Antitussives, expectorants, and antiasmatic drugs

1. Pharmacology for respiratory diseases Antitussives, expectorants, and antiasmatic drugs 胡薇薇, huww@zju.edu.cn

2. Respiratory diseases

3. Drugs acting on respiratory system Cough Sputum Asthma ----- antitussive drugs （镇咳药） ----- expectorant drugs （祛痰药） ------ antiasthmatic drugs （平喘药）

4. Drugs acting on respiratory system centrally acting (中枢性镇咳药) peripherally acting (外周性镇咳药) Antitussive drugs （镇咳药） Expectorant drugs （祛痰药） Antiasthmatic drugs （平喘药） sputum-diluting drugs (痰液稀释药) mucolytic drugs (粘痰溶解药) bronchial dilators (支气管扩张药)： receptor agonists theophyllines （茶碱） muscarinic antagonists anti-inflammatory drugs (抗炎平喘药)：glucocorticosteroids mediator release inhibitors

5. 1. Antitussives

6. 1. Antitussives • Centrally acting Narcotic antitussives: codeine 可待因 Non-narcotic antitussives: dextromethorphan 右美沙芬 pentoxyverine 喷托维林(咳必清) • Peripherally acting benzonatate 苯佐那酯

7. 1. Antitussives- narcotic antitussives Codeine 可待因 Morphine 吗啡

8. Codeine 1. Pharmacological effects - suppression of cough (1/4 of morphine) - analgesia (1/10 of morphine, stronger than NSAIDs) 2. Pharmacokinetics - oral bioavailability 40%-70%, 15% converted to morphine - metabolized by liver and excrete through kidney

9. Codeine 3. Clinical uses Cough without sputum 4. Adverse effects Respiratory depression (at large doses) Addiction Contraindicated in patients with thick sputum Other centrally acting narcotic antitussives: Dihydrocodeine（双氢可待因）; Drotebanol（羟蒂巴酚）; Pholcodine（福尔可定）

10. 1. Antitussives dihydrocodeine 双氢可待因 • Similar to codeine in structure; • Lasts longer; • Stronger than codeine as antitussive; • Stronger analgesia; • Lower toxicity

11. 1. Antitussives Drotebanol 羟蒂巴酚 • Derivate of morphine; • Lasts longer; • Stronger antitussive; • Lower toxicity Drotebanol (羟甲吗啡)

12. 1. Antitussives Pholcodine 福尔可定（吗啉吗啡） • Similar to codeine; • Less addictive; • Can be used for children and infants

13. 1. Antitussives - Non-narcotic antitussives Dextromethorphan右美沙芬 左吗喃甲基醚

14. Dextromethorphan 1. Pharmacological effects Suppression of cough No analgesia, respiratory depression, tolerance and addiction 2. Clinical uses Upper respiratory infection, cough without sputum 3. Adverse effects Atropine-like side effects Contraindicated in patients with glaucoma, pregnancy (< 3 months), psychotic disorders, etc.

15. Pentoxyverine 喷托维林(咳必清) • Suppression of cough Weak muscarinic antagonism and local anesthetic effects • Uses and adverse effects are similar to dextromethorphan Other centrally acting non-narcotic antitussives: Ploperastine（氯哌啶）; Promolate（普罗吗酯）; Fominoben（福米诺苯）；Zipeprol（齐培丙醇）

16. 1. Antitussives- peripherally acting Benzonatate 苯佐那酯Benproperin苯丙哌林dioxopromethazine 二氧丙嗪noscapine 那可丁prenoxdiazin 普诺地嗪eprazinone 依普拉酮 • Local anesthetic effects • Blocking cough reflex • Relieving bronchial spasm • CNS depression • H1 receptor antagonism • Anti-muscarinic effect

17. 2. Expectorants • Sputum-diluting drugs: Stimulating bronchial secretion Amonium chloride 氯化铵 Potassium iodide 碘化钾 Glyceryl guaiacolate 愈创木酚甘油醚

18. 2. Expectorants • Mucolytic drugs Acetylcysteine 乙酰半胱氨酸Mesna 美司钠 Carbocisteine 羧甲司坦 DNAase 脱氧核糖核酸酶 Mecysteine 半胱甲酯，美司坦 • Mucus regulator Bromhexine 溴己新 Ambroxol 氨溴索(沐舒坦) Brovanexine 溴凡克新

19. Hydration: Sputum dilution Mucolysis Mucous glycoprotein network

20. LudwigvonBeethoven John F. Kennedy Charles Dickens Elizabeth Taylor Dennis Rodman Deng Li-jun

22. Asthma • A common chronic disorder of the airways that is complex and characterized by variable and recurring symptoms, airflow obstruction, bronchial hyperresponsiveness (bronchospasm), and an underlying inflammation. • Symptom: dyspnea, wheezing, stridor, coughing, an inability for physical exertion. The cough may sometimes produce clear sputum.

23. Asthma • Between episodes, most patients feel well but can have mild symptoms and they may remain short of breath after exercise for longer periods of time than the unaffected individual. • Nonspecific bronchial hyperreactivity---characteristic of asthma: tendency to develop bronchospasm upon encountering stimuli that do not affect healthy nonasthmatic airways related to inflammation (eosinophil) (the fall in forced expiratory volume in 1 second (FEV1)provoked by inhaling serially increasing concentrations of aerosolized histamine or methacholine.)

25. Asthma • Its pathologic features are contraction of airway smooth muscle, mucosal thickening from edema and cellular infiltration, and inspissation in the airway lumen of abnormally thick, viscid plugs of mucus.

