BRONCHIAL ASTHMA

Introducation

Asthma derived from Greek word- To stay awake in order to breath

ORDifficulty in breathing

Asthma is a chronic inflammatory disease in which patient suffers with reversible episodes of airway obstruction due to bronchial hyper responsiveness.

Early phase (Acute)

-Due to bronchial smooth muscle spasm.

- Excessive secretion of mucus.

Chronic phase Continuous

Inflammation, fibrosis, oedma, necrosis of bronchial epithelial cells.

It has 2phases

Clinical hallmarks

Recurrent episodic coughing Shortness of breathing Chest tightness Wheezing

Symptoms are worsening at night

Asthma described as two type Extrinsic(Atopic extrinsic asthma)It is associated with

exposure of specific allergen

Ex:- House dust, pollen It is episodic and less

prone to develop to status asthmaticus.

Intrinsic(Non atopic extrinsic asthma)It is associated with

some non specific stimulants

Ex:- chemical irritantsIt is perenial and prone

to develop to status asthmaticus.

Pathophysiology Allergen enter (Foreign body)

Immunological reaction (AG:AB Complex formation)

Circulation in blood

Basophiles, Neutrophilis engulf

Cause neutralization contd..,

Whenever same allergen re exposed

Activation of AG:AB complex

Reacts with lung mast cells (Degranulation of mast cells)

Spasmogens release(Like Histamine,5HT,PGs,LT4, Cytokines)

Bronchial Tone

IgE-Antigen Complex

BasophilActivatio

n

Eosinophil

Activation

Chemical mediatorsHistamine, LTC4, LTD4, LTB4,Cytokines, Adenosine, PGD2, PAF,ECP and Neuropeptides

Cause inflammation, oedema, bronchospasm, muscus secretion, epithelial damage

Mast CellDegranulation

In early phase these mediators leads to bronchoconstriction

In late phase inflammation, pulmonary oedema, mucous secretion bronchial hypersensivity and epithelial damage

It divided into two categories

1. Short term relievers.( Bronchodilators)

2. Long term controllers.

Asthma therapy

Bronchial Tone

Bronchoconstriction

Bronchodilitation

Bronchial Smooth Muscle

β2

SALBUTAMOLβ2 AGONISTS 5AMP

AC

ATP

THEOPHYLLINE

M3

GTP

GC

cGMP

IPRA

TROPI

UM

M 3 A

GONI

STS

Adenosine

cAMPPDE

Bronchial Tone

Bronchoconstriction

Bronchodilitation

Bronchial Smooth Muscle

IgE-Antigen Complex

BasophilActivatio

n

Eosinophil

Activation

Chemical mediatorsHistamine, LTC4, LTD4, LTB4,Cytokines, Adenosine, PGD2, PAF,ECP and Neuropeptides

Cause inflammation, oedema, bronchospasm, muscus secretion, epithelial damage

CARTICOSTEROIDS

LT-ANTAGONISTLeukotrienes

SOD. CROMOGLYCATEStabilises Mast Cells

Mast CellDegranulation

INFECTION

NITRIC OXIDE

DONORS

Drugs Used in Bronchial Asthma

1. Selective β2– Agonists

Short acting Salbutamol, Terbutaline, Remiterol, Fenoterol, BitolterolLong-acting Salmeterol, Formoterol, Bambuterol

2. Non-Selective Sympathomimetics

Adrenaline, Ephedrine, Isoprenaline, Orciprenaline

(Metaproterenol), Isoetharine

BRONCHODILATORS

3. AnticholinergicsIpatropium, Tiotropium, Oxitropium

4. Methyl XanthinesTheophylline, Aminophylline, Diprophylline, Choline theophyllinate

Anti inflammatory Drugs (Controllers)Corticosteroids1. Oral : Prednisolone, Methylprednisolone2. Parenteral : Methyl prednisolone, Hydrocortisone3. Inhalational : Beclomethasome, Fluticasone, Triamcinolone, Budesonide, Flunisolide

Mast Cell StabilisersSodium Cromoglycate, Nedocromil, Ketotifen

Leukotriene Modulators:1. 5-Lipoxygenase Inhibitor : Zileuton2. LT – Receptor Antagonists : Zafirlukast, Montelukast, Iralukast, Pranlukast

Monoclonal Anti-IgE AntibodyOmalizumab

Miscellaneous: NO, Calcium channel blockers

Sympathomimetic agents ß2 receptors are present in the airway

smooth muscle. cause Bronchodilatation These are only provide relief M.O.A:

cAMP Bronchodilatation Release of broncho constricting mediators from mast cells Inhibit macrovascular leakage Mucociliary clearance

Epinephrine:

Rapid bronchodilator when SC/inhaled(320µg/puff) Onset of action 15min after inhalation Duration of action:60-90min.

ADR:- Acts on β1 receptor cause Tachycardia Arrhythmias Worsening angi So rarely prescribed.

Ephedrine: α,β1, β2

Ephedrine has a longer action

Oral activity

Lower potency

Pronounced central effects.

β2 Selective Short acting : Terbutaline, Salnutamol On inhalation they have rapid onset(1-5Min) Short duration of action preferred for acute attack Route: Inhalation 100-200µg/6hourly Other MDI, Oral, IM, IV

Terbutaline is the only one drug safely used during the pregnancy.

