氨基糖苷类抗生素(2)

第42章氨基糖苷类抗生素Chapter42TheAminoglycosides山西医科大学药理学教研室张轩萍aminoglycosides链霉素streptomycin妥布霉素tobramycin卡那霉素kanamycin大观霉素spectinomycin新霉素neomycin庆大霉素gentamicin小诺霉素micronomicin阿司米星astromicin西索米星sisomicin天然来源SelmanA.Waksmanaminoglycosides半合成品阿米卡星amikacin地贝卡星dibekacin阿贝卡星arbekacin半合成品奈替米星netilmicin依替米星etilmicin异帕米星isepamicinOR8NH2R7HCNHR3OHNH2OOHR5OHNHR4R6R1NHR2OOStructureofaminoglycosidesIIIIIICommonPropertiesofAminoglycosides氨基糖苷类的共性抗菌作用及机制细菌耐药性体内过程临床应用不良反应aminoglycosides﹒antibacterialeffects氨基糖苷类﹒抗菌作用抗菌谱(antibacterialspectrum)：1.对需氧G-杆菌作用强大2.大部分对铜绿假单胞菌有效除外链霉素、大观霉素、卡那霉素aminoglycosides﹒antibacterialeffects氨基糖苷类﹒抗菌作用抗菌谱(antibacterialspectrum)：3.对G+、G-球菌有一定抗菌作用4.少数对结核杆菌有抗菌作用链霉素、卡那霉素aminoglycosides﹒antibacterialeffects氨基糖苷类﹒抗菌作用抗菌特点：1.属静止期杀菌药2.对需氧菌有效，对厌氧菌无效（厌氧菌天然耐药）G-cellenvelope氧依赖性主动转运系统aminoglycosides﹒antibacterialeffects氨基糖苷类﹒抗菌作用抗菌特点：3.有浓度依赖性4.有初次接触效应（firstexposureeffect,FEE）aminoglycosides﹒antibacterialeffects氨基糖苷类﹒抗菌作用抗菌特点：5.有明显的抗菌后效应（postantibacterialeffect,PAE）6.在碱性环境中抗菌作用增强Aminoglycosidesantibacterialmechanisms氨基糖苷类﹒抗菌机制aminoglycosides﹒antibacterialmechanisms氨基糖苷类﹒抗菌机制抑制细菌蛋白质合成干扰细菌胞浆膜通透性aminoglycosidesTarget:核糖体30Ｓ亚基细菌蛋白质合成AP肽链延伸阶段起始阶段终止阶段RAP转肽酶转位酶肽链延伸阶段起始阶段终止阶段RAPAPaminoglycosidesaminoglycosdes﹒antibacterialmechanisms氨基糖苷类﹒抗菌机制抑制细菌蛋白质合成1.起始阶段：抑制70S始动复合物形成2.肽链延伸阶段：造成ｍRNA密码错译，合成无功能的蛋白质3.终止阶段：阻止肽链的脱落和核糖体循环aminoglycosdes﹒antibacterialmechanisms氨基糖苷类﹒抗菌机制aminoglycosides与核糖体30S亚基结合干扰细菌蛋白合成的全过程aminoglycosides﹒NEWREPORTBorisFrancois,etal.CrystalstructuresofcomplexesbetweenaminoglycosidesanddecodingAsiteoligonucleotides:roleofthenumberofringsandpositivechargesinthespecificbindingleadingtomiscoding.NucleicAcidsResearch,2005,33(17):5677–5690细菌核糖体真核细胞核糖体aminoglycosdes﹒antibacterialmechanisms氨基糖苷类﹒抗菌机制干扰细菌胞浆膜的通透性破坏细菌体屏障保护作用G-cellenvelopeaminoglycosdes﹒antibacterialmechanisms氨基糖苷类﹒抗菌机制干扰细菌胞浆膜的通透性离子吸附作用插入异常膜蛋白aminoglycosdes﹒antibacterialmechanisms氨基糖苷类﹒抗菌机制抑制细菌蛋白质合成全过程干扰细菌胞浆膜的通透性aminoglycosides﹒resistance氨基糖苷类﹒耐药性耐药机制：钝化酶modifyingenzymeAcetylase,AC乙酰化酶Adenylase,AD腺苷化酶Phosphorylase,P磷酸化酶ONHCCH(CH2)2NH2OOOOHONH2OHOHCH2OHHHONH2NH2HOHCOHOHOHHCHONH2NH2HOHCH2OHNH2OHOHNH2NH2HOOOOOHCR1NHR2NH2H3CNHCH3OHOHNH2NH2HOOOOOInthefigure:ACADACACACⅡACⅠACⅢACⅡACⅠACⅢPACACxADADxOHH3CHNC2H5NH2OHOHNH2HOOOOONHCH3HCNH2HxACACⅡACⅠACⅢACⅡACⅠACⅢACPⅡPⅠACACxxxxxxADADxxacetylase;protectedfromenzyme.phoshorylase;adenylase;gentamicinamikacinnetilmicintobramycinONHCCH(CH2)2NH2OOOOHONH2OHOHCH2OHHHONH2NH2HOHCOHOHOHHCHONH2NH2HOHCH2OHNH2OHOHNH2NH2HOOOOOHCR