Asthma Management Pharmacological Therapy

Asthma Management Pharmacological Therapy
[add speaker info] What is expected of the facilitator of this topic? A working knowledge of the NAEPP EPR-3 and asthma management including– pathophysiology; classifying asthma severity depending on age; determining control based on age; pharmacological therapy; alternative therapies; asthma medicine delivery devices. Participants will need a brief understanding of the differences between these factors and ways to reduce exposure. About this section…Asthma Management: Pharmacological Therapy is intended to be taught in 90 minutes and contains 75 slides. There are five case studies (see slide 68) at the end of the presentation that should take approximately 20 minutes to complete. There is one handout on Inhaled Medications that should be handed out and referred to during this presentation. Presented by: Hengameh Raissy, PharmD

Four Components of Asthma Management
Assessment and Monitoring Control of Factors Contributing to Asthma Severity Education for a Partnership in Asthma Care Pharmacological Therapy This talk will focus on Pharmacology. (We have covered the first three components in previous lessons.) The expert panel organized the recommendations for the treatment of asthma around four components of effective asthma management: Use of objective measures of lung function to assess the severity of asthma and to monitor the course of therapy Environmental control measures to avoid or eliminate the factors that precipitate asthma symptoms or exacerbations Patient education that fosters a partnership among the patient, his or her family, and clinicians; and Comprehensive pharmacological therapy for long-term management designed to reverse and prevent the airway inflammation characteristic of asthma as well as pharmacological therapy to manage asthma exacerbations. NAEPP. EPR-3, page 1.

This lesson will cover:
Asthma Classification Schemes Stepwise Approach to Asthma Therapy Asthma Medications and Delivery Devices New/Complementary/Alternative In this lesson, we will cover: [read slide]

Asthma is a chronic inflammatory disorder of the airways
What is Asthma? Asthma is a chronic inflammatory disorder of the airways A key principle of therapy is regulation of chronic airway inflammation Sets the stage once again for “What is asthma?” Just a quick review (this has been covered in a previous lesson). Bronchospasm is what you see as cough and wheeze Inflammation is what you don’t see but is at the center of the process

Pathophysiology of Asthma
Environmental Risk Factors Genetic Predisposition INFLAMMATION Airway Hyperresponsiveness bronchospasm Airflow Limitation Note to presenter: This has been covered in detail in lesson 3: Asthma Overview. Review, but don’t spend too much time on this slide. Precipitants Symptoms Cough Wheeze Shortness of Breath Adapted with permission from Stephen T. Holgate, MD, D. Sc.

(exacerbating) Disease:
The Pharmacological Treatment of Asthma can focus on one or both aspects of the disease… The Chronic disease: Intermittent Mild Persistent Moderate Persistent Severe Persistent The Acute (exacerbating) Disease: Mild Moderate Severe Respiratory Failure Setting the stage of what will be talked about with this slide.

Asthma: The Chronic Disease
Classification of Severity Stepwise Approach to Therapy Assessment of Control Again, this will be detailed in a later slide. We will have hand outs for the 0-4, 5-11 and 12 and older to refer to through out the presentation.

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 Major Criterion Parental history of asthma Physician-diagnosed atopic dermatitis Allergic sensitization to ≥1 aeroallergen Minor Criterion Wheezing unrelated to colds Blood eosinophils ≥4% Allergic sensitization to milk, eggs, or peanuts OR API=Asthma Predictive Index NPV=Negative Predictive Value +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

Classifying Asthma Severity: 0 – 4 years
The Chronic Disease Components of Severity Intermittent Persistent Mild Moderate Severe Impairment Symptoms  2 days/week >2 days/week but not daily Daily Throughout the day Nighttime awakenings None 1-2x/ month 3-4x/month >1x/ week B-agonist use (not prevention of EIB) Several times per day Activity limits Minor Limitation Some Extremely Limited Risk Exacerbations requiring OSC 0-1/yr  2 exacerbations in 6 months requiring oral systemic corticosteroids, or  4 wheezing episodes/ 1 year lasting >1 day AND risk factors for persistent asthma [at the click of the mouse, the slide will highlight two rows (nighttime awakenings and risk for persistent classifications). This helps to distinguish the two age groups under 12.] Note to presenter – there tends to be confusion about severity level, so you may need to spend some time explaining this. Severity level is used to establish a baseline Once severity level is established, then the focus in on assessing asthma control and adjusting therapy accordingly Remember, these charts are for classifying severity in children who are not currently taking long-term control medication. Classifying severity in children who are not currently taking long-term control medication.

