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1、第35章 氨基糖苷类与多黏菌素类Aminoglycosides and polymyxins 彭 军中南大学药理学系,第一节 氨基糖苷类抗生素 aminoglycosides,化学结构：氨基糖苷类抗生素的基本结构是由苷 元和氨基糖分子通过氧桥连接而成Chemical structure:The basic structure of this group consists of aglycone and amino sugar molecule which are linked by oxygen bridge.氨基糖+氨基环醇（苷元）氨基糖苷 amino sugar+aminocycloalc
2、ohol(aglycon)aminoside,氧桥,天然氨基糖苷类Nature aminoglycosides,分 类 Classification,来自链霉菌属 From Streptomyces,来自小单胞菌属From small Monas,链霉素,卡那霉素(streptomycin,kanamycin)新霉素,妥布霉素,大观霉素(neomycin,Tobramycin,Spectinomycin),庆大霉素、西索米星Gentamicin,sisomycin 小诺米星、福提米星 micronomicin,Astromicin,根据来源-based on the source：,阿米卡星、
3、奈替米星amikacin,netilmicin卡那霉素B(Kanamycin B)异帕卡星、阿贝卡星arbekacin,半合成氨基糖苷类Semisynthesis aminoglycosides,一、氨基糖苷类抗生素的共性Common characteristics of aminoglycoside antibiotics,（一）化学结构相似 similar chemical structure（二）体内过程相似-similar physiological disposition（三）抗菌谱相似 similar antibacterial spectrum（四）抗菌机理相似-similar
4、mechanisms of antibacteria（五）耐药性相似-similar drug resistance（六）不良反应相似-similar reverse effect,（二）体内过程相似Similar physiological disposition1.吸收：为有机强碱，口服难吸收，仅用于肠道感染 和肠道消毒。(高极性化合物)Absorption:it is the organic strong base and hard to be absorbed by oral.It is only used in intestinal infection and intestinal
5、tract disinfection.,2.分布：血浆蛋白结合率低，主要分布于细胞外液在耳淋巴液和肾皮质中,浓度高可透过胎盘屏障，不易透过血脑屏障Distribution:low ratio of binding with plasma protein.It is mainly distributed in extracellular fluid,ear lymph fluid and renal cortex.It is able to pass the placental barrier if concentration is high but it is unable to pass t
6、he blood-brain barrier.,3.消除：不被代谢，原形肾小球滤过排泄，在肾小管无再吸收过程（奈替米星除外）,尿中浓度高,碱性尿中作用增强。Elimination:it is not metabolized and is excreted by glomerular filtration as original form.The concentration in urine is high and alkaline urine could enhance its effect.,（三）抗菌谱-antibacterial spectrum 特点：静止期杀菌剂，抗菌谱广charac
7、teristic:bactericide for rest period,broad 1、G-菌 对需氧G-杆菌（包括酮氯假单孢菌）有强大的 杀灭作用；对 G-球菌效差（如脑膜炎双球菌、淋球菌无效）Strong bactericide for aerobic G-bacterial(pseudomonas aeruginosa),poorly effective to G-coccus(Diplococcus intracellularis,no effect to diplococcus gonorrhoeae),2、G+球菌：抗菌作用微弱。Poor effect to G+coccus3、
8、肠球菌和厌氧菌不敏感，和内酰胺类合用增加疗效。Not sensitive to enterococcus and anaerobe.Increase the therapeutic effect by combination with-lactam antibiotics.,4、结核杆菌：链霉素、卡那霉素、阿米卡星Effective to Bacillus tuberculosis:streptomycin,kanamycin,amikacin5、对酮绿假单孢菌无效：链、卡那、新霉素、大观霉素no effect on pseudomonas aeruginosa:streptomycin,ka
9、namycin,neomycin,Spectinomycin6、淋球菌：大观霉素Effective to diplococcus gonorrhoeae:Spectinomycin,（四）抗菌机理(Mechanism of antibiosis)抑制蛋白质合成的全过程（起始、延伸、终止）静止期杀菌药首次解触效应（first exposure effect,FEE）:细菌首次接触、暴露在抗生素的环境里，即被迅速杀灭，当再次或多次接触同一抗生素时，抗生素的杀菌作用明显降低。1.起始阶段：抑制30S亚基始动复合物和70S亚基始 动复合物的形成(50S亚基),2.延伸阶段：与30S亚基的P10蛋白结合
