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Mohammad Shariful Alalm (Shohan)

BRONCHIAL ASTHMA
Bronchial asthma: Bronchial asthma is characterized by chronic airway inflammation and increased airway hyper-responsiveness leading to symptoms of wheeze, cough, chest tightness and dyspnoea. It is characterized functionally by the presence of airflow obstruction which is variable over periods of time, or is reversible with treatment. Cardinal features of bronchial asthma: 1. Recurrent episodes of wheezing, chest tightness, breathlessness and cough. 2. Vesicular breath sound with prolonged expiration. 3. Widespread high-pitched polyphonic expiratory wheezes. Pathophysiology: The bronchi become hyperactive as a result of a persistent inflammatory process or response to a number of stimuli which include biological agents, e.g., allergen, viruses, and environmental chemicals such as ozone. Inflammatory mediators are liberated from mast cell, eosinophil, neutrophil, monocyte and macrophage. Some mediators are: i) Preformed: Histamine ii) Others are formed after cell activation (PGD2, LT, PAF) Produce mucosal edema and cause damage to the ciliated epithelium Breaching of protective epithelial barrier Hypersensitivity Wheezing, breathlessness Main path physiological features:
i) Reversible bronchoconstriction increase resistance to air flow for smooth muscle contraction. ii) Bronchial inflammation mucosal thickening from oedema and cellular infiltration. iii) Bronchial hyper-reactivity. iv) Bronchial mucosal hyper secretion leads to blocking of airway lumen by abnormal thick viscid mucous plug.

As a result there is decrease efficiency with which air is carried to and from alveoli. Types of asthma: A) Aetilogical: i. Extrimsic/atopic/early onset asthma: When a definite external cause can be identified. ii. Intrinsic/cryptogenic/non-atopic/late onset asthma: When no causative agent can be identified. B) Clinical: i. Episodic asthma
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Mohammad Shariful Alalm (Shohan)


ii. Chronic asthma iii.Severe acute asthma. Phases of asthma:
In many subjects the asthmatic attack consists of two main phases as can be demonstrated by tests of FEV: The immediate phase The late phase. The immediate phase: The immediate phase, i.e. the initial response, occurs abruptly and is due mainly to spasm of bronchial smooth muscle. The cells involved in this phase are predominantly mast cell (activated to release histamine, in the case of allergic asthma, by interaction of antigen with cell-fixed IgE), but other cells could contribute. Both platelets and macrophages have receptors for IgE, albeit of low affinity, and there is clinical evidence of platelet activation in vivo during allergic bronchospasm. It is possible that in non-allergic asthma, irritants may stimulate the irritant receptors and may cause release of peptide mediators by antidromic impulse in sensory nerve fibers, and that these mediators then activate mast cells and other cells. Exercise induced asthma appears to involve only the phenomena of this first phase. The late phase: The second, late-phase response, i.e. the delayed response, occurs at a variable time after exposure to the eliciting stimulus and may be nocturnal. This phase is in essence an acute inflammatory reaction. The inflammation has special characteristics because asthma is not consistently associated with the inflammation seen, for example in bronchitis. There is infiltration not only by the usual inflammatory cells but also, and more specifically, by eosinophils and platelets. There is usually a blood eosinophilia and also some degree of loss of bronchial epithelium. In view of the increasing evidence for the seminal role of the eosinophils and the epithelial loss, some authorities have stated that asthma should be redefined as 'chronic, desquamating eosinophilic bronchiolitis'. However, in some subjects, only one of the phases may be obvious.

Types of asthma and causes:


Extrinsic Asthma
Atopic Early onset More commonest

Intrinsic Non Atopic


Episodic Exercise induced Chronic Severe acute asthma (Status asthmaticus)

Idiopathic Late onset

Allergen
o Viral infection o Emotional status o Exercise o Chemicals- Ozone (O3), SO2 o Occupation o Drugs- blocker, NSAID, Aspirin o Environment- Cold air, dust, mite, tobacco smoke, pollens, animal dander

o Chemical agents-Isocyanides, Epoxy resins Aims and objectives of treatment:

i) Prevention of exposure to antigen


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Mohammad Shariful Alalm (Shohan)


