藥理學(xué)

Pharmacology

朱亮上海交通大學(xué)醫(yī)學(xué)院1精選課件

藥物（Drug）定義影響機(jī)體生理功能或生化過程,用于預(yù)防、診斷、治療疾病或用于計(jì)劃生育的物質(zhì)Achemicalwhichisutilizedforthediagnosis,prevention,

cureoralleivationofanunwantedhealthcondition2精選課件藥物在醫(yī)學(xué)中的地位內(nèi)/外/婦/兒神經(jīng)循環(huán)消化…病因/機(jī)制

診斷

治療

藥物治療

其他治療手段

3精選課件SourceofdrugsAncient–NaturalproductsPlantsAnimalsMineralsModernActiveprinciplesofnaturalproductsArtificialsynthetics

FullsyntheticSemi-syntheticProductsofgeneticengineering精選課件DrugSources基因工程藥物過程示意圖①從細(xì)胞中分離出DNA①③④⑥②限制酶截取DNA片斷③分離大腸桿菌中的質(zhì)粒④DNA重組⑤用重組質(zhì)粒轉(zhuǎn)化大腸桿菌⑥培養(yǎng)大腸桿菌克隆大量基因6精選課件BacteriaMicroorganismstoproducesimplechemicalsformanufactureprocessMicroorganismstoproducefulllengthpolypeptidesBacteriaproducehumaninsulin“PharmAnimals”TransgenicSheepcarrygeneforhumanFactorIXCowsthatproducehumanantibodiesExampleProductionMethods精選課件現(xiàn)代生物藥突飛猛進(jìn)biopharmaceutical/biologicalmedicalproduct/biologic/biologicalmanufacturedinorextractedfrom

biologicalsources.distinctfrom

chemically

synthesizedpharmaceuticalproducts.include

vaccines,

blood

orbloodcomponents,allergenics,genetheraphies,tissues,

recombinanttherapeuticprotein

andlivingcells.精選課件2014全球暢銷藥物Mannsetal.Sofosbuvir:thefinalnailinthecoffinforhepatitisC?LancetInfectDis20159精選課件與藥物相關(guān)的概念藥物，藥品，毒物，毒品Drug,Medicine,Poison,Toxin,Narcotics10精選課件藥品用于預(yù)防、治療、診斷人的疾病，有目的地調(diào)節(jié)人的生理功能并規(guī)定有適應(yīng)證、功能主治和用法用量的物質(zhì)，包括中藥材、中藥飲片、中成藥、化學(xué)原料藥及其制劑、抗生素、生化藥品、放射性藥品、血清疫苗、血液制品和診斷藥品等。《中華人民共和國(guó)藥品管理法》（主席令第45號(hào)）201111精選課件DrugandMedicine(andnarcotics)Drug

……Ineverydayparlance,theworddrugisoftenassociatedwithaddictive,narcoticormind-alteringsubstances-anunfortunatenegativeconnotationthattendstobiasopinionagainstanyformofchemicaltherapy.MedicineAmedicineisachemicalpreparation,whichusuallybutnotnecessarilycontainsoneormoredrugs,administeredwiththeintentionofproducingatherapeuticeffect.Medicinesusuallycontainothersubstances(excipients,stabilisers,solvents,etc.)besidestheactivedrug,tomakethemmoreconvenienttouse.Tocountasadrug,thesubstancemustbeadministeredassuch,ratherthanreleasedbyphysiologicalmechanisms.Manydrugsarenotusedinmedicinesbutareneverthelessusefulresearchtools.12精選課件毒物POISONpoisonsaredrugthathavealmostexclusivelyharmfuleffectsandfallstrictlywithinthedefinitionofdrugs.However,Paracelsus(1493–1541)famouslystatedthat"thedosemakesthepoison,"meaningthatanysubstancecanbeharmfuliftakeninthewrongdosage.

