Drugs for treatment of respiratory diseases. Huifang Tang Department of pharmacology Zhejiang University, school of medicine
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1 Drugs for treatment of respiratory diseases Huifang Tang Department of pharmacology Zhejiang University, school of medicine
2 Antiasthmatic drugs Immunological and non-immunological stimuli Airway inflammation glucocorticosteroids disodium cromoglycate leukotriene modifiers bronchoconstriction 2 receptor agonists theophylline muscerinic antagonists Airway hyperresponsiveness Wheezing (asthmatic symptoms)
3 Antiasthmatic drugs Airway pathological changes in pathogenesis of bronchial asthma
4 Anti-inflammatory drugs 抗 炎 平 喘 药 Glucocorticosteroids: Inhaled steroids: beclomethasone( 倍 氯 米 松 ), budesonide( 布 地 奈 德 ), fluticasone( 氟 替 卡 松 ) Systemic steroids: hydrocortisone( 氢 化 可 的 松 ), prednisone( 强 的 松 ), dexamethasone( 地 塞 米 松 ) PDE4 inhibitors: Roflumilast ( 罗 氟 司 特 ) Leukotriene (LT) modifiers: LT receptor antagonists: montelukast ( 孟 鲁 司 特 ), zafirlukast ( 扎 鲁 司 特 ) 5-lipoxygenase inhibitors: zileuton ( 齐 留 通 ) 抗 过 敏 平 喘 药 Inhibitors of mediator release: cromolyn sodium( 色 甘 酸 钠 ), nedocromil ( 奈 多 罗 米 ) H1 receptor antagonists: ketotifen ( 酮 替 芬 )
5 Antiasthmatic drugs Glucocorticosteroids Systemic corticosteroids hydrocortisone 氢 化 可 的 松 prednisone 泼 尼 松 dexamethasone 地 塞 米 松 Inhaled corticosteroids (ICS) beclomethasone dipropionate 二 丙 酸 倍 氯 米 松 budesonide 布 地 奈 德 fluticasone propionate 丙 酸 氟 替 卡 松 flunisolide 氟 尼 缩 松
6 A. Glucocorticoid drugs 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
7 A. Glucocorticoid drugs Anti-inflammatory effects Acute: inhibiting microvascular leakage leukocyte infiltration Chronic: inhibiting fibroblast proliferation deposition of collagen cicatrization ( 瘢 痕 形 成 )
8 Mechanism of anti-inflammatory action of corticosteroids in asthma.
9 Action mode of glucocorticoid drugs CBG: corticosteroid binding globulin S: glucocorticoid steroids GR: glucocorticoid receptor HSP: heat shock protein IP: immunophilin GRE: glucocorticoidresponse element
10 Effect of glucocorticoids on transcription of genes relevant to asthma Increased transcription (trans-activation) Lipocortin-1 β2-adrenoceptors Secretory leukocyte inhibitory protein IkB-a (inhibitor of NF-kB) MKP1 (inhibits MAP kinase pathways) Glucocorticoid inducible leucine zipper (GILZ) Anti-inflammatory or inhibitory cytokines IL-10, IL-12, IL-1 receptor antagonist Decreased transcription (trans-repression) Inflammatory cytokines: IL-2, IL-3, IL-4, IL-5, IL-6, IL-13, IL-15, TNF-a, GM-CSF, SCF, TSLP Chemokines: CCL1, CCL5, CCL11, CXCL8 Inflammatory enzymes: Inducible nitric oxide synthase (inos), inducible cyclo-oxygenase (COX-2) Inducible phospholipase A2 (cpla2) Inflammatory peptides: Endothelin-1 Mediator Receptors: Neurokinin (NK1)-, bradykinin (B2)-receptors Adhesion molecules: ICAM-1,VCAM-1
11 Non-genomic mechanisms of action of glucocorticoids. C. Boardman et al. / Pulmonary Pharmacology & Therapeutics 29 (2014) 129e143
12 Effect of corticosteroids on inflammatory and structural cells in the airways.
13 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.)