10、，致A位歪曲，mRNA错译，阻止移位 Elongation stage:binding with P10 protein of 30S subunit leads to distorting of A site and in turn the mistranslation of mRNA,resulting in the blockade of site shift.3.终止阶段：阻止终止密码子与A位结合；阻止70S 亚基的解离Termination stage:block the A site binding withtermination codon;block the disassoci
11、ation of 70S subunit.,氨基苷抗菌素,与30s亚基结合,阻止氨酰tRNA在A位正确定位，阻碍甲硫氨酸tRNA的结合，阻止70s形成,Initiation,氨基苷类,阻止终止符号与A位结合,氨基苷类,阻止70S解体,（五）细菌的耐药机制相似 Similar mechanism of drug resistance1.产生钝化酶乙酰化酶 如磷酸化酶、腺苷酰化酶，将乙酰基磷酰基、腺苷酰基连接到氨基苷类的氨基或羟基上 Generation of inactive enzyme acetylase such as phosphorylase,adenylylation enzyme,
12、transfer the acetyl phosphoryl group,adenylyl-group to amino and hydroxyl group of aminoglycosides2.细胞膜通透性下降或细胞内转运功能异常。如绿脓杆菌对链霉素的耐药,Decrease in membrane permeability,change of membrane protein structure.Such as aeruginosus Bacilluss resistance to streptomycin3.修饰靶蛋白（30S 亚基S12蛋白的1个氨基酸被替代）如结核杆菌对链霉素的耐药
13、 Modify the targeting protein(a amino acid of S12 protein from 30S subunit is replaced).Such as Bacillus tuberculosiss resistance to streptomycin,耳毒性：损害第8对脑神经，包括：前庭神经损害：眩晕、头昏、恶心、呕吐 新霉素 卡那霉素链霉素西索米星庆大霉素Ototoxicity:damage the 8th pair of cerebral nervesHurt the vestibular nerve:vertigo,dizzy,nausea,vom
14、iting,（六）主要不良反应(major side effects),听神经损害：耳鸣、听力降低、甚至永久性耳聋.新霉素卡那霉素阿米卡星 西索米星庆大霉素妥布霉素链霉素Injury of acoustic nerve:tinnitus,impairment of hearing ability,permanent deafness。,原因：内耳淋巴液中有较高浓度，干扰内耳柯蒂氏器内、外毛细胞的能量产生与利用,细胞膜Na-K-ATP酶功能障碍，毛细胞损伤。Reason:there is high concentration of drug in lymph fluid inner ear,wh
15、ich interfere energy generation and use of outer acoustic hair cell;dysfunction of Na-K-ATP pump;injury of acoustic hair cell.,预防：询问早期症状（眩晕、耳鸣），检查听力 避免与有耳毒性的药物合用，如万古霉素、高效利尿药呋噻米、依他尼酸、顺铂等合用 H1受体阻断剂可掩盖其耳毒性，避免合用 Prevention:inquire early symptom,examine hearing ability avoid combination with ototoxic dru
16、gs,such as vancomycin,high-ceiling diuretic:Furosemide,Etacrynic Acid,Cisplatin avoid combination with H1 receptor antagonist,which could cover its ototoxicity,2、肾毒性(renal toxicity)表现：蛋白尿、管型尿、血尿、氮质血症等 以新霉素最强，链霉素最小，卡那霉素、妥布霉素、奈替米星、阿米卡星居中Symptoms:proteinuria,cylindruria,blood urine,azotemiaNeomycinGent
17、amicin,Tobramycin,netilmicin,AmikacinStreptomycin,预防：避免与肾毒性的药物合用，如第一代头孢菌 素、万古霉素、多粘菌素等；Prevention:avoid the combination with renal toxic drugs,such as the first generation of cephalosporin,vancomycin,polymyxin,3.神经-肌肉阻滞作用：(blockage of nerves muscle interaction)氨基苷类可阻滞运动神经-肌肉接头 原因：可能是氨基苷类与Ca2+络合，或在突触前
18、膜与Ca2+竞争钙结合部位，阻止Ca2+参与乙酰胆碱的释放所致 aminoglycosides could block the connection of nerves muscle.Reason:complexation of aminoglycosides with Ca2+,or compete the Ca+binding site with Ca2+at presynaptic membrane to inhibit Ca2+participation in acetylcholine release.,防治：避免与肌松药合用；一旦发生可采用新斯的明和钙剂抢救。Prevention:
19、avoid the combination with muscle relaxant;to rescue the patients with neostigmine and Ca2+once intoxication happens,4、变态反应（以链霉素多见）Allergic reaction 表现：嗜酸性粒细胞、皮疹、药热、过敏性休 克等过敏性休克发生率低，但死亡率高 防治：（1）皮试（2）葡萄糖酸钙+肾上腺素Symptoms:eosinophile granulocyte increase,rash,drug fever,allergic shock.The ratio is low b
20、ut mortality is high.,二、主要氨基糖苷类抗生素的特点及应用The application and main characteristics aminoglycoside antibiotics,链霉素（Streptomycin）第一个用于临床的氨基糖苷类抗生素，亦是第一个抗结核药（1944）。The first one of this group used in clinic and also the first one used against tuberculosis.,1.抗菌谱：对结核杆菌、G-杆菌作用强，对铜绿假单胞菌无效。Antibacterial spect
21、rum:strong effective to Bacillus tuberculosis,G-bacillus,not effect to Pseudomonas aeruginosa.2.耐药性：细菌对链霉素易产生耐药性 Drug resistance:easily resistant to streptomycin,3.临床应用：clinical application（1）兔热病、鼠疫首选，与四环素有协同作用 Rabbit fever,plague-first option,synergistic effect with tetracycline（2）结核病：+其他抗结核药 Tuber
22、culosis:combine with other antituberculosis drugs（3）细菌性心内膜炎：+青霉素（肠、草绿色、溶血性链球菌）Bacterial endocarditis:combine with penicillin(intestine,Viridans,hemolytic streptococcus),4.不良反应：耳毒性最常见（前庭损害为主），其次为肌毒性，过敏性休克（注射后10min），亦有肾毒性，已少用。Side effects:ototoxicity is the most common(mainly hurt vestibule),muscle to
23、xicity,allergic reaction(10 m later after injection),renal toxicity,not use frequently,庆大霉素（Gentamycin）临床最常用的氨基糖苷类抗生素 The most common use of aminoglycoside antibiotics in clinic1、对G-杆菌包括绿脓杆菌作用强，金葡菌有效，结核杆菌疗效差或无效 Strongly effective to G-bacillus including aeruginosus Bacillus,effective to SA,poor or n
24、o effect on Bacillus Tuberculosis.,2、临床用于（1）一般G-杆菌感染首选（2）绿脓杆菌感染：+羧苄青霉素Use for infection by G-bacillusfirst option;Pseudomonas aeruginosa infection:combine with Carbenicillin,（3）泌尿系统手术前后预防感染，口服用于肠道感染及术前准备Prevent the infection before or after the operation on urinary system;oral administration for int
25、estinal infection and preoperative preparation（4）局部用于皮肤、粘膜及五官的感染 Local application for infections of skin,mucous membrane and five sensory organs3、耳毒性以前庭损害为主，可逆性肾损害也多见 vestibule injury is the main ototoxicity and the reverse renal injury is also common.,阿米卡星（Amikacin，丁胺卡那霉素）1.抗菌谱最广的氨基糖苷类，对结核、绿脓杆菌均 有
26、效The most broad-spectrum aminoglycosides,effective to tuberculosis and aeruginosus Bacillus 2.对钝化酶稳定，不易产生耐药性Stable against inactive enzyme and not easy to be drug resistance.3.用于对常用氨基糖苷类耐药菌株的感染首选Use for bacterial resistant to aminoglycosides-first option.,卡那霉素（Kanamycin）1.抗菌谱与链霉素相似，对结核杆菌有效，对绿脓杆菌无效 S
27、imilar antibacterial spectrum with streptomycin,effective to Bacillus tuberculosis,not effective to aeruginosus Bacillus,2.耳毒性、肾毒性大，仅次于新霉素，易耐药 Strong ototoxicity and renal toxicity following neomycin,easy to be resistant 3.临床少用，可作为二线抗结核药 Use seldom in clinic and it is the second option for antiuberc
