Asthma Management Pharmacological Therapy

1. Asthma Management Pharmacological Therapy • Presented by: • Hengameh Raissy, PharmD

2. Four Components of Asthma Management NAEPP. EPR-3, page 1. Assessment and Monitoring Control of Factors Contributing to Asthma Severity Education for a Partnership in Asthma Care Pharmacological Therapy

3. This lesson will cover:

4. What is Asthma? • Asthma is a chronic inflammatory disorder of the airways • A key principle of therapy is regulation of chronic airway inflammation • Bronchospasm is what you see as cough and wheeze • Inflammation is what you don’t see but is at the center of the process

5. Pathophysiology of Asthma Environmental Risk Factors Genetic Predisposition INFLAMMATION Airway Hyperresponsiveness Airflow Limitation bronchospasm Precipitants Symptoms Cough Wheeze Shortness of Breath Adapted with permission from Stephen T. Holgate, MD, D. Sc.

6. The Pharmacological Treatment of Asthma can focus on one or both aspects of the disease…

7. Asthma: The Chronic Disease

8. The Risk of Asthma in a Wheezing Child 0-3 years: Modified Asthma Predictive Index In the past 12 months, >3 episodes of wheezing with at least OR +strict API = 9.8x likely to have active asthma when 6-13y/o +loose API= 5.5x likely to have active asthma when 6-13 y/o - strict API = NPV ≥ 95% no asthma Guilbert TW, et al JACI 2004

9. Classifying Asthma Severity: 0 – 4 years The Chronic Disease Classifying severity in children who are not currently taking long-term control medication.

10. Initial Therapies / Stepwise Approach: Asthma Patients 0-4 Years of Age D D Step 6 Preferred: High-dose ICS + either LABA or Montelukast OSC Step Up If Needed (first, check adherence, inhaler technique, environmental control) Recommend consult D Step 5 Preferred: High-dose ICS + either LABA or Montelukast D Step 4 Preferred: Medium-dose ICS + either LABA or Montelukast Consider consult Step 3 Preferred: Medium-dose ICS A Step 2 Preferred:Low-dose ICS Alternative:Cromolyn or Montelukast Step 1 Preferred:SABA PRN AssessControl Step Down If Possible (and asthma is well controlled at least 3 months) Mild Moderate Severe Intermittent Persistent Each Step: Patient education, environmental control, management of co morbidities If alternative treatment is used and response is inadequate, discontinue it and use the preferred treatment before stepping up ICS = inhaled corticosteroid; LABA = long-acting beta2-agonist; OSC = Oral Systemic Corticosteroids.; SABA = inhaled short-acting beta2-agonist.

11. Assessing Control: 0 – 4 years

12. Classifying Asthma Severity: 5 – 11 years The Chronic Disease Classifying severity in children who are not currently taking long-term control medication.

13. Initial Therapies / Stepwise Approach:Asthma Patient 5-11 Years of Age D B Step 6 Preferred:High-doseICS + LABA + OSC Alternative: High dose ICS + either LTRA or Theophylline +OSC Step Up If Needed (first, check adherence, inhaler technique, environmental control) B Step 5 Preferred: High-dose ICS + LABA Alternative: High dose ICS + either LTRA ortheophylline Recommend consult B Step 4 Preferred: Medium-dose ICS + LABA Alternative: Medium-dose ICS +either LTRA or theophylline Consider consult Step 3 Preferred Medium-dose ICS OR Low-dose ICS + either LABA, LTRA or theophylline A Step 2 Preferred:Low-dose ICS Alternative:Cromolyn LTRA Nedocromil or theophylline Step 1 Preferred:SABA PRN AssessControl Step Down If Possible (and asthma is well controlled at least 3 months) Mild Moderate Severe Intermittent Persistent Each Step: Patient education, environmental control, management of co morbidities Steps 2-4: Consider subcutaneous allergen immunotherapy for patients with allergic asthma ICS = inhaled corticosteroid; LABA = long-acting beta2-agonist; LTRA= leukotriene receptor antagonist; OSC = Oral Systemic Corticosteroids; SABA = short-acting beta2-agonist.

14. Asthma Control: 5 – 11 years

15. Classifying Asthma Severity: 12 and older The Chronic Disease Classifying severity for patients who are not currently taking long-term control medication.

16. Initial Therapies /Stepwise Approach: Asthma Patients > 12 Years of Age B Recommend consult B Step 6 Preferred:High-doseICS + LABA + OSC And Consider Omalizumab for patients who have allergies Step Up If Needed (first, check adherence, inhaler technique, environmental control) B/D Step 5 Preferred:High-dose ICS + LABA And Consider Omalizumab for patients who have allergies Consider consult A/B/D Step 4 Preferred:Medium-dose ICS + LABA Alternative: medium dose ICS + LTRA, theophylline or zileuton Step 3 Preferred: Medium-dose ICS or Low-dose ICS + LABA Alternative: Low dose ICS + LTRA, theophylline or zileuton A Step 2 Preferred:Low-dose ICS Alternative:CromolynLTRA or theophylline Step 1 Preferred:SABA PRN Step 1 Preferred:SABA PRN AssessControl Step Down If Possible (and asthma is well controlled at least 3 months) Mild Moderate Severe Intermittent Persistent Each Step: Patient education, environmental control, management of co morbidities Steps 2-4: Consider subcutaneous allergen immunotherapy for patients with allergic asthma ICS = inhaled corticosteroids; OSC = Oral Systemic Corticosteroids; SABA = short-acting beta2-agonist; LABA = long-acting beta2-agonist; LTRA= leukotriene receptor antagonist.

