pharmacology1优秀公开课课件

Pharmacology

药理学

Chapter1

Introduction1Whatispharmacology?Drug药物PharmacologyisthestudyofinteractionsbetweendrugsandthebodyBody身体2Whatispharmacology?Drug药物PharmacologyisthestudyofinteractionsbetweendrugsandthebodyBody身体Pharmacodynamics药物效应动力学isthestudyofwhatthedrugdoestothebody3ActiononthebodyDrug药物5ActiononthebodyDrug药物Poison毒物6ActiononthebodyDrug药物Poison毒物Indication适应征UnwantedEffectsContra-indication7ActiononthebodyDrug药物Dose剂量Poison毒物Indication适应征AdversereactionContra-indicationClinicalpharmacologyToxicology

临床药理学

毒物学9Highlightsofthe

HistoryofPharmacologyTheEgyptian«

Ebers

»papyrusfromthe16thcenturyBCistheoldestcompletemedicaldocumentstillinexistence.Itismainlyacollectionofprescriptions(处方)forvarioussymptoms(症状).神农本草经

(Shennong’sClassicofHerbalMedicine)isconsideredtobetheearliestChinesepharmacologicalwork,acompilationofallmedicinalknowledgeaccumulatedaroundthefirstcenturyBC.TangDynasty’s新修本草

(RevisedCanonofMateriaMedica)isthefirstofficialpharmacopoeia(药典)intheworld,datingfrom659.MingDynasty’s李时珍

writesthe本草纲目

(CompendiumofMateriaMedica)in1596.ItistheclassicalreferenceofTraditionalChineseMedicine,orTCM.Itconsistsof52volumesdetailingmorethan1800drugs.Itisamust-haveforTCMscholarstoday.10GermanchemistF.

W.

Sertürner(1783-1841)isthefirstto

isolatemorphine(分离提纯吗啡)fromthepoppy.Experimentationondogsprovesitsanalgesicaction.ISOLATION(分离)OFCOMPOUNDSGermanmicrobiologistP.

Ehrlichtestshundredsofchemicalsubstancesonsyphilis.The606thsubstancetested,anarseniccompound,proveseffective.SCREENING(筛选出)OFCOMPOUNDSPharmacologybecomesanindependantdisciplinewhenR.

Buchheim

(1820-1879)setsupthefirstlaboratoryofpharmacologyinGermany,writesthefirstpharmacologytextbook,andbecomesthefirstprofessorofpharmacology.In1869,Buchheim’sstudentO.

Schmiedeberg(1838-1921)showsthatmuscarineproducesthesameeffectontheheartaselectricalstimulationofthevagusnerve.STUDYOFDRUGTARGETS(药物的作用部位)In1940inBritain,Florey,onthebasisofFleming’sworkin1928,isolatespenicillin(分离出青霉素)fromacultureofbluemold,andinitiates

theclinicaluseofantibiotics(抗生素).MODERNCLINICALPHARMACOLOGY11DevelopmentofNewDrugsPreclinicaltestsonisolatedtissuesandanimalsClinicaltests:Phase1:testofactivityandtoxicityonafewhealthyhumansPhase2:testonafewpatients,anddosagestudyPhase3:double-blindtestingonalargenumberofpatientsPhase4:post-marketingsurveillance13Genetherapy14Chapter2Pharmacokinetics

Part1

Absorption吸收

Distribution分布

Elimination消除(includingof)

ofdrugs15Passageofadrugthroughamembrane(跨膜转运)Thecell(细胞)iscontainedwithinamembraneAmembraneismadeoftwolipidic(油脂)filmsProteins(蛋白质)floatonthemembrane,oracrossthemembraneThemembraneislipophilic(疏水的)initsmiddlelayer17(1)Simplediffusion(简单扩散)、Passivediffusion(被动扩散)：Themostcommonpassageofdrug

Fromahigherconcentration(浓度) toalowerconcentration

(2)Transportbyacarrier(主动转运)

Canalsogofromalower concentrationtoahigher concentration(3)Diffusionthroughachannel(易化扩散)

