asthma management

Bronchial asthma pharmacotherapy

1. Dr. Bushra Hasan Khan Deptt of Pharmacology JNMC, AMU Management of Bronchial Asthma

2. Introduction Asthma is a chronic inflammatory disorder of the airways that is characterized: clinically by recurrent episodes of wheezing, breathlessness, chest tightness, and cough, particularly at night / early morning. physiologically by reversible narrowing of the bronchial airways and a marked increase in bronchial responsiveness.

3. 300 million people around the globe suffer from Asthma. World-wide, deaths from this condition have reached over 180,000 annually. In Western Europe as a whole, asthma has doubled in ten years. India has an estimated 15-20 million Asthmatics. In India, rough estimates indicate a prevalence of between 10% and 15% in 5-11 year old children. The human and economic burden associated with this condition is severe. WHO

4. Classification A heterogenous disorder, no universally accepted classification Atopic /extrinsic /allergic (∼70%) – IgE mediated immune responses to environmental antigens. Non-atopic/ intrinsic /non-allergic(∼30%) –triggered by non immune stimuli. Patients have negative skin test to common inhalant allergens and normal serum concentrations of IgE .

5. The ultimate humoral and cellular mediators of airway obstruction are common to both atopic and non-atopic variants of asthma, and hence they are treated in a similar way.

6. Pathophysiology Chronic inflammation Airway Hyper-responsiveness

7. Inflammation Chronic inflammatory state Superimposed acute inflammatory episodes Involves respiratory mucosa from trachea to terminal bronchioles, predominantly in the bronchi. Eosinophilic bronchitis, mast cell infiltration. T-helper type 2 response - IL-4, IL-5, and IL-13.

8. Inflammation… IL-4 – stimulates IgE production IL-5 – activates eosinophils IL-13 – stimulates mucus production Inflammatory mediators

9. Inflammation…

10. Asthma Triggers Allergens Virus Infections Drugs Exercise Food Air pollutants Stress Occupational factors

11. Cellular mechanisms of asthma

12. Inflammation… Exact cause of airway inflammation is unknown. Thought to be an interplay between endogenous and environmental factors. Endogenous factors – Atopy – Genetic predisposition to IgE mediated type I hypersensitivity An excessive T H 2 reaction against environmental antigens The major risk factor for asthma Asthma is commonly associated with other atopic diseases – allergic rhinitis(80%), atopic dermatitis, urticaria , etc. Genetics : Polymorphism of gene on chr . 5q , ADAM-33, DPP-10 , GPRA gene .

13. Inflammation… Environmental factors Viral infections – RSV, Mycoplasma , Chlamydia Air pollution Allergens – house dust mite Hygeine hypothesis

14. Airway Hyper-responsiveness Bronchial hyper-responsiveness is a state characterised by easily triggered  bronchospasm . Bronchial hyper-responsiveness can be assessed with a bronchial challenge test. Concentration of a bronchial spasmogen ( methacholine /histamine), needed to produce a 20% increase in airway resistance in asthmatics is often only 1% to 2% of the equally effective concentration in healthy control subjects.

15. Effects of inflammation Airway epithelium – damage and shedding may lead to AHR. Mucus hypersecretion Nerves –sensitization of nerve terminals and reflex activation of cholinergic nerves. Vessels – increased in number, blood flow is increased. Smooth muscle – hyperplasia and hypertrophy Fibrosis – subepithelial .

16. Clinical presentation Wheezing, dyspnea and cough. Tenaceous mucus production. Symptoms worse at night. Limitation of activity. Signs  ↑ respiratory rate, use of accessory muscles Hyper-resonant percussion note Expiratory wheeze May be SILENT CHEST No findings when asthma is under control or b/w attacks

17. Investigations Pulmonary function tests  Spirometry estimate degree of obstruction ↓FEV 1 , ↓FEV 1 /FVC, ↓PEF. >12% increase in FEV 1 , 15 minutes after β 2 agonist inhalation. AHR – histamine / methacholine provocation test > 20% fall in FEV 1 CXR – hyperinflated Arterial blood-gas analysis hypoxia & hypocarbia (severe acute asthmahypercarbia ) Skin hypersensitivity test Sputum & B lood eosinophilia Elevated serum IgE levels

18. Aims of anti asthmatic drugs : To relieve acute episodic attacks of asthma (bronchodilators, quick relief medications). To reduce the frequency of attacks, and nocturnal awakenings ( anti-inflammatory drugs, prophylactic or control therapy ).

