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    镇咳祛痰药.ppt

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    镇咳祛痰药.ppt

    Drugs for treatment of respiratory diseases,Huifang Tang Department of pharmacology Zhejiang University, school of medicine tanghuifangzju.edu.cn,Various diseases of respiratory system Common symptoms: cough sputum wheezing,. Antitussive drugs: 1. Centrally acting: Codeine 2. Peripherally acting: Benzonatate . Mucoactive drugs : 1. Expectorants: Guaifenesin 2. Mucoregulators:Carbocysteine 3. Mucolytics: N-Acetylcysteine 4. Mucokinetic drugs: Ambroxol . 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,Classification of drugs acting on respiratory system,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,A. Antitussives,Clinical perspective - cough: an unmet need. Curr Opin Pharmacol. 2015 Jun;22:24-8,Antitussive drugs-past, present, and future. Pharmacol Rev. 2014 Mar 26;66(2):468-512.,Multiple vagal afferent nerve subtypes innervate the airways and lungs,The distribution and responsiveness of airway afferent subtypes in the guinea pig. RARs, rapidly adapting receptors; SARs, slowly adapting receptors.,Am J Physiol Regul Integr Comp Physiol 2008, 295:R1572-R1584.,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,A. Antitussives,Codeine 可待因,Narcotic Antitussives,1. Pharmacological effects suppression of cough (1/4 of morphine) analgesia (1/71/10 of morphine) 2. Clinical uses Cough without sputum 3. Adverse effects Respiratory depression (at larger doses) Addiction Contraindicated in patients with thick sputum,Narcotic Antitussives,Other narcotic antitussives:,Dihydrocodeine(双氢可待因); Drotebanol(羟蒂巴酚); Pholcodine(福尔可定),Narcotic Antitussives,Drotebanol (Oxymethebanol) 羟蒂巴酚,A morphinan derivative that acts as an opiod agonist,Narcotic Antitussives,cough suppressant effects : around 10x more potent than codeine. analgesic effects : several times stronger than codeine, but weaker than morphine,Pholcodine(福尔可定),Narcotic Antitussives,an opioid cough suppressant,mild sedative effect little or no analgesic effects lower potential for dependence,Dextromethorphan(右美沙芬, DXM),Codeine,Dextromethorphan,Non-Narcotic Antitussives,Antitussive drugs-past, present, and future. Pharmacol Rev. 2014 Mar 26;66(2):468-512.,Metabolism of dextromethorphan.,dextrorphan(右啡烷),3-methoxymorphinan (3-甲氧基吗啡喃),3-hydroxymorphinan (3-羟基吗啡南),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.,Non-Narcotic Antitussives,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.,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.,Non-Narcotic Antitussives,(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).,others,Cloperastine(氯哌斯汀) Promolate (普罗吗酯) Fominoben (福米诺苯) Zipeprol(齐培丙醇),Non-Narcotic Antitussives,Cloperastine(氯哌斯汀),(1)Pharmacological effects: a mild bronchorelaxant antihistaminic activity acting on the central nervous system or the respiratory center.,Non-Narcotic Antitussives,Zipeprol(齐培丙醇),A centrally acting cough suppressant developed in 1970s Pharmacological effects: a local anaesthetic mucolytic antihistamine properties anticholinergic properties Zipeprol has been misused mainly for the hallucinations(幻觉),Non-Narcotic Antitussives,Levocloperastine Fendizoate (左旋氯哌斯汀-联苯酰苯酸盐),an antitussive agent that acts centrally action: on the bulbar cough center peripherally action:on the cough receptors in the tracheobronchial tree. This dual mechanism of action makes levocloperastine fendizoate effective in the treatment of cough associated with many chronic and acute conditions in patients of all ages.,Non-Narcotic 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),A. Antitussives,Benproperine(苯丙哌林),It has a peripheral and central action The antitussive activity is comparable to that of codeine, but is devoid of the undesirable codeines side effects widely used as a cough suppressant for non-productive coughs.,Peripheral Antitussives,Levodropropizine(左羟丙哌嗪),It is the levoisomer of Dropropizine. It acts as a peripheral antitussive, with no action in the central nervous system. It does not cause side effects such as constipation or respiratory depression which can be produced by opioid antitussives such as codeine and its derivatives.,Peripheral Antitussives,Narcodine,Noscapine(那可丁),a benzylisoquinoline alkaloid from plants of the Papaveraceae family, without significant painkilling properties. Noscapine's antitussive mechanism: sigma receptor agonist . The effects, beginning around 45 to 120 mins after consumption, are similar to dextromethorphan. Unlike dextromethorphan, noscapine is not an NMDA receptor antagonist,Peripheral Antitussives,Moguisteine 莫吉司坦,novel peripheral non-narcotic antitussive drug.,Peripheral Antitussives,常用镇咳药比较表,Antitussive drugs-past, present, and future. Pharmacol Rev. 2014 Mar 26;66(2):468-512.,B. Mucoactive drugs,Mucous glycoprotein network,Hydration: Sputum dilution,Mucolysis,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,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,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.,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,Expectorants,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.,Mucoregultor,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:,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.,Mucolytic drugs,Ambroxol ( 氨溴索,沐舒坦),Mucokinetic drugs,全肺动力型排痰剂,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;,Mucokinetic 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.,Expectorants/Mucokinetics 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,Expectorants/Mucokinetics 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.,Mucokinetic drugs,祛痰药作用比较表,Mucoactive drugs.Eur Respir Rev 2010; 19: 116, 127133,

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