chemotherapeutic drugs wei-ping zhang, phd 张纬萍 dept. of pharmacology, school of medicine,...

Chemotherapeutic DrugsChemotherapeutic Drugs

Wei-Ping Zhang, PhDWei-Ping Zhang, PhD

张纬萍张纬萍Dept. of Pharmacology, Dept. of Pharmacology,

School of Medicine, Zhejiang UniversitySchool of Medicine, Zhejiang [email protected]@zju.edu.cn

2013.12.16

General ConsiderationsGeneral Considerationsfor chemotherapeutic drugsfor chemotherapeutic drugs

Chapter 34Chapter 34

OverviewOverview

I. ChemotherapyI. Chemotherapy

II. Chemotherapeutic agentsII. Chemotherapeutic agents

III. Mechanisms under the action of III. Mechanisms under the action of chemotherapeutic agentschemotherapeutic agents

IV. Bacterial ResistanceIV. Bacterial Resistance

V. Basic principle of clinical usage of V. Basic principle of clinical usage of antimicrobial agentsantimicrobial agents

The Birth of Modern Chemotherapy: Dreams of a “Magic Bullet”

I. Chemotherapy

Louis Pasteur 1822-1895

Robert Koch 1843-1910

Rebecca Lancefield 1896-1981

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

I. Chemotherapy

1928 Fleming discovers penicillin1928 Fleming discovers penicillin

History of Antimicrobial TherapyHistory of Antimicrobial TherapyI. Chemotherapy

1928

History of Antimicrobial TherapyHistory of Antimicrobial Therapy• 1928 Fleming discovers penicillin ( 青霉素 ) • 1932 Domagk discovers sulfonamides （磺胺类）• 1940s Penicillin and streptomycin （链霉素） used widely,

cephalosporins （头孢霉素） 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 ，大环内脂

类 )• 1956 Vancomycin （万古霉素） used for penicillin-resistant S.

aureus• 1957 Kanamycin （卡那霉素） discovered (aminoglycosides ，氨

基糖苷类 )• 1962 Nalidixic acid （奈啶酸） discovered (quinolones ，喹诺酮类 )• 1980s Fluoroquinolones （氟喹诺酮） , broad spectrum

cephalosporins （广谱头孢类）• 2000s Newer agents to combat resistant pathogens

I. Chemotherapy

History of Antimicrobial TherapyHistory of Antimicrobial Therapy

I. Chemotherapy

Endless way ………………

Superbug……drug resistance

MRSAMRSA ，， NAM-1NAM-1

II. Chemotherapeutic agents

Pharm

acokineti

Pharm

acokineti

cscs

Adverse

Adverse

effects

effects

pathogenicipathogenicityty

ImmunologicalImmunologicalresponsesresponses

Ther

apeu

tic

Ther

apeu

tic

Effec

ts

Effec

ts

Res

ista

nce

Res

ista

nce

Host FactorsHost Factors ：： patient’s age, patient’s age, gender, gender, constitution, constitution, hepatic, renal hepatic, renal function function



Antimicrobial drugsAntimicrobial drugs

Antibacterial drugsAntibacterial drugs

Antifungal drugsAntifungal drugs

Antiviral drugsAntiviral drugs

Antiparasitic durgsAntiparasitic durgs

Antineoplastic / anticancer drugsAntineoplastic / anticancer drugs

Ideal antimicrobial drugsIdeal antimicrobial drugs

High sensitivityHigh sensitivity Nontoxic or low-toxic (safety)Nontoxic or low-toxic (safety) NonresistanceNonresistance Satisfied pharmacokinetic Satisfied pharmacokinetic

propertiesproperties Good priceGood price


Antibacterial drugs (Antibacterial drugs ( 抗菌药抗菌药 ))

kill bacteria and arresting its growthkill bacteria and arresting its growth

antibioticsantibiotics and and synthetic synthetic

antimicrobial agentsantimicrobial agents such as such as

sulfonamidessulfonamides(( 磺胺类磺胺类 )) and and

quinolones quinolones (( 喹诺酮类喹诺酮类 ))..


