抗糖尿病藥-胰島素與口服降血糖藥課件

抗糖尿病藥-胰島素與口服降血糖藥抗糖尿病藥－胰島素與口服降血糖藥

抗糖尿病藥-胰島素與口服降血糖藥Overview糖尿病（diabetesmellitus）

Achronicconditionassociatedwithabnormallyhighbloodsugar.Resultsfromeitherdeficiencyoforaresistancetoinsulin-ahormoneproducedbythepancreaswhosefunctionistolowerbloodsugar.抗糖尿病藥-胰島素與口服降血糖藥Overviewmorbidity：

300,000people－→>0.67％

40yearsold―→2.53％199425~64yearsold－→2.51％199620~75yearsold－→3.21％1997―→13,500,000people(allovertheword)Prediction:2025―→>30,000,000people抗糖尿病藥-胰島素與口服降血糖藥OverviewCausebymanyofreasons――chronichyperglycemia－→metabolicdisorderHyperglycemia――agroupofdiseasescharacterizedbyhighlevelsofbloodglucoseresultingfromdefectsininsulinproduction,insulinaction,orboth.Insulin:Bcells――synthesis－→secretion――bloodcirculation－→targetcells－→bindingwithinsulinreceptor－→intracellularsubstancemetabolismanylinkgoingwrong－→diabetesmellitus抗糖尿病藥-胰島素與口服降血糖藥OverviewDiabetesMellitus

――long-termdisease――multisystemdamage－→functionaldefectandfailureSevere－→diabeticketoacidosis－→comaEtiopathogenisis――heredity,autoimmunity,environmentalfactorDiagnosis：urineglucose,bloodglucose抗糖尿病藥-胰島素與口服降血糖藥OverviewTherapy:earlytreatment,longtermtherapy,combinedtherapyandtherapeuticmeasureindividualizationPurpose：bloodglucose－→normal,tocorrectmetabolicdisorder,increaseinlifespan,decreasedeathPrinciple：persevere(cannotcure)抗糖尿病藥-胰島素與口服降血糖藥OverviewDrinkandfood：grosscalorificvalueKg＝height－105DailyKg＝105～125.5K（25～30Kcal）(25～40Kcal)Therapy：beforemeals抗糖尿病藥-胰島素與口服降血糖藥SubstanceMetabolicDisorderandClinicalSituationofDiabeticglucoseutilizationdisorder→glucosedecompositiondecrease→energyinsufficient→starvationcondition

→polyphagiahyperglycemia→glucosuria→hypertonicitydiuresis→polyuriaproteindegradationaccentuation┤↓athrepsydehydrationthirst→polydipsia↓

lipolysisexcessivehyperosmolarnonketoticdiabeticcomaketonurialipolysisexcessive→ketoplasiaexcessive→Ketonemia→acidosiscoma抗糖尿病藥-胰島素與口服降血糖藥ClassificationofDiabetesMellitus(WHO1998)TypeⅠ:

insulindependentdiabetesmellitus，IDDMTypeⅡ:

non-insulindependentdiabetesmellitus，NIDDMOthers：

secondarydiabetes抗糖尿病藥-胰島素與口服降血糖藥

DiabetesMellitusType1Diabetes

-cellsthatproduceinsulinaredestroyed -resultsininsulindependence -commonlydetectedbefore30Type2Diabetes -bloodglucoselevelsrisedueto 1)Lackofinsulin production 2)Insufficientinsulin action(resistantcells) -commonlydetectedafter40 -effects>90% -eventuallyleadstoβ-cellfailure(resultingininsulindependence)GestationalDiabetes

3-5%ofpregnantwomenintheUSdevelopgestationaldiabetes抗糖尿病藥-胰島素與口服降血糖藥Diabetes-InsulinDiscoveredin1921byBantingandBestConsistofA&Bchainslinkedby2disulfidebonds(plusadditionaldisulfideinA)~

~

~

A=21aminoacids

B=30aminoacids抗糖尿病藥-胰島素與口服降血糖藥Diabetes–Insulin

(synthesis,storage,secretion)ZnProducedwithinthepancreasbyβcells

isletsofLangerhansinsulinmRNAistranslatedasasinglechainprecursorcalledpreproinsulinremovalofsignalpeptideduringinsertionintotheendoplasmicreticulumgeneratesproinsulinWithintheendoplasmicreticulum,proinsulinisexposedtoseveralspecificendopeptidaseswhichexcisetheCpeptide,therebygeneratingthematureformofinsulinStoredasβgranules抗糖尿病藥-胰島素與口服降血糖藥Diabetes–Insulin

