化学治疗药物

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,化学治疗药物,Chemotherapeutic Drugs,学习提要,掌握喹诺酮及磺胺类药物的作用机制及区别点,掌握各组喹诺酮药物的抗菌特性,掌握喹诺酮及磺胺类药物的临床应用及常见不良反应及产生耐药机制,化学治疗药物,Ideal:,对细菌等病原微生物、寄生虫和癌细胞有选择性杀灭作用,对,Host,无毒或轻度毒性,Note,Host,Pathogen and Drugs,Reasonable,Safety and Effective,治疗指数=LD,50,/ED,50,Certain Safety Factor 确实安全系数,化疗指数越大则说明药物毒性越低,治疗指数大于,5,，可做临床研究,治疗效果越高？,化疗指数,Chemotherapeutic index,Unsatisfactory of safety margin,不满意的安全界量系数,安全系数=LD,5,/ED,95,Or =LD,1,/LD,99,基本无害剂量/基本有效剂量,CELL MEMBERANE,CELL WALL,DNA,Ribosomes,PABA,THFA,mRNA,Sulfonamaides,Trimethoprim,Inhibitors of metablism,Fluoroquinolones,Rifampin,Inhibitors of nucleic acid function or synthesis,Tetracyclines,Aminoglycosides,Macrolides,Clindamycin,Chloramphenicol,Inhibitors of protein synyhesis,B-Lactams,Vancomycin,Inhibitors of cell wall synthesis,磺胺类,Sulphonamides,甲氧苄啶类 Trimethprim,Sulfonamides,Trimethoprim,1932年德国Domagk发现带有磺酰胺基团的一种染料白浪多息可有效地治疗受细菌致命感染的实验动物。之后他用此药治好了自己小女儿的链球菌感染的细菌性血液中毒磺胺新药诞生了。1939年他获得了诺贝尔生理及医药奖。,洁尔灭,Zephirol,白浪多息,Prontosil,Streptozon,氨苯磺胺,异烟肼,Neoteben,Supercoiled,DNA,DNA,Gyrase,Pteridine,+,PABA,二氢叶酸还原酶,二氢蝶酸合成酶,嘌呤,嘧啶,二氢蝶酸,四氢叶酸,二氢叶酸,Relaxed,DNA,甲氧苄啶,-,复方新诺明,叶酸合成抑制剂,-,磺胺类,Woods Fildes 学说,Antifolate,drugs,磺胺药,+TMP,：,双重阻断细菌的叶酸代谢,【作用机制】,抗叶酸药：,干扰细菌叶酸的合成,TMP,对细菌二氢叶酸还原酶的敏感性,哺乳类二氢叶酸还原酶,50000,倍,Trimethoprim,:,dihydrofolate,reductase,Sulphonamides,:,dihydropteroate,synthetase,Fig.,Synergism between trimethoprim and sulfamethoxazole on the inhibition of growth of,Escherichia coli.,Number of bacteria,(Arbitrary units),Hours,100,50,0,5,10,0,No drug,Trimethoprim,Sulfamethoxazole,Co-trimoxazole,二氢喋酸合成酶,敏感性,大量产生,PABA,细胞膜对,磺胺药的通透性下降,【耐药机制】,【抗菌谱】,革兰氏阳性菌、阴性菌、诺卡氏菌、衣原体、弓形体、疟原虫、放线菌和卡氏肺囊虫有抑制作用,对支原体、螺旋体无效,可以刺激立克次体生长,【临床应用】,主要用于敏感菌引起尿路感染,多采用复方制剂,co-trimethoprim-sulphamethoxazole,co-trimoxazole,卡氏肺囊虫性肺炎,诺卡氏菌感染,弓形体病,氯喹耐药的恶性疟疾,过敏反应，药物毒性,5%,患者出现明显不适,过敏反应：磺胺类产生交叉过敏,泌尿系统损害：结晶尿,造血系统反应：血小板机能不全、溶血性或再生障碍性贫血、粒细胞减少、白血病样反应,妊娠后期服用：新生儿出现核黄疸,艾滋病患者：,50,以上产生不良反应,【不良反应】,奎诺酮类 Quinolones,负超螺旋DNA,DNA,回旋酶,嘌呤,嘧啶,子代DNA,DNA双链,喹诺酮,-,核酸合成抑制剂,拓扑异构酶IV,细胞分化,-,正超螺旋DNA,后链切口,后链前移封口,Action of type II DNA,topoisomerase,【药理作用】,【耐药机制】,细菌,DNA,螺旋酶基因的单核苷酸改变,螺旋酶突变,外膜通透性的改变,主动将药物泵出体外,第一代：萘啶酸 部分,G-,菌有效，抗菌谱窄。,第二代：吡哌酸尿路和肠道感染。