第42章

氨基糖苷類抗生素

Chapter42TheAminoglycosides山西醫(yī)科大學(xué)藥理學(xué)教研室張軒萍aminoglycosides鏈霉素streptomycin妥布霉素tobramycin卡那霉素kanamycin大觀霉素spectinomycin新霉素neomycin慶大霉素

gentamicin小諾霉素micronomicin阿司米星

astromicin西索米星sisomicin天然來源SelmanA.

Waksmanaminoglycosides半合成品阿米卡星

amikacin地貝卡星dibekacin阿貝卡星arbekacin

半合成品奈替米星

netilmicin依替米星etilmicin異帕米星isepamicinStructureofaminoglycosidesIIIIIICommonPropertiesofAminoglycosides

氨基糖苷類的共性抗菌作用及機(jī)制細(xì)菌耐藥性體內(nèi)過程臨床應(yīng)用不良反響aminoglycosides﹒antibacterial

effects

氨基糖苷類﹒抗菌作用抗菌譜(antibacterialspectrum)：對(duì)需氧G-桿菌作用強(qiáng)大大局部對(duì)銅綠假單胞菌有效除外鏈霉素、大觀霉素、卡那霉素aminoglycosides﹒antibacterial

effects

氨基糖苷類﹒抗菌作用抗菌譜(antibacterialspectrum)：對(duì)G+、G-球菌有一定抗菌作用少數(shù)對(duì)結(jié)核桿菌有抗菌作用鏈霉素、卡那霉素aminoglycosides﹒antibacterial

effects

氨基糖苷類﹒抗菌作用抗菌特點(diǎn)：屬靜止期殺菌藥對(duì)需氧菌有效，對(duì)厭氧菌無效〔厭氧菌天然耐藥〕G-cellenvelope氧依賴性主動(dòng)轉(zhuǎn)運(yùn)系統(tǒng)aminoglycosides﹒antibacterial

effects

氨基糖苷類﹒抗菌作用抗菌特點(diǎn)：有濃度依賴性有初次接觸效應(yīng)〔firstexposureeffect,FEE〕aminoglycosides﹒antibacterial

effects

氨基糖苷類﹒抗菌作用抗菌特點(diǎn)：有明顯的抗菌后效應(yīng)〔postantibacterialeffect,PAE〕在堿性環(huán)境中抗菌作用增強(qiáng)

Aminoglycosidesantibacterialmechanisms

氨基糖苷類﹒抗菌機(jī)制aminoglycosides﹒antibacterialmechanisms

氨基糖苷類﹒抗菌機(jī)制抑制細(xì)菌蛋白質(zhì)合成干擾細(xì)菌胞漿膜通透性

aminoglycosidesTarget:核糖體30Ｓ亞基細(xì)菌蛋白質(zhì)合成AP肽鏈延伸階段起始階段終止階段RAP轉(zhuǎn)肽酶轉(zhuǎn)位酶肽鏈延伸階段起始階段終止階段RAPAPaminoglycosidesaminoglycosdes﹒antibacterialmechanisms

氨基糖苷類﹒抗菌機(jī)制抑制細(xì)菌蛋白質(zhì)合成起始階段：抑制70S始動(dòng)復(fù)合物形成肽鏈延伸階段：造成ｍRNA密碼錯(cuò)譯，合成無功能的蛋白質(zhì)終止階段：阻止肽鏈的脫落和核糖體循環(huán)aminoglycosdes﹒antibacterialmechanisms

氨基糖苷類﹒抗菌機(jī)制aminoglycosides與核糖體30S亞基結(jié)合干擾細(xì)菌蛋白合成的全過程aminoglycosides﹒NEWREPORTBorisFrancois,etal.Crystalstructuresofcomplexesbetweenaminoglycosides

anddecodingAsiteoligonucleotides:roleofthenumberofringsandpositivechargesinthespecificbindingleadingtomiscoding.NucleicAcidsResearch,2005,33(17):5677–5690細(xì)菌核糖體真核細(xì)胞核糖體aminoglycosdes﹒antibacterialmechanisms

氨基糖苷類﹒抗菌機(jī)制干擾細(xì)菌胞漿膜的通透性破壞細(xì)菌體屏障保護(hù)作用G-cellenvelopeaminoglycosdes﹒antibacterialmechanisms

氨基糖苷類﹒抗菌機(jī)制干擾細(xì)菌胞漿膜的通透性離子吸附作用插入異常膜蛋白aminoglycosdes﹒antibacterialmechanisms

氨基糖苷類﹒抗菌機(jī)制抑制細(xì)菌蛋白質(zhì)合成全過程干擾細(xì)菌胞漿膜的通透性aminoglycosides﹒resistance

氨基糖苷類﹒耐藥性耐藥機(jī)制：鈍化酶

modifyingenzyme

Acetylase,AC

乙?；窤denylase,AD

腺苷化酶Phosphorylase,P磷酸化酶aminoglycosides﹒resistance

氨基糖苷類﹒耐藥性耐藥機(jī)制：鈍化酶不完全交叉耐藥完全交叉耐藥膜對(duì)藥物通透性降低G-cellenvelopeaminoglycosides﹒resistance

氨基糖苷類﹒耐藥性耐藥機(jī)制：鈍化酶

膜對(duì)藥物通透性降低靶位改變

aminoglycosides﹒resistance

氨基糖苷類﹒耐藥性Jun-ichiWachino,KunikazuYamane,etal.NovelPlasmid-Mediated16SrRNAMethylase,RmtC,FoundinaProteusmirabilisIsolateDemonstratingExtraordinaryHigh-LevelResistanceagainstVariousAminoglycosidesANTIMICROBIALAGENTSANDCHEMOTHERAPY,2006,50(1):178–184aminoglycosides﹒pharmacokinetics

