人工合成抗菌药PPT.ppt

Syntheticantimicrobialagents(人工合成抗菌药),HuifangTangtanghuifang,ClassificationofSyntheticantimicrobialagents,.Quinolones(喹诺酮类);.Sulfonamides(磺胺类);.Othersyntheticantimicrobialagents:Trimethoprim(甲氧苄啶)Nitrofurans(硝基呋喃类),etc.,GeneralfeaturesBroadantimicrobialactivityandareeffectiveafteroraladministrationforthetreatmentofawidevarietyofinfectiousdisease.Relativelyfewsideeffects.Microbialresistancetotheiractiondoesnotdeveloprapidly.,Quinolones,Quinolones,ChemistryDerivedfrombasicstructureofnalidixicacid(萘啶酸)andhavesubstituentsatN-1,C-5,C-7,position8andafluorineatomatposition6.Fluorineatposition6enhancesgyraseinhibitionandcellpenetration.,Quinolones,Quinolones,Chemicalstructure,Quinolones,(诺氟沙星),(环丙沙星),(萘啶酸),Quinolones,GenerationExamples1st(1962-1969)Nalidixicacid,萘啶酸2nd(1969-1979)Pipemidicacid吡哌酸Cinoxacin西诺沙星3rd(1980-1996)Norfloxacin诺氟沙星Levofloxacin左氧氟沙星Ciprofloxacin环丙沙星Ofloxacin氧氟沙星sparfloxacin司帕沙星4th(1997-)Grepafloxacin格帕沙星Clinafloxacin克林沙星Gatifloxacin加替沙星Moxifloxacin莫西沙星,Classification,Quinolones,Summaryofantimicrobialspectrumofquinolones.,Typicaltherapeuticapplicationsofuoroquinolones.,First-generationagents(1962-1969)Nalidixicacid,萘啶酸ThefirstgenerationdrugofthequinoloneantibioticsModerategram-negativeactivityandminimalsystemicdistributionClinicalapplicationsUncomplicatedurinarytractinfections,Quinolones,Quinolones,Second-generationquinolones(1969-1979)Pipemidicacid吡哌酸Cinoxacin西诺沙星Expandedgram-negativeactivityandatypicalpathogencoverage,butlimitedgram-positiveactivity.Mostactiveagainstaerobicgram-negativebacilliCiprofloxacinremainsthequinolonemostactiveagainstPseudomonasaeruginosa,Quinolones,Quinolones,Second-generationquinolones(1969-1979)Activeagainstgram-positiveandgram-negativebacteria,mycobacteria,mycoplasma支原体andlegionellaspecies军团杆菌属.Longerhalf-livesduetoslowelimination,distributionintomanytissuesandbodyfluidsandpenetrationintohumancells.,Quinolones,Quinolones,Third-generationquinolones(1980-1996)Norfloxacin诺氟沙星，Levofloxacin左氧氟沙星，Ciprofloxacin环丙沙星，Ofloxacin氧氟沙星，Sparfloxacin司帕沙星Addedpotencyagainstgram-negativebacteria,anaerobesandmycobacteria.Retainexpandedgram-negativeandatypicalintracellularactivitybuthaveimprovedgram-positivecoverage,Quinolones,Quinolones,Fourth-generationagents(1997-)Grepafloxacin格帕沙星，Clinafloxacin克林沙星，Gatifloxacin加替沙星，Moxifloxacin莫西沙星Improvegram-positivecoverage,maintaingram-negativecoverage,andgainanaerobiccoverage.,Quinolones,Quinolones,Antimicrobialactivity&spectrum(1)BactericidalandhavesignificantPAE.(2)Excellentactivityagainstaerobicgram-negativebacteria,someagentshaveactivityagainstPesudomonas.(3)Severalneweragentswithimprovedactivityagainstaerobicgram-positivebacteria.,Quinolones,Quinolones,Antimicrobialactivity&spectrum(4)TheyalsoareeffectiveagainstChlamydiaspp.（衣原体）,Legionellapneumophila(军团菌),anaerobicbacteria,mycobacteria(分枝杆菌).(5)Someagentshavelimitedactivityagainstmultiple-resistancestrains.