1. Drugs used in Bronchial asthma

2. Bronchial asthma Objectives:  To define bronchial asthma and classify the types.  To discuss the causes and explain the underlying immunohistopathology and pathophysiology of asthma.  To classify with suitable examples the drugs used in the management of asthma.  To describe the relevant pharmacology of routinely used prototype drugs of different classes of anti-asthma drugs.  To outline the management of asthma through stepwise approach.  To outline the management of status asthmaticus.  To list the common causes of cough and classify drugs available to manage cough and to insist that they should not be indiscriminately used.  To suggest topics for self learning - Inhalation devices, role of mucolytics immunosuppressants in asthma, management of asthma in special situations – pregnancy, hypertensive patients, drugs contraindicated in obstructive lung diseases, and patient education & teaching them on use of inhalers.

3. Bronchial asthma Learning outcomes: The learner should be able to  define bronchial asthma and classify the types.  discuss the causes and explain the underlying immunohistopathology and pathophysiology of asthma.  classify the drugs used in the management of asthma.  describe the relevant pharmacology (mechanism of action, relevant pharmacokinetics, adverse effects, uses and routes of administration) of routinely used prototype drugs of different classes of anti-asthma drugs (glucocorticoids, bronchodilators, leukotriene modifiers, mast cell stabilisers, anticholinergics, xanthines).  explain the advantages of inhalation therapy and write the name of at least one commonly used drug that can be administered by inhalation (for an acute attack and for prophylaxis) in asthma.  outline the management of status asthmaticus.  trace the stepwise approach in the management of asthma.  classify with at least one example, of drugs to manage cough and state that non-pharmacological measures are better in productive cough.

4. Definition A syndrome of bronchial inflammation, airway hyper-responsiveness and reversible airways obstruction Inflammation of bronchial tree causes spasm & obstruction

5. Asthma - Reversible, chronic, obstructive, inflammatory lung disease, with recurrent wheezing episodes, chest tightness & cough; with alternating periods of relatively normal breathing. - Symptoms-spontaneous or triggered by stress allergens, exercise, cold air, infection, etc. - has no cure - With proper management, most can lead normal lives.

6. Immunohistopathology  IgE directed against common environmental antigens (house-dust mites, animal proteins, fungi etc.  Non-IgE asthma have nasal polyps, sinusitis, aspirin/NSAID sensitivity  Idiosyncratic form less understood

7. Immunohistopathology.. Inflammatory cell infiltration (mast cells, eosinophils, T lymphocytes, macrophages, neutrophils, & epithelial cells). Mediator release - mast cell (LT, histamine, 5HT, PGs, tryptase) Airway inflammation (AI) bronchoconstriction, edema, mucus plug, airway wall remodeling. AI causes symptoms- hyperresponsiveness,  airflow, & chronicity Preventing mast cells degranulation halts the damage process

8. Pathophysiology mediators   se microvascular leakage / permeability   se mucosal thickening & airway swelling airway rigidity airway edema bronchial muscles constrict air passages lining swell,  sed airflow & wheeze  sed mucus production

9. collagen deposition beneath basement membrane edema mast cell activation denudation of airway epithelium Early intervention with anti-inflammatory therapy may prevent permanent airflow limitation pathophysiology

11. Asthma - causes Inherited- Eczema / hay fever Modern Lifestyle - Diet / Lifestyles Environmental pollution workplace/home irritants -Dust mites/ cat dog fur / pollen Low temperatures Exercise Smoking during pregnancy- risk of baby developing

12. Triggers Irritants - smoke, cold, occupational, pollution, strong smells Infection - rhinitis, chronic sinusitis- consider if frequent attacks GERD - treat empirically, surgery can benefit Drugs - beta-blocker, NSAIDs (aspirin) Exercise

13. History & Physical Cough, dyspnea, wheeze- particularly at night/early morning Expectorate thick mucous F/H atopic diseases Activity levels & effects Home environment Other allergies  sed accessory muscles use Prolonged exhalation phase Nasal polyps Nasal secretions Serous Otitis Media Eczema

14. Diagnosis Mainly -Clinical - 3 Key aspects Episodic symptoms Reversible obstruction (even partially) Exclude other diagnoses Spirometry – in office Peak flow meter - at home - to confirm treatment effectiveness

15. Peak Flow Meter Green- means asthma in good control Yellow -an attack might be starting Red- asthma needs help, take drug right away

