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Drugs for Respiratory System GAO Fen-Fei Introduction Symptom of respiratory system: no sputum---antitussives Cough sputum --- expectorants Asthma ----- antiasthmatic drugs 支气管痉挛、 粘膜水肿 平喘药 喘息 管腔狭窄 阻塞细支气管 继发感染、加重症状 呼气阻力增加 排痰困难 呼吸道积痰 刺激气管粘膜 咳嗽 排痰 镇咳药 祛痰药 ANTITUSSIVES Classification: 一.Central antitussives 1. 2. Dependent central antitussives Independent central antitussives 二.Peripheral antitussives Dependent Central Antitussives Opioid alkaloids. Morphine is the most effective drug for the suppression of cough, but have addiction. Mechanism: suppressing of cough center 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 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. Independent Central Antitussives Stereoisomers of opioid molecules that are devoid of analgesic effects and addiction liability. Classification: 1) -orphan(吗啡南类)-antitussives : dextromethorphan(右美沙芬) 2) Amido(胺基)-antitussives: pentoxyverine(喷托维林; 咳必清), clofedanol(氯苯达诺;敌退咳) 3) piperidine(哌啶基)-antitussives: cloperastine(氯哌斯 汀) 4) morpholine(吗啉基)-antitussives: promolate(普罗吗 酯), fominoben(福米诺苯); 5) Others: eprazinone(依普拉酮), zipeprol(齐培丙醇). Dextromethorphan Dextrorotatory stereoisomers of a methylated derivative of levorphanol(羟甲左吗南). Clinical Use: • Dry cough. Often + Antihistamine drug Pentoxyverine Suppression of cough: ≈1/3 of codeine. Direct suppression of cough center Atropine-like action and local anesthesia action. Cloperastine Derivative of diphenhydramine(苯海拉 明). Suppression of cough center Blocking H1-receptor Peripheral Antitussives Inhibiting receptor, afferent nerve, efferent nerve of cough reflex arc → cough suppression. 1. local anesthesia action: narcotine(那可 丁), benzonatate(苯佐那酯); 2. Alleviative action: extractum glycyrrhizae liquidum(甘草流浸膏), Syrup(糖浆) Expectorants I. Mucokinetic drugs Classification: By the mechanism of action: 1. 2. Mucus secretagogue drugs: stimulating gastric mucosa → reflex secretion of bronchial gland↑ → dilution of sputum. ammonium chloride. Mucolytic drugs: 1) 2) 3) 4) 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 II. By route of administration: 1. Oral drugs: 2. Fog inhalation drugs: 1.8%NaCl, 2%~7.5%NaHCO3. 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: 1) 2) Inflammatory changes in the airway; Bronchial hyperreactivity to stimuli. • Important mediators: histamine, LTC4, LTD4, etc. Antiasthmatic Drugs Bronchodilators I. 1. 2. 3. β receptor agonists Theophylline Muscarinic antagonists Anti-inflammatory agents II. 1. 2. Steroids Anti-leukotriene agents Anti-allergic agents III. 1. 2. Stabilizer of inflammatory cell membrane H1 receptor blocker Bronchodilators 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): intermediateacting long-acting Adverse Reactions of β2 agonists: 1) Skeletal muscle tremor 2) Cardiac effect: tachycardia(心悸亢进), arrhymias 3) Metabolism disturbance: ketone bodies↑, acidosis, [K+]o↓ Theophylline Methylxanthine derivatives. Mechanism of Action: 1. Inhibit phosphdiesterase (PDE); 2. Block adenosine receptors; 3. Increase endogenous catecholamine (CA) releasing; 4. Interfere with receptor-operated Ca2+ channels → [Ca2+]i↓; 5. Anti-inflammatory action Clinical Use: 1. Asthma: maintenance treatment 2. Chronic obstructive pulmonary disease (COPD) 3. 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. 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. Anti-inflammatory Agents Glucocorticoids (GCs) Mechanism of Action: 1. Broad anti-inflammatory efficacy ① ② Block the synthesis of arachidonic acid(花生 四烯酸) by phospholipase A2. Reduce bronchial reactivity. 2. Increase the responsiveness of βadrenoceptors in the airway. Routes of administration: • Systemic administration: including oral and injection. More severe toxicity. • Inhalation: Common inhalant GCs: • FP, BDP, BUD, TAA, FNS 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. Common agents: I. zafirlukast and montelukast: LTD4-receptor antagonists II. zileuton: 5-lipoxygenase inhibitor 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. Disodium Cromoglycate (SCG) Mechanism of Action: 1. Stabilizer of mass cell membrane: decrease the release of mediators from mast cells. 2. Inhibit the function of sensory nerve ending and neurogenic inflammation in airway. 3. Decrease bronchial hyperreactivity. Ketotifen H1 receptor blocker. Prevent and inverse down-regulation of β2-receptor.