TOXINToxins

areusuallydefinedaspoisonsofbiologicorigin,ie,synthesizedbyplantsoranimals,incontrasttoinorganicpoisonssuchasleadandarsenic13精選課件藥物or毒物食物氯化鈉水藥物補(bǔ)液毒物高鈉血癥高血壓藥食同源，藥毒難分All

substancescanundercertaincircumstancesbetoxic,andthechemicalsinbotanicals(herbsandplantextracts)arenodifferentfromchemicalsinmanufactureddrugsexceptfortheproportionofimpurities(greaterinbotanicals)精選課件問題何為藥物，何為毒物？?jī)烧哂泻畏N聯(lián)系？現(xiàn)實(shí)中對(duì)兩者如何區(qū)別？能否舉出兩者間關(guān)系的典型事例？藥物-毒物關(guān)系理論對(duì)臨床和科研有何指導(dǎo)意義？滬府發(fā)[2015]12號(hào)《上海市人民政府關(guān)于表彰2014年度上海市科學(xué)技術(shù)獎(jiǎng)獲獎(jiǎng)人員（項(xiàng)目）的決定》…授予“髓系白血病發(fā)病機(jī)制和新型靶向治療研究”項(xiàng)目特等獎(jiǎng)君：砷劑臣：丹參酮佐：靛玉紅15精選課件16精選課件DrugNamingChemicalnameascientificnamethatpreciselydescribesitsatomicandmoleculardescribechemicalstructure(rarelyseeninmedicalliterature)CodeNameshortletter-numbercombinationusedforexperimentaldrugsGeneric/nonproprietarynameanabbreviationofthechemicalnameanameassignedtodrugthatcanbeusedbyanyoneTrade/brand/proprietarynameProprietarynamegiventothedrugbythemanufacturer3,3-二甲基-7-氧代-6-[(苯乙酰基)氨基]-4-硫雜-1-氮雜二環(huán)[3.2.0]庚烷-2-羧酸單鈉鹽17精選課件通用名：國(guó)際非專有名稱，全球通用，是國(guó)家藥典或藥品標(biāo)準(zhǔn)采用的法定名稱。不論何處生產(chǎn)的同種藥品都可用的名稱。商品名/品牌名：又稱為商標(biāo)名，具有企業(yè)專屬性，受到法律的保護(hù)，常在右上角標(biāo)示?。習(xí)用名：又稱為別名、是不規(guī)范的名稱，但由于一定歷史原因曾在一段時(shí)間長(zhǎng)期廣泛應(yīng)用。國(guó)食藥監(jiān)注[2006]99號(hào)《關(guān)于進(jìn)一步規(guī)范藥品名稱管理的通知》中華人民共和國(guó)衛(wèi)生部令第53號(hào)《處方管理辦法》（2007）18精選課件通用名 習(xí)用名頭孢氨芐 先鋒4號(hào)諾氟沙星 氟哌酸鹽酸小檗堿 黃連素對(duì)乙酰氨基酚 撲熱息痛吲哚美辛 消炎痛吡羅昔康 炎痛喜康19精選課件藥理學(xué)(Pharmacology)Pharmacologyisthescienceofstudyingtheeffectofdrugsonlivingorganisms.

Scientificstudyoftheinteractionsbetweendrugsandthebody20精選課件藥理學(xué)

研究藥物與機(jī)體(病原體)相互作用及作用規(guī)律的學(xué)科

既研究藥物效應(yīng)動(dòng)力學(xué)

也研究藥物在機(jī)體的影響下所發(fā)生的變化及規(guī)律21精選課件藥物效應(yīng)動(dòng)力學(xué)（Pharmacodynamics）藥物代謝動(dòng)力學(xué)（Pharmacokinetics）作用、作用機(jī)制吸收、分布、代謝、排泄22精選課件血液循環(huán)示意圖精選課件藥物效應(yīng)動(dòng)力學(xué)-Whatadrugdoestothebody

藥物對(duì)機(jī)體的作用及作用機(jī)制藥物代謝動(dòng)力學(xué)-Whatthebodydoestoadrug機(jī)體對(duì)藥物的處置、轉(zhuǎn)運(yùn)、轉(zhuǎn)化ADME過程藥物濃度隨時(shí)間變化的規(guī)律Pharmacodynamicsgovernstheconcentration-effectpartoftheinteraction,whereaspharmacokineticsdealswiththedose-concentrationpart(Holford&Sheiner,1981).24精選課件藥理學(xué)研究?jī)?nèi)容藥效學(xué)藥理作用作用機(jī)制臨床應(yīng)用不良反應(yīng)藥動(dòng)學(xué)體內(nèi)過程時(shí)量關(guān)系消除動(dòng)力學(xué)及相關(guān)參數(shù)穩(wěn)態(tài)血藥濃度藥物相互作用25精選課件藥理學(xué)是橋梁學(xué)科基礎(chǔ)醫(yī)學(xué)臨床醫(yī)學(xué)藥理學(xué)藥學(xué)醫(yī)學(xué)生物學(xué)26精選課件教育部學(xué)科分類10醫(yī)學(xué)1001基礎(chǔ)1002臨床1003口腔1004公衛(wèi)1005中醫(yī)1007藥學(xué)100701藥化100702藥劑100703生藥100704藥分100705生物藥100706藥理07理學(xué)0780藥學(xué)078006藥理學(xué)精選課件“三段式”體系下的藥理學(xué)課程安排學(xué)期23456-臨床細(xì)胞生物

