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BRONCHIAL ASTHMA
• Definition
• Prevalence
• Etiology
• Pathogenesis
• Pharmacology of anti asthmatic drugs
• Management
2
Bronchial asthma
Bronchial asthma is a chronic inflammatory disorder of the
airways associated with airway hyper responsiveness
presents with:
• Wheezing
• Breathlessness
• Chest tightness
• Nighttime or early morning cough
Airway obstruction is reversible
either spontaneously or with treatment.
3
Bronchial asthma
• Bronchial asthma is a disease of the lungs in which an obstructive ventilation disturbance of the respiratory passages evokes a feeling of shortness of breath.
• The cause is a sharply elevated resistance to airflow in the airways.
• Despite its most strenuous efforts, the respiratory musculature is unable to provide sufficient gas exchange.
• The result is a characteristic asthma attack, with spasms of the bronchial musculature, edematous swelling of the bronchial wall and increased mucus secretion.
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WHO Definition of Asthma
• "A chronic inflammatory disorder of the airways in which many cells play a role, in particular mast cells, eosinophils, and T lymphocytes. In susceptible individuals this inflammation causes recurrent episodes of wheezing, breathlessness, chest tightness, and cough particularly at night and/or in the early morning. These symptoms are usually associated with widespread but variable airflow limitation that is at least partly reversible either spontaneously or with treatment. The inflammation also causes an associated increase in airway responsiveness to a variety of stimuli."
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• 235-330 million affected individuals
• 1% -18% - global prevalence rate
• 2,50,000-3,45,000 people die per year from the disease
• It is more common in developed than developing countries
• Common in both gender
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GENETICS Higher concordance in Monozygotic twins↑ed incidence in primary relatives
• ADAM-33 1st gene identified as Asthma susceptibility gene• 10 most common genes a/w Asthma
Innate immunity (CD-14,HLA DRB1,DQB1) Th₂ cell signalling (IL-4,IL-13,IL-4Ra) Cellular inflammation (TNF,FCEDR1B) Lung development (ADAM33,ADRB2)
Genome-wide association studies (GWAS) : 17 q 21,11 p 14,5 q 23,Chr 18
Environment : Epigenetic modifications
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ATOPIC ASTHMA
Begins in childhood.
A positive family history of atopy is common,
Asthmatic attacks are often preceded by allergic rhinitis, urticaria, or eczema.
The disease is triggered by environmental antigens, such as dusts, pollen, animal dander, and foods, but potentially any antigen is implicated.
A skin test with the offending antigen results in an immediate wheal-and-flare reaction, a classic example of the type I IgE-mediated hypersensitivity reaction .
9
NON ATOPIC ASTHMA• The mechanism of bronchial inflammation and hyper-
responsiveness is much less clear in individuals with non-atopic asthma.
• Viral infections of the respiratory tract (most common) and inhaled air pollutants such as sulfur dioxide, ozone, and nitrogen dioxide.
• In asthmatic subjects however, the bronchial response, manifested as spasm, is much more severe and sustained.
• A positive family history is uncommon• Serum IgE levels are normal• There are no associated allergies• Virus-induced inflammation of the respiratory mucosa lowers the
threshold of the subepithelial vagal receptors to irritants. • The ultimate humoral and cellular mediators of airway
obstruction (e.g., eosinophils) are common to both atopic and non-atopic variants of asthma.
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Extrinsic (Allergic) Triggers:
Dust mites
Mould
Certain foods
Animal dander
Pollen
Intrinsic (Non-Allergic) Triggers:
Exercise
Infections (cold and flu)
Cold or humid air
Intense emotions (ex. Stress)
Medications (aspirin)
Hormones
Air pollution
Fragrances and chemicals
Occupational irritants 11
Pathophysiology of Asthma
• Asthma is a disease characterized by airway
inflammation and episodic, reversible
bronchospasm.
– Two characteristic features:
1) Inflammatory changes in the airway;
2) Bronchial hyperreactivity to stimuli.
