药理学教学课件：Chapter 32 Insulin and Oral Hypoglycemic Agents

Chap32InsulinandOralHypoglycemicAgentsInsulinOralhypoglycemicagentsSulfonylureasBiguanidesαglucosidaseinhibitoreuglycemicagentsDiabetesMellitusisagroupofsyndromescharacterizedby

HyperglycemiaAlteredmetabolismoflipids,carbohydratesandproteinAnincreasedriskofcomplicationsfromvasculardiseaseWhatisDiabetesMellitus?Theclassicsymptomsofdiabetesare:excessiveurination,includingfrequenttripstothebathroominthemiddleofthenightintensethirstandhungerseverefatigue.Othersymptomsofdiabetesmayinclude:dryskinblurredvisionunexplainedweightlossthin,malnourishedappearance.DifferentformsofDiabetesMellitusIDDM(InsulindependentDiabetesMellitus)NIDDM(non-insulindependentDiabetesMellitus)GestationaldiabetesMellitusOthersSection1Insulin

Pancreaticisland

Acell

25%，secreteglucagon

Bcell

60%，secreteinsulin

Dcell

less，secretesomatostatinItisamicromoleculeprotein，twopolypeptidechainsjoinedtogetherbydisulfidelinkages.InsulinAbstractedfrompancreasofdomesticanimal.Semisynthesis

DNArecombination

Itrepresentsalandmarkinmedicalhistory.BantingandMacleodwasawardedNobelPrizeinMedicine1923becauseofthediscoveryofinsulinThediscoveryofInsulinThediscoveryofinsulinin1921allowedthepreviouslyfataldisordersofinsulin–dependentdiabetesmellitustobetreated.Insulinissynthesizedbythebeta-cellofthepancreasThebeta-cellsynthesizeinsulinfromasinglepolypeptidechainpreproinsulin,whichiscleavedtoyieldtheinsulinprecursor,proinsulin.IntheGolgicomplex,proinsulinenzymaticallycleavedtoinsulin.BiosythesisofInsulinPhysiologicalActions

—glycometabolism

fatmetabolism

proteinmetabolismlowerserumK+long-termeffect1.GlycometabolismDecreasebloodglucoseIncreaseuptakeandutilizationDecreasesourceCardiacmuscle,skeletalmuscleanddipocyte:transportationofglucose↑Liver:oxydationandzymolysis（酵解

）↑Liverandmuscle:glycogensynthesis↑Transformation:fatandaminoacids↑Inhibitglyconeogenesis（糖异生

）,glycogenolysis：Antagonizeglycagon,ADandglucocorticosteroidInsulindeficiencyresultsinplasmaglucoserisebloodglucose80~120mg%hepaticglycogenglucogensynthesisglyconeogenesisfat,aminoacidoxygenolysisfoodRenalGlucoseThresholdWhenthebloodglucoselevelisnormal(about80mg/dl(4.4mmol/l))the"renaldam"holdsthesugarback.Sugarcannotbedetectedintheurine.Onlywhenthebloodglucoselevelrisesabove160mg/dl(8.9mmol/l)-forinstancewhenitreaches180mg/dl(10mmol/l)-issugarexcretedintheurine.Inhibitlipodieretic（脂肪分解）effectoflypase,AD,growthhormone；PromoteFFAentercell

2．FatMetabolismInhibitdecompose,promotesynthesisDeficiencyofinsulin：fatmetabolicdisorder3．ProteinMetabolism

PromoteaminoacidstoentercellsIncreaseproteinsynthesisInhibitproteindecompose（分解）Positivenitrogenbalance5.Long-termeffectPromoteK+enterthecell4．LowertheconcentrationofplasmaK+enzymeexpression

MechanismofAction

MechanismReceptorgatherandinternalize(聚集和内化

)Long-termeffect：Raspassway,partiallyTheappropriatesignalingthroughtheinsulinpathwayiscriticalfortheregulationofglucoselevelsandtheavoidanceofdiabetes.InsulinformsacomplexwiththeInsulinReceptor(IR)andbchainstoformtheactivesignalingcomplex.ThroughrecruitmentofadaptormoleculesandtheactivationofRAS,theactivatedIRcancausetranscriptionalactivation.Itcannotbetakenorallybutmustbeadministeredparenterally(Sc,iv)Intravenouslyinjectedinsulinhasat1/2of5-6minutes.Themajorsiteofcatabolismistheliver,where50%isdestroyedinasinglepassage.Disulfidebondisdeoxidizedtohydrosulfidegroupbytransportase.