,第三代：氟喹诺酮类抗菌谱广,敏感菌引起的呼吸道、泌尿道、皮肤软组织、肠道、细菌性前列腺炎等感染,【临床应用】,氧氟沙星&环丙沙星:,偶尔用于结核病,诺氟沙星,norfloxacin,依诺沙星,enoxacin,Gram-,阴性和阳性菌引起的尿路感染和前列腺炎有效,对全身感染无效,抗菌谱与诺氟沙星相似,口服吸收好、血药浓度和组织浓度高于诺氟沙星,体内抗菌作用强于诺氟沙星,对,MRSA,不敏感,I,II,环丙沙星Ciprofloxacin,氧氟沙星,ofloxacin,对肠杆菌科细菌和革兰氏阴性菌感染尤其效佳,可用于伴随囊肿性纤维化的假单胞菌属细菌感染,与,b,-,内酰胺类合用，具有增效作用,最初用于前列腺炎和性传播感染,对皮肤感染有益,上呼吸道感染,氟罗沙星,fleroxacin,斯帕沙星,Sparfloxacin,特点：,抗革兰氏阳性菌的作用增强,抗阴性菌作用 环丙沙星,抗菌活性强于诺氟沙星、氧氟沙星及环丙沙星,III,克林沙星,Clinafloxacin,抗菌活性:环丙沙星和司帕沙星的4-8倍,对多药耐药菌也有极好活性,本品对厌氧菌活性高，是司帕沙星和环丙沙星的8和16倍,Warner-Lambert公司,IV,曲伐沙星 trovafloxacin,莫西沙星 moxifloxacin,抗,G+,菌：强；抗厌氧菌,非典型性肺炎（,Atypical pneumonia agents,）；,衣原体（,chlamydia,）,;,支原,(,质,),体（,mycoplasma,）；,军团杆菌属（,legionela,）,Respiratory fluoroquinolones,Levofloxacin 左氧氟沙星,Gatifloxacin 加替沙星,Gemifloxacin 吉米沙星,Moxifloxacin 莫西沙星,口服吸收好，生物利用度在,70,95,【体内过程】,药物的组织穿透性好，分布广泛,培氟沙星,&,氧氟沙星进入脑脊液,胃肠道发生螯合,:,铝、镁等抗酸药,难溶性物质,影响吸收,多数经肾脏排出,特点:,部分经肝,P450,酶代谢,抑制肝,P450,酶对其他药物的代谢,如,theophylline,的血浓度增加产生惊厥,【药物相互作用】,消化道症状：恶心、食欲不振、腹泻等,中枢神经系统：焦虑、烦躁、失眠、头晕、癫痫,软骨发育,从乳汁分泌,光敏反应,抗菌后效应,Postantibiotic,Effects(PAE,),PAE=T-C,PAE,in vivo,PAE,in vitro,【注意事项】,Approved and Investigational Fluoroquinolones in the United States,Fluoroquinolone(brandname),Manufacturer,Formulations,Comments,FDA-approved,Norfloxacin(Noroxin),Merck&Co,Inc,400-mg tablets,Essentially limited to urinary tract infections,Ciprofloxacin(Cipro),Bayer Corporation,100-,250-,500-,and 750-mg tablets;solution for IV infusion(200 mg/20 mL in vials and flexible containers),Improved antibacterial activity;broad indications for systemic use,Ofloxacin(Floxin),Ortho-McNeil Pharmaceuticals,200-,300-,and 400-mg tablets;solution of IV infusion(4 mg/mL,50 mL),Improved antibacterial activity;broad indications for systemic use,Enoxacin(Penetrex),Rhne-Poulenc Rorer,200-and 400-mg tablets,Improved antibacterial activity;broad indications for systemic use,Lomefloxacin*(Maxaquin),Unimed,400-mg tablets,Improved antibacterial activity;broad indications for systemic use,Levofloxacin(Levaquin),Ortho-McNeil Pharmaceuticals,250-and 500-mg tablets;solution for IV infusion(500 mg/20 mL),Improved activity against gram-positive and atypical pathogens,Sparfloxacin*(Zagam),Rhne-Poulenc Rorer,200-mg tablets,Improved activity against gram-positive and atypical pathogens,Trovafloxacin (Trovan),Pfizer Inc,100-and 200-mg tablets;solution for IV infusion in single-use vials,Improved activity against gram-positive and atypical pathogens,Investigational fluoroquinolones,Moxifloxacin,Improved activity against gram-positive bacteria,atypical pathogens,and anaerobes,Gatifloxacin,Clinafloxacin,Gemifloxacin,Sitafloxacin,硝基呋喃类 Nitrofurans,呋喃妥因,nitrofurantoin,泌尿道抗菌药 Urinary antiseptics,呋喃唑酮,furanzolidone,（痢特灵）,肠道感染肠炎、菌痢,抗幽门螺杆菌胃溃疡,硝基咪唑类 Nitromidazoles,甲硝唑,metronidazole,厌氧菌、混合性腹腔感染,细菌性或滴虫性阴道炎,抗幽门螺杆菌胃溃疡,自学！,