医学chemotherapeutic-Drugs-II课件

Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Chemotherapeutic Drugs,Yun-Bi Lu, PhD,Dept. of Pharmacology,School of Medicine, Zhejiang University,2013.12.19,According to the chemical structure：,-lactams,(-,内酰胺类,),；,Penicillins,(,青霉素类,),；,Cephalosporins,(,头孢菌素类,);,Aminoglycosides,(,氨基糖苷类,);,Macrolides,(,大环内酯类,);,Lincosamides,(,林可胺类,);,Vancomycins,(,万古霉素类,),Tetracyclines,(,四环素类,),；,Chloramphenicol,(,氯霉素,),Antimicrobial drugs,-Characteristics,5. Quinolones (喹诺酮类 ),6. Sulphonamides (磺胺类 ),7. Nitrofurans (硝基呋喃类),8. Antimycobacterial agents (抗结核分支杆菌类 ),9. others:,Oxazolidinones (恶唑烷酮类),Streptogramins (链阳菌素类),Chapter 39,-Lactam Antibiotics,(,-,内酰胺类抗生素,),Classification,Penicillins,（,青霉素类）,Cepharosporins,（,头孢菌素类）,Non-classical,-Lactams,Cephamycins,（,头霉素类）,Carbapenems,（,碳青霉烯类）,Monobectams,（,单环,-,内酰胺类）,Oxacephalosporins,(,氧头孢烯类,),-,lactamase,inhibitors,(,-,内酰胺酶抑制剂,),Paul Ehrlich introduced an arsenic-containing chemical called salvarsan,(,阿斯凡纳明,),to treat syphilis,(,梅毒,),(1910).,“,Magic bullet,” for treatment of syphilis,Chemotherapy,1928 Fleming discovers penicillin,History of Antimicrobial Therapy,1928,1928,found and named by Fleming,1940,the crude material was used on infected mice,1941,conduct therapeutic trials (10% purity),1942,USA (Yale Uni.) begin the first clinical trial,1945,the Noble Prize for Medicine,1950,the commercial cost became,several $/100,000U,1960,History,Mechanism of action,Inhibit penicillin-binding proteins (,青霉素结合蛋白,PBPs,),Enhance the activity of cell,autolytic,enzyme(,自溶酶,),the Role of Penicillins in Blocking,Transpeptidase Enzymes,Synthesis of Peptidoglycan,Mechanism of action,1 Site of action of,b,-lactamase,2 Site of action of amidase,A Thiazolidine ring,B,b,-Lactam ring,b,-lactamase,（酰胺酶）,（,b,-内酰胺酶）,Mechanism of resistance,（6-氨基青霉烷酸）,Mechanism of resistance,陷阱/牵制机制,trapping mechanism,1. 产生水解酶,2. 与药物结合,3. 改变PBPs,4. 改变膜通透性,5. 增强药物外排,6. 缺乏自溶酶,Mechanism of resistance,-lactamase,Altered PBPs decreased,affinity for the antibiotic,Changes of Porins,Active efflux system,Mechanism of action and resistance,Classification,Penicillins,（,青霉素类）,Cepharosporins,（,头孢菌素类）,Non-classical,-Lactams,Cephamycins,（,头霉素类）,Carbapenems,（,碳青霉烯类）,Monobectams,（,单环,-,内酰胺类）,Oxacephalosporins,(,氧头孢烯类,),-,lactamase,inhibitors,(,-,内酰胺酶抑制剂,),1. Natural penicillins,（天然青霉素）,penicillin G,2. Semisynthetic penicillins （,半合成青霉素,）, Oral penicillins,penicillin V (phenoxymethylpenicillin), Penicillinase-resistant penicillins,methicillin 甲氧西林，cloxacillin 氯唑西林,dicloxacillin 双氯西林, nafcillin萘夫西林, Extended-spectrum penicillins,ampicillin 氨苄西林, amoxicillin 阿莫西林, Anti-pseudomonas penicillins,carbenicillin 羧苄西林，piperacillin 哌拉西林, Anti-gram-negative bacilli penicillins,mecillinam 美西林， temocillin 替莫西林,Penicillins,- Classification,Penicillins,-,penicillin G,(,benzylpenicillin,苄青霉素,),Properties,The