药理学教学课件：8 hypoglycemic drugs 7+8 3

InsulinandAntidiabeticDrugs

Diabetesmellitus(DM)isametabolicdisordercharacterizedbyhyperglycaemia,glycosuria,andhyperlipemiaresultfromabsentorinadequatepancreaticinsulinsecretion,withorwithoutconcurrentimpairmentofinsulinaction.Twomajortypesofdiabetesmellitusare:

Type1Insulindependentdiabetesmellitus(IDDM)

Type2Noninsulindependentdiabetesmellitus(NIDDM)

Type1Insulindependentdiabetesmellitus(IDDM)Thereisβcelldestructioninpancreaticislets.Inalltype1casescirculatinginsulinlevelsareloworverylow,andpatientsaremorepronetoketosis.AdministrationofinsulinlifelongisessentialinpatientswithIDDMIDDMisfurthersubdividedintoimmuneandidiopathiccauses.TheimmuneformisthemostcommonformofIDDM.Theonsetcanoccuratanyage.Type2Noninsulindependentdiabetesmellitus(NIDDM)Ischaracterizedbytissueresistancetotheactionofinsulincombinedwitharelativedeficiencyininsulinsecretion.IndividualswithNIDDMmaynotrequireinsulintosurvive.

Generallyhasalateonset(pastmiddleage).Over90%casesaretypeⅡDM.ComparisonofType1andType2diabetesClassificationinsulininsulin-secretingagentsBiguanidesinsulinsensitizerothers

Ⅰ.

Insulin

Insulinisa51-aminoacidpeptidemadeupofanα-andaβ-chainlinkedbydisulphidebonds.Insulinissynthesizedintheβcellsofpancreaticislets.MW:5808

Insulinpreparations:

Theconventionalcommercialpreparationsofinsulinarederivedfrombeefandporkpancreas.short-,intermediate-andlong-actingpreparationsShort-actinginsulins

aresolubleandthepresenceofZn2+inthesolutionmaintainsthesolubility.Thesepreparationsmostresembleendogenousinsulin.Regularinsulin

isgivenS.C.(orivinemergencies)2-3timesdaily.Itrapidlylowersbloodglucose.

Intermediate-actinginsulins

Neutralprotaminehagedorn(NPH)insulinisasuspensionofcrystallinezincinsulincombinedatneutralpHwithapositivelychargedpolypeptide,protamine.Itsdurationofactionisintermediate.

NPHinsulinshouldonlybegivensubcutaneously(neveriv).Itisusuallymixedwithregularinsulinandgiven2-4times/dforinsulinreplacementinIDDM.

Long-actinginsulin

Ultralenteinsulin,

Protaminezineinsulin

rarelyused

MonocomponentinsulinMcIRouteofadministration:

Insulinmustalwaysbegivenparenterally(intravenously,intramuscularlyorsubcutaneously),asitisapeptideandthusdestroyedinthegastrointestinaltract.Short-actinginsulinisgivenintravenouslyinemergenciesbutadministrationoftheinsulinpreparationsinmaintenancetreatmentisusuallysubcutaneous.

PendevicesFountainpenlike:useinsulincartridgesfors.c.injectionthroughaneedle.Presetamountsarepropelledbypushingaplungerortrigger;convenientincarryingandinjecting.InsulinsecretionInsulinisreleasedfrompancreaticβcellsatlowbasalrateandatamuchhigherstimulatedrateinresponsetoavarietyofstimuli,especiallyglucose.Otherstimulantssuchasothersugars(eg.mannose),certainaminoacids(eg.Leucine,arginine),andvagalactivityarerecognized.Effectsofinsulin:

Carbohydrate:

Insulinfacilitatesglycogensynthesisfromglucoseinliver,muscleandfatbystimulatingtheglycogensynthetase.Insulininhibitphosphorylase→decreaseglycogenolysisinliver.

Insulinalsoinhibitsgluconeogenesis(fromprotein,FFAandglycerol)inliver.

Protein:InsulinfacilitatesAAsynthesisintoproteinsandinhibitproteinbreakdowninmuscleandmostcells.Insulindeficiencyleadstoproteinbreakdown

→AAsarereleasedinblood→takenupbyliverandconvertedtopyruvate,glucoseandurea.Theexcessureaproducedisexcretedinurineresultinginnegativenitrogenbalance.Adiposetissue:

InhibitlipolysisIncreasetriglyceridesynthesisandstorage.decreaseproductionoffreefattyacidandketonebody.Mechanismofaction

Insulinactsonspecificreceptorslocatedonthecellmembraneofpracticallyallcells,buttheirdensitydependsonthecelltype:liver,muscleandfatcellsarerich.Theinsulinreceptorconsistoftwoα-andtwoβ-subunitslinkedbydisulphidebonds.T2DMInsulinisneededbysuchcases:Notcontrolledbydietandexerciseorwhenthesearenotpracticable.Primaryorsecondaryfailureoforalhypoglycaemicsorwhenthesedrugsarenottolerated.ClinicalUses:

T1DM

Insuliniseffectiveinallformsofdiabetesmellitusandisamustfortype1case.