PharmacokineticsClinicalUsesIDDMNIDDMDiabeteswithacuteorseriouscomplicationsDiabeteswithseriousinfection,wastingdisease,pregnancy,surgery,hyperpyrexia,delivery,wound1．Allkindsofdiabetes2.Otherclinicaluses（1）Hyperpotassaemia（2）CorrectpotassiumdeficiencyofcellGIK:glucose,insulinandKCI,ivdrip,topreventarrhythmiacausedbymyocardialinfarction,decreasemortalityAdversereactionsStarvationWeaknessSweatingCardiopalmus(心悸)PallorHeadacheTremorEmotionalinstability

1．hypoglycemiaoverdosehypoglycemicshockEclampsiaComaDeathdrinksacchar-waterortakefoodiv50%glucosesolutionH1receptorblockageGlucocorticosteroid2．hypersensitivereactionnettlerash(风疹

)acutecircumscribededema(血管神经性水肿

)allergicshock-seldomForeignprotein:antigenicityProinsulinorfragment:immunogenicityTherapeutics3．TolerationAcutetoleration:stringentstate（应激状态）Chronictoleration:insulinresistance4．Flare(潮红)

、induration(硬结)

andlipoatrophy(脂肪萎缩

)

Preparationregularinsulinglobinzineinsulin珠蛋白锌胰岛素isophaneinsulinsuspension中性精蛋白胰岛素悬液protaminezincinsulin鱼精蛋白锌胰岛素(长效)purepreparationsingle-peakinsulin单峰胰岛素Single-componentinsulin单成分胰岛素Section2OralHypoglycemicAgentsSulfonylureasBiguanidesαglucosidaseinhibitoreuglycemicagent胰岛素增敏剂

SulfonylureasPowerful，rapid，remain8-10hStrongerthanfirst-generation,remian>24h。hypoglycemiaActonthesulfonylureareceptorofβ-cell,increasereleaseofinsulin

tolbutamide,(D860甲苯磺丁脲)

chlorpropamide(氯磺丙脲)

gluburide（格列苯脲,优降糖）

glipizide（格列吡嗪,美必达）

gliclazide

（格列齐特,达美康）

glimepiride(格列美脲)

gliquidone(格列奎酮)MechanismofAction

1.StimulateB-celltoreleaseinsulinItiseffectivetohealthadultsanddiabetes30%functionisnecessaryK+channelblockerItbindstosulfonylureasreceptorofBcell(ATP-sensitivepotassiumchannel)andinhibitstheeffluxofpotassiumionsthroughthechannel,andresultsindepolarization.Openavoltage-gatedcalciumchannelandresultsincalciuminflux,insulinrelease.

2.Enhancethesensitivityoftargetcelltoinsulin3.Decreasebindingofinsulintoplasmaprotein4.Increasesomatostatinreleaseandinhibitglucagonrelease刺激胰岛素分泌降低肝糖生成增加葡萄糖摄取胰腺刺激胰岛

细胞分泌胰岛素肌肉肝脏血糖控制磺脲类药物的作用机制(一)磺脲类药物的作用机制(二)葡萄糖ATP敏感的K+通道关闭GLUT-2胰岛素Ca2+通道开放胰岛素葡萄糖6-磷酸葡萄糖葡萄糖激酶去极化细胞排颗粒作用颗粒转位K+通道关闭糖酵解K+ATP去极化K+磺脲类药物磺脲类药物的受体ClinicalUsesNIDDM；Diabetesinsipidus:chlorpropamideAdverseReactionsRash,photosensitivedermatitisGranulocytopenia

Cholestasisjaundice,hepaticlesion3.HypoglycemiaPeriodicinspection：HepaticfunctionHemogram1.Gastrointestinaltract2.Hypersensitivereaction（1-2m）DrugInteraction1.Plasmaproteinbinding：salylicacid,sulfanilamide,butalidon,dicoumarinandmethotrexate2.Inhibitorsofdrug-metabolizingenzymes：chloromycin,INH3.Thiadiazides,corticosteroids:decreasetheeffectsofsulfonylureasItisasthesameassulfonylurea,blockK+channelandstimulateβcelltoreleaseinsulin.Repaglinide（瑞格列奈）Biguanidecompoundsphenformin(苯乙双胍，苯乙福明，降糖灵)metformin(二甲双胍，甲福明，降糖片)Itisnoeffectstohealthadult.Pharmacological

Actions1.Inhibittheabsorptionofglucosefromsmallinstestinal2.Enhanceintakeandutilazation,promoteanaerobicglycolysis（无氧糖酵解）ofmuscle3.Inhibitthereleaseofglucagon4.Inhibitglyconeogenesis5.Enhancethesensitivityoftargetcelltoinsulin，inhibitinsulinantagonist；6.LowerthelevelofLDLandVLDL（metformin）ClinicalUsesNIDDM：mildcase，corpulentsufferer（肥胖患者）；ArtherosclerosisAdverseReaction1.Digestivetract2.Ketonuria,lacticemia：promoteanaerobicglycolysis,producelacticacidα-GlucosidaseinhibitorsAcarbose（阿卡波糖）DecreasepostprandialglucoseItreducesintestinalabsorptionofstarch,dextrin（糊精）anddisaccharides（双糖）byinhibitingtheactionofintestinalbrushborderα-glucosidase.

Inhibitionofthisenzymeslowstheabsorptionofcarbohydrates;thepostprandialriseinplasmaglucoseisbluntedinbothnormalanddiabeticsubjects.ClinicalUses

Allsortsofdiabetes，corpulentsuffererEuglycemicAgentsthiazalidinedione

(噻唑烷二酮)Include：troglitazone（曲格列酮）rosiglitazone（罗格列酮）pioglitazone（吡格列酮）

Pharmacologi