（6）Bactericidalconcentrationbacteriostaticconcentration,Quinolones,Quinolones,MechanismofactionsTopoisomerases:enzymesthatcontrolandmodifythetopologicalstatesofDNAincells.TopoisomeraseI，IIIcatalysemerelytherelaxationofDNATopoisomeraseII（DNAgyrase）catalysethesupercoilingofDNATopoisomeraseIVinvolvedintheseparationprocessoftheDNAdaughterchainsafterchromosomeduplication.,Quinolones,Quinolones,MechanismofactionsThequinoloneantibioticstargetbacterialDNAgyrase(gram-negativebacteria)TopoisomeraseIV(gram-positivebacteria).,Quinolones,Quinolones,TopoisomeraseIV:involvedintheseparationprocessoftheDNAdaughterchainsafterchromosomeduplication.unabletocatalysethesupercoilingofDNA,merelyitsrelaxation.Theenzymecomprisestwosubunits,ParCandParE.TheParCproteinishomologoustothegyraseAprotein,whiletheParEsubunitishomologoustothegyraseBprotein.,Mechanismofaction,Quinolones,InhibitionoftopoisomeraseIVinterfereswithseparationofreplicatedchromosomalDNAintotherespectivedaughtercellsduringcelldivision.,InhibitionofDNAgyrasepreventstherelaxationofpositivelysupercoiledDNAthatisrequiredfornormaltranscriptionandreplication.,Mechanismofaction,Quinolones,IntrinsicresistanceisrareWithafrequencyofaboutonein107109,especiallyamongstaphylococci,pseudomonas,andserratia(沙雷氏菌).,ResistanceMechanism,Quinolones,(1)MutationofthegyrAgenethatencodedtheAsubunitpolypeptidecanconferresistancetothesedrugs.(2)MutationofthegenecfxBandnfxBthatencodedtheporindecreasedpermeabilityofcellmembrance.(3)ThehighexpressionofnorAgene(encodedactivepumpprotein)increaseddrugsefflexbyaactivetransportproteinpump.(4)Plasmidmediatedresistance.,ResistanceMechanism,Quinolones,(1)Wellabsorbedafteroraladministration.(2)Distributedwidelyinbodytissue,eveninCSF.(3)Excretedmainlyinurine.RoutesofeliminationdifferamongtheQuinolones.,ADMEofQuinolones,Quinolones,Urinarytractinfections.ThemainindicationforquinolonesInthetreatmentofuncomplicatedandcomplicatedUTIs,cureratescanexceed90%and80%,respectively.PotentagentstouseagainstHaemophilusducreyi(软性下疳嗜血杆菌)andpenicillin-sensitiveandpenicillin-resistantNeisseriagonorrhoeae淋(病双)球菌.,ClinicalUses,Quinolones,(2)GIandabdominalinfections.Excellentinvitroactivityagainstmanyentericpathogens,includingEscherichiacoli大肠杆菌,Aeromonas气单胞菌属,Shigella志贺(氏)杆菌,Salmonella沙门氏菌,Campylobacter弯曲杆菌属,Vibrio弧菌属,andYersiniaspecies耶尔森菌Furthermore,quinolonedrugconcentrationsinfecesareexceedinglyhigh.,ClinicalUses,Quinolones,(3)Respiratorytractinfections.Haveinferioractivityagainststreptococci链球菌andshouldnotbeusedasprimarytherapyforcommonupperrespiratorytractinfections.Alternativesfortreatmentofacuteexacerbationofchronicbronchitisinpatientswithobstructivepulmonarydiseasewhoareintolerantoforhavedevelopedresistancetofirst-lineantibiotics.antibioticswithactivityagainstStreptococcuspneumoniae,Haemophilusinfluenzae流感(嗜血)杆菌,andMoraxellacatarrhalis粘膜炎莫拉菌.(4)Otherinfections：Bone,jointandsofttissueinfections.,ClinicalUses,Quinolones,(1)Gastrointestinaleffects.Themostcommonreactions(2)CNSsideeffects.PenetrateBBBGABA(3)Allergicreaction.Skinrashses,itchs,angioneuroedema,etc.Photosensitivity(4)othereffects.Cardiactoxicity：Q-TintervalLiverandrenalinjury,Adversereactions,Quinolones,(4)othereffects.MuscleskeletalsystemAmyasthenia肌无力,myosalgia肌痛,jointpainandinflammationIncreaseintracranialpressureininfants,Adversereactions,Quinolones,Pipemidicacid(吡哌酸)Norfloxacin(诺氟沙星)Ciprofloxacin(环丙杀星)Ofloxacin（氧氟沙星）Levofloxacin（左氧氟沙星）Lomefloxacin（洛美沙星）Fleroxacin（氟罗沙星）Sparfloxacin（司帕沙星）,Quinolonesagents,Quinolones,PharmacokineticPropertiesofFluoroquinolones,Quinolones,盐酸安妥沙星-我国第一个具有自主知识产权的沙星类抗菌药,盐酸安妥沙星与细菌作用2到4小时，即可杀灭99%以上细菌。