It is approximate for existence asthmatics - Avoiding an allergen - Hypo sensitization ii) Reduction of the bronchial inflammation and hypersensitivity Here the use of anti-inflammatory drug is sensible a) Corticosteroid b) Sodium chromoglycate c) Nedocromyl sodium iii) Dilation of narrowed bronchi a) 2 adrenoceptor agonist b) Methyl xanthine c) Anti-muscarinic bronchodilators Classification of anti-asthmatic drug: (1) Bronchodilator
Selective 2-adrenoceptor a. Short acting (2-6 hours) Salbutamol agonistTerbutaline Albuterol Metaproterenol Pirbuterol b. Long acting (>12 hours) Salmeterol Formeterol a. Methylxanthine derivative: Xanthine derivative Natural: Theophylline Theobromine Caffeine

Anti-muscarinic(2) Anti-inflammatory Coticosteroids-

Synthetic: Aminophylline b.Propyl-xanthine derivative: Enprophylline o Ipratropium bromide Systemic: Prednisolone (Oral) Hydrocortisone (IV)
Topical or inhalation: Beclomethasone Fluticasone Budesonide o Sodium chromoglycate o Nedocromyl sodium o Ketotifen o Azalastin o Zileutin

Mast cell stabilizer Anti-histamine(3) Newer dugs o Leukotriene synthesis inhibitoro Leukotriene receptor antagonistso Anti IgE monoclonal antibody therapy-

o Zafirlukust o Montelukast o Omalizumab

Approaches to treatment:
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Mohammad Shariful Alalm (Shohan)


Step I :Short acting 2 agonist Step II : Low dose steroid inhaler, or, Other anti-inflammatory agent High dose steroid inhaler, or, Low dose steroid inhaler +

Step III: Long acting 2 agonist Step IV:

High dose steroid inhaler + Regular bronchodilator / Ipratropium bromide / Methylxanthine / LT pathway inhibitor Step V : Addition of best of 4 + Regular steroid therapy (oral

prednisolone).

Status asthmaticus/Acute severe asthma: Acute severe asthma is an acute medical emergency characterized by severe wheeze, breathlessness to such extent that the pt. cannot speak, tachycardia, central cyanosis and sometimes pulsus paradoxes may develop. Pt. must be hospitalized immediately. Mx of acute severe asthma: i) ii) iii) iv) Immediate hospitalization Propped up position O2 inhalation: High flow (60%) Nebulization with Salbutamol or terbutaline Ipratropium bromide Normal saline Every 20 min for 3 doses. v) Prednisolone 30-60 mg orally or Hydrocortisone 200 mg i.v. 6 hourly for 2-3 days vi) If not improved, Inj. Aminophylline by slow infusion Loading dose 5 mg/kg Continuous infusion 0.5 mg/kg/hour vii) If not improved, refer the patient to ICU. But if ICU is not available Inj. Magnesium sulphate. Rx of chronic asthma:
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Mild asthma: Less than 2 bronchoconstrictive episode in a week.

Rx. Shorter acting 2 agonist in inhalation form during bronchoconstriction. It is not regularly taken. 2. Moderate asthma: More than 2 broncho constriction episodes in a week.

Rx. Long acting 2 agonist (Salmetarol) Inhaled chromolyn Inhaled glucocorticoid 3. Severe asthma: Daily bronchoconstrictive episodes.

Rx. Long acting 2 agonist Chromolyn inhalation Inhaled glucocorticoid Theophylline Oral glucocorticoid- Prednisolone
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Mohammad Shariful Alalm (Shohan)

Selective 2 Adrenoceptor Agonists


Salbutamol is the most widely used drug. It is the main stay of modern bronchodilation. Thereby can be given in oral or parenteral form and is safe and effective. Metabolized in the liver and excreted mainly by kidney. Mechanism of action: 1) Bronchus Stimulate 2 receptor Activates adenyl cyclase In presence of Mg++ convert ATP to cAMP Inactivation of myosin light chain kinase Relax bronchial smooth muscle Decrease airway resistance Salbutamol Mast cell Stimulate 2 receptor Activates adenyl cyclase In presence of Mg++ convert ATP to cAMP Stabilize mast cell Inhibits release of histamine, leukotrienes No bronchoconstriction

