药理学英文版教学课件：Chapter 41 synthetic antibacterial drugs

SyntheticAntibacterialAgentsCase152yrsoldmalecollegeteacherFeverwithcoughandstickyphlegmfor6days.Ineffectiveaftertreatedwithazithromycin,cefuroximeaxetilandlevofloxacin5days.PE:T38.5℃,increasedbronchialbreathing,diffusedmoistralesbesoundatbothlungbottoms.Lab-testsshowedincreasedWBC,sputumculturefoundklebsiellapneumoniae(肺炎克雷伯杆菌).Diagnosis:pneumoniaSyntheticantibacterialagentsQuinolones(喹诺酮类)Sulfonamides(磺胺类)Trimethoprim(甲氧苄氨嘧啶)Nitrofurans(硝基呋喃类)Metronidazole(甲硝唑)§1QuinolonesClassificationofQuinolones1stgenerationofquinolones1962Nalidixicacid,oxolincacid,cinoxacin,Usefulonlyfortreatmentoflowerurinarytractinfections.2ndgenerationofquinolones1973Pipemidicacid,itsactivityagainstG-bacilliismorepowerful.Theresistancetothesedrugsisless.3rdgenerationofquinolones1990sFluoroquinolones,theywereoriginallydevelopedbecauseoftheirexcellentactivityagainstG-aerobicbacteria;theyhadlimitedactivityagainstG+organisms.Thenewerfluoroquinolones

