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Asthma Update

Asthma Update. Suneel Kumar MD. Definition of Asthma. National Asthma Education and Prevention Program (NAEPP) defined as: Airway obstruction that is reversible (but not completely so in some subjects), either spontaneously or with treatment Airway inflammation

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Asthma Update

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  1. Asthma Update Suneel Kumar MD

  2. Definition of Asthma • National Asthma Education and Prevention Program (NAEPP) defined as: • Airway obstruction that is reversible (but not completely so in some subjects), either spontaneously or with treatment • Airway inflammation • Increased airway responsiveness to a variety of stimuli

  3. 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."

  4. Symptoms • Cough • Wheezing • Chest tightness • Shortness of breath

  5. Update in Asthma • Current guidelines for treatment of asthma • Beta agonist use • Inhaled corticosteroids • Leukotriene modifiers • Chromones • Anti-IgE therapy • Use of exhaled nitric oxide in monitoring asthma • Asthma during pregnancy

  6. Current Guidelines for Treatment

  7. Mild Intermittent Asthma • Symptoms < 2 days/week • Symptoms < 2 nights/month • PEF or FEV1> 80% • PEF variability < 20% • No daily medication needed • PRN beta agonists • Course of systemic steroids for exacerbations

  8. Mild Persistent Asthma • Symptoms > 2 days/wk but < 1x/day • > 2 nights/month • PEF or FEV1> 80% • PEF variability 20-30% • Preferred treatment low dose inhaled corticosteroids • Alternatives include cromolyn, leukotriene modifiers, necromodil, or sustained release theophylline

  9. Moderate Persistent Asthma • Symptoms daily • > 1 night/week • PEF or FEV1 > 60% and < 80% • PEF variability > 30% • Preferred treatment is low to medium dose inhaled corticosteroid and a long acting inhaled beta 2 agonist • Alternative includes increasing ICS within moderate dose range, or low to medium dose ICS with either leukotriene modifier or theophylline

  10. Severe Persistent Asthma • Continual symptoms • Frequent nocturnal attacks • PEF or FEV1< 60% • PEF variability > 30% • Preferred treatment is high dose inhaled corticosteroid and long acting beta 2 agonists • If needed, can add systemic corticosteroids

  11. Goals of Therapy • Minimal or no chronic symptoms day or night • Minimal or no exacerbations • No limitations on activities; no school/work missed • Maintain (near) normal pulmonary function • Minimal use of short-acting inhaled beta 2 agonist • Minimal or no adverse effects from medications

  12. Stepwise Approach • Review treatment every 1 to 6 months, and gradually step down treatment • If asthma controlled not maintained, then a step up in treatment may be warranted

  13. Reasons for Poor Asthma Control • Inhaler Technique • Compliance • Environment • Also assess for an alternative diagnosis • “All that wheezes is not asthma, and not all asthma wheezes”

  14. Factors Affecting Compliance • Support of health care professional and family • Route of drug administration (inhaled vs. oral) • Complexity of drug regimens • Side effects of medications • $$ Cost $$

  15. Beta 2 Agonists

  16. Beta 2 Agonists • Most potent and rapidly acting bronchodilators currently available for clinical use • Given in different forms: • short acting = isoproterenol • intermediate acting = albuterol, metaproterenol, pirbuterol, levalbuterol, terbutaline (IV only), fenoterol [not available in the US] • long acting = salmeterol, formoterol

  17. Mechanism of Action • Beta 2 agonists interact with beta 2 receptors on the surface of a variety of cells that may play a role in asthma pathogenesis • Beta agonists have the potential to relax bronchial smooth muscle, decrease mast cell mediator release, inhibit neutrophil, eosinophil, and lymphocyte functional responses, increase mucociliary transport, and affect vascular tone and edema formation

  18. MDI with Spacer vs. Nebulizer • Equivalent bronchodilation can be achieved by giving beta 2 agonist with a spacer/holding chamber or by nebulizer therapy • Continuous administration with a nebulizer may be more effective in severely obstructed adults and in those who have difficulty with an MDI plus spacer

  19. Chronic Use of Beta Agonists • Arguments against chronic use: • Mortality may be increased • Control of asthma may worsen • Equal or superior efficacy can be achieved with inhaled corticosteroids

  20. Increased Mortality with Chronic Use? • A case-control study using linked health insurance databases in Saskatchewan, Canada* • Increased risk of death or near-death from asthma was associated with the regular use of inhaled beta agonists, especially fenoterol (adjusted OR 6.1; 4.1 for albuterol) • Did not appear to be confounded by asthma severity, and there was no relation to non–asthma mortality *Spitzer et al, NEJM Feb 1992;326(8):501-6

  21. Increased Mortality with Chronic Use? • However, increased odds ratios were also noted for theophylline (OR 2.4) and oral corticosteroids (OR 2.5) • The case-control design precludes the establishment of causality *Spitzer et al, NEJM Feb 1992;326(8):501-6