Preferred: Low-dose ICS Alternative:Cromolyn or Montelukast
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 Assess Control Step Down If Possible (and asthma is well controlled at least 3 months) Step 2: Evidence category A (Randomized controlled trials with a rich body of evidence) Step 3, 4, 5 recommendations for 0-4 yrs are based on consensus opinion (D) distinguished in orange (different for the 5-11 age group) 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.

Assessing Control: 0 – 4 years
Components of Control Classification of Asthma Control Well Controlled Not Well Controlled Very Poorly Impairment Symptoms  2 days/wk >2 days/wk Throughout the day Nighttime awakenings  1x/month >1x/month >1x/week Activity limits None Some limitation Extremely limited B-agonist use (not prevention of EIB)  2 days/week >2 days/week Several times per day Risk Exacerbations requiring OSC 0-1/year 2-3/year >3/year Treatment-related adverse effects Medication side effects can vary in intensity from none to very troublesome and worrisome. The level of intensity does not correlate to specific levels of control but should be considered in the overall assessment of risk. For young children, fewer nighttime symptoms when compared to older age groups signify loss of control If well controlled for at least 3 months, the clinician may consider stepping down

Classifying Asthma Severity: 5 – 11 years
The Chronic Disease Components of Severity Intermittent Persistent Mild Moderate Severe Impairment Symptoms  2 days/wk >2 days/wk but not daily Daily Throughout the day Nighttime awakenings  2x/month 3-4x/month >1x/wk but not nightly Often 7x/wk B-agonist use (not prevention of EIB)  2 days/wk Several times per day Activity limits None Minor limitation Some Limitation Extremely limited Lung Function FEV1 FEV1/FVC >80% >85% 80% 60 – 80% % <60% <75% Risk Exacerbations requiring OSC 0-1/yr  2/year Lung function assessment is added in the 5-11 year age group and emphasized in the new guidelines Nighttime awakenings [at click will highlight] suggesting loss of control are different for this age group compared to the 0-4 year age group Classifying severity in children who are not currently taking long-term control medication.

Initial Therapies / Stepwise Approach: Asthma Patient 5-11 Years of Age
D B Step 6 Preferred: High-dose ICS + LABA + OSC Alternative: High dose ICS + either LTRA or Theophylline +OSC Step Up If Needed (first, check adherence, inhaler technique, environmental control) Recommend consult B Step 5 Preferred: High-dose ICS + LABA Alternative: High dose ICS + either LTRA or theophylline 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 Assess Control Step Down If Possible (and asthma is well controlled at least 3 months) Category B evidence (randomized control trials with limited body of evidence) supports recommendations for Steps 3, 4, 5 in children 5-11 years of age. 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.

Asthma Control: 5 – 11 years
Components of Control Classification of Asthma Control Well Controlled Not Well Very Poorly Impairment Symptoms  2 days/wk but not more than once on each day >2 days/wk or multiple times  2 days/wk Throughout the day Nighttime awakenings 1x/month ≥2x/month ≥2x/week Activity limits None Some limitation Extremely limited B-agonist use (not prevention of EIB) 2 days/wk >2 days/wk Several times per day Lung function FEV1 or PF FEV1/FVC 80% >80% 60 – 80% 75-80% <60% <75% Risk Exacerbations requiring OSC 0-1/year ≥2/year Reduction in lung growth Evaluation requires long-term follow-up Treatment-related adverse effects Medication side effects can vary in intensity from none to very troublesome and worrisome. The level of intensity does not correlate to specific levels of control but should be considered in the overall assessment of risk. Action steps for this group are similar the 0-4 year age group This is a good place to emphasize the NHLBI recommendation to: Review adherence to medications, inhaler technique, and environmental control when asthma control is an issue AND before stepping up on therapy.