19. Efferent nerves (motor) Parasympathetic supply M3 receptors in bronchial smooth muscles and glands. No sympathetic supply but ß2 receptors in bronchial smooth muscles and glands

20. Classification of drugs RELIEVERS (RESCUE MEDICATIONS) β 2 Agonists Anticholinergic Agents Methylxanthines CONTROLLERS Glucocorticoids Leukotrienes pathway inhibitors Cromones Anti- IgE therapy

21. Drugs Adenyl cyclase cAMP Short acting main choice in acute attack of Asthma Inhalation B2 agonists Salbutamol , Terbutaline Long acting, Prophylaxis Nocturnal Asthma Salmeterol , Formoterol Blocks M 3 receptors Main drugs For COPD Inhalation Inhalation Antimuscarinics Ipratropium (Short) Tiotropium (long) Inhibits phosphodiesterase  cAMP (orally) (parenterally) Xanthine derivatives Theophylline Aminophylline Bronchodilators (relievers for bronchospasm )

22. Inhalation Corticosteroids (Inhibits phospholipase A2) Beclomethasone , Fluticasone , Budesonide Orally prednisolone parenterally Hydrocortisone Inhalation, prophylaxis in children Mast cell stabilizers Cromoglycate ( Cromolyn ), Nedocromil orally Cysteinyl Leukotriene antagonists Zafirlukast Injection, SC Omalizumab (Anti IgE antibody) Anti-inflammatory drugs (prophylactic)

23. β 2 Agonists in asthma Bronchodilators, Usually given by inhalation route. MOA: Relaxation of airway smooth muscle Non-bronchodilator effects Inhibition of mast cell mediator release Reduction in plasma exudation Increased mucociliary transport Inhibition of sensory nerve activation Inflammatory cells express β 2 receptors but these are rapidly downregulated . No effect on airway inflammation and AHR.

24. β2 Agonists in asthma Short-Acting β 2 Agonists Salbutamol Terbutaline Bambuterol Pirbuterol Metaproterenol Long-Acting β 2 Agonists Salmeterol Formoterol

25. Short-Acting β 2 Agonists Duration of action : 3-6 hrs. Convenient, rapid onset, without significant systemic side effect Bronchodilator of choice in acute severe asthma Used for symptomatic relief on as required basis. Only treatment required for mild, intermittent asthma. Use >2 times a week indicates need of a regular controller therapy.

26. Long-Acting β 2 Agonists Duration of action >12 hrs. Used in combination with inhaled corticosteroid (ICS) therapy. Improve asthma control and reduce frequency of exacerbations. Allow asthma to be controlled at lower dose of ICS. Fixed dose combination of corticosteroid with long acting β 2 agonist : e.g. Salmeterol + Fluticasone , Formoterol + Budesonide .

27. Long-Acting β 2 Agonists Should not be used as monotherapy (increased mortality). Combination shows synergistic action. Not effective for acute bronchospasm . Salmeterol : slow onset, 2 puffs of 25 μg twice a day Formoterol : rapid onset , 2 puffs of 6 μg twice a day

28. Risks with LABA monotherapy Meta-analyses have shown that LABAs are associated with increased risk of overall death when used as monotherapy . The use of LABAs concomitantly with inhaled corticosteroids significantly reduces asthma hospitalizations and is not associated with life-threatening events and asthma-related deaths. The evidence appears to support the use of LABAs plus inhaled steroids in a single inhaler device for patients with moderate to severe asthma. Thorax 2012;67:342-349

29. ADRs – β 2 agonists Muscle tremors Tachycardia Hypokalemia Hypoxemia Restlessness Cautious use – Hypertension Ischemic heart disease

30. Anticholinergic agents Ipratropium bromide, Tiotropium . Prevent cholinergic nerve induced bronchoconstriction . Block M 3 receptor on bronchial smooth muscles. Less effective than β 2 agonists. Response varies with existing vagal tone.

