1. Drugs for treatment of respiratory diseases Huifang Tang Department of pharmacology Zhejiang University, school of medicine tanghuifang@zju.edu.cn Research building C422 2012-3-28

2. Antiasthmatic drugs Bronchial asthma ： inflammation; bronchoconstriction; airway hyperresponsiveness

3. Antiasthmatic drugs Airway inflammation bronchoconstriction Airway hyperresponsiveness Immunological and non-immunological stimuli Immunological and non-immunological stimuli Wheezing (asthmatic symptoms) glucocorticosteroids disodium cromoglycate leukotriene modifiers  2 receptor agonists theophylline muscerinic antagonists

4. Antiasthmatic drugs Airway pathological changes in pathogenesis of bronchial asthma

5. Antiasthmatic drugs Airway pathological changes in pathogenesis of bronchial asthma

6. Drugs used in the treatment of asthma - Classification in Grash Course: Respiratory system (2nd Edition) - §Relievers - Bronchodilators §  2 agonists § short-acting: salbutamol, terbutaline § long-acting: salmeterol, formoterol § Anticholinergics (muscarinic antagonists): ipratropine § Xantines (theophyllines): aminophylline §Preventers - Anti-inflammatory drugs §Glucocorticosteroids: § Inhaled steroids: beclomethasone, budesonide, fluticasone § oral steroids: hydrocortisone, prednisone, dexamethasone §Leukotriene (LT) receptor antagonists (leukotriene modifiers): § LT antagonists: montelukast ( 孟鲁司特 ), zafirlukast ( 扎鲁司特 ) § 5-lipoxygenase inhibitors: zileuton ( 齐留通 ) §Inhibitors of mediator release: cromolyn sodium, nedocromil

7. Antiasthmatic drugs §Glucocorticosteroids § Systemic: § hydrocortisone 氢化可的松 § prednisone 泼尼松 § dexamethasone 地塞米松 § Inhaled: § beclomethasone dipropionate 二丙酸倍氯米松 § budesonide 布地奈德 § triamcinolone acetonide 曲安奈德 § fluticasone propionate 丙酸氟替卡松 § flunisolide 氟尼缩松

8. Adrenocorticoid drugs  Adrenocortical hormones  Mineralocorticoids  Glucocorticoids  (Glucocorticosteroids)  Sex hormones

10. §1. Pharmacological effects §Mechanisms of glucocorticoid actions §(1) Effects on metabolisms §(2) Permissive action §(3) Anti-inflammatory effects §(4) Effects on immune and allergy §(5) Anti-shock §(6) Other effects § antipyretic effects § effects on blood and blood-forming organs § skeletal system § CNS effects A. Glucocorticoid drugs

11. §Mechanisms of glucocorticoid actions §binding to glucocorticoid receptor (GR) § nuclear translocation § binding to GR element § regulating related gene transcription § biological effects (usually slow) A. Glucocorticoid drugs

12. Action mode of glucocorticoid drugs CBG: corticosteroid binding globulin S: glucocorticoid steroids GR: glucocorticoid receptor HSP: heat shock protein IP: immunophilin GRE: glucocorticoid- response element

13. Examples of glucocorticoid actions: Inhibition of proinflammatory gene transcription (AP-1 and NF  B)

14. §(1) Effects on metabolisms §a) Carbohydrate: blood glucose ↑ : gluconeogenesis ↑, § glucose utilization ↓ §b) Protein: synthesis ↓, degradation ↑ §c) Lipid: plasma cholesterol ↑, fat redistribution (central obesity: moon face, buffalo hump) §d) Water and electrolytic: Na + excretion ↓,  K + excretion ↑, Ca 2+ excretion ↑ and absorption ↓ A. Glucocorticoid drugs

15. §(2) Permissive action §Potentiating the effects of catecholamines and glucagon § §(3) Anti-inflammatory effects §Acute: inhibiting microvascular leakage § leukocyte infiltration §Chronic: inhibiting fibroblast proliferation § deposition of collagen § cicatrization ( 瘢痕形成 ) A. Glucocorticoid drugs

16. Inhibition of leukocyte infiltration and plasma leakage by glucocorticoid drugs

17. §a) Increasing inflammation related proteins or enzymes § inducing lipocortin, inhibiting phospholipase A 2 activity, decreasing mediators: PGs, LTs, PAF § inducing vasocortin, decreasing microvascular permeability § inhibiting the expression of PLA 2, COX-2, inducible NOS, etc. §b) Inhibiting cytokinins: decreasing the transcription and activities of TNFα, IL-1, IL-2, IL-5, IL-6, IL-8, etc. §c) Inhibiting adhesion molecules §d) Inducing the apoptosis of inflammatory cells A. Glucocorticoid drugs