Classifying Asthma Severity: 12 and older
The Chronic Disease Components of Severity Intermittent Persistent Mild Moderate Severe Impairment Normal FEV1/FVC: 8-19yrs 85% 20-39yrs 80% 40-59yrs 75% 60-80yrs 70% Symptoms  2 days/wk >2 days/wk but not daily Daily Throughout the day Nighttime awakenings  2x/month 3-4x/month >1x/wk but not nightly Often 7x/week B-agonist use (not prevention of EIB)  2 days/week >2 days/wk but not daily, and not more than 1x on any day Several times per day Activity limits None Minor limitation Some Limitation Extremely limited Lung Function FEV1 FEV1/FVC >80% normal 80% >60 -80% reduced 5% <60% reduced >5% Risk Exacerbations requiring OSC 0-1/yr  2/yr Spend time on the FEV1/FVC norms for varied age groups [at click, row will highlight]. Include discussion about new NHLBI terminology of impairment and risk. Assessment is generally determined by patient recall of the last 4 weeks, unless you are seeing them during an exacerbation; then review the weeks prior to the current exacerbation. For mild persistent asthma, Beta-agonist should not be needed more than once in any day when not experiencing an exacerbation If the patient is new to you (or periodically during re-evaluation) and already on medications, the classification is based on the lowest amount of medication required to maintain control. Classifying severity for patients who are not currently taking long-term control medication.

Initial Therapies /Stepwise Approach: Asthma Patients > 12 Years of Age
B Recommend consult B Step 6 Preferred: High-dose ICS + LABA + OSC And Consider Omalizumab for patients who have allergies Step Up If Needed (first, check adherence, inhaler technique, environmental control) Consider consult B/D Step 5 Preferred: High-dose ICS + LABA And Consider Omalizumab for patients who have allergies 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:Cromolyn LTRA or theophylline Step 1 Preferred: SABA PRN Step 1 Preferred: SABA PRN Assess Control Step Down If Possible (and asthma is well controlled at least 3 months) Levels of evidence for 12 and over for each step: A= Randomized control trials, rich body of evidence; B= Randomized control trials, limited body of evidence; D= panel consensus judgment Consider consultation with a sub-specialist at Step 3; Recommend a consultation with a sub-specialist (Allergy/ Immunology specialist or Pulmonologist) 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.

Asthma Control: 12 and older
Components of Control Classification of Asthma Control Well Controlled Not Well Very Poorly Impairment Symptoms  2 days/week >2 days/week Throughout the day Nighttime awakenings  2x/month 1-3x/week >4x/week Activity limits None Some limitation Extremely limited B-agonist use (not prevention of EIB) Several times per day Lung function FEV1 or PF >80% FEV1 or PF = % FEV1 or PF <60% QOL indicator ACT ≥20 ACT =16-19 ACT ≤15 Risk Exacerbations requiring OSC 0-1/year > 2/ year Reduction in lung growth Evaluation requires long-term follow-up Treatment-related adverse effects Medication side effects can vary in intensity from none to very troublesome and worrisome. The level of intensity does not correlate to specific levels of control but should be considered in the overall assessment of risk. A good place to talk about the QOL questionnaires referenced in EPR3, this version includes the ACT (Asthma Control Test) as an example of what can be used.

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) [each bullet will display one at a time as you advance the slide] This slide explains what’s in the new guidelines pertaining to emergency departments and hospitals NAEPP. EPR-3, pages

Severity Assessment of Acute Flares
Signs and Symptoms Initial FEV1 or PF Clinical Course Mild Dyspnea only with activity; RR in young PF/FEV1 > 70% home Relief w/ SABA Moderate Dyspnea interferes/limits usual activity PF/FEV1 = 40-69% Office or ED visit Response to SABA OCS Severe Dyspnea at rest; interferes w/ conversation; In infants use exam PF/ FEV1 < 40% O2 sat < 90% ED / Hospitalization + SABA response Adjunctive therapy Life Threatening Too dyspneic to speak / perspiring Hospitalization / ICU No relief SABA IV CS/ adjunctive Oxygen saturation is not usually necessary in the 2007 guidelines for mild and moderate exacerbations SABA= short-acting beta agonist; OCS =Oral corticosteroids; IV CS= intravenous corticosteroids

