《抗菌药物与抗癌药物》由会员分享，可在线阅读，更多相关《抗菌药物与抗癌药物（101页珍藏版）》请在金锄头文库上搜索。
1、抗微生物药的发现与医学的发展 (古代埃及木乃伊制作技术及消毒防腐/无菌技术) （磺胺与青霉素的发现） 药物、微生物、机体相互作用 基本概念与一些常用术语 抗菌药物作用原理 细菌耐药性 抗菌药物的合理应用,抗微生物药物概论,概念,抗微生物药(antimicrobial drugs) 抑制或杀灭各种细菌和其他病原微生物的药物的总称包括抗菌药、抗真菌药、抗病毒药化学治疗学(chemotherapy)针对细菌和其他微生物以及癌细胞所致疾病的药物治疗化疗药物 包括抗微生物药、抗寄生虫药、抗肿瘤药,药物 微生物 机体相互作用,抗菌药物机体 微生物,药动学 不良反应,杀灭细菌 耐药性,抗病能力,致病作用,常
2、用术语,化疗指数 衡量化疗药物价值 LD50/ED50 抗菌药 抑制和杀灭细菌的药物 包括抗生素和人工合成药物 抗生素(antibiotics) 由微生物产生的以及在微生物产生的物质基础上加以改造 用以抑制或杀灭其他微生物的药物 抗菌谱 各种药物对抗细菌的作用范围广谱 磺胺类 窄谱 青霉素 抗菌活性 药物抑制或杀灭微生物的能力抑菌药 红霉素 杀菌药 青霉素最小抑菌浓度 最小杀菌浓度 抗菌药物后效应,抗菌药物作用机制,抑制细菌壁合成青霉素影响胞浆膜通透性制霉菌素抑制DNA合成喹诺酮影响叶酸代谢磺胺类影响蛋白质合成庆大 红霉素,细菌耐药性,微生物的耐药性 自然界微生物普遍存在为求生存而产生的自身防
3、御能力增强、相互制约的抗生现象在药物反复应用后微生物形成对人为使用药物的抵抗抗菌药物的滥用是大量耐药性产生的重要原因 固有耐药性 微生物对药物的天然耐药 由染色体介导获得耐药性 细菌与药物多次接触后对药物敏感性下降 多由质粒介导 也可由染色体介导获得性耐药性产生机制 微生物产生灭活酶菌体内靶位结构改变改变胞浆膜通透性增强细菌体内主动流出系统外排药物,化学结构中含内酰胺环 包括青霉素类及头孢菌素类、头霉素类、碳氢霉烯类等 青霉素类母核6氨基青霉烷酸 头孢菌素类母核7氨基头孢烷酸 化构改造产生了不同抗菌谱的药物 杀菌活性强 毒性低 适应证广,内酰胺类抗生素,青霉素类,历史,History of t
4、he Discovery of PenicillinThe history of the brilliant research that led to the discovery and development of penicillin has been recorded by the chief participants. In 1928, while studying Staphylococcus variants in the lab at St. Marys Hospital in London, Alexander Fleming observed that a mold cont
5、aminating one of his cultures caused the bacteria in its vicinity to undergo lysis. Broth in which the fungus was grown was markedly inhibitory for many microorganisms. Because the mold belonged to the genus Penicillium, Fleming named the antibacterial substance Penicillin. A decade later, penicilli
6、n was developed as a systemic therapeutic agent by the concerted research of a group of investigators at Oxford University headed by Florey, Chain, and Abraham. By May 1940, the crude material then available was found to produce dramatic therapeutic effects when administered parenterally （胃肠外） to mi
7、ce with experimentally produced streptococcal infections.,History of the Discovery of Penicillin （cont）Despite great obstacles to its laboratory production, enough penicillin was accumulated by 1941 to conduct therapeutic trials in several patients desperately ill with staphylococcal and streptococc
8、al infections to all other therapy. At this stage, the crude, amorphous (非结晶型) penicillin was only about 10% pure, and it required nearly 100 liters of the broth in which the mold had been grown to obtain enough of the antibiotic to treat one patient for 24 hours. Herrell (1945) recorded that bedpan