18. §(4) Effects on immune and allergy §Suppressing immunological functions and allergy §a) inducing apoptosis of T and B lymphocytes §b) inhibiting transcription factor － nuclear factor κB (NFκB) activity A. Glucocorticoid drugs

19. §(5) Anti-shock § Septic shock §a) improving cardiovascular functions §b) inhibiting the production of inflammatory factors §c) stabilizing lysosome membrane: decreasing the release of myocardial depressant factor (MDF) §d) increasing the tolerance to endotoxin from bacteria A. Glucocorticoid drugs

20. §(6) Other effects §a) antipyretic effects §b) effects on blood and blood-forming organs §red cell  ; lymphocytes  ; neutrophils  (function  ); eosinophils  ; platelets  §c) skeletal system: osteoporosis §d) CNS: increasing excitability (elevated mood, euphoria, insomnia, restlessness, increased motor activity) A. Glucocorticoid drugs

21. §2. ADME and properties of commonly used drugs §Cortisone and prednisone are reduced and transformed to hydrocortisone and prednisolone (active forms) in the liver §Metabolism will be increased by hepatic enzyme inductors (phenobarbital, phenytoin, rifampine, etc.) A. Glucocorticoid drugs

22. §3. Clinical uses §(1) Immune diseases §a) autoimmune disorders: reumatic fever, reumatic carditis, rhumatic arthritis, rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, polyarthritis nodosa, nephritic syndrome, etc. §b) rejection of organ transplantation §c) allergic diseases: urticaria, serum sickenss, contact dermatitis, drug allergic reactions, chronic severe asthma, status asthmaticus, angioneurotic edema, etc. A. Glucocorticoid drugs

23. §(2) Severe infection and inflammation §a) acute severe infections: merely suppressing inflammatory manifestations but at times lifesaving §Causion: combination with effective antimicrobial drugs ! §Usually be not used in viral and fungal infections except for those with cerebral edema or severe systemic symptoms §b) prevention of sequelae of some types of inflammation, such as in brain, heart, eye, joint, etc. A. Glucocorticoid drugs

24. §(3) Septic shock: larger dose, short-term, combined with antimicrobial drugs §(4) Hemological diseases: acute lymphocytic leukemia, lymphomas, aplastic anemia, hemolytic anemia, leukocytopenia, thrombocytopenia, etc. §(5) Topical applications: skin, eye, respiratory tract, joint (local injection) §(6) Some types of tumors: breast and prostatic cancers, acute lymphocytic leukemia, etc. A. Glucocorticoid drugs

25. §4. Adverse effects §(1) Effects resulting from continued used of large doses §a) Hypercorticism-like syndrome: central obesity (moon face, buffalo hump, etc.); hypertension; glycosuria, hypokalemia; etc. §b) Increasing susceptibility to infections: specfic antimicrobial drugs should be administered with GCs §c) Ingestive system: peptic ulcers, etc. A. Glucocorticoid drugs

26. §d) Cardiovascular system: hypertension, arteriosclerosis §e) Myopathy and osteoporosis: vertebral compression fractures, spontaneous fractures, especially in postmenopausal women §f) CNS: behavioral disturbances, induction of epileptic seizures §g) Inhibition or arrest of growth in children A. Glucocorticoid drugs

27. Adverse effects of glucocorticoid drugs: Effects resulting from continued used of large doses

28. §(2) Withdrawal syndrome §a) Suppression of hypothalamic-pituitary- adrenal axis §b) Exacerbation of the underlying diseases (rebound) § (3) Contraindications §psychiatric disorders; epilepsy; active peptic ulcers; fractures; hypercorticism; severe hypertension; diabetes mellitus; viral or fungal infections, etc. A. Glucocorticoid drugs

29. §5. Applications §(1) Replacement therapy: usually using hydrocortisone §(2) Prompt intensive treatment: i.v. gtt hydrocortisone, dexamethasone §(3) Long-term therapy: oral prednisone or prednisolone § morning single dose § alternate-day therapy § Notes: for less severe and less sustained patients; §less suppression on hypothalamic-pituitary-adrenal (HPA) axis §(4) Tipical applications: skin; eye; respiratory tract A. Glucocorticoid drugs

