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Management of Bronchial Asthma

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Management of Bronchial Asthma

  2. 2. In the Name of Allah the Most Gracious, the Most Merciful
  3. 3. MODERN TRENDS IN THE MANAGEMENT OF BRONCHIAL ASTHMA SummaryAirway inflammation is recognized as the most criticalcomponent of asthma, and this may be present even inthe absence of severe symptoms. Present day therapycomprises bronchodilators i.e. B-agonists, t heophyllineand anticholinergic, and anti inflammatory drugs i.e.Corticosteroids, Leukotrein Inhibitors and cromolyn.Inhaled corticosteroids and Leukotrein Inhibitors, are thefirst-line therapy both to prevent and control symptoms.In recommended dosages these medications are safeand well tolerated.
  4. 4. Definitions:Asthma is a complex and heterogeneous disordercharacterised by:a) Reversible airway constrictionb) Airway inflammation andc) Airway hyper-responsiveness to a wide variety ofstimuli.In asthma, there is paroxysmal bronchospasm, mucosaloedema, mucus hypersecretion, inflammatory infilterates inthe bronchial wall,bronchial epithelial damage anddesquamation, and glandular hypertrophy. The degree ofbronchial hyper-responsivences is related to the extant ofinflammation in airways.
  5. 5. Histopatholoqic Findings in Asthma:Airway inflammation is exhibited even in patientswith mild disease as seen in the following:-1) Denudation (Damage) of airway epithelium andits shedding.2) Deposition of collagen beneath the basement membrane (thicking of basement membrane).3) Mast Cell degranulation4) Oedema5) Inflammatory Cell infiltration  Eosinophils  Lymphocytes
  6. 6. Triggers of Asthma:1. Allergic - Immunological mechanisms plays important part.2. Non-allergic -without immunological mechanism. i) Infections ii) Aspirin Iii) Exercise iv) Irritants v) Occupational Exposures, vi) Emotional Upset. Both groups exhibit hyper reactive airways.
  8. 8. Inflammatory Cells:1. Mast Cells2. Eosinophils3. Epithelial Cells
  9. 9. Inflammatory Mediators:- Contribute to various features of asthmatic response.------Br: constriction, Microvascular leakage & mucus secretion.----- PG D2 and leukotrienes contribute to B.H.----- P.A.F. (Lipid Mediator) Stimulates a. Adhesion of Eosi: to vascular endothelium b. Release of Basic Proteins from Eosino. Epithelial Damage/Shedding Loss of Protective Epi. relaxing factor Bronchial Hyper responsiveness Exposes sensory nerves ----- Triggered More readily
  10. 10. Inflammatory Cells Involved in Asthma:-
  11. 11. Clinical Features of Asthma:- MILD MODERATE SEVERESymptoms Intermittent Chronic Continuous brief symptoms >2 times/week < 1-2 times/weekActivity/ Normal Affected Affected &Sleep LimitedNocturnal < 1-2 times/month > 2 times / month FrequentAsthmaSymptomsBetween Asymptomatic +/- FrequentExacerbations exacerbationsPEFR or FEV 1 > 80% predicted 60 - 80 % of < 60% predicted predictedPEFRorFEVI < 20% 20-30% > 30%VariabilityB-Agonists --- + ++daily requirement
  12. 12. Management of Asthma:- Control of Asthma means:-1. Minimal chronic symptoms including nocturnal symptoms2. Minimal exacerbations.3. Minimal or no need for B2 agonists.4. Normal activities, including exercise, can be undertaken.5. PEF circadian variation < 20%6. Near Normal PEF.7. Minimal or no adverse effects from medication. Asthma may be mild, moderate or severe.
  13. 13. Management of Bronchial Asthma:-a. Bronchodiators SOSb. Anti Inflammatory Drugs i) Steroid ii) Anti Leukotriene
  14. 14. Bronchodilator Drugs:-a. B-Adrenergic Agonist drugs.b. Methylxanthines (Theophylline),c. Anticholinergic Drugs.
