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Drugs for treatment of respiratory diseases

Drugs for treatment of respiratory diseases. 2013-4-17. Global asthma rates. 全球 3 亿 中国 2 500 万（ 1 000 万儿童 ）. 哮喘的现代观点-气道炎症. 抗原. 巨噬细胞/ 树突状细胞. 肥大细胞. 中性粒细胞. Th2 细胞. 嗜酸性细胞. 粘 液 栓. 上皮脱落. 神经激活. 上皮纤维 化. 血浆渗出 水肿形成. 感觉神经激活. 胆碱能反射. 粘液分泌过多. 血管扩张 新血管形成. 平滑肌收缩 肥大 / 增生. Barnes PJ.

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Drugs for treatment of respiratory diseases

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  1. Drugs for treatment of respiratory diseases 2013-4-17

  2. Global asthma rates 全球3亿 中国2 500万（1 000万儿童）

  3. 哮喘的现代观点-气道炎症 抗原 巨噬细胞/ 树突状细胞 肥大细胞 中性粒细胞 Th2 细胞 嗜酸性细胞 粘 液 栓 上皮脱落 神经激活 上皮纤维化 血浆渗出水肿形成 感觉神经激活 胆碱能反射 粘液分泌过多 血管扩张 新血管形成 平滑肌收缩 肥大 / 增生 Barnes PJ

  4. 慢性 炎症 气道 重塑 急性 炎症 哮喘的病理学基础 支气管痉挛 粘膜水肿 气道分泌增多 炎症细胞数量增加 上皮损伤 细胞增生 细胞外基质增加 气道可逆性降低 气道狭窄 气道高反应性 症状 哮喘恶化/加重

  5. 哮喘症状 疾病进程 • 发作性呼吸困难 • 喘憋 • 胸闷 • 咳嗽 • 反复发作 • 夜间加重 • 季节性和家族史

  6. 哮喘成功治疗应该: • 控制症状 • 预防发作 • 保持正常的肺功能 • 防止不可逆的气流受限 • 维持正常的活动水平(包括运动) • 避免药物副作用 • 减少死亡率 Global Initiative for Asthma

  7. 哮喘的治疗机制 舒张支气 管平滑肌 消除支气管粘 膜的炎症水肿 避免诱发因素

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

  9. 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(倍氯米松）, budesonide（布地奈德）, fluticasone（氟替卡松) • oral steroids: hydrocortisone（氢化可的松）, prednisone（,强的松），dexamethasone（地塞米松） • 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(色甘酸钠）, nedocromil（奈多罗米)

  10. 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

  11. Adrenocorticoid drugs • Adrenocortical hormones • Mineralocorticoids（球状带，15%） • Glucocorticoids （束状带，78%） (Glucocorticosteroids) • Sex hormones（网状带，7%）

  12. 1855年，Addison’s病(肾上腺皮质功能低下） • 1920s，认识到肾上腺皮质对于维持功能的重要性 • 1936，自肾上腺皮质提取物制备了多种固醇化合物结晶 • 1948，人工制备了可的松 • 1950，氢化可的松具有治疗作用 • 1958，地塞米松 • 倍他米松，倍氯米松。。。

  13. A. Glucocorticoid drugs • 1. Pharmacological effects • Mechanisms of glucocorticoid actions • (1) Effects on metabolisms：增加肝、肌糖原含量，升高血糖 • (2) Permissive action：可增加儿茶酚胺的缩血管效应和胰高血糖的升血糖作用 • (3) Anti-inflammatory effects • (4) Effects on immune and allergy：用于解除许多过敏性疾病的症状，抑制因过敏反应而产生的病理变化，抑制排异反应 • (5) Anti-shock：广泛用于各种严重休克（内毒素和出血性休克） • (6) Other effects • effects on blood and blood-forming organs

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

  15. 糖皮质激素(GCS)的作用机制 GCS • 细胞因子 • 诱导型一氧化氮合成酶 • 环氧酶－2 (COX-2) • 磷脂酶 A2 • NK2-受体 • 内皮素-1 • 脂皮素 -1 • -受体 • 内核酶 • 中性肽链内切酶 皮质激素受体 mRNA 热休克蛋白90 X 核膜 GRE糖皮质激素反应分子 nGRE +GRE 激素反应靶基因