17. Asthma Control: 12 and older

18. What’s New: The ED / Hospital • Severity assessment has been simplified and lung function measurement is emphasized • Lower doses of systemic corticosteroids (OCS); 1mg/kg may be enough • Education on site and as part of discharge plan • Initiation of controller inhaled corticosteroids (ICS) for persistent asthma recommended • If hospitalized, ipratropium is not recommended (2 studies) NAEPP. EPR-3, pages 102-106.

19. Severity Assessment of Acute Flares

20. Classifying Severity- of Acute Disease (Asthma Exacerbations)

21. Managing Asthma: Acute Exacerbations The Acute Disease Impending respiratory failure: oxygen; iv access; alb/atrovent; bolus solumedrol; admit to ICU; prepare for intubation Severe: oxygen; 3 albuterol nebs w/ atrovent or continuous albuterol; i.v. or oral methylpred 1-2 mg/kg admit to hospital Moderate: oxygen; albuterol nebulization q 20 min x 3; oral corticosteroids 1-2 mg/kg for 3-5 days; treat co-morbidities Mild: albuterol MDI (w/ spacer), or nebulizer treatment up to 3 times; consider oral corticosteroid

22. Medications

23. Pharmacological Therapy Inhaled Medication: • In general, inhaled therapy is favored over systemic (oral) therapy for asthma • The medication is delivered on site and avoids most adverse side effects NAEPP. EPR-3, page 216.

24. Inhaled Medication Delivery Devices

25. Metered Dosed Inhalers Transition to non-CFC containing inhalers: • Many MDIs used chlorofluorocarbons (CFCs) as propellants. • CFCs were phased out globally in 2008 to protect the earth’s ozone layer • Hydrofluroalkaline (HFA) inhalers are the non-CFC alternative • DPIs (breath actuated Dry Powder Inhalers) are non-CFC compliant

26. Overview of Asthma Medications Daily Long-Term Control: • Corticosteroids (inhaled and systemic) • Long-acting beta2-agonists (salmeterol, formoterol) when in combination with ICS • Leukotriene modifiers (montelukast) • Leukotriene inhibitors (zileuton) • Mast cell stabilizers (cromolyn or nedocromil) • Methylxanthines (theophylline)

27. Long-Term Control Inhaled Corticosteroids (ICS): • Most effective long-term-control therapy for persistent asthma • Risk for adverse events is minimal at recommended low/medium inhaled doses • Risk depends on dose and delivery method

28. Inhaled Corticosteroids • Benefit of daily use: • Reduced airway inflammation • Improved lung function • Reduced use of quick-relief medicine • Fewer symptoms and exacerbations • In usual doses ICS do not provide short-term relief • Must be used daily for full benefit

29. Low-dose ICS and the Prevention ofDeath from Asthma 2.5 2.0 1.5 1.0 0.5 0.0 Rate Ratio for Death from Asthma 1 2 3 4 5 6 7 8 9 10 11 12 No. of Canisters of Inhaled Corticosteroids per Yr. Suissa S et al. N Engl J Med. 2000;343:332-336.

30. Effects of Inhaled Steroids on Airway Inflammation Pre– and post–3-month treatment with budesonide (BUD) 600 mcg b.i.d. E = Epithelium; BM = Basement Membrane J Allergy Clin Immunol. 1992;90:32-42.

31. Inhaled Corticosteroids Possible Dose-Dependent side effects: • Oral candidiasis (thrush) • Dysphonia • Reflex cough and bronchospasm • Slowed linear growth velocity • Decreases in bone mineral density • Dermal thinning and skin bruising • Ocular effects: glaucoma, cataracts

32. CAMP Trial and Follow-up Design Screening and Baseline Treatment Trial Follow-up Transition Routine Care 2 visits 5visits 1-4 visits per year 3 visits per year 2 - 4 months 4 – 6 years 13 years 4 months Enroll in follow-up study Refer back to PCP for Rx per NAEPP guidelines Study Rx Discontinued Randomize Budesonide Nedocromil Placebo Enrollment in trial: Dec 1993 – Sept 1995 1,041 children age 5-13 years at randomization Mild to moderate persistent asthma

33. Change in Bone Densityat End of CAMP Trial Budesonide vs. Placebo = - 0.01, P = 0.53 Nedocromil vs. Placebo = - 0.01, P = 0.15 Budesonide Nedocromil Placebo (n = 304) (n = 306) (n = 410)

34. Bud vsPlbo: P=0.001 P=0.001 P=0.10 Ned vsPlbo: P=0.61 P=0.26 P=0.98 Bud by sex interactio, P=0.10 Mean Obtained Adjusted Adult Height cm Bud–Plbo diff.: (95% CI) -1.8 cm (-2.9 to -0.7) -0.8 cm (-1.8 to 0.2) -1.2 cm (-1.9 to -0.5) *Means adjusted for race/ethnicity, clinic, and age, asthma duration and severity, skin test reactivity, and height at trial entry. Total panel also adjusted for sex.