Classifying Severity- of Acute Disease (Asthma Exacerbations)
Symptoms/Exam Lung Function Mild -alert and oriented -speaks in sentences -expiratory wheezes; ↑ rr PF or FEV1 >70% O2 sat > 95% Moderate -agitated, not playful -speaks in phrases -wheeze; ↑ rr -may use access. muscles PF or FEV1=40-69% O2 sat = 90-95% Severe -breathless at rest -speaks in words -loud wheeze; ↑↑ rr PF or FEV1 <40% O2 sat < 90% Impending Failure -altered consciousness -silent chest - ↑↑ rr or slowing rr Reference page 380 NHLBI guidelines

Managing Asthma: Acute Exacerbations
The Acute Disease Managing Asthma: Acute Exacerbations 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 This is a simplified version of the NHLBI guidelines pg. 380 [Note to presenter: Go to Part 2. The next segment of this presentation covers medications and then case studies dealing with .] Mild: albuterol MDI (w/ spacer), or nebulizer treatment up to 3 times; consider oral corticosteroid

Medications [This is a continuation from Asthma Management – Pharmacological Therapy Part 1. Case Studies will follow this segment of the presentation.] Please note the American Lung Association does not endorse specific products. All products mention is to inform the audience for the purposes of the Certification Exam and should not be construed as an endorsement.

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 According to the EPR-3, ICS are the most potent and consistently effective long-term control medication for asthma (Evidence A). NAEPP. EPR-3, page 216.

Inhaled Medication Delivery Devices
Metered-Dose Inhaler (MDI) Dry Powder Inhaler (DPI) Spacer/ Holding Chamber Holding Chamber and Face Mask Nebulizer Pg 220, essentially no studies to support use of VHC and HFA- however, knowledge of the slower fine particular matter and negative charges would lead us to recommend a non-plastic spacing device over a plastic, positively charged device. Actual hands on of devices will be part two of this lecture in the format of stations or small groups.

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 [each bullet will display one at a time as you advance the slide] Discuss Montreal Protocol and how CFC’s were phased out in Dec 08. HFA molecule is a smaller and finer particle which feels different when inhaled Basic review of differences w/ devices.

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) [each medicine category will display one at a time as you advance the slide] 6

Inhaled Corticosteroids (ICS):
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 [each bullet will display one at a time as you advance the slide] 8

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 [each bullet will display one at a time as you advance the slide] 9

Low-dose ICS and the Prevention of Death from Asthma
2.5 2.0 1.5 1.0 0.5 0.0 Rate Ratio for Death from Asthma Population-based cohort study of 30,569 subjects from 5 to 44 years of age, followed from Of 562 deaths, 77 were classified due to asthma and 66 of these were matched to control patients (n=2681) who also had severe asthma. The rate of death from asthma decreased by 21% with each additional canister used during the previous year. The rate of death from asthma among users of inhaled corticosteroids compared with nonusers was reduced by 50% with the use of more than 6 canisters per year. No. of Canisters of Inhaled Corticosteroids per Yr. Suissa S et al. N Engl J Med. 2000;343:

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.

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 These effects are definitely dose dependent Despite the potential side effects, although rare, the EPR3 says, “The potential risks of ICS’s are well balanced by their benefits. ICS are front line therapy for managing asthma.”

CAMP Trial and Follow-up Design
AAAAI, March 2011 CAMP Trial and Follow-up Design Screening and Baseline Treatment Trial Transition Follow-up Routine Care 5 visits 2 visits 1-4 visits per year 3 visits per year 2 - 4 months 4 – 6 years 4 months 13 years Budesonide – 200 mcg by Turbuhaler™ bid Nedocromil – 8 mg by MDI bid Placebo All patients used albuterol for rescue Prednisone, for exacerbations 5 mg/kg up to 60 mg for 2 days 2.5 mg/kg up to 30 mg for 2 more days Randomize Study Rx Discontinued Enroll in follow-up study Refer back to PCP for Rx per NAEPP guidelines Budesonide Nedocromil Placebo Enrollment in trial: Dec 1993 – Sept 1995 1,041 children age 5-13 years at randomization Mild to moderate persistent asthma

Change in Bone Density at End of CAMP Trial
Budesonide vs. Placebo = , P = 0.53 Nedocromil vs. Placebo = , P = 0.15 Budesonide Nedocromil Placebo (n = 304) (n = 306) (n = 410)

Mean Obtained Adjusted Adult Height
Bud vs Plbo: P= P= P=0.10 Ned vs Plbo: P= P= P=0.98 Mean Obtained Adjusted Adult Height Bud by sex interactio, P=0.10 cm Bud–Plbo diff.: (95% CI) -1.2 cm (-1.9 to -0.5) -1.8 cm (-2.9 to -0.7) -0.8 cm (-1.8 to 0.2) *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.