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Pathophysiology of Asthma
• Antigens (pollen and house-dust mites) sensitize patients
by eliciting the production of IgE type of antibodies, which
remain either circulating in the blood or become attached to
the mast cells of nasal or bronchial tissues and basophils.
• On re-exposure the same antigen, the resulting antigen-
antibody reaction in the early phase causes degranulation
of the lung mast cells and releasing of the powerful
bronchoconstrictors: histamine, 5-HT, PGD2 and
cysteinyl leucotriens (LTB4, LTC4 and LTD4).
13
• Lung mast cells also release ILs (IL-4, IL-5 and IL-13).
In the late (delayed) phase of asthma, these mediators
activate additional inflammatory cells (eosinophils,
basophils, and alveolar macrophages) which also release
LTs and ILs.
• Other mediators of inflammation, in delayed phase,
are: adenosine (causing bronchconstriction), neuropeptides
( causing mucus secretion and increase in vascular
permeability; neurokinin A, causing bronchoconstriction),
PAF etc.
•The normal tone of bronchial smooth muscle is influenced
by a balance between parasympathetic, sympathetic and
non-adrenergic–non-cholinergic (NANC) mediators
activity.14
Lung Morphology in Asthma
• Bronchial inflammation
• Edema, Mucousplugging
• Bronchospasm
• Obstruction
• Over inflation
Airways Innervations
Afferent nerves (sensory)
Irritant receptors in upper airways.
C-fiber receptors in lower airways.
Stimulated by :
Exogenous chemicals
Physical stimuli (cold air)
Endogenous inflammatory mediators
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Efferent nerves (motor)
Parasympathetic supply
M3 receptors in smooth muscles and glands.
No sympathetic supply but B2 receptors in
smooth muscles and glands
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Aims of anti asthmatic drugs:
• To relieve acute episodic attacks of asthma
(bronchodilators, quick relief medications).
• To reduce the frequency of attacks, and
nocturnal awakenings (anti-inflammatory
drugs, prophylactic or control therapy ).
25
Anti asthmatic drugs
Bronchodilators
(Quick relief medications)
treat acute episodic attack of asthma
• Short acting 2-agonists
• Antimuscarinics
• Xanthine preparations
Anti-inflammatory Agents(control medications or prophylactic therapy)
reduce the frequency of attacks
• Corticosteroids• Mast cell stabilizers• Leukotrienes antagonists•Anti-IgE monoclonal antibody• Long acting ß2-agonists
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Classification of Antiasthmatic Drugs
1. Bronchodilators
• Selective β2-agonists: Clenbuterol, Salbutamol,
Fenoterol, Indacaterol, Levosalbutamol, Salmeterol,
Terbutaline
• Nonselective β-agonists: Epinephrine, Isoprenaline,
Orciprenaline; Ephedrine
• M-cholinolytics: Ipratropium, Tiotropium, Oxitropium
• Methyl Xanthines: Theophylline, Aminophylline,
Theotard
2. Mast Cell Stabilizers: Sodium Cromoglycate,
Ketotifen, Nedocromil
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3. Glucocorticosteroids (GCS)
• Oral: Prednisone, Methylprednisolone
• Parenteral: Methylprednisolone, Betamethasone
• Inhalational: Beclomethasone, Budenoside,
Fluticasone, Triamcinolone
4. Inhalational β2-agonists/Glucocorticosteroids
Seretide® (fluticasone/salmeterol)
Symbicort® (budenoside/formoterol)
5. Leukotriene Modulators
• 5-Lipoxygenase Inhibitor: Zileuton
• LTD4-antgonists: Zafirlukast, Montelukast
6. Monoclonal Anti-IgE Antibody: Omalizumab
7. Miscellaneous: NO-donors, Calcium antagonists
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Sympathomimetics
- adrenoceptor agonistsMechanism of Action
direct 2 stimulation stimulate adenyl
cyclase Increase cAMP
bronchodilation
Inhibit mediators release from mast cells.
Increase mucus clearance by (increasing
ciliary activity).
