胰島素及口服降糖藥幻燈片

胰島素及口服降糖藥26128胰島素及口服降糖藥

胰島素及口服降糖藥26128InsulinandOralHypoglycemicDrugs目的掌握胰島素和口服降糖藥的作用原理。臨床應(yīng)用和應(yīng)用注意，熟悉葡萄糖苷酶抑制劑的作用特點(diǎn)。胰島素及口服降糖藥26128InsulinandOralHypoglycemicDrugs內(nèi)容復(fù)習(xí)胰島素的生化，促進(jìn)肝糖元生成和糖酵解，調(diào)節(jié)機(jī)體糖的代謝。胰島素缺乏引起糖尿病，胰島素用于糖尿病只是補(bǔ)充治療。胰島素治療糖尿病的劑量原則。常用之制劑分短效（如普通胰島素）。中效（如低精蛋白鋅胰島素）。長效（如精蛋白鋅胰島素）的原理和選用原則。不良反應(yīng)和應(yīng)用注意。胰島素及口服降糖藥26128InsulinandOralHypoglycemicDrugs口服降血糖藥有兩類：磺酰脲類有甲苯磺丁脲，氯磺丙脲和格列苯脲（優(yōu)降糖）。能刺激胰島

細(xì)胞釋放胰島素，只對胰腺功能未完全喪失的患者有效。雙胍類于胰腺功能完全喪失的患者有效。引起乳酸性酸血癥。胰島素及口服降糖藥26128InsulinandoralhypoglycemicdrugsGeneralconsiderationsInsulinInsulinactionenhancerOralhypoglycemiaagents胰島素及口服降糖藥26128GeneralconsiderationsClassificationofdiabetesmellitusInsulin-dependentdiabetesmellitus,IDDM,Ⅰtype,Non-insulin-dependentdiabetesmellitus,NIDDM,Ⅱtype,胰島素及口服降糖藥26128GeneralconsiderationsIntroductionDiabetesmellitusinvolvesnotonlyadeficiencyofinsulinbutalsoanexcessofcertainotherhormones,suchasgrowthhormone,glucocorticoidsandglucagons.胰島素及口服降糖藥26128Generalconsiderationsnotonlythepancreasisinvolvedinglucosehomeostasis,butalsotheanteriorpituitaryglandandtheadrenalcortex.

胰島素及口服降糖藥26128Generalconsiderations3.EtiologyofdiabetesmellitusItiscurrentlybelievedthatthejuvenile-onset(insulin-dependent)fromhasanautoimmuneetiology.

Virusesmayalsoplayaroleintheetiologyofdiabetes.胰島素及口服降糖藥26128GeneralconsiderationsCoxsackieB,mumpsandrubellavirusesallhavebeenshowntoproducemorepathologicchangesintheislet-cellstructure.Thegeneticroleintheetiologyofdiabetesiscontroversial.Possiblyagenetictraitmakesanindividual’spancreasmoresusceptibletooneoftheaboveviruses.胰島素及口服降糖藥26128InsulinandoralhypoglycemicdrugsGeneralconsiderationsInsulinInsulinactionenhancerOralhypoglycemiaagents胰島素及口服降糖藥26128Insulin

ChemistryofinsulinClassificationofinsulinpreparationPharmacokineticsPharmacodynamics胰島素及口服降糖藥26128InsulinChemistryofinsulinInsulinisasmallproteinwithamolecularweightinhumansof5808.itcontains51aminoacidsarrangedintwochains(AandB)linkedbydisulfidebridges,therearespeciesdifferencesintheaminoacidsofbothchains.胰島素及口服降糖藥26128InsulinProinsulin,insulinprecursor,isprocessedwithintheGolgiapparatusandpackagedintogranules.ItishydrolyzedintoinsulinandaresidualconnectingsegmentcalledtheC-peptidebyremovaloffouraminoacids.胰島素及口服降糖藥26128InsulinInsulinandC-peptidesaresecretedinequimolaramountsinresponsetoallinsulinsecretagogues,asmallquantityofunprocessedorpartiallyhydrolyzedproinsulinisreleasedaswell.胰島素及口服降糖藥26128InsulinClassificationofinsulinpreparationUltra-short-actingShort-acting

