利尿藥和降血糖藥Medicinalchemistry利尿藥和降血糖藥Chapter10Diureticsand

SyntheticHypoglycemicDrugsSection1HypoglycemicDrugsSection2Diuretics利尿藥和降血糖藥Section1

HypoglycemicDrugsTheclassictriadofsymptomsindiabetesispolyphagia,polydypsia(thirst),andpolyuria(excessurine).Allthreeresultdirectlyfromexcessiveserumglucoselevels.Type1diabetesusuallydevelopsinanacutemanner,althoughthedestructiveautoimmuneprocessmayhavebeenunderwayforsometime.Type2diabeteshasamoreinsidious,oftenasymptomaticonsetanditspresenceisusuallydetectedbyroutinemedicalexaminations.利尿藥和降血糖藥Definitions

TypeIDiabetes.Insulin-dependentdiabetesmellitus(IDDM),thisconditionoccurswhentheβ-cellsofthepancreaticisletsofLangerhansaredestroyed,probablybyanautoimmuneprocess,suchthatinsulinproductionisdeficient.Type2Diabetes.Noninsulin-dependentdiabetesmellitus(NIDDM)isveryfrequentlyassociatedwithobesityinitsmainlyadultvictims.Seruminsulinlevelsarenormalorelevated,soinessencethisisadiseaseofinsulinresistance.利尿藥和降血糖藥BiochemistryandPathogenesisofDiabetes利尿藥和降血糖藥ClassificationsFirstGenerationSulfonylureas:tolbutamide.SecondGenerationSulfonylureas:glibenclamide.ThirdGenerationSulfonylureas:glimepiride,repaglinide.Biguanides:metformin.α-GlucosidaseInhibitors:Acarbose,Miglitol.利尿藥和降血糖藥

MechanismofActionSulfonylureasinteractwithreceptorsonpancreaticβ-cellstoblockATP-sensitivepotassiumchannels.Thisinturnleadstoopeningofvoltage-sensitivecalciumchannelswhichproducesaninfluxofcalcium;theinfluxofcalciumresultsinβ-cellsproductionofinsulin.Anadditionaleffectofsulfonylureasissuppressionofgluconeogenesisintheliver.利尿藥和降血糖藥

Physical-ChemicalPropertiesSulfonylureasareweakacidsduetothemarkeddelocalizationofthenitrogenloneelectronpairbythesulfonylgroup.TheirpKa'sclusteraround5.0andtheyarestronglyproteinbound.利尿藥和降血糖藥

Structure-activityRelationshipsTheremustbereasonablebulkontheureanitrogen;methylandethylcompoundsarenotactive.Usually,thereisonlyone(normallysubstituentpara)onthesulfonylaromaticring.利尿藥和降血糖藥Manysimplesubstituentsonthesulfonylaromaticringareactive.Thep-(β-arylcarboxamidoethyl)groupingseeninsecondgenerationcompoundsisconsistentwithhighpotency.Itisthoughtthatthespatialrelationshipbetweentheamidenitrogenofthesubstituentandthesulfonamidenitrogenisimportant.利尿藥和降血糖藥

TolbutamideN-[(Butylamino)carbonyl]-4-methylbenzene–sulfonamideButylgroupontheureanitrogen;Para-methylbenzeneonthesulfonylgroup.利尿藥和降血糖藥

Properties

Tolbutamidehavesulfonylureastructurewithweakacid,andthispropertymaybeusedforassay.利尿藥和降血糖藥Instability:Tolbutamideishydrolyzedtopara-toluenesulfonamidebyacids.Heatingofitsfiltratewithsodiumhydroxidesolutionproducesn-butylamineodour.利尿藥和降血糖藥Metabolism

Tolbutamideismetabolizedinthelivertop-hydroxyltolbutamide,retainingabout35%oftheactivityoftheparentcompound.itisconvertedveryrapidlytotheinactivetolbutamide4-carboxylicacid.利尿藥和降血糖藥Glibenclamide5-Chloro-N-[2-[4-[[[(cyclohexylamino)carbonyl]amino]sulfonyl]phenyl]-2-methoxybenzamideIntroductionofcyclohexaneontheureanitrogen;Introductionofsidechainonthesulfonylaromaticring.

利尿藥和降血糖藥Properties

Itisnotstabletomoistureandishydrolyzedtosulfamidederivate.利尿藥和降血糖藥MetabolismGlibenclamideaffordstrans-4'-hydroxy-glyburideasthemajorproduct.The3'-hydroxymetaboliteretainsabout15%oftheactivityoftheparentcompound.利尿藥和降血糖藥TherapeuticApplicationIngeneral,theeffectsofthefirst-andsecond-generationsulfonylureasaresimilar.Allproducereliablehypoglycemiaintype2diabetics.Theseagentsworkbestinpatientswhosetype2diabetesisrelativelymild.利尿藥和降血糖藥SyntheticRoute利尿藥和降血糖藥Third-generationsulfonylureaGlimepirideisasulfonylureawithaquickonsetofactionandalongdurationofaction.Itmaybindtoadifferentproteinintheputativesulfonylureareceptorthanearlierdrugs,andmayexertitshypoglycemiceffectwithlesssecretionofinsulin.利尿藥和降血糖藥

Metforminhydrochloride

N,N-DimethylimidodicarbonimidicdiamidehydrochlorideMetformin,Biguanides,hasbeeninusethroughouttheworld,withtheexceptionoftheU.S.,fordecades.利尿藥和降血糖藥