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Classification of agonists
Non selective agonists:
epinephrine - isoprenaline
Selective 2 – agonists (Preferable).
Salbutamol (albuterol)
Terbutaline
Salmeterol
Formeterol
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Non selective -agonists.Epinephrine
• Potent bronchodilator
• rapid action (maximum effect within 15 min).
• S.C. or by inhalation (aerosol or nebulizer).
• Has short duration of action (60-90 min)
• Drug of choice for acute anaphylaxis
(hypersensitivity reactions).
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Disadvantages Not effective orally.
Hyperglycemia
CVS side effects:
tachycardia, arrhythmia, hypertension
Skeletal muscle tremor
Not suitable for asthmatic patients with
hypertension or heart failure.
Contraindication:
CVS patients, diabetic patients
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Selective 2 –agonists
drugs of choice for acute attack of asthma
Are mainly given by inhalation (metered dose
inhaler or nebulizer).
Can be given orally, parenterally.
Short acting ß2 agonists
e.g. salbutamol, terbutaline
Long acting ß2 agonists
e.g. salmeterol, formeterol
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• Beta agonists or adrenergic agents, can be thought of as rescue medications because they provide rapid relief of labored breathing during an asthma episode.
• All of the currently available beta agonists are superior to both adrenaline and ephedrine for duration of action and less-pronounced side effects.
• These potent , when inhaled, provide rapid relief of bronchial obstruction. Duration of action varies from four to six hours. An exception is salmeterol(Serevent®) which works for up to twelve hours but has a slower onset of action of about an hour.
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• These agents are excellent for the prevention of wheezing triggered by exercise or cold air if taken before the activity or exposure.
• Individuals may prefer one agent to another for reasons of taste, cost, or personal preference. Generic agents are now available for albuterol.
• Users of generic substitutes should be aware of the potential problem of dosage variability.Side effects are mild affecting less than 10% of users.
36
Short acting ß2 agonists
Salbutamol, inhalation, orally, i.v.
Terbutaline, inhalation, orally, s.c.
Have rapid onset of action (15-30
min).
short duration of action (4-6 hr)
used for symptomatic treatment of
acute
episodic attack of asthma.
37
• Salmeterol is a bronchodilator. It works
by relaxing muscles in the airways to
improve breathing.
• Salmeterol inhalation is used to prevent
asthma attacks. It will not treat an asthma
attack that has already begun.
Salmeterol inhalation is also used to treat
chronic obstructive pulmonary disease
(COPD) including emphysema and
chronic bronchitis.
LONG ACTING ß2 AGONIST
38
Adverse Reactions of β2 agonists:
1) Skeletal muscle tremor - which results from a direct stimulation of 2-adrenoceptors in skeletal muscle.
• This effect is most notable on the initiation of therapy and gradually improves on continued use.
2) Cardiac effect - 2-Agonists also cause tachycardia and palpitations in some patients.
• When administered by inhalation, the 2-agonists produce only minor side effects.
3) Metabolism disturbance - ketone bodies↑, acidosis, [K+]o↓ 39
Theophylline
• Methylxanthine derivatives.
• Mechanism of Action:
1. Inhibit phosphdiesterase (PDE);
2. Block adenosine receptors;
3. Increase endogenous catecholamine (CA) releasing;
4. Interfere with receptor-operated Ca2+ channels → [Ca2+]i↓;
5. Anti-inflammatory action
40
• Clinical Use:
1. Asthma: maintenance treatment
2. Chronic obstructive pulmonary disease (COPD)
3. Central sleep apnea (CSA)
• Adverse Reactions:
– Narrow margin of safety. Toxic effects are related to its plasma concentrations.
– Gastrointestinal distress, tremor, and insomnia.
– Cardiac arrhythmias, convulsions → lethal.
41
Muscarinic Antagonists
• There are M1, M2, M3 receptor subtype in the airway.
• Selectively blocking M1, M3 receptor is resulted in
bronchodilating effect.
• Ipratropium bromide binds to all M-R subtypes (M1,
M2 and M3 ), and inhibits acetylcholine-mediated
bronchospasm.
