Block Ⅴ : pharmacology Chemotherapeutic drugs ( 化学治疗药物 )

1. BlockⅤ: pharmacologyChemotherapeutic drugs(化学治疗药物) 汤慧芳 tanghuifang@zju.edu.cn Tel:88208230

2. (1)Chemotherapy(化学治疗, 简称化疗) (2)Chemotherapeutic drugs: Antimicrobial drugs(抗微生物药); Antiparasitic durgs(抗寄生虫药); Antineoplastic drugs(抗肿瘤药). (3)Antimicrobial drugs: Antibacterial drugs(抗菌药); Antifungal drugs(抗真菌药); Antiviral drugs(抗病毒药).

3. Contents Part 1.General considerations of anti-microbial agents Part2.-Lactam antibiotics Part 3. Macrolides (大环内酯类), lincomycins (林可霉素类), and vancomycins (万古霉素) Part 4. Aminoglycosides (氨基糖苷类) & polymyxins(多黏菌素类) Part 5. Tetracyclines(四环素类)& chloramphenicol(氯霉素) Part 6. Synthetic antimicrobial agents(人工合成抗菌药) Part 7. Antituberculous drugs & antileprotic drugs Part 8. Antifungal agents & Antiviral agents Part 9. The drugs treated parasitic infections

4. Antimicrobial drugs classification According to bioactivity • Anti G+ antibiotic • Anti G- antibiotic • Broad-spectrum antibiotic • Anti mycobacterium（分支杆菌） antibiotic • Anti anaerobe（厌氧菌） antibiotic • β- lactamase inhibitor

5. History of Antimicrobial Therapy 1909 Ehrlich discovers Salvarsan（撒尔佛散，治疗梅毒特效剂） “Magic bullet” for treatment of syphilis（梅毒） 1928 Fleming discovers penicillin(青霉素) 1932 Domagk discovers sulfonamides（磺胺类药物） 1940s Penicillin and streptomycin （链霉素）used widely, cephalosporins （头孢菌素）discovered 1947 Chloramphenicol （氯霉素）discovered, first broad spectrum agent 1950s Tetracycline （四环素）in use 1952 Erythromycin （红霉素）discovered (macrolides大环内酯类) 1956 Vancomycin （万古霉素）used for penicillin-resistant S. aureus 1957 Kanamycin（卡那霉素） discovered (aminoglycosides氨基苷类) 1962 Nalidixic acid （萘啶酸）discovered (quinolones喹诺酮类) 1980s Fluoroquinolones（氟喹诺酮类）, broad spectrum cephalosporins 2000s Newer agents to combat resistant pathogens

10. Part-1 General considerations of antimicrobial agents (抗微生物药物概论)

11. Contents 1.Overview 2. Term and definition 3. Classification and mechanism of antibacterial action 4. Bacterial resistance

12. 1. Overview: Antimicrobial drugs: Antibacterial drugs(抗菌药); Antifungal drugs(抗真菌药); Antiviral drugs(抗病毒药).

13. The relationship of the host, microorganisms, antimicrobial drugs. Adverse effects Resistance Pharmacokinetics Therapeutic Effects pathogenicity Immunological responses

14. Terminology 1. Antibacterial drugs(抗菌药) 2. Antibiotics(抗生素) 3. Bacteriostatic drugs(抑菌药) 4. Bactericidal drugs(杀菌药) 5. Antibacterial spectrum(抗菌谱) 6. Chemotherapetic index (化疗指数,CI) 7. Minimum inhibitory concentration (最小抑菌浓度, MIC) 8. Minimum bactericidal concentration (最小杀菌浓度, MBC) 9. Concentration Dependent killing 10. Post antibiotic effect (抗生素后效应,PAE) 11. Time-dependent killing

15. 2. Terms and definition: (1)Antibacterial drugs(抗菌药): Substances that can kill bacteria and/or inhibit its growth. including: ①Antibiotics(抗生素); ②Synthetic antimicrobial agents,such assulfonamides(磺胺类)andquinolones(喹诺酮类), etc.

16. Termsand definition (2)Antibiotics(抗生素): Substances produced by various species of microorganisms(bacteria, fungi, actinomyces, etc.), which can kill other microorganisms or inhibittheir growth.

17. Terms and definition (3)Chemotherapetic index: LD50/ED50,orLD5/ED95 (4)Antibacterialspectrum(抗菌谱); (5)Bacteriostatic drugs(抑菌药); (6)Bactericidal drugs(杀菌药);

18. Termsand definition agents

19. Termsand definition (7)Minimum inhibitory concent-ration(MIC); (8)Minimum bactericidal concen-tration(MBC): MBC ≥ MIC; if MBC > 32 times MIC  resistance.

20. Antimicrobial Susceptibility Testing 7. Minimum inhibitory concentration (MIC) 8. Minimum bactericidal concentration (MBC): 99.9% decrease in growth over 24 hours

21. Incubate 18 to 24 hr at 37℃ Measure diameters of nongrowth zones Disk diffusion method for testing bacteria for susceptibility to specific antimicrobial drugs.

