chapter 4 analgesics, antitussiveand expectorants

Chapter 4 Analgesics, antitussives and expectorants,4.1 Analgesics,疼痛：是由创伤和疾病等多种原因引发的症状，剧烈的疼痛可引起生理功能紊乱，甚至休克。Classification of Painkiller: Narcotic Anangesics :作用于中枢神经系统，抑制痛觉神经从而消除或缓解疼痛，多用于剧痛（acute pain）。Antipyretic analgesics:具有解热、镇痛、抗炎作用，用于钝痛(chronic pain)如牙痛或头痛。Difference: different mechanismOpioid receptor for the formerArachidonic acid cyclooxygenase inhibitor of the latter,Opioid receptors: discovered in 1973 with three subtypes receptor agonist: strong addiction receptor agonist, addiction receptor agonist,Narcotic analgesics includes opioid alkaloid morphine, its synthetic analogues and endogenous substance such as enkephalin, endorphin and dynorphin.,4.1.1 Morphine and its analogues,Opium是罂粟科植物罂粟的未成熟的蒴果被划破后流出的白色浆汁，干燥后呈棕黑色膏状物。The immature fruit of Opium contains alkaloids, triterpenoids and steroids. Morphine was seperated from Opium in 1805 and its chemical structure was identified in 1923. The total synthesis was finished in 1952.,Molecular structure and activity of morphine,天然的吗啡呈左旋性，右旋体无活性 5个手性中心：5R, 6S,9R,13S,14R5个环 ，A、B和C构成部分氢化的菲环，C和E构成部分氢化的异喹啉环B/C呈顺式，C/D呈反式，C/E呈顺式立体构像：三维的TPhysiological activity：analgesiaSide-effects: addiction, respiratory depression,Vomiting, constipation, euphoria,1. To simplify the chemical structure of morphine to develop synthetic morphine analogues and morphine antagonists.,2.To discover the mixed agonist-antagonist analgesics with small addiction.,3.To discover the efficient analgesics, such as the discovery of Etorphine,4.To discover the endogenous opioid-like analgesics such as enkephalin,Modifications towards morphine,Heroine,Codeine,Ethylmorphine,Heterocodeine,Oxycodone,Hydromorphone,Oxymorphone,Hydrocodone,N-phenylethylnormorphine,N-CH3用其他烷基、链烯烃或芳烃修饰,活性为吗啡的4倍,Mixed agonist-antagonist,Nalorphine,-receptor partial agonist, very weak analgesic effect.,Opioid antagonists and Antagonist analgesics,Naloxone and naltrexone are -receptor antagonists, without exciting activity.,Naloxone,naltrexone,是研究阿片受体的工具药物，可用于吗啡类中毒后的解救,解除呼吸抑制并使血压上升。,SAR of morphine,叔胺是镇痛活性的关键基团，N原子上引入不同的取代基可使受体激动剂变为拮抗剂。,酚羟基被酰化和醚化后，活性和成瘾性均下降。,双键被还原后，活性和成瘾性均增加。,酚羟基被烃化酯化氧化或去除后，活性和成瘾性均增加。,-receptor agonist,(5,6 ）-7,8-二脱氢-4,5-环氧-17-甲基吗啡喃-3,6- 二醇盐酸盐三水合物 (5,6 ）-7,8-didehydro-4,5-epoxy-17-methylmorphinan-3,6- diol hydrochloride trihydrateOptical activity: Levorotary,Representative: Morphine Hydrochloride,(1) Acidic and alkaline.(2) Easily to be oxidized into pseudomorphine. Stability has relationship with pH, stable under acidic conditions (stablest at pH4), easily be oxidized under neutral or alkaline conditions in sunlight (UV) and the reaction can be catalyzed by heavy metal ions.,Chemical properties,盐酸吗啡水溶液与三氯化铁试液反应显蓝色；与甲醛硫酸试液反应呈紫堇色后变为蓝色；与钼硫酸试液反应呈紫色。 盐酸吗啡水溶液加入稀铁氰化钾试液后再与三氯化铁试液反应，生成蓝色的亚铁氰化铁, 区别可待因。 吗啡与盐酸或磷酸加热反应生成阿扑吗啡，阿扑吗啡氧化生成暗紫红色邻醌化合物。阿扑吗啡水溶液在碳酸氢钠碱性条件下，加碘试液生成的氧化产物能溶于乙醚显宝石红色，水层显绿色。用于检查盐酸吗啡中的阿扑吗啡。,暗紫色,阿扑吗啡,Identification,apomorphine,Apomorphine is used as emetic,Mechanism: opioid-receptor agonistPhysiological activity: analgesic,antitussive and sedative effects.Side-effects: addiction, respiratory depression,Vomiting, constipation, euphoriaUsage: acute pain of cancer,4.1.2 Synthetic analgesics,4.1.2.1 Morphinanes,N-methylmorphinane,levorphanol,butorphanol,活性只有吗啡的1/5,-receptor agonist活性是吗啡的4倍,-receptor antagonist-receptor agonist用作镇痛药成瘾性小,Pentazocine:-receptor agonist and -receptor weak antagonist. Phenazocine:-receptor agonist with analgesic effect 10 times than morphine. 