35. ICS Metabolism

36. Inhaled Corticosteroids Reduce potential for adverse events by: • Rinsing mouth • Using lowest dose possible that results in control • Use in combination with long-acting beta2-agonists (LABA) or a leukotriene modifier if moderate/severe disease

37. Inhaled Corticosteroids Comparative Dosages: HFA ≠ DPI ≠ MDI ≠ respules • Preparations are not equivalent per puff or per microgram • Comparative doses are estimated. • Few data directly compare preparations

38. Chemical Structure of Inhaled Corticosteroids

39. Inhaled Corticosteroids 40, 80 ug/puff Beclomethasone (QVAR) Budesonide (Pulmicort) Flexhaler: 90, 180 110 ug/puff 44 ug/puff 220 ug/puff Budesonide (Pulmicort) .5mg, 1.0mg Mometasone (Asmanex) Fluticasone (Flovent HFA) 110, 220 ug/puff

40. Estimated Comparative Daily Dosages of Inhaled Corticosteroids for Adults

41. Long-Acting Beta2-Agonists (LABA)salmeterol (serevent), formoterol (foradil) May be beneficial when added to inhaled corticosteroids as an adjunct Do not have anti-inflammatory properties alone Asthma may worsen if used as mono-therapy LABA’s are not recommended for use as mono-therapy for long term control of persistent asthma Not appropriate for quick relief

42. Use of Salmeterol Alone to Treat Asthma • 28 week, randomized, double-blind, placebo-controlled; 164 patients; 12 - 65 yrs. old • Persistent asthmatics controlled on Triamcinolone 400 mcg bid Treatment Failure Rate Treatment arms: Placebo Change to Salmeterol Continue ICS JAMA 2001;285:2583-93.

43. Is there a problem with inhaled long-acting B-adrenergic agonists (LABA)?Harold Nelson, MD J Allergy Clin Immunol Jan. 2006 LABA’s by themselves have no significant anti-inflammatory effects and should be used with ICS When used with ICS most studies have not identified an increased risk of death or near death from asthma Re-analysis of the pattern of asthma deaths suggest that in patients with limited access to care, symptomatic relief provided by LABA’s may result in delays in seeking medical care in the face of increasing airway inflammation

44. Long-Term Control Leukotriene Modifiers • Mechanisms • 5-LO inhibitors –zileuton (Zyflo) • Cysteinyl LeukoTriene Receptor Antagonists montelukast (Singulair), zafirlukast (Accolate) • Indications • Monotherapy in mild persistent asthma • Add-on therapy in moderate to severe persistent asthma

45. Combination Therapy Dulera • MomestasoneFuroate • FormoterolFumarate • MDI • 100/5 mcg • 200/5 mcg • Patients 12 and older

46. Combination Therapy Symbicort • Budesonide • FormoterolFumarate • MDI • 80/4.5 mcg • 160/4.5 mcg • Patients 12 and older

47. Advair® • -DPI: Breath Actuated Dry Powder Inhaler • MDI HFA • Fluticasone propionate and samleterol DPI Doses: 100/50* mcg 250/50 mcg 500/50 mcg MDI doses 45/21 mcg 115/21 mcg 230/21 mcg *approved > 4 yrs The rest of the doses are approved for 12 years and older

48. Why use fixed combinations? DO NOT use unless both medications are necessary to control asthma…. • The asthmatic who needs moderate persistent therapy and who has failed on appropriate doses of inhaled corticosteroids • The challenging patient • Facilitate compliance • Decrease the number of inhalation devices • Improve patient inventory control

49. Currently Approved Controller Therapy for Asthma in Children Montelukast Nebulized Budesonide Budesonide and Formoterol DPI Budesonide DPI Fluticasone and Salmeterol DPI Mometasone DPI Beclomethasone HFA Flunisonide Triamcinolone 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 FDA-Approved Ages (Years) for Use in Children

50. Cationic Protein Release , Decreased Mucus Transport Mucus Transport Epithelial Cell Damage Airway Epithelium Eosinophil Influx Sensory Nerves Increased Mucus Secretion (C-Fibers) Contraction & LTD4 Edema Proliferation Blood Vessel Airway Smooth Muscle Inflammatory Cells (e.g. Mast Cells, Eosinophils) Role of Leukotrienes in Asthma Adapted from Hay DWP et al. Trends Pharmacol Sci 1995;16:304-309