ICS Metabolism The bioavailability of an inhaled corticosteroid is dependent on the absorption of the dose delivered to the lungs and the oral bioavailability of the swallowed portion of the dose received. Approximately 10 to 30 percent of the dose from the MDI is delivered to the lungs. This amount varies among preparations and delivery devices. Nearly all of the amount delivered to the lungs is bioavailable. Approximately 80 percent of the dose from the MDI without a spacer/holding chamber is swallowed. Either a high first-pass liver metabolism or the use of a spacer/holding chamber with an MDI can decrease oral bioavailability, thus enhancing safety The approximate oral bioavailability of inhaled corticosteroids has been reported as: Beclomethasone diproprionate 20%; Flunisolide 1%;Triamcinolone acetonide 10.6%; Budesonide 11%; Fluticasone propionate 1% (1997 NHLBI NAEPP Guidelines for the Diagnosis and Management of Asthma) 68 68 81 68

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 [each bullet will display one at a time as you advance the slide] 8

Comparative Dosages: HFA ≠ DPI ≠ MDI ≠ respules Preparations are not equivalent per puff or per microgram Comparative doses are estimated. Few data directly compare preparations [bullets will display one at a time as you advance the slide] 13

Chemical Structure of Inhaled Corticosteroids
For visual learners this picture can be helpful in showing the differences, ever so slight, but different. Notice how all the drugs are the same except for small changes.

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

Estimated Comparative Daily Dosages of Inhaled Corticosteroids for Adults
Drug Low Dose Medium Dose High Dose Beclomethasone HFA mcg mcg >640 mcg Budesonide DPI mcg mcg >1200 mcg Mometasone DPI 220 mcg 440 mcg mcg Fluticasone mcg mcg >660 mcg Triamcinolone 400 -1,000 mcg 1, ,000 mcg >2,000 mcg

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 [each bullet will display one at a time as you advance the slide] Generic and trade names are on the test! Good to reference both. LABA’s not recommended for mono-therapy for persistent asthma pg 230 16

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

J Allergy Clin Immunol Jan. 2006
Is there a problem with inhaled long-acting B- adrenergic agonists (LABA)? Harold Nelson, MD 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 This is a review of the SMART trial by Dr. Harold Nelson (not the study itself); This is a good place to review black box labeling and the SMART trial. J Allergy Clin Immunol Jan. 2006

Leukotriene Modifiers Mechanisms
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 [each bullet will display one at a time as you advance the slide] Montelukast does have an indication for EIA and allergic rhinitis, but it is the ONLY LTRA that has an indication for EIA and allergic rhinitis; montelukast is NOT first line therapy for either condition (SABA is preferred for EIA pretreatment) and montelukast should not be used for non-allergic rhinitis 18

Dulera MDI 100/5 mcg 200/5 mcg Patients 12 and older
Combination Therapy Dulera Momestasone Furoate Formoterol Fumarate MDI 100/5 mcg 200/5 mcg Patients 12 and older Dulera is the new kid on the block!

Symbicort MDI 80/4.5 mcg 160/4.5 mcg Patients 12 and older Budesonide
Combination Therapy Symbicort Budesonide Formoterol Fumarate MDI 80/4.5 mcg 160/4.5 mcg Patients 12 and older Dulera is the new kid on the block!