AntibioticsAntibiotics （抗生素）（抗生素） Produced by various species of Produced by various species of

microorganisms (bacteria, fungi , microorganisms (bacteria, fungi ,

actinomycetes) and semi-syntheticactinomycetes) and semi-synthetic

Suppress the growth of other Suppress the growth of other

microorganisms.microorganisms.


Antibacterial spectrumAntibacterial spectrum （抗菌谱）（抗菌谱）• Narrow?Narrow?• Broad?Broad?

Chemotherapetic index (CI)Chemotherapetic index (CI) （化疗指（化疗指数）数）

• CI= LDCI= LD50 50 / ED/ ED50 50

• CI= LDCI= LD5 5 / ED/ ED9595


TD50

药理作用药理作用

ED95 LD5


中毒作用中毒作用致死作用致死作用

Bacteriostatic drugs Bacteriostatic drugs （抑菌药）（抑菌药）inhibit the growth of microorganisms inhibit the growth of microorganisms

e.g. Sulfonamides, Tetracyclinee.g. Sulfonamides, Tetracycline

Bactericidal drugs Bactericidal drugs （杀菌药）（杀菌药）• kill microorganismskill microorganisms

e.g. Penicillin, Aminoglycosidese.g. Penicillin, Aminoglycosides


Bactericidal vs Bacterostatic


Minimum inhibitory concentration Minimum inhibitory concentration (MIC)(MIC)

最低抑菌浓度最低抑菌浓度

Minimum bactericidal concentration Minimum bactericidal concentration (MBC)(MBC)

最低杀菌浓度最低杀菌浓度

Post antibiotic effect Post antibiotic effect (PAE) (PAE)

抗生素后效应抗生素后效应

Resistance Resistance （（耐药性耐药性））

Cross Resistance Cross Resistance （（交叉耐药性交叉耐药性））

First expose effect First expose effect （（首次接触效应首次接触效应））


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.


III. Mechanism of action

1. Inhibit synthesis of bacterial cell walls1. Inhibit synthesis of bacterial cell walls

2. Affecting permeability of cell membrane 2. Affecting permeability of cell membrane

and leading to leakage of intracellular and leading to leakage of intracellular

compoundscompounds

3. Inhibit protein synthesis3. Inhibit protein synthesis

4. Affect bacterial nucleic acid metabolism4. Affect bacterial nucleic acid metabolism

5. Block essential enzymes of folate 5. Block essential enzymes of folate

metabolism metabolism


1.1. Inhibiting synthesis of bacterial cell wallsInhibiting synthesis of bacterial cell walls e.g. penicillins, e.g. penicillins, -lactams-lactams



乙酰胞壁酸乙酰胞壁酸 -5-5 肽肽乙酰胞壁酸乙酰胞壁酸 -5-5 肽肽

UDP-UDP- 乙酰葡萄糖胺乙酰葡萄糖胺

2. Affecting permeability of membrane2. Affecting permeability of membrane

Ionic- sorbent （离子吸附剂离子吸附剂） e.g. Aminoglycosides e.g. Aminoglycosides （氨基糖苷类）（氨基糖苷类）

Binding to ergosterol Binding to ergosterol （麦角固醇）（麦角固醇） e.g. Nystatin (e.g. Nystatin ( 制霉菌素制霉菌素 ))

Amphotericin BAmphotericin B （（两性霉素两性霉素））

Cationic detergentCationic detergent

e.g. polymyxinse.g. polymyxins （多粘菌素）（多粘菌素）


Lipopoly-saccharide

Outermembrane

Peptidoglycan

Cytoplasmicmembrane

polymyxinspolymyxins

2. Affecting permeability of membrane 2. Affecting permeability of membrane


Ribosomal structure

• Bacteria 30S + 50S 70S30S subunit

• binds mRNA in initiation complex• holds growing peptide chain

50S subunitaccepts / translocates charged tRNAs

• "A" site --> Aminoacyl-tRNA (acceptor) site • "P" site --> Peptidyl-tRNA (donor) site