Relief of asthma 2) It increases mucocilliary function & clears mucous. It decreases capillary permeability. Preparation and doses: Oral tablet: 2-4 mg four times daily Aerosol: 1-2 puffs 4-6 hour interval 90 gm/puff (each inhalation) IM/IV form Advantage of inhaled salbutamol: Drugs are directly delivered to the site of action. So minimum systemic absorption. Selective stimulation of pulmonary 2 receptor. Rapid onset of action i.e. within 15 min. Long duration of action (4-6 hour) Minimum toxic effect and unwanted cardiovascular effects are less Less dose required Suitable for acute asthma Disadvantage of oral route: Undergoes first pass metabolism. So, dose requirement is high and therapeutic effect. Delayed onset of action More toxic effect Not suitable for acute asthma
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Mohammad Shariful Alalm (Shohan)

Indication: uterine smooth muscle). Adverse effects:


ii. Chronic use of inhaler: Dryness of airways Irritation of airways Oropharyngeal candidiasis iii. Due to systemic use: Tremor Tachycardia Arrhythmia Palpitation Hypokalaemia.

Bronchial asthma Prevents premature labor (as it relieves

Xanthine Derivatives
Mechanism of action: Theophylline/Aminophylline High concentration Inhibit Phosphodiesterase enzyme (PDE) No conversion of cAMP to 5AMP Increase cAMP accumulation Relaxation of bronchial smooth muscle Bronchodilation Low concentration Inhibit adenosine receptor Inhibit antigen induced release of histamine Prevent brochoconstriction

Relief of asthma Indication: i. ii. iii. iv. v. vi. Secondary drug in both acute and chronic asthma Congestive cardiac failure Emergency heart failure with asthma Migraine Ordinary headache Apnoea in preterm baby.

Q. Briefly discuss the advantages and disadvantages of Aminophylline in the treatment of bronchial asthma. Ans: Advantages of Aminophylline: 6

Mohammad Shariful Alalm (Shohan)


1. Rapid onset of action (15-30 min) 2. Suitable for acute attack 3. Suitable in severe asthma 4. Not irritative as salbutamol 5. Less side effect Disadvantages of Aminophylline: 1. Short duration of action (4-6 hours) 2. No inhalational form 3. Narrow therapeutic index 4. It causes tachycardia, palpitation. Pharmacological effects:
1) Respiratory system: Bronchodilatation 2) CNS: CNS stimulant Nervousness, anxiety, insomnia Tremor Stimulates respiratory center 3) CVS: Positive ionotrpic action Positive chronotropic action 4) GIT: HCl secretion Pepsin secretion 5) Kidney: GFR Tubular reabsorption 6) Skeletal muscle: Contraction of skeletal muscle

Side effect: I. CNS: II. CVS: Insomnia Headache Dizziness Severe restlessness Agitation

Tachycardia Palpitation Hypotension Precordial pain

III. Others: Nausea Vomiting Mild diuresis Contraindication (C/I): I. Cardiac or liver failure II. Peptic ulcer III. Pregnancy Type of asthma and Aminophylline: 1) Acute asthma:
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Mohammad Shariful Alalm (Shohan)


Intravenously 5mg/kg body wt. over 20 min followed by slow I/V infusion mixed with 20ml 5% DA. 2) Chronic asthma: Oral 100mg (1+1+1) Aminophylline overdose and treatment: Aminophylline overdose leads to Cerebral hypoxia Gastric levage then activated charcoal. Hypokalaemia K+ replacement. Seizure Diazepam. Severe vomiting Tachypnoea. Q. Why Aminophylline given slowly not rapidly in IV infusion? Ans. Aminophylline has positive chronotropic and ionotropic effect. Its therapeutic and toxic effects are related to its plasma concentration. Rapid I/V administration of Aminophylline sometimes cause sudden death due to cardiac arrhythmia. So, the drug should be injected slowly over 20-40 minutes to avoid severe toxic symptoms. Difference between Salbutamol and Aminophylline:
Traits 1.Group 2. M/A Salbutamol Adrenergic drug It stimulates 2 receptor activate adenyl cyclase convert ATP to cAMP relaxation of bronchial muscle bronchodilation Slow High Inhalation Absent Less No action High Suitable (inhaler) Mild asthma with intermittent attack Not needed Aminophylline Xanthine derivative Inhibit enzyme PDE prevents conversion of cAMP to 5AMP conc. of cAMP relaxation of bronchial smooth muscle Bronchodilation Rapid Shorter IV, Oral Present More Increase GFR Narrow Suitable (IV) Moderate to severe asthma in both acute & chronic cases Close observation is needed