26. 3. Antiasthmatic drugs

27. Antiasthmatic drugs Immunological non-immunological stimuli inflammation bronchoconstriction Glucocorticosteroids Disodium cromoglycate Leukotriene pathway inhibitors 2 receptor agonists Theophylline Muscerinic antagonists Wheezing (asthmatic symptoms)

28. Antiasthmatic drugs • Anti-inflammatory drugs • Glucocorticoids: Systemic: hydrocortisone, dexamethasone Inhalation: beclomethasone, budesonide • Inhibitors of mediator release: cromolyn sodium, nedocromil • Leukotriene pathway inhibitors • Bronchial dilators •  Receptor agonists Non-selective：adrenaline, isoprotererol 2-selective: moderate-acting:salbutamol, terbutaline long-acting:salmeterol, formoterol • Theophyllines:aminophylline • Muscarinic antagonists:ipratropine

29. Anti-Inflammatoryeffect of glucocorticoids • Effects on leukocyte function • Reducing lipid-derived autocoids (prostaglandin, leukotriene, and platelet-activating factor)

30. Glucocorticoids • Systemic (oral or i.v.): • hydrocortisone • prednisone • dexamethasone Urgent treatment (combined with bronchodilators) • Adverse effect (hypercorticism-like syndrome; increasing • susceptibility to infections; peptic ulcers; • hypertension; adrenal suppression, • osteoporosis, etc)

31. Glucocorticoids • Inhalation: • beclomethasone dipropionate (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)

32. Beclomethasone dipropionate

33. Beclomethasone dipropionate 1. Pharmacological effects (Antiinflammation) • Inhibit inflammatory cell activities, • Inhibit antibody production, mediator release, • Inhibit increased responsiveness of the trachea and bronchi 2. Clinical uses • Controlling chronic symptoms (addition of long-acting inhaled  receptor agonist) • Ineffective for acute symptoms, so combined with Bronchodilators • Replace systemic glucocorticosteroids administration

34. Adverse effects • Local oropharyngeal candidiasis － gargle water and spit － using spacer • Systemic effects less than systemic administration of glucocorticoids

36. Spacer will aid patients 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

37. Inhibitors of mediator release Disodium cromoglycate( cromolyn )

39. Disodium cromoglycate • 1. Pharmacological effects • Inhibiting mediator release from mast or other cells • 2. Clinical uses (only inhalation) • Prevention of allergic asthma (7-10d before) • Acting slowly (2-4 weeks) • Useful for symptom occurs seasonally, after exercise or exposure to animal，but not very effective to infection induced asthma • Useful in reducing symptom of allergic rhinoconjunctivitis • Use in children, especially at ages of rapid growth • 3. Adverse effects • minor (throat irritation, cough)

40. Other inhibitors of mediator release • Nedocromil sodium (奈多罗米钠): bitter taste, GI effect • Tranilast (曲尼司特): GI effect • Ketotifen (酮替芬):also block H1 receptor, good for children, need use 12 weeks, sedative effect

41. 3. Antiasthmatic drugs Leukotriene modifiers Membrane phospholipid PLA2 Arachidonic acid (AA) COX-1/2 5-LOX chemotaxis PGs LTB4 LTs Receptor CysLTs: LTC4, D4, E4 inflammation CysLT1 , CysLT2

42. Leukotriene pathway inhibitors • Airways LTC4, LTD4, LTE4----bronchoconstrictors, increase microvascular permeability, mucus secretion LTB4----chemoattractant for neutrophils • Leukotriene pathway inhibitors (orally) CysLT1 receptor antagonist (Zafirlukast扎鲁司特，Montelukast 孟鲁司特, Pranlukast 普鲁司特): 5-LOX inhibitor (zileuton) for mild or moderate asthma and aspirin-induced asthma, but not use alone for acute asthma

43. Antiasthmatic drugs • Anti-inflammatory drugs • Glucocorticoids: Systemic: hydrocortisone, dexamethasone Inhalation: beclomethasone, budesonide • Inhibitors of mediator release: cromolyn sodium, nedocromil • Leukotriene pathway inhibitors • Bronchial dilators •  Receptor agonists Non-selective：adrenaline, isoproterenol 2-selective: moderate-acting: salbutamol, terbutaline long-acting: salmeterol, formoterol • Theophyllines: aminophylline • Muscarinic antagonists: ipratropine

45. Selectivity of 2agonists

46. Salbuterol • 1. Pharmacological effects • Relaxing bronchial smooth muscles • 2. Clinical uses • Controlling asthmatic symptoms mild, occasional--only inhaled  Receptor agonists severe, nocturnal symptom--combined with anti-inflammatory agent • Given by inhalation (soon), oral • 3. Adverse effects • Skeletal muscle tremor • Cardiac stimulation (larger doses) • Dysfunction of metabolism (hypokalemia, etc.) • Disensitization (stop 1-2 weeks)

47. Formoterol 福莫特罗 Salbuterol 沙丁胺醇 Terbutaline 特布他林 Salmeterol 沙美特罗 3. Antiasthmatic drugs • Bronchial dilators Selective 2 receptor agonists Short acting agonists (4-8 hrs) Clenbuterol 克伦特罗 Clorprenalineine 氯丙那林 Long acting agonists (8-12 hrs)

48. Bronchial dilators Theophyllines Aminophylline

50. Theophyllines 1. Pharmacological effects Antiasthmatic effect • Bronchus dilation • Inhibiting PDE; • Blocking adenosine receptors; • Increasing catecholamine release; • Anti-inflammation • Increasing respiratory muscle contractility CNS stimulation, diuretic, positive chronotropic and inotropic effects, etc.