Drugs for Respiratory System

1. Drugs for Respiratory System GAO Fen-Fei

2. Introduction • Symptom of respiratory system: nosputum---antitussives • Cough sputum --- expectorants • Asthma ----- antiasthmatic drugs

4. 支气管痉挛、 粘膜水肿 管腔狭窄 排痰困难 平喘药 喘 息 阻塞细支气管 呼吸道积痰 继发感染、加重症状 刺激气管粘膜 呼气阻力增加 咳 嗽 排 痰 镇咳药 祛痰药

5. ANTITUSSIVES • Classification: • Central antitussives • Dependentcentral antitussives • Independent central antitussives • Peripheral antitussives

6. DependentCentral Antitussives • Opioid alkaloids. • Morphine is the most effective drug for the suppression of cough, but have addiction. • Mechanism: suppressing of cough center

7. Codeine • Selectively suppress cough center in medulla oblongata(延髓). • Potency: • Suppression of cough: ≈1/10 of morphine • Analgesia: ≈1/7 of morphine • Respiratory depression, constipation, tolerance, dependence ＜ that of morphine

8. Pharmacokinetics: • Well absorbed from oral and injection. • 10% converted to morphine through demethyl. • Clinical Uses: • Dry cough • Adverse Reactions: • Respiratory suppression in high dose; • Tolerance and physical dependence with frequently repeated administration; • Suppress secretion of bronchial gland and movement of cilia.

9. Independent Central Antitussives • Stereoisomers of opioid molecules that are devoid of analgesic effects and addiction liability. • Classification: • -orphan(吗啡南类)-antitussives : dextromethorphan(右美沙芬) • Amido(胺基)-antitussives: pentoxyverine(喷托维林;咳必清), clofedanol(氯苯达诺;敌退咳) • piperidine(哌啶基)-antitussives: cloperastine(氯哌斯汀) • morpholine(吗啉基)-antitussives: promolate(普罗吗酯), fominoben(福米诺苯); • Others: eprazinone(依普拉酮), zipeprol(齐培丙醇).

10. Dextromethorphan • Dextrorotatory stereoisomers of a methylated derivative of levorphanol(羟甲左吗南). • Clinical Use: • Dry cough. Often + Antihistamine drug

11. Pentoxyverine • Suppression of cough: ≈1/3 of codeine. • Direct suppression of cough center • Atropine-like action and local anesthesia action.

12. Cloperastine • Derivative of diphenhydramine(苯海拉明). • Suppression of cough center • Blocking H1-receptor

13. Peripheral Antitussives • Inhibiting receptor, afferent nerve, efferent nerveof cough reflex arc → cough suppression. • local anesthesia action: narcotine(那可丁), benzonatate(苯佐那酯); • Alleviative action: extractum glycyrrhizae liquidum(甘草流浸膏), Syrup(糖浆)

15. Expectorants • Mucokinetic drugs • Classification: • By the mechanism of action: • Mucus secretagogue drugs: stimulating gastric mucosa → reflex secretion of bronchial gland↑ → dilution of sputum. ammonium chloride. • Mucolytic drugs: • break acid mucin: bromhexine(溴己新;必嗽平) • drug-SH S-S of mucin → Fragmentation: acetylcysteine(乙酰半胱氨酸) • Enzymolysis: α-chymotrypsin(糜蛋白酶) • Surfactant: tyloxapol(泰洛沙泊)----Fog inhalation

16. By route of administration： • Oral drugs: • Fog inhalation drugs: 1.8%NaCl, 2%~7.5%NaHCO3.

17. Asthma • Pathophysiology: • Asthma is a disease characterized by airway inflammation and episodic(发作性的), reversible bronchospasm(支气管痉挛). • Two characteristic features: • Inflammatory changes in the airway; • Bronchial hyperreactivity to stimuli. • Important mediators: histamine, LTC4, LTD4, etc.

19. Antiasthmatic Drugs • Bronchodilators • β receptor agonists • Theophylline • Muscarinic antagonists • Anti-inflammatory agents • Steroids • Anti-leukotriene agents • Anti-allergic agents • Stabilizer of inflammatory cell membrane • H1 receptor blocker

20. Bronchodilators

21. intermediate- acting long-acting Beta Adrenoceptor Agonists • Adrenaline: α,β agonist • Ephedrine: α,β agonist • Isoprenaline：β1 ,β2 agonist • β2-selective agonists • Salbutamol(沙丁胺醇，舒喘灵): • Terbutaline(特布他林，博利康尼) : • Clenbuterol(克仑特罗): • Formoterol(福莫特罗): • Salmeterol(沙美特罗): • Bambuterol(班布特罗):

23. Adverse Reactions of β2 agonists: • Skeletal muscle tremor • Cardiac effect: tachycardia(心悸亢进), arrhymias • Metabolism disturbance: ketone bodies↑, acidosis, [K+]o↓

24. Theophylline • Methylxanthine derivatives. • Mechanism of Action: • Inhibit phosphdiesterase (PDE); • Block adenosine receptors; • Increase endogenous catecholamine (CA) releasing; • Interfere with receptor-operated Ca2+ channels → [Ca2+]i↓; • Anti-inflammatory action

25. Clinical Use: • Asthma: maintenance treatment • Chronic obstructive pulmonary disease (COPD) • Central sleep apnea (CSA) • Adverse Reactions: • Narrow margin of safety. Toxic effects are related to its plasma concentrations. • Gastrointestinal distress, tremor, and insomnia. • Cardiac arrhythmias, convulsions(惊厥) → lethal.

26. Muscarinic Antagonists • There are M1, M2, M3 receptor subtype in the airway. • Selectively blocking M1, M3 receptor is resulted in bronchodilating effect. • Ipratropium bromide binds to all M-R subtypes (M1, M2 and M3 ), and inhibits acetylcholine-mediated bronchospasm.

27. Anti-inflammatoryAgents

28. Glucocorticoids (GCs) • Mechanism of Action: • Broad anti-inflammatory efficacy • Block the synthesis of arachidonic acid(花生四烯酸) by phospholipase A2. • Reduce bronchial reactivity. • Increase the responsiveness of β-adrenoceptors in the airway.

29. Routes of administration: • Systemic administration: including oral and injection. More severe toxicity. • Inhalation: • Common inhalant GCs: • FP, BDP, BUD, TAA, FNS

30. Anti-leukotriene agents • Cysteinyl leukotrienes is a important inflammatory mediator: • Bronchoconstriction, increased bronchial reactivity, mucosal edema, mucus hypersecretion, etc. • Leukotrienes resulte from the action of 5-lipoxygenase on arachidonic acid.

31. Common agents: • zafirlukast and montelukast: LTD4-receptor antagonists • zileuton: 5-lipoxygenase inhibitor

32. Anti-allergic Agents • Madiators release inhibitors. • No bronchodialator action but can prevent bronchoconstriction caused by a challenge with antigen to which the patient is allergic.

33. Disodium Cromoglycate (SCG) • Mechanism of Action: • Stabilizer of mass cell membrane: decrease the release of mediators from mast cells. • Inhibit the function of sensory nerve ending andneurogenic inflammation in airway. • Decrease bronchial hyperreactivity.

34. Ketotifen • H1 receptor blocker. • Prevent and inverse down-regulation of β2-receptor.