  15. 15. B-adrenergic Agonist Drugs:-Mode of Action:-B-adrenergic agents —> stimulate enzyme adenyl cyclase —> which converts ATP intocyclic AMP. This increase of cyclic AMP leads to activation of protein kinase A, whichinhibits the phosphorylation of myosin and lowers intracellular ionic calciumconcentration, resulting in relaxation. B-Adrenergic agonists relax smooth muscle of allairways, from trachea to terminal bronchioles. B-Adrenergic agonists may inhibit the release of mediators from mast cells in the airways and release ofacetylcholine from postganglionic cholinergic nerves in the airways.B-Adrenergic agonists do not inhibit either the late response to allergens or thesubsequent brochial hyper-responsiveness. These actions may be related to the factthat B-Adrenergic agonists do not have an inhibitory effect on inflammatory cells thathave been implicated in both the late reponse and bronchial hyperresponsiveness.Clinical Use:-Sympathomimetics: L.A. = Long Acting i) Salbutamol (Ventolin) ii) Terbutaline(Bricanyl) iii) Fenoterol (Berotec) iv) Formoterol (L.A) v) Salmeterol (L.A) vi) TulobuterolBreemax(L.A)vii) Rimiterol(Pulmadil) viii) Porbuterol (Exirel)ix) Reproterol (Bronchodil). x) Others
  16. 16. Methylxanthines Theophylline:a. Mechanism of Actionb. Dosage and Clinical Use
  17. 17. Anti Inflammatory Drugs:-1. Cortico Steroids2. Cromolyn Sodium3. Leukotreins Inhibitors
  18. 18. Corticosteroids:-a. Effect on inflammatory & Airway Cellsb. Effect on Asthmatic Inflammationc. Effect on Air-way Hyper Responsiveness
  19. 19. Inhaled steroids and Dosages:-1. First Line Therapy for Chronic Asthma.2. Steroids required to control asthma in majority of Adults3. Doses upto 800 ug daily in adults and 400 ug daily in children are safe.4. Twice daily administration of inhaled steroids are quite effective.5. Orally administered steroids, such as prednisolone ormethylpredinsolone, are still required to control Asthma insome patients, but then there is risk of side effects, with dailydose exceeding 10 mg.
  20. 20. Guidelines for Oral Steroid Therapy are:-1. Start with high doses for exacerbation (e.g. prednisolone 30-60 mg/day). Dose will depend upon extent of exacerbation, and patients oral maintenance dose.2. After control of symptoms, tapper rapidly (within 5-7 days) to baseline steroid dose.3. For "Chronic" patients, try to keep daily dose of prednisolone below 10 mg/day.4. Give daily morning dose only. This will eliminate or reduce the suppression of hypothalamic pituitary-adrenal axis (HPA axi).5. Attempt alternate-day steroids if more than 7.5mg prednisolone/day is required. Then "On" days initial dose is to be 2-3 times.6. Use beclomethasone dipropionate aerosol or otherinhaled steroids alongwith for ultimately eliminating or reducing dose of oral prednisolone.
  21. 21. Asthma Therapy:- MILD MODERATE SEVERECORTICOSTEROIDSInhaled _ +200 to 1000 ug +800 to 1400 ugOral _ _ +Parenteral _ _ +CROMOLYN +/- +/- _B-AGONISTSInhaled + + +Oral + + +THEOPHYLLINE _ +SR + SR
  22. 22. Importance of Inflammation in AsthmaAdapted from National Institutes of Health Global Initiative for Asthma: Global Strategy for Asthma Management andPrevention: A Pocket Guide for Physicians and Nurses. Publication No. 95-3659B. Bethesda, MD: National Institutesof Health, 1998; Bjermer L Respir Med 2001;95:703-719.
  23. 23. Leukotrienes: Important in Early Asthma and Throughout the Disease Other inflammatory mediators Leukotrienes No Inflammation Asthma InflammationAdapted from Holgate ST, Peters-Golden M J Allergy Clin Immunol 2003;111(1 suppl):S1-S4; Holgate ST et al J AllergyClin Immunol 2003;111(1 suppl):S18-S36; Henderson WR Jr et al Am J Respir Crit Care Med 2002;165:108-116; Peters-Golden M, Sampson AP J Allergy Clin Immunol 2003;111(1 suppl):S37-S42; Varner AE, Lemanske RF Jr. In Asthma andRhinitis. Oxford, UK: Blackwell Science, 2000:1172-1185.