28、ulotic drug.,其他氨基糖苷类抗生素,妥布霉素 对绿脓杆菌的作用较庆大强，且无交叉（Tobramycin）耐药；主要用于绿脓杆菌的严重感染 奈替米星 对G+球菌的作用强于其他氨基糖苷类（Netilmicin）不易产生耐药性，与其他药物无交叉耐药 耳毒性、肾毒性最小 新 霉 素 耳毒性、肾毒性最大（Neomycin）禁止全身使用，仅口服用于肠道感染 肠道手术前消毒及肝昏迷患者 大观霉素 对淋球菌高度敏感（Spectinomycin）用于耐青霉素菌株和对青霉素过敏的（淋必治）淋病患者,小 结,1、氨基糖苷类抗生素的共性（六个相似）2、氨基糖苷类抗菌谱3、氨基糖苷类抗菌机理4、氨基糖苷类不
29、良反应（四个）5、肌毒性的抢救措施6、过敏性休克的抢救措施7、兔热病、鼠疫首选,小 结,1、氨基糖苷类抗生素的共性（六个相似）2、氨基糖苷类抗菌谱3、氨基糖苷类抗菌机理4、氨基糖苷类不良反应（四个）5、肌毒性的抢救措施6、过敏性休克的抢救措施7、兔热病、鼠疫首选,8、一般G-杆菌感染首选9、一般氨基糖苷类耐药株的感染首选10、抗菌谱最广的氨基糖苷类11、毒性最小的氨基糖苷类12、毒性最大的氨基糖苷类13、对淋球菌敏感的氨基糖苷类,庆大霉素,阿米卡星,阿米卡星,奈替米星,新 霉 素,大观霉素,多黏杆菌及黏杆菌培养液提取（ABCDEM）。多粘菌素B（polymyxin B）多粘菌素E（polymy
30、xin E，抗敌素）,特点：,仅作用于G-杆菌:only use for G-bacillus2.毒性大（BE):highly toxic2.主要局部应用于G-杆菌，特别是绿脓杆菌感染（已少用于全身感染）Only local use for infections by G-bacillus,Particularly b y aeruginosus Bacillus.(little use in systemic infection),多黏菌素类,抗菌作用-antibacterial activity,抗菌谱：属窄谱慢效抗生素，对生长和静止期细菌均有杀菌作用。G-杆菌：肺炎杆菌、嗜血杆菌、大肠杆
31、 菌、肠杆菌属、沙门菌、志贺菌（痢疾 杆），尤对绿脓杆菌作用强。,机制：增加胞浆膜通透性，其多肽含有带正电荷的 游离氨基与G 菌胞浆膜磷脂中带负电荷的磷酸 根结合，破坏其完整性，损伤胞浆膜，使 膜通透性增加。Mechanism:increase the permeability of plasma membrane,the binding of positive charge amino-groupWith negative charge phosphate group destroys the intact of membrane results in its damage and the
32、increase in its permeability,药动学-pharmacokinetics,口服：不吸收（强碱性），用于肠道消毒Oral:no absorption(strong alkalinity),use for disinfection in intestinal tractIm：疼痛（碱性）静脉给药：肾损Im:painfulI.V.:renal injury,毒性较大，少作全身给药 highly toxic,seldom systemic medication,临床应用-clinical application,全身（im、静脉给药）少用Systemic medication
33、(im,i.v.)little use,1）其他抗生素耐药的G-杆菌（本药强，不易耐药）G-bacillus resistant to other antibiotics(this group is strong and not easy to be resistant)2）绿脓杆菌引起的严重感染：烧伤、败血症、心内膜炎Severe infection by aeruginosus Bacillus:fire burn,septicaemia,endocarditis,2.局部应用 眼、耳、皮肤、粘膜感染及绿脓杆菌感染Local medication:infections of eyes,ea
34、rs,skin and mucous membrane or Pseudomonas aeruginosa infection3.口服 用于术前肠道消毒，大肠杆菌性肠炎，细菌性痢疾Oral administration:Preoperative disinfection of intestinal tract,E coli enteritis,bacillary dysentery,不良反应-side effect,肾损害：血尿、蛋白尿，发生率22%，注射给药3-4天即可出现，停药可恢复。Kidney damage:hematuria,proteinuria,incidence rate is
35、 22%,it happens 3-4 days later after injection and recover after stopping medication神经毒性：头晕，面部麻木，周围神经炎，严重者出现共济失调、昏迷，大剂量快速静注可阻滞神经肌肉接头致呼吸抑制。避免与氨基苷类合用。Neurotoxicity:dizziness,prosopo numbness,peripheral neuritis.Ataxia,coma happen in severe situation,inhibiting nerve and muscle joint leads to Respiratory depression if quick high-dose i.v.Avoid combination with aminoglycosides,2.过敏反应：皮疹、瘙痒、药热、支气管痉挛等allergic response:rash,pruritus,drug fever,bronchiospasm3.其他：刺激性 im疼痛，iv 给药可致静脉炎；偶见粒细胞减少与肝损。Others:stimulant-im pain,iv leads to phlebitis,granulocytopenia and liver damage once in a while,