解剖

組胚

生理

生化

免疫微生物

寄生蟲

病理

病生

遺傳

藥理

28精選課件“器官系統(tǒng)”體系下的藥理學(xué)學(xué)期（5or8年制）2or33or44or55or6人體構(gòu)造

分子細(xì)胞組織

代謝能量

遺傳發(fā)育

防御免疫

病理病生總論

病原生物

藥理學(xué)總論

神經(jīng)系統(tǒng)

循環(huán)系統(tǒng)

消化系統(tǒng)

呼吸系統(tǒng)

血液系統(tǒng)

泌尿系統(tǒng)

內(nèi)分泌系統(tǒng)

29精選課件指導(dǎo)臨床合理用藥闡明機(jī)體生命現(xiàn)象研究開發(fā)新藥藥理學(xué)的學(xué)科任務(wù)30精選課件藥理學(xué)與諾貝爾獎(jiǎng)王來有2008西北醫(yī)學(xué)教育31精選課件藥理學(xué)的形成和發(fā)展

(HistoricalHighlights)32精選課件1．藥物學(xué)階段33精選課件古埃及、巴比倫、印度1500BC,埃及,亞伯斯古醫(yī)籍(Eberspapyrus)1500BC，印度草醫(yī)學(xué)，100BC~100用梵語編撰草藥方劑34精選課件“神農(nóng)本草經(jīng)”(ShengNong’sHerbalClassic)中國(guó)2700BC，草藥方劑治病漢代正式編撰“神農(nóng)本草經(jīng)”

（大約公元一世紀(jì)成）載藥365種，不少流傳至今，如人參、甘草、當(dāng)歸、麻黃、大黃歷代均有修訂、增補(bǔ)，愈臻完善35精選課件歷27年,明末1578年完成52卷,190萬字收藥1892種 插圖1160幅藥方11000條英、日、德、俄、法、拉丁7種文字“本草綱目”（CompendiumofMateriaMedica)李時(shí)珍36精選課件Materiamedicathescienceofdrugpreparationandthemedicaluseofdrugstheprecursortopharmacology.37精選課件2．藥理學(xué)形成階段38精選課件18世紀(jì)末生理學(xué)和化學(xué)學(xué)科的發(fā)展為現(xiàn)代藥理學(xué)發(fā)展奠定基礎(chǔ)Inthelate18thandearly19thcenturies,Fran?oisMagendie,andlaterhisstudentClaudeBernard,begantodevelopthemethodsof

experimentalphysiology

and

pharmacology.1806年德國(guó)藥劑師FredrickSerturner(1783-1841)從罌粟中分離出嗎啡。純化合物的出現(xiàn)使能重復(fù)定量給藥，從而產(chǎn)生科學(xué)藥理學(xué).Initsbeginnings,beforetheadventofsyntheticorganicchemistry,pharmacologyconcerneditselfexclusivelywithunderstandingtheeffectsofnaturalsubstances,mainlyplantextracts-andafew(mainlytoxic)chemicalssuchasmercuryandarsenic.Thepurifiedcompoundsshowedthatchemicals,notmagicorvitalforces,wereresponsiblefortheeffectsthatplantextractsproducedonlivingorganisms。39精選課件阿托品

(atropine;d,l-hyoscyamine)Atropos:goddessesoffateanddestinytheoldestoftheThreeFates,andwasknownasthe"inflexible"or"inevitable."ItwasAtroposwhochosethemechanismofdeathandendedthelifeofeachmortalbycuttingtheirthreadwithher"abhorredshears.“精選課件嗎啡morphine詞根來源“Morpheus”,意為“夢(mèng)神”,被稱為“God’sownmedicine”41精選課件Advancesinchemistryandthefurtherdevelopmentofphysiologyinthe18th,19th,andearly20thcenturieslaidthefoundationneededforunderstandinghowdrugsworkattheorganandtissuelevels.42精選課件RudolfBuchheim(1820–1879)foundedthefirstinstituteofpharmacologyattheUniversityofDorpat(Tartu,Estonia)in1847,usheringinpharmacologyasanindependentscientificdiscipline.OswaldSchmiedeberg(1838–1921),togetherwithhismanydisciples(12ofwhomwereappointedtochairsofpharmacology),helpedtoestablishthehighreputationofpharmacology.Fundamentalconceptssuchasstructure-activityrelationship,drugreceptor,andselectivetoxicityemergedfromtheworkof,respectively,T.Frazer(1841–1921)inScotland,J.Langley(1852–1925)inEngland,andP.Ehrlich