Fromahigherconcentration toalowerconcentration181.Absorption吸收OraladministrationDrugsaremainlyabsorbedbytheintestine(肠)becauseofitssurfaceofabsorption(200m2)Theemptyingofthestomach(胃)isthefactorlimitingtherateFoodslowstheemptyingofthestomachDrugsdiffusingslowlyaretakenwithfoodOtherdrugsaretakenonanemptystomachforfasteronsetSomedrugsaretakenonanemptystomachtoavoidinteractionwithfood(ex:tetracycline,levothyroxine,etc.)19First-passelimination2122Parenteraladministration(肠胃外)IVintravenousFastReliableEvenforbigorlabilemoleculesIMintramuscularandSCsubcutaneousMoreconvenientSlower(especiallyincaseofnonwateryvehicles)23TheBlood-BrainBarrierJunctionsbetweencellsliningthebloodvesselsinthebrainaretightlyknit,sothatdrugshavetocrossmembranestoreachthebrain25BindingtoProteins蛋白质Manydrugsbindtoplasmaproteins(albumin,a1-glycoprotein,..)whichmayconstituteareservoirforthosedrugsClass1:Drugsinconcentrationslowerthansaturation饱和

(=mostdrugs)[bounddrug]>[freedrug]Class2:Drugsinconcentrationsabovesaturation[freedrug]>[bounddrug]Possibledruginteraction:Aclass1drugdisplacedbyaclass2drugExample:Tolbutamidedisplacedbyasulfonamideantimicrobial263.1Metabolism

代谢

Occursmainlyintheliver

肝脏,alsointheintestine肠Isperformedbyenzymes酶 (ex:P450monooxygenasesystem)Producesmetabolites代谢物

that:aregeneralymorewater-solublemaybeinactive(mostoften)maybeactive(ex:diazepam地西泮g

nordazepam)maybetoxic(ex:paracetamol

对乙酰氨基酚gacetyl-benzo-quinoneimine)2930PhaseI FunctionalizationOxidation氧化 additionof0:RHgROH,etc.Reduction还原removalofCH2OorNH2Hydrolysis水解R1-COO-R2gR1-COOH+R2-OHPhaseII ConjugationIfmetabolitesfromphaseInotyetexcreted;mayoccurinthesamehepatocyteGlucuronidation葡萄糖醛酸化,sulfatation硫酸化,acetylation乙酰化,…Mostdrugsaremetabolizedthroughseveralpathways31CYP450Monooxygenasesystem

细胞色素P450单氧化酶系统

Asuperfamilyofheme-thiolateprotein亚铁血红素-硫醇盐蛋白Beinvolvedinthemetabolismofaplethoraofchemicallydiverse,endogenousandexogenouscpmpouds,includingdrugs.32TheoxidationofadrugbytheP450monooxygenasesystem.ElectronsaresuppliedbyNADPH(NicotinamideAdenineDinucleotide)33SubstratesofhumanCYPsCYP1A2 verapamil,imipramine,amitryptiline,

caffeine(arylamineN-oxidation)...CYP2A6 nicotine,coumarin

CYP2C9 diclofenac,naproxen,piroxicam,warfarinCYP2C19 diazepam,omeprazole,propanololCYP2D6 amitryptiline,captopril,codeine, mianserin,chlorpromazine... CYP2E1 dapsone,ethanol,halothane,paracetamolCYP2B6 cyclophosphamidCYP3A4 testosterone,alprazolam,cisapride,terfenadine,...CYPs Substrate34Somedrugsareenzyme-inducers

(kmetabolism)CYP1A2 omeprazole,insulin,aromatichydrocarbons (cigarettesmoking,charbroiledmeat)CYP2C9 rifampicin,secobarbital,CYP2C19 carbamazepine,prednisoneCYP2D6 dexamethasonCYP2E1 ethanol,isoniazidCYP3A4 glucocorticoide,phenobarbitone,rifampicin, nevirapine,sulfadimindine,nevirapine, sulfinpyrazone,troglitazoneCYPs Inducer35Somedrugsareenzyme-inhibitors

