朱亮《药学导论》1绪论-zhuliang.ppt

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1、1,药 理 学Pharmacology,朱亮上海交通大学医学院,药物（Drug）定义,影响机体生理功能或生化过程,用于预防、诊断、治疗疾病或用于计划生育的物质A chemical which is utilized for the diagnosis,prevention,cure or alleivation of an unwanted health condition,2,药物在医学中的地位,3,Source of drugs,Ancient Natural productsPlantsAnimals MineralsModernActive principles of natural

2、productsArtificial synthetics Full syntheticSemi-syntheticProducts of genetic engineering,Drug Sources,6,基因工程药物过程示意图,从细胞中分离出DNA,BacteriaMicroorganisms to produce simple chemicals for manufacture processMicroorganisms to produce full length polypeptidesBacteria produce human insulin“Pharm Animals”Tra

3、nsgenic Sheep carry gene for human Factor IX Cows that produce human antibodies,Example Production Methods,现代生物药突飞猛进,biopharmaceutical/biological medical product/biologic/biologicalmanufactured in or extracted frombiological sources.distinct fromchemicallysynthesized pharmaceutical products.includev

4、accines,bloodor blood components,allergenics,gene theraphies,tissues,recombinant therapeutic proteinand living cells.,2014全球畅销药物,9,Manns et al.Sofosbuvir:the final nail in the coffin for hepatitis C?Lancet Infect Dis 2015,与药物相关的概念,药物，药品，毒物，毒品Drug,Medicine,Poison,Toxin,Narcotics,10,药品,用于预防、治疗、诊断人的疾病，

5、有目的地调节人的生理功能并规定有适应证、功能主治和用法用量的物质，包括中药材、中药饮片、中成药、化学原料药及其制剂、抗生素、生化药品、放射性药品、血清疫苗、血液制品和诊断药品等。,11,中华人民共和国药品管理法（主席令第45号）2011,Drug and Medicine(and narcotics),Drug In everyday parlance,the word drug is often associated with addictive,narcotic or mind-altering substances-an unfortunate negative connotation

6、that tends to bias opinion against any form of chemical therapy.MedicineA medicine is a chemical preparation,which usually but not necessarily contains one or more drugs,administered with the intention of producing a therapeutic effect.Medicines usually contain other substances(excipients,stabiliser

7、s,solvents,etc.)besides the active drug,to make them more convenient to use.To count as a drug,the substance must be administered as such,rather than released by physiological mechanisms.Many drugs are not used in medicines but are nevertheless useful research tools.,12,毒物,POISONpoisons are drug tha

8、t have almost exclusively harmful effects and fall strictly within the definition of drugs.However,Paracelsus(14931541)famously stated that the dose makes the poison,meaning that any substance can be harmful if taken in the wrong dosage.TOXINToxinsare usually defined as poisons of biologic origin,ie

9、,synthesized by plants or animals,in contrast to inorganic poisons such as lead and arsenic,13,药物 or 毒物,食物氯化钠水,药物补液,毒 物高鈉血症高血压,药食同源，药毒难分,All substances can under certain circumstances be toxic,and the chemicals in botanicals(herbs and plant extracts)are no different from chemicals in manufactured dr

10、ugs except for the proportion of impurities(greater in botanicals),问题何为药物，何为毒物？两者有何种联系？现实中对两者如何区别？能否举出两者间关系的典型事例？药物-毒物关系理论对临床和科研有何指导意义？,15,沪府发201512号 上海市人民政府关于表彰2014年度上海市科学技术奖获奖人员（项目）的决定 授予“髓系白血病发病机制和新型靶向治疗研究”项目特等奖,君：砷剂臣：丹参酮佐：靛玉红,16,Drug Naming,Chemical name a scientific name that precisely describe

11、s its atomic and moleculardescribe chemical structure(rarely seen in medical literature)Code Name short letter-number combination used for experimental drugsGeneric/nonproprietary namean abbreviation of the chemical namea name assigned to drug that can be used by anyoneTrade/brand/proprietary name P

12、roprietary name given to the drug by the manufacturer,17,3,3-二甲基-7-氧代-6-(苯乙酰基)氨基-4-硫杂-1-氮杂二环3.2.0庚烷-2-羧酸单钠盐,18,通用名：国际非专有名称，全球通用，是国家药典或药品标准采用的法定名称。不论何处生产的同种药品都可用的名称。商品名/品牌名：又称为商标名，具有企业专属性，受到法律的保护，常在右上角标示。习用名：又称为别名、是不规范的名称，但由于一定历史原因曾在一段时间长期广泛应用。,国食药监注200699号关于进一步规范药品名称管理的通知中华人民共和国卫生部令第53号处方管理办法（2007）,