(1854–1915)inGermany.AlexanderJ.Clark(1885–1941)inEnglandfirstformalizedreceptortheoryintheearly1920sbyapplyingtheLawofMassActiontodrug-receptorinteractions.43精選課件44精選課件“藥物發(fā)現(xiàn)”標(biāo)志性事件16thcentury——Diethylether1799,mid-19thcentury——nitrousoxide1859——Amylnitrite1853,1897——AspirinBeginninginthe20thcentury——barbituratesandlocalanaesthetics1909——arsenicalcompoundsfortreatingsyphilis45精選課件1935——sulfonamidesBeforeandduringtheSecondWorldWar——penicillin............46精選課件中國(guó)藥理學(xué)家在麻黃堿嗎啡鎮(zhèn)痛作用部位青蒿素研究方面做了重要貢獻(xiàn)47精選課件新藥開發(fā)藥品：加工成某一劑型，并規(guī)定有適應(yīng)證、用法及用量的藥物。藥品是特殊的商品，受到法律嚴(yán)格規(guī)范管制。精選課件新藥化學(xué)品新藥“未曾在中國(guó)境內(nèi)上市銷售的藥品”；已上市藥品改變劑型、改變給藥途徑，亦按照新藥管理。中藥、天然藥物新藥“未在國(guó)內(nèi)上市銷售的從植物、動(dòng)物、礦物等物質(zhì)中提取的有效成分及其制劑”生物制劑《藥品注冊(cè)管理辦法》局令第28號(hào)（2007年）精選課件新藥的研究與開發(fā)Newdrugresearchanddevelopment藥學(xué)

理化性質(zhì)工藝路線質(zhì)量標(biāo)準(zhǔn)臨床前研究臨床研究藥效學(xué)藥動(dòng)學(xué)毒理學(xué)臨床試驗(yàn)Ⅰ期Ⅱ期Ⅲ期Ⅳ期50精選課件“反應(yīng)停”致海豹肢畸形兒事件1953年，瑞士Ciba藥廠合成了一種thalidomide（沙利多胺，反應(yīng)停）ThisdrugwasmarketedbytheGermanyfirmChemieGrünenthalasasafealternativetobarbituratehypnotics,especiallyforpregnantwomenonOctober1,195751精選課件52精選課件53精選課件InPhaseItrials,researcherstestanewdrugortreatmentinasmallgroupofpeople(20-80)forthefirsttimetoevaluateitssafety,determineasafedosagerange,andidentifysideeffects.InPhaseIItrials,thestudydrugortreatmentisgiventoalargergroupofpeople(100-300)toseeifitiseffectiveandtofurtherevaluateitssafety.InPhaseIIItrials,thestudydrugortreatmentisgiventolargegroupsofpeople(1,000-3,000)toconfirmitseffectiveness,monitorsideeffects,compareittocommonlyusedtreatments,andcollectinformationthatwillallowthedrugortreatmenttobeusedsafely.InPhaseIVtrials,postmarketingstudiesdelineateadditionalinformationincludingthedrug'srisks,benefits,andoptimaluse.ClinicalTrials精選課件新藥臨床試驗(yàn)各期特點(diǎn)55精選課件56精選課件合成篩選TheLongRoadtoaNewMedicineI期臨床試驗(yàn)II期臨床試驗(yàn)III期臨床試驗(yàn)臨床前安全有效性藥物制劑候選化合物初步安全有效性研究設(shè)計(jì)申請(qǐng)證書上市ProcessofDrugDevelopment

57精選課件HighRiskProcess:11-15Years,$1B+臨床前藥理學(xué)臨床前毒理學(xué)篩選數(shù)百萬化合物IdeaDrug11-15Years1–2產(chǎn)品PhaseIPhaseIIPhaseIII015510臨床藥理學(xué)和毒理學(xué)~100設(shè)計(jì)方案Pre-clinical58精選課件59精選課件60精選課件61精選課件Highrisk,highreturnDevelopmentofnewdrugsisenormouslyexpensive,andtosurviveandprosper,bigpharmamustpaythecostsofdrugdeve