JNMC AMU Management of Bronchial Asthma Introduction Asthma is a chronic inflammatory disorder of the airways that is characterized clinically by recurrent episodes of wheezing breathlessness chest tightness and cough particularly at night early morning ID: 999218
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1. Dr. ShujauddinDepartment of PharmacologyJNMC, AMUManagement of Bronchial Asthma
2. Introduction Asthma is a chronic inflammatory disorder of the airways that is characterized:clinically by recurrent episodes of wheezing, breathlessness, chest tightness, and cough, particularly at night / early morning. physiologically by reversible narrowing of the bronchial airways and a marked increase in bronchial responsiveness.
3. 300 million people around the globe suffer from Asthma.World-wide, deaths from this condition have reached over 180,000 annually.In Western Europe as a whole, asthma has doubled in ten years.India has an estimated 15-20 million Asthmatics.In India, rough estimates indicate a prevalence of between 10% and 15% in 5-11 year old children. The human and economic burden associated with this condition is severe. WHO
4. Classification A heterogenous disorder, no universally accepted classificationAtopic /extrinsic /allergic (∼70%) – IgE mediated immune responses to environmental antigens.Non-atopic/ intrinsic /non-allergic(∼30%) –triggered by non immune stimuli. Patients have negative skin test to common inhalant allergens and normal serum concentrations of IgE.
5. The ultimate humoral and cellular mediators of airway obstruction are common to both atopic and non-atopic variants of asthma, and hence they are treated in a similar way.
6. Pathophysiology Chronic inflammationAirway Hyper-responsiveness
7. Inflammation Chronic inflammatory stateSuperimposed acute inflammatory episodesInvolves respiratory mucosa from trachea to terminal bronchioles, predominantly in the bronchi.Eosinophilic bronchitis, mast cell infiltration.T-helper type 2 response - IL-4, IL-5, and IL-13.
8. Inflammation…IL-4 – stimulates IgE production IL-5 – activates eosinophilsIL-13 – stimulates mucus productionInflammatory mediators
9. Inflammation…
10. Asthma TriggersAllergensVirus InfectionsDrugsExerciseFoodAir pollutantsStress Occupational factors
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12. Cellular mechanisms of asthma
13. Inflammation…Exact cause of airway inflammation is unknown.Thought to be an interplay between endogenous and environmental factors.Endogenous factors –Atopy – Genetic predisposition to IgE mediated type I hypersensitivityAn excessive TH2 reaction against environmental antigensThe major risk factor for asthmaAsthma is commonly associated with other atopic diseases – allergic rhinitis(80%), atopic dermatitis, urticaria, etc.Genetics : Polymorphism of gene on chr. 5q , ADAM-33, DPP-10 , GPRA gene .
14. Inflammation…Environmental factorsViral infections – RSV, Mycoplasma, ChlamydiaAir pollutionAllergens – house dust miteHygeine hypothesis
15. Airway Hyper-responsivenessBronchial hyper-responsiveness is a state characterised by easily triggered bronchospasm.Bronchial hyper-responsiveness can be assessed with a bronchial challenge test.Concentration of a bronchial spasmogen (methacholine/histamine), needed to produce a 20% increase in airway resistance in asthmatics is often only 1% to 2% of the equally effective concentration in healthy control subjects.
16. Effects of inflammationAirway epithelium – damage and shedding may lead to AHR.Mucus hypersecretionNerves –sensitization of nerve terminals and reflex activation of cholinergic nerves.Vessels – increased in number, blood flow is increased.Smooth muscle – hyperplasia and hypertrophyFibrosis – subepithelial.
17. Clinical presentationWheezing, dyspnea and cough.Tenaceous mucus production.Symptoms worse at night.Limitation of activity.Signs↑ respiratory rate, use of accessory musclesHyper-resonant percussion noteExpiratory wheeze May be SILENT CHESTNo findings when asthma is under control or b/w attacks
18. Investigations Pulmonary function testsSpirometry estimate degree of obstruction↓FEV1, ↓FEV1/FVC, ↓PEF. >12% increase in FEV1, 15 minutes after β2 agonist inhalation.AHR – histamine / methacholine provocation test> 20% fall in FEV1 CXR – hyperinflatedArterial blood-gas analysishypoxia & hypocarbia (severe acute asthmahypercarbia)Skin hypersensitivity testSputum & Blood eosinophiliaElevated serum IgE levels
19. 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 ).