(mmetabolism),druginteraction!

ex,phenobarbital

苯巴比妥inhibitingthemetabolismofdicoumarol

双香豆素CYPsInhibitorCYP1A2Furafylline,fluvoxamine,cimetidine,ciprofloxacineCYP2A6Methoxsalen,pilocapine,chloramphenicol,amiodarone,omeprazole,...CYP2C9Sulfaphenazole,fluoxetine,fluvastatin,sertraline,...CYP2C19Teniposide,fluconazoleCYP2D6Quinidine,fluoxetine,paroxetine,haloperidol,ritonavir,...CYP2E1Diethyldithiocarbamate,disulfiram,cimetidine,...CYP3A4Troleandomycin,ketoconazole,gestodene363.2.Excretion1.Renal(肾)Filtration:ofallmolecules<Mr5000Re-absorption:weakacidswillbereabsorbedmoreiftheurineismoreacidic,etc.(ex:aspirin)LipophilicdrugsarepassivellyreabsorbedActivesecretionofsomedrugsintheproximaltubule,suchasthepenicillins,furosemide,thiazides,etc.2.BiliaryandFecalExcretionThereexistsanentero-hepatic(intestine-liver)cycleforsomedrugs3.Otherroutes:sweat,saliva,tears3738Part2 Pharmacokinetics药物动力学Thestudyofdrugconcentrationsovertime39(1)One-compartmentmodel一室模型AbsorptionEliminationkCompartment房室1.TheCompartmentModel房室模型40AbsorptionEliminationkCompartment1Compartment2MoreslowlyequilibratingtissuesEx:adipocytes,etc.(2)Two-compartmentmodel二室模型412.KineticsofElimination消除动力学423.1.First-Order(一级)EliminationRateofeliminationConcentration=constantdC/dt=-keC43dC/dt=-keClgCt=lgC0–ket/2.303443.2.Zero-Order(零级)EliminationMetabolizationbysaturatedenzymesand/orEliminationbyasaturatedactivetransportAppliestomanydrugsathighconcentration,andsomeothers,suchasaspirinorphenytoindC/dt=-k0Ct=C0–k0t453.Relationshipbetweenplasmaconcentrationandtime463.1

Single-AdministrationAUC:areaundercurve曲线下面积Cmax：peakconcertration峰浓度Tmax：peaktime达峰时间47Css:steady-stateconcentration稳态浓度Concentrationsaddupwhiletheeliminationrateincreases,untilasteadystateisreachedThemeansteady-stateconcentrationobeysthesamerulesaswhenthedrugisinfusedcontinually3.2RepeatedAdministration484.Importantparametersofpharmacokinetics

4.1ThePlasmaHalf-Lifet1/2消除半衰期t½isthetimetakenforanyplasmaconcentrationtodecreaseby50%49505152534.1.1t1/2ofFirst-OrderEliminationlnCp=lnCp(o)–ktt=t1/2

gCp=Cp(o)/2ln(Cp(o)/2)=lnCp(o)–kt1/2ln(1/2)=ln1–kt1/2kln1–ln(1/2)t1/2=

0.693=k常数，不受药物初始浓度和给药剂量的影响544.1.2t1/2ofZero-OrderEliminationCp=Cp(o)–k0tt=t1/2

gCp=Cp(o)/2Cp(o)/2=Cp(o)–k0t1/2k00.5Cp(o)t1/2=

与血浆药物初始浓度成正比554.2DrugClearance,Cl

清除率Cl=couldbedescribedas“thevolumeofplasmaclearedofdrugperunittime”.(usuallyinml/min)Clearance=eliminationrateplasmaconcentration=Dose/AUCHepaticClearance,RenalClearanceandTotalBodyClearance：Cltotal=Clhepatic+Clrenal+Clpulmonary+Clothers564.3apparentVolumeofDistribution(Vd)表观分布容积D=doseadministeredIV剂量Cp(o)=concentration浓度inplasmaatt=0Vdisnotarealvolume