Temporarilytotideoverinfections,trauma,surgery,pregnancy.Anycomplicationofdiabetes,e.g.ketoacidosis,gangreneofextremities.Wheninstituted,insulintherapyisgenerallystartedwithregularinsulingivens.c.beforeeachmajormeal.Therequirementisassessedbytestingurineorbloodglucoselevels.Diabeticketoacidosis(Diabeticcoma)

generallyoccursinIDDM,themostcommoncauseisinfection,trauma,stroke,e.g.Regularinsulinisusedtorapidlycorrectthemetabolicabnormalities;Itisvitaltocorrectdehydration,normalsalineisinfusedi.v..Adverseeffect

HypoglycemiaThemostfrequentandpotentiallythemostseriousreaction.sympatheticsymptoms,parasympatheticsymptoms,mayprogresstoconvulsionsandcomaifuntreated.Simplesugarandglucosemustbegivenorallyori.v.(forseverecases)—reversesthesymptomsrapidly.Adverseeffect

AllergicreactionsThisisduetocontaminatingproteins;veryrarewithhuman/highlypurifiedinsulins.

LipoatrophyLipoastrophyisalocalatrophyofsubcutaneousfattytissueatthesiteofinjections.Thisisnotseenwithmorepurifiedinsulin--whichmayevenfacilitatereversaloflipoatrophywheninjectedatthesamesites.Adverseeffect

Insulinresistance

InsulinrequirementisincreasedAcute—developsrapidlyandisusuallyashorttermproblem.Treatmentistoovercometheprecipitatingcauseandtogivehighdosesofregularinsulin.Chronic—seeninpatientstreatedforyears.ItismorecommoninNIDDM.Treatmentistousethemorepurifiedinsulinpreparation.Ⅱ.OralHypoglycemicDrugsinsulin-secretingagents:

sulfonylureas

non-sulfonylureas(e.g.repaglinide)

agonistofglucagons-likepeptide1(GLP-1)

antagonistofdipeptidylpeptidaseIV(DPP-IV)2.Biguanides3.insulinsensitizer4.others1.Sulfonylureas

First-generation:

Tolbutamide

chlorpropamideSecond-generation:

glyburideglipizideThird-generation:

gliclazideActions:Increasereleaseofinsulinfrompancreas

IncreaseinperipheralinsulinsensitivityReduceserumglucagonlevelsIndications

:

Sulfonylureasaregivenfordiabetesmellitus,inpatientswithsomeβ-cellsactivity

urorrhagia(chlorpropamidesensitizesthekidneytoADH)

Adverseeffects:

Nonspecificsideeffectsnausea,vomiting,diarrhoeaorconstipation,headache,weightgain.

Adverseeffects:

HypoglycaemiaItismorecommonprobleminelderly,liverandkidneydiseasepatients.Treatment–giveglucose,maybeforfewdaysbecausehypoglycaemiamayrecur.

HypersensitivityTolbutamide:

islesspopularduetolowpotency,butmaybeemployedintheelderlytoavoidhypoglycaemia.Chlorpropamide:isnotrecommendedbecauseoflongdurationofaction,greaterriskofhypoglycaemiaandotheradverseeffects.Glipizide:aresuitableformostpatients.Gliclazide:ispreferredwhenafasterandshorteractingdrugisrequired.Non-sulfonylureas(repaglinide)

Mechanism

:

notSulphonylureasbutactsinananalogousmannerbybindingtosulphonylureareceptor→blockATP-dependentpotassiumchannelsinthemembraneofthepancreaticβ-cells,causingdepolarization,calciuminfluxandinsulinrelease.Repaglinideinducesrapidonsetshortlastinginsulinrelease.Itisadministeredbeforeeachmajormealtocontrolpostprandialhyperglycaemia.usedinNIDDM.Sideeffectsaremildheadache,dyspepsiaandweightgain.Theincidenceofhypoglycemiaappearstobelowerthanthatwiththesulfonylureas.2.Biguanides

Metformin

differmarkedlyfromsulfonylureas:causelittleornohypoglycaemiainnondiabeticsubjectsanddonotstimulatepancreaticβ

cells.Mechanism

Metforminincreasestheperipheralutilizationofglucosebyincreasinguptakeanddecreasesgluconeogenesis.

Mechanism

suppresshepaticgluconeogenesisandglucoseoutputfromliver:themajoraction.enhanceinsulinmediatedglucosedisposalinmuscleandfat.increasestheperipheralutilizationofglucosebyenhancinganaerobicglycolysis.inhibitintestinalabsorptionofglucose,aminoacidsandvitB12.Indications:

MetforminisgivenforT2DMwheredietingandsulphonylureashavebeenprovedineffective.thebestuse:obeseperson(Thepatientoftenlosesweightbecauseoflossofappetite)Adverseeffects:

anorexia,nausea,vomiting,headacheLacticacidosisisthemostseriouscomplication.VitB12deficiency

3.InsulinsensitizerThiazolidinediones(e.g.rosiglitazone)

Action:

ChangeinsulinresistanceanddecreasesugarlevelChangefatmetabolism-lowersserumtriglyceridelevelandraisesHDLlevel.

Improveβcellfunction

Mechanismofaction:

Selectiveagonistforthenuclearperoxisomeproliferator-activatedreceptorγ(PPARγ)whichenhancethetranscriptionofseveralinsulinresp