Pharmacotherapy of drugs used in bronchial asthma & COPD

1. By Prof. M.ABDELAZIZ Pharmacotherapy of drugs used inbronchial asthma & COPD

2. Disorders of Respiratory Function Main disorders of the respiratory system are : 1. Bronchial asthma 2. Cough 3. Allergic rhinitis 4. Chronic obstructive pulmonary disease (COPD, also called emphysema)

3. Asthma Asthma is a chronic inflammatory disorder of bronchial airways that result in airway obstruction in response to external stimuli (as pollen grains, cold air and tobacco smoke).

4. Characters of airways in asthmatic patients : • Airway hyper-reactivity: abnormal sensitivity of • the airways to wide range of external stimuli. • Inflammation • Swelling • Thick mucus production. • Bronchospasm (constriction of the bronchial muscles).

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6. Symptoms of asthma Asthma produces recurrent episodic attack of • Acute bronchoconstriction • Shortness of breath • Chest tightness • Wheezing • Rapid respiration • Cough Symptoms can happen each time the airways are irritated by inhaled irritants or allergens.

7. Causes • Infection • Emotional conditions • Stress • Exercise • Pets • Seasonal changes • Some drugs as aspirin, β bockers

8. Some allergens which may cause asthma Spittle, excrements, hair and fur of domestic animals House-dust mites which live in carpets, mattresses and upholstered furniture Plant pollen Dust of book depo-sitories Food components (stabilizers, genetically modified products) Pharmacological agents (enzymes, antibiotics, vaccines, serums)

9. Asthma pathophysiology is quite difficult and insufficiently studied. Undoubtedly, in most cases the disease is based on 1 type hypersensitivity reaction. The genesis of any allergic reaction may be divided into immune, pathochemical and pathophysio-logic phases. Pathophysiology

10. After involving into the airways allergens activate immunocompetent cells. As a result B-lymphocytes produce antibodies of Ig E class. In case of asthma T-lymphocytes are inhibited, so the activation of B-lympocytes and Ig E production are excessive, exceeding normal needs. Immune phase Allergens Allergen-specific IgE B-cell T-cell

11. Further these antibodies bind to the surface of mast cells, basophils and eosinophils of bronchial mucous. When a new portion of allergen involves the respiratory system, it interacts with IgE-antibodies. This is a first, immune phase of allergic reaction.

12. As a result of antigen-antibody reaction the peculiar “explosion” occurs. The membranes of mast cells, basophils and eosinophils of bronchial mucous wreck with output of biologically active substances (histamine, serotonin, chemotaxis factors, heparin, proteases, thromboxane, leukotrienes, prostaglandins), Pathochemical phase which induce hyperergic inflammation, mucous edema, spasm of smooth myocytes, glands hypersecretion, viscous exudate formation in bronchial lumen. Airway fill with mucus Muscles contract Airways swell

13. Asthma exacerbation, occurring as a result, is a clinical manifestation of the 3rd, pathophysiolo-gical, phase of allergic reaction. The indicated mechanism is specific for atopic (exogenous) asthma genesis. In addition to this,autosensibilization of damaged pulmonary tissue, neuropsychic disturbances, corticoid insufficiency, adrenergic imbalance, impairment of arachidonic acid metabolism, genetic and some other factors probably play a certain role in genesis of nonatopic (endogenous) asthma.

14. Depending on etiology asthma is divided into: 1-exogenous (atopic) 2- and endogenous (non-atopic). Byclinical course asthma is divided into 1-intermittent (beginning, early) 2-and persistent (chronic, late). Depending on frequency of exacerbations, limitations of patient’s physical activity and lung function persistent asthma is divided into: mild, moderate and severe (lung function is assessed by forced expiratory volume in 1 second (FEV1) and peak expiratory flow (PEF) and daily variability of these parameters). There are also remission phase and exacerbations. Classification

15. Clinical course, severity Daytime asthma symptoms Nighttime awakenings FEV1, PEF Intermittent < 1 /week 2 and < /month >80% predicted. Daily variability < 20% Mild persistent  1 /week but not daily > 2 /month >80% predicted. Daily variability – 20-30% Moderate persistent Daily > 1 /week > 60 but < 80% predicted. Variability>30%. Severe persistent Persistent, which limit normal activity Daily <60% predicted. Variability > 30%. Asthma severity classification

16. In recommendations of Global Initiative for Asthma (GINA) asthma is classified on the base of control assessment andis divided into well-controlled, partially controlled and uncontrolled. Asthma control is considered as: • daytime symptoms  2 /week; • ability to engage in normal daily activity; • the absence of nighttime awakenings as a result of asthma symptoms; • need in bronchodilators administration  2 /week; • the absence of asthma exacerbations; • normal or near normal lung function parameters.

17. Classic signs and symptoms of asthma are: • attacks of expiratory dyspnea • shortness of breath • cough • chest tightness • wheezing (high-pitched whistling sounds when breathing out) • sibilant rales Clinical manifestations

18. In typical cases in development of asthma exacerbation there are 3 periods – prodromal period, the height period and the period of reverse changes. At theprodromal period: • vasomotoric nasal reaction with profuse watery discharge, • sneezing, dryness in nasopharynx, • paroxysmal cough with viscous sputum, • emotional lability, • excessive sweating, • skin itch and other symptoms may occur.

19. At the peackof exacerbation there are: • expiratory dyspnea • forced position with supporting on arms • poorly productive cough • cyanotic skin and mucous tunics • hyperexpansion of thorax with use of all accessory muscles during breathing • at lung percussion: tympanitis, shifted downward lung borders • at auscultation: diminished breath sounds, sibilant rales, prolonged breathing-out, tachycardia. • in severe exacerbations: the signs of right-sided heart failure (swollen neck veins, hepatomegalia), overload of right heart chambers on ECG.

20. At the period of the reverse changes, • which comes spontaneously or under • pharmacologic therapy, • dyspnea and breathlessness relieve or disappear, • sputum becomes not so viscous, • cough turns to be productive, • patient breathes easier.

21. The severe and prolonged asthma exacerbation with intensive progressive respiratory failure, hypoxemia, hypercapnia, respiratory acidosis, increased blood viscosity and the most important sign is blockade of bronchial b2-receptors. Stages:1st- refractory response to b2-agonists (may be paradoxical reaction with bronchospasm aggravation) 2nd - “silent” lung because of severe bronchial obstruction and collapse of small and intermediate bronchi; 3rd stage – the hypercapnic coma. Asthmatic status

22. In many cases asthma, particularly intermittent, manifests with few and atypical signs: • episodic appearance of wheezing; • cough, heavy breathing occurring at night; • cough, hoarseness after physical activity; • “seasonal” cough, wheezing, chest tightness (e.g., during pollen period of ambrosia); • the same symptoms occurring during contact with allergens, irritants; • lingering course of acute respiratory infections.

23. Asthma complications The complications of asthma exacerbations are: • pneumothorax • lung atelectasis • pneumonia • acute or subacute cor pulmonale • asthmatic status. Persistent asthma causes: • fibrosing bronchitis • small bronchi deformation and obliteration • emphysema • pneumosclerosis, • chronic respiratory failure • chronic cor pulmonale. Asthma in childhood leads to growth inhibition and thoracic deformation.

24. Eosinophilia, moderate leukocytosis in blood count as well as increased serum level of Ig E can be found in patients with asthma, especially at asthma exacerbations. Inflammatory cells, Curschmann's spirals (viscous mucus which copies small bronchi) and Charcot-Leyden crystals (crystallized enzymes of eosinophils and mast cells) can be observed in sputum. Investigations Lab Data

25. hyperlucency of lung fields • low standing and limited mobility of diaphragm • expanded intercostal spaces • horizontal rib position. Chest X-ray reveals:

26. especially in case of severe, persistent asthma, shows hypertrophy of right heart chambers. ECG Right axis deviation, Rs type complex in V1 lead, low amplitude R in V5-V6 leads

27. Mild Intermittent Asthma Mild Persistent Asthma Moderate Persistent Asthma Severe Persistent Asthma Classification of Asthma

28. forced expiratory volume in 1 second (FEV1) and peak expiratory flow (PEF), which Lung function assessment The diagnosis and severity assessment of asthma is based mainly on parameters of lung function.The most important of them are: • are measured during spirometry at forced breathing-out.

29. FEV1 and PEF directly depend on bronchial lumen size and elastic properties of surrounding lung tissue. PEF FEF Expiration FEF Flow Volume Inspiration PIF

30. Increase in FEV1 and PEF after inhalation of bronchodilators (b2-agonists) of 15% and more is specific for asthma.

31. PEF also can be measured with the help of individual devices – peak flow meters

32. Typical clinical manifestations and lung function assessment are sufficient for diagnosis of asthma. Diagnosis

33. Airways Innervations Afferent nerves (sensory) • Irritant receptors in upper airways. • C-fiber receptors in lower airways. Stimulated by : Exogenous chemicals Physical stimuli (cold air) Endogenous inflammatory mediators

34. Efferent nerves (motor) • Parasympathetic supply M3 receptors in smooth muscles and glands. • No sympathetic supplybut B2 receptors in smooth muscles and glands

38. 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 ).

39. Anti asthmatic drugs Bronchodilators (Quick relief medications) treat acute episodic attack of asthma • Short acting 2-agonists • Antimuscarinics • Xanthine preparations Anti-inflammatory Agents (control medications or prophylactic therapy) • reduce the frequency of attacks • Corticosteroids • Mast cell stabilizers • Leukotrienes antagonists • Anti-IgE monoclonal antibody • Long acting ß2-agonists

40. Anti asthmatic drugs Bronchodilators : (Quick relief medications) are used to relieve acute attack of bronchoconstriction 1. 2 - adrenoreceptor agonists 2. Antimuscarinics 3. Xanthine preparations

41. Sympathomimetics - adrenoceptor agonists Mechanism of Action • direct 2stimulation  stimulate adenyl cyclase  Increase cAMP  bronchodilation • Inhibit mediators release from mast cells. • Increase mucus clearance by (increasing ciliary activity).

42. Classification of  agonists • Non selective  agonists: epinephrine - isoprenaline • Selective 2 – agonists (Preferable). Salbutamol (albuterol) Terbutaline Salmeterol Formeterol

43. Non selective -agonists. Epinephrine Potent bronchodilator rapid action (maximum effect within 15 min). S.C. or by inhalation (aerosol or nebulizer). Has short duration of action (60-90 min) Drug of choice for acute anaphylaxis (hypersensitivity reactions).

44. Nebulizer Inhaler

45. Disadvantages • Not effective orally. • Hyperglycemia • CVS side effects: tachycardia, arrhythmia, hypertension • Skeletal muscle tremor • Not suitable for asthmatic patients with hypertension or heart failure. Contraindication: CVS patients, diabetic patients

46. Selective 2 –agonists • drugs of choice for acute attack of asthma • Are mainly given by inhalation (metered dose inhaler or nebulizer). • Can be given orally, parenterally. • Short acting ß2 agonists e.g. salbutamol, terbutaline • Long acting ß2 agonists e.g. salmeterol, formeterol

47. Short acting ß2 agonists Salbutamol, inhalation, orally, i.v. Terbutaline, inhalation, orally, s.c. • Have rapid onset of action (15-30 min). • short duration of action (4-6 hr) • used for symptomatic treatment of acute episodic attack of asthma.

48. Long acting selective ß2 agonists • Salmeterol & formoterol: • Long acting bronchodilators (12 hours) • have high lipid solubility (creates depot effect) • are given by inhalation • are not used to relieve acute episodes of asthma • used for nocturnal asthma (long acting relievers). • combined with inhaled corticosteroids to control asthma (decreases the number and severity of asthma attacks).

49. Advantages of ß2 agonists • Minimal CVS side effects • suitable for asthmatic patients with hypertension or heart failure. Disadvantages of ß2 agonists • Skeletal muscle tremors. • Nervousness • Tolerance (B-receptors down regulation). • Tachycardia over dose (B1-stimulation).

50. Muscarinic antagonists Ipratropium – Tiotropium • Act by blocking muscarinic receptors. • Given by aerosol inhalation • Quaternary derivatives of atropine • Does not diffuse into the blood • Do not enter CNS, minimal systemic side effects. • Delayed onset of action • Ipratropium has short duration of action 3-5 hr • Tiotropium has longer duration of action (24 h).