BlockⅤ: pharmacology Chemotherapeutic drugs

( 化学治疗药物 )

汤慧芳tanghuifang@zju.edu.cn

Tel:88208230

(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 ).

ContentsContents

Part 1.Part 1. General considerations of anti-microbial General considerations of anti-microbial agentsagents

PartPart 2.2. -Lactam antibiotics-Lactam antibioticsPart 3. Macrolides Part 3. Macrolides (( 大环内酯类大环内酯类 )), lincomycins , lincomycins (( 林可霉素林可霉素

类类 ),), and vancomycins and vancomycins (( 万古霉素万古霉素 ))Part 4. Aminoglycosides Part 4. Aminoglycosides (( 氨基糖苷类氨基糖苷类 ) ) & polymyxins& polymyxins(( 多多

黏菌素类黏菌素类 ))Part 5. Tetracyclines(Part 5. Tetracyclines( 四环素类四环素类 ))& chloramphenicol& chloramphenicol(( 氯氯

霉素霉素 ))Part 6. Synthetic antimicrobial agentsPart 6. Synthetic antimicrobial agents(( 人工合成抗菌药人工合成抗菌药 ))Part 7. Antituberculous drugs & antileprotic drugsPart 7. Antituberculous drugs & antileprotic drugsPart 8. Antifungal agents & Antiviral agentsPart 8. Antifungal agents & Antiviral agentsPart 9. The drugs treated parasitic infectionsPart 9. The drugs treated parasitic infections

According to bioactivityAccording to bioactivity

Anti GAnti G++ antibiotic antibiotic Anti GAnti G-- antibiotic antibiotic Broad-spectrum antibioticBroad-spectrum antibiotic Anti mycobacteriumAnti mycobacterium （ 分 支杆菌） （ 分 支杆菌）

antibioticantibiotic Anti anaerobeAnti anaerobe （厌氧菌） （厌氧菌） antibioticantibiotic β- lactamase inhibitorβ- lactamase inhibitor

Antimicrobial drugs Antimicrobial drugs classificationclassification

History of Antimicrobial TherapyHistory 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, cephalos

porins （头孢菌素） discovered1947 Chloramphenicol （氯霉素） discovered, first broad spectrum a

gent1950s Tetracycline （四环素） in use1952 Erythromycin （红霉素） discovered (macrolides 大环内酯类 )1956 Vancomycin （万古霉素） used for penicillin-resistant S. aureus1957 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 cephalosp

orins2000s Newer agents to combat resistant pathogens

Part-1Part-1

General General considerations of considerations of antimicrobial antimicrobial agentsagents(( 抗微生物药物概论抗微生物药物概论 ))

Contents

1. Overview2. Term and definition3. Classification and

mechanism of antibacterial action

4. Bacterial resistance

1. Overview:

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

Pharm

acokineti

Pharm

acokineti

cscs

Adverse

Adverse

effects

effects

pathogenicipathogenicityty

ImmunologicalImmunologicalresponsesresponses

Ther

apeu

tic

Ther

apeu

tic

Effec

ts

Effec

ts

Res

ista

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Res

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The relationship of the host,

microorganisms, antimicrobial drugs.

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 killing10. Post antibiotic effect ( 抗生素后效应 ,PAE) 11. Time-dependent killing

TerminologyTerminology

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 as sulfonamides( 磺胺类 ) and quinolones( 喹诺酮类 ), etc.

(2)Antibiotics( 抗生素 ):

Substances produced by various species of microorganisms(bacteria, fungi, actinomyces, etc.), which can kill other microorganisms or inhibit their growth.

Terms and definition

(3)Chemotherapetic index: LD50/ED50, or LD5/ED95

(4)Antibacterial spectrum( 抗菌谱 );

(5)Bacteriostatic drugs( 抑菌药 );

(6)Bactericidal drugs( 杀菌药 );

Terms and definition

agentagentss

Terms and definition

(7)Minimum inhibitory concent-ration(MIC);

(8)Minimum bactericidal concen-tration(MBC):

MBC ≥ MIC;

if MBC > 32 times MIC resistance.

Terms and definition

Antimicrobial Susceptibility Testing

7. Minimum inhibitory 7. Minimum inhibitory concentration concentration (MIC)(MIC)

8. Minimum 8. Minimum bactericidal bactericidal concentration concentration (MBC): (MBC): 99.9% decrease in growth over 24 hours

Incubate 18 to 24 hr at 37℃

Measure Measure diameters ofdiameters ofnongrowthnongrowthzoneszones

Disk diffusion method for testing bacteria for susceptibility to specific antimicrobial drugs. Disk diffusion method for testing bacteria for susceptibility to specific antimicrobial drugs.

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) (PAE) : Persistence of suppression of bacterial growth after limited exposure to an antimicrobial agent. e.g. aminoglycosides

Terms and definition

(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.

Classification and mechanism of antibacterial action:

①①

②②

③③

④④

⑤⑤

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

Classification and mechanism of action

transpeptidasetranspeptidase

vancomycivancomycinn

-Lactam -Lactam antibioticsantibiotics

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).

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.

Classification and mechanism of action

氨基苷类

氨基苷类

氨基苷类

四环素类

大环内酯类 氯霉素类

林可霉素类

Inhibiting protein synthesis

利奈唑胺

(4)Affecting bacterial nucleic acid metabolism: quinolones, etc.

