《利尿药和降血糖药》PPT课件

Medicinalchemistry,Chapter10DiureticsandSyntheticHypoglycemicDrugsCollegeofPharmacy,SDUShutaoMaEmail:mashutao,Chapter10DiureticsandSyntheticHypoglycemicDrugs,Section1HypoglycemicDrugsSection2Diuretics,Section1HypoglycemicDrugs,Theclassictriadofsymptomsindiabetesispolyphagia,polydypsia(thirst),andpolyuria(excessurine).Allthreeresultdirectlyfromexcessiveserumglucoselevels.Type1diabetesusuallydevelopsinanacutemanner,althoughthedestructiveautoimmuneprocessmayhavebeenunderwayforsometime.Type2diabeteshasamoreinsidious,oftenasymptomaticonsetanditspresenceisusuallydetectedbyroutinemedicalexaminations.,Definitions,TypeIDiabetes.Insulin-dependentdiabetesmellitus(IDDM),thisconditionoccurswhenthe-cellsofthepancreaticisletsofLangerhansaredestroyed,probablybyanautoimmuneprocess,suchthatinsulinproductionisdeficient.Type2Diabetes.Noninsulin-dependentdiabetesmellitus(NIDDM)isveryfrequentlyassociatedwithobesityinitsmainlyadultvictims.Seruminsulinlevelsarenormalorelevated,soinessencethisisadiseaseofinsulinresistance.,BiochemistryandPathogenesisofDiabetes,Classifications,FirstGenerationSulfonylureas:tolbutamide.SecondGenerationSulfonylureas:glibenclamide.ThirdGenerationSulfonylureas:glimepiride,repaglinide.Biguanides:metformin.-GlucosidaseInhibitors:Acarbose,Miglitol.,MechanismofAction,Sulfonylureasinteractwithreceptorsonpancreatic-cellstoblockATP-sensitivepotassiumchannels.Thisinturnleadstoopeningofvoltage-sensitivecalciumchannelswhichproducesaninfluxofcalcium;theinfluxofcalciumresultsin-cellsproductionofinsulin.Anadditionaleffectofsulfonylureasissuppressionofgluconeogenesisintheliver.,Physical-ChemicalProperties,Sulfonylureasareweakacidsduetothemarkeddelocalizationofthenitrogenloneelectronpairbythesulfonylgroup.TheirpKasclusteraround5.0andtheyarestronglyproteinbound.,Structure-activityRelationships,Theremustbereasonablebulkontheureanitrogen;methylandethylcompoundsarenotactive.Usually,thereisonlyone(normallysubstituentpara)onthesulfonylaromaticring.,Manysimplesubstituentsonthesulfonylaromaticringareactive.Thep-(-arylcarboxamidoethyl)groupingseeninsecondgenerationcompoundsisconsistentwithhighpotency.Itisthoughtthatthespatialrelationshipbetweentheamidenitrogenofthesubstituentandthesulfonamidenitrogenisimportant.,Tolbutamide,N-(Butylamino)carbonyl-4-methylbenzenesulfonamideButylgroupontheureanitrogen;Para-methylbenzeneonthesulfonylgroup.,Properties,Tolbutamidehavesulfonylureastructurewithweakacid,andthispropertymaybeusedforassay.,Instability:Tolbutamideishydrolyzedtopara-toluenesulfonamidebyacids.Heatingofitsfiltratewithsodiumhydroxidesolutionproducesn-butylamineodour.,Metabolism,Tolbutamideismetabolizedinthelivertop-hydroxyltolbutamide,retainingabout35%oftheactivityoftheparentcompound.itisconvertedveryrapidlytotheinactivetolbutamide4-carboxylicacid.,Glibenclamide,5-Chloro-N-2-4-(cyclohexylamino)carbonylaminosulfonylphenyl-2-methoxybenzamideIntroductionofcyclohexaneontheureanitrogen;Introductionofsidechainonthesulfonylaromaticring.,Properties,Itisnotstabletomoistureandishydrolyzedtosulfamidederivate.,Metabolism,Glibenclamideaffordstrans-4-hydroxy-glyburideasthemajorproduct.The3-hydroxymetaboliteretainsabout15%oftheactivityoftheparentcompound.,TherapeuticApplication,Ingeneral,theeffectsofthefirst-andsecond-generationsulfonylureasaresimilar.Allproducereliablehypoglycemiaintype2diabetics.Theseagentsworkbestinpatientswhosetype2diabetesisrelativelymild.,SyntheticRoute,Third-generationsulfonylurea,Glimepirideisasulfonylureawithaquickonsetofactionandalongdurationofaction.Itmaybindtoadifferentproteinintheputativesulfonylureareceptorthanearlierdrugs,andmayexertitshypoglycemiceffectwithlesssecretionofinsulin.,Metforminhydrochloride,N,N-DimethylimidodicarbonimidicdiamidehydrochlorideMetformin,Biguanides,hasbeeninusethroughouttheworld,withtheexceptionoftheU.S.,fordecades.,MechanismofAction,Metforminisusuallysaidtobeanantihyperglycemicratherthanahypoglycemicagent.Overall,thedrugappearstoincreaseglucoseutilization.Inhibitionofgluconeogenesisappearstobeanimportantcomponentofthedrugsactivity.,ActionsandUses,Unlikesulfonylureas,Metforminisnotproteinbound,isnotmetabolized,andisrapidlyeliminatedbythekidney.Itiswidelyusedasmonotherapyorincombinationwithasulfonylureaintype2diabetes,particularlywhenthepatientisobeseandinsulin-resistant.,-GlucosidaseInhibitors,Tobeabsorbedfromthegastrointestinaltractintothebloodstream,thecomplexcarbohydratesweingestaspartofourdietmustfirstbehydrolyzedtomonosaccharides.Therationaleforthe-glucosidaseinhibitoristhatbypreventingthehydrolysisofcarbohydratestheirabsorptioncouldbereduced.,Metabolismofcomplexcarbohydrades,Section2Diuretics,Diureticsarechemicalsthatincreasetherateofurineformation.Diureticusageleadstotheincreasedexcretionofelectrolytes(especiallysodiumandchlorideions)andwaterfromthebodywithoutaffectingprotein,vitamin,glucoseoraminoacidreabsorption.,StructureClassification,Thediureticscurrentlyinusetodayareclassifiedasfollows:Thiazides(bytheirchemicalclasses);Carbonicanhydraseinhibitors,osmotics(bymechanismofaction);Loopdiuretics(bysiteofaction);Potassium-sparingdiuretics(byeffectsonurinecontents).,Furosemide,5-(Aminosulfonyl)-4-chloro-2-(2-furanylmethyl)aminobenzoicacidFurosemideisanexampleofahigh-ceilingdiureticandmayberegardedasaderivativeofanthranilicacids.,Structure-activityRelationships,Thechlorineandsulfonamidesubstitutionsarefeaturesofthisclassdrugs.Furosemideisastrongeracidthanthethiazidediuretics(pKa3.9).Thisdrugisexcretedprimarilyunchanged.Asmallamountofmetabolism,however,cantakeplaceonthefuranring.,TherapeuticApplications,Furosemidehasasalureticeffect8-10timesthatofthethiazidediuretics,however,ithasashorterdurationofaction,about6-8hours.Itiseffectiveforthetreatmentofedemasconnectedwithcardiac,hepatic,andrenalsites.Clinicaltoxicityoffurosemideinvolvesabnormalitiesoffluidandelectrolytebalance.,Hydrochlorothiazide,6-Chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide1,1-dioxideThethiazidediureticsareweaklyacidicwithabenzothiadiaze1,1-dioxidenucleus.,MechanismofAction,Themajorsiteofactionofthesecompoundsisinthedistaltubule,wherethesedrugscompeteforthechloridebindingsiteoftheNa+-C1-symporterandinhibitthereabsorptionofsodiumandchlorideions.Theyalsoinhibitthereabsorptionofpotassiumandbicarbonateionsbuttoalesserdegree.,Structure-activityRelationship,Thehydrogenatomatthe2-Nisthemostacidic.Theseacidicprotonsmakepossibletheformationofawater-solublesodiumsalt.Anelectron-withdrawinggroupisnecessaryatposition6fordiureticactivity.Replacementorremovalofthesulfonamideatposition7yieldscompoundswithlittleornodiureticactivity.,Saturationofthedoublebondtogivea3,4dihydroderivativeproducesadiureticthatis10timesmorethantheunsaturatedderivative.Substitutionlipophilicgroupatposition3givesamarkedinthediureticpotencywithalongerdurationofaction.Alkylsubstitutiononthe2-Npositionalsodecreasesthepolarityandincreasesthedurationofdiureticaction.,TherapeuticApplications,Hydrochlorothiazideisindicatedinthemanagementofhypertensioneitherasthesoletherapeuticagent,orincombinationwithotherantihypertensives.,Acetazolamide,N-5-(Aminosulfonyl)1,3,4-thiadiazol-2-ylacetamideAcetazolamidewasthefirstofthecarbonicanhydraseinhibitorswithadiureticeffectthatlastsabout8-12hours.Itisusedprimarilyforthetreatmentofglaucomaandabsenceseizures.,MechanismofAction,Theactionoftheenzymecarbonicanhydrasecatalyzestheformationofcarbonicacidfromcarbondioxideandwater.Carbonicanhydraseinhibitorsinducediuresisbyinhibitingtheformationofcarbonicacidwithinproximalanddistaltubularcellstolimitthenumberofhydrogenionsavailabletopromotesodiumreabsorption.,Spironolactone,Theadrenal(7-17)-7(Acetylthio)-17-hydroxy-3-oxopregn-4ene-21-carboxylicacid-lactoneSpironolactoneisacompetitiveantagonisttothemineralocorticoidssuchasaldosterone.,MechanismofAction,Theadrenalcortexsecretesapotentmineralocorticoidcalledaldosteronewhichpromotessaltandwaterretentionandpotassiumandhydrogenionexcretion.Spironolactoneinhibitsreabsorptionofsodiumandchlorideionandincreasedpotassiumionexcretion.,Metabolism,Spironolactoneissignificantlymetabolizedinlivertoitsmajoractivemetabolite,canrenone,whichis