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

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 [Bullets will display as you advance the slide] By using a fixed combination device, one can side step the need to teach more than one inhalation method (e.g. slow breath vs. faster breath) An opportunity here to introduce step wise approach examples

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 FDA-Approved Ages (Years) for Use in Children

Role of Leukotrienes in Asthma
Mucus Transport Airway Smooth Muscle Inflammatory Cells (e.g. Mast Cells, Eosinophils) Airway Epithelium Sensory Nerves (C-Fibers) LTD4 Edema Blood Vessel Increased Mucus Secretion Decreased Mucus Transport Eosinophil Influx Epithelial Cell Damage Cationic Protein Release , Contraction & Proliferation Central Role of Cysteinyl leukotrienes in Asthma First identified in the late 1970s, the cysteinyl leukotrienes, including LTD4, are key mediators in asthma. Early evidence of the importance of leukotrienes in asthma was provided by their recovery in the blood, bronchoalveolar lavage fluid, and urine of patients after spontaneous or induced bronchospasm. The ability of specific leukotriene-receptor antagonists to increase airflow and reduce symptoms further supports leukotriene involvement in this disease. Cysteinyl leukotrienes, including LTD4, are generated by inflammatory cells such as mast cells and eosinophils. Through multiple mechanisms, cysteinyl leukotrienes and leukotriene receptor occupation have been correlated with: Increased vascular permeability and edema formation Increased mucus production with decreased mucociliary transport Recruitment of inflammatory cells, such as eosinophils, from bloodstream to airway. Eosinophil influx is a component in the inflammatory process that underlies asthma. Eosinophils in the airway release inflammatory mediators, including cationic proteins, that can damage the epithelium. Epithelial damage can then expose sensory fibers to allow stimulation of cough or other bronchial reflexes. In addition, cysteinyl leukotrienes cause profound bronchoconstriction, and are about 1000 times more potent than histamine. Cysteinyl leukotrienes also appear to stimulate proliferation of human smooth muscle cells, when tested in vitro. Hay et al. Cysteinyl leukotrienes in asthma: old mediators up to new tricks. Trends Pharmacol Sci. 1995;16: Adapted from Hay DWP et al. Trends Pharmacol Sci 1995;16:

Montelukast (Singulair)
Oral pharmacokinetics: Rapidly and well absorbed Not affected by food ingestion Minimal accumulation with multiple dosing No dosage adjustments required based on: Renal insufficiency Mild to moderate hepatic insufficiency The elderly Anecdotal Reports: Recent reports about behavioral side effects

Dosing Regimen in Adults and Children
Montelukast (SINGULAIR™†) (montelukast sodium, MSD) Administered once daily ( bedtime) Available for adults and children as young as 6 months C.A.I.R Cherry-Flavored Chewable Tablets 4 mg mg Ages 2– Ages 6–14 Granule Packets Film-Coated Tablet 10 mg Ages  15 years CAIR: Can be mixed with carrots, applesauce, ice cream and rice 4mg Ages 6 mos–5yrs †Trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA

Short-acting Asthma Medications
Urgent control of Inflammation Systemic corticosteroids (IV or PO) Burst Tx (PO) or hospitalization/ER (IV) As-needed: Quick Relief Short-acting (selective) beta2-agonists (albuterol, pirbuterol, levalbuterol) Anticholinergics (Ipratropium bromide) EPR-3 supports use of anticholinergics in the ED setting

Quick Relief Beta2-agonists
Albuterol HFA ProAir Proventil HFA Ventolin HFA Levalbuterol (Xopenex HFA) Nebulizer Solutions Pirbuterol (Maxair)

Short-Acting Beta2-Agonists
Quick Relief Short-Acting Beta2-Agonists albuterol* (Proventil, Ventolin, ProAir), pirbuterol** (Maxair), levalbuterol*** (Xopenex) Most effective medication for relief of acute bronchospasm (more so than anticholinergics) Effective as a pre exercise medication More than one canister per month suggests inadequate asthma control * available as HFA MDI and in several nebulizer forms * * available as breath actuated brand name MDI * * * available as HFA MDI or liquid for nebulization (.31mg, .63mg, 1.25mg)

Short-Acting Beta2-Agonists:
Regularly scheduled use is not generally recommended May lower effectiveness and increase side effects May increase airway hyper-responsiveness Using >2 canisters per month-risk factor for death [each bullet will display one at a time as you advance the slide] NAEPP. EPR-3, page 377.

