1、Drugs for treatment of respiratory diseases,Huifang Tang Department of pharmacologyZhejiang University, school of medicinetanghuifang@zju.edu.cnResearch building C4222012-3-28,Antiasthmatic drugs,Bronchial asthma：

2、 inflammation; bronchoconstriction; airway hyperresponsiveness,Antiasthmatic drugs,Airway inflammation,bronchoconstriction,Airway hyperresponsiveness,Immunological and non-immunological stimuli,Wheezing (asthmati

3、c symptoms),,,,,glucocorticosteroidsdisodium cromoglycateleukotriene modifiers,?2 receptor agoniststheophyllinemuscerinic antagonists,,,Antiasthmatic drugs,Airway pathological changes in pathogenesis of bronchial ast

4、hma,,,,,,Antiasthmatic drugs,Airway pathological changes in pathogenesis of bronchial asthma,Drugs used in the treatment of asthma- Classification in Grash Course: Respiratory system (2nd Edition) -,Relievers - Bronchod

5、ilators ?2 agonists short-acting: salbutamol, terbutaline long-acting: salmeterol, formoterol Anticholinergics (muscarinic antagonists): ipratropine Xantines (theophyllines): aminophyllinePr

6、eventers - Anti-inflammatory drugsGlucocorticosteroids: Inhaled steroids: beclomethasone, budesonide, fluticasone oral steroids: hydrocortisone, prednisone, dexamethasoneLeukotriene (LT) receptor antagonists (le

7、ukotriene modifiers): LT antagonists: montelukast (孟魯司特), zafirlukast (扎魯司特) 5-lipoxygenase inhibitors: zileuton (齊留通)Inhibitors of mediator release: cromolyn sodium, nedocromil,Antiasthmatic drugs,Glucocorticoste

8、roids Systemic: hydrocortisone 氫化可的松 prednisone 潑尼松 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

9、德 fluticasone propionate 丙酸氟替卡松 flunisolide 氟尼縮松,Adrenocorticoid drugs,Adrenocortical hormones Mineralocorticoids Glucocorticoids (Glucocorticosteroids) Sex hormones,,,,1. Pharmaco

10、logical effectsMechanisms 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 e

11、ffects effects on blood and blood-forming organs skeletal system CNS effects,A. Glucocorticoid drugs,,,,,,Mechanisms of glucocorticoid actionsbinding to glucocorticoid receptor (GR) nuclear

12、 translocation binding to GR element regulating related gene transcription biological effects (usually slow),,,,,A. Glucocorticoid drugs,Action mode of glucocorticoid drugsCBG: corticosteroid bi

13、nding globulinS: glucocorticoid steroidsGR: glucocorticoid receptorHSP: heat shock proteinIP: immunophilinGRE: glucocorticoid-response element,Examples of glucocorticoid actions: Inhibition of proinflammatory gene

14、transcription (AP-1 and NF?B),(1) Effects on metabolismsa) Carbohydrate: blood glucose ↑: gluconeogenesis ↑, glucose utilization↓ b) Protein: sy

15、nthesis ↓, degradation ↑c(diǎn)) Lipid: plasma cholesterol ↑, fat redistribution (central obesity: moon face, buffalo hump)d) Water and electrolytic: Na+ excretion ↓, K+ excretion ↑, Ca2+ excretion↑and absorption↓,A

16、. Glucocorticoid drugs,(2) Permissive actionPotentiating the effects of catecholamines and glucagon  (3) Anti-inflammatory effectsAcute: inhibiting microvascular leakage leukocyte in

17、filtrationChronic: inhibiting fibroblast proliferation deposition of collagen cicatrization (瘢痕形成),A. Glucocorticoid drugs,Inhibition of leukoc

18、yte infiltration and plasma leakage by glucocorticoid drugs,a) Increasing inflammation related proteins or enzymes inducing lipocortin, inhibiting phospholipase A2 activity, decreasing mediators: PGs, LTs, PAF induci

19、ng vasocortin, decreasing microvascular permeability inhibiting the expression of PLA2, COX-2, inducible NOS, etc.b) Inhibiting cytokinins: decreasing the transcription and activities of TNFα, IL-1, IL-2, IL-5, IL-6,

