalizumab-IgE complexes cannot bind to IgE receptors on inflammatory cells, thereby preventing the allergic reaction at a very early step in the process

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