  24. 24. Dual Pathways of Inflammation Effects of the CysLT1 Receptor on Inflammatory CellsLung Macrophage Eosinophils Smooth- muscle cell Monocytes PBMC CysLT=cysteinyl leukotriene; PBMC=peripheral blood mononuclear cells Adapted from Figueroa DJ et al Am J Respir Crit Care Med 2001;163:226-233.
  25. 25. Dual Pathways of Inflammation Expression of the CysLT1 Receptor CD19 LN5 B Lymphocyte Macrophage Mast Cell M-CSF LTC4 Basophil LTD4 CysLT1R GM-CSF LTE4 M-CSF, GM-CSF, IL-3 CD14 LTC4, LTD4, LTE4 Monocyte IL5Rβ IL-5 CD34+ IL-3 Neutrophil Pluripotent GM-CSF LTC4 CCR3 hemopoietic LTE4 LTD4 stem cell T Cells Eosinophil Represents the CysLT1 receptor CD4+ CD8+Adapted from Figueroa DJ et al Am J Respir Crit Care Med 2001;163:226-233; Mellor et al Proc Natl Acad Sci USA 2001;98:7964-7969
  26. 26. Dual Pathways of InflammationLeukotrienes Are Powerful Inflammatory Mediators CysLT Other Mediator CysLTreceptor mediators receptor Adapted from Peters-Golden M, Sampson AP J Allergy Clin Immunol 2003;111(suppl 1):S37-S48.
  27. 27. Dual Pathways of Inflammation Actions of LTRAsLeukotrienes are highly specific but catalyzea massive inflammatory cascade  Suppress many inflammatory mediators  Suppress inflammatory processes  Via the leukotriene pathway  Via the steroid-sensitive pathway LTRAs = leukotriene receptor antagonists Adapted from Peters-Golden M, Sampson AP J Allergy Clin Immunol 2003;111(suppl 1):S37-S48.
  28. 28. Dual Pathways of Inflammation Central Role of CysLTs in Asthma Decreased Mucus Transport Cationic Protein Release, Epithelial-Cell Damage AirwayEpithelium Eosinophil Sensory Increased Influx Nerves Mucus (C fibers) Secretion Contraction and Edema CysLTs Proliferation Blood Vessel Inflammatory Cells Airway Smooth Muscle (mast cells, eosinophils) Adapted from Hay DWP et al Trends Pharmacol Sci 1995;16:304-309.
  29. 29. Airway Inflammation Persisted Despite Corticosteroid UseIn a clinical study of 74 patients p<0.01 p<0.001 20,000 10,000 p<0.001 p<0.01 1,000Eosinophil × 103/g sputum 100 10 1 Control ICS ICS OCS OCS ± ICS group low-dose high-dose (n=10) (n=7) (n=10) (n=15) Mild to moderate Severe asthmaICS=inhaled corticosteroids; OCS ± ICS=received oral corticosteroids with or without ICSAdapted from Louis R et al Am J Respir Crit Care Med 2000;161:9-16.
  30. 30. Dual Pathways of Inflammation Long-Acting Beta2 Agonists Did Not Have Anti-inflammatory EffectsLTRA montelukast further reduced inflammation whenadded to ICS ICS + LABA + ICS + ICS + Montelukast Montelukast LABA ICS 0Change ineosinophils (× 106/L) –100from run-in –200 p<0.05 p<0.05 LABA = long-acting beta2 agonist Adapted from Currie GP et al Am J Respir Crit Care Med (in press).
  31. 31. Dual Pathways of Inflammation LTRA Montelukast Further Reduced Asthmatic Inflammation Complementary therapy that targets dual pathways of inflammation provided better control of inflammation 0.12 * 0.10 Eosinophil 0.08 counts (change 0.06from baseline × 103/µl) 0.04 0.02 <1* 0 Placebo Montelukast Beclomethasone Montelukast + beclomethasone Treatment group *p<0.05 compared with beclomethasone Adapted from LaViolette M et al Am J Respir Crit Care Med 1999;160:1862-1868.
