Drugs for treatment of respiratory diseases

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

2. Classification of drugs acting on respiratory system Ⅰ. Antitussive drugs:1. Centrally acting:Codeine 2. Peripherally acting:BenzonatateⅡ. Mucoactive drugs : 1. Expectorants: Guaifenesin 2. Mucoregulators:Carbocysteine 3. Mucolytics: N-Acetylcysteine 4. Mucokinetic drugs:AmbroxolⅢ. Antiasthmatic drugs: 1. Bronchial dilators (1) receptor agonists: Salbuterol (2)theophyllines: Aminophylline (3)muscarinic antagonists: Ipratropine 2. Anti-inflammatory drugs(1)glucocorticosteroids: Budesonide (2)mediator release inhibitors: Disodium cromoglycate

3. A. Antitussives 物理、化学 刺激 感受器（刺激感受器、牵张感受器等） 传入神经（迷走、喉上神经） 咳嗽中枢（延髓） 传出神经（迷走、喉返、膈神经） 效应器（声门、 呼气肌） 咳嗽反射 咳嗽反射示意图

4. Clinical perspective - cough: an unmet need. Curr Opin Pharmacol. 2015 Jun;22:24-8

5. Multiple vagal afferent nerve subtypes innervate the airways and lungs Antitussive drugs--past, present, and future. Pharmacol Rev. 2014 Mar 26;66(2):468-512.

6. A. Antitussives Central antitussives Narcotic drugs: codeine 可待因 pholcodine福尔可定 Drotebanol 羟蒂巴酚 Non-Narcotic drugs: dextromethorphan 右美沙芬 pentoxyverine 喷托维林(咳必清) Peripheral antitussives benzonatate 苯佐那酯

7. NarcoticAntitussives Codeine 可待因 Clinical use: Severe cough without sputum, such as cough induced by tumor, pleurisy(胸膜炎)with pain

8. Narcotic Antitussives Clinical use: Severe cough without sputum

9. Non-NarcoticAntitussives Dextromethorphan(右美沙芬， DXM) Codeine Dextromethorphan

10. Metabolism of dextromethorphan. 3-methoxymorphinan (3-甲氧基吗啡喃) 3-hydroxymorphinan (3-羟基吗啡喃) dextrorphan(右啡烷) Antitussive drugs--past, present, and future. Pharmacol Rev. 2014 Mar 26;66(2):468-512.

11. Non-Narcotic Antitussives Dextromethorphan • Mechanism of action • nonselective serotonin reuptake inhibitor • sigma-1 receptor agonist • Major metabolite dextrorphan(右啡烷) as an NMDA receptor antagonist, producing effects similar to ketamine and phencyclidine (PCP,苯环利啶,俗称天使尘), • Active metabolite 3-methoxymorphinan, which produces local anesthetic effects in rats with a potency above dextrorphan but below dextromethorphan itself.

12. Non-Narcotic Antitussives (1)Pharmacological effects: Depression of coughing center; (2)Clinical uses: Upper respiratory infection and dry cough. (3)Adverse reaction: Atropine-like side effects. Contraindication: In the patients with glaucoma, pregnancy(< 3 months), psychotic disorders, etc.

13. Non-Narcotic Antitussives Pentoxyverine(喷托维林, 咳必清) Also known as Carbetapentane (1)Pharmacological effects: Depression of coughing center, Local anesthetic effects, and Muscarinic antagonism.

14. (2)Clinical uses: Upper respiratory infection, Cough without sputum. (3)Adverse reaction: Atropine-like side effects. Uses and adverse effects are similar to dextromethorphan However, there is very little published clinical data to suggest clinical efficacy with carbetapentane leading the FDA (2007) to conclude that this drug should not be made available as an OTC treatment of cough in the USA (2007).

15. Non-Narcotic Antitussives Others

16. A. Antitussives • Peripheral antitussives • Benzonatate苯佐那酯 (退嗽) • Blocking cough reflex • Local anesthetic effects • CNS depression • Others: • Benproperine(苯丙哌林) • Dropropizine (羟丙哌嗪) • Noscapine (那可汀); moguisteine (莫吉司坦) • Prenoxdiazine (普诺地嗪) • Dioxopromethazine (二氧丙嗪)

17. 常用镇咳药比较表

18. Antitussive drugs--past, present, and future. Pharmacol Rev. 2014 Mar 26;66(2):468-512.

19. B. Mucoactive drugs Hydration: Sputum dilution Mucolysis Mucous glycoprotein network

20. B. Mucoactive drugs • Expectorants （Stimulating bronchial secretion痰液稀释药） • Ammonium chloride 氯化铵 • Glyceryl guaiacolate (Guaifenesin )愈创木酚甘油醚 • Potassium iodide 碘化钾 • Ipecac syrup 吐根糖浆 • 酒石酸锑钾、桔梗、远志等。 • Mucoregulators • Carbocisteine 羧甲司坦* • Anticholinergic agents • Glucocorticoids • Macrolide antibiotics

21. B. Mucoactive drugs • Mucolytic drugs(粘痰溶解药) • N-Acetylcysteine 乙酰半胱氨酸 • Erdosteine 厄多司坦 • Dextran • Heparin Mucokinetics drugs（痰液调节药） • Bromhexine 溴己新 • Ambroxol 氨溴索 • Surfactants

22. Expectorants Ammonium chloride 氯化铵 • 恶心性祛痰药的代表药 • This causes the production of excess respiratory tract fluid which presumably is easier to cough up. • Ammonium salts are an irritant to the gastric mucosa and may induce nausea and vomiting.