Moxifloxacinandtrovafloxacin,theyhaveenhancedG+activity,alsohavegoodactivityagainstanaerobicbacteria,whichotherfluoroquinoloneslack.ChemistryofQuinolonesTheyaresyntheticfluorinatedanalogsofnalidixicacid.Finsite6AntimicrobialeffectsofQuinolonesBroadspectrum---BactericidalFirst-generation,G-aerobicbacteria;Second-generation,moreactivity---againstG-aerobicbacteria;Third-generation(沙星类),fluoroquinolones,possessexcellentG-activity&moderatetogoodactivityagainstG+bacteria,anaerobes,Fluoroquinolonesalsoareactiveagainstagentsofatypicalpneumonia,suchasmycoplasmasandchlamydiae,andintracellularpathogens,e.g.legionellaspeciesandsomemycobacteria,includingMycobacteriumtuberculosis.Ciprofloxacin(环丙沙星)isthemostactiveagentagainstG-bacteria,particularlyPaeruginosa.MechanismofactionToformaDNAgyrase-DNA-quinolonecomplexblockbacterialDNAsynthesisbyinhibitingbacterialtopoisomeraseⅡ(DNAgyrase，回旋酶)andtopoisomeraseⅣ（拓扑异构酶）.InhibitonofDANgyrasepreventstherelaxationofpositivelysupercoiledDNAthatisrequiredfornormaltranscriptionandreplication.InhibitonoftopoisomeraseⅣprobablyinterfereswithseparationofreplicatedchromosomalDNAintotherespectivedaughtercellsduringcelldivision.ThegyraseiscomposedoftwoAsubunitsandtwoBsubunits.TheAsubunitscancutoneofdoublestrandsoftheDNAtopermitpassageoftheothersegmentofDNAthroughthebreakandnegativesupercoilisformed;thebreakisthenreseated.ThisisanATP-dependentreaction.TheenergyisprovidedbyBunits.QuinolonesisaninhibitorofAsubunits.Therefore,theactionofgyraseisinhibitedandDNAreplicationortranscriptionisblockedasresultofthedeathofbacteria.ResistancetoQuinolonesOneormorepointmutationsinthequinolonebindingregionofthetargetenzymeAchangeinthepermeabilityoftheorganismDNAgyraseistheprimarytargetinEcoli,withsingle-stepmutantsexhibitingaminoacidsubstitutionintheAsubunitofgyrase.TopoisomeraseⅣisasecondarytargetinEcolithatisalteredinmutantsexpressinghigherlevelsofresistance.Instaphylococciandstreptococci,thesituationisreversed,topoisomeraseⅣistheprimarytarget,andgyraseisthesecondarytarget.Resistancetoonefluoroquinolone,particularlyifofhighlevel,generallyconferscross-resistancetoallothermembersofthisclass.PharmacokineticsofQuinolonesOralgiven,readilyabsorbed,F=80-95%,beimpairedbydivalentcations,includingthoseinantacids,Distributedwidelyinbodyfluidsandtissues,passplacentareachtothefetus,BiotransformationofthedrugsintheliverMosteliminatedbykidney,eithertubularsecretionorglomerularfiltration.ClinicalusesofQuinolonesNalidixicacidisonlysecond-linedrugtreatingurinaryinfectionwithgram-negativebacilliPipemidicacidnotonlyisusedtreatinginfectionofurinarytractbutalsotreatingintestinalandbiliarytractinfectionwithsensitivebacteria.Fluoroquinolonesareextensivelyusedtreatinggeneralinfection.urinarytractinfections,evenwhencausedbymultifrug-resistantbacteria,IntestinalandbiliarytractinfectionsSofttissueinfectionsBone,jointandinintra-abdominalRespiratorytractinfectionsCiprofloxacinandofloxacinareeffectiveforgonococcal(淋球菌)infection.Theyareoccasionallyusedfortreatmentoftuberculosisandatypicalmycobacterialinfections.Theyaresuitableforeradicationofmeningococcifromcarriers.Ciprofloxacinisasecond-lineagentforlegionellosis.Ofloxaciniseffectiveforchlamydialurethritisorcervicitis.Levofloxacin,sparfloxacin(司帕)areusedfortreatmentofupperandlowerrespiratorytractinfections.AdverseeffectsofQuinolonesGI:Themostcommoneffectsarenausea,vomiting,anddiarrhea.CNS:Headache,dizziness,insomnia,skinrash,occasionally.Photosensitivityoccurswithlomefloxacin(洛美沙星)andpefloxacin(培氟沙星).Fluoroquinolonesmaydamagegrowingcartilage（软骨）andcauseanarthropathy（关节病变）.Theyarenotusedinpatientsunder18yearsofage.Thearthropathyisreversible.Sincefluoroquinolonesareexcretedinbreastmilk,theyarecontraindicatedfornursingmothers,alsoforgravida(孕妇).§2SulfonamidesChemistryofSulfonamides磺胺嘧啶,SDChemistryofSulfonamides磺胺甲噁唑,SMZClassificationofSulfonamidesOral,absorbable;Short-actingMedium-actingLong-actingOral,nonabsorbable;Topicaluse;Oral,absorbable;Short-acting(＜10hours)sulfisoxazole,SIZ;Medium-acting(10～24hours)sulfamethoxazole,SMZ;sulfadiazine,SD;Long-acting(＞24hours)sulfadoxine,Oral,nonabsorbable;Sulfasalazine(柳氮磺吡啶