  32. 32. Dual Pathways of Inflammation Montelukast Combined with a Steroid Affects the Dual Pathways of Inflammation CysLTs Steroid-sensitive play a key role mediators in asthmatic play a key role inflammation in asthmatic inflammation Steroids do NOT inhibit CysLT formation in the airways of asthmatic patients Montelukast Inhaled steroids blocks the block effects of steroid- CysLTs sensitive mediators DUAL PATHWAYAdapted from Peters-Golden M, Sampson AP J Allergy Clin Immunol 2003;111(1 suppl):S37-S42; Bisgaard H Allergy 2001;56(suppl 66):7-11.
  33. 33. Dual Pathways of Inflammation Airway Inflammation Correlated with Lung Function and Clinical Control PEFR Daily symptom FEV1 variability score 0 –0.2 rS –0.4 –0.36 –0.43 –0.49 –0.51 –0.51 –0.52 –0.6 Absolute eosinophil counts ECP concentrationsFEV1 = forced expiratory volume in one second; PEFR = peak expiratory flow rate; rS = Spearman’s rank coefficient ofcorrelation; ECP = eosinophilic cationic proteinAdapted from Louis R et al Am J Respir Crit Care Med 2000;161:9-16.
  34. 34. Leukotriene Inhibitor:- Montelukast
  35. 35. Leukotriene Inhibitor:- Montelukast 5mg / 10mg Tablets (Montelukast) blocks cystienyl, receptors in human airwaysinhibiting LTD4 leukotriene attachment to these receptors leading to: 1. Minimized airway odema (Bronchial smooth muscles relaxation) 2. Minimized mucus secretion (By inhibiting the inflammation process)(Montelukast) Provides significant relief from symptomsof allergic rhinitis while also conferring a benefit for asthma inpatients with both allergic rhinitis and asthma.(Montelukast) administered once daily improved efficacywas well tolerated in pediatric patients with chronic persistentasthma establishing itself as a valuable treatment option to currentasthma therapies in 6 to 14 years old patients.
  36. 36. Others:1. Cromolyn Sodium2. Ketotifen3. Methotraxate4. Gold
  38. 38. Clinical1. Increased dyspnoea, fatigue, and stage of exhaustion.2. Altered mental state; cannot complete sentences.3. Increased bronchodilator needs.4. History of previous severe asthma attack.5. Recent upper respiratory tract infection – viral or bacterial.6. A more persistent obstruction due to mucus impaction.
  39. 39. Signs & Criteria1. Cyanosis2. Pulse rate > 120/minute3. Pulses paradoxus greater than 18-20 mmHg.4. Silent chest5. PEFR below 100/L minute or PEVI less than 0.5L, and failure to improve with bronchodilators.6. PaO2< 60 mmHg.7. PacO2 > mmHg.8. Low blood pH.9. Low serum Potassium.10. ECG – P Pullmonate.
  40. 40. Possible Complications.1. Mucus Plugging.2. Tension pneumothorax or pneumoperitoneum.3. Pulmonary oedema.4. Massive pulmonary collaspe.5. Arrhythmias.6. Hypovolemia.
  42. 42. TREATMENT1. I.V. route established.2. Oxygen by mask 6 L/min. & continue.3. High dose of Beta2 – agonist given & repeat every 20 minutes during 1st hour – preferably by nebulizer (10-15 puffs by spacer if nebulizer not available) – Repeat 4 hourly.4. Salbutamol subcut :/I.V.5. Oral prednisolone 30-60 mg or I.V. hydrocortisone 200 mg. & repeat 4 hourly.6. Slow I.V. aminophylline 250 mg. (if not taken orally)7. Arrange hospialization.8. If danger of imminent arrest – mechanical ventalation/oxygen mask +.
  43. 43. Conclusion:- SummaryTargeting Dual Pathways of Inflammation Improves Asthmacontrol1. Drug Inhalation is better than oral Administration2. Mild Asthmatics-Inhaled B2-Adrenergic against may be enough.3. Chronic Asthma-Anti Inflammatory Therapy must be introduced earlier.4. Cys LTs and steroid-sensitive mediators are two important pathway of inflammation in asthma5. Corticosteroids do not block the leukotriene-mendiated pathway of inflammation6. Treating dual pathways of inflammation in the airway of asthmatic patients may provide better control of inflammation and effective asthma control