喹諾酮類藥物藥理與安全性肖永紅課件

喹諾酮類藥物

—藥理與不良反應(yīng)肖永紅PartIPharmacology氟喹諾酮類藥物IsolatesCiproOfloLevoMoxiS.pneumoniaeCIP-S1210.25S.pneumoniaeCIP-R6432164H.influenzae0.0160.060.030.06M.catarrhalis0.030.1250.1250.125S.aureusCIP-S0.50.50.250.06S.aureusCIP-R>12832164P.aeruginosaCIP-S0.5428P.aeruginosaCIP-R128>128>128>128M.pneumoniae410.50.125常用氟喹諾酮類體外抗菌活性(MIC90)氟喹諾酮類對(duì)E.coli活性比較E.coli(100)MIC(mg/L)%SusceptibilityRange50%90%Ciprofloxacin≤0.03-0.12≤0.030.03100Moxifloxacin≤0.03-0.250.030.06100Gatifloxacin≤0.03-0.50.060.12100Levofloxacin≤0.03-0.120.030.03100Pip/tazobactam0.12->1280.5490Imipenem≤0.03-0.50.120.25100K.Pneumoniae(40)MIC(mg/L)%susceptibilityRange50%90%Ciprofloxacin≤0.03-1.00.060.12100Moxifloxacin0.06-2.00.251100Gatifloxacin0.06-2.00.52100Levofloxacin≤0.03-1.00.060.25100Pip/tazobactam0.12-64.01890Imipenem≤0.03-1.00.120.5100氟喹諾酮類對(duì)K.pneumoniae活性比較不同細(xì)菌對(duì)左氧沙星的耐藥情況30%藥物單次口服Cmaxmg/LTmax(h)T1/2(h)AUCmg·h/L生物利用度(%)蛋白結(jié)合率(%)尿回收(%)氧氟沙星400mg5.850.645.035.0902080環(huán)丙沙星500mg2.561.254.012.07036.740左氟沙星200mg2.690.926.2419.31003280加替沙星400mg4.11.47.833.5962682莫西沙星400mg3.12.51236914025吉米沙星320mg1.481.86.659.309056.935常用氟喹諾酮類藥物PK比較不同藥物不同濃度殺菌曲線Time（h）LogCFUTobramycinCiprofloxacinTicarcillin喹諾酮類藥物PK/PD2/7/202311ABPK/PD環(huán)丙沙星治療感染與AUC0-24/MIC關(guān)系A(chǔ)UC0-24/MICEffectiverates2/7/202313ABPK/PD1.抗生素的抗菌活性隨藥物濃度增加而增加

2.臨床用藥目的：取得抗生素Cmax/MIC>10；AUC/MIC≥125

3.這類藥物有：氨基甙類、喹諾酮類、阿奇霉素、四環(huán)素、鏈陽(yáng)霉素、萬(wàn)古霉素。濃度依賴性抗菌作用2/7/202314ABPK/PD第四代:moxifloxacingatifloxacinSitafloxacingemifloxacin第三代:grepafloxacin(第二組)levofloxacinsparfloxacin第三代:ofloxacin(第一組)norfloxacinciprofloxacin第二代:pipemidicacid第一代:nalidixicacid腸桿菌銅綠假單胞菌非典型菌陽(yáng)性菌厭氧菌喹諾酮類分類泌尿道感染全身感染藥物不良反應(yīng)&分類藥物不良反應(yīng):指合格藥品在正常用法用量下出現(xiàn)的與用藥目的無(wú)關(guān)的或意外的有害反應(yīng).分類:量效關(guān)系密切型;量效關(guān)系不密切型;長(zhǎng)期用藥致病型;藥后效應(yīng)型.FQ中樞神經(jīng)系統(tǒng)不良反應(yīng)輕中度不良反應(yīng)頭昏\頭疼眩暈失眠視覺(jué)異常重度不良反應(yīng)神志異常幻覺(jué)抽搐/驚厥Drug,2002,62:13-59CID1999,28:352-364FQCNS不良反應(yīng)機(jī)制與率抑制GABA與受體結(jié)合,刺激中樞神經(jīng)系統(tǒng),與其7位側(cè)鏈結(jié)構(gòu)有關(guān);其他途徑:N-甲基-D-門冬酰腺苷受體激活;興奮性氨基酸受體激活發(fā)生率:Trova>Norf,Gati,Moxi>Spar>Cipro>Oflo>Levotorsadesdepointes(TdP)多因素效應(yīng)氟喹諾酮藥物對(duì)hERGIC50值比較AgentsCYP底物CYP抑制劑依據(jù)腎功能調(diào)整劑量hERGIC50（human）CIPROFLOXACINX1A2YES966GATIFLOXACINXXYES130,329GEMIFLOXACINXXYES260GREPAFLOXACINX1A2NO93LEVOFLOXACINXXYES430,827,915MOXIFLOXACINXXNO65,129,354SPARFLOXACINXXYES18-37ClinicalInfectiousDiseases2006;43:1603–11肝損害表現(xiàn):轉(zhuǎn)氨酶升高黃疸肝衰竭

藥物:曲伐沙星:撤市所有藥物均有,程度不同而已氟喹諾酮藥物肝損害司帕沙星(1800mg/kg)在不同組織濃度測(cè)定

AAC1998,6:1470-1475環(huán)丙沙星/氧氟沙星對(duì)人體關(guān)節(jié)軟骨作用的體外研究

AAC1997,11:2562-2565喹諾酮類對(duì)人體軟骨細(xì)胞有體外毒性喹諾酮類體外孵育14天,顯微鏡下測(cè)量軟骨細(xì)胞壞死與硫酸軟骨素空泡數(shù),藥物與對(duì)照間差異明顯,不同藥物間沒(méi)有差異副作用喹諾酮(頻率)危險(xiǎn)人群嚴(yán)重肝損傷曲伐(0.006%)嚴(yán)重CNS左氧：意識(shí)錯(cuò)亂(0.026%)

氟羅：失眠(8%)合用NSAID或CYP450抑制劑QT間期延長(zhǎng)司帕(9-28ms)>格帕(10ms)>莫西(6