Transcript INTRODUCTION TO CHEMOTHERAPEUTIC DRUGS

Chapter 38
Introduction To
Chemotherapeutic Drugs
Brief History of
Chemotherapeutic Drugs
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1910 Ehrlich Arsphnamine(砷凡纳明 )
chemotherapy
1929 Fleming
1940 Florey and Chain
Penicilin
1935 Domagk Prontosil（百浪多息）
1960’s β-Lactam antibiotics
1970’s Fluoroquinolones
1980’s New Macrolides
Paul Ehrlich
青霉素发明者、英国科学家
弗莱明在他的实验室内
澳大利亚病理学家霍华德.弗罗里因进行
青霉素化学制剂的研究，而与弗莱明
1945年诺贝尔生理学和医学奖
Domagk
Relationship between pathogen ,
chemotherapeutic drugs and patients
host
Antimicrobial action
Antimicrobial agents
mycrobacterium
resistance
Several Terms related to Chemotherapy
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Antimicrobial drugs(Antibacterial drugs, antifