Drugs used to treat respiratory disease

1. Drugs used to treat respiratory disease A. Kohút

2. Bronchial asthma

4. ASTHMA • Asthma - syndrom with recurrent reversible obstruction • of the airways in response to stimuli. • The patient has intermittent attacks of : • dyspnoea, wheezing, cough disorder of breathing • Its pathologic features are: • contraction of airway smooth muscle • . mucosal thickening from edema  • . cellular infiltration, viscid plugs of mucus • - airway obstruction, contraction of smooth muscle • is most easily reversed by BRONCHODILATORS • - edema and cellular infiltration requires sustained • treatment with ANTI-INFLAMMATORY AGENTS

5. Causes of asthma - allergens – pollen and household dust - air pollutants – burning leaves, solvents - respiratory infection - stress – exercise in dry & cold climates - chemicals – drugs (aspirin) - food – shellfish & nuts

6. Pathology

7. Schematic diagram of a cross-section of a bronchiole showing the changes that canoccur with severe chronic asthma. Dilated blood vessels Submucosa Eosinophil Mucosa Thickened basement membrane Inflammatory cells Mucus plug with eosinophils  desquamated epithelial cells Hypertrophied smooth muscle Mast cell Mononuclear cell Oedema

8. airway obstruction, contraction of smooth muscle is most easily reversed by • BRONCHODILATORS 1. Methylxanthines 2. Sympathomimetic agents 3. Muscarinic antagonists 4. New bronchodilators • edema and cellular infiltration requires sustained treatment with • ANTI-INFLAMMATORY AGENTS

10. Antiasthmatic agents are often used by : inhalation - aerosol - dry powder orally i.v.

11. Two phases of asthma Late phase inflammation Early phase bronchoconstriction bronchodilators antiinflamatory drugs

12. DRUGS FOR ASTHMA TREATMENT ANTIINFLAMMATORY DRUGS BRONCHODILATORS

13. ANTIINFLAMMATORY DRUGS

14. ANTIINFLAMMATORY DRUGSCorticosteroids

15. Corticosteroids work by inhibiting or otherwise modifying the inflammatory response in airways

16. 1. Systemic corticosteroidsp.o. or i.v. prednisone Because of severe adverse effects are generally reserved for patients: who do not improve adequately with inhalatory corticosteroids Treatment: oral dose of 30-60 mg of per day In most patients, systemic corticosteroids can be discontinued in a week or 10 days

17. Systemic adverse effects of glucocorticoids • administered p.o. or i.v. • - hyperglycemia • - hypertension • - immunosuppresion • -adrenal suppresion • - osteoporosis • growth retardation • in children • - cataract • - glaucoma • CUSHING SYNDROM

18. 2. Corticosteroids administered by inhalation (ICS) - the most effective method of decreasing systemic adverse effects - are currently the most effective long-term preventive medications - long-term treatment with minimal daily doses of ICS

20. Corticosteroids for inhalations are: beclomethasone, budesonide, fluticasone with minimal systemic absorption  reduced adverse effects An average daily dose - from 100-2000 g/day inhalation according to asthma severity Systemic steroid effects are minimal if compared with those of the oral prednisone: oropharyngeal candidiasis- mouthwashes can alleviate this problem

21. ICS  the growth in children Long-term  retrospective studies proved that treatment with ICS (BUD 200-800 g/day) does not significantly influenced the growth

22. Chronic use of inhaled corticosteroids: - effectively reduces symptoms and improves pulmonary function in patients - reduces bronchial hyperreactivity - the maximal reduction may not be achieved until the ninth to twelfth months of therapy

23. INHIBITORS OF MAST CELL DEGRANULATION

24. Sodium cromoglycate - inhibition of mast cell degranulation - inhibition of inflammatory cells - very good effectivity in children - 4-6 week of therapy - in prevention Clinical use: - reversible bronchospasm - bronchial asthma (allergic) - allergic rhinitis, conjuctivitis Unwanted effects: Rare: cought, bad taste, headache

25. Sodium nedocromil - inhibition of mast cell degranulation - inhibition of inflammatory cells (IC) - inhibition of IC cummulation in bronchial mucosa - prevention of immediate an late bronchoconstr. - decrease of bronchial hyperreactivity Clinical use: - prevention of astma (allergic, non-allergic) • excersise induced asthma Unwanted effects: - bad taste, headache

26. New drugs Cysteinyl leukotriene-receptor antagonists Montelucast prevents antigen-induced and exercise-induced asthma. It relaxes the airways in mild asthma, its effects are additive with 2- adrenoceptors agonists 5-lipoxygenase inhibitors Zileuton prevents the production not only LTC4 LTD4but also LTB4, a chemotaxin that recruits leukocytes into the bronchial mucosa  then activates them