31. Anticholinergic agents Use in asthma Intolerance to inhaled β 2 agonist. Status asthmaticus – additive effect with β 2 agonist. Ipratropium -- bitter taste, precipitate glaucoma Tiotropium – longer acting, approved for treatment of COPD.

32. Methylxanthines Theophylline , Theobromine , Caffeine Recently interest has declined in this class of drugs: Side effects Need for plasma drug levels monitoring Pharmacokinetics Availability of other effective drugs Still widely used in developing countries due to their lower cost. Availability of slow release tablets – stable plasma levels

33. Methylxanthines : MOA Inhibition of several members of the phosphodiesterase (PDE) enzyme family Inhibition of cell-surface receptors for adenosine Enhancement of histone deacetylation .

34. Methylxanthines Theophylline base is poorly soluble in water. Soluble salts of theophylline : Aminophylline -85% Etophylline – 80% Oxtriphylline -64%

35. ADRs of Theophylline At conc >20 mg/L : Anorexia, nausea, vomiting, abdominal discomfort, headache, and anxiety start (PDE4 inhibition) At conc.>40 mg/L : Seizures or arrhythmias (A1 receptor antagonism)

36. Doxoyphylline Long acting, oral Inhibit PDE Adenosine A1 & A2 reduced affinitysafe Dose - 400mg OD

37. Corticosteroids – asthma Effective drugs for treatment of asthma. Development of inhaled corticosteroids is a major advance in asthma therapy. Used prophylactically as a controller therapy. Reduce the need for rescue β 2 agonist. Benefit starts in 1week but continues upto several months. If asthma not controlled at low dose of ICS :- addition of long acting β 2 agonist is more effective than doubling steroid dose.

38. Glucocorticoids Mechanism of action Inhibition of phospholipase A2 ↓ prostaglandin and leukotrienes ↓ Number of inflammatory cells in airways. Mast cell stabilization →↓ histamine release. ↓ capillary permeability and mucosal edema. Inhibition of antigen-antibody reaction. Upregulate β 2 receptors (have additive effect to β2 agonists).

39. ICS Beclomethasone dipropionate Budesonide Fluticasone hemihydrate Fluticasone propionate Ciclesonide Triamcinolone Flunisolide Mometasone furoate

40. Budesonide , fluticasone , mometasone , and ciclesonide : lower oral bioavailability than beclomethasone dipropionate This results in reduced systemic absorption from the fraction of the inhaled drug that is swallowed and thus reduced adverse effects. Ciclesonide is a prodrug - converted to the active metabolite by esterases in the lung : low oral bioavailability and a high therapeutic index. When doses of inhaled steroid exceed 800 µg beclomethasone dipropionate daily, a large volume spacer is recommended to reduce oropharyngeal deposition and systemic absorption.

41. ADRs of inhaled corticosteroids Oropharyngeal candidiasis , dysphonia , cough – frequent at high doses. Reduced by using spacer device. Decreased bone mineral density . Hypothalamic-pituitary-adrenal axis suppression- >1500µg/d of budesonide . Metabolic abnormalities Skin thinning, purpura - dose related effect. Growth retardation in children – controversial.

42. Systemic steroids in asthma Indication Acute exacerbation Chronic severe asthma A 5-10 day course of Prednisolone 30-40 mg/d is used. 1% of patients may require regular maintenance therapy. Side effects of long-term oral corticosteroid therapy : Fluid retention, increased appetite, weight gain, osteoporosis, capillary fragility, hypertension, peptic ulceration, diabetes, cataracts, and psychosis.

43. Leukotrienes pathway inhibitors Two approaches to interrupt the leukotriene pathway : Inhibition of 5-lipoxygenase, thereby preventing leukotriene synthesis - Zileuton . Inhibition of the binding of LTD 4 to its receptor on target tissues, thereby preventing its action - Zafirlukast , Montelukast , Pranlukast . Oral route. Side effects :- Hepatic dysfunction Churg –Strauss synd.( vasculitis with eosinophilia )

44. Leukotrienes pathway inhibitors They are less effective than ICSs in controlling asthma Use in asthma Patients unable to manipulate inhaler devices. Aspirin induced asthma. Mild asthma – alternative to ICS. Moderate to severe asthma – may allow reduction of ICS dose.