9、s actually were used by the Oxford group for growing cultures of Penicillium notatum. Case 1 in the 1941 report from Oxford was that of a policeman who was suffering from a mixed staphylococcal and streptococcal infection. He was treated with penicillin, some of which had been recovered from the uri
10、ne of other patients who had been given the drug.,History of the Discovery of Penicillin (cont.)A vast research program soon was initiated in the United States. During 1942, 122 million units of penicillin were made available, and the first clinical trials were conducted at Yale University and the M
11、ayo Clinic, with dramatic results. By the spring of 1943, 200 patients had been treated with the drug. The results were so impressive that the surgeon general of the US army authorized trial of the antibiotic in a military hospital. Soon thereafter, penicillin was adopted throughout the medical serv
12、ices of the US Armed Forces. The deep-fermentation procedure for the biosynthesis of penicillin marked a crucial advance in the large-scale production of the antibiotic. From a total production of a few hundred million units a month in the early days, the quantity manufactured rose to over 200 trill
13、ion units (about 150 tons) by 1950.,青霉素类,历史 概况 杀菌力强 毒性低 价格低廉易引起过敏 不耐酸 不耐青霉素酶 抗菌谱窄基本结构 6氨基青霉烷酸（内酰胺环）结构改造（母核6氨基青霉烷酸）半合成青霉素类 抗菌谱扩大,1,6,*青霉素 penicillin G*,*抗菌作用与抗菌谱* 以抗革兰氏阳性菌为主的杀菌药 抗菌谱窄 以抗革兰氏阳性菌为主大多数革兰氏阳性球菌及杆菌（溶血性链球菌 肺炎球菌 葡萄球菌 白喉杆菌 破伤风杆菌等） 革兰氏阴性球菌（脑膜炎双球菌 淋球菌）少数革兰氏阴性杆菌（流感杆菌 百日咳杆菌） 梅毒螺旋体及钩端螺旋体,*抗菌机制* 干扰细菌
14、细胞壁合成通过抑制胞壁转肽酶活性即青霉素结合蛋白（penicillinbiding proteins, PBPs)活性，从而阻碍细菌细胞壁粘肽合成，胞壁缺损，菌体膨胀裂解；激发细菌自溶酶 哺乳动物细胞无细胞壁故对宿主毒性小,青霉素（内酰胺类）,内酰胺类抗生素,*青霉素 penicillin G*,体内过程天然青霉素 结晶粉稳定 易溶于水 水溶液不稳定遇酸易分解 肌注吸收快完全 半衰期为0.5小时 广泛分布于细胞外液 不易进入细胞内房水及脑脊液中少几乎全部以原形由尿中排出长效青霉素 混悬剂普鲁卡因青霉素 一次肌注60万单位 维持24hr苄星青霉素 一次肌注120万单位 维持15天用于预防感染,*
15、青霉素临床应用*,溶血性链球菌感染所致的蜂窝织炎 丹毒 猩红热 咽炎 扁桃体炎 心内膜炎敏感葡萄球菌所致的皮肤感染 疖 痈 败血症肺炎球菌所致的大叶性肺炎 脑膜炎球菌所致的流行性脑膜炎气性坏疽 梅毒 钩端螺旋体病 鼠咬热破伤风 白喉 炭疽 (需同时合用相应抗毒素血清以对抗细菌产生的外毒素)放线菌病,青霉素不良反应与用药注意点,毒性低过敏反应 *过敏性休克* 药疹 血清病样反应（降解物如青霉唑蛋白青霉烯酸 6氨基青霉烷酸）过敏史 皮试 备急救药肾上腺素注射局部肿痛 大剂量青霉素钾盐治疗螺旋体病时的赫氏反应 全身不适 发热 肌痛 咽痛 心跳加快等症状加重大量病原体死后释放的毒性物质所致,青霉素（内
16、酰胺类）的耐药性,1细菌产生内酰胺酶 使药物水解或与药物结 合使药物不能达到靶位发挥作用2青霉素结合蛋白PBPs结构变化或产生新的PBPs 对药物的亲和力降低 3菌膜通透性改变药物无法在细菌体内作用部位达有效浓度(孔道蛋白缺损或主动流出加速),内酰胺酶,内酰胺酶,半合成青霉素,广谱半合成青霉素 氨苄西林 对革兰氏阴性菌较强 iv阿莫西林（对羟基氨苄西林）po对肺炎球菌及变形杆菌强抗铜绿假单胞菌（绿脓杆菌）类广谱青霉素羧苄西林哌拉西林,头孢菌素类,7氨基头孢烷酸（7ACA）,7,1,头孢菌素类药物分类,一代 头孢氨苄 先锋IV头孢唑啉 先锋V头孢啦啶 先锋VI 二代 头孢孟多头孢呋辛 三代 头孢哌酮（先锋必）头孢曲松（头孢三嗪 菌必治）长效头孢他定 抗绿脓杆菌强 四代,头孢菌素类抗菌作用及机制,杀菌药 抗菌谱广 与青霉素、氨基甙类有协同作用细菌对头孢与青霉素之间有交叉耐药性抗菌机制 似青霉素 与细胞膜上PBPs结合 妨碍粘肽形成 阻止细胞壁合成,