20、 IL-8, etc.c) Inhibiting adhesion moleculesd) Inducing the apoptosis of inflammatory cells,A. Glucocorticoid drugs,(4) Effects on immune and allergy Suppressing immunological functions and allergya) inducing apop

21、tosis of T and B lymphocytesb) inhibiting transcription factor － nuclear factor κB (NFκB) activity,A. Glucocorticoid drugs,(5) Anti-shock Septic shocka) improving cardiovascular functionsb) inhibit

22、ing the production of inflammatory factorsc) stabilizing lysosome membrane: decreasing the release of myocardial depressant factor (MDF)d) increasing the tolerance to endotoxin from bacteria,A. Glucocorticoid drugs,(6)

23、 Other effectsa) antipyretic effectsb) effects on blood and blood-forming organsred cell ?; lymphocytes ?; neutrophils ? (function ?); eosinophils ?; platelets ?c) skeletal system: osteoporosisd) CNS: increasi

24、ng excitability (elevated mood, euphoria, insomnia, restlessness, increased motor activity),A. Glucocorticoid drugs,2. ADME and properties of commonly used drugsCortisone and prednisone are reduced and transformed to h

25、ydrocortisone and prednisolone (active forms) in the liverMetabolism will be increased by hepatic enzyme inductors (phenobarbital, phenytoin, rifampine, etc.),A. Glucocorticoid drugs,3. Clinical uses(1) Immune diseas

26、esa) autoimmune disorders: reumatic fever, reumatic carditis, rhumatic arthritis, rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, polyarthritis nodosa, nephritic syndrome, etc.b) rejection of organ

27、transplantationc) allergic diseases: urticaria, serum sickenss, contact dermatitis, drug allergic reactions, chronic severe asthma, status asthmaticus, angioneurotic edema, etc.,A. Glucocorticoid drugs,(2) Severe infect

28、ion and inflammationa) acute severe infections: merely suppressing inflammatory manifestations but at times lifesavingCausion: combination with effective antimicrobial drugs !Usually be not used in viral and fungal i

29、nfections except for those with cerebral edema or severe systemic symptomsb) prevention of sequelae of some types of inflammation, such as in brain, heart, eye, joint, etc.,A. Glucocorticoid drugs,(3) Septic shock: lar

30、ger dose, short-term, combined with antimicrobial drugs (4) Hemological diseases: acute lymphocytic leukemia, lymphomas, aplastic anemia, hemolytic anemia, leukocytopenia, thrombocytopenia, etc.(5) Topical applica

31、tions: skin, eye, respiratory tract, joint (local injection) (6) Some types of tumors: breast and prostatic cancers, acute lymphocytic leukemia, etc.,A. Glucocorticoid drugs,4. Adverse effects(1) Effects resulting fr

32、om continued used of large dosesa) Hypercorticism-like syndrome: central obesity (moon face, buffalo hump, etc.); hypertension; glycosuria, hypokalemia; etc.b) Increasing susceptibility to infections: specfic antimicro

33、bial drugs should be administered with GCsc) Ingestive system: peptic ulcers, etc.,A. Glucocorticoid drugs,d) Cardiovascular system: hypertension, arteriosclerosise) Myopathy and osteoporosis: vertebral compression fr

34、actures, spontaneous fractures, especially in postmenopausal womenf) CNS: behavioral disturbances, induction of epileptic seizuresg) Inhibition or arrest of growth in children,A. Glucocorticoid drugs,Adverse effects

35、of glucocorticoid drugs:Effects resulting from continued used of large doses,(2) Withdrawal syndromea) Suppression of hypothalamic-pituitary-adrenal axisb) Exacerbation of the underlying diseases (rebound) (3)

36、Contraindicationspsychiatric disorders; epilepsy; active peptic ulcers; fractures; hypercorticism; severe hypertension; diabetes mellitus; viral or fungal infections, etc.,A. Glucocorticoid drugs,5. Applications(1)

