藥理學英文版教學課件：Chapter 34 Insulin-oral hypoglycemics

Insulinand

OralHypoglycemicDrugsInsulinand

OralHypoglycemicDrugsDiabetesMellitus(糖尿病)Agroupofsyndromescharacterizedbyhyperglycemia,alteredmetabolismoflipids,carbohydratesandproteinsandincreasedriskofcomplicationsfromvasculardisease.Associatedwitharelativeorabsoluteinsufficiencyofinsulinsecretionwithvariousdegreesofinsulinresistance.PreviousClassificationofDiabetesMellitus:TypeI：insulin-dependentdiabetesmellitus（IDDM,?cellsdysfunction）TypeII：Non-insulin-dependentdiabetesmellitus(NIDDM,?cellsnormalorhypofunction,Insulinresistance，INR)。Accountsformorethan95%pts。ClinicalCharacteristics: ①fastinghyperglycemia(空腹高血糖),②atheroscleroticandmicroangiopathicvasculardisease,③neuropathy（神經(jīng)病變）complications（并發(fā)癥）ofdiabetesThechronichyperglycemiaofdiabetesisassociatedwithlong-termdamage,dysfunction,andfailureofvariousorgans,especiallytheeyes,kidneys,nerves,heartandbloodvessels.InJuly1997,TheAmericanDiabetesAssociationadoptedthefollowingguidelines fortheclassificationofdiabetestypes,basedonetiology.Type1-resultsfromanautoimmuneresponsetopancreatic?-cellcomponent(s) triggeredbyviralinfectionType2-hyperglycemiamaybedueto: a.Increasedhepaticglucoseproduction b.Impairedinsulinsecretion c.Receptorandpostreceptordefects(insulinresistance)Nowclassification1.Type1diabetes-~10%ofallpatients-

-celldestructionleadingtoabsoluteinsulindeficiency:ImmunemediatedorIdiopathic（特發(fā)性）2.Type2diabetes-~90%ofallpatientsMayrangefrompredominantlyinsulinresistantwithrelativeinsulindeficiencytoapredominantlysecretorydefectwithinsulinresistance.Largergeneticcomponentthantype13.OtherspecifictypesIncludesgeneticdefectsof

-cellfunction,geneticdefectsofinsulinaction,exocrinepancreaticdisease,endocrinopathies,drug-orchemicalinducedforms,infections,andothergeneticdefectssometimesassociatedwithdiabetesmellitus.e.g.,MaturityOnsetDiabetesofYouth=Glucokinasemutation-increasedthresholdforinsulinsecretion,causingmild,persistenthyperglycemiaCausesofInsulinResistanceAbnormal?-cellsecretoryproduct Abnormalinsulinmolecule IncompleteconversionofproinsulintoinsulinCirculatinginsulinantagonists:Elevatedlevelsofcounterregulatoryhormones,e.g., growthhormone,cortisol,glucagon,orcatecholaminesAnti-insulinantibodiesAnti-insulinreceptorantibodies Targettissuedefects InsulinreceptordefectsorPostreceptordefects21stCenturyPandemic（流行?。?“Diabesity”（糖胖病）type2diabetesinchildrenHowtodealwithdiabetes：Comprehensivetreatment：dietPhysicalexercisemedicationDrugclassification：insulinoralhypoglycemic(antihyperglycemic)agentsagentswhichincreasethesensitivityoftargetorganstoinsulin§1