MechanismofActionMetforminisusuallysaidtobeanantihyperglycemicratherthanahypoglycemicagent.Overall,thedrugappearstoincreaseglucoseutilization.Inhibitionofgluconeogenesisappearstobeanimportantcomponentofthedrug'sactivity.利尿藥和降血糖藥

ActionsandUsesUnlikesulfonylureas,Metforminisnotproteinbound,isnotmetabolized,andisrapidlyeliminatedbythekidney.Itiswidelyusedasmonotherapyorincombinationwithasulfonylureaintype2diabetes,particularlywhenthepatientisobeseandinsulin-resistant.利尿藥和降血糖藥

α-GlucosidaseInhibitorsTobeabsorbedfromthegastrointestinaltractintothebloodstream,thecomplexcarbohydratesweingestaspartofourdietmustfirstbehydrolyzedtomonosaccharides.Therationalefortheα-glucosidaseinhibitoristhatbypreventingthehydrolysisofcarbohydratestheirabsorptioncouldbereduced.利尿藥和降血糖藥Metabolismofcomplexcarbohydrades

利尿藥和降血糖藥

Section2DiureticsDiureticsarechemicalsthatincreasetherateofurineformation.Diureticusageleadstotheincreasedexcretionofelectrolytes(especiallysodiumandchlorideions)andwaterfromthebodywithoutaffectingprotein,vitamin,glucoseoraminoacidreabsorption.利尿藥和降血糖藥

StructureClassificationThediureticscurrentlyinusetodayareclassifiedasfollows:Thiazides(bytheirchemicalclasses);Carbonicanhydraseinhibitors,osmotics(bymechanismofaction);Loopdiuretics(bysiteofaction);Potassium-sparingdiuretics(byeffectsonurinecontents).利尿藥和降血糖藥Furosemide5-(Aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoicacidFurosemideisanexampleofahigh-ceilingdiureticandmayberegardedasaderivativeofanthranilicacids.利尿藥和降血糖藥

Structure-activityRelationshipsThechlorineandsulfonamidesubstitutionsarefeaturesofthisclassdrugs.Furosemideisastrongeracidthanthethiazidediuretics(pKa3.9).Thisdrugisexcretedprimarilyunchanged.Asmallamountofmetabolism,however,cantakeplaceonthefuranring.利尿藥和降血糖藥

TherapeuticApplicationsFurosemidehasasalureticeffect8-10timesthatofthethiazidediuretics,however,ithasashorterdurationofaction,about6-8hours.Itiseffectiveforthetreatmentofedemasconnectedwithcardiac,hepatic,andrenalsites.Clinicaltoxicityoffurosemideinvolvesabnormalitiesoffluidandelectrolytebalance.利尿藥和降血糖藥Hydrochlorothiazide6-Chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide1,1-dioxideThethiazidediureticsareweaklyacidicwithabenzothiadiaze1,1-dioxidenucleus.利尿藥和降血糖藥

MechanismofActionThemajorsiteofactionofthesecompoundsisinthedistaltubule,wherethesedrugscompeteforthechloridebindingsiteoftheNa+-C1-symporterandinhibitthereabsorptionofsodiumandchlorideions.Theyalsoinhibitthereabsorptionofpotassiumandbicarbonateionsbuttoalesserdegree.利尿藥和降血糖藥

Structure-activityRelationshipThehydrogenatomatthe2-Nisthemostacidic.Theseacidicprotonsmakepossibletheformationofawater-solublesodiumsalt.Anelectron-withdrawinggroupisnecessaryatposition6fordiureticactivity.Replacementorremovalofthesulfonamideatposition7yieldscompoundswithlittleornodiureticactivity.利尿藥和降血糖藥Saturationofthedoublebondtogivea3,4dihydroderivativeproducesadiureticthatis10timesmorethantheunsaturatedderivative.Substitutionlipophilicgroupatposition3givesamarkedinthediureticpotencywithalongerdurationofaction.Alkylsubstitutiononthe2-Npositionalsodecreasesthepolarityandincreasesthedurationofdiureticaction.利尿藥和降血糖藥TherapeuticApplicationsHydrochlorothiazideisindicatedinthemanagementofhypertensioneitherasthesoletherapeuticagent,orincombinationwithotherantihypertensives.利尿藥和降血糖藥AcetazolamideN-[5-(Aminosulfonyl)1,3,4-thiadiazol-2-yl]acetamideAcetazolamidewasthefirstofthecarbonicanhydraseinhibitorswithadiureticeffectthatlastsabout8-12hours.Itisusedprimarilyforthetreatmentofglaucomaandabsenceseizures.利尿藥和降血糖藥MechanismofActionTheactionoftheenzymecarbonicanhydrasecatalyzestheformationofcarbonicacidfromcarbondioxideandwater.Carbonicanhydraseinhibitorsinducediuresisbyinhibitingtheformationofcarbonicacidwithinproximalanddistaltubularcellstolimitthenumberofhydrogenionsavailabletopromotesodiumreabsorption.利尿藥和降血糖藥SpironolactoneTheadrenal(7β-17α)-7(Acetylthio)-17-hydroxy-3-oxopregn-4ene-21-carboxylicacid

-lactone

Spironolactoneisacompetitiveantagonisttothemineralocorticoidssuchasaldosterone.利尿藥和降血糖藥

MechanismofActionTheadrenalcortexsecretesapotentmineralocorticoidcalledaldosteronewhichpromotessaltandwaterretentionandpotassiumandhydrogenionexcretion.Spironolactoneinhibitsreabsorptionofsodiumandchlorideionandincreasedpotassiumionexcretion.利尿藥和降血糖藥

Metabolism