overview

2. 402 articles reviewed from July 1, 2008 to June 30, 2009, with 23 articles identified as having impact on the GINA Report (updated 2009)..

4. overview

5. asthma chronic inflammatory disorder of airways in which many cells and cellular elements play a role 300 million affected worldwide Host factors (genetic) and environmental Airway hyperresponsiveness: wheezing, breathlessness, chest tightness, coughing (night or early am) Widespread but variable airflow obstruction within the lung that is often reversible Manifestations can be controlled

6. Multiple genes • 4 areas • 1) production of allergen-specific IgE antibodies (atopy) • 2)expression of airway hyperresponsiveness • 3) generation of inflamamtory mediators (cytokines, chemokines, growth factors) • 4) determination of Th1/Th2 immune responses ratio (as relevant to hygiene hypothesis of asthma

7. mechanism Inflammatory disorder affecting all airways, most pronounced in medium sized bronchi Activated mast cells, increased eosinophils, increased T cell receptor invariant natural killer T cells and T helper 2 lymphocytes (Th2) releasing mediators

9. Special mechanisms ACUTE EXACERBATIONS: transient worsening due to exposure to triggers (exercise, pollutants, thunderstorm, infections, other allergens) NOCTURNAL ASTHMA: not clear but may be related to circadian rhythms of circulating hormones (epinephrine, cortisol, melatonin)

10. special mechanisms • DIFFICULT TO TREAT ASTHMA -accounts for those who are difficult to manage and relatively insensitive to effects of glucocorticosteroids -not well understood -associated with poor compliance and psychologic/psychiatric disorders; also genetic -difficult to treat from the onset vs progressing from milder asthma -airway closure leads to air trapping and hyperinflation -with an increase in neutrophils, more small airways involvement and more structural changes

11. SMOKING AND ASTHMA: • More difficult to control, with more frequent exacerbations and hospital admissions, with rapid decline in lung function, increased risk of death • Neutrophil predominant inflammationpoorly responsive to glucocorticoster • oids

12. Diagnosis and classification

13. diagnosis

14. Some definition Spirometry: forced expiratory volume in 1 sec and forced vital capacity • REVERSIBILITY: rapid improvements in FEV1 or PEF measured within minutes after inhalation of rapid acting bronchodilator (eg 200-400 ugsalbutamol) or more sustained improvement over days or weeks after introduction of effective controller treatment (inhaled GCS). • In spirometry, ≥12% and ≥200 ml from pre-bronchodilator value. • may not exhibit variability in each assessment esp if in tx, hence lacks sensitivity. • Repeated testing at different visit is advised. • Airflow limitation FEV1/FVC normally >.75-.80 (>.90 in children). • In PEF: a 60 L/min (or ≥20% prebronchodilator PEF) improvement after bronchodilator or diurnal variation of PEF of >20% (with 2x daily readings, more than 10%) suggests ASTHMA • VARIABILITY: improvement or deterioration in symptoms and lung function occurring over time may be diurnal, month to month or seasonal.

16. classification

18. treatment

20. treatment Relievers: rapid-acting inhaled beta-2 agonists, inhaled anti-cholinergics, short-acting theoophylline, short-acting oral beta2-agonists Controllers: inhaled and systemic GCS,leukotriene modifiers, long acting inhaled beta-2 agonists with inhaled GCS, sustained-release theophylline, cromones, anti-IgE

22. treatment

23. CONTROLLER : INHALED GLUCOCORTICOSTEROIDS • ACTION: • Decrease number and activity of cells in airways inflammation-macrophages, eosinophils and T-lymphocytes • Anti-inflammatory: reverses mucosal edema, decreasing capillary permeability, inhibit release of leukotrienes • Efficacy in reducing asthma sx, improving QOL, improving lung function, decreasing airway hyperresponsiveness, controlling airway inflammation and reducing frequency/severity of exacerbations and mortality • Do NOT cure ASTHMA • Deterioration of control within weeks to months if discontinued • Most benefit from low dose, equivalent to 400ug of budesonide per day. • Increasing doses=little benefit, greater side effect. Better to add another class of controller. • Higher doses for smokers • SE: oropharyngealcandidiass, dysphonia, coughing. At higher doses, rarely brusing and skin thinning, rarely adrenal suppression • Prevent by: mouthwashing, use of spacer devices, some prodrugs (ciclesonide) activated in lungs but not in pharynx • NO evidence of increased risk for pulmonary infections and is NOT contraindicated in active PTB