20. Efferent nerves (motor)Parasympathetic supply M3 receptors in bronchial smooth muscles and glands.No sympathetic supply but ß2 receptors in bronchial smooth muscles and glands
21. Classification of drugsRELIEVERS (RESCUE MEDICATIONS)β2 Agonists Anticholinergic AgentsMethylxanthines CONTROLLERS GlucocorticoidsLeukotrienes pathway inhibitorsCromonesAnti-IgE therapy
22. DrugsAdenyl cyclase cAMP Short acting main choice in acute attack of Asthma InhalationB2 agonists Salbutamol, Terbutaline Long acting, Prophylaxis Nocturnal AsthmaSalmeterol, FormoterolBlocks M3 receptorsMain drugs For COPDInhalationInhalationAntimuscarinicsIpratropium (Short)Tiotropium (long)Inhibits phosphodiesterase cAMP(orally)(parenterally)Xanthine derivativesTheophyllineAminophyllineBronchodilators (relievers for bronchospasm)
23. InhalationCorticosteroids (Inhibits phospholipase A2)Beclomethasone, Fluticasone, Budesonide OrallyprednisoloneparenterallyHydrocortisoneInhalation, prophylaxis in childrenMast cell stabilizersCromoglycate (Cromolyn), NedocromilorallyCysteinyl Leukotriene antagonistsZafirlukastInjection, SCOmalizumab (Anti IgE antibody)Anti-inflammatory drugs (prophylactic)
24. β2 Agonists in asthma Bronchodilators, Usually given by inhalation route. MOA: Relaxation of airway smooth muscleNon-bronchodilator effectsInhibition of mast cell mediator releaseReduction in plasma exudationIncreased mucociliary transportInhibition of sensory nerve activation Inflammatory cells express β2 receptors but these are rapidly downregulated.No effect on airway inflammation and AHR.
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26. β2 Agonists in asthmaShort-Acting β2 Agonists Salbutamol Terbutaline Bambuterol PirbuterolMetaproterenol Long-Acting β2AgonistsSalmeterol Formoterol
27. Short-Acting β2 Agonists Duration of action : 3-6 hrs.Convenient, rapid onset, without significant systemic side effectBronchodilator of choice in acute severe asthmaUsed for symptomatic relief on as required basis.Only treatment required for mild, intermittent asthma.Use >2 times a week indicates need of a regular controller therapy.
28. Long-Acting β2AgonistsDuration of action >12 hrs.Used in combination with inhaled corticosteroid (ICS) therapy.Improve asthma control and reduce frequency of exacerbations.Allow asthma to be controlled at lower dose of ICS.Fixed dose combination of corticosteroid with long acting β2 agonist : e.g. Salmeterol + Fluticasone, Formoterol + Budesonide.
29. Long-Acting β2AgonistsShould not be used as monotherapy (increased mortality).Combination shows synergistic action.Not effective for acute bronchospasm.Salmeterol : slow onset, 2 puffs of 25 μg twice a dayFormoterol : rapid onset, 2 puffs of 6 μg twice a day
30. Risks with LABA monotherapyMeta-analyses have shown that LABAs are associated with increased risk of overall death when used as monotherapy. The use of LABAs concomitantly with inhaled corticosteroids significantly reduces asthma hospitalizations and is not associated with life-threatening events and asthma-related deaths.The evidence appears to support the use of LABAs plus inhaled steroids in a single inhaler device for patients with moderate to severe asthma. Thorax 2012;67:342-349
31. ADRs – β2 agonistsMuscle tremorsTachycardiaHypokalemiaHypoxemiaRestlessnessCautious use –HypertensionIschemic heart disease
32. Anticholinergic agentsIpratropium bromide, Tiotropium.Prevent cholinergic nerve induced bronchoconstriction.Block M3 receptor on bronchial smooth muscles. Less effective than β2 agonists.Response varies with existing vagal tone.
33. Anticholinergic agentsUse in asthmaIntolerance to inhaled β2 agonist.Status asthmaticus – additive effect with β2 agonist.Ipratropium -- bitter taste, precipitate glaucomaTiotropium – longer acting, approved for treatment of COPD.
34. Methylxanthines Theophylline, Theobromine, CaffeineRecently interest has declined in this class of drugs:Side effectsNeed for plasma drug levels monitoringPharmacokineticsAvailability of other effective drugsStill widely used in developing countries due to their lower cost.Availability of slow release tablets – stable plasma levels
35. Methylxanthines: MOAInhibition of several members of the phosphodiesterase (PDE) enzyme familyInhibition of cell-surface receptors for adenosineEnhancement of histone deacetylation.
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37. Methylxanthines Theophylline base is poorly soluble in water.Soluble salts of theophylline:Aminophylline -85%Etophylline – 80%Oxtriphylline -64%
38. ADRs of TheophyllineAt conc >20 mg/L : Anorexia, nausea, vomiting, abdominal discomfort, headache, and anxiety start (PDE4 inhibition)At conc.>40 mg/L : Seizures or arrhythmias (A1 receptor antagonism)
39. DoxoyphyllineLong acting, oralInhibit PDEAdenosine A1 & A2 reduced affinitysafeDose - 400mg OD
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