1. Asthma Primer Wayne Kradjan, Pharm. D.

2. Definition of Asthma A chronic inflammatory disorder of the airways… In susceptible individuals, this inflammation causes episodes of wheezing, breathlessness, chest tightness and coughing, particularly at night or early morning. Usually associated with widespread but variable airflow obstruction (bronchospasm) that is often reversible, either spontaneously or with treatment. Inflammation also causes an increase in bronchial hyperresponsiveness to a variety of stimuli (triggers)

3. Large, “central” airways Small, “peripheral” Airways Only site of gas exchange

4. Causes of Airflow Obstruction Bronchospasm- Hyperresponsiveness and narrowing of airways (bronchi) due to muscle spasm. Airway edema (swelling of walls) Mucous plugging All made worse by airway inflammation

5. Bronchial Hyperresponsiveness More easily induced bronchospastic response to a variety of stimuli that may not otherwise cause a response in the general population. –Allergens –Chemicals, irritants –Exercise Response may also be more intense and prolonged Non-asthma patients may develop a transient BHR after viral upper respiratory infection.

8. Asthma Triggers Allergens (seasonal/ perennial) –Grass, weeds, pollen, mold, mildew –Animal dander, saliva, dust mites Chemical irritants and fumes –Cigarette smoke, pollution, perfume –Household cleaners, occupational Viral infections, rhinitis, sinusitis, (“post nasal drip”) Gastroesophageal reflux (GERD) Exercise; cold, dry air Extreme emotions Drugs (aspirin, beta blockers)

9. Measuring Airflow Obstruction Assessing air outflow –Peak flow: Maximum rate (L/min) of airflow out of the lung during a forced exhalation. –FEV 1 : Forced expiratory volume in one second. Actual volume (L) of air expired in the first second of a forced exhalation. –FVC: Forced vital capacity. Total volume of air expired during a forced exhalation.

10. Peak Flow Meter

11. Obstructive Airways Disease: Sequence of Events Inflammation, nerve exposure Hyperresponsiveness “Trigger”: allergen or irritant exposure (cold air, exercise) Bronchospasm (  FEV1, peak flow) mucous, edema, cough OBSTRUCTION

12. Epidemiology 5% of US population 5,000 deaths per year in US Higher incidence in inner city, especially African Americans and Hispanic populations. –Racial vs. socioeconomic?

13. Environmental Factors Increased time spent indoors –Indoor allergens (molds, mites, cockroaches) Tobacco smoke exposure –maternal smoking risk for child Increased childhood infections associated with lower risk –Having older or multiple siblings or day care center attendance may lower risk (more childhood infection) –Hygienic hypothesis

14. Childhood onset Most common chronic disease of children (6.9% of population) –More likely to be allergic basis –Common: child with positive family history of asthma and allergy to tree and grass pollen, house dust mites, household pets and molds. –30-70% markedly improve or symptom free as adult

15. Adult onset May be allergic or non-allergic Often negative family history and negative skin tests to common allergens Often history of nasal polyps, aspirin sensitivity and chronic sinusitis Environmental exposure: wood dust, chemicals, pollutants at workplace or in air Chemical sensitizers: viral infection, tobacco smoke, diet, perfume

16. Expert Panel 2 Report Guidelines for the Diagnosis and Management of Asthma NIH Publication #97-4051A National Institutes of Health. National Heart, Lung and Blood Institute May 1997 http://www.nhlbi.nih.gov/ guidelines/index.htm Schering, Astra-Zeneca, or Glaxo-Wellcome

17. Update on Selected Topics 2002 Guidelines for the Diagnosis and Management of Asthma NIH Publication #02-5075 National Institutes of Health. National Heart, Lung and Blood Institute November 2002 http://www.nhlbi.nih.gov/ guidelines/asthma/asthsumm.htm J Allergy Clin Immunol. 2002;110:S1-S219 (Nov supplement)

18. Step Approach to Classification Mild Intermittent –Sxs <2/week, PM sxs < 2/month –PFTs >80%, < 20 variability Mild Persistent –Sxs 3-6x/ week; PM sxs 3-4/month –PFTs >80%, 20-30% variability Moderate Persistent –Sxs daily; PM sxs > 5 per/month –PFTs 60-80%, >30% variability Severe Persistent –Sxs continual; PM sxs frequent –PFTs 30% variability Acute exacerbations

19. Staging: Further Considerations Seasonality Nocturnal symptoms Exercise induced Peak flow monitoring Daily fluctuations Cough variant “Wheezy bronchitis” in children

20. “Reliever”, “Rescue” Drugs Rapid acting bronchodilators –beta adrenergic agonists –intermediate duration (3-6 hrs) »Often called “short acting” –metered dose inhaler (MDI), dry powder inhaler (DPI, breath actuated), solution for nebulization Albuterol (salbutamol) (Proventil, Ventolin) Levalbuterol (Xopenex) Bitolterol (Tornalate) Metaproterenol (Alupent, Metaprel) Pirbuterol (Maxair) Terbutaline (Bricanyl, Brethine) (Epinephrine, isoproterenol, isoetharine)