13、19,通用名习用名,头孢氨苄先锋4号诺氟沙星氟哌酸盐酸小檗碱黄连素对乙酰氨基酚扑热息痛吲哚美辛消炎痛吡罗昔康炎痛喜康,20,药理学(Pharmacology),Pharmacology is the science of studying the effect of drugs on living organisms.Scientific study of the interactions between drugs and the body,21,药理学,研究药物与机体(病原体)相互作用及作用规律的学科 既研究药物效应动力学 也研究药物在机体的影响下所发生的变化及规律,22,作用、作用机制,

14、吸收、分布、代谢、排泄,血液循环示意图,24,药物效应动力学-What a drug does to the body 药物对机体的作用及作用机制药物代谢动力学-What the body does to a drug机体对药物的处置、转运、转化ADME过程药物浓度随时间变化的规律Pharmacodynamics governs the concentration-effect part of the interaction,whereas pharmacokinetics deals with the dose-concentration part(Holford&Sheiner,1981)

15、.,25,药理学研究内容,药效学药理作用作用机制临床应用不良反应药动学体内过程时量关系消除动力学及相关参数稳态血药浓度药物相互作用,26,药理学是桥梁学科,基础医学,临床医学,药理学,药学,医学,生物学,教育部学科分类,10医学1001基础 1002临床 1003口腔 1004公卫 1005中医 1007药学100701药化 100702药剂 100703生药 100704药分 100705生物药 100706药理07理学0780药学078006药理学,“三段式”体系下的药理学课程安排,28,“器官系统”体系下的药理学,29,30,指导临床合理用药,阐明机体生命现象,研究开发新药,药理学的学科

16、任务,药理学与诺贝尔奖,31,王来有 2008 西北医学教育,32,药理学的形成和发展,(Historical Highlights),33,1药物学阶段,34,35,“神农本草经”(Sheng Nongs Herbal Classic)中国2700BC，草药方剂治病 汉代正式编撰“神农本草经”（大约公元一世纪成）载药365种，不少流传至今，如人参、甘草、当归、麻黄、大黄 历代均有修订、增补，愈臻完善,36,历27年,明末1578年完成 52卷,190万字 收药1892种插图1160幅 药方11000条 英、日、德、俄、法、拉丁7种文字,“本 草 纲 目”（Compendium of Mate

17、ria Medica),李时珍,Materia medica the science of drug preparation and the medical use of drugsthe precursor to pharmacology.,37,38,2药理学形成阶段,39,18世纪末生理学和化学学科的发展为现代药理学发展奠定基础,In the late 18th and early 19th centuries,Franois Magendie,and later his student Claude Bernard,began to develop the methods ofexpe

18、rimental physiologyandpharmacology.1806年德国药剂师Fredrick Serturner(1783-1841)从罂粟中分离出吗啡。纯化合物的出现使能重复定量给药，从而产生科学药理学.In its beginnings,before the advent of synthetic organic chemistry,pharmacology concerned itself exclusively with understanding the effects of natural substances,mainly plant extracts-and a

19、few(mainly toxic)chemicals such as mercury and arsenic.The purified compounds showed that chemicals,not magic or vital forces,were responsible for the effects that plant extracts produced on living organisms。,阿托品(atropine;d,l-hyoscyamine),Atropos:goddesses of fate and destinythe oldest of the Three

20、Fates,and was known as the inflexible or inevitable.It was Atropos who chose the mechanism of death and ended the life of each mortal by cutting their thread with her abhorred shears.“,41,吗啡morphine词根来源“Morpheus”,意为“梦神”,被称为“Gods own medicine”,Advances in chemistry and the further development of phys

21、iology in the 18th,19th,and early 20th centuries laid the foundation needed for understanding how drugs work at the organ and tissue levels.,42,43,Rudolf Buchheim(18201879)founded the first institute of pharmacology at the University of Dorpat(Tartu,Estonia)in 1847,ushering in pharmacology as an ind

22、ependent scientific discipline.,Oswald Schmiedeberg(18381921),together with his many disciples(12 of whom were appointed to chairs of pharmacology),helped to establish the high reputation of pharmacology.Fundamental concepts such as structure-activity relationship,drug receptor,and selective toxicit

