人工合成抗菌药教学课件

ClassificationQuinolonesSulfonamidesNitrofuransandnitroimidazole(Metronidazole)taskUnderstandingthemechanismsofdrugaction,pharmacokineticsanddruginteractionsMasteringantibacterialactivities,therapueticapplicationsandthemajoradversereactions.FluoroquinolonesClassificationofquinolonesThefirstgeneration：nalidixicacid（1962）Thesecondgeneration：pipemidicacid（1973）Thethirdgeneration：fluoroquinolones（1980s）Theforthgeneration：fluoroquinolones（theendof1990s）FluoroquinolonesNorfloxacinCiprofloxacinOfloxacinLevofloxacinLomefloxacinFleroxacinSparfloxacinMoxifloxacinAntibacterialspectrum1.Broad-spectrum;GoodactivityagainstG-.Includinglegionella,pseudomonasaeruginasaandMRSA.2.Someiseffecttotuberculebacillus,mycoplasma,chlamydiaandanaerobianetc.Sparfloxacin’sactivityisthestrongest.3.TheforthgenerationsuchasmoxifloxacinimprovedactivityagainstG+.MechanismofactionInhibitingtypeIItopoisomerases(DNA

gyrase)andtopoisomeraseIVPharmacokineticsWellabsorptionafteroraladministrationanddistributionwidelyinbodyfluidsandtissues.TherelativelylongT1/2Renalclearancepredominatesformostfluoroquinolones.ResistanceCrossresistanceamongthedrugsofthisclass；Commondrug-risistancebacteria:Staphylococcusaureus,enterococcus,Escherichiacoli

and

Pseudomonasaeruginosa

etc.MechanismofresistanceMutationsinthebacterialchromosomalgenesencodinggyrA,ortopoisomeraseIV.Achangeinthepermeabilityoftheorganism;e.g.Escherichiacoli

Activetransportofthedrugoutofthebacteria

;e.g.

StaphylococcusaureusClinicalapplicationUrinarytractinfections:urethritis,cervicitis,prostatitis.thefirstchoiceisciprofloxacin,gatifloxacinorofloxacinRespiratoryinfectionsIntestinalinfectionandtyphusBone,joint,skin,parenchyma,surgery,E.N.Tinfections.Adverse

reaction

GastrointestinaleffectsCNSreaction：excitedSkinandphotosensitivityCartilagedamageLiverorrenalfunctionallesion，Achillestendinitis，hearttoxicity，eyetoxicity.ContraindicationChildren,pregnantwomen

,sucklingwomen,insanepatientorpatientofepilepsyhistoryAllergicpatientCommonfluoroquinolonesinclinicNorfloxacinitsabsorptionisaffectedbyfood.（35-45%）LowplasmadrugconcentrationHighurineandintestinaltractdrugconcentrationNoclinicalvalueformycoplasma,chlamydia,legionellaCiprofloxacinThestrongestantibacterialactioninvitroBioavailabilityis38-60%StrongeffectforG-bacillianddrug-resistanceG+/G–TherapeuticapplicationismainlyforinfectionsofotherdrugresistanceG-bacilli.Noeffectformostanaerobian.ThesameantibacterialcharactertociprofloxacinInaddition,ofloxacinhaseffectformycobacteriumtuberculosis,chlamydiatrachomatisandsomeanaerobian.Thesecond-lineagentfortreatmentoftuberculosisLevofloxacinItsantibacterialactivityisdoubleofofloxacin’s.

Ofloxacin

goodabsorptionbyoraladministrationItsbioacailabilityisabout99%.DistributedwidelyinbodyfluidsandtissuesStrongantibacterialactivityinvivoAdversereactionismore.FleroxacinSulfnamidesBroadspectrum，stable，convenience，easytoproduce，cheapChemicalconstitution

O

R2NH

S

NH

R1O

sulfanilamideclassificationSystemicinfection：Short-acting：SIZMiddle-acting：SD、SMZProlonged-acting：SMM、SDMIntestinaltract：SASPExternalusetoLocalinfection：SA-Na、SD-Ag、SMLAntibacterialspectrumBroad-spectrumbacteriostaticItiseffectivetomostofG+andG-,chlamydia,plasmodiumandactinomycesSML、SD-AgexternalusediseffecttoPseudomonasaeruginosa

ActionofmechanismDihydropteroicacidL-glumateDihydropteroicacidsynthaseFH2FH2reductaseFH4bacteriumPurine,PyrimidineSyntheticproteinTMPPABAMechanismofactionSulfonamidescompletitivelyinhibitdihydropteroatesynthaseandpreventnormalbacterialutilizationofPABA.MechanismofresistanceLoweredaffinityofdihydropteroatesynthasetosulfonamides;Decreasedbacterialpermeabilityoractiveeffluxofsulfonamides;Analterativemetabolicpathwayforsynthesisofanessentialmetaboliteorover-productionofPABA.CROSS-RESISTANCEPharmacokineticsSystemicinfectiondrugsbyoraladministrationisabsorbedwellanddistributedwidely.AdverseeffectUrinarytractdisturbancesAllergicreactionHematopoieticsystemdisordersNervoussystemreactionMiscellaneousreaction：nausea,vomiting,diarrhea,headache

,etcTrimethoprim（TMP）TMPinhibitsbacterialdihydrofolicacidreductase.TMPgiventogetherwithsulfonamides,producessequentialblockingoffolicacidsynthesis,resultinginmarkedenhancement(synergism)ofthebacteriostaticactivity.ActionofmechanismDihydropteroicacidL-glumateDihydropteroicacidsynthaseFH2FH2reductaseFH4bacteriumPurine,PyrimidineSyntheticproteinTMPPABAsulfadiazine（SD）SDachievestherapeuticconcentrationsincerebrospinalfluidandisafirst-linetherapyfortreatmentofepidemiccerebrospinalmeningitis.Sulfisoxazole(SIZ)andsulfamethoxazole(SMZ)SIZandSMZareoftenusedtotreaturinarytractinfections.SMZgiventogetherwithTMP,SMZcoisusedwidelyforrespiratorytractinfections.SASPitselfisnoantibacterialactivity.Resolvingintosulfapyridine

and5-aminosalicylateinintestinaltractacuteorchronic