activity of penicillin G was originally defined in units.,Semisynthetic,penicillins,are prescribed by weight (mg) rather than units.,Most,penicillins,are dispensed as the sodium or potassium salt (,钠盐或钾盐,) of the free acid.,Properties,In dry crystalline form, penicillin salts are stable for long periods (e.g., for years at 4,C,). Solutions lose their activity rapidly (e.g., 24 hours at 20 C) and must be prepared fresh for administration.,Penicillins,-,penicillin G,Penicillins,-,penicillin G,Antimicrobial activity,The penicillin-susceptible organisms are non-penicillinase-producing strains of most cocci,（球菌）, gram-positive bacilli（杆菌）, and spirochetes（螺旋体）,.,Clinical Uses,(1) Streptococcal（链球菌）,infections (pharyngitis咽炎, scarlet,fever猩红热, pneumonia肺炎, arthritis,关节炎, endocarditis心内膜炎,etc,.),(2) Meningococcal（脑膜炎球菌）,infections,Penicillins,-,penicillin G,Adverse effects,(1) Hypersensitivity reactions,itching, rashes, fever, serum sickness, angioneurotic oedema（血管神经性水肿）, anaphylactic shock （过敏性休克）(0.4-1.5/10, 000，0.1/10,000).,(2) Others,Phlebitis (静脉炎); injection site inflammatory reactions; degeneration of nerve tissue; and central nervous system excitability.,(3) Herxheimer reaction(赫氏反应),Penicillins,-,penicillin G,Treatment/prevention for Adverse effects,询问病史,/,过敏史,;,避免滥用与局部应用,;,避免饥饿时注射,;,不可在无急救药物与抢救设备条件下使用,;,初次使用、用药间隔,3,天以上、换用不同批次药物需做皮试，皮试阳性者禁用；,注射液需现配现用,;,患者注射后需留观,30min,，无反应者方可离开,;,一旦发生过敏性休克，,First aid treatment Epinephrine (,sc.,),Glucocorticoids, Anti-histamines.,Penicillins,-,penicillin G,药物相互作用,药动学：抑制,-,内酰胺类的肾小管分泌，如丙磺舒,;,药效学：协同作用,-,氨基糖苷类药物，,拮抗作用,-,抑菌药,配伍禁忌：不可与重金属配伍，不可与其他抗生素混合后静脉滴注给药（易浑浊）；氨基酸营养液增强其抗原性。,Penicillins,-,penicillin G,Antibacterial spectrum(,抗菌谱,),Narrow?,Broad?,Chemotherapetic index (CI)(,治疗指数,),CI= LD,50,/ ED,50,CI= LD,5,/ ED,95,Chemotherapeutic agents,Bactericidal vs Bacterostatic,Chemotherapeutic agents,1. Pencillins,for Oral administrition,Phenoxymethylpenicillin (,苯氧甲基青霉素, Penicillin V),It is,resistant to gastric acid, and be well absorbed (60%) when it is given on an empty stomach.,Its half-life is longer than that of penicillin G.,Penicillins,-,Semisynthetic Penicillins,2. The Penicillinase-resistant Penicillins,Methicillin(甲氧西林)，Oxacillin(苯唑西林)，Cloxacillin（氯唑西林），Dicloxacillin（双氯西林）,stable in an acidic medium,（exp. Methicillin ）, and,resistant to,cleavage by,-lactamase,.,used for treatment of Penicillin G-resistance staphylococcal infection.,Methicillin-resistant strains of staphylococcus aureus (MRAS)： new PBPs,Penicillins,-,Semisynthetic Penicillins,3. Broad-spectrum Penicillins,Amipicillin(氨苄西林)，,Amoxicillin(,阿莫西林）,Pseudomonas aeruginosa(,铜绿假单胞菌,),-resistance；can,be destroyed by-lactamase.,Clinical Uses,Upper respiratory infections,(上呼吸道感染),Urinary tract infections,(尿路感染),Meningitis,(脑膜炎),Salmonella infections,(沙门氏菌感染),Penicillins,-,Semisynthetic Penicillins,4. Broad