40a-Antifungal-Drugs

Chapter40aAntifungalDrugs抗真菌药21.Fungi真菌类2.Polyenesandflucytosine多烯,氟胞嘧啶3.Azoles咪唑,三唑4.TerbinafineandGriseofulvin特比萘酚,灰黄霉素抗真菌药31.Fungi真菌类HoneyfungusPenicillium青霉菌roquefortiCandidaalbicans白念珠菌Fungiarenon-photosyntheticeukariotes真核生物widelypresentintheenvironment4Mycoses霉菌病Somefungiarecommensals共生物,naturallypresentontheskinandmucosa黏膜.Those,aswellasfungifromtheenvironment,cansometimesovercomeourimmunedefenses免疫,resultinginamycosis霉菌病Candidaalbicans白念珠菌Dermatophytessp.皮肤真菌5InfectionsClassExamplesDiseasesMolds(sporulate)Dermatophytesspecies皮肤真菌•ringworm,ortinea癣•athlete’sfoot脚癣Aspergillus麴菌•pulmonaryordisseminatedaspergillosisHistoplasma组织浆霉菌•pulmonaryordisseminatedhistoplasmosisYeastsCryptococcus隐球菌•meningitis(particularlyifHIV)•pneumoniaCandidaalbicans白念珠菌•oralorvaginalcandidosis•endocarditis•septicemia6SystemicMycoses全身的霉菌病MainresponsiblefungusspeciesincludecommensalorganismssuchasCandidaalbicans白念珠菌-themostfrequent-Aspergillus麴菌,andCryptococci隐球菌,whicharecommensalspecies共生物Therouteofinfectionisoftentheskinorlungs.Itcanspreadtoanyorgan.MostsystemicmycosesarefatalwithouttherapyContributingfactors:•useofbroad-spectrumantibacterialdrugs•useofcorticosteroidsorimmunosupressors•invasivesurgery•HIVinfection•metastaticcancer7ClassificationofAntifungalDrugsAccordingtotheuse:•Drugsfordeep,orsystemic,mycoses•Drugsforsuperficialmycoses:skin,mucosa黏膜,toenails脚趾甲,etc.Accordingtotheclass:•Polyenes(amphotericinB,nystatin)•Azoles:imidazolesandtriazoles•Others(terbinafine,griseofulvin)8AdministrationofAntifungalDrugsClassDrugAdministrationPoly-enesamphotericinBIV,intrathecal,topicalnystatintopical,includingmouthImidazolesketoconazoleoral,butnowmostlytopicalmiconazoletopicalclotrimazoletopicalTriazolesfluconazoleoralitraconazoleoralOthersterbinafineoral,topicalgriseofulvineoralflucytosineoral92.Polyenes多烯:AmphotericinB两性霉素BandNystatin制霉菌素Membranephospholipid磷脂similarityPolyenedrugsressemblemembranelipids油脂.Theyhavebothlipophilicandhydrophilicpoles.Theyhaveabroad-spectrumofactivity.Nystatinisusedtopically,whileamphotericinBisusedagainstsystemicinfectionsbyAspergillusandHistoplasma10MechanismofActionofAmphotericinBandNystatinfungianimalsMembranesofanimalcellscontaincholesterol胆固醇toensurestabilityandfluidityCellsoffungiratheruseergosterol麦角固醇11Formationofpores毛孔Thepolyenedrug(amphotericinBornystatin)formsacomplexwithergosterolItopensaporeinthemembrane,allowingionssuchasK+toleakoutside,whichcausescelldeath12PharmacokineticsofAmphotericinBveryslow:overweeksrenaltoxicity!13AdverseReactionsofAmphotericinBTherapeuticindex(TI)islow.UnwantedeffectsofamphotericinBarecommonandcanbeserious:•renaltoxicity,possiblyinrelationwithlossofsodium-creatinineclearancemustbemonitoredtodetecttoxicitydamage•hypokaliema(lowplasmaK+)andhypotension•anaemia贫血,bysuppressionoferythrocyte红血球production•anaphylacticreactions过敏性休克Nystatineistootoxictobeinjectedrenaltoxicity14FormulationofAmphotericinBLiposomesdistributeverydifferentlyfromfreedrugs.Theytendtoaccumulateintheliverandlungs,andatsitesofinfection.Activityispreserved,buttoxicityisloweredAmphotericinBcanbeincorporatedintoliposomes脂质体forinjection15Flucytosine氟胞嘧啶5-fluoro-deoxy-uridylicaciddUMPdTMPthymidylatesynthetase(-)cytosinepermease,absentfromourcellsfunguscellFlucytosineisasyntheticantimetabolitethatinterfereswithDNAandRNAformation.ItisgivenorallyincombinationwithamphotericinBtotreatsystemicmycosesandmeningitiscausedbyCryptococcusandCandida.Amphotericinallowstheentryofmoreflucytosinebonemarrowtoxicity163.AzoleDrugs比利时的PaulJanssen保罗·杨森discoveredketoconazole(“Nizoral”),miconazole(“Daktarin”)anditraconazole(“Sporanox”)onthebasisoftheimidazole/triazolepharmacophoreImidazolesarenowveryseldomusedorally.Theyareusedtopically,whiletriazolesareusedorally.Theirfirstindicationissuperficialmycoses17Imidazoles咪唑(2N)Ketoconazoleinhibitsthesynthesisofergosterol麦角固醇,therebycausingadisruptionincellmembraneItalsoinhibitsthesynthesisofcortisol考的索andtestosterone睾丸激素,andisaP450inhibitorOtherimidazoledrugsareclotrimazole,miconazoleandeconazole,whichhavethesameactivity,butaretootoxicforsystemicuse.Theyareusedinskin,mouthandvaginapreparationsKetoconazole苯并二氢呋喃酮hasanarrowspectrum:essentiallyCandidaandHistoplasma(exceptincaseofAids)Itdoesnotreachthebrain18Triazoles三唑(3N)Fluconasoleisusedforthesamesystemicinfectionsasthecombinationofamphotericinandflucytosine.Itraconazoleisusedorallyagainstsuperficialmycoseswheretopicaldrugsdonotsuffice.Triazoleshaveabroaderspectrumthanimidazoles,anddonotblockthesynthesisofcortisol考的索andtestosterone睾丸激素.Themechanismofactionissimilar19PharmacokineticsofTriazolesFluconazolereachesthebrain.Itraconazoledoesnot,butiseffectiveinHIV-infectedpatients(人类免疫缺陷病毒)(butriskislowerthanwithketoconazole)20SecondGenerationofTriazolesLimitationsinspectrumandkinetics,aswellasemergingresistances–particularlywithaspergillus–ledtothecurrentdevelopmentofasecondgenerationoftriazoles:voriconazole,posaconazoleandravuconazoleThosestillveryexpensivedrugsarereservedforthetreatmentofsystemicmycoses214.Terbinafine特比萘酚Terbinafi