• Mammals 40S + 60S 80S

3. Inhibiting protein synthesis 3. Inhibiting protein synthesis


3. Inhibiting protein synthesis3. Inhibiting protein synthesis

PP AA


3. Inhibiting protein synthesis3. Inhibiting protein synthesis

PP AA


氨基糖苷类四环素

大环内酯类

氨基糖苷类

氯霉素林可霉素

4. Affecting bacterial nucleic acid metabolism4. Affecting bacterial nucleic acid metabolism

quinolones

(-)(-)

Break back Break back segmentsegment

(+)(+)

(-)(-)


Rifampicin ( 利福平 ): inhibit DNA-dependent RNA polymerase

Ridarabine ( 阿糖腺苷 ), Ganciclovir ( 更昔洛韦 ) inhibit DAN polymerase

Pteridine + PABA

Blocked by sulfonamides

Dihydropteroic acid

Dihydrofolic acid

glutamate

Tetrahydrofolic acid

Blocked by trimethoprim

NADPH

NADPH

Dihydropteroatesynthase

Dihydrofolatereductasease

5. block essential enzymes of folate metabolism5. block essential enzymes of folate metabolism


蝶啶对氨基苯甲酸

二氢蝶酸

甲氧苄啶

Intrinsic resistanceIntrinsic resistance – – Inherent features Inherent features ，， usually expressed by usually expressed by chromosomal geneschromosomal genes

Acquired resistanceAcquired resistance – – Emerge from previously sensitive bacterial Emerge from previously sensitive bacterial populationspopulations – – Caused by mutations in chromosomal Caused by mutations in chromosomal genesgenes – – Or by acquisition of plasmids or Or by acquisition of plasmids or transposonstransposons

IV. Bacterial Resistance

• The drug is not active.The drug is not active.

• The target is altered.The target is altered.

• The drug does not reach its target. The drug does not reach its target.

Bacterial Resistance- MechanismsBacterial Resistance- Mechanisms


Production of aminoglycoside-modifying Production of aminoglycoside-modifying enzymes and β-lactamase;enzymes and β-lactamase;

1.The drug is not active.1.The drug is not active.


2.The target is altered2.The target is altered

Mutation of the natural Mutation of the natural

target (quinolone target (quinolone

resistance)resistance)

Substitution with a Substitution with a

resistant alternative to the resistant alternative to the

native, susceptible target native, susceptible target

(methicillin(methicillin （甲氧西林）（甲氧西林） resistance) resistance)


Target modification Target modification

(ribosomal protection (ribosomal protection

type of resistance to type of resistance to

macrolides and macrolides and

tetracyclines)tetracyclines)

2.The target is altered2.The target is altered


Absence, mutation or Absence, mutation or

loss of the appropriate loss of the appropriate

transportertransporter or or porins porins

(( 膜孔蛋白）膜孔蛋白）

3.The drug does not reach its target 3.The drug does not reach its target


Active efflux system Active efflux system (( 主主动排出系统动排出系统 ) )

Efflux transporterEfflux transporter（转运子）（转运子）

Accessory protein Accessory protein （附加蛋白）（附加蛋白）

Outer membrane Outer membrane channelchannel （外膜蛋白）（外膜蛋白）

3.The drug does not reach its target 3.The drug does not reach its target


Active efflux systemActive efflux system （主动排出系统）（主动排出系统）

transportertransporter Accessory proteinAccessory protein

Outer membraneOuter membranechannelchannel


Laura J. V. PiddockNature Reviews Microbiology 4, 629-636 (August 2006)


Mutations Mutations 突变突变 Transduction Transduction 转导转导 Transformation Transformation 转化转化 Conjugation Conjugation 接合接合