23、y emerged from the work of,respectively,T.Frazer(1841 1921)in Scotland,J.Langley(18521925)in England,and P.Ehrlich(18541915)in Germany.Alexander J.Clark(18851941)in England first formalized receptor theory in the early 1920s by applying the Law of Mass Action to drug-receptor interactions.,44,45,“药物

24、发现”标志性事件,16th centuryDiethyl ether1799,mid-19th century nitrous oxide1859Amyl nitrite1853,1897AspirinBeginning in the 20th centurybarbiturates and local anaesthetics1909arsenical compounds for treating syphilis,46,1935sulfonamidesBefore and during the Second World War penicillin.,47,中国药理学家在麻黄碱吗啡镇痛作用

25、部位青蒿素研究方面做了重要贡献,新药开发,药品：加工成某一剂型，并规定有适应证、用法及用量的药物。药品是特殊的商品，受到法律严格规范管制。,新药,化学品新药“未曾在中国境内上市销售的药品”；已上市药品改变剂型、改变给药途径，亦按照新药管理。中药、天然药物新药“未在国内上市销售的从植物、动物、矿物等物质中提取的有效成分及其制剂”生物制剂,药品注册管理办法局令第28号（2007年）,50,新药的研究与开发 New drug research and development,药学,理化性质工艺路线质量标准,临床前研究,临床研究,药效学药动学毒理学,临床试验期期期期,51,“反应停”致海豹肢畸形儿事件

26、,1953年，瑞士Ciba药厂合成了一种thalidomide（沙利多胺，反应停）This drug was marketed by the Germany firm Chemie Grnenthal as a safe alternative to barbiturate hypnotics,especially for pregnant women on October 1,1957,52,53,In Phase I trials,researchers test a new drug or treatment in a small group of people(20-80)for th

27、e first time to evaluate its safety,determine a safe dosage range,and identify side effects.In Phase II trials,the study drug or treatment is given to a larger group of people(100-300)to see if it is effective and to further evaluate its safety.In Phase III trials,the study drug or treatment is give

28、n to large groups of people(1,000-3,000)to confirm its effectiveness,monitor side effects,compare it to commonly used treatments,and collect information that will allow the drug or treatment to be used safely.In Phase IV trials,post marketing studies delineate additional information including the dr

29、ugs risks,benefits,and optimal use.,Clinical Trials,新药临床试验各期特点,55,56,57,Process of Drug Development,58,High Risk Process:11-15 Years,$1B+,临床前药理学,临床前毒理学,筛选数百万化合物,Idea,Drug,11-15 Years,1 2 产品,Phase I,Phase II,Phase III,0,15,5,10,临床药理学和毒理学,100 设计方案,Pre-clinical,59,60,61,High risk,high return,Developmen

30、t of new drugs is enormously expensive,and to survive and prosper,big pharma must pay the costs of drug development and marketing and return a profit to its shareholders.But,if a drug succeed,.e.g.The top-selling drug in 2007 was Lipitor with about US$12 billion in salesand the top biopharmaceutical

31、 was Enbrel,which brings in about US$2.5 billion revenue.,62,Blockbuster,A blockbuster drug is a drug generating more than$1billion of revenue for thepharmaceutical companythat sells it each year.Cimetidinewas the first drug ever to reach more than$1 billion a year in sales,thus making it the first

32、blockbuster drug,63,Pharmaceutical Industries,Forbes全球制药企业2015榜单,65,R&D Expenditure in R&D-Based Companies,66,67,2011年4月和2014年11月，中国自主研制的1.1类新药盐酸埃克替尼（表皮生长因子受体酪氨酸激酶抑制剂）和甲磺酸阿帕替尼（血管内皮生长因子受体酪氨酸酶抑制剂）各自获批上市，分别治疗晚期非小细胞肺癌和晚期胃癌。问题新药临床试验有哪些过程，各有何特点？为何要进行IV期临床试验？II、III期临床试验可否使用安慰剂对照？作为临床医生，在新药临床试验过程中将起到何种作用？,新药的昂贵：Bevacizumab（Avastin）治疗转移性结直肠癌，每延长一年生命花费近75,000美元（V.Shankaran et al.Oncologist 19,892899;2014）Sofosbuvir（Sovaldi）400毫克一片，每瓶含28片，售价2.8万美元，即每片1000美元。病人每天一片，大多数患者需服用3瓶来完成整个疗程，一个疗程（12个星期）84,000美元,68,69,学习药理学的方法,联系基础知识结合临床实际重视药理实验注重知识的内在联系,