Long acting: Salmeterol, bambutarol

Long acting but slow onset of action Preferred for maintenance therapy Not useful in acute attack due to slow onset of

actionRoute: Inhalation 50µg twice daily.

Formoterol: Long acting Rapid onset Preferred for prophylaxis due to long actingRoute: Inhalation 12-24µg twice daily

ADR of Sympathomimetics By oral route stimulate β2 receptors in skeletal

muscle cause tremors, Orthostatic hypotension.

Tachycardia (High dos also stimulate β1 receptors in heart)

Restlessness

Tolarance occurs.

Antimuscurnic agent Less effective then β agonists

MOA: By blocking M3 receptors on air way smooth muscle and prevents Ach action.

-They acts by cGMP levels in bronchial smooth muscle.

Ipatropium:- -Poor absorption from bronchi into systemic

circulation -Do not cross BBB.-Also mucus secretion

Ipatropium + β2 (Salbutamol) work better in serve asthma and long duration of action

Methyl Xanthenes MOA:

i) Inhibition of PDE 3,4. These enzyme are responsible for metabolism of cAMP.

ii) Blockade of Adenosine receptors.

Actions: Theophyline exhibits bronchodilatory action Anti Inflammatory Immunomodulator Respiratory stimulation Diaphragmatic contractility Mucociliary clearance

Pharmaco Kinetics:

Oral/ParentalFood delay the rate of absorptionWell distributedCross placental & BBBMetabolized in LiverExcreted in urine

ADR: Low therapeutic window, CNS stimulant drugs Plasma levels 10-20µg/ml, Narrow safety

Restlessness, insomnia, headache, tremors

Nausea,VomitingPeptic ulcer

Tachycardia, palpitation, hypotension, arrythimiasTheophyline: potent vasodilator, reflex tachcardia, oral route Aminophyline: Slow IV infusion

XanthenesGIT Diuresis

Heart

CNS

20µg/ml40µg/ml

20µg/ml

Corticosteroids (Controllers) Glucocorticosteriods induce synthesis of lipocotrin

which inhibits pholipaseA2 there by preventing formation of mediators such as PGs,TAX2, LTand other mediators.

Actions: Anti allergic, anti inflammatory, immunosuppressant ( AG:AB reactions ), Mucosal oedema, bronchial hyperactivity, Enhance β adrenergic action by up regulation of β2 receptors in lung.

Inhalator glucocorticosteriods such as beclomethasone, budesonide and fluticasone are used as prophylactic agents in asthma.

PK: Well tolerated less systemic side effects.

Common side effects: Dryness of mouth Voice change Oropharangeal candidiats.Systemic are used in acute severe and chronic severe

asthma.

Mast cell stabilizers Non bronchodilating, Non steroid drugs, used for prophylactic

treat.MOA: Prevent degranulation and release of chemical mediators from

the mast cells. They stabilize the mast cells by preventing transmembarane

influx of Ca ions.PK: Highly ionized Least systemic absorption well tolerated.Uses: Allergic asthma, allergic conjunctivitis, allergic rhinitis,

allergic dermatitis.Ketotifen (Mast stab.+ Antihistamincs)

LT Modulators LT are powerful bronchoconstrictors. Action by preventing their synthesis or blocking

effect on cys LT receptors

Synthesis inhibitors (Lipooxygenase) Zafirlukast,Montelukast

PK: Well absorbed after oral administration Highly bound to plasma protein Metabolized by liver Effective for prophylactic treat of mild asthma.

ADR: Head ache skin rashes rarely eosinophilia Zileuton cause hepatic toxicity.

Monoclonal anti IgE antibody MOA:- AG:Ab complex formation by AB action Omalizumab: Recombinant humanized

monoclonal antibody. Inhibit the binding site of IgE to mast cells and

basophils PK: administered parentarally Uses: Moderate to severe asthma and allergic

disorders. Indicated for asthmatic patients who are not

adequately controlled by inhalational corticosteroids.

ADR: Inj site redness, itching, stinging.

Miscellaneous

NO: It dilate pulmonary blood vessels and relax airway smooth muscle.

Uses: For acute severe asthma and management of pulmonary hypertension.

Ca channel blockers: Broncho constriction ultimately involves

some degree of ca into cells Nefedpine / Verapamil should provide relief in asthma.

RX Status asthmatics (Acute severe asthma)

Status asthmatics a severe acute asthma, which is a life threatening condition involving exhaustion, cyanosis, bradicardia,hypotension, dehydration and metabolic acidosis.

Humidified O2 inhalation Neubulized β2 adrenergic agonist + anti

cholinergic agent Systemic glucocorticosteroids IV

(Hydrocortisone 200mgIV) IV fluids to correct dehydration. K supplements: To correct hypokalemia

produced by repeated administration of salbutamol.

NaHCo3 (Sodium bicarbonate) to treat acidosis.

Antibiotics to treat infection

DRUGS TO BE AVOIDED IN ASTHMA

β adrenergic blockers

Cholinergic agents

NSAIDS ( cause hyperapoenia) except paraceatamol.