Insulin(Ins,胰島素)secretedby?cellsinthepancreaticislets,acidicproteinThebirthofanideaInOctober,1920FrederickBanting,ayoungsurgeoninOntario,Canada,firstconceivedtheideathatledtothediscoveryofinsulin.Oneevening,afterdeliveringalectureonthepancreastomedicalstudents,hewasstruckbyanidea:Couldtheinternalsecretionsofthepancreasbeisolatedfromtheexternalsecretionstokeepdogswithdiabetesalive?-tie-off（結(jié)扎）pancreaticductstocauseacinar（腺泡）tissuedegeneration,therebyremovingproteaseswhichweredestroyingtheanti-diabeticprincipleduringitsextraction（提?。?BantingbeganhisresearchonMay19,1921,withMacleodasformalsupervisorandCharlesBestashisassistant.InAugustof1921afternumerousfailures,BantingandBestpreparedanewextractfromtheatrophiedpancreasofoneofthedogs.Theythenisolatedtwootherdogswithdiabetes,administeringtheextracttooneandleavingtheseconduntreated.Fourdayslater,theuntreateddogdiedofseverediabetes.Thedogthatreceivedtheextractlivedforthreemoreweeks,dyingonlywhentheextractwasusedup.FirstHumanPatientOnJan.11,1922,14-year-oldLeonardThompsonwasthefirsthumanpatienttoreceiveinsulinmadebyBantingandBest.Theinitialtestfailed,causingonlyslightreductionsinbloodglucoselevels.Asecondseriesof"purified"insulininjections,producedbyJ.B.Collip,achievedthedesiredresults.Leonard'sbloodglucosedroppedtonormal,andhebegantogainweight.Structureofinsulin:Consistsof2polypeptidechains(AandB)connectedbydisulfidebondsOrigin:AnimalpancreaDNArecombinanttechnologyInsulinAction：I.MajorregulatorofoverallbodyfuelmetabolismIncreasedglycogensynthesis–forcesstorageofglucoseinliver(andmuscle)cellsintheformofglycogen;Decreasedgluconeogenesis–decreasesproductionofglucosefromnon-sugarsubstratesIncreasedfattyacidsynthesis–insulinforcesfatcellstotakeinbloodlipidswhichareconvertedtotriglycerides;Increasedesterificationoffattyacids–forcesadiposetissuetomakefats(i.e.,triglycerides)fromfattyacidesters;Decreasedlipolysis–forcesreductioninconversionoffatcelllipidstoresintobloodfattyacids;Decreasedproteolysis–decreasingthebreakdownofprotein.Increasedproteinsynthesis.Increasesaminoacidtransport.EffectsonK+transportMetabolicEffectsofInsulinTriglyceridesAdiposeTissueGlycogenLiverProteinMuscleGlucoseAminoAcidsFattyAcidsStimulatedbyinsulinIncreasedbyfeedingInhibitedbyinsulinIncreasedbyfastingandindiabetesFattyAcidsmechanismInsulinbindstoan

subunitoftheinsulinreceptor,activatingthetyrosinekinasedomainonits

subunitsReceptorautophosphorylationleadstoactivationofcellulareffectorsandabiologicresponse.AkeyresponseisrecruitmentofglucosetransporterstothecellsurfaceinskeletalmuscleandadiposetissueNocompetitiveantagonistsorpartialagonistsofinsulinexistuntilnowOralinsulin-mimetichasbeendescribed

