Bronchodilators ( 支气管扩张药 ) Huifang Tang ( 汤慧芳 ) Department of Pharmacology School of Medicine Zhejiang university

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1 Bronchodilators ( 支气管扩张药 ) Huifang Tang ( 汤慧芳 ) Department of Pharmacology School of Medicine Zhejiang university tanghuifang@zju.edu.cn

2 Drugs acting on respiratory system Cough antitussive drugs centrally acting centrally acting peripherally acting peripherally acting Sputum expectorant drugs sputum-diluting drugs sputum-diluting drugs mucolytic drugs mucolytic drugs Asthma antiasthmatic drugs Bronchodilators Bronchodilators  receptor agonists  receptor agonists theophyllines theophyllines muscarinic antagonists muscarinic antagonists Anti-inflammatory drugs Anti-inflammatory drugs glucocorticosteroids glucocorticosteroids mediator release inhibitors mediator release inhibitors

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4 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

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7 Bronchodilators §  Receptor agonists § Non-selective ： adrenaline, isoprenaline §  2 -selective: salbutamol, terbutaline, salmeterol, formoterol §Theophyllines: aminophylline  Muscarinic antagonists: ipratropium bromide

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9  receptor agonists 去甲肾上腺素 异丙肾上腺素 沙丁胺醇 福莫特罗 肾上腺素 non-selectivity non-selectivity §  2 receptor selective agonists

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11 β 2-AR agonists  Short-acting β 2-adrenergic receptor agonists(SABAs) Salbuterol 沙丁胺醇  1. Albuterol (Salbuterol 沙丁胺醇 )  2. Fenoterol （菲诺特罗，酚间羟异丙肾上腺素）  3. Terbutaline ( 特布他林 )  Long-acting β 2-adrenergic receptor (LABAs) 福莫特罗  1. Formoterol ( 福莫特罗 )  2. Salmeterol ( 沙美特罗 )

12 Ultra-long-acting β 2-adrenergic receptor agonists (ultra-LABA)  1. Indacaterol ( 茚达特罗 )  2. Olodaterol ( 奥达特罗 )  3. Vilanterol ( 维兰特罗 )  4. Carmoterol ( 卡莫特罗 )  5. LAS100977  6. PF-610355  7. AZD3199.

13 1900 1970 1980 肾上腺素 异丙肾上腺素 沙丁胺醇 福莫特罗 沙美特罗 2010 茚达特罗 β 2 受体激动剂在临床中拥有超过百年的使用经验

14 肾上腺素异丙肾上 腺素 沙丁胺醇沙美特罗 福莫特罗 茚达特罗 特异性 α/β 激动剂 β 1 和 β 2 激动剂 选择性 β 2 激动剂 选择性 β 2 激动剂 选择性 β 2 激动剂 选择性 β 2 激动剂 起效速度快速起效 起效慢快速起效起效快 作用时间短效 长效

15 Selectivity of  2 agonists

16 Dysfunction of metabolism (ketoacidosis,raises blood sugar levels, elevated blood levels of fatty acids and glyceroletc.) mild appetite suppression, headache, nausea, and sleep disturbances

17 Short-acting β 2-AR agonists (SABAs) Salbuterol 沙丁胺醇 1. Pharmacological effects Relaxing bronchial smooth muscles Relaxing bronchial smooth muscles 2. Clinical uses Controlling asthmatic symptoms Controlling asthmatic symptoms Given by inhalation, oral or injection Given by inhalation, oral or injection

18  2 receptor selective agonists ： Long-acting  2 receptor agonists (LABA) Salmeterol 沙美特罗 Formoterol 福莫特罗 Bronchial dilators

19 福莫特罗全身效应短暂 吸入福莫特罗以后肺部效应和全身效应示意图 a ：吸入型福莫特罗作 用时间长（ 12 小时） 1 b ：典型吸入型短效 β 2 激 动剂一般作用时间为 4-6 小时 2 c 和 d ：两个研究已经证 明，福莫特罗在高剂量 时全身效应时间短，与 传统的吸入型 β 2 激动剂 相似，在治疗剂量时， 其全身效应一般很小以 致无法测量

20 Ultra-long-acting β 2-adrenergic receptor agonists (ultra-LABA) Vilanterol ( 维兰特罗 ) Vilanterol which was approved in May 2013 in combination with fluticasone furoate for sale as Breo Ellipta by GlaxoSmithKline for the treatment of chronic obstructive pulmonary disease (COPD).fluticasone furoateBreo ElliptaGlaxoSmithKlinechronic obstructive pulmonary disease Vilanterol is available in following combinations: with inhaled corticosteroid fluticasone furoate — fluticasone furoate/vilanterol (trade names Breo Ellipta (U.S.), Relvar Ellipta (EU, RU) )corticosteroidfluticasone furoatefluticasone furoate/vilanterolU.S.EURU with muscarinic antagonist umeclidinium bromide — umeclidinium bromide/vilanterol (trade name Anoro Ellipta)muscarinic antagonistumeclidinium bromideumeclidinium bromide/vilanterol