),Topical;Sodiumsulfacetamide(磺胺醋酰)ophthalmicsolutionorointment,Mafenideacetate,SML;Silversulfadiazine,(磺胺嘧啶银,SD-Ag);AntimicrobialeffectsBroadspectrumBothG+&G-bacteria,nocardia,chlamydiatrachomatis,someprotozoa,someentericbacteria(Ecoli,klebsiella,salmonella,shigella,&enterobacter)Sulfonamidesstimulaterickettsiaeintheirgrowth.BacteriostaticdrugsMechanismofactionSusceptiblebacteriarequireextracellularPABAinordertoformdihydrofolicacid,anessentialstepintheproductionofpurinesandthesynthesisofnucleicacids.SulfonamidesarestructuralanalogsofPABAthatcompetitivelyinhibitdihydropteroatesynthase.Drugsinhibitgrowthbyreversiblyblockingfolicacidsynthesis.ResistancetoSulfonamidesOver-productionofPABA;Producedihydropteroatesynthasewithlowsulfonamideaffinity;Losspermeabilitytothesulfonamide;Useexogenoussourcesoffolate;Bymutationsorencodedonaplasmid,cross-resistances,PharmacokineticsOraladministration,absorbedwell,Distributedwidelytotissuesandbodyfluids,includingCNSandcerebrospinalfluid,placenta,andfetus;20-90%proteinbindingrate;Acetylatedorglucuronidatedintheliver,Sulfonamidesandinactivemetabolitesareexcretedintotheurine,theyaremoresolubleatalkalinethanatacidpH.Inrenalfailurepatient,drugdosemustbereduced.ClinicalusesofSulfonamidesSMZ+TMPTreatmentofurinarytractinfectionsRespiratorytractinfections,sinusitis,bronchitis,pneumonia,otitismedia,anddysentery,SD+TMPFirst-linetherapyfortreatmentoftoxoplasmosis(弓形虫)Sulfadoxine+TMPUsedasasecond-lineagentintreatmentformalaria.Sulfasalazinewidelyusedinulcerativecolitis,enteritis,andotherinflammatoryboweldisease.AdverseeffectsofSulfonamides1.Allergenicreactionsfever,skinrashes,exfoliative(剥脱性)dermatitis,photosensitivity,urticaria(风团),nausea,vomiting,diarrhea.Stevens-Johnsonsyndrome(重症多型红斑),2.UrinarytractdisturbancesSulfonamidesmayprecipitateinurine,especiallyatneutraloracidpH,producingcrystalluria,hematuria,orevenobstruction.SD&SMZ,wheninlargedoses,fluidintakeispoor,cancausecrystalluria.Sodiumbicarbonatetoalkalinizetheurine,adequatefluids,3.Hematopoieticdisturbances:Hemolyticoraplasticanemia,granulocytopenia,thrombocytopenia,orleukemoidreactions.Provokehemolyticreactionsinpatientswhoseredcellsaredeficientinglucose-6-phosphatedehydrogenase.Trimethoprim(甲氧苄啶TMP)ItInhibitsbacterialdihydrofolicacidreductaseabout50000timesmoreefficientlythanthesameenzymeofmammaliancells.Pyrimethamine,inhibitstheactivityofdihydrofolicacidreductaseofprotozoamorethanthatofmammaliancells.Dihydrofolicacidreductasesconvertdihydrofolicacidtotetrahydrofolicacid,astepleadingtothesynthesisofpurinesandultimatelytoDNA.Sulfonamides&TrimethoprimTheyproducessequentialblockinginthismetabolicsequence,resultinginmarkedenhancementoftheactivityofbothdrugs.Thecombinationoftenisbactericidal,comparedtothebacteriostaticactivityofasulfonamidealone.TMP+SMZ=SMZcoResistancetotrimethoprim

ReducedcellpermeabilityOverproductionofdihydrofolatereductase,ProductionofanalteredreductasewithreduceddrugbindingBymutation,plasmid-encoded,§3Othersyntheticantibacterialdrugs

Nitrofurans(硝基呋喃类)Nitrofurantoin(呋喃妥因,呋喃坦啶)Furazolidone(呋喃唑酮,痢特灵):ItisnotabsorbedfromGItractafteroraladministration,usedtotreatGItractinfections.Antibioticactivityandadversesaresameasnitrofurantoin.Nitrofurantoin(呋喃妥因,呋喃坦啶）ActivityofnitrofurantoinisgreatlyenhancedatpH5.5orbelow.bacteriostaticorbactericidalformanyG+andG-bacteria.wellabsorbedafteroralingestion.excretedintotheurinebybothglomerularfiltrationandtubularsecretion.Itisusedtotreaturinarytractinfection.ItisResistanceemergesslowly,thereisnocross-resistancebetweennitrofurantoinandotherantimicrobialagents.S/EincludeAnorexia,nausea,andvomitingaretheprincipalsideeffects.Neuropathiesandhemolyticanemiaoccuringlucose-6-phosphatedehydrogenasedificiency.Rashes,pulmonaryinfiltrationandotherhypersensitivityreactionsmayoccur.InhibitalcoholmetabolisminliverMetronidazole(甲硝唑)Itisanitroimidazoleantiprotozoalandantibacterialdrug.Activityagainstanaerobes,includingbacteroidesandclostridiumspecies.HPWellabsorbedafteroraladministration,widelydistributedintiss