Chemotherapeutic Drugs Wei-Ping Zhang, PhD 张纬萍 Dept. of Pharmacology, School of Medicine,...
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Transcript of 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
II. Chemotherapeutic agents
II. Chemotherapeutic agents
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
II. Chemotherapeutic agents
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 ))..
II. Chemotherapeutic agents
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.
II. Chemotherapeutic agents
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
II. Chemotherapeutic agents
TD50
药理作用药理作用
ED95 LD5
II. Chemotherapeutic agents
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
II. Chemotherapeutic agents
Bactericidal vs Bacterostatic
II. Chemotherapeutic agents
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))
II. Chemotherapeutic agents
II. Chemotherapeutic agents
最低抑菌浓度最低抑菌浓度
最低杀菌浓度最低杀菌浓度
最低抑菌浓度最低抑菌浓度
最低杀菌浓度最低杀菌浓度
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.
II. Chemotherapeutic agents
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
III. Mechanism of action
1.1. Inhibiting synthesis of bacterial cell wallsInhibiting synthesis of bacterial cell walls e.g. penicillins, e.g. penicillins, -lactams-lactams
III. Mechanism of action
III. Mechanism of action
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)
III. Mechanism of action
Lipopoly-saccharide
Outermembrane
Peptidoglycan
Cytoplasmicmembrane
polymyxinspolymyxins
2. Affecting permeability of membrane 2. Affecting permeability of membrane
III. Mechanism of action
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
III. Mechanism of action
3. Inhibiting protein synthesis3. Inhibiting protein synthesis
PP AA
III. Mechanism of action
3. Inhibiting protein synthesis3. Inhibiting protein synthesis
PP AA
III. Mechanism of action
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
(+)(+)
(-)(-)
III. Mechanism of action
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
III. Mechanism of action
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
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
IV. Bacterial Resistance
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.
IV. Bacterial Resistance
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)
IV. Bacterial 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
IV. Bacterial Resistance
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
IV. Bacterial Resistance
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
IV. Bacterial Resistance
Active efflux systemActive efflux system (主动排出系统 )(主动排出系统 )
transportertransporter Accessory proteinAccessory protein
Outer membraneOuter membranechannelchannel
IV. Bacterial Resistance
Laura J. V. PiddockNature Reviews Microbiology 4, 629-636 (August 2006)
IV. Bacterial Resistance
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
IV. Bacterial Resistance
From human From human human human
From bacteria From bacteria bacteria bacteria
IntracellularIntracellular
Mutations Mutations 突变突变
IV. Bacterial Resistance
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
IV. Bacterial Resistance
Transduction Transduction 转导转导
IV. Bacterial Resistance
•Transformation Transformation 转化转化 •Conjugation Conjugation 接合接合
IV. Bacterial Resistance
IV. Bacterial Resistance
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 ))
IV. Bacterial Resistance
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
IV. Bacterial Resistance
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
Multi-drug resistance MDR Multi-drug resistance MDR
IV. Bacterial Resistance
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
Multi-drug resistance MDR Multi-drug resistance MDR
IV. Bacterial 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
Antimicrobial drugsAntimicrobial drugs -Characteristics -Characteristics
Basic principle of clinical usage of antimicrobial agentsBasic principle of clinical usage of antimicrobial agents
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 ))
Antimicrobial drugsAntimicrobial drugs -Characteristics -Characteristics
Basic principle of clinical usage of antimicrobial agentsBasic principle of clinical usage of antimicrobial agents
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)
Basic principle of clinical usage of antimicrobial agentsBasic principle of clinical usage of antimicrobial agents
Basic principle of clinical usage of antimicrobial agentsBasic principle of clinical usage of antimicrobial agents
Some clinical situation in which prophylactic antibiotics
Basic principle of clinical usage of antimicrobial agentsBasic principle of clinical usage of antimicrobial agents
Some clinical situation in which prophylactic antibiotics
Basic principle of clinical usage of antimicrobial agentsBasic principle of clinical usage of antimicrobial agents
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