Intermediate-actingLong-actingInsulinlispro,Humalog(Lilly),S.C.Regularinsulin,Crystallinezincinsulin,iv(emergence),S.C.Isophaneinsulin,themostcommonused,S.C.Globinzincinsulin,S.C.Protamineinsulin,S.C.胰島素及口服降糖藥26128InsulinPharmacokineticsInsulinlisproRegularinsulin(Crystallinezincinsulin):GlobinzincinsulininjectionProtaminezincinsulin,peak

Noanyeffectwhengivenorally,allpreparationmustbegivenbyinjection.RapidabsorptionbyS.C.injection,withrapidonsetofactionandshortduration.Wheninjectedsubcutaneously,itquicklydissociatesintomonomersandisabsorbedveryrapidly,reachingpeakserumvaluesasearlyas1hour.

peakactionin2-4hrs,itsdurationis5-7hrs.Itcanbeadministeredsubcutaneouslyorintravenously.Itisagoodagentforexertingrapidcontrolfordiabeticketoacidosis.peakeffectin8-12hours,durationofaction18-24hours.actionin16-18hours,durationofaction24-36hours.

Boththeliverandthekidneyareofprimaryimportanceinthedegradationofinsulinbyaproteolyticenzyme.Eachiscapableofdestroying40%oftheinsulin.胰島素及口服降糖藥26128InsulinPharmacodynamicsPharmacologicaleffectsMechanismofactionClinicalusesAdverseeffects胰島素及口服降糖藥26128InsulinPharmacologicaleffectsMetabolismofglucoseMetabolismoffatMetabolismofproteinInsulinpromotesthestorageoffataswellasglucose(bothsourcesofenergy)withinspecializedtargetcellsandinfluencescellgrowthandthemetabolicfunctionsofawidevarietyoftissues.Bloodsugardecreases,bloodpyruvateandlactateincrease,inorgancphosphatedecreases,potassiumdecreases,Insulinpromotessynthesis(fromcirculatingnutrients)andstorageofglycogen,triglycerides,andproteininitsmajortargettissues:liver,fat,andmuscle.Thereleaseofinsulinfromthepancreasisstimulatedbyincreasedbloodglucose,vagalnervestimulation,andotherfactors.胰島素及口服降糖藥26128InsulinMechanismofaction胰島素及口服降糖藥26128InsulinClinicalusesTeatmentofdiabetesshortofpotassiuminthecellTypeⅠ(juvenile-onset,insulin–dependent)diabetesTypeⅡ(maturity-onset,non-insulin-dependent)DiabeteDiabetesaccompaniedbyotherdisease,suchasfever,seriousinfection,operation,trauma,pregnancy,andsoon.Ketoacidosisandhyperosmoticnonketoniccoma.Beadministeredsolutionwhichcontainsglucose,insulin,andpotassiumchloride.胰島素及口服降糖藥26128InsulinAdverseeffectsHypoglycemiaInsulinallergyLocalreactionsImmuneinsulinresistanceEarlysymptoms:sweating,tremor,anxiety,tachycardiaandhungerfeeling.severesymptomsincludementalconfusion,convulsion,andultimatelycomaanddeath.Itisbesttreatedbyadministeringglucoseorbygivingfruitjuiceoranysugar-containingbeverageorfood.Ifnotavailable,20-50mlof50%glucosesolutionbyiv.overaperiodof2-3minutes,or1mgglucagoninjectedeitherim.orsc.Theorderofantigenicpotency,indescendingorder,isbeef﹥pork﹥highlypurified(singlepeak)pork﹥humaninsulin.AcuteresistanceChronicresistanceItcausesextremelyhighinsulinrequirementsoftenmore200unitsdaily.Switchingtoalessantigenic(porkorhuman)purifiedinsulinmaymakepossibleadramaticreductionininsulindosageormayatleastshortenthedurationofimmuneresistance.Irritationatthesiteofinsulininjectioncanleadtolipodystrophyandhypertrophy.Siteofinjectionshouldberotated.胰島素及口服降糖藥26128InsulinandoralhypoglycemicdrugsGeneralconsiderationsInsulinInsulinactionenhancerOralhypoglycemiaagents胰島素及口服降糖藥26128InsulinactionenhancerTypeofinsulinresistanceDrugsEffectsandmechanismofactionClinicalusespharmacokineticsAdverseeffects胰島素及口服降糖藥26128InsulinactionenhancerTypeofinsulinresistanceAcquiredinsulinresistanceⅠtypediabetesmellitusHereditaryinsulinresistanceⅡtypediabetesmellitus胰島素及口服降糖藥26128InsulinactionenhancerDrugsRosiglitazone,羅格列酮Pioglitazone,比格列酮Troglitazone,曲格列酮*Ciglitazone,西格列酮,1999,Englitazone,恩格列酮,1999,胰島素及口服降糖藥26128InsulinactionenhancerEffectsandmechanismofactionThiazolidinediones(TDs)compoundsarearecentlyintroducedclassoforalantidiabeticdrugsthatenhancetargettissueinsulinsensitivity.胰島素及口服降糖藥26128InsulinactionenhancerTheyhaveanacutepost-receptorinsulin-mimeticactivityaswellaschroniceffectsonthetranscriptionofgenesinvolvedwithglucoseandlipidmetabolismmediatedthroughtheperoxisomeproliferator-activedreceptor-γ-nuclearreceptor.胰島素及口服降糖藥26128InsulinactionenhancerDimishinsulinresistancebyincreasingglucoseuptakeandmetabolisminmuscleandadiposetissues,restrainhepaticgluconeogenesisandexertadditionaleffectsonlipidmetabolism,systemicbloodpressureandthefibrinolyticsystem.胰島素及口服降糖藥26128InsulinactionenhancerWhenusedalone,theycanrestoreglucoselevelsintothenormalornondiabeticrangewithoutcausinghypoglycemia.ChronictherapyisassociatedwithadropintriglyceridelevelsandaslightriseinHDLandLDLcholesterolvalues.胰島素及口服降糖藥26128InsulinactionenhancerClinicaluseUseintype2diabetesasmonotherapyorincombinationwithabiguanide.胰島素及口服降糖藥26128InsulinactionenhancerpharmacokineticsmetabolizedthroughthehepaticcytochromeP450system,andtheirinductionofdifferentpathwaysmayaffectthebioavailabilityofothermedicationssuchasoralcontraceptives.胰島素及口服降糖藥26128InsulinactionenhancerAdverseeffectAnadverseeffectcommontoalltheagentsismildanemia.Edema,hypoglycemia.胰島素及口服降糖藥26128InsulinandoralhypoglycemicdrugsGeneralconsiderationsInsulinInsulinactionenhancerOralhypoglycemiaagents胰島素及口服降糖藥26128OralhypoglycemiaagentsClassificationPharmacokineticsPharmacodynamics