spectrum Penicillins against,Pseudomonas aeruginosa,Carbenicillin（羧苄西林），Piperacillin（哌拉西林）,with activity against,Pseudomonas aeruginosa,and some,Proteus,(变形杆菌）,etc,.,Clinical Uses,severe infection caused by gram-negative bacteria, usually in combination with aminoglycoside,（氨基苷类）,.,Penicillins,-,Semisynthetic Penicillins,5. Penicillins,against gram-negative rod,Mecillinam( 美西林）,Temocillin（替莫西林）,They have narrow antibacterial spectrum,.,Penicillins,-,Semisynthetic Penicillins,Cephalosporins(头孢菌素),More stable to,-lactase,Broader spectrum,Higher anti-bacteria strength,Less hypersensitivity,Lower toxicity,7-氨基头孢烷酸,1.,Classification,The well-accepted system of classification by “generations” is based on general features of antimicrobial activity.,Cephalosporins,Based on: Spectrum, stable to,-,lactase, effect on G-negative bacteria and the toxicity to kidney.,Classification and Features,Cefadroxil,头孢羟氨苄,Cephalothin,头孢噻吩,Cephapirin,头孢匹林,No sensitivity to MRSA,Classification and Features,Cefonicid 头孢尼西,Ceforanide 头孢雷特,Classification and Features,Cefoperazone头孢哌酮,Cefotaxime,Ceftizoxime,Cefixime,Cefodizime,Classification and Features,5,th,generation？Ceftobiprole and Ceftaroline,powerful antipseudomonal characteristics and,appears,to be less susceptible to development of resistance,Other -lactam antibiotics,Stable to,-lactase, however sensitive to,metalloenzyme,（金属酶）,.,in combination with,cilastatin,（,西司他丁）, a drug that inhibits the degradation of,imipenem,by a renal tubular,dipeptidase,(,二肽酶,).,Central nervous side effects,1. Carbapenems（碳青霉烯类）,Imipenem,(亚胺培南/亚胺硫霉素),2. Cephamycins（头霉素类）,Cefoxitin (头孢西丁)，Cefmetazole（头孢美唑）,has the similar antibacterial activity and spectrum to the 2,nd,generation,Cephalosporins。,Very sensitive to anaerobic infections（厌氧菌）.,Other -lactam antibiotics,3,. Oxacephalosporins(氧头孢烯类),Latamoxef（拉氧头孢）,Flomoxef（氟氧头孢）,Broad-spectrum antibiotic (anaerobic infections) , has the similar antibacterial activity and spectrum to the 3,rd,generation,Cephalosporins.,High concentration in CSF,Other -lactam antibiotics,Other -lactam antibiotics,Narrow-spectrum antibiotic.,For the treatment of aerobic gram-negative bacilli infections or,Pseudomonas,aeruginosa,.,No effect on anaerobic or gram-positive,Less cross anaphylaxis,4. Monobectams（单环类）,Aztreonam （氨曲南）,Carumonam（卡芦莫南）,Clavulanic acid(克拉维酸),Sulbactam(舒巴坦),Tazobactam(三唑巴坦),Binding to,b,-lactamases and inactivate them.,-lactamase inhibitors (,-,内酰胺酶抑制剂),Compound Preparation of,-lactamase,Inhibitors :,优立新,unsayn,=,阿莫西林,+,舒巴坦,(2:1),I. Mechanism of action and resistance,II. Classification,Penicillins,（,青霉素类）,Cepharosporins,（,头孢菌素类）,Non-classical,-Lactams,Cephamycins,（,头霉素类）,Carbapenems,（,碳青霉烯类）,Monobectams,（,单环,-,内酰胺类）,Oxacephalosporins,(,氧头孢烯类,),-,lactamase,inhibitors,(,-,内酰胺酶抑制剂,),Compound Preparation of,-,lactamase,inhibitors,Summary II,Thanks!,