23. Expectorants Guaifenesin 愈创木酚甘油醚 • 刺激性祛痰药的代表药 • Effect and mechanism of action • increasing the volume and reducing the viscosity of secretions in the trachea and bronchi. • stimulates the flow of respiratory tract secretions, • allowing ciliary movement to carry the loosened secretions upward toward the pharynx • increase the efficiency of the cough reflex • facilitate removal of the secretions

24. Mucoregultor Carbocysteine 羧甲司坦 • Carbocisteine is produced by alkylation of cysteine with chloroacetic acid. • Pharmacological effect • Reduces the viscosity of sputum allowing the sufferer to bring up sputum more easily. • Carbocisteine should not be used with antitussives (cough suppressants) or medicines that dry up bronchial secretions.

25. Mucolytic drugs N-Acetylcysteine N乙酰半胱氨酸,NAC • Pharmacological effect: • Antioxidant and liver protecting effects-- a dietary supplement : • Breaks disulfide bonds in mucus and liquefies it, making it easier to cough up.-- cough therapy:

26. Mucolytic drugs Erdosteine 厄多司坦 • it is a thiol derivative. Action • Mucolytic • free radical scavenging activity. • modulates mucus production and viscosity • increases mucociliary transport, • It also exhibits inhibitory activity against the effects of free radicals produced by cigarette smoke. Clinical use: • chronic obstructive lung disease : reduced cough (both frequency and severity) and sputum viscosity more quickly and more effectively than placebo and reduced the adhesivity of sputum more effectively than bromhexine 30 mg twice daily. • Co-administration of erdosteine and amoxicillin in patients with acute infective exacerbation of chronic bronchitis resulted in higher concentrations of the antibiotic in the sputum, leading to earlier and more pronounced amelioration of clinical symptoms compared with placebo. • a low incidence of adverse events, most of which are gastrointestinal and generally mild.

27. Mucokinetic drugs Ambroxol ( 氨溴索,沐舒坦) • 全肺动力型排痰剂

28. Mucokinetic drugs • Mucoactive action • secretolytic and secretomotoric actions that restore the physiological clearance mechanisms of the respiratory tract • stimulates synthesis and release of surfactant by type II pneumocytes. • promotes mucus clearance, facilitates expectoration and eases productive cough • local anaesthetic effect • a very potent inhibitor of the neuronal Na+ channels • anti-inflammatory properties Clinical use: • upper respiratory tract infections and other lung problems, including chronic inflammatory pulmonary conditions;

29. Mucokinetic drugs Ambroxol Side Effects Gastrointestinal Side Effects • including diarrhea, heartburn, indigestion, and occasionally nausea and vomiting. Allergic Reactions • rarely, mainly involve skin rashes, hives and dermatitis, as well as possible swelling. Intravenous Side Effects • Intravenous ambroxol has been associated with chills, intense headaches, shortness of breath and weakness.

30. Mucolytic drugs Bromhexine 溴己新 • Bromhexine is a synthetic derivative of the herbal active ingredient vasicine(鸭嘴花碱) • used in the treatment of respiratory disorders associated with viscid or excessive mucus.

31. Mucolytic drugs Pharmacological effect • Bromhexine supports the body's own natural mechanisms for clearing mucus from the respiratory tract. • Secretolytic effect : • increases the production of serous mucus in the respiratory tract • enhances mucus transport by reducing mucus viscosity • secretomotoric effect: • enhances mucus transport by activating the ciliated epithelium • antioxidant effect

32. Mucoactive drugs Fudosteine (福多司坦) • a cysteine derivative • Inhibit MUC5AC mucin hypersecretion by reducing MUC5AC gene expression • Iihibition of extracellular signal-relatedI kinase and p38 mitogen-activated protein kinase in vivo and extracellular signal-related kinase in vitro.

33. Mucoactive drugs Myrtol (稀化黏素,桃金娘油) • an essential oil derived from the Myrtle plant (Myrtus communis) • consisting mainly of three monoterpenes: • (+)α-pinene（蒎烯 ） • d-limonene （柠檬烯 ） • 1,8-cineole （桉叶素 ） Pharmacological effects: • Increases mucociliar clearance • Mucosecretolytic effects. • Anti-inflammatory and antioxidative properties Clinical use: • acute and chronic bronchitis and sinusitis

34. Mucoactive drugs.Eur Respir Rev 2010; 19: 116, 127–133

35. 祛痰药作用比较表

36. Bronchodilators (支气管扩张药)

37. 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)

39. Bronchodilators •  Receptor agonists • Non-selective：adrenaline, isoprenaline • 2-selective: salbutamol, terbutaline, salmeterol, formoterol • Theophyllines:aminophylline • Muscarinic antagonists:ipratropium bromide

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

43. β2-AR agonists • Short-acting β2-adrenergic receptor agonists(SABAs) • 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 β2-adrenergic receptor (LABAs) • 1. Formoterol (福莫特罗) • 2. Salmeterol (沙美特罗)

44. Ultra-long-acting β2-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.

45. Short-acting β2-AR agonists (SABAs) Salbuterol 沙丁胺醇 1. Pharmacological effects Relaxing bronchial smooth muscles 2. Clinical uses Controlling asthmatic symptoms Given by inhalation, oral or injection

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

47. Selectivity of 2agonists

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

49. Bronchial dilators • Theophyllines Aminophylline 氨茶碱 Theophyllines: One type of xanthine derivatives (甲基黄嘌呤类衍生物)

50. Theophyllines