24. CONTROLLERS: LEUKOTRIENE MODIFIERS ACTION: inihibit 5-lipooxygenase (Zileuton), and cysteinyl-leukotriene 1 (CysLT1) receptors (Montelukast, pranlukast, zafirlukast). Small and variable bronchodilator effectreduce cough, improve lung function and reduce airway inflammation and exacerbation Good response from pts with aspirin-sensitive asthma Less effective than low dose i-GCS when used alone as controller; and less effective than long acting inhaled beta2 agonists as add-ons SE: liver toxicity (Zileuton)

25. CONTROLLERS: LONG ACTING INHALED BETA 2 AGONISTS • NOT for monotherapy as they do not influence airway inflammation; effective when combined with inhaled GCS • Hence the development of fixed combination inhalers delivering both GCS and inhaled LABA simultaneously (e.g.fluticasone propionate + salmeterol, budesonide + formoterol) which is as effective as giving each drug separately • Favors convenience, compliance, and ensures that LABA is always accompanied by GCS • formoterol+budesonide: both as rescue and maintenance • Formoterol has more rapid onset of action than salmeterol, making it more suitable both for symptom relief and symptom prevention • Prevent exercise induced bronchospasm, longer protection than rapid B2agonists • SE: CVS stimulation, tremor, hypokalemia • Possible increased risk of asthma-related death in a small group of individuals (use of salmeterol) hence should not be used as substitute for inhaled GCS

26. CONTROLLER: THEOPHYLLINE Bronchodilator with modest anti-inflammatory properties Sustained-release formulation OD/BID although little effect as first-line controller May benefit as add-on therapy for those who do not achieve control on inhlaed GCS alone Less effective then LABA as add-on Metabolized by liver SE: at higher doses (10mg/kg/body wt/day or more). GI sx (nausea,vomiting; if >20 mg/L), loose stools, arrythmia (if >40mg/L), seizures, death Narrow therapeutic window, toxicity related to plasma concentrations Should closely monitor if at high dose Interactions: febrile illnes, pregnancy, anti-Kochs reduce levels while liver dse, CHF, cimetidine, some quinolones/macrolides increase toxicity

27. CONTROLLER: CROMONES ACTION: alter function of delayed chloride channels in cell membrane, inhibiting cellular activationaction on airway nerves thought to cause nedocromil’s inhibition of cough, on mast cells for inhibition of early response to antigen challenge and on eosinophils for inhibition of inflammatory response to inhalation of allergens (Katzung) Limited role, weak antiinflammatory, less effective vs low dose iGCS Monotherapy with cromones no longer alternative to monotherapy with low dose inhaled GCS SE: sore throat, cough, unpleasant taste

28. CONTROLLER: LONG ACTING ORAL BETA 2 AGONIST Slow release fomulations of salbutamol, terbutaline and bambuterol (prodrug converter to terb in the body) Rarely used; PRN for bronchodilation SE: tachycardia, anxiety, skeletal muscle tremor, adverse CVS reactions (if +theophylline) Harmful if regularly used alone

29. CONTROLLER: ANTI-IgE Omalizumab Limited to pts with elevated serum IgE, for pts with severe allergic asthma, uncontrolled on GCs SE: safe as add-on tx (study on >12 yo who were already receiving (i/o) GCS and LABA

30. CONTROLLER: SYSTEMIC GLUCOCORTICOSTEROIDS Long-term (>2 weeks) for severity of uncontrolled asthma Oral > parenteral (IM/IV) due to lower mineralocortocoid effect, relatively short half-life and lesser effect on striated muscles, with great dosing flexibility permiting titration to lowest acceptable dose that maintains control SE: osteoporosis, arterial HPN. DM, HPA-axis suppression, obesity, cataratc, glaucoma, skin thinning, easy brusing, muscle weakness Rarely, if withdrawn: adrenal failure or may unmask Churg-strauss syndrome Caution with those who have PTB, sever parasitic infections, ospeoprorosis, glaucoma, diabetes, peptic ulcer, fatal hepres virus.