3.Onset of action 4.Duration of action 5.Usual form 6.Cardio toxic effect 7.CNS toxicity 8.Action on GFR 9.TI 10.In acute asthma 11.Drug of choice for 12.Caution during administration

Corticosteroids in Asthma
Mechanism of action of corticosteroids in asthma: The most important action of corticosteroids in asthmatic patient is inhibition of the lymphocytic, eosinophilic mucosal inflammatory reactions in
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Mohammad Shariful Alalm (Shohan)


the airway. Thus corticosteroids reduce the frequency of acute asthma exacerbation if it is taken regularly. They dont relax the airway smooth muscle directly. Cell membrane phospholipids Steroid Synthesis of lipocortin (Mediator protein) (-) Phospholipase A2

Arachidonic acid Lipo-oxygenase pathway Synthesis of Leukotriene, PAF (Bronchoconstrictor) Role of glucocorticoids in asthma: 1. Anti-inflammatory action: a) Regulation of cytokine and chemokine production b) Inhibition of synthesis of arachidonic acid metabolites (LT, PG & PAF) Decrease bronchial hyper-reactivity c) Marked inhibition in accumulating basophil, eosinophil & other leukocytes in lung tissue d) Decrease capillary permeability Decrease bronchial oedema and congestion. e) Reduce inflammation by relieving mucosal oedema. Cyclo-oxygenase pathway Synthesis of PG (Inflammatory mediator)

2. Permissive action: Potentiate the action of adrenaline Increase cAMP Bronchodilation. Ultimately there is limitation of inflammatory process & inhibition of immune responses; thus reduce the asthmatic attack. Adverse effects: A. Due to inhalation: i) Oropharyngeal candidiasis ii) Dryness of mouth iii) Hoarseness of voice B. Due to systemic absorption: i) Hypertension ii) Aggravation of peptic ulcer disease iii) Osteoporosis iv) Weight gain v) Impaired glucose control in DM vi) Susceptibility to infection vii) CNS depression Corticosteroids in asthma: Acute asthma: Immediately:
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Mohammad Shariful Alalm (Shohan)


or Subsequent: or Tab. Prednisolone 30-60 mg Intravenous Hydrocortisone 200mg should be give initially. Tab. Prednisolone 30-60 mg/day Intravenous hydrocortisone 200 mg 16 hourly

Chronic asthma: Mild to moderate: Beclomethasone dipropionate, Budesonide or fluticasone propionate inhalation 800-2000 mg Severe: Inhaled (800-2000mg) plus Tab. Prednisolone 30-60mg/day Comparison of Salbutamol with Beclomethasone: Both Salbutamol & Beclomethasone are used in the treatment of asthma but they differ in the following pointsTraits 1.Group 2. Mechanism of action 3.Onset of action 4.Adverse effect Salbutamol 2 agonist It relaxes the smooth muscle of airway causing bronchodilation Rapid relief of symptoms. So suitable in emergency management Fine tremor, tachycardia, hypokalaemia etc Beclomethasone Steroid It reduces the number & activity of cells involved in airway inflammation Slow onset of action. So not suitable in emergency management Hoarseness of voice, oral candidiasis, rarely rash

Mast Cell Stabilizers


Mechanism of anti-allergic action of Nedocromyl sodium: Nedocromyl sodium/Na chromoglycate Reduce the accumulation of intracellular Ca++ induced by antigen in stabilized mast cells Thus prevent degranulation of mast cell Prevent release of inflammatory mediator Prevent broncho constriction Indication: i. ii. iii. Prophylaxis of bronchial asthma Prophylaxis of allergic rhinitis Allergic conjunctivitis

Dose: 2 puff twice per day Adverse effects: i. Throat irritation


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Mohammad Shariful Alalm (Shohan)


ii. iii. iv. v. Cough Mouth dryness Wheezing Chest tightness.

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