Special Considerations
Older adults: Older adults esp. those with ischemic heart disease may show Increased sensitivity to B-agonists (tremor, tachycardia) Systemic corticosteroids can provoke: confusion agitation changes in glucose metabolism Inhaled corticosteroids May be associated with dose-dependent reduction in bone mineral content Physician may consider concurrent treatment with Calcium supplements and Vitamin D Bone-sparing medications (e.g. bisphosphonates) [each bullet will display one at a time as you advance the slide] 43

Patients with other medical issues: Medications for other diseases may exacerbate asthma NSAIDs (ASA induced asthma) Nonselective beta-blockers Beta-blockers found in some eye drops ACE inhibitors 44

Exercise Induced Asthma (EIA) Exercise Induced Bronchospasm (EIB) Transient narrowing of the airways associated with: Physical exertion Coughing, wheezing or shortness of breath occurring within minutes of starting exercise: Exercise duration = 2-8 min. (85-95% max HR) Maximal at 8-15 minutes post exercise Diagnosis = 12-15% drop in FEV1 (7% in elite athlete) Explain that Exercise Induced Asthma and Exercise Induced Bronchospasm are used interchangeably. [EIB is covered elsewhere in the curriculum.]

Exercise Induced Asthma
Occurrence: 90% of asthmatics 40% of patients with allergic rhinitis 22% of 1998 Olympic athletes 9% of persons with EIB have no hx of asthma or allergies 10-50% of asthmatics on ICS still display EIB

Managing Exercise-Induced Asthma
Management Strategies: Short-acting inhaled beta2-agonists used shortly before exercise last 2 to 3 hours Salmeterol may prevent EIB for 10 to 12 hours Cromolyn if side effects a concern A lengthy warm-up period before exercise An aerobic conditioning program Long-term-control therapy, if appropriate Avoid asthma triggers during exercise

Over-The-Counter (OTC) Asthma Medicines: Always include OTC’s in medical history OTC products may provoke asthma (ASA) Short acting bronchodilators (e.g. Primatene mist): not a substitute for prescription medicines Often indicate need for physician referral Very short acting and non-selective The test talks about a patient using his ‘epinephrine inhaler’.

Subcutaneous Allergy Immunotherapy
Consists of small injections of relevant allergens in increasing concentrations over a 3-6 month build-up followed by maintenance injections every 2-4 weeks over 3-5 years beneficial effects occur over months (not immediately) Reports have concluded that over time it can prevent the development of new sensitivities to allergens Controlled studies have demonstrated reduction in asthma symptoms caused by exposure to cat, dust mites, mold, ragweed, and grass Sublingual therapy has yet to be proven as effective Subcutaneous Allergy Immunotherapy: Consists of small injections of relevant allergens in increasing concentrations over a 3-6 month build-up followed by maintenance injections every 2-4 weeks over 3-5 years beneficial effects occur over months (not immediately) Several reports conclude that subcutaneous immunotherapy over time can prevent the development of new sensitivities to allergens Controlled studies have demonstrated reduction in asthma symptoms caused by exposure to cat, dust mites, mold, ragweed, and grass Sublingual therapy has yet to be proven as effective

Subcutaneous Allergen Immunotherapy is considered for:
Patients with persistent asthma if evidence is clear of a relationship between symptoms and exposure to an allergen Candidates for immunotherapy are generally > 5 years of age Administration should occur in an office prepared to treat a systemic allergic reaction EPR-3 pg 177 supported evidence for when to consider/start immunotherapy. NAEPP. EPR-3, page 177. 16

Anti-IgE Therapy – Omalizumab (Xolair)
Newer Therapy Anti-IgE Therapy – Omalizumab (Xolair) Humanized IgG (5% murine) Binds IgE regardless of specificity Does not activate complement Rarely has caused anaphylaxis

Dosed every 2-4 weeks; SQ dosing
Xolair (Omalizumab) Indicated for adults and adolescents(>12) with severe persistent asthma inadequately controlled on high-dose ICS and LABA Selected patients must have a positive skin test or in vitro reactivity to aeroallergens Dosed every 2-4 weeks; SQ dosing May allow these patients to improve control, decrease dose of ICS and decrease reliance on oral corticosteroids

Alternative Therapies
40% of pts who use non-provider prescribed therapies do not report alternative medication use because they are not asked or because they do not think it is important for their medical provider to know (Eisenberg 2001). Use of Alternative medicines may result in: allergic reactions intensification of drug side effects Users may not be aware of: potency contaminants covert additives Recommended that clinician ask patient about complementary and alternative medicine use (CAM) EPR-3 pages NAEPP. EPR-3, pages