(BiochemicalRole)TyrosineKinasereceptorsarethelocksinwhichtheinsulinkeyfits-Involvedinsignal

transduction(insulinhormonebeing1stmessenger)抗糖尿病藥-胰島素與口服降血糖藥Diabetes–Insulin

(Mechanism)抗糖尿病藥-胰島素與口服降血糖藥Stage1Insulinwasextractedfromtheglandsofcowsandpigs.(1920s)Stage2Convertpiginsulinintohumaninsulinbyremovingtheoneaminoacidthatdistinguishesthemandreplacingitwiththehumanversion.Insulindrugevolution抗糖尿病藥-胰島素與口服降血糖藥Stage3InsertthehumaninsulingeneintoE.coliandculturetherecombinantE.colitoproduceinsulin(tradename=Humulin?).Yeastisalsousedtoproduceinsulin(tradename=Novolin?)(1987).RecombinantDNAtechnologyhasalsomadeitpossibletomanufactureslightly-modifiedformsofhumaninsulinthatworkfaster(Humalog?andNovoLog?)orslower(Lantus?)thanregularhumaninsulin.抗糖尿病藥-胰島素與口服降血糖藥PhysiologicaldispositionofinsulinInsulinmustbeadministeredparenterally,usuallybys.c.injection.Itismetabolisedbytheliverandthekidneyandhasahalf-lifeof9-10minutes.Toextenditsperiodofaction,showreleasepreparationshavebeendeveloped.抗糖尿病藥-胰島素與口服降血糖藥Typesofinsulin

Regularinsulin

InsulinanalogsPre-mixedinsulinShortpeptidemimicsInsulinaffectsmanyorgans:

Itstimulatesskeletalmusclefibers.Itstimulateslivercells.ItactsonfatcellsItinhibitsproductionofcertainenzyme.Ineachcase,insulintriggerstheseeffectsbybindingtotheinsulinreceptor.glucoseuptakeglycogensynthesisproteinsynthesis

aminoacidsuptake

enzymeproductionglycogenbreakingfatsynthesis抗糖尿病藥-胰島素與口服降血糖藥ThePharmacologicalActionofInsulinItallowstheactiveuptakeofglucoseanditsutilisationinmuscleandfatcells.Itstimulatessynthesisofglycogenintheliver.Itinhibitsformationofglucose(gluconeogensis)intheliver.Itinhibitsbreakdownoflipids.Itstimulatesproteinsynthesis.Itstimulatessomecelliontransportmechanisms(e.g.Na+/K+-ATPase).抗糖尿病藥-胰島素與口服降血糖藥Whoneedinsulinmedicine?TypeI(insulindependent)diabetespatientswhosebodyproducesnoinsulin.Type2diabetespatientsthatdonotalwaysproduceenoughinsulin.diabeticketoacidosis,hypertonicityhyperglycemiacomaandlacticacidosisaccompanywithhyperglycemiadiabetesmellitusaccompanywithsevereinfection,wastingdisease,hyperpyrexia,pregnancy,woundandoperation.secondarydiabetesiscausedbypancreatectomy.抗糖尿病藥-胰島素與口服降血糖藥PreparationsandClinicalUseofinsulinShort-actingpreparations.Intermediateactingpreparations.Longactingpreparations.Newvery-short-andvery-long-actinginsulinanalogues.抗糖尿病藥-胰島素與口服降血糖藥抗糖尿病藥-胰島素與口服降血糖藥InsulinRegimensDoseandchoiceofpreparationsmustbedeterminedforeachpatientindividually.Manypatientswillmonitortheirbloodglucoseathomeandmakeminoradjustmentsindoseaccordingly.抗糖尿病藥-胰島素與口服降血糖藥InsulinRegimensDiabeticKetoacidosisanddiabeticcoma:Insulin(S.C.Injection)willbegiventolowerbloodsugarandtopreventfurtherketoneformation.Oncebloodglucoselevelshavefallento250mg,additionalglucosemaybegiventoallowcontinuedinsulinadministrationwithouthypoglycemia(lowbloodsugar).抗糖尿病藥-胰島素與口服降血糖藥InsulinRegimensHyperpotassaemia:Insulincoadminidtratewithglucose（helpK＋getintocell）(1)PreventionandTreatmentofarrhythmiacausedbymyocardialinfarction.

thecombinationtreatmentofinsulin,glucoseandKCl(2)

Insulinshocktherapyhasbeenusedtotreatschizophrenia.抗糖尿病藥-胰島素與口服降血糖藥AdverseEffectsHypoglycemia

AllergicreactionInsulinresistanceHypokalemia

Lipoatrophy抗糖尿病藥-胰島素與口服降血糖藥AdverseEffects1.Allergicreaction:foreignproteinenterintohumanbodyInsulinhasantigenicity,theslightreactionincludeslocalswelling,itch,ache.Itrarelyoccursurticaria,angioedemaandanaphylacticshock.Itoftenusesantihistaminedrugandadrenalcortexhormonetotreatwithsevereallergicreaction，andthesepatientsshouldchangetousehighpurityinsulinorhumaninsulin.抗糖尿病藥-胰島素與口服降血糖藥AdverseEffects2.Hypoglycemia