16. Spirometry Usually before & after bronchodilator FEV 1 /FVC ratio Reversibility significant if >12% or FEV 1 200 ml Limitation in children < 6 Yrs

17. Other tests Bronchoprovocation– methacholine challenge helpful if NEGATIVE Chest X-Ray Allergy tests - Skin test

18. Classification Severe Persistent Constant Sx Limits activity Frequent Night SxFEV 1 <60% Moderate Persistent Daily sx Many exac Night Sx >1/wkFEV 1 <80% Mild Persistent Sx >2/wk Many exac Night Sx >2/monFEV 1 >80% Mild Intermittent Sx <2/wkNight Sx <2/monFEV 1 >80% Sx=symptoms

19. Medications (Drugs) Anti-inflammatory drugs (controllers/preventers) - Steroids - Cromolyn Bronchodilators (relievers) - Beta 2 -agonists - Methylxanthines - Anticholinergics Antiinflammatory & bronchodilator - Leukotriene modifiers

20. Corticosteroids Used for any classification of asthma Children - growth inhibition risk not an issue Systemic steroids - in severe cases & for prompt control But - systemically ADR is severe Now inhalational forms - routinely used Start with high dose  taper  maintain  se the dose in case of stress Do not stop abruptly

21. Corticosteroids Beclomethasone, budesonide, triamcinolone, fluticasone – inhaled Antiinflammatory action - mechanism 1.  ses number & activity of airway inflammatory cells 2. Inhibit release of arachidonic acid metabolites 3. Prevent  sed vascular permeability 4. Suppress IgE binding 5.  ses beta adrenergic responsiveness

22. Inhalation route - advantages Direct respiratory action Short onset of action Low doses needed Less systemic side effects Simultaneous O 2 delivery possible Humidification of airways

23. Delivery devices MDI (metered dose inhaler) DPI (dry powder inhaler) Spacer devise for coordination Nebulizer

24. Systemic corticosteroids Injection (iv, im) - hydrocortisone - dexamethasone - betamethasone - methylprednisolone Oral - prednisone - prednisolone - dexamethasone - betamethasone

25. Corticosteroids 1. Aerosol (inhalation) - Low & high dose forms available - Few serious side effects - Favored for treatment of > 2 wks 2. Oral or IV (systemic) - Use these routes if high doses needed - Serious ADR possible (Cushing's) - Use for shortest period possible - Use for severe episode

26. Side effects Inhaled steroids 1. Dysphonia 2. Oropharyngeal candidiasis Both can be  sed by rinsing the mouth with water Systemic Corticosteroids 1. Cushing habitus 2. Hyperglycemia 3. Proximal myopathy 4. Opportunistic infections 5. Delayed wound healing 6. Osteoporosis 7. Glaucoma & cataract

27. Clinical uses 1. For severe episodes 2. For prophylaxis – routine use 3. For patients who respond inadequately to Cromolyn

28. Bronchodilators 1. B 2 adrenoceptor agonists: Albuterol Terbutaline Salmeterol 2. Anticholinergics: Ipratropium bromide Oxitropium bromide 3. Xanthines: Theophylline Aminophylline

29. Beta 2 adrenergic agonists B 2 receptors mediate bronchodilation Adrenaline (non selective, B 1 & B 2 agonist) used earlier  May be given as injection/inhalation but not oral  Short duration of action  Cardiac side effects So selective B 2 agonists -1960’s – less cardiac effects Terbutaline, Salbutamol, salmeterol, fenoterol  First line therapy  Short onset of action (2-5 min)  Long duration of action (3-6 h)  Different routes possible

30. Beta 2 agonists - mechanism 1. Relax constricted bronchial smooth muscle 2. Prevent bronchoconstriction by various stimuli 3.  se mucus clearance 4. Prevent mast cell mediator release 5. Prevent edema by histamine -  vascular permeability

31. Beta 2 agonists 1. Effective bronchodilators with minimal cardiac effect. 2. Not a substrate for COMT- so longer action 3. Inhalation, oral, parenteral use - possible. 4. long acting beta2-agonists - Salmeterol inhalation; used only for prophylaxis. 5. Short acting beta2-agonists - salbutamol inhalation; for relief of acute symptoms