45. Montelukast is effective as a once-daily oral preparation (10 mg in adults, 5 mg in children). In addition, oral administration may treat Concomitant allergic rhinitis.

46. Cromones Cromolyn sodium & Nedocromil sodium On chronic use (four times daily) reduce the bronchial reactivity. These drugs have no effect on airway smooth muscle tone and are ineffective in reversing asthmatic bronchospasm ; they are only of value when taken prophylactically . Inhalation route

47. Cromones Exact mechanism of action unknown Alteration in the function of delayed chloride channels in the cell membrane, inhibiting cell activation. Mast cells - inhibition of mediator release Eosinophils - inhibition of the inflammatory response to inhalation of allergens.

48. Cromones : Uses Asthma - Prevention of asthmatic attacks in mild to moderate asthma Adverse effects Well tolerated drugs Minor side effects- Throat irritation, Nausea, Headache.

49. Anti- IgE therapy Omalizumab - recombinant humanized monoclonal antibody targeted against IgE . MOA - IgE bound to Omalizumab cannot bind to IgE receptors on mast cells and basophils :- preventing the allergic reaction at a very early step in the process. Pharmacokinetics Single subcutaneous injection every 2 to 4 weeks. Peak serum levels after 7 to 8 days.

50. Omalizumab Use in asthma Persons >12 years of age with moderate-to-severe persistent asthma. Omalizumab is not an acute bronchodilator and should not be used as a rescue medication or as a treatment of status asthmaticus . Expensive drug Has to be given under direct medical supervision due to the risk of anaphylaxis.

51. Classification of Asthma severity (GINA) Grade Symptoms Night-time Symptoms Intermittent Symptoms ≤ 2 times/week ≤ 2 times/month Mild persistent Symptoms ≥ 2 times/week but ≤1/day ≥ 2 times/month Moderate persistent Daily Symptoms ≥ 1/week Severe persistent Daily symptoms Limited physical activity Frequent

52. Stepwise approach to asthma

53. Aerosol delivery of drugs Topical application of drugs to lungs. Least systemic delivery Poor absorbtion from GIT High first pass metaobolism Therpeutic index of drugs is Increased. Drug particles of 1-5µ are produced. Devices - Metered dose inhalers, nebulisers , dry powder inhaler.

54. Disposition of inhaled drugs

55. Status asthmaticus Severe airway obstruction Symptoms persist despite initial standard acute asthma therapy. Severe dyspnoea & cough Patient adopts upright position fixing shoulder girdle to assist accessory muscles of respiration Sweating, central cyanosis, tachycardia URTI  mc precipitant

56. Treatment of Status asthmaticus High flow humidified Oxygen through facemask Hydrocortisone hemisuccinate 100 mg i.v . stat, followed by 100-200mg, 4-8 hrly infusion. Nebulised Salbutamol (5mg) in Oxygen given immediately Ipratopium bromide (0.5mg) + Salbutamol (5mg) nebulised in oxygen,who don’t respond within 15-30 min Terbutaline  (0.25-0.5mg) s.c . or (0.1 μ g/kg/min) i.v .  excessive coughing or too weak to inspire adequately. ET intubation & mechanical ventilation if above Treatment fails

57. Asthma medicines and pregnancy A review of the animal and human studies on the effects of asthma medicines taken during pregnancy found few risks to the woman or her fetus. It is safer for a pregnant woman who has asthma to be treated with asthma medicines than for her to have asthma symptoms and asthma attacks. Poor control of asthma is a greater risk to the fetus than asthma medicines are. Budesonide is labeled by the U.S. Food and Drug Administration (FDA) as the safest inhaled corticosteroid to use during pregnancy. One study found that low-dose inhaled budesonide in pregnant women seemed to be safe for the mother and the fetus.

58. Thank you