1NHR2NH2H3CNHCH3OHOHNH2NH2HOOOOOInthefigure:ACADACACACACACⅡACⅠACⅢACⅡACⅠACⅢACⅡACⅠACⅢACⅡACⅠACⅢPACACACACxADADADADxOHH3CHNC2H5NH2OHOHNH2HOOOOONHCH3HCNH2HxACACⅡACⅠACⅢACⅡACⅠACⅢACPⅡPⅠACACxxxxxxADADxxacetylase;protectedfromenzyme.phoshorylase;adenylase;gentamicinamikacinnetilmicintobramycinaminoglycosides﹒resistance氨基糖苷类﹒耐药性耐药机制：钝化酶不完全交叉耐药完全交叉耐药膜对药物通透性降低G-cellenvelopeaminoglycosides﹒resistance氨基糖苷类﹒耐药性耐药机制：钝化酶膜对药物通透性降低靶位改变aminoglycosides﹒resistance氨基糖苷类﹒耐药性Jun-ichiWachino,KunikazuYamane,etal.NovelPlasmid-Mediated16SrRNAMethylase,RmtC,FoundinaProteusmirabilisIsolateDemonstratingExtraordinaryHigh-LevelResistanceagainstVariousAminoglycosidesANTIMICROBIALAGENTSANDCHEMOTHERAPY,2006,50(1):178–184aminoglycosides﹒pharmacokinetics氨基糖苷类﹒体内过程吸收absorption：口服用于肠道术前消毒或肠道感染注射用于全身感染/非肠道感染aminoglycosides﹒pharmacokinetics氨基糖苷类﹒体内过程分布distribution：1.主要分布在细胞外液2.不易进入细胞内3.不易进入脑脊液4.易透过胎盘屏障5.肾脏和内耳淋巴液中浓度高aminoglycosides﹒pharmacokinetics氨基糖苷类﹒体内过程消除elimination：以原形从肾脏排出，尿中药物浓度高碱性尿中作用增强肾功能不良时慎用aminoglycosides﹒clinicaluses氨基糖苷类﹒临床应用需氧Ｇ-杆菌引起的全身感染铜绿假单胞菌感染Ｇ+球菌感染结核杆菌感染aminoglycosides﹒adversereactions氨基糖苷类﹒不良反应四大毒性aminoglycosides﹒adversereactions氨基糖苷类﹒不良反应1.耳毒性ototoxicity2.肾毒性nephrotoxicity3.神经肌肉接头阻滞neuromuscularblockade4.过敏反应allergyaminoglycosides﹒adversereactions氨基糖苷类﹒不良反应ototoxicity：第八对脑神经的损害前庭功能损害发生率：neomycinkanamycinstreptomycingentamicin,amikacin,tobramycinnetilmicinaminoglycosides﹒adversereactions氨基糖苷类﹒不良反应ototoxicity：第八对脑神经的损害耳蜗功能受损：耳鸣、听力减退、永久性耳聋。其发生率：neomycinkanamycinamikacingentamicintobramycinnetilmicinstreptomycinaminoglycosides﹒adversereactions氨基糖苷类﹒不良反应ototoxicity：可能机制耳蜗内淋巴液中药物浓度过高g/mlHOURS816240Plasmaconcentrationsafterintravenousadministrationofgentamicinassingledoseorasthreedivideddosesduring24h.引起耳毒性的阈浓度单次给药一日三次给药aminoglycosides﹒adversereactions氨基糖苷类﹒不良反应ototoxicity：可能机制耳蜗内淋巴液中药物浓度过高毛细胞损伤线粒体基因突变NucleicAcidsRes.2005;33(3):1132–1139线粒体12SrRNAaminoglycosides﹒adversereactions氨基糖苷类﹒不良反应Prophylaxisofototoxicity：1.严格控制适应证，儿童，老人，孕妇更应慎重2.用药期间注意发现早期毒性，及早停药3.有条件时监测听力4.避免与其他的耳毒性药合用（呋塞米，依他尼酸、万古霉素类、顺铂等）5.避免合用镇静催眠药aminoglycosides﹒adversereactions氨基糖苷类﹒不良反应nephrotoxicity：表现：蛋白尿，管型尿、血尿、肾功能不良发生率：neomycinkanamycingentamicintobramycinamikacinstreptomycinnetilmicin机制：损伤肾近曲小管上皮细胞aminoglycosides﹒adversereactions氨基糖苷类﹒不良反应nephrotoxicity：预防：长期应用要定期检查肾功能肾功能不良的患者慎用或禁用避免与其他肾毒性药物合用万古霉素、多粘菌素、两性霉素B、第一代头孢菌素类等aminoglycosides﹒adversereactions氨基糖苷类﹒不良反应neuromuscularblockade：与剂量、给药途径、用药种类有关多在胸、腹腔给药时产生大量、快速静脉滴注时易引起发生率：neomycinstreptomycinamikacin，kanamycingentamicintobramyc