  22. Increased Mortality with Chronic Use? • A subsequent analysis demonstrated a relationship between CV death and use of beta agonists taken orally or by nebulizer (RR = 2.4) but not when taken by MDI (RR = 1.2) • Risk of CV death was also greater in patients who used theophylline (RR = 2.7) • Most of CV deaths in patients with underlying CV disease, including acute coronary insufficiency and congestive cardiomyopathy* *Suissa et al, Am J Respir Crit Care Med 1996 Dec;154(6 Pt 1):1598-602

  23. Increased Mortality with Chronic Use? • A similar case-control study design demonstrated no evidence of any adverse effects on mortality with prolonged use of long-acting beta agonists • Use of short-acting beta agonists in the 12 months prior to an index event was not associated with an increased risk of death from asthma, suggesting a direct causal relationship was unlikely* *Anderson et al, BMJ 2005 Jan 15;330(7483):117

  24. Long Acting Beta Agonist Monotherapy • Prolonged treatment with long-acting beta agonists and without inhaled corticosteroids has been associated with increased mortality • 28-week placebo-controlled trial assessing the safety of the long-acting beta agonist salmeterol enrolled over 25,000 patients, but was stopped early when interim analysis revealed a significantly increased risk of death in those not taking concomitant inhaled corticosteroids and, independent of steroid therapy, in African-American patients* *"The Pink Sheet" FDC Reports. Chevy Chase, MD. 2003; 65(4):10

  25. Tolerance to Beta Agonists • More frequent in chronic use • Induced more with oral rather than inhaled preparations • Tolerance to long acting beta agonists may or may not occur (conflicting data)

  26. Corticosteroids

  27. Glucocorticoids • Most potent antiinflammatory agents available for the treatment of asthma • More effective than beta agonists, theophylline, and cromolyn sodium in reducing airway hyperresponsiveness during maintenance therapy

  28. Glucocorticoid Mechanisms • Alleviating airway inflammation • Reducing collagen and tenascin deposition, two features associated with airway remodeling • Inhibit the synthesis of almost all known cytokines • Alteration of the number and availability of circulating leukocytes • Reduction in vascular permeability • Inhibition of mediator synthesis and release

  29. Steroids and Long Acting Beta Agonists • Results in greater improvements in lung function and symptom control than monotherapy with escalating doses of inhaled glucocorticoid • Act synergistically to activate transcription factors, decrease smooth muscle proliferation, and impair eosinophil adhesion

  30. Potency of Inhaled Corticosteroids

  31. Can ICS Cause Osteoporosis? • Three year prospective study looked at dose of inhaled triamcinolone and rate of bone loss in premenopausal women with asthma • There was a dose-related decline in bone density in the total hip and trochanter • No dose-related decline in the femoral neck or spine* *Israel et al, NEJM Sept 2001;345:941-47

  32. Leukotriene Modifiers

  33. Leukotriene Modification • 5-lipoxygenase pathway is a series of biochemical reactions that result in the transformation of arachidonic acid into leukotrienes • Produced by eosinophils and mast cells when appropriately activated

  34. Leukotriene Modifiers • Zafirlukast (Accolate) and montelukast (Singulair) are inhibitors of the action of LTD4 at its receptor • Zileuton (Zyflo) is an inhibitor of 5-lipoxygenase • All are oral

  35. Leukotriene Modifiers • Superior effect when compared to placebo in the treatment of patients with mild to moderate asthma • Associated with both a significant decrease in the need for rescue beta agonist therapy and improved asthma symptoms, especially at night • Similar in magnitude to those achieved with inhaled steroids given at recommended doses

  36. Montelukast vs. Beclomethasone • Both agents demonstrated similar efficacy with respect to preventing asthma exacerbations in moderate persistent asthma • However, beclomethasone was significantly superior to montelukast in its capacity to improve objective measures of lung function as measured by average responses

  37. Cause of Churg-Strauss? • Rarely (1 out of 25,000 to 150,000 patient-years of treatment) Churg-Strauss vasculitis has been seen in patients started on leukotriene modifiers who were on systemic steroids • It is unlikely that this is a direct effect of leukotriene inhibition in these patients, and is more probably due to preexisting CSS unmasked as a result of steroid withdrawal

  38. Chromones

  39. Chromones • Cromolyn sodium and nedocromil • Act as mast cell stabilizers by inhibiting chloride channels (thereby stopping degranulation) • Remarkably favorable therapeutic indices

  40. Use of Chromones • Children and young adults with mild to moderate asthma requiring an antiinflammatory agent • Patients with a strong allergic component to their asthma • Patients with exercise-induced bronchospasm • Patients who require an antiinflammatory agent but for whom ICS are contraindicated or undesirable

  41. Anti-IgE Therapy

  42. Anti-IgE Therapy • Most asthmatic patients have elevated circulating IgE concentrations when levels are adjusted for age • IgE is produced by B lymphocytes

  43. Anti-IgE Therapy • Recombinant humanized antibody omalizumab (Xolair) binds IgE with high affinity • Developed for the treatment of allergic diseases • Binds to the C-epsilon-3 domain of circulating IgE but does not bind to Fc-epsilon-RI, and therefore does not activate mast cells or basophils • Specific to IgE; does not bind to IgG or IgA

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