28. BRONCHODILATORS 1. sympathomimetic agents 2. methylxanthines 3. muscarinic antagonists

29. Sympathomimetic agents Nonselective Adrenaline is an effective, rapidly acting bronchodilator when injected s.c.(1:1000 solution) or inhaled as a microaerosol maximal bronchodilation is achieved 15 min after inhalation  lasts for 60-90 min Adverse effects: tachycardia, arrhythmias, worsening of angina pectoris

30. 2-selective agonists

31. 2-selectiveagonist the most widely used drugsfor the treatment of asthma a.Salbutamol, terbutaline, fenoterol bronchodilation begins in 5 minutes, is maximal by 30-60 min  persists for 2 h Terbutaline is also prepared in tabletform one tablet 3 times daily is the usual regimen Salbutamol, terbutaline are used to prevent premature labour

32. . Bronchial deposition depends on the particle size. Even with particles in the optimal size range of 2-5 m, 70-50% of the total dose is deposited in the mouth or pharynx

33. b. Newer 2-selective agonists developed for an increased duration of action (12 h or more) vs. older 2 agonists (4-6 h): f o r m o t e r o l , s a l m e t e r o l (for inhalation) c l e n b u t e r o l , p r o c a t e r o l (p.o.) are prescribed in preventionof attacks because - Their high lipid solubility permits them to dissolve in the smooth muscle cell membrane and reach high concentration (slow release depot) that provides the drug available to -receptors over a long period

34. Adverse effects of -agonists -cardiac arrhythmias from β1-receptor stimulation - muscle tremor - headache and insomnia - flushing - tolerance

35. Notice • With high doses, certain beta-2-agonists showed muscular anabolic properties. • It is the case of clenbuterol, released on the market in some countries as a bronchodilator, which was used in animal diet and also by athletes to induce muscular development. Its principal adverse effects are tremors and tachycardia.

36. Methylxanthines

37. Methylxanthines Theophylline, theobromine,caffeine (alkaloids from tea, cocoa, coffee) Actions : central nervous system effects cardiovascular effects effects on the GIT effects on kidney effects on smooth muscle

38. Central nervous system effects increased alertness, tremor  nervousness, stimulant effects on respiration Cardiovascular effects stimulation of the heart (possitive chronotropic  inotropic actions) Effects on the GIT spasmolytic action, increase in HCl secretion Effects on kidney weak diuretic effect, involving both increased GF  reduced reabsorption in the tubules Effects on smooth muscle vasodilation, bronchodilation

39. Clinical use of methylxanthines Theophylline is used as a salt aminophylline, which contains 86% of theophylline Improvements in theophylline preparations: anhydrous theophylline in a microcrystalline form in which the increased surface area facilitates solubilization for complete  rapid absorption after oral administration

40. Theophylline blood level should be m o n i t o r e d Therapeutic  toxic effect of theophylline are related to the plasma concentrations of the drug. - 5-20 mg/L plasma concentration - improvement in pulmonary function - greated than 20 mg/L - anorexia, nausea, vomiting, abdominal discomfort, headache  anxiety become common at concentrations - higher levels (> 40 mg/L) may cause seizures or arrhythmias,

41. Drug-drug interaction the half-life of theophylline -is increased by erythromycin, cimetidine ciprofloxacin, oral contraceptives -is decreased by concurrent use of phenytoin, carbamazepine, rifampicin, phenobarbital

42. several sustained-release preparations with aminophyllinetheophylline are available and can produce therapeutic bloodlevels of theophylline for up to 12 or 24 h These preparations offer the advantages of - less frequent drug administration - less fluctuation of theophylline blood levels - more effective treatment of nocturnal bronchospasm

43. Muscarinic antagonists

44. Muscarinic antagonists - muscarinic antagonists competitively inhibit the effect of ACh at M-receptors - ipratropium bromide - short-acting drug is used for patients with heart disease or thyreotoxicosis in whom -agonists are unsuitable

48. Treatment of status asthmaticus 1. Oxygen 1. Salbutamol by nebuliser in a dose of 2.5-5 mg over about 3 min. Repeted in 15 min. Terbutaline 5-10 mg is an alternative. 2. Prednisolone 30-60 mg by mouth, or Hydrocortisone i. v. to very sick patient. • No sedatives of any kind. • If life-thretening features are present: 1. Ipratropium 0.5 mg add to the Salbutamol or Terbutaline. 2. Aminophylline 5mg/kg over 20 min. i.v.

49. Antitussives

50. Cough physiology Cough reflex - induces coughing  expectoration - initiated by irritation of sensory receptors in the respiratory tract To remove secretions or foreign objects