32. Long acting Beta 2 agonists e.g. salmeterol, formoterol Especially useful for nocturnal symptoms stick to cells on which they act, so long action (12 hrs) stimulates beta receptors - relax bronchi Not useful for acute condition prevents exercise-induced bronchospasm Tolerance does not develop can cause tachycardia, hypokalemia, QT prolongation used concomitantly with steroids for long-term symptom control

33. ADR 1. muscle tremor (B 2 stimulation) 2. palpitation 3. ankle edema 4. hypokalemia all less with inhalational use.

34.  2 stimulants.. 1. most effective & widely used bronchodilators 2. inhalers - easy to use 3. rapid action 4. few side effects 3. also protect against cold air, exercise & allergens 4. bronchodilator of choice in acute asthma – used as nebulizer/MDI/DPI (with spacer for children) 5. also used for long term control

35. Anticholinergics Atropine like drugs cause bronchodilation by blocking cholinergic (vagal) tone Less efficacious than sympathomimetics & methylxanthines, but adds to their response. COPD respond better to anticholinergics. Better for regular prophylaxis than for control of acute attack. Not for 1 st line therapy, except in patients who cannot tolerate ß 2 agonists Especially useful in elderly Ipratropium inhaler

36. Methylxanthines Used since 1930 e.g. Theophylline, aminophylline as tablet, syrup, im, iv Pharmacological actions:  Relaxes bronchial smooth muscles   ses mast cell mediator release   ses mucociliary clearance  Prevents microvascular leakage

37. Mechanism Phosphodiesterase inhibition  cAMP ATP cAMP 5-AMP Adenosine receptor antagonism causes bronchoconstriction. Also  ses adrenaline secretion from medulla Antagonizes some PGs in smooth muscle Adenyl cyclase Phosphodiesterase Inhibited by Theophylline

38. Methylxanthines mild-moderate bronchodilation mild anti-inflammatory not preferred as 1st-line or for chronic therapy may be as alternative to  sed doses of inhaled glucocorticoids titrate dose slowly Sustained release form - as adjuvant to inhaled steroids to prevent nocturnal symptoms numerous - ADR, toxicity risk, drug interactions, needs lab monitoring

39. ADR head ache, restlessness  sed gastric acid secretion convulsions cardiac arrhythmias Control of ADR: small initial dose,  se gradually therapeutic plasma level monitoring

40. Status Less potent than beta agonists Not effective by inhalation IV for acute severe asthma Sustained release form gives a steady plasma conc. > 24 hrs - so good for nocturnal asthma Individualize dosage by therapeutic drug monitoring theophylline & B 2 agonists are additive - so may be combined.

41. Sodium cromoglycate Anti-inflammatory effect inhibit response to allergy & exercise prevents early & late responses to allergens &  ses bronchial hyperreactivity Less predictable response than steroids  se beta-agonist need So primarily prophylactic - before exercise or exposure to allergens may be used initially in children Safe

42. Mechanism Not a bronchodilator Mast cell stabilizer modulate mediator release modulate eosinophilic recruitment Inhibits LT production - through inhibition of Ca 2+ influx in to mast cells So inhibits degranulation by various stimuli

43. Cromoglycate as powder for inhalation - capsule use in turbo inhaler Dose - 4 times/day as 4% solution - aerosol spray or nebulizer Uses: - mild to moderate asthma - prophylaxis initial albuterol inhalation ensures better access of cromolyn to distal airways. - allergic rhinitis.

44. ADR: Generally well tolerated bronchospasm cough laryngeal edema, occasionally Joint swelling head ache nausea rash anaphylaxis-rare Cromoglycate

45. Nedocromil sodium same mechanism & uses as cromolyn but more potent inhibits bronchospasm (exercise, cold dry air) improve PF  se need for short acting beta 2 agonists strong safety profile

46. Leukotriene (LT) modifiers LTs (C4, D4 & E4) attract eosinophils LTs- potent bronchoconstrictors,  mucous secretion, recruit inflammatory cells,  vascular permeability,  mucociliary clearance, & cause airway smooth muscle proliferation LT receptor antagonists - Zafirlukast, montelukast LT synthesis inhibitor - Zileuton is a 5-lipoxygenase inhibitor Uses - aspirin, exercise induced asthma & concomitant allergic rhinitis alternative to low dose inhaled steroids/cromolyn

47. LT modifiers… widely approved in children (over 2 years) Few side effects - reported liver effects Drug interactions with theophylline, warfarin, terfenadine Oral formulations once daily mostly studied on mild asthma-improves symptoms &  se peak flow

48. Treatment choice 1. Mild chronic asthma: Salbutamol inhalation 2. Exacerbation of chronic asthma: a) Salbutamol or terbutaline inhalation at onset of attack. b) Cromoglycate prophylaxis - tried if attacks frequent.

