磺胺类药物及抗菌增效剂-20min

Antibacterials磺胺与复方磺胺甲噁唑(Sulfonamides&Cotrimoxazole)北京协和医学院基础学院药理学系郭磊History21932:Farbenindustriespatentedprontosilazo-dyesGerhardDomagkprovedefficacyinmiceawardedNobelprizeinPhysiologyorMedicinein1939Pasteurinstitute:discoveredsulfanilamideastheactivecomponent(bioactivation)FirstAidPacketcarriedbyU.S.SoldiersinWorldWarIIMechanismofactionp-aminobenzoicacid,PABASulfonamidebasestructureH2NCOOH★CatalysisandSulfaDrugResistanceinDihydropteroateSynthase.Science,2012;335:1110GlutamicAcidDihydrofolicacid2ATPDihydropteridineDihydropteroicacidTetrahydrofolicacidDihydropteroatesynthaseH2NCOOHH2NSO2NH2Antibacteralspectrum-Broad,bacteriostaticGram-negativeGram-positiveOthersNocardiasppMeningococcusEscherichiacoliStreptococcussppPneumococcusS.aureusSalmonellaSomeprotozoaChlamydiatrachomatisP.jiroveciiT.gondii5nearlycompleteabsorption,nevergivens.cori.mAwide,PPB-10-95%,crossplacenta&BBB,CSFconc=PlasmaconcDacetylation,metaboliteinactivebuttoxic.Mlesssolubleinacidicurine,precipitate-crystalluriaEPharmacokineticsPreparationsandClinicalUses•Oralabsorbableagents•Sulfamethoxazole(磺胺甲噁唑)•Sulfadiazine(磺胺嘧啶)•Sulfadoxine(磺胺多辛)6•Oralnonabsorbableagents•Sulfasalazine(柳氮磺胺吡啶)•Topicalagents•Sulfacetamide(磺胺醋酰)•Mafenide(甲磺米隆)UTI,Parasiticdiseases(combinedwithotherantimicrobials)-malaria,toxoplasmosis,PCPulcerativecolitis,enteritis,otherIBDOphthalemic,infectionsofburnandwoundAdverseeffects7Crystalluria&renaltoxicityHypersensitivity:rashes,stevens-johnsonsyndrome,drugfeverHemolyticanemia(inG6PDdef)SulfonamidesincreasetheriskofkernicterusinnewbornsH2NCH2OCH3OCH3OCH380mgtrimethoprimCotrimoxazole(TMP-SMZ)•Combinationoftrimethoprim+sulfamethoxazoleH2NSO2NHNCH3400mgsulfamethoxazoleOp-aminobenzoicacidDihydrofolicacidTetrahydrofolicacidDihydrofolatesynthetaseDihydrofolatereductaseThymidinePurinesMethionine9DNAMechanismofactionSulfonamides(completewithPABA)Trimethoprim•Urinarytractinfections.•Bacterialrespiratorytractinfections.•Pneumocystisjirovicii(carinii)pneumonia(PCP)TherapeuticusesAdverseeffectsHypersensitivityreactionsHeadache,GIHematologicaleffectsStevens-Johnson综合征SummarySulfonamides-Mechanism-Spectrum-PK-Uses-AECotrimoxazoleComposition?Advantages?Uses?AE?17Folateantagonists18Thanks!