The transfer of Resistance genes The transfer of Resistance genes


From human From human human human

From bacteria From bacteria bacteria bacteria

IntracellularIntracellular

Mutations Mutations 突变突变


May occur in the gene encodingMay occur in the gene encoding

The target proteinThe target protein

A protein involved in drug transportA protein involved in drug transport

A protein important for drug activation A protein important for drug activation

A regulatory gene or promoter affecting A regulatory gene or promoter affecting expression of the target, a transport protein, expression of the target, a transport protein, or an inactivating enzyme or an inactivating enzyme

Mutations Mutations 突变突变


Transduction Transduction 转导转导


•Transformation Transformation 转化转化 •Conjugation Conjugation 接合接合


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

1.1. Methicillin-resistant staphylococcus Methicillin-resistant staphylococcus aureus, MRSAaureus, MRSA

甲氧西林耐药金黄色葡萄球菌甲氧西林耐药金黄色葡萄球菌

Methicillin-resistant coagulase Methicillin-resistant coagulase negative staphylococci, MRCNS negative staphylococci, MRCNS 甲氧西林凝固酶阴性葡萄球菌甲氧西林凝固酶阴性葡萄球菌

PBP-2a PBP-2a （（ a 78kD new PBa 78kD new PBPP ））


Multi-drug resistance MDR Multi-drug resistance MDR

2.2. Penicillin-resistant streptococcus pneumoniae, Penicillin-resistant streptococcus pneumoniae,

PRSPPRSP ，，青霉素耐药肺炎链球菌青霉素耐药肺炎链球菌• PBP-1a, PBP-2a, PBP-2x, PBP-2b PBP-1a, PBP-2a, PBP-2x, PBP-2b （（ 78-100 kD78-100 kD ））• Active efflux system Active efflux system （（ express mef(A)express mef(A) 对大环内酯对大环内酯

类）类）

3.3. Vancomycin-resistant Enterococcus, VREVancomycin-resistant Enterococcus, VRE

万古霉素耐药肠球菌万古霉素耐药肠球菌• PBP avidity ↓PBP avidity ↓

• van-A, van-B, van C-1, van C-2, van D, van Evan-A, van-B, van C-1, van C-2, van D, van E


4. The 34. The 3rdrd generation-cephalosporins -resistant generation-cephalosporins -resistant

• Extended spectrumβ-lactamases, ESBLExtended spectrumβ-lactamases, ESBL

超广谱超广谱 β- β- 内酰胺酶内酰胺酶 • Class I chromosone mediated β-lactamases Class I chromosone mediated β-lactamases

II 类染色体介导的类染色体介导的 β- β- 内酰胺酶内酰胺酶 • E.g. E.g. 大肠埃希菌、克雷伯肺炎杆菌、阴沟肠杆菌大肠埃希菌、克雷伯肺炎杆菌、阴沟肠杆菌



5.5. Carbapenem (Carbapenem ( 碳青霉烯碳青霉烯 ) –resistant) –resistant ：对亚胺：对亚胺培南的铜绿假单胞菌敏感培南的铜绿假单胞菌敏感

• OprD porinOprD porin• Metalβ-lactamases Metalβ-lactamases （金属（金属 β- β- 内酰胺酶内酰胺酶））6. Quinolone-resistant escherichia coli6. Quinolone-resistant escherichia coli （大肠（大肠

埃希菌）埃希菌） , AREC, AREC• Active efflux systemActive efflux system• Cross-resistanceCross-resistance



superbug or super bacterium

Antimicrobial drugsAntimicrobial drugs -Characteristics -Characteristics

Basic principle of clinical usage of antimicrobial agentsBasic principle of clinical usage of antimicrobial agents

Some laboratory techniques that are useful in the diagnosis of microbial diseases

According to bio-activityAccording to bio-activity

Anti GAnti G++ antibiotic antibiotic Anti GAnti G-- antibiotic antibiotic Broad-spectrum antibioticBroad-spectrum antibiotic Anti mycobacterium antibioticAnti mycobacterium antibiotic Anti anaerobe antibioticAnti anaerobe antibiotic - lactamase inhibitor- lactamase inhibitor