胰島素及口服降糖藥26128OralhypoglycemiaagentsClassificationSulfonylureasBiguanides-glucosidaseinhibitors胰島素及口服降糖藥26128OralhypoglycemiaagentsSulfonylureasFirst-generationsulfonylureasSecond-generationsulfonylureasThird-generationsulfonylureasNotonlydecreasebloodglucoselevelbutalsoimprovethefunctionofbloodplateletGliclazipe,格列齊特,達(dá)美康

Gliquidone,格列喹酮Themoreefficacious,thefeweradverseeffectsthanfirst-generationGlibenclamide,格列本脲，優(yōu)降糖Glipizide,吡磺環(huán)己脲Glimepiride,格列美脲Wellabsorbed,rapidlyorslowlymetabolizedintheliver,t1/2=4-5or32hours,excretionbykidney

Tolbutamide,D860甲苯磺丁脲

Chlorpropamide,氯磺丙脲胰島素及口服降糖藥26128OralhypoglycemiaagentsPharmacokineticsWellabsorptionorallyadministration,highbloodproteinbindingrate,metabolismintheliver,metabolizedandoriginalproductionexcretionbykidney,胰島素及口服降糖藥26128OralhypoglycemiaagentsPharmacodynamicsMechanismEffectsClinicaluseAdverseeffects胰島素及口服降糖藥26128OralhypoglycemiaagentsMechanismInsulinreleasefrompancreaticβcellsReductionofserumglucagonconcentrationsPotentiationofinsulinactionontargettissues.胰島素及口服降糖藥26128OralhypoglycemiaagentsEffectsDecreasebloodglucoselevelPromoteADHsecretionandenhanceitseffectsDecreasethefunctionofbloodplatelets胰島素及口服降糖藥26128OralhypoglycemiaagentsClinicaluseusedinthetreatmentofpatientswhohavenon-insulin-dependentdiabetesandwhocan’tbetreatedwithdietaloneorwhoareunwillingtotakeinsulinifdietarycontrolfails.胰島素及口服降糖藥26128OralhypoglycemiaagentsTheuseoftheseagentswasassociatedwithahighercardiovascularmortalityratethanthatoccurringwithdietarycontrolaloneorwithinsulintherapy.Nostudytodatehasdemonstratedthatsulfonylureaagentspreventthelong-termcomplicationsofdiabetes.胰島素及口服降糖藥26128OralhypoglycemiaagentsDiabetes(尿崩癥)Chlorpropamide,氯磺丙脲胰島素及口服降糖藥26128OralhypoglycemiaagentsUntowardeffectsHypoglycemiacanoccurinpatientswithhepaticorrenalinsufficiencybecausetheagentwillhavealongerthanexpecteddurationofaction.

Cutaneousreactionsincluderashesandphotosensitivity.Gastrointestinalreactionsincludenauseaandvomiting.

Hematologicreactionsleukopenia,agranulocytosis,thrombocytopenia,pancytopeniaandhemolyticanemiahaveoccurred.Transientcholestaticjaundice

InappropriatesecretionofAntidiuretichormone

胰島素及口服降糖藥26128OralhypoglycemiaagentsBiguanidesPharmacodynamicsCurrentlyproposedmechanismsofactionincludeClinicaluseAdverseeffects.Metformin,甲福明，二甲雙胍Phenformine,苯乙福明，苯乙雙胍胰島素及口服降糖藥26128OralhypoglycemiaagentsPharmacokineticsMetforminhasahalf-lifeof1.5-3hours,isnotboundtoplasmaproteins,isnotmetabolized,andisexcretedbythekidneysastheactivecompound.胰島素及口服降糖藥26128OralhypoglycemiaagentsPhenforminisboundtoplasmaprotein.Thehalf-lifeisapproximately11hours.Inpatientswithrenalinsufficiency,unmetabolizedphenforminaccumulatesinhighconcentration.胰島素及口服降糖藥26128OralhypoglycemiaagentsAsaconsequenceofmetformin’sblockadeofgluconeogenesis,thedrugmayimpairthehepaticuptakeoflacticacid,increasetheriskoflacitcacidosis,adose-relatedcomplication.胰島素及口服降糖藥26128OralhypoglycemiaagentsPharmacodynamicsTheirbloodglucose-loweringactiondoesnotdependentonthepresenceoffunctioningpancreaticβcells.胰島素及口服降糖藥26128OralhypoglycemiaagentsCurrentlyproposedmechanismsofactioninclude:Directstimulationofglycolysisintissues,withincreasedglucoseremovalfromblood胰島素及口服降糖藥26128OralhypoglycemiaagentsReducedhepaticgluconeogenesisSlowingofglucoseabsorptionfromthegastrointestinaltract,withincreasedglucosetolactateconversionbyenterocytesReductionofplasmaglucagonslevels.胰島素及口服降糖藥26128OralhypoglycemiaagentsClinicaluseHyperglycemiapatientswithrefractoryobesityduetoineffectiveinsulinaction.Combinewithsulfonylureasisusedinnon-insulin-dependentdiabeticsinwhomsulfonylureatherapyaloneisinadequate.胰島素及口服降糖藥26128OralhypoglycemiaagentsAdverseeffects.Lacticacidosisisthemostseriousuntowardeffect.Themostfrequenttoxiceffectsofmetforminaregastrointestinal(nausea,vomiting,diarrhea).胰島素及口服降糖藥26128Oralhypoglycemiaagents

-glucosidaseinhibitorsAcarbose(阿卡波糖)Voglibose(伏格列波糖)Onlymonosaccharides,suchasglucoseandfructose,canbetransportedoutoftheintestinallumenandintothebloodstream.胰島素及口服降糖藥26128OralhypoglycemiaagentsComplexstarches,oligosaccharides,anddisaccharidesmustthereforebebrokendownintoindividualmonosaccharidemoleculesbeforebeingabsorbedintheduodenumandupperjejunum.胰島素及口服降糖藥26128Oral