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

  17. A. Glucocorticoid drugs • (1) Effects on metabolisms • a) Carbohydrate:blood glucose ↑: gluconeogenesis ↑, • glucose utilization↓（用药期间少食高糖食物） • b) Protein:synthesis ↓, degradation ↑（用药期间多食高蛋白食物） • c) Lipid（短期应用影响不大）:plasma cholesterol ↑, fat redistribution (central obesity: moon face, buffalo hump) • d) Water and electrolytic:Na+ excretion ↓, • K+ excretion ↑, Ca2+ excretion↑and absorption↓

  18. A. Glucocorticoid drugs • (2) Permissive action • Potentiating the effects of catecholamines （儿茶酚胺） and glucagon（胰高血糖素） • (3) Anti-inflammatory effects • Acute: inhibiting microvascular leakage减轻渗出和水肿 • leukocyte infiltration 改善红肿热痛 • Chronic:inhibiting fibroblast proliferation • deposition of collagen • cicatrization (瘢痕形成) • 注意：在抑制炎症减轻症状的同时，也降低了机体防御功能，使用不当可使感染扩散，阻碍创伤愈合。

  19. A. Glucocorticoid drugs • a) Increasing inflammation related proteins or enzymes • inducing lipocortin（炎症抑制蛋白脂皮素）, inhibiting phospholipase A2 activity, decreasing mediators: PGs, LTs • inducing vasocortin（缩血管物质血管皮素）, 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, IL-8, etc. • c) Inhibiting adhesion molecules：transcriptional inhibiting E-selectin and ICAM-1 • d) Inducing the apoptosis of inflammatory cells: downregulating proliferative genes including c-myc and c-myb, activating apoptotic-related enzymes (GR-dependent)

  20. 糖皮质激素(GCS)的抗炎作用分子机制 基因效应 非基因效应 • 对炎症抑制蛋白及某些靶酶的影响 • 增加脂皮素 -1转录，抑制PLA2，使PGs和LTs减少 • 抑制NO合酶和Cox-2 • 诱导ACE生成 • 对细胞因子和粘附因子影响 • 抑制TNF-a等生成 • 抑制E-选择素和ICAM-1 表达 • 增加NF-kB的抑制因子IKB表达 • 对炎细胞凋亡的影响 • 非基因的受体介导效应 • 细胞膜类固醇受体 • 生化效应 • 溶解于细胞膜，影响其生化特性，对线粒体内膜影响直接导致例子通透性增加，进而致使氧化磷酸化偶联的解离。 • 特点：起效快 • 对转录和蛋白质合成抑制 剂不敏感

  21. 抗炎作用：抑制巨噬细胞和嗜酸粒细胞释放介质；抑制炎性细胞（主要是嗜酸细胞）进入肺内；诱导磷脂酶A2抑制蛋白的产生，抑制磷脂酶A2，阻止膜磷脂分解为花生四烯酸，避免进一步转化为白三烯、前列腺素等；减轻炎症的渗出、水肿和毛细血管扩张，降低血管通透性。抗炎作用：抑制巨噬细胞和嗜酸粒细胞释放介质；抑制炎性细胞（主要是嗜酸细胞）进入肺内；诱导磷脂酶A2抑制蛋白的产生，抑制磷脂酶A2，阻止膜磷脂分解为花生四烯酸，避免进一步转化为白三烯、前列腺素等；减轻炎症的渗出、水肿和毛细血管扩张，降低血管通透性。 • 抗过敏作用。 • 舒张支气管：抑制细胞内磷酸二酯酶活性，另外对支气管平滑肌有直接松驰作用。 • 抑制支气管腺体的过度分泌，增强粘液－纤毛清除功能，参与支气管上皮纤毛的形成，对受损的上皮起抗炎和再生作用。 • 增加β受体的合成，并可增强β受体的功能，合用时可减少β受体激动剂耐药性的产生。

  22. ß2-受体激动剂 激素 激素受体 支气管扩张作用 • 激素对ß2-受体的作用 抗炎作用 • ß2-激动剂对激素受体的作用， 激素与2受体激动剂之间的相互作用 ß2-受体 Barnes Nice 2001

  23. A. Glucocorticoid drugs • (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 • 应用：抑制组织器官的移植排异反应 • 对自身免疫性疾病也发挥一定近期疗效

  24. A. Glucocorticoid drugs • (5) Anti-shock（大剂量） • 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

  25. A. Glucocorticoid drugs • (6) Other effects • a) antipyretic（退热） 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)