氟痛新：analgesic effect is stronger than pentazocine.,4.1.2.2 Benzomorphans,Representative: pentazocine,Mixed agonist- antagonist : - receptor agonist and - receptor antagonist,The first clinical non-narcotics analgesic. It can not be used as oral dosage because of first-pass effect and low bioavailability. Clinical for moderate pain.,吗啡,A typical -receptor agonist, analgesic effect is l / 6 l / 8 to that of morphine.,4.1.2.3 Piperidines,pethidine,Alphaprodine,Betaprodine,Anileridine,Piminodine,Fentanyl is opioid -receptor agonist, analgesic effect is about 500 times than that of pethidine and 80 times than that of morphine.,Fentanyl,Configuration of Fentanyl,alfentanil,sufentanil,carfentanil,-receptor agonist, Lovorotary-body presents stronger analgesic effect than dextrorotary-body, effect intensity of L-body similar to that of morphine.,4.1.2.4 Aminoketones,methadone,Configuration of Methadone,（四）高效激动剂,镇痛作用强于埃托啡，动物实验结果其戒断症状及精神依赖性潜力均明显的轻于吗啡，但在临床使用中发现有较强的精神依赖性和躯体依赖性，耐受性形成快，成瘾性强，滥用潜力很大,Endogenous opioid peptides,Structure-Activity Relationship of Opiod Analgesics,1、分子中应具有一个平坦的芳香结构，可以和受体相应部位通过范德华引力相结合2、应有一个碱性中心，通常为一个叔胺N原子，在生理PH条件下，可大部分电离为阳离子，以便与受体表面的阴离子部位结合。3、碱性中心和平坦结构芳环应处在同一平面上，以便与受体结合，烃链部分在立体构型中应突出于平面前方，以便与受体空穴部分相契合。4、芳环与一个季碳原子相连，通过季碳原子与叔胺N原子之间的距离相隔二个碳5、分子中其它部位可与受体结合（如氢键）可增加镇痛效力。,structure-activity relationship of -receptor agonist,Models of the Opiod Receptor,a. 阴离子受点,b. 适合芳环的平坦区,c. 凹槽,具有一个碱性中心。此碱性中心在生理pH下部分解离后带有正电荷，与受体表面的阴离子受点缔合。具有一个平面的芳环结构与受体的平坦区，通过范德华力相互作用。烃基链部分（吗啡结构中C15C16）凸出于平面，正好与受体的凹槽相适应,1、三点结合的受体模型,A,B,C,D,埃托啡PEO,2、 四点结合的受体模型,A 亲脂部位 B 负离子部位C 凹槽 D 亲脂部位（适合芳环的平坦区）,Codeine Phosphate,Chemical name: (5, 6 ) -7,8 - didehydrogen -4,5 - epoxy -3 - methoxy-17 - methyl morphinans - 6 - alcohol phosphate hemihydrate L-Optica Rotation,3、*盐酸哌替啶（Pethidine Hydrochloride）,2）特征反应：其水溶液与苦味酸（三硝基苯酚）的乙醇溶液反应，生成黄色哌替啶苦味酸盐沉淀。,1）化学名：1-甲基-4-苯基-4-哌啶甲酸乙酯盐酸盐，又名度冷丁。,3）代谢：,哌替啶酸,去甲基哌替啶,去甲哌替啶酸,4、*盐酸美沙酮（Methadone Hydrochloride）,1）化学名：6-二甲氨基-4，4-二苯基-3-庚酮盐酸盐2）鉴别：水溶液与甲基橙试液反应生成黄色复盐沉淀。,3）代谢：,枸橼酸芬太尼（Fentanyl Citrate）,Chemical name: N-phenyl-N-1 - (2 - phenylethyl) -4 - piperidine-yl amide citrate Effect: receptor agonist with efficient, high lipophilicity and short time acting. Analgesic effect happens quickly,analgesic effect 75-100 times stronger than morphine. Application: used in clinical surgery and post-operative analgesics for clinical cancer pain.,3）合成：,Butorphanol Tartrate,Chemical name: 17 - (cyclobutanemethyl) - morphinan -3,14 - diol tartrate Effect: -opioid receptor antagonist and receptor agonist. It can not be used as a oral dosage medicine bcause of first-pass effect.Application: to severe moderate pain and assistant narcosis.it is not in the list of abuse potential drug because of small addiction .,Nalbuphine Hydrochloride,Chemical name: 17 - (cyclobutanemethyl) -4,5 - epoxy - morphinan -3,6,14 - triol hydrochloride Effect: -opioid receptor antagonist, antagonist activity is l / 4 that of naloxone. opioid receptor agonist, analgesic effect is stronger than pentazocine but same to morphine. Application: t