14 理 想 的 ICS 需 具 备 药 代 动 力 学 的 特 性 合 适 的 粒 径 适 宜 的 油 / 水 分 布 比 值 高 受 体 亲 和 力 : 脂 溶 性 高 气 道 滞 留 率 : 水 溶 性 酯 化 作 用 脂 溶 性 适 宜 的 表 观 分 布 容 积 适 宜 的 半 衰 期 肝 脏 首 过 效 应 强, 生 物 利 用 度 低 2015/4/22
15 Antiasthmatic drugs Chemical structure of 4 kinds inhalation glucocorticosteroids 二 丙 酸 倍 氯 米 松 (BDP) HO CH 2 OCOC 2 H 5 C = O OCOC 2 H 5 CH 3 布 地 奈 德 (BUD) HO CH 2 OH C = O O O C H C 3 H 7 O Cl H O H 丙 酸 氟 替 卡 松 (FP) HO SCH 2 F C = O OCOC 2 H 5 CH 3 糠 酸 莫 米 他 松 (MF) HO Cl O C = O O C- CH 3 O F O Cl F
16 Receptor-binding affinity of inhaled corticosteroids to the glucocorticoid receptor
17 布 地 奈 德 布 地 奈 德 是 新 一 代 糖 皮 质 激 素, 具 有 呼 吸 道 选 择 性 16 α 和 17α 位 加 入 了 亲 脂 基 团 - 增 加 了 糖 皮 质 激 素 受 体 的 亲 和 力 - 增 加 了 摄 取 及 局 部 的 应 用 - 全 身 吸 收 后 快 速 代 谢 失 活
18 布 地 奈 德 肺 内 酯 化 作 用 O = -C-(CH 2 ) n CH 3 布 地 奈 德 酯 化 作 用 延 长 了 抗 炎 作 用 时 间 增 加 了 呼 吸 道 的 选 择 性 Atp,adenosine triphosphate;coa,coenzyme A. Tunek A et al.drug Metob Dispos 1997;25: ;Miller-Larsson A et al.drug Metab Dispos 1998;26:
19 ICS 药 理 学 和 药 代 动 力 学 参 数 对 全 身 效 应 的 影 响 布 地 奈 德 氟 替 卡 松 倍 氯 米 松 糖 皮 质 激 素 效 应 高 高 中 等 / 低 脂 溶 性 中 等 / 高 高 低 分 布 容 积 (L) 气 道 滞 留 率 最 高 高 低 经 口 吸 收 药 物 的 首 过 清 除 高 较 高 低 半 衰 期 2.8h 14.4h 0.1h 全 身 效 应 低 中 等 高
20 A. Glucocorticoid drugs 3. Clinical uses ICS are now recommended as first-line therapy for all patients with persistent asthma, including children. Current guidelines suggest that high doses of ICS should be used only in patients with severe disease (FEV1 < 50% predicted) who have frequent exacerbations ( 2 per year) which would comprise about 10% of patients, whereas currently high-dose ICS are used in approximately 80% of patients with a clinical diagnosis of COPD.
21 Interaction with β2-adrenergic receptors Clinical Reviews in Allergy & Immunology, 2006:231
22 Interactions and effects on gene expression that may occur between long-acting b2-adrenoceptor agonists, or other camp-elevating agents, and glucocorticoids
23 4.Adverse effects
24 Adverse effects of glucocorticoid drugs: Effects resulting from continued used of large doses
25 B. PDE4 inhibitors Roflumilast ( 罗 氟 司 特 ) 1. Pharmacological effects Inhibits inflammation Bronchial dilating effect Attenuates bronchial remodeling 2. Clinical uses Approved for the treatment of asthma and COPD (2010), once daily 3. Adverse effects Diarrhea, abdominal pain, nausea, weight loss, headache, insomnia, depression, etc.
26 B. PDE4 inhibitors Klaus F. Rabe, BJP,2011
27 B. PDE4 inhibitors Combination of PDE4 inhibitor with ICS: Enhanced the glucocorticoid function, suggesting its use as a glucocorticoid sensitising Combination of PDE4 inhibitor with LABAs(long-acting β2-adrenoceptor agonist): Enhance anti-inflammatory glucocorticoid activity above the level produced by an inhaled glucocorticoid/laba combination therapy alone. because LABAs and PDE4 inhibitors act on the same signaling pathway (i.e. they increase camp synthesis and block camp degradation, respectively), they may act synergistically. F1000Prime Rep Feb 3;7:16.
28 C. Leukotriene modifiers (LTM) CysLT1 receptor antagonist montelukast ( 孟 鲁 司 特 ) zafirlukast ( 扎 鲁 司 特 ) 5-lipoxygenase inhibitors zileuton ( 齐 留 通 )
29 Effects of cysteinyl-leukotrienes on the airways and their inhibition by anti-leukotrienes. AS, aspirin sensitive; 5-LO, 5-lipoxygenase; LT, leukotriene; PAF, platelet-activating factor.
30 C. Leukotriene modifiers (LTM) Zafirlukast (Accolate, 扎 鲁 司 特 ) an oral LTRA Reducing constriction of the airways and buildup 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.
31 C. Leukotriene modifiers (LTM) 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.
32 C. Leukotriene modifiers (LTM) Adverse effects generic adverse reactions: gastrointestinal disturbances Headaches hypersensitivity reactions sleep disorders increased bleeding tendency Churg Strauss syndrome Drowsiness
33 C. Leukotriene modifiers Zileuton (Zyflo, 齐 留 通 ) an orally active inhibitor of 5-lipoxygenase Inhibits leukotrienes (LTB4, LTC4, LTD4, and LTE4) formation. 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 )
34 D. Inhibitors of mediator release Disodium cromoglycate 色 甘 酸 二 钠 ( cromolyn ) ( 色 甘 酸 钠 ) Sodium nedocromil ( 萘 多 罗 米 钠 )
35 D. Inhibitors of mediator release 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
36 Cromolyn Inhibits mediator release from mast cells
37 D. 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 antagonizing H 1 receptor.
38 GINA stepwise approach for managing asthma in patients 5 years of age with persistent mild or moderate disease, focus on step 3
39 World Allergy Organ J Feb; 3(2):
40 Expert Opin. Pharmacother. (2014) 15(1):85-96
41
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