（themostcommonandseriousadverse）Itistheresultofanimbalancebetweenglucoseintake(e.g.missingameal),glucoseutilisation(e.g.unusualexercise)andinsulindose.Theresultissympatheticactivationandneuroglycopenia.抗糖尿病藥-胰島素與口服降血糖藥AdverseEffectsPatientsandtheirfamiliesshouldbetrainedtospotthewarningsignsandhowtotreathypoglycaemia,includingpossiblyadministrationofglucagonifthepatientlosesconsciousness.Treatmentisbyadministrationofcarbohydrateorallytoaconsciouspatient,ori.v.glucoseori.m.glucagon.抗糖尿病藥-胰島素與口服降血糖藥AdverseEffects4.Hypokalemia:mayoccurintheacidosispatientswhousealotofinsulinandglucose,itcanleadtothepatientdeathwithabnormalheartbeat.5.Lipoatrophy:

istheatrophyorhypertrophyoffatatthesiteofinjection.抗糖尿病藥-胰島素與口服降血糖藥InsulinResistance(INR)

Insulinresistanceisaprominentfeatureinobeseindividualsandinnon-insulin-dependentdiabetes.Someresistancemaybecausedbydefectsinbindingofinsulin.OtherpossiblemechanismsincludesecretionofanabnormalB-cellsecretoryproductorthepresenceofcirculationinsulinantagonists.抗糖尿病藥-胰島素與口服降血糖藥Diabetes-InsulinActionEnhancersRosiglitazone（羅格列酮）Pioglitazone(吡咯列酮)

抗糖尿病藥-胰島素與口服降血糖藥TheActionofInsulinActionEnhancersImproveinsulinresistance，decreasehyperglycemia.Improvefatmetabolismdisorder.PreventandtreatthebloodvesselcomplicationoftypeIIdiabetesmellitus.

ImprovepancreaticBcellfunction.

抗糖尿病藥-胰島素與口服降血糖藥Diabetes–OralMedicationsSulfonylureasBiguanidesSulfonylureasandbiguanidecombinationdrugsThiazolidinedionesAlpha-glycosidaseinhibitorsMeglitinides抗糖尿病藥-胰島素與口服降血糖藥OralAutidiabeticDrugsSulfonylureas(磺酰脲類)

甲苯磺酰脲（Tolbutamide）氯磺丙脲（Chlorpropamide）優(yōu)降糖（Glibouclamide

格列本脲）格列吡嗪（Glipizide吡磺環(huán)己脲）格列齊特（Gliclazipe

達美康）糖適平（Glurenorm）抗糖尿病藥-胰島素與口服降血糖藥OralAutidiabeticDrugsBiguanides(雙胍類）苯乙雙胍（Phenformin

苯乙福明）二甲雙胍（Metformin甲福明）α-glucosidaseinhibiors(α-葡萄糖苷酶抑制劑)阿卡波糖（Acarbose）抗糖尿病藥-胰島素與口服降血糖藥Sulfonylureas[physiologicaldisposition]

Thesulfonyureasareadministeredorallyandundergovaryingdegreesofhepaticmetabolismandrenaleliminationoftheparentcompoundandmetabolites.Mostofthesulfonylureasaremetabolizedtoinactiveorlessactivecompoundsintheliver.抗糖尿病藥-胰島素與口服降血糖藥TheMechanismofActionSulfonylureasinteractwithreceptorsonpancreaticb-cellstoblockATP-sensitivepotassiumchannels.This,inturn,leadstoopeningofcalciumchannels.Whichleadstotheproductionofinsulin.抗糖尿病藥-胰島素與口服降血糖藥ThePharmacologicalEffectofSulfonylureas

1.HypoglycemicActivity

Sulfonylureasactprimarilybyincreasingthesecretionofinsulinandsecondarilybydecreasingthesecretionofglucagon.2.Antidiuresiseffect:treatwithdiabetesinsipidus.3.Decreaseplateletadhesionreaction,stimulateplasminogensynthesis.

抗糖尿病藥-胰島素與口服降血糖藥TheClinicalApplicationofSulfonylureasDiabetesMellitus：AsulfonylureadrugisoftenusedtotreattypeIIDMthatcannotbecontrolledwithdietaryrestrictions.DiabetesInsipidus：coadministratingwithHydrochlorothiazidecanimprovetheeffect抗糖尿病藥-胰島素與口服降血糖藥AdverseEffectsofSulfonylureasHypoglycaemiaGastrointestinalupsetsHypersensitivity:rashesetc.Weightgain:stimulationofappetitecanbeaprobleminobesepatients.抗糖尿病藥-胰島素與口服降血糖藥DrugInteractionsSulfonylureasareheavilyproteinboundandtheiractionsmaybeincreasedbyotherdrugs(e.g.sulfonamides)thatcompeteforthebindingsites.抗糖尿病藥-胰島素與口服降血糖藥Biguanides[PhysiologicalDisposition]

Metforminisadministeredorallyfromtwotofourtimesadayandiseliminatedbyrenalexcretionoftheparentcompound.Itsdurationofactionisabout18hours.抗糖尿病藥-胰島素與口服降血糖藥MechanismsandPharmacologicalEffectsMetforminisnowconsideredafirst-linedrugforthetreatmentoftypeIIDM.InpatientswithtypeIIDM,italleviateshyperglycemiaprimarilybydec