Classification and mechanism of action

Pteridine(Pteridine( 蝶啶蝶啶 )) ++ PABA(PABA( 对氨苯甲对氨苯甲酸酸 ))

Blocked by sulfonamidessulfonamides

Dihydropteroic acid(Dihydropteroic acid( 二氢蝶酸二氢蝶酸 ))

Dihydrofolic acid(Dihydrofolic acid( 二氢叶酸二氢叶酸 ))

Glutaminic Glutaminic acidacid

Tetrahydrofolic acid(Tetrahydrofolic acid( 四氢叶四氢叶酸酸 ))

Blocked by trimethoprimtrimethoprim

NADPHNADPH

NADNADPP

Dihydropteroate

synthase

Dihydrofolate

reductasease

(5)Blocking enzymes of folate (5)Blocking enzymes of folate metabolism:metabolism:

Classification and mechanism of action

Bacterial ResistanceBacterial Resistance

4. Bacterial resistance:

(1)Category of resistance:(1)Category of resistance: ①①Intrinsic resistance:Intrinsic resistance: Inherent features Inherent features usually expressed by chromosomal usually expressed by chromosomal

genesgenes ② ②Acquired resistance:Acquired resistance: emerge from previously sensitive emerge from previously sensitive

bacterial populationsbacterial populations Caused by mutations in chromosomal genesCaused by mutations in chromosomal genes Or by acquisition of plasmids or Or by acquisition of plasmids or

transposonstransposons

Bacterial Resistance (2)Mechanism of bacterial resistance:

①Enzymatic inactivation and modification;

②to inhance active efflux system:③Decreased permeability;④Target alteration;

IM

OM

Penicillin

-lactamPenicillinase

Inactive

1A. Enzymatic inactivatione.g. b-lactamase

①To produce inactivated enzyme:

Kanamycin

Acetylation

Phosphorylation

Adenylyation

1B. Enzymatic modification e.g. Aminoglycoside modification

Bacterial Resistance Mechanism of bacterial resistance

② To enhance active efflux system(主动外排系统 ):

Bacterial Resistance Mechanism of bacterial resistance

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 effective drug concentration at the

target site.

Bacterial Resistance Mechanism of bacterial resistance

Porin channel( 膜孔蛋白通道 )

Bacterial Resistance Mechanism of bacterial resistance

④ Target alteration : Mutation of 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 as methicillin resistance in staphylococci).

Bacterial Resistance Mechanism of bacterial resistance

The transfer of resistance genes:

Bacterial Resistance

①Mutations( 突变 );

②Transduction( 转导 );

③Transformation( 转化 );

④Conjugation( 接合 ).

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.

such as aminoglycosides, quinolones, etc.

Bacterial Resistance The transfer of resistance genes

Mutations Mutations

May occur in the gene encodingMay occur in the gene encoding

i) The target proteini) The target protein

ii) A protein involved in drug transportii) A protein involved in drug transport

iii) A protein important for drug activation iii) A protein important for drug activation

iv) A regulatory gene or promoter iv) A regulatory gene or promoter

affecting expression of the target, a affecting expression of the target, a

transport protein, or an inactivating transport protein, or an inactivating

enzyme. enzyme.

②Transduction( 转导 ): acquisition of bacterial DNA from bacteriophage( 噬菌体 ) that has incorporated DNA from a previous

host bacterium within its outer protein coat. Some phages can carry plasmids that code for penicillinase, or genes encod-ing resistance to erythromycin, tetracy-cline, or chioramphenicol.

Bacterial Resistance The transfer of resistance genes

Transduction Transduction

Bacterial Resistance The transfer of resistance genes

③Transformation( 转化 ):

Uptake and incorporation of DNA that is free in the environment into the host genome by homologous recombination.

Bacterial Resistance The transfer of resistance genes

Bacterial Resistance The transfer of resistance genes

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 ).

Transformation Transformation Conjugation Conjugation

Bacterial Resistance

Multi-drug resistance MDR Multi-drug resistance MDR (( 了解了解 ))

1.1. 耐甲氧西林金葡菌耐甲氧西林金葡菌 MRSAMRSA 社区获得性耐甲氧西林金葡菌（社区获得性耐甲氧西林金葡菌（ community-associatedcommunity-associated 。。

CA—MRSACA—MRSA ）） 医院获得性耐甲氧西林金葡菌（ 医院获得性耐甲氧西林金葡菌（ Hospital-associated Hospital-associated ，，

HA-MRSAHA-MRSA2.2. Methicillin-resistant coagulase negative staphylococci, Methicillin-resistant coagulase negative staphylococci,

MRCNS MRCNS PBP-2aPBP-2a

3.Penicillin-resistant streptococcus pneumoniae, PRSP3.Penicillin-resistant streptococcus pneumoniae, PRSP PBP-1a, PBP-2a, PBP-2x, PBP-2bPBP-1a, PBP-2a, PBP-2x, PBP-2b Active efflux systemActive efflux system4.Vancomycin-resistant Enterococcus, VRE4.Vancomycin-resistant Enterococcus, VRE van-A, van-B, van C-1, van C-2, van C-3, van D, van Evan-A, van-B, van C-1, van C-2, van C-3, van D, van E

5. The 35. The 3rdrd generation-cephalosporins - generation-cephalosporins -resistant resistant

• Extended spectrumβ-lactamases, Extended spectrumβ-lactamases, ESBLESBL

• Class I chromosone mediated β-Class I chromosone mediated β-lactamaseslactamases

6.Carbapenem -resistant6.Carbapenem -resistant

• OprD porinOprD porin

7.Quinolone-resistant escherichia coli, 7.Quinolone-resistant escherichia coli, ARECAREC

• Active efflux systemActive efflux system

Multi-drug resistance MDR Multi-drug resistance MDR (( 略略 ))

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