22. Termsand definition 9. Concentration Dependent killing: situation in which the bactericidal activity of a drug depends by how much the drug concentration exceeds the Minimum inhibitory concentration of the organism in question. e.g. aminoglycosides and quinolones 10. Time-dependent killing: situation in which the bactericidal activity of a drug depends how long the drug concentration exceeds the Minimum inhibitory concentration of the organism in question. e.g. -lactams and vancomycin 11. Post antibiotic affect (PAE) : Persistence of suppression of bacterial growth after limited exposure to an antimicrobial agent. e.g. aminoglycosides

23. Classification and mechanism of antibacterial action: (1) inhibit synthesis of bacterial cell walls; (2) act directly on the cell membrane of the microorganism and affect its permeability, and leading to leakage of intracellular compounds; (3) inhibit protein synthesis; (4) affect bacterial nucleic acid metabolism; (5) The anti-metabolites of folic acid, that can block essential enzymes of folic acid synthetic metabolism.

24. Classification and mechanism of action ① ④ ⑤ ③ ②

25. Classification and mechanism of action (1)Inhibiting synthesis of bacterial cell walls: UDP-乙酰胞壁酸-5肽 双糖十肽聚合物

26. Classification and mechanism of action -Lactam antibiotics vancomycin transpeptidase

27. Classification and mechanism of action (2)Affecting permeability of membrane: ①Ionic-adsorbed(streptomycin); ②binding to ergosterol(amphotercin B); ③Inhibiting the synthesis of ergosterol (imidazoles); ④Surface-active agent, that interact strongly with phospholipids(polymixins).

28. Classification and mechanism of action (3)Inhibiting protein synthesis: affecting the function of 30S：streptomycin, Tetracyclines(四环素类) affecting the function of 50S： streptomycin, Macrolides (大环内酯类), lincomycins, chloramphenicol etc.

29. Inhibiting protein synthesis 利奈唑胺 氨基苷类 氨基苷类 氨基苷类 四环素类 氯霉素类 大环内酯类 林可霉素类

30. Classification and mechanism of action (4)Affecting bacterial nucleic acid metabolism: quinolones, etc.

31. Classificationandmechanismofaction (5)Blocking enzymes of folate metabolism: Pteridine(蝶啶)+PABA(对氨苯甲酸) Dihydropteroate synthase Blocked bysulfonamides Dihydropteroic acid(二氢蝶酸) Glutaminic acid Dihydrofolic acid(二氢叶酸) NADPH Dihydrofolate reductasease Blocked bytrimethoprim NADP Tetrahydrofolic acid(四氢叶酸)

32. Bacterial Resistance

33. 4. Bacterial resistance: (1)Category of resistance: ①Intrinsic resistance: • Inherent features • usually expressed by chromosomal genes ②Acquired resistance: • emerge from previously sensitive bacterial populations • Caused by mutations in chromosomal genes • Or by acquisition of plasmids or transposons

34. Bacterial Resistance (2)Mechanism of bacterial resistance: ①Enzymatic inactivation and modification; ②to inhance active efflux system: ③Decreased permeability; ④Target alteration;

35. Penicillin Bacterial Resistance Acetylation OM Phosphorylation Penicillinase b-lactam Kanamycin Inactive Adenylyation IM Mechanismofbacterialresistance ①To produce inactivated enzyme: 1B. Enzymatic modification e.g. Aminoglycoside modification 1A. Enzymatic inactivation e.g. b-lactamase

36. BacterialResistance Mechanismofbacterialresistance ②To enhance active efflux system(主动外排系统):

37. BacterialResistance Mechanismofbacterialresistance ③ Decreased permeability : Absence of, mutation in, or loss of the appropriate porins(膜孔蛋白) channel can slow the rate of drug entry into the cell, or prevent entry altogether, reducing the effectivedrugconcentrationat thetarget site.

38. Bacterial Resistance Mechanismofbacterialresistance Porin channel(膜孔蛋白通道)

39. BacterialResistance Mechanismofbacterialresistance ④ Target alteration : Mutationof the natural target(such as resistance to fluoroquinolone). Target modification(ribosomal protection type of resistance to macrolides and tetracyclines). Substitution with a resistant alternative to the natural, susceptible target (such asmethicillinresistance in staphylococci).

40. BacterialResistance The transfer of resistance genes: ①Mutations(突变); ②Transduction(转导); ③Transformation(转化); ④Conjugation(接合).

41. Bacterial Resistance The transfer of resistance genes ①Mutations(突变): which may occur in the gene encoding. 1)The target protein; 2)The protein involved in drug transport; 3)Act on regulatory gene or promoter(启动子)affecting expression of the target, a transport protein, or an inactivating enzyme. suchas aminoglycosides,quinolones,etc.

42. BacterialResistance Thetransferofresistancegenes

43. Mutations May occur in the gene encoding i) The target protein ii) A protein involved in drug transport iii) A protein important for drug activation iv) A regulatory gene or promoter affecting expression of the target, a transport protein, or an inactivating enzyme.

44. BacterialResistance Thetransferofresistancegenes ②Transduction(转导): acquisition of bacterial DNA from bacteriophage(噬菌体) that has incorporated DNAfromaprevioushostbacteriumwithin its outer protein coat. Some phages can carry plasmids that code for penicillinase, or genes encod-ing resistance to erythromycin, tetracy-cline, or chioramphenicol.

45. Transduction

46. Bacterial Resistance Thetransferofresistancegenes ③Transformation(转化): Uptake and incorporation of DNA that is free in the environment into the host genome by homologous recombination.

47. BacterialResistance Thetransferofresistancegenes

48. BacterialResistance Thetransferofresistancegenes ④Conjugation(接合): The passage of genes from cell to cell by direct contact through a sex pilus(性菌毛) or bridge(桥接).

49. BacterialResistance • Conjugation • Transformation