Drugs Affecting the Respiratory System

1. Drugs Affecting theRespiratory System anjie Institute of Pharmacology, School of Medicine, Shandong University

2. introduction • Cough, sputum and Asthma are main symptoms in respiratory systemic diseases. • So we are going to learn agents used in therapy of Cough, sputum and Asthma..

3. Antiasthmatic drugs

4. Asthma • Asthma is a chronic inflammatory pulmonary disorder that is characterized by reversible obstruction of the airways. • Asthma affects 4 to 5% of the whole population.

5. Asthma SYMPTOMS • recurrent dyspnea • Shortness of breath • Coughing • Chest tightness • Whistling

6. Asthma • Most people have a mild form of the disease, with symptoms occurring only occasionally .( e.g, on exposure to allergens or certain pollutants , on exercise, or after a viral infection.)

7. Allergens molds, dust mites, cockroaches, animal dander, pollens,foods Irritants secondhand smoke, strong odors, aerosols, volatile organic compounds, ozone, particulate matter Other Viral respiratory infections Changes in weather (cold air, wind, humidity) Exercise Medication Endocrine factors (menstrual period, pregnancy, thyroid disease) Common Triggers asthma * 5 major indoor asthma triggers

8. Pathogenesis of asthma • 1.allergic reaction (Ⅰ-type) : mediate d by IgE antibodies . Symptoms: (1)mediators (HA, PGs) release (2)broncho-constriction (3)vascular leakage.

9. Pathogenesis of asthma • 2.inflammation of airway mucosa: • nonspecific bronchial hyper-reactivity to some stimuli (eg. allergen inhalation , or infection with virus.) • Neural mechanism:

11. Treatment of asthma • Treatment should be directed toward reduction of inflammation, as well as to management of bronchoconstriction.

12. Classification Branchodilator 1.2 – adrenoceptor agonists : salbutamol 2.Theophylline : aminophylline 3.M – Receptor blockers: ipratropine Anti-inflamation agents 1.Glucocorticoids:beclomethasone 2.inhibitors of leukotirenes(LTs) Anti-hypersensitive agents 1. inhibitors of mediator release : cromolyn sodium

13. means of administration • Drugs can be delivered tothe lungs by inhalation,oral,or injection. • Inhalation is often preferred because the drug is delivered directly to the targettissueand is effective in doses that do not cause significant systemic side effects.

14. AntiasthmaticDrugs The drugs most commonly used drugs for management of asthma are adrenoceptor agonists (used as “relievers” or broncho-dilators ) and inhaled corticosteroids (used as “controllers” or anti-inflamatory agents)

15. Bronchodilators The major drugs used to treat bronchospasm are the β2- adrenoceptor agonistsand the theophylline.

16. adrenoline receptor agonists

17. adrenaline pharmacological actions: • AD is a nonselective adrenoceptor agonist which can activate all of the α, β-receptors nonselectively.

18. ★ mechanism of anti-asthma actions 1. activate β2-R → ↑AC→↑cAMP→↑PKA →↓Ca2+ →relaxation of airway smooth muscle 2. activate α-R→vascular constriction of bronchial mucosa→edema lightened →airflow improved 3. inhibit mast cell degranulation →release of alergicmediators decreased

19. clinical use: • S.C(subcutanous) : acute attacks of asthma side effects: • stimulatesβ1 as well asβ2 receptors, can result in cardiac adverse reactions (eg. tachycardia, arrhythmias)

20. Ephedrine ★ characteristics (VS AD): slow onset; moderate effect; long duration; vasoconstriction and CNS excitation. ★clinical use The oldest agents used to treat asthma, and can be used in prevention and treatment of mild asthma.

21. Isoprenaline (Isop) was introduced in the 1940s as a pure β-agonist. ★anti-asthmatic action: potent , quick-onset used in acute asthma ★ severe toxicity on heart: arrythmia

22. Selectiveβ2- R agonists • The most widely used adrenoceptor agonist for the treatment of asthma at the present time . • They are effective after inhaled or oral administration and have a long duration of action and significant β2 selectivity.

23. Selectiveβ2- R agonists • Salbutamol(沙丁胺醇), p.o. ＆ inhale，ivd • Clenbuterol(克伦特罗）, potent effect • Terbutaline (特布他林) p.o. ＆ s.c. long duration • formaterol(福莫特罗), sameterol(沙美特罗) : long duration, also inhibit release of inflammatory mediator. Mainly used in chronic asthma and Chronic obstructive lung disease. • Bambuterol(班布特罗) P.O.