According to the chemical structureAccording to the chemical structure ：：1.1. -lactams (-lactams (-- 内酰胺类）；内酰胺类）； PenicillinsPenicillins （青霉（青霉

素类）；素类）； CephalosporinsCephalosporins （头孢菌素类）（头孢菌素类） ;;

2.2. Aminoglycosides(Aminoglycosides( 氨基糖苷类氨基糖苷类 ););

3.3. MacrolidesMacrolides （大环内酯类）（大环内酯类） ; Lincosamides; Lincosamides（林可胺类）（林可胺类） ;Vancomycins;Vancomycins （万古霉素类）（万古霉素类）

4.4. TetracyclinesTetracyclines （四环素类）；（四环素类）； Chloramphenicol (Chloramphenicol ( 氯霉素氯霉素 ))



5. Quinolones (5. Quinolones ( 喹诺酮类喹诺酮类 ))

6. Sulphonamides (6. Sulphonamides ( 磺胺类磺胺类 ))

7. Nitrofurans (7. Nitrofurans ( 硝基呋喃类硝基呋喃类 ))

8. Antimycobacterial agents (8. Antimycobacterial agents ( 抗结核分抗结核分支杆菌类支杆菌类 ) )

9. others: 9. others:

OxazolidinonesOxazolidinones （恶唑烷酮类）（恶唑烷酮类） StreptograminsStreptogramins （链阳菌素类）（链阳菌素类）



Some clinical situation in which prophylactic antibiotics


防止抗菌药物的不合理应用的注意点：防止抗菌药物的不合理应用的注意点：

11 ）抗菌药物对病毒无治疗作用，除非伴有细菌感染或）抗菌药物对病毒无治疗作用，除非伴有细菌感染或继发感染，一般病毒感染不应该使用抗菌药物；继发感染，一般病毒感染不应该使用抗菌药物；

22 ）原因未明的发热者，除非伴有感染，一般不使用抗）原因未明的发热者，除非伴有感染，一般不使用抗菌药物治疗；菌药物治疗；

33 ）应尽量避免抗菌药物的局部应用，否则可引起细菌）应尽量避免抗菌药物的局部应用，否则可引起细菌耐药和变态反应；耐药和变态反应；

44 ）使用抗菌药物剂量要适宜，疗程要足够。）使用抗菌药物剂量要适宜，疗程要足够。

I. ChemotherapyI. Chemotherapy

II. Chemotherapeutic agentsII. Chemotherapeutic agents

terminologyterminology

III. Mechanisms under the action of III. Mechanisms under the action of chemotherapeutic agentschemotherapeutic agents

Inhibiting synthesis of bacterial cell wallsInhibiting synthesis of bacterial cell walls

Affecting permeability of membraneAffecting permeability of membrane

Inhibiting protein synthesisInhibiting protein synthesis

Affecting bacterial nucleic acid metabolismAffecting bacterial nucleic acid metabolism

Block essential enzymes of folate metabolismBlock essential enzymes of folate metabolism

Summary

IV. Bacterial ResistanceIV. Bacterial Resistance Intrinsic resistanceIntrinsic resistance

– – Inherent features Inherent features ，， usually expressed by usually expressed by

chromosomal geneschromosomal genes Acquired resistanceAcquired resistance

– – Emerge from previously sensitive bacterial Emerge from previously sensitive bacterial

populationspopulations

– – Caused by mutations in chromosomal Caused by mutations in chromosomal

genesgenes

– – Or by acquisition of plasmids or Or by acquisition of plasmids or

transposonstransposons

V. Basic principle of clinical usage of antimicrobial V. Basic principle of clinical usage of antimicrobial agentsagents

chemotherapeutic drugs wei-ping zhang, phd 张纬萍 dept. of pharmacology, school of medicine,...

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