21 §Theophyllines Theophyllines: One type of xanthine derivatives ( 甲基黄嘌呤类衍生物 ) One type of xanthine derivatives ( 甲基黄嘌呤类衍生物 ) Bronchial dilators

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23 Aminophylline 氨茶碱

24 §1. Pharmacological effects Inhibiting phosphodiesterase(PDE); Inhibiting phosphodiesterase(PDE); Blocking adenosine receptors; Blocking adenosine receptors; Increasing catecholamine release; Increasing catecholamine release; Immunomodulation; Immunomodulation; Increasing contractility of respiratory muscle(diaphragm muscle); Increasing contractility of respiratory muscle(diaphragm muscle); Diuretic, Diuretic, CNS stimulation, CNS stimulation, Gastric acid secretion, etc. Gastric acid secretion, etc. Bronchial dilators

25 2. Clinical uses Bronchial asthma (p.o., i.v.) Bronchial asthma (p.o., i.v.) Others: acute pulmonary edema, etc. Others: acute pulmonary edema, etc.  Slow-release theophylline (for control of nocturnal asthma) is the most commonly used methylxanthine.  Aminophylline  pentoxifylline, is promoted as a remedy for intermittent claudication; Bronchial dilators

26 Common adverse effects: Gastrointestinal distress, tremor, and insomnia. Severe nausea and vomiting, hypotension, cardiac arrhythmias, Seizures Very large overdoses (eg, in suicide attempts) are potentially lethal because of arrhythmias and seizures. Beta blockers are useful in reversing severe cardiovascular toxicity from theophylline.

27 Muscarinic antagonists Ipratropium bromide 异丙托溴铵 （异丙托溴铵） Oxitropium bromide 氧托溴铵 （氧托溴铵） Tiotropium bromide 噻托溴铵 （噻托溴铵）

28 Presynaptic mediator involved in ACh release (neurojunctional plaque).

29 Muscarinic antagonists Short-acting muscarinic acetylcholine receptor (mAChR) antagonists(SAMAs) 1. Atropine methonitrate 异丙托溴铵 2. Ipratropium bromide （异丙托溴铵） 氧托溴铵 3. Oxitropium bromide （氧托溴铵） Long-acting long mAChR antagonists （ LAMAs ） 噻托溴铵 Tiotropium bromide （噻托溴铵） Novel long-acting mAChR antagonists 1.Glycopyrronium bromide （格隆溴铵） 2. Aclidinium bromide （阿地溴铵） 3. Umeclidinium （芜地溴铵） Other muscarinic acetylcholine receptor antagonists under development.

30 ipratropium bromide ( 异丙托溴铵 ); oxitropium bromide ( 氧托溴铵 ); oxitropium bromide ( 氧托溴铵 ); tiotropium bromide ( 噻托溴铵 ). tiotropium bromide ( 噻托溴铵 ). 气道松弛作用强度 : 异丙托溴铵＜氧托溴铵＜噻托溴铵 ; 作用持续时间 : 异丙托溴铵＜氧托溴铵＜噻托溴铵. §Muscarinic acetylcholine receptor (mAChR) antagonists

31 Mechanism of Action and Effects  When given by aerosol, ipratropium and tiotropium competitively block muscarinic receptors in the airways and effectively prevent bronchoconstriction mediated by vagal discharge （迷走神经放电）  When given by aerosol, ipratropium and tiotropium competitively block muscarinic receptors in the airways and effectively prevent bronchoconstriction mediated by vagal discharge （迷走神经放电）.  Muscarinic antagonists reverse bronchoconstriction in some asthma patients (especially children) and in many patients with COPD.  They have no effect on the chronic inflammatory aspects of asthma.

32 Clinical Use and Toxicity  Ipratropium and tiotropium are useful in one third to two thirds of asthmatic patients; β2 agonists are effective in almost all.  For acute bronchospasm, therefore, the β agonists are usually preferred.  However, in COPD, which is often associated with acute episodes of bronchospasm, the antimuscarinic agents may be more effective and less toxic than β agonists.

33 Umeclidinium( 芜地溴铵 ) 新型长效抗胆碱能药芜地溴铵 (Umeclidinium) 推荐吸入剂量为 62.5μg ， 1 次 /d 。 Umeclidinium 干粉剂 ( 商品名 Incruse) ，已获得欧盟、加拿大、 美国和日本等国家食品药品监督管理局 (FDA) 的批准用于治疗 慢阻肺，可更好地改善患者肺功能，减少短效 β 2 受体激动剂的 应用，其疗效优于噻托溴铵。 Long-acting Muscarinic antagonists(LAMA)

