1. Treatment of Bronchial Asthma I D. Laila.M. Matalqah Respiratory System Faculty of Medicine 1

2. Asthma 2 Asthma is a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role particular, mast cells, eosinophils, T- lymphocytes, macrophages, neutrophils, and epithelial cells. Asthma is characterized by recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night or in the early morning.

3. Asthma 3 Asthmatic symptoms are due to : 1. Constriction of bronchial smooth muscle (bronchospasm) 2. Oedema of the mucosa lining the small bronchi, 3. Plugging of the bronchial lumen with viscous mucus and inflammatory cells (hypersecretion)

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5. Pathophysiology of asthma 5 1. Early Phase allergic reaction Presentation of antigens to T lymphocytes causes activation of the T-Helper cell type 2 leading to B-cell production of antigen-specific immunoglobulin E (IgE) and cytokines.  exposure to the antigen results in:  cross-linking of cell-bound IgE in mast cells and macrophages  causing the release or generation of inflammatory mediators such as histamine, leukotrienes and prostaglandins  results in acute bronchoconstriction in <1 hour, mucus secretion, vasodilation, and exudation of plasma in the airways

6. Pathophysiology of asthma 6 1. Early Phase allergic reaction This early phase response can be blocked by pretreatment with an inhaled β 2-agonist or cromolyn.

7. 7 2. Late Phase Activation of T lymphocytes lead to release cytokines (TH2-cells) mediate allergic inflammation  that activate eosinophils, neutrophils, and alveolar macrophages  The late phase response occurs 6 to 9 hours after the initial allergen challenge  results in a less intense bronchoconstriction  increased airway hyperresponsiveness and airway inflammation. Pathophysiology of asthma

8. ASTHMA 8 Chronic Asthma : episodic dyspnea associated with wheezing, dry cough Spirometry demonstrates obstruction: FEV1/FVC <80% (80% - 120% normal). with reversibility after inhaled β 2-agonist administration (at least a 12% improvement in FEV1). Severe Acute Asthma inflammation, airway edema, excessive mucus accumulation, severe bronchospasm that is poorly responsive to usual bronchodilator therapy. FEV1 are less than 50% of normal predicted values. Pulse oximetry reveals decreased arterial oxygen saturations.

9. Goals of therapy 9 1. Reducing impairment: decreasing the intensity and frequency of asthma symptoms Prevent chronic symptoms. Require infrequent use (≤2 days a week) of inhaled short-acting β 2 agonist for quick relief of symptoms. Maintain (near) “normal” pulmonary function. Maintain normal activity levels (including exercise, other physical activities, 2. Reducing risk: Prevent recurrent exacerbations of asthma, and minimize the need for emergency or hospitalizations. Provide optimal pharmacotherapy with minimal or no adverse effects.

10. Non-pharmacological treatment 10 Avoidance of known allergenic triggers can improve symptoms and reduce medication use Environmental triggers (e.g., animals) should be avoided in sensitive patients Smoker should be encouraged to stop. Patients with acute severe asthma should receive supplemental oxygen therapy to maintain arterial oxygen saturation above 90% (above 95% in pregnant women and patients with heart disease).

11. Drugs Used To Treat Asthma 11 Bronchodilator: Acute treatment β 2-Agonists Muscarinic Receptor Antagonists Methylxanthines

12. Drugs Used To Treat Asthma 12 Anti-inflammatory agent: Chronic and prophylactic Glucocorticosteroids Cromoglicate and Nedocromil Leukotriene Modulators Anti-IgE Monoclonal Ab

13. Bronchodilator: β 2-Adrenergic agonists Selective β 2- agonists: The drugs of choice for treating acute severe asthma and symptoms of chronic asthma. MOA: activates adenyl cyclase, which produces an increase in intracellular cAMP. This results in smooth muscle relaxation, mast cell membrane stabilization, ( inhibits the release of allergy mediators such as histamines from mast cells)

14. Short-acting β -adrenoceptor agonist bronchodilators 14 Salbutamol and terbutaline are selective β 2-agonists An inhaled β 2-agonist is the first-line agent in the management of asthma This is used as required by the patient for the symptomatic relief of breathlessness and wheezing have few β 1-mediated side effects such as cardiotoxicity. β 2-Receptors also present in myocardial tissue; cardiovascular stimulation resulting in tachycardia and palpitations is still the main dose-limiting toxicity with these agents when used in high dosage.

15. 2. Long-term control: Salmeterol, xinafoate and formoterol Slower : Onset 20 minutes to 1 hour have a long duration of action, providing bronchodilation for 4 -12 hours, as adjunctive long-term control for patients with symptoms who are already on low to medium doses of inhaled corticosteroids Long-acting agents are ineffective for acute severe asthma Uses: In nocturnal asthma Long acting β -adrenoreceptor agonist bronchodilators

16. Bronchodilator: β 2-Adrenergic agonists 16 Route of administration: 1. Inhalation formulations include: metered-dose inhaler – aerosol. aerosol administered via a nebulizer; In acute severe asthma, continuous nebulization of short-acting β -agonists (e.g., albuterol) is recommended for patients having an unsatisfactory response after three doses (every 20 minutes) of aerosolized 2. Oral formulations, including slow-release preparations 3. I.V

17. High-dose β 2-agonists 17 High-dose β 2-agonists are only considered if conventional doses do not achieve adequate symptom control. Nebulised drugs such as salbutamol 2.5–5 mg per dose are given. Terbutaline has been given by continuous subcutaneous infusion in the maintenance treatment of difficult to treat asthma.

18. Bronchodilator: β 2-Adrenergic agonists 18 Common side effects include Tremor, Tachycardias, Vasodilatation, Hypokalaemia Hyperglycaemia

19. Anticholinergics Ipratropium bromide 19 These block muscarinic (M1, M2, M3) receptors in bronchial smooth muscle but are generally of little additional value in asthma management. Ipratropium has a slower onset of action than β 2-agonists but a longer duration of action. Anticholinergics may be helpful in patients who also have a degree of obstructive airways disease. They do not block, allergen- or exercise-induced asthma in a dose-dependent fashion

20. Anticholinergics Ipratropium bromide 20 The time to reach maximum bronchodilation from aerosolized ipratropium is longer than from aerosolized short-acting β 2-agonists (30 to 60 minutes vs. 5 to 10 minutes). Inhaled ipratropium bromide is only indicated as adjunctive therapy in severe acute asthma not completely responsive to β 2-agonists alone because it does not improve outcomes in chronic asthma

21. Anticholinergics 21 Adverse effects bitter taste (this may compromise compliance); acute urinary retention (in patients with prostatic hypertrophy); acute glaucoma has been precipitated when nebulized doses are given via a face mask; May: paradoxical bronchoconstriction due to sensitivity to benzalkonium chloride, which is the preservative in the nebulizer solution.

22. Methylxanthines 22 Theophylline (Orally) and Aminophylline (I.V) MOA: inhibiting phosphodiesterases, which result in antiinflammatory and bronchodilator activity through decreased mast cell mediator release, decreased eosinophil basic protein release decreased T-lymphocyte proliferation decreased T-cell cytokine release. Methylxanthines are ineffective by aerosol and must be taken systemically (orally or IV).

23. Theophylline 23 Sustained-release theophylline is the preferred oral preparation, Theophylline is eliminated primarily by metabolism via hepatic cytochrome P450 mixed-function oxidase It has narrow therapeutic window Routine monitoring of serum theophylline concentrations is essential for safe and effective use. A steady-state range of 5 to 15 mcg/mL is effective and safe for most patients multiple drug interactions (e.g. clarithromycin, ciprofloxacin).

24. Theophylline 24 Side effects 1. Gastro-intestinal: nausea, vomiting, anorexia. 2. Cardiovascular: (1) dilatation of vascular smooth muscle – headache, flushing and hypotension; (2) tachycardia and cardiac dysrhythmias (atrial and ventricular). 3. Central nervous system: insomnia, anxiety, hyperventilation, headache and fits. Overdose may cause: seizures or potentially fatal arrhythmias

25. Theophylline 25 The mild side effects such as nausea and vomiting are seen at concentrations as low as 13 mg/L but are more common over 20 mg/L. Significant cardiac symptoms, tachycardia and persistent vomiting are usually seen at concentrations of 40 mg/L while severe CNS effects, such as seizures, have been seen at 30 mg/L but are more common above 50 mg/L.

26. Theophylline 26 Slow-release forms should be used, usually twice daily, although these can be used in a single night-time dose if nocturnal symptoms are troublesome. Theophylline should be started at a dose of 400–500 mg/day in adults and, if required, increased after 7 days to 800–1000 mg/day.

27. Anti-inflammatory agent Corticosteroids 27 Preferred long-term control therapy for persistent asthma in all patients of any degree (mild, moderate, or severe) Most patients with moderate disease can be controlled with twice-daily dosing Because the inflammatory response of asthma inhibits steroid receptor binding, patients should be started on higher and more frequent doses and then tapered down once control has been achieved. The response to inhaled corticosteroids is delayed; symptoms improve in most patients within the first 1 to 2 weeks and reach maximum improvement in 4 to 8 weeks

28. Inhaled corticosteroids 28 recommends considering ICS for patients with any of the following: Exacerbations of asthma in the past 2 years Using inhaled β 2-agonists three times a week or more Symptoms three times a week or more Waking one night a week with symptoms

29. Inhaled corticosteroids 29 All ICSs have dose-related side effects. Adrenal suppression occurs at around doses of >1500 μ cg/day of beclometasone in adults. In children, doses of 400 μ cg/day of beclometasone or more are associated with growth failure and adrenal suppression Oropharyngeal side effects such as candidiasis are also more common at higher doses Measures to minimise this can be tried, such as using a large-volume spacer device and rinsing the mouth with water or brushing teeth after inhalation,

30. Inhaled corticosteroids 30 ICSs are the initial drugs of choice, with a starting dose for an adult of beclometasone or budesonide 400 μ cg/day (or an equivalent) given in divided doses Beclomethasone dipropionate (BDP) Budesonide (BUD) Flunisolide (FLU) Fluticasone propionate (FP) Mometasone furoate (MF) Triamcinolone acetonide (TAA)

31. Corticosteroids Systemic Corticosteroids 31 Hydrocortisone (I.V) Prednisone (oral) Methylprednisolone (I.V) Dexamethasone indicated in all patients with acute severe asthma not responding completely to initial inhaled β 2- agonist administration (every 20 minutes for three to four doses). Prednisone, 1 to 2 mg/kg/day (up to 40 to 60 mg/day), is administered orally in two divided doses for 3 to 10 days.

32. Mast Cell Stabilizers 32 1. Cromolyn sodium Metered-dose inhalers and as nebulizer solution 2. Nedocromil sodium MOA: inhibits mast cell degranulation and release of histamine do not cause bronchodilation. Cromolyn should not replace ICS or quick-relief β 2 agonists as the mainstay of asthma therapy Adverse effects: Cough and wheezing, and headache The powder can (very rarely) produce bronchospasm or hoarseness. Nedocromil has a bitter taste.

33. Mast Cell Stabilizers 33 Cromolyn and nedocromil are indicated for the prophylaxis of exercise-induced asthma and mild persistent asthma in children, pregnant women and adults Less effective than inhaled corticosteroids for controlling persistent asthma can be used in conjunction for patients not responding completely to inhaled β 2-agonists Patients should initially receive cromolyn or nedocromil four times daily; reduced to two times after stabilization

34. Leukotriene Modifiers 34 1. leukotriene receptor antagonists : Zafirlukast and montelukast (inhibitors of the cysteinyl leukotriene-1 receptor) 2. Inhibitor of leukotriene synthesis: Zileuton (oral) inhibit 5-lipooxygenase Action: reduce the proinflammatory : decreased microvascular permeability and airway edema and bronchoconstriction effects of leukotriene D4. They are less effective in asthma than low-dose inhaled corticosteroids

35. Leukotriene Modifiers 35 S/E: elevated hepatic enzymes (especially in the first 3 months of therapy), Serum alanine aminotransferase should be monitored before treatment and then periodically thereafter inhibition of the metabolism of some drugs metabolized by CYP3A4 (e.g., theophylline, warfarin).

36. Omalizumab 36 It is an anti-IgE antibody approved for the treatment of allergic asthma not well controlled by oral or inhaled corticosteroids Side effects: rashes, urticaria, pruritus, sinusitis, gastro- intestinal upsets, injection site reactions and possibly secondary haematologic malignancies. It can be used in children, but is a very expensive therapy