  26. 皮质激素药代动力学－半衰期

  27. 皮质激素抗炎作用比较 激素 等效抗炎剂量 抗炎强度 无氟激素 氢化可的松 20 1 强的松 5 4 强的松龙 5 4 甲泼尼龙 4 5 含氟激素 去炎松 4 5 地塞米松 0.75 25 *Data from PNU file

  28. 吸入激素使用剂量换算表(成人) 药物 低剂量 中剂量 高剂量 二丙酸倍氯米松 布地奈德 丙酸氟替卡松 200–500 µg 200–400 µg 100–250µg 500–1000µg 400–800 µg 250–500 µg >1000 µg >800 µg >500 µg 应根据病人对治疗的反应来决定给予药物的剂量，这是最重要的。 全球哮喘防治创议(GINA 2002年)

  29. A. Glucocorticoid drugs • 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.)

  30. A. Glucocorticoid drugs • 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.

  31. A. Glucocorticoid drugs • (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.

  32. A. Glucocorticoid drugs • (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.

  33. A. Glucocorticoid drugs • 4. Adverse effects • (1) Effects resulting from continued used of large doses • a) Hypercorticism（肾上腺功能亢进）-like syndrome:central obesity (moon face, buffalo hump, etc.); hypertension; glycosuria（糖尿病）, hypokalemia（低钾血症）; etc. • b) Increasing susceptibility to infections:specific antimicrobial drugs should be administered with GCs • c) Ingestive system:peptic ulcers（胃、十二指肠溃疡）, etc.

  34. A. Glucocorticoid drugs • d) Cardiovascular system:hypertension, arteriosclerosis（动脉硬化) • 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

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

  36. A. Glucocorticoid drugs • (2) Withdrawal syndrome • a) Suppression of hypothalamic-pituitary-adrenal axis(下丘脑-垂体-肾上腺皮质轴，HPA） • b) Exacerbation of the underlying diseases (rebound)

  37. Antiasthmatic drugs Chemical structure of 4 kinds inhalation glucocorticosteroids 二丙酸倍氯米松 (BDP) 布地奈德 (BUD) CH2OCOC2H5 CH2OCOC2H5 CH2OH C = O C = O C = O OCOC2H5 OCOC2H5 O H C HO HO C3H7 CH3 CH3 O Cl O O H H 糠酸莫米他松 (MF) 丙酸氟替卡松 (FP) SCH2F Cl O C = O C = O OCOC2H5 O C- CH3 CH3 HO HO Cl F O O F

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

  39. A. Glucocorticoid drugs • 1. Pharmacological effects • Antiinflammation: • 抑制多种参与哮喘发病的炎症细胞及免疫细胞 • 抑制细胞因子与炎症介质的产生 • 抑制气管高反应性 • 增加支气管及血管平滑肌对儿茶酚胺的敏感性 • 2. Clinical uses • As first-line drugs, currently • Controlling chronic symptoms（用于扩张药不能很好控制病情的慢性哮喘患者） • Ineffective for acute symptoms!

  40. A. Glucocorticoid drugs Adverse effects Local:口咽部念珠菌感染——用药后漱口可减少发生 Systemic effects 治疗剂量作用不明显 • 肾上腺功能亢进 • 易感染

  41. B. Inhibitors of mediator release Disodium cromoglycate 色甘酸钠

  42. B. Inhibitors of mediator release • 1. Pharmacological effects • 抑制抗原引起的肥大细胞释放炎性介质 • 抑制非特异性支气管痉挛 • 2. Clinical uses • Prevention of allergic asthma（外源性效果好，内源性效果差） • Acting slowly (2-4 weeks) • 8周无效可放弃 • 3. Adverse effects • 咽喉和器官刺激，胸部紧迫感，甚至诱发哮喘（β激动剂可防止）

  43. CromolynInhibits mediator release from mast cells

  44. B. Inhibitors of mediator release 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 antagonizingH1 receptor.

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

  46. C. Leukotriene modifiers Leukotriene metabolism pathway LTC4, LTD4, LTE4----CysLT1 receptor bronchoconstrictors, increase microvascular permeability, mucus secretion LTB4----BLT receptor chemoattractant for neutrophils

  47. C. Leukotriene modifiers 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.

  48. C. Leukotriene modifiers 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 • it is not useful for the treatment of acute asthma attacks.

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