在沙星类药物安全性的重要指标光毒性方面，它的毒性明显低于现有主要产品洛美沙星、司帕沙星、氟罗沙星、环丙沙星。盐酸安妥沙星具有优异的药物代谢性质，与最新的第四代沙星类药物相比，它的口服剂量最低，每天只需服用1次，属长效抗菌药物。盐酸安妥沙星治疗呼吸道、泌尿道、皮肤软组织等三大系统细菌感染性疾病，疗效确切而不良反应少，总有效率超过95%。,喹诺酮类研究两大动向,继续研发第四代氟喹诺酮近年上市的:吉米沙星(gemifloxacin),巴洛沙星目前正在研发中的:西他沙星(sitafloxacin),奥鲁沙星(olamufloxacin)。注意研究结构变幅更大的喹诺酮近年上市的帕珠沙星(pazufloxacin)、鲁利沙星(prulifloxacin)非氟喹诺酮格林沙星(garenoxacin),Sulfonamides,Sulfonamides,Sulfonamides,(1)Sulfonamideshaveawiderangeofantimicrobialactivity.G+,G-bacteria,Nocardia诺卡菌属,Bedsoniatrachomatis沙眼衣原体,etc.Entericbacteriaetc.lesseffectiveRickettsorganism(2)Sulfonamidesexertonlybacteriostaticeffect.,Antimicrobialactivity,Sulfonamides,Structuralanalogsandcompetitiveantagonistsofpara-aminobenzoicacid(对氨基苯甲酸PABA)PreventnormalbacterialutilizationofPABAforthesynthesisoffolicacid.,Mechanismofaction,Sulfonamides,Mechanismofaction,Sulfonamides,Originatebyrandommutationandselectionorbytransferofresistancebyplasmaides.Suchresistanceusuallyispersistentandirreversible.,MechanismofResistance,Sulfonamides,Theresistancecharacterizedby:(1)Aloweraffinityforsulfonamidesbythedihydropteroatesynthase(2)Decreasedcellpermeabilityoractiveeffluxofthedrug(3)Analternativepathwaytosynthesistheessentialmetabolites(4)Anincreasedproductionofessentialmetaboltes,MechanismofResistance,Sulfonamides,(1)OralabsorbableagentsShort-actingagentsMedium-actingagentsLong-actingagents(2)Oralnonabsorbableagents(3)Topicalagents.(4)Combinationagents.,Classification,Sulfonamides,systemicinfections.cerebralmeningitisTympanitis中耳炎UncomplicatedurinarytractinfectionsCombinedwithTMPintreatingcomplicatedurinarytractinfections,respiratoryinfections,GIinfections(2)intestinalinfections.Sulfasalazine柳氮磺吡啶(3)infectionsofburnandwound.Sulfadiazinesliver(磺胺嘧啶银),Clinicaluses,Sulfonamides,(1)Urinarytractdisturbances(2)Hypersensitivityreaction(3)Hematopoieticsystemdisturbances(4)Kernicterus脑核黄疸causedbybilirubin胆红素replacement(5)Hepatitis(6)GIdisturbances,Adversereactions,Sulfonamides,(1)Approximately70%-100%ofanoraldoseisabsorbed.(2)Sulfonamidesaredistributedthroughoutalltissuesofthebody,eveninCSFSulfadiazine磺胺嘧啶andsulfisoxazole磺胺异恶唑,maybeeffectiveinmeningealinfections.(3)Sulfonamidesreadilypassthoughtheplacenta.,ADMEofsulfonamides,Sulfonamides,(4)Sulfonamidesaremetabolizedintheliverbyacetylation.(5)Sulfonamideseliminatedmainlyintheurineastheunchangeddrugandmetabolicproduct.Inacidurine,theeliminatedareinsolubleandmayprecipitate,thusinducedrenaldisturbance.,ADMEofsulfonamides,Sulfonamides,Increasetheeffectsoftolbutamide甲苯磺丁脲,warfarin,trexan甲氨喋呤Thereasonis:allsulfonamidesareboundinvaryingdegreetoplasmaprotein.,Drugsinteractions,Sulfonamides,(1)OralabsorbableagentsShort-actingagentsSulfafurazole(SIZ,菌得清)Sulfadimidine,(SN2,磺胺二甲嘧啶)Medium-actingagentsSulfadiazine(SD,磺胺嘧啶)Sulfamethoxazole(SMZ,新诺明)Long-actingagentsSulfamonomethoxine(SMM，磺胺间甲氧嘧啶),SulfonamidesAgents,Sulfonamides,(2)OralnonabsorbableagentsSulfasalazine(柳氮磺吡啶)(3)Topicalagents.Mafenide(SML,磺胺米窿)Sulfadiazinesliver(磺胺嘧啶银)Sulfacetamide(SA,磺胺醋酰）,SulfonamidesAgents,Sulfonamides,(4)Combinationagents.Co-trimoxazole(复方新诺明）Trimethoprim(甲氧苄啶)incombinationwithSulfamethoxazole(1:5)exertsasynergisticef