31. CONTROLLER: oral antiallergic compound E.g. Tranilast, repirinast, tazanolast, pemirolast, ozagrel, celatrodast, amlexanox, ibudilast Limited anti-asthma effects, need mpre studies SE: sedation

32. Other controllers Low-dose methotrexate: two metaanalyses of its steroid sparing effects showed small over-all benefit, but high adverse effects Cyclosporin and gold: effective in some Macrolide, troleanromycin: small steroid-sparing effect when used with systemic methylprednisolone (but macrolide may decrease GCS metabolism) IV immunoglobulin: NOT recommended SE: nausea, vomting, abdominal pain, occ liver toxicity (macrolide)

33. Allergen specific immunotherapy Limited role Need to identify and use single well-defined clinically relevant allergenadminister in progressively higher dosetolerance 75 RCT of specific immunotherapy vs placebo confirmed efficacy in reducing symptom scores, med requirements, improving allergen-specific and non-specific airway hyperresponsiveness

34. RELIEVERS: RAPID ACTING INHALED BETA 2 AGONISTS Meds of choice for bronchospasm relief during exacerbations, and pretreatment of exercise-induced bronchoconstriction E.g. salbutamol, terbutaline, fenoterol, levalbuterol HFA, reproterol, pributerol Formoterol: also for sx relief due to rapid onset (reserve for those on inhaled GCS) Only as PRN, lowest dose and frequency required Increase use (to daily): deterioration of asthma control, need to reassess tx SE: tremor, tachycardia, inhaled preparations

35. RELIEVERS: SYSTEMIC GLUCOCORTICOIDS • Not usually as relievers • Important in severe acute exacerbations as they prevent progression of asthma exacerbation, reduce need for referral to ER and hospitaliztion, prevent early relapse, reduce morbidity of illness. • Effects seen in 4-6 hrs. • Oral>IV • 40-50 mg prednisolone OD or 5-10 days depending on severity. • SE: abn glucose metabolism, increase appetite, fluid retention, weight gain, rounding of face, mood ateration, hypertension, PUD, Aseptic necrosis of femur.

36. RELIEVERS; ANTICHOLINERGICS E.g. Ipatropium bromide (IB), ixitropium bromide Inhaled IB less effective reliever vs rapid inhaled Beta2 agonist Metaanalysis showed stat significant albeit modest improvement in pulmofucntion and significantly reduces risk of hospitalization No established long-term benefit; but is recognized as alternative to those with adverse effect: tachycardia, arrythmia, tremors SE: dryness of mouth, bitter taste

37. RELIEVER: THEOPHYLLINE Not for patients already on sustained release theophylline unless se concentration of theophyllline is known to be low or monitored

38. RELIEVER: SHORT ACTING ORAL BETA 2 AGONIST If unable to use inhaled meds Associated with higher adverse effects

44. No longer 6 but FIVE-PART ASTHMA MANAGEMENT PROGRAM Component 1: Develop Patient/Doctor Partnership Component 2: Identify and Reduce Exposure to Risk Factors Component 3: Assess, Treat and Monitor Asthma Component 4: Manage Asthma Exacerbations Component 5: Special Considerations

45. COMPONENT 1: • Partnership bw patient and health care professionals • Strengthened by discussing and agreeing on goals of treatment, developing personalized, written self-management action plan (self-monitoring), periodically reviewing pt’s tx and level of control • Education is the key

46. COMPONENT 3 • Overall concept for asthma management now focusing on CONTROL • Treatment initiated and adjusted in continuous cycle (assess control, treating to achieve control, and monitoring to maintain control) driven by level of asthma control

47. Treatment options: 5 steps • Reflect increasing Tx intensity (dosages and/or number of meds • At ALL steps, RELIEVER meds should be provided PRN • STEPS 2-5, with variety of controller meds

48. STEP-UP if not controlled with current regimen When control maintained, may step down to find the lowest step and dose of treatment that maintains control

50. STEP 1: prn reliever • Rapid-acting inhaled b2agonist (A) • Alternative: Inhaled anticholinergic, short-acting oral B2agonist, short acting theophylline, but slow onset, high risk of side effects (A) • Exercise induced asthma: rapid acting inhaled B2 agonist (oral or inhaled) prior to exercise or to relieve sx after exercise. Alternative leukotriene modifier or cromone (A) • Training and sufficient warm up also reduce exercise induced asthma in athletes (B)