37、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-d

38、ay 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,Antiasthm

39、atic drugs,Chemical structure of 4 kinds inhalation glucocorticosteroids,,,F,O,HO,,,,,,,,,,C = O,SCH2F,,,,,,OCOC2H5,CH3,,F,丙酸氟替卡松(FP),布地奈德(BUD),,,O,HO,,,,,,,,,,C = O,CH2OH,,,,,,O,O,H,,,C,,,H,C3H7,糠酸莫米他松(MF),,,Cl,O,HO,

40、,,,,,,,,,C = O,Cl,,,,,,O,CH3,,C-,O,,,,,,,,Cl,,HO,,,,,,,,,,C = O,CH2OCOC2H5,,,,,,OCOC2H5,CH3,H,二丙酸倍氯米松(BDP),,,O,,,,,,,,,,C = O,CH2OCOC2H5,,,,,,OCOC2H5,CH3,,,,Beclomethasone dipropionate 二丙酸倍氯米松,A. Glucocorticoid drugs,

41、,1. Pharmacological effects Antiinflammation: inhibiting inflammatory cell activities, antibody production, mediator releaseInhibit increased responsiveness of the trachea and bronchi 2. Clinical uses As first-

42、line drugs, currently Controlling chronic symptoms Ineffective for acute symptoms,A. Glucocorticoid drugs,Adverse effects,Local: oropharyngeal candidiasis－using spacer Systemic effects Hypercorticism-like syn

43、drome: central obesity (moon face, buffalo hump, etc.); hypertension; glycosuria, hypokalemia; etc.Increasing susceptibility to infectionsIngestive system: peptic ulcers, etc.Cardiovascular system:

44、hypertension, arteriosclerosisMyopathy and osteoporosis: vertebral compression fractures, spontaneous fractures, especially in postmenopausal womenAdrenal suppression,A. Glucocorticoid drugs,B

45、. Inhibitors of mediator release,Disodium cromoglycate 色甘酸二鈉 ( cromolyn ) (色甘酸鈉),1. Pharmacological effects Inhibiting mediator release from mast or other cells Inhibiting sensory neuropeptid

46、e release2. Clinical uses Prevention of allergic asthma Acting slowly (2-4 weeks)3. Adverse effects Oropharyngeal irritation,B. Inhibitors of mediator release,Cromolyn Inhibits mediator release from mast ce

47、lls,Other inhibitors of mediator release: Sodium nedocromil(萘多羅米鈉) Inhibiting mediators release from mast cell or other cells, the effect is better than disodium cromoglycate.Ketotifen(酮替芬) Inhibiting m

48、ediators release, and antagonizing H1 receptor.,B. Inhibitors of mediator release,Leukotriene receptor antagonists (LTRA) (CysLT1 receptor antagonist) montelukast (孟魯司特) zafirlukast (扎魯司特)5-lipoxygenase inhibitor

49、szileuton (齊留通),C. Leukotriene modifiers,Leukotriene metabolism pathway,LTC4, LTD4, LTE4----CysLT1 receptor bronchoconstrictors, increase microvascular permeability, mucus secretion LTB4----BLT receptorchemoattract

50、ant for neutrophils,C. Leukotriene modifiers,,,,,,,Zafirlukast (Accolate, 扎魯司特),an oral LTRAReducing constriction of the airways and build-up of mucus in the lungs and inflammation of the breathing passages.Clinical us

51、e: twice dailymaintenance treatment of asthma, often used in conjunction with an inhaled steroid and/or long-acting bronchodilator.,C. Leukotriene modifiers,Montelukast (Singulair and Montelo-10, 孟魯司特),it blocks the ac

52、tion 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 bronchoconstrictionClinical use: once dailyAst

53、hma：maintenance treatment of asthma and to relieve symptoms of seasonal allergiesexercise induced bronchospasmallergic rhinitisurticariait is not useful for the treatment of acute asthma attacks.,C. Leukotriene modif

54、iers,Adverse effects,generic adverse reactions： gastrointestinal disturbancesHeadacheshypersensitivity reactionssleep disorders increased bleeding tendency Churg–Strauss syndrome Drowsiness,Zileuton (Zyflo, 齊留通),

55、an orally active inhibitor of 5-lipoxygenaseinhibits leukotrienes (LTB4, LTC4, LTD4, and LTE4) formation. Clinical use: taken four times per dayZileuton is used for the maintenance treatment of asthma.Adverse effect