Drugs Affecting the Respiratory S ystem

1. Drugs Affecting the Respiratory System Dr. Alia Shatanawi 17/3/2013

2. Asthma • A disease of the airways that is characterized by hyper-responsiveness of the tracheobronchial tree to a multiplicity of stimuli • Manifested physiologically by a widespread narrowing of the air passages and clinically by wheezing, shortness of breath, chest tightness, and coughing. Dr. Shatanawi 2013

3. Asthma • In the United States, more than 22 million people are known to have asthma. Nearly 6 million of these people are children. • In Jordan the asthma incidence in children is approximately 15 % in boys and 10 % in girls. Dr. Shatanawi 2013

4. Pathogenesis of Asthma The airway obstruction in asthma is due to: • Contraction of the smooth muscles , • Inflammation of the bronchial wall • Increased mucous secretion. Dr. Shatanawi 2013

5. Asthma pathophysiology and therapeutic approach Dr. Shatanawi 2013

6. Asthma treatment • The overall objectives of anti-asthma therapy are to return lung function to near normal and to prevent further exacerbations • Drugs used to treat these conditions can be delivered by inhalation, oral, or parental routes. • Inhalation is often preferred because the drug is delivered directly to the target tissue and does not cause significant side effects. Dr. Shatanawi 2013

7. Asthma treatment A. Quick-relief Medications • Short acting B2-agonists • Short-acting Inhaled Anticholinergics • Short Course Systemic Corticosteroids • Maintenance Medications • Long-Acting Inhaled B2-Agonists • Leukotriene Modifiers • Inhaled Corticosteroids • Theophylline • Omalizumab Dr. Shatanawi 2013

8. Anti-asthma Drugs • β2 adrenergic agonists • muscarinic receptor antagonists • Corticosteroids • leukotriene modifiers • methylxanthines (Theophylline) • Inhibitors of IgE (omalizumab) • sodium cromolyn metered dose inhalers (MDI) Dr. Shatanawi 2013

9. Beta-2 agonists Dr. Shatanawi 2013

10. Short acting B2-agonists • Salbutamol • Pirbuterol • Albuterol • Turbutaline These direct-acting 2 agonist provide maximal bronchodilation with little of undesired effects of  and 1 stimulation Dr. Shatanawi 2013

11. Long acting B2-agonists • Salmeterol • Formoterol • They provide bronchodilationfor at least 12 hr • This long duration of action make it suitable for prophylactic use • Salmeterolhas a slow onset of action and should not used in acute asthma attacks (prescribed only for administration at regular interval). Dr. Shatanawi 2013

12. B2-agonists mechanism of action • Relax bronchial smooth muscle • Inhibit mediator release from mast cells • Inhibit vagal tone and increase mucous clearance • Mostly by inhalation: also orally or by injection • Variable duration of action • Most common side effect: tremor • Tolerance may occur, especially in non-BSM cells. • May cause hypokalemia when used together with xanthinesor glucocorticoids Dr. Shatanawi 2013

13. INFLAMMATION • Th-2 cells- increase in the production of IL4, IL5, IL13 • IgEsynthesis in B cells • cytokines and chemokines activation of other cells • epithelial shedding & reorganization • mucous hypersecretion • airway remodeling • subendothelialfibrosis • smooth muscle cell hyperplasia • airway hyperresponsiveness Dr. Shatanawi 2013

16. Anti-inflammatory agents: Corticosteriods • Beclomethasone • Budesonide • Triamcinolone • Flunisolide • Fluticasone Dr. Shatanawi 2013

17. Corticosteroids • Inhaled corticosteroids are the drug of choice for the treatment of mild, moderate and severe persistent asthma. • Corticosteroids administered orally or inhaled have a potent anti-inflammatory effect. • Nomajor long-term improvement of airway remodeling. • Inhalation reduce the number of exacerbations and diminishes the need for oral corticosteroids and their inherent debilitating side effects. Dr. Shatanawi 2013

18. Corticosteroids • Anti-inflammatory action of steroids summarized in • reversing mucosal edema, • decreasing the permeability of capillaries, • and inhibiting the release of leukotrienes. • Patient with severe exacerbation of asthma may require intravenous administration of steroids such as, methylprednisolone or oral prednisone. • Once the patient has improved , the dose of drug is gradually reduced, leading to discontinuance in one to two weeks. Dr. Shatanawi 2013

19. Local Side Effects • Oral candidiasis • Dysphonia • reflex cough • Bronchospasm • Large doses may produce adrenal suppression Dr. Shatanawi 2013

20. Short-acting Inhaled Anticholinergics • blocks M-3 receptors on bronchial smooth muscle • Ipratropium bromide • Form: inhaled medication. • New analog: tiotropium, for COPD. Dr. Shatanawi 2013

21. Ipratropium bromide vs. B-agonists • Ipratropium has a slower onset, and longer duration of action compared with the short acting beta-agonists. • In the asthmatic, Ipratropium is about 60% as potent compared with beta-agonists. • For the emphysema patient, a group generally regarded as refractory to beta-agonist bronchodilation, ipratropium produces maximal bronchodilation • Clinically, B2 agonists and Ipratropium are often used together and the resulting bronchodilation is prolonged somewhat compared to beta-agonist used alone. Dr. Shatanawi 2013

22. Leukotrienes • are metabolites of arachidonic acid that are released from mast cells, eosinophils, and basophils. • Induce contraction of airway smooth muscle • Increase vascular permeability and mucus secretion • attract and activate inflammatory cells • Examples LTA4, LTB4, LTC4, LTD4, LTE4, and LTF4. Dr. Shatanawi 2013

23. Leukotriene Modifiers • Zafirlukast(Accolate) • Montelukast (Singulair) • Competitive antagonist of leukotriene receptor • Given orally; excellent bioavailability • Zafirlukast: half-life: 10hrs; metabolized by CYP2C9 • Montelukast: half-life: 3-6hrs; metabolized by CYP3A4 and CYP2C9 • Prevent antigen-and exercise-induced bronchospasm • Effects are additive to those of B2 agonists Dr. Shatanawi 2013

24. Methylxanthine drugsTheophylline • A direct acting oral or IV administered bronchodilator. • it has a narrow therapeutic index • Mechanism of action • inhibit the enzyme phosphodiesterasethat hydrolyses cyclic nucleotide This result in high concentration of cAMP smooth muscle relaxation • inhibition of cell surface receptors for adenosine • anti-inflammatory effect • Other drugs: caffeine, theobromide Dr. Shatanawi 2013

25. Dr. Shatanawi 2013

26. Theophylline • Side Effects: • nausea • diarrhea • increase in heart rate, arrhythmias • CNS excitation (headaches, insomnia, irritability, dizziness and lightheadedness). Dr. Shatanawi 2013

27. Omalizumab • A recombinant, humanized monoclonal antibody which binds human IgE into small complexes that are cleared by the reticuloendothelial system. • Administered subcutaneously • Significant anti-inflammatory effects. • Trials demonstrate a reduction in total circulating IgE and eosinophils • Significant reduction in asthma exacerbations, corticosteroid use • improvement in quality of life has been shown in control trials. Dr. Shatanawi 2013

28. Sodium cromolyn Not a bronchodilator • prophylactically reduce immediate and late phases of asthma • effective in exercise- and irritant- induced asthma • children are more likely to respond • depress exaggerated neuronal reflexes triggered by the “irritant receptors” • inhibit mediator release from neutrophils and activation of leukocytes • inhibit release of histamine Dr. Shatanawi 2013