30. Antiasthmatic drugs Chemical structure of 4 kinds inhalation glucocorticosteroids F O HO C = O SCH 2 F OCOC 2 H 5 CH 3 F 丙酸氟替卡松(FP) 布地奈德(BUD) O HO C = O CH 2 OH O O H C H C3H7C3H7 糠酸莫米他松(MF) Cl O HO C = O Cl O CH 3 C- O Cl HO C = O CH 2 OCOC 2 H 5 OCOC 2 H 5 CH 3 H 二丙酸倍氯米松(BDP) O C = O CH 2 OCOC 2 H 5 OCOC 2 H 5 CH 3

31. Beclomethasone dipropionate二丙酸倍氯米松 A. Glucocorticoid drugs

32. §1. Pharmacological effects § Antiinflammation: inhibiting inflammatory cell activities, antibody production, mediator release §Inhibit increased responsiveness of the trachea and bronchi §2. Clinical uses § As first-line drugs, currently § Controlling chronic symptoms § Ineffective for acute symptoms A. Glucocorticoid drugs

33. Adverse effects Local: oropharyngeal candidiasis － using spacer Systemic effects  Hypercorticism-like syndrome: central obesity (moon face, buffalo hump, etc.); hypertension; (moon face, buffalo hump, etc.); hypertension; glycosuria, hypokalemia; etc. glycosuria, hypokalemia; etc.  Increasing susceptibility to infections  Ingestive system: peptic ulcers, etc.  Cardiovascular system: hypertension, arteriosclerosis arteriosclerosis  Myopathy and osteoporosis: vertebral compression fractures, spontaneous fractures, compression fractures, spontaneous fractures, especially in postmenopausal women especially in postmenopausal women  Adrenal suppression A. Glucocorticoid drugs

34. B. Inhibitors of mediator release Disodium cromoglycate 色甘酸二钠 ( cromolyn ) ( 色甘酸钠 )

35. §1. Pharmacological effects § Inhibiting mediator release from mast or other cells § Inhibiting sensory neuropeptide release §2. Clinical uses § Prevention of allergic asthma § Acting slowly (2-4 weeks) §3. Adverse effects § Oropharyngeal irritation B. Inhibitors of mediator release

36. CromolynInhibits mediator release from mast cells Cromolyn Inhibits mediator release from mast cells

37. Other inhibitors of mediator release: Sodium nedocromil( 萘多罗米钠 ) Inhibiting mediators release from mast cell or other cells, the effect is better than disodium cromoglycate. Ketotifen( 酮替芬 ) Inhibiting mediators release, and antagonizing H 1 receptor. B. Inhibitors of mediator release

38.  Leukotriene receptor antagonists (LTRA) (CysLT1 receptor antagonist) (CysLT1 receptor antagonist)  montelukast ( 孟鲁司特 )  zafirlukast ( 扎鲁司特 )  5-lipoxygenase inhibitors  zileuton ( 齐留通 ) C. Leukotriene modifiers

39. Leukotriene metabolism pathway LTC 4, LTD 4, LTE 4 ----CysLT1 receptor bronchoconstrictors, increase microvascular permeability, mucus secretion LTB 4 ----BLT receptor chemoattractant for neutrophils C. Leukotriene modifiers

40. (Accolate, 扎鲁司特 ) Zafirlukast (Accolate, 扎鲁司特 )  an oral LTRA  Reducing constriction of the airways and build- up of mucus in the lungs and inflammation of the breathing passages.  Clinical use: twice daily  maintenance treatment of asthma, often used in conjunction with an inhaled steroid and/or long- acting bronchodilator. C. Leukotriene modifiers

41. Montelukast (Singulair and Montelo-10, 孟鲁司特 )  it blocks the action of leukotriene D4 (and secondary ligands LTC4 and LTE4) on the cysteinyl leukotriene receptor CysLT1 in the lungs and bronchial tubes by binding to it.  reduces the bronchoconstriction  Clinical use: once daily  Asthma ： maintenance treatment of asthma and to relieve symptoms of seasonal allergies  exercise induced bronchospasm  allergic rhinitis  urticaria  it is not useful for the treatment of acute asthma attacks. C. Leukotriene modifiers

42. Adverse effects  generic adverse reactions ：  gastrointestinal disturbances  Headaches  hypersensitivity reactions  sleep disorders  increased bleeding tendency  Churg–Strauss syndrome  Drowsiness

43. Zileuton (Zyflo, 齐留通 )  an orally active inhibitor of 5-lipoxygenase  inhibits leukotrienes (LTB4, LTC4, LTD4, and LTE4) formation. taken four times per day  Clinical use: taken four times per day  Zileuton is used for the maintenance treatment of asthma.  Adverse effects  sinusitis （鼻窦炎）, nausea, pharyngolaryngeal pain （咽喉疼痛） C. Leukotriene modifiers