34 GOLD 2015 更新版首次把长效 β 2 受体激动剂 (LABA) 与长效抗胆碱能药 (LAMA) 的复合制剂 ( 即将两种长效 支气管扩张剂置于同一个吸入装置 ) ，列入慢阻肺的药 物治疗表中，包括印达特罗 / 格隆溴铵复合制剂 (85/43μg) 和维兰特罗 / 芜地溴铵复合制剂 (25/62.5 μg) 。 研究显示，与吸入维兰特罗和芜地溴铵单药相比，吸 入维兰特罗 / 芜地溴铵复合制剂 (1 次 /d) 可以发挥更大 化的支气管扩张效应，更好地改善肺功能，减轻呼吸 困难，提高生活质量，降低急性加重频率，并且患者 耐受性良好。

35 Long-acting muscarinic antagonists in COPD Melani AS. Long-acting muscarinic antagonists.Expert Rev Clin Pharmacol. 2015;8(4):479-501. Review.

36 Novel class of Brochodilators

37 1. Nebulizer( 雾化器 ) 2. pMDI( 压力定量气雾剂 ) 3. pMDI ＋ Spacer( 储雾罐 ) 4. D.P.I( 干粉剂 ) － Turbuhaler( 都保 ) － Accuhaler( 准纳器 ) 常见吸入装置的种类 37

38 Aerosol inhalation

39 Spacer used for aerosol inhalation 定量手控气雾器

40 Spacer will aid patients to inhale the aerosolized drugs easier Outcome of different sized particles: > 10μm: mouth and oropharynx < 0.5μm: inhaled to the alveoli and subsequently exhaled without being deposited in the lung 1-5μm: the most effective

41 Stepwise approach to asthma treatment 2016 GINA pocket Guide

42 2016 GOLD pocket Guide

43 哮喘 -COPD 重叠综合征 (asthma-chronic obstructive pulmonary disease overlap syndromes, ACOS) ACOS 不是一种单独的疾病，包括了各种不同类型的气道呼吸疾病 ( 表型 ) 。关于 哮喘和 COPD 的一系列不同潜在机制很可能将会被 ACOS 一一验证。 Some patients with COPD have predominantly eosinophilic inflammation and might respond to high doses of inhaled corticosteroids and newly developed specific antieosinophil therapies, including blocking antibodies against IL-5, IL-13, IL-33, and thymic stromal lymphopoietin, as well as oral chemoattractant receptor-homologous molecule expressed on TH2 cells antagonists. Barnes PJ.Therapeutic approaches to asthma-chronic obstructive pulmonary disease overlap syndromes. J Allergy Clin Immunol. 2015 Sep;136(3):531-45.

44 Other patients have severe asthma or are asthmatic patients who smoke with features of COPD-induced inflammation and might benefit from treatments targeting neutrophils, including macrolides, CXCR2 antagonists, phosphodiesterase 4 inhibitors, p38 mitogen- activating protein kinase inhibitors, and antibodies against IL-1 and IL-17. Other patients appear to have largely fixed obstruction with little inflammation and might respond to long-acting bronchodilators, including long-acting muscarinic antagonists, to reduce hyperinflation. Highly selected patients with severe asthma might benefit from bronchial thermoplasty( 支气管热成形术 ). Some patients with overlap syndromes can be conveniently treated with triple fixed-dose combination inhaler therapy with an inhaled corticosteroid, long- acting β2-agonist, and long-acting muscarinic antagonist, several of which are now in development. Corticosteroid resistance is a feature of asthma-COPD overlap syndrome, and understanding the various molecular mechanisms of this resistance has identified novel therapeutic targets and presented the prospect of therapies that can restore corticosteroid responsiveness.

45 Reference Pharmacology and therapeutics of bronchodilators. Cazzola M, Page CP, Calzetta L, Matera MG. Pharmacol Rev. 2012 Jul;64(3):450-504. doi: 10.1124/pr.111.004580. Review. Hansel TT, Neighbour H, Erin EM, et al. (October 2005). "Glycopyrrolate causes prolonged bronchoprotection and bronchodilatation in patients with asthma". Chest 128 (4): 1974–9. Jump up, Gilman MJ, Meyer L, Carter J, Slovis C (November 1990). "Comparison of aerosolized glycopyrrolate and metaproterenol in acute asthma". Chest 98 (5): 1095–8. Tzelepis G, Komanapolli S, Tyler D, Vega D, Fulambarker A (January 1996). "Comparison of nebulized glycopyrrolate and metaproterenol in chronic obstructive pulmonary disease". Eur. Respir. J. 9 (1): 100–3. Pleasants RA, Wang T, Gao J, Tang H, Donohue JF. Inhaled Umeclidinium in COPD Patients: A Review and Meta-Analysis. Drugs. 2016 Mar;76(3):343-61 Melani AS. Long-acting muscarinic antagonists.Expert Rev Clin Pharmacol. 2015;8(4):479-501. Review. Barnes PJ.Therapeutic approaches to asthma-chronic obstructive pulmonary disease overlap syndromes. J Allergy Clin Immunol. 2015 Sep;136(3):531-45.