氨基糖苷類﹒體內(nèi)過程吸收absorption：口服用于腸道術(shù)前消毒或腸道感染注射用于全身感染/非腸道感染aminoglycosides﹒pharmacokinetics

氨基糖苷類﹒體內(nèi)過程分布distribution：主要分布在細(xì)胞外液不易進(jìn)入細(xì)胞內(nèi)不易進(jìn)入腦脊液易透過胎盤屏障腎臟和內(nèi)耳淋巴液中濃度高aminoglycosides﹒pharmacokinetics

氨基糖苷類﹒體內(nèi)過程消除elimination：以原形從腎臟排出，尿中藥物濃度高堿性尿中作用增強(qiáng)腎功能不良時(shí)慎用aminoglycosides﹒clinicaluses

氨基糖苷類﹒臨床應(yīng)用需氧Ｇ-桿菌引起的全身感染銅綠假單胞菌感染Ｇ+球菌感染結(jié)核桿菌感染aminoglycosides﹒adversereactions

氨基糖苷類﹒不良反響四大毒性aminoglycosides﹒adversereactions

氨基糖苷類﹒不良反響耳毒性ototoxicity腎毒性nephrotoxicity神經(jīng)肌肉接頭阻滯neuromuscularblockade過敏反響allergyaminoglycosides﹒adversereactions

氨基糖苷類﹒不良反響ototoxicity：

第八對(duì)腦神經(jīng)的損害前庭功能損害發(fā)生率：neomycin>

kanamycin

>streptomycin>gentamicin,amikacin,tobramycin

>

netilmicinaminoglycosides﹒adversereactions

氨基糖苷類﹒不良反響ototoxicity：

第八對(duì)腦神經(jīng)的損害耳蝸功能受損：耳鳴、聽力減退、永久性耳聾。其發(fā)生率：neomycin>

kanamycin

>amikacin

>gentamicin>tobramycin

>netilmicin

>streptomycinaminoglycosides﹒adversereactions

氨基糖苷類﹒不良反響ototoxicity：可能機(jī)制耳蝸內(nèi)淋巴液中藥物濃度過高

g/mlHOURS816240Plasmaconcentrationsafterintravenousadministrationofgentamicinassingledoseorasthreedivideddosesduring24h.引起耳毒性的閾濃度單次給藥一日三次給藥aminoglycosides﹒adversereactions

氨基糖苷類﹒不良反響ototoxicity：可能機(jī)制耳蝸內(nèi)淋巴液中藥物濃度過高毛細(xì)胞損傷線粒體基因突變NucleicAcidsRes.2005;33(3):1132–1139線粒體12SrRNAaminoglycosides﹒adversereactions

氨基糖苷類﹒不良反響Prophylaxisofototoxicity：嚴(yán)格控制適應(yīng)證，兒童，老人，孕婦更應(yīng)慎重用藥期間注意發(fā)現(xiàn)早期毒性，及早停藥有條件時(shí)監(jiān)測聽力防止與其他的耳毒性藥合用〔呋塞米，依他尼酸、萬古霉素類、順鉑等〕防止合用鎮(zhèn)靜催眠藥aminoglycosides﹒adversereactions

氨基糖苷類﹒不良反響nephrotoxicity：表現(xiàn)：蛋白尿，管型尿、血尿、腎功能不良發(fā)生率：neomycin>

kanamycin

>

gentamicin>

tobramycin

>amikacin>streptomycin>

netilmicin機(jī)制：損傷腎近曲小管上皮細(xì)胞aminoglycosides﹒adversereactions

氨基糖苷類﹒不良反響nephrotoxicity：預(yù)防：長期應(yīng)用要定期檢查腎功能腎功能不良的患者慎用或禁用防止與其他腎毒性藥物合用萬古霉素、多粘菌素、兩性霉素B、第一代頭孢菌素類等aminoglycosides﹒adversereactions

氨基糖苷類﹒不良反響neuromuscularblockade：與劑量、給藥途徑、用藥種類有關(guān)多在胸、腹腔給藥時(shí)產(chǎn)生大量、快速靜脈滴注時(shí)易引起發(fā)生率：neomycin>streptomycin>amikacin

，kanamycin>gentamicin>tobramycin

aminoglycosides﹒adversereactions

氨基糖苷類﹒不良反響neuromuscularblockade：發(fā)生機(jī)制aminoglycosidesaminoglycosides﹒adversereactions

氨基糖苷類﹒不良反響neuromuscularblockade：治療措施

鈣劑、新斯的明Guinea

Pig

豚鼠aminoglycosides﹒adversereactions

氨基糖苷類﹒不良反響allergy：以鏈霉素過敏反響最明顯過敏反響發(fā)生率不如青霉素G高，但休克死亡率高于青霉素Ｇ皮試準(zhǔn)確性不如青霉素Ｇ治療：腎上腺素+鈣劑aminoglycosides﹒adversereactions

氨基糖苷類﹒不良反響耳毒性ototoxicity腎毒性nephrotoxicity神經(jīng)肌肉接頭阻滯neuromuscularblockade過敏反響allergy四大毒性streptomycin對(duì)結(jié)核桿菌作用強(qiáng)大，腎毒性小易產(chǎn)生耐藥性〔較頑固〕，耳毒性、過敏反響、神經(jīng)肌肉阻斷發(fā)生率高應(yīng)用：結(jié)核病〔一線藥〕鼠疫、土拉菌病、布氏桿菌病〔合用四環(huán)素〕細(xì)菌性心