24. Selectiveβ2- R agonists • Clinical use acute attacks of asthma. • interact with inhaled corticosteroids to improve asthma control. • Adverse effects: cardiac reaction skeletal muscle tremor (β2- R) metabolic disorder

25. Theophylline aminophylline(氨茶碱), choline theophylline(胆茶碱), glyphylline(甘油茶碱, 喘定)

26. ※ Effects: • relaxation of smooth muscle • cardiac stimulation • CNS stimulation • Excitation of skeletal muscle • diuresis

27. ※ Mechanism 1) ↓PDE ( phosphodiesterase ) 2) ↑Release of CA (catecholamine) 3) Block adenosine (a bronchoconstrictor) 4) Anti-inflammatory effect

29. Therapeutic uses • Chronic asthma • Chronic obstructive lung disease

30. Theophylline • ※ adverse reactions: gastrointestinal distress CNS stimulation Cardiovescular reaction: arrythmia, ↓BP Acute nephridial failure

31. 3. M-receptor blocker: • ipratropium(异丙阿托品) Slow onset • Oxitropium (氧托品) • Tiotropium (泰乌托品)： potent effect, long duation

32. Anti-inflammatory steroids • Glucocorticoids Most effective anti-inflamatory drugs Used in continuous and severe asthma attack

33. Glucocorticoids • Effect : • effective in improving all index of asthma control and can improve quality of life. (1) reduce bronchial reactivity; (2)increase airway caliber; (3) reduce the frequency of asthma ecurrence

34. Mechanisms: • 1) reduce microvascular leakage. • 2) inhibit influx of inflammatory cells into the lungs. • 3) inhibit of production of inflammatory cytokines. • 4) increase the effect of β-R agonists

35. Beclomethasone（倍氯米松） • Characteristics: 1) inhaled: potent local anti-inflammatory action (500 times than Dex). 2)far fewer systemic adverse reaction 3) slow onset, used in prevention of attack of moderate or severe asthma flunisolide(氟尼缩松) , budesonide(布地萘德，布的松)

36. leukotrienes (LTs) pathway inhibitors • LTs:LTC4 and LTD4: • inflimatory reaction • increased bronchial reactivity • mucosal edema • mucus hypersecretion

37. two approaches: 1) inhibition of 5-lipoxygenase: zileuton(齐留通) 2) LTD4 -receptor antagonists: zafirlukast(扎鲁司特), montelukast(孟鲁司特) • Principle advantage can be taken orally • Clinical use : all kinds of asthma , especially aspirin-induced asthma.

38. Drugs stabilizing cellular membrane

39. ☆ Sodium cromoglycate Mechanism of action: stabilizing cellular membrane 1)on mast cell: inhibits the early response to antigen challenge. 2) on eosinophils: inhibit the inflammatory response to inhalation of allergens. 3) inhibit sensory nerve endings

40. Clinical use: • pretreatmentof asthma caused by antigen inhalation, by exercise, by aspirin, etc. • administrated shortly before exercise or before unavoidable exposure to an allergen. Adverse reactions: throat irritation

41. Nadocrimil sodium(奈多罗米钠) • Ketotifen(酮替芬)

42. Antitussives

43. Overview • Coughing is a protective mechanism through which foreign materials and secretions are cleared from the respiratory tract. But severe and prolonged coughing can be painful and exhausting.

44. Overiew • Some drugs act at one or more sites within the respiratory tract; others act at the cough center to inhibit activation of the efferent limb of the response.

45. Classification Ⅰ Central antitussives ⅰ Dependence : Codeine（可待因） , Dihydrocodeine（二氢可待因 ） ⅱ Nondependence: Dextromethorpham, Cloperastine, Pentoxyverine Ⅱ Peripheral antitussives: Benzonatate（苯佐那酯）, narcotin(那可丁）

46. Central antitussives Codeine and dihydrocodeine: opium receptor agonists, mainly used in dry cough . • Mechanism: Act on cough center to suppress cough. Dextromethorphan (a synthetic non- opium compound) Pentoxyverine:Act on cough center and sensory nerve ending in branchial tract

47. Peripherial antitussives Benzonatate • Have a local anesthetic action • Two mechanisms: (1)the selective anesthesia of stretch receptors within the lungs (2) central suppression of cough.

48. Section 3 Expectorants Ⅰ Agents promoting mucous secretion ammonium chloride [ Effects] (1)Expectorant action (2) Diuretic action (3) Acidified urine and blood

49. [Uses ] (1) Expectoration (2) Alkalemia (3) Influence on excretion of some drugs

50. Ⅱ Mucolytics Acetylcysteine(乙酰半胱氨酸) Bromhexine（溴己新） Ⅲ Hypertonic saline NaCl ( 1.8%）solution, NaHCO3 (2%-7.5%) solution