21. Metered Dose Inhaler Albuterol (Proventil HFA)

22. Air Jet Nebulizer

23. Anticholinergic bronchodilators Ipratropium (Atrovent) Tiotropium (Spiriva) MDI (Atrovent and Spiriva) –Also combination with albuterol: Combivent Solution for nebulization (Atrovent) –Also combination with albuterol: DuoNeb (500 mcg/2.5 mg) Slower onset, longer acting than albuterol –Atrovent QID; Spiriva QD Dry mouth and blurred vision Greater role in COPD than in asthma

24. “Controller” Drugs: Antiinflammatory Inhaled corticosteroids –Beclomethasone (Beclovent, Vanceril) –Budesonide (Pulmicort) (Turbuhaler, and Respules) –Flunisolide (Aerobid, Aerobid M) –Fluticasone (Flovent) (Advair = combo with salmeterol) –Triamcinolone (Azmacort) Important to note –Low, intermediate, high dose –dosage form and strengths

25. Non-Steroid “Controllers” Antiinflammatory Mast cell stabilizers (inhaled: MDI or nebs) –Cromolyn (Intal) –Nedocromil (Tilade) Leukotriene modifiers (Oral) –Lipooxygenase inhibitor: Zileuton (Zyflo) –Receptor blockers: Zafirlukast (Accolate) Montelukast (Singulair)

26. Long acting bronchodilators Inhaled beta agonist –Salmeterol (Serevent MDI and Diskus) –Formoterol (Foradil Aerolizer) –Night time, exercise or adjunct to anti-inflammatory drugs Oral beta adrenergic agonists –albuterol, metaproterenol, terbutaline –sustained release for night time Proventil Repetabs, Volmax –syrups for children (albuterol, metaproterenol

27. Salmeterol (Serevent) Diskus 50 mcg/dose; 60 doses Open door to reveal mouthpiece Slide lever. “Click” indicates dose in place. Dose counter advances. Hold level to hold powder in place. Inhale quickly. Close door to reset.

28. Long acting bronchodilators (continued) Theophylline –rapid acting, sustained release (many products recently removed from the market) –intravenous (aminophylline) –Possibly mild anti-inflammatory –Increased diaphragm contractility (“diaphragmatic inotrope”) –Primarily reserved for COPD

29. Other asthma medications Oral or injectable steroids –Prednisone, prednisolone, methylprednisolone –“burst therapy” for rapid decline –Emergency and hospital use Methotrexate Allergy desensitization Soluble IL-4 receptor (IL4R) to bind IL-4 and prevent binding of IL-4 to tissue receptors. 3 mg Q week via inhalation Olizumab: recombinant monoclonal antibody to IgE 150-300 mg SC Q 2- 4 weeks

30. Therapeutic goals: Individualize to patient Minimal, infrequent episodes –Freedom from symptoms; Day and night. Maintain normal activity including exercise Maintain best possible pulmonary function –Consider what is realistic Prevent acute episodes –< 3 beta agonist per week –No emergency room visits or hospitalizations.

31. Therapeutic goals (cont.) Avoid medication adverse effects Prevent asthma related death Meet patient/family expectations Patient/family education: –symptoms –triggers –metered dose inhaler technique (have patient demonstrate) –“reliever” vs “controller” drugs –peak flow meter monitoring (Green, yellow and red zones)

32. Environmental Control Same as for allergic rhinitis Bedding Carpets Stuffed animals Pets Avoidance of allergens and triggers

33. Step Approach to Classification and Therapy Mild Intermittent –PRN bronchodilators Mild Persistent –Symptoms 3-6 times/ week –Add antiinflammatory Moderate Persistent –Combinations of antiinflammatories and long acting bronchodilators Severe Persistent Acute exacerbations

34. Staging: Further Considerations Seasonality Nocturnal symptoms Exercise induced Peak flow monitoring Daily fluctuations Cough variant “Wheezy bronchitis” in children

35. COPD: Chronic Obstructive Pulmonary Disease Any lung condition causing longstanding airflow limitation with impaired expiratory outflow… …airflow obstruction due to chronic bronchitis (and/or) emphysema Generally progressive, may be accompanied by airway hyperreactivity, and may be partially reversible …caused by abnormal inflammatory reaction to chronic inhalation of particles 2-10% of US population over age 55 4 th to 5 th leading cause of death

36. Assessing Peak Flow Rate

37. Pulmonary function: Bronchodilator tone Peak expiratory flow rate (PEFR) in liters/ minute Forced expiratory volume in one second (FEV 1 ) in liters Normal values vary according to sex, age, height –Reported as absolute values or –Percentage of normal or of personal best Establish patient zones –Green = 80-100% of normal –Yellow = 50-79% of normal –Red = <50% of normal

38. Peak Expiratory Flow Rate First blast of air exhaled by the patient reaches this flow rate almost immediately. The flow rate quickly slows as more air is exhaled. –Less elastic recoil by lung Indirect measure of lumen size of large airways and strength of expiratory muscles during maximal effort.

39. True Zone Peak Flow Meter

40. Peak Flow Meter

41. Directions for use of Peak Flow Meter “zero the pointer” –Move indicator to bottom of numbered scale on meter. Stand upright Breathe in as deeply and completely as possible Close lips around mouthpiece to form tight seal –Do not put tongue in opening Quickly blow out as hard and fast as you can. Note reading; repeat 3 times