According to the 2007 NAEPP EPR-3:
Insufficient evidence to recommend the following for asthma management: Chiropractic therapy Acupuncture Hypnosis Homeopathy and herbal medicine Breathing techniques Yoga See pages inclusive NAEPP. EPR-3, pages

However, some people find these therapies helpful:
Acupuncture may relax and calm breathing Biofeedback may help control involuntary physical responses Hypnosis may allow more self discipline through suggestion Massage, relaxation, art/music therapy, yoga may reduce anxiety and help to relax

Alternative Medicines
Potential for Allergic Responses Daisy family Horse chestnut Natural plant salicylates Royal jelly Royal Jelly Echinacea Willow bark

Intensification of Drugs CNS stimulants Ma huang (ephedra) Ginseng Yohimbe Goldenseal Gingko Potentiate steroids Licorice Ginseng

Deactivation of Drugs Decreases theophylline levels St John’s wort Decreases prednisolone levels xiao hu tang sho-saiko-to St. John’s Wort We should site our source here, NHLBI guidelines do not cover this. BAC do you know where we got this?

Asthma Pharmacological Therapy
Focus is on treating inflammation Severity classification of the chronic disease determines therapy Inhaled corticosteroids are the best therapy for treatment of persistent disease New therapies on the horizon …. Updates on the guidelines are the best resources

Asthma Management Pharmacological Therapy: Case Studies
Guide participants through each of the five scenarios. Presented by:

Case Study #1 19 mo old with nighttime cough and 3 spells in last 6 months treated with oral corticosteroids (OCS) He is thought to have intermittent asthma. What do you think? What is the best treatment? His mom has asthma and he has milk allergy. Will he have asthma when older? Mild – Moderate Persistent Inhaled Corticosteroids - Asthma education [each answer will show as you advance the slide] Note: Some have suggested, depending on your presenting style, you may want to mix these case studies into the talk instead of doing them all after. Very Likely

Case Study #2 3 year old on montelukast who wakes up at night once per week with cough Is he controlled? What should be done? Not well controlled Switch to Inhaled Corticosteroid Assess adherence; evaluate for co morbidities; educate Follow-up in 2-6 weeks [each answer will show as you advance the slide]

6 year old with daily cough, FEV1=80%, FEV1/FVC=76%
Case Study #3 6 year old with daily cough, FEV1=80%, FEV1/FVC=76% How severe is her asthma? What medications should be prescribed? Anything else? Moderate Persistent Budesonide DPI puffs bid or Budesonide puff bid with Montelukast 5 mg or Advair 100/50 1 puff bid—consider black box warning Check technique [each answer will show as you advance the slide] Write an action plan; Provide asthma self-management education; assess triggers; consider referral to an asthma specialist Bring her back in 2-6 weeks

Case Study #4 15 year old who uses albuterol 3 times each basketball game/practice despite daily fluticasone What could the physician do next to help? Check pre and post spirometry Perform exercise challenge [each answer will show as you advance the slide] Consider more in depth studies and co morbidities Consider asthma specialist consultation You could try combination therapy but the work-up is most important

Case Study #5 13 month old infant (3rd episode) with inspiratory and expiratory wheeze, RR=60, O2 Sat=90% after 1 hour in the emergency department Is this asthma? He’s had 2 treatments, what next? Should he be in the hospital? Probably; need more family/personal history [each answer will show as you advance the slide] Oral corticosteroids; evaluate for co-morbidities Of course

Barbara Chilmonczyk, MD
Acknowledgements Barbara Chilmonczyk, MD Allergy and Asthma Associates of Maine; AH! Asthma Health Program Director, MaineHealth and the Barbara Bush Children’s Maine Medical Center, Portland, ME (207) Rhonda Vosmus, RRT-NPS, AE-C Asthma Education Specialist Maine Medical Center and MaineHealth, Portland, ME (207) Janice H. Howell, MD, FRCPC, FAAP Faculty Physician, Medical Education-Pediatrics, Orlando FL (321) Chris Garvey, FNP, MSN, MPA, FAACVPR Manager Pulmonary and Cardiac Rehabilitation Seton Medical Center (650) Donna Beal, MPH, CHES Regional Program Director ALACA Santa Barbara, CA (805) NIH. NAEPP Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma, October 2007.

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