BRONCHIAL ASTHMA

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BRONCHIAL ASTHMA

• Definition

• Prevalence

• Etiology

• Pathogenesis

• Pharmacology of anti asthmatic drugs

• Management

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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.

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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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Asthma Prevalence and Mortality

Source: Masoli M et al. Allergy 20047

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 .

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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).

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• 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

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http://link.brightcove.com/services/player/bcpid236059233?bctid=34780680218

Lung Morphology in Asthma

• Bronchial inflammation

• Edema, Mucousplugging

• Bronchospasm

• Obstruction

• Over inflation

Lung Hyperinflation in Asthma

Thick bronchi with Mucous plugs

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 ).

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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.

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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.

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• 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

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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

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• 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.

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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.

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• 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

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Corticosteroids

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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).

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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).

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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

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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%)

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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.

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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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Summary

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Antiinflammatory drugs

Bronchodilators

Antiinflammatory drugs

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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

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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

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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.

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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)

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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

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Diagnosing Asthma:

Spirometry

Test lung function when diagnosing asthma

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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

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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

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PREVENTION

Primary

Secondary

Tertiary

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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.

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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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THANK YOU

THANK YOU94