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• In the treatment of asthma, anticholinergic drugs are both old and new. One hundred years ago, atropine, the parent drug of this class, was smoked as a cigarette for asthma.
• Its usefulness was limited by unacceptable side effects of rapid heart rate, hot skin, and dry mucous membranes. Excessive doses could even provoke delusions and irrational behavior.
• Ipratropium (Atrovent®) preserves the bronchodilator effects while eliminating these adverse effects.
• Atrovent® is not as potent as the sympathomimetics and is not considered a first choice medication. It has an additive effect when beta agonists are insufficient for symptom relief. It can serve as an acceptable alternate when sympathomimetics aren’t tolerated.
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Anticholinergic Drugs
•Atrovent® should be inhaled four times daily for maximum effectiveness. • It's available in multidose inhaler form and in unit dose ampoules for nebulizer use. • The only common side effect is dry mouth. • Combivent® is a convenient, combination product composed of albuterol and ipratropium.
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Typical Spirometric (FEV1) Tracings
1Time (sec)
2 3 4 5
FEV1
Volume
Normal Subject
Asthmatic (After Bronchodilator)
Asthmatic (Before Bronchodilator)
Note: Each FEV1 curve represents the highest of three repeat measurements
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Anti-inflammatory agents
• Act at several points in this process. Cromolyn and nedocromil stabilize mast cells and nerve endings preventing initiation of the inflammatory process.
• Leukotriene antagonists block the production of leukotrienes, a potent mast cell messenger chemical, or block the transmission of their message to receptor cells.
• Corticosteroids stabilize blood vessels reducing vascular leakiness. They also restore sensitivity of receptor cells to beta-agonists and down-regulate the production and release of inflammatory chemicals. This results in decreased numbers of eosinophils in the airway walls. Corticosteroids have considerably greater anti-inflammatory activity than any of the other drugs. The result is a gradual resolution of the asthmatic condition.
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• Since these drugs do not relax bronchial muscle, they
don’t provide the immediate relief characteristic of
bronchodilators.
• With regular and continued use of anti-inflammatory
agents however, the need for bronchodilators is
gradually reduced.
• Inhaled corticosteroids may trigger cough during an
acute asthma attack. Oral prednisone may be substituted
at such times.
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Glucocorticoids (GCs)
• Mechanism of Action:
1. Broad anti-inflammatory efficacy
① Block the synthesis of arachidonic acid by
phospholipase A2.
② Reduce bronchial reactivity.
2. Increase the responsiveness of β-adrenoceptors
in the airway.
49
• The anti-inflammatory actions of GCS are mediated by
stimulation of synthesis of lipocortin, which inhibits pathways
for production of PGs, LTs and PAF. These mediators
would normally contribute to increased vascular
permeability and subsequent changes including
oedema, leucocyte migration, fibrin deposition.50
• Glucocorticosteroids provide long-term
stabilization of the symptoms due to their anti-inflammatory
effects. Inhaled GCS, along with beta-2-agonists are the
first choice drugs for chronic asthma.
• GCS inhibit the release of PGs and LTs and thus prevent
smooth muscle contraction, vascular permeability and
airway mucus secretion.
• GCS produce eosinopenia which prevents cytotoxic effects
of the mediators released from eosinophils.
• GCS enhance beta-2-adrenergic response by up-regulating
the beta-2-receptors in lung cells and leuckocytes.
•Several hours are required for DNA transcription and RNA
translation to occur after administering GCS.51
Routes of administration
Inhalation:
e.g. Budesonide & Fluticasone, beclometasone
–Given by inhalation, given by metered-dose
inhaler
– Have first pass metabolism
–Best choice in asthma, less side effects
Orally: Prednisone, methyl prednisolone
Injection: Hydrocortisone, dexamethasone
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Glucocorticoids in asthma
Are not bronchodilators
Reduce bronchial inflammation
Reduce bronchial hyper-reactivity to stimuli
Have delayed onset of action (effect usually
attained after 2-4 weeks).
Maximum action at 9-12 months.
Given as prophylactic medications, used alone or
combined with beta-agonists.
Effective in allergic, exercise, antigen and
irritant-induced asthma,
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Systemic corticosteroids are reserved for:
– Status asthmaticus (i.v.).
Inhaled steroids should be considered for adults,
children with any of the following features
• using inhaled β2 agonists three times/week
• symptomatic three times/ week or more;
• or waking one night/week.
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• Cushing’s syndrome• Osteoporosis• Tendency to hyperglycaemia• Negative nitrogen balance• Increased appetite• Increased susceptibility
to infections• Obesity etc.
Adverse
effects
of GCS
Cushing’s
syndrome
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Side effects due to systemic corticosteroids
– Adrenal suppression
– Growth retardation in children
– Osteoporosis
– Fluid retention, weight gain, hypertension
– Hyperglycemia
– Susceptibility to infections
– Glaucoma
– Cataract
– Fat distribution, wasting of the muscles
– Psychosis
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Inhalation has very less side effects:
– Oropharyngeal candidiasis (thrush).
– Dysphonia (voice hoarseness).
Withdrawal
– Abrupt stop of corticosteroids should be
avoided and dose should be tapered (adrenal
insufficiency syndrome).
59
Leukotrienes antagonists
Leukotrienes
produced by the action of 5-lipoxygenase on
arachidonic acid.
Synthesized by inflammatory cells found in the
airways (eosinophils, macrophages, mast cells).
Leukotriene B4: chemotaxis of neutrophils
Cysteinyl leukotrienes C4, D4 & E4:
– bronchoconstriction
– increase bronchial hyper-reactivity
– mucosal edema, mucus hyper-secretion60
Leukotriene receptor antagonists
e.g. zafirlukast, montelukast, pranlukast
are selective, reversible antagonists of cysteinyl
leukotriene receptors (CysLT1receptors).
Taken orally.
Are bronchodilators
Have anti-inflammatory action
Less effective than inhaled corticosteroids
Have glucocorticoids sparing effect (potentiate
corticosteroid actions).
61
Uses of leukotriene receptor antagonists
Are not effective to relieve acute attack of
asthma.
Prophylaxis of mild to moderate asthma.
Aspirin-induced asthma
Antigen and exercise-induced asthma
Can be combined with glucocorticoids (additive
effects, low dose of glucocorticoids can be
used).
Side effects:
Elevation of liver enzymes, headache, dyspepsia63
Mast cell stabilizers
e.g. Cromolyn (cromoglycate) - Nedocromil
act by stabilization of mast cell membrane.
given by inhalation (aerosol, microfine powder,
nebulizer).
Have poor oral absorption (10%)
65
Pharmacodynamics
These are Not bronchodilators.
Not effective in acute attack of asthma.
Prophylactic anti-inflammatory drug.
Reduce bronchial hyper-reactivity.
Effective in exercise, antigen and irritant-induced
asthma.
Children respond better than adults.
66
Uses Prophylactic therapy in asthma especially in
children. Allergic rhinitis. Conjunctivitis.
Side effects Bitter taste minor upper respiratory tract irritation (burning
sensation, nasal congestion)
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Omalizumab
is a monoclonal antibody directed against human IgE.
prevents IgE binding with its receptors on mast cells & basophiles.
↓ release of allergic mediators.
used for treatment of allergic asthma.
Expensive-not first line therapy.
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Medications to Treat Asthma:
How to Use a Spray Inhaler
The health-care provider should evaluate inhaler technique at each visit.
Source: “What You and Your Family Can Do About Asthma” by the Global Initiative for Asthma Created and funded by NIH/NHLBI
74
Used by some (usually moderate or severe) asthma patients to monitor ongoing lung function to detect changes
Also known as a “spacer” or valved holding chamber (VHC)
Delivery of medication over 100% more effective
75
Medications to Treat Asthma:
Inhalers and Spacers
Spacers can help
patients who have
difficulty with inhaler
use and can reduce
potential for adverse
effects from
medication.
76
Medications to Treat Asthma:
Nebulizer
• Machine produces a mist of the medication
• Used for small children or for severe asthma episodes
• No evidence that it is more effective than an inhaler used with a spacer
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Establishing the diagnosisNot all that wheezes is asthma
• The medical history!
• Pulmonary function testing with bronchodilator– Reversibility: 12% AND 200 cc change in FEV1
– Obstructive physiology on pulmonary function test (FEV1
reduced much more than FVC)
• Bronchoprovocation testing– Methacholine, histamine, exercise
• Exhaled nitric oxide (NO)
80
Methods of investigation
• Objectively: Tachypnoe with prolonged expiration, wheezing, dry rales
• Sputum analysis: eosinophils, Kurshman spirals (mucus from small bronchi), Sharko-Leiden crystals (enzymes of eosinophils)
• General blood analysis: mild leucocytosis, eosinophilia
• Spyrometry: decreased FVC, FEV1, FEV1/FVC, increased daily variability
81
Nitric OxideExhaled NO
• Exhaled nitric oxide is a biological marker that correlates with eosinophilic inflammation in asthma.
• Exhaled NO measurement can provide diagnostic and predictive value for a corticosteroid response.
• More longitudinal studies are required to clarify the clinical significance of exhaled NO in asthma.
Kim et al, Curr Opin Allergy Clin Immunol 2014,14:49–5483
Indicators of Severe Asthma
Anxious and diaphoretic appearance, upright position
Breathlessness at rest and inability to speak in full sentences
Tachycardia (HR>120) and Tachypnoea (RR>30)
Pulse oximetry <91% (on room air)
PaCO2 normal or increased
PEFR <150 L/min or <50% predicted
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controlled
partly controlled
uncontrolled
exacerbation
LEVEL OF CONTROL
maintain and find lowest controlling step
consider stepping up to gain control
step up until controlled
treat as exacerbation
TREATMENT OF ACTION
TREATMENT STEPSREDUCE INCREASE
STEP
1STEP
2STEP
3STEP
4STEP
5
RED
UC
EIN
CR
EASE
85
Step-wise approach to the treatment of asthma according to recent guidelines. LTRA, leukotriene receptor antagonist; SR, slow release. The dose of inhaled corticosteroids refers to
beclomethasone dipropionate
88
Prevention: Primary
• Patient awareness/education
Efficacy of patient education and parental awareness has also been shown to be
effective in individual studies from India (Singh et al. 2002; Gupta et al. 1998; Ghosh et al. 1998; Lal et al. 1995).
• Lifestyle Modifications: Regular balanced diet and avoidance of obesity.
Short acting beta-2 agonists should be used prior to anticipated exercise, in a
patient with exercise-induced Asthma, to alleviate symptoms (Consensus on Guidelines of Management of Clinical Asthma 2005).
• Alternative System of Medicine:
Yogic breathing exercise technique, Pranayama, was been shown to reduce in
histamine reactivity
(Singh et al. 1990).
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Prevention: Secondary
Avoidance of precipitating factors
Avoid dusting when subject is around
Avoid using carpets, stuffed toys, open bookshelves, smoking, chemical sprays in house. Prefer mosquito nets to repellants
Food containing allergen to be avoided
Maintain record of daily symptoms
*Involves avoidance of allergens and nonspecific triggers when Asthma is established. (Custovic et al. 1998; Strachan and Cook 1998; Chalmers et al. 2002; Jindal et al. 1997) 91
The Reality
• Asthma is not yet curable *
• Under diagnosis & Under management
• Therapy is still evolving
Hope • Better understanding of Pathology
• New line of Promising Drugs.
• Proper management normal life.
92
REFRENCES• Goodman & Gilman’s - pharmacological basis of
therapeutics 11th edition
• Katzung - Basic & Clinical pharmacology 12th edition
• K D Tripathi – Essentials of medical pharmacology
7th edition
• Lippincott – modern pharmacology with clinical
application
• Harrison’s principles of internal medicine 18th edition
• GINA guidelines 2014
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