IRS-1/2MechanismofInsulinActionGlucoseGlucoseTransporterInsulinReceptorPPPPPIRS-1/2PPPPPPTranslocationofGlucoseTransportersSkeletalmuscleAdiposeTissueRecruitmentofEffectorsProtein:ProteinInteractionsSignalTransductionNetworksActivationofPhosphorylationCascadesBiologicResponsepharmacokineticsNooraladminis.Subcutaneouslyinjection，ori.vt1/29—10min，Metabolizedatliverandkidney.Orhydrolyzedbyinsulinase(whatanti-insulinasewilldo?)Clinicaluses1.insulininjectionType1diabetesType2diabetescan’tcontrolbyothertreatmentDiabeteswithcomplicationketoacidosis(酮癥酸中毒)orhyperosmolarcoma（高滲昏迷）DiabeteswithinfectionIntracellularK+deficiencyInsulininjection：Short-acting：regularinsulin（正規(guī)胰島素,i.vavailable)lisproinsulin（賴脯胰島素）Median-acting:Lanteinsulin(低精蛋白鋅胰島素),globinzincinsulin(珠蛋白鋅混懸液),Long-acting:Protaminezincinsulin,(精蛋白鋅胰島素)monocomponentinsulin(單組分：純度高)，2.Insulininhalants：Marketat2006,lowF，9%，smokingcanincreaseFAdversereaction：1allergicreaction2hypoglycemia3insulinresistance:dosage>200U/day,acuteresistance：relatedwithincreasedcatecholaminesChronicresistance：antibodytoinsulinreceptorsordecreasedantibodynumbers.4adiposeatrophy§2OralHypoglycemicAgentsInsulinsensitizersSulfonylurea(磺酰脲類)：tolbutamide（甲糖寧，甲苯磺丁脲，D860)；glibenclamide,glipizideBiguanide(雙胍類)：metformin（二甲雙胍）Alpha-glucosidase（葡糖苷酶）inhibitors:acarbosePrandial(膳食)glucoseregulators：一、InsulinsensitizerThiazolidinediones(噻唑烷酮類化合物)bindtoPPARγ(過氧化物酶增殖體受體γ),atypeofnuclearregulatoryproteinsinvolvedintranscriptionofgenesregulatingglucoseandfatmetabolism.ThesePPARsactonPeroxysomeProliferatorResponsiveElements(PPRE),influenceinsulinsensitivegenes,whichenhanceproductionofmRNAsofinsulindependentenzymes.Thefinalresultisbetteruseofglucosebythecells.Decreasetheinsulinresistanceintype2diabetesrosiglitazone(羅格列酮)pioglitazone(吡格列酮)troglitazone(曲格列酮)Pharmacologicaleffects1、improveinsulinresistance,reducethebloodglucose2、correctlipidmetabolismdisturbance：3、preventinsulincomplication4、improvethefunctionofBcells,decreasethedeathClinicalusesTypeIIdiabetesordiabetesresistanceAdversereactionDrowsy,headache,edema,muscularpaindigestivesystemdisordersHepatotoxicity,effectonCYP450二、sulfonylurea(磺酰脲類)Pharmacologicaleffects：1hypoglycemiafornormalandtype2diabeticpeople,facilitatesecretionofinsulinfrompancreaticislets,2antidiuresischlorpropamide(氯磺丙脲),promotesecretionofADH3onblood:inhibitplateletadherenceincreasethesynthesisofprofibrinolysinMechanismofaction：

Theyareinsulinsecretagogues,triggeringinsulinreleasebydirectactionontheKATPchannelofthepancreaticbetacells.Byblockingthechannels,lessK+flowoutofcellsleadtomembranedepolarization,theCa++channelopening,increasedintracellularCa++triggeringinsulinrelease.Inhibitthesecretionofglucagon(胰高血糖素)UpregulationofinsulinreceptorsintargetcellsClinicalusesDiabetes：typeIIdiabeteswithafewpancreaticfunctionorcan’tcontrolondietDiabetesinspidus(尿崩癥):ChlorpropamideAdversereaction：GIoutofcondition,allergicreactionLiverdamage&jaundiceBlooddisorder,decreasesplatelet&WBCLong-lastinghypoglycemia2009年1月19日，新疆喀什地區(qū)食品藥品監(jiān)督管理局接到莎車縣食品藥品監(jiān)督管理局報告。報告稱接到莎車縣衛(wèi)生局報告，一名叫葉丹軍的男子租借房屋，以“中國慢性病康復(fù)協(xié)會”(據(jù)查：該中國慢性病康復(fù)協(xié)會不存在)的名義進行講課、診療糖尿病，并對聽課人員免費檢測血糖，暗地銷售藥品“糖脂寧膠囊”(國藥準字：B20020169，生產(chǎn)企業(yè)：廣西平南制藥廠，批號：20081101)。1月17日、19日莎車縣有兩名糖尿病患者(吐某、女、53歲，買某、女、62歲)在服用該藥品后，出現(xiàn)疑似低血糖并發(fā)癥，兩人相繼死亡。經(jīng)與廣西壯族自治區(qū)食品藥品監(jiān)督管理局聯(lián)系，協(xié)同核查結(jié)果，廣西平南制藥廠未生產(chǎn)過批號為081101的“糖脂寧膠囊”。經(jīng)喀什地區(qū)藥品檢驗所和新疆維吾爾自治區(qū)藥品檢驗所檢驗，該藥品中非法添加了化學物質(zhì)格列本脲，超過正常劑量的6倍，致人死亡的藥品為假冒產(chǎn)品。DruginteractionHighproteinbinding,interactionwithotherdrugs。IncreasedhypoglycemiceffectwithalcoholSomedrugcandecreasetheeffects:glucocortico