49. Treatment choice 3. Severe chronic asthma: a) inhaled salbutamol + ipratropium bromide + theophylline oral b) beclomethasone inhalation oral prednisolone if no control – switch to inhaled steroid later.

50. Treatment choice 4. Status asthmaticus (Refractory asthma) a) Hydrocortisone 100 mg IV b) Salbutamol nebulizer c) O 2 inhalation d) Antibiotics for chest infections e) Aminophylline 250 mg slow IV if poor response to above measures f) Correct dehydration & acidosis: saline & sodium bicarbonate IV

51. Stepwise approach Severe PersistentHigh dose corticosteroid Long acting bronchodilator Oral steroids Moderate PersistentAirway anti-inflammatory agents Long acting bronchodilator Mild PersistentAirway anti-inflammatory or Leukotriene modifier Mid IntermittentNo daily medications

52. DIAGNOSIS BASED ON SYMPTOMS & OBJECTIVE ASSESSMENT ASSESS SEVERITY MILDMODERATESEVERE ENVIRONMENTAL CONTROL AND EDUCATION ADDITIONAL THERAPY INHALED CORTICOSTEROIDS INHALED SHORT-ACTING BETA 2 -AGONIST PRN

53. Chronic obstructive pulmonary disease (COPD) Chronic bronchitis & emphysema Often occur together in heavy smokers Chronic bronchitis - disorder with excessive cough & sputum. Causes alveolar hypoventilation, hypercapnia, hypoxia. Secondary pulmonary hypertension develop - leads to right heart failure - Cor pulmonale

54. Chronic bronchitis - treatment Bronchodilators:  2 agonists/methyl xanthines Mucolytics: N-acetyl cysteine, bromhexine Antibiotics: for secondary infection If not treated - later stages emphysema

55. Rhinitis & Rhinorrhea Allergy or viral infection Treatment: 1. Antihistamines: chlorpheniramine, promethazine 2. Antiinflammatory: Beclomethasone 3. Cromolyn sodium 4. Nasal decongestants: Oxymetazoline, xylometazoline, naphazoline – as nose drops beware of rebound congestion & rhinitis medicamentosa.

56. Cough Cough is a forceful release of air from the lungs that can be heard. Coughing protects respiratory system by clearing it of irritants & secretions. Irritants/secretions  Receptors  message to cough center in brain  cough Cough types – dry, productive

57. Cough-causes Colds or influenza - most common causes Bronchitis viral croup - bark-like cough in children Whooping cough - bacterial - high-pitched cough Pneumonia - bacterial - discolored/bloody mucus TB - bacterial - bloody sputum Fungal - aspergillosis, histoplasmosis Environmental - cigarette smoke/dust/smog Post-nasal drip- mucus trickle into throat- allergies/sinusitis Chronic conditions - asthma, chronic bronchitis, emphysema, cystic fibrosis

58. Cough-Treatment Do not suppress a productive cough - it aids in clearing infective agents/irritants Drugs may be given if troublesome or dry But always try to address underlying condition pneumonia - antibiotics asthma - bronchodilator allergy – antihistamine Gastroesophageal reflux - omeprazole

59. Drugs for cough Antitussives Act by depressing cough center (brain) Narcotics- codeine ADR - drowsiness, nausea, constipation. Dextromethorphan- similar to codeine, ingredient in many OTC remedies but less ADR

60. Drugs for cough.. Expectorants make mucus thin so easy to cough up. Guaifenesin, terpin hydrate - in most OTC expectorants. BUT simply  sing fluid intake, breathing in warm, humidified air has the same effect.

61. Self learning Detailed pharmacology of drugs discussed in the class Current guidelines for asthma Why older drugs (adrenaline, ephedrine, antihistamines etc) are not much used? Inhalation devices in respiratory therapy Mucolytics & their role in respiratory diseases Role of immunosuppressants in asthma Asthma in special situations – pregnancy, hypertensive patients etc Common respiratory infections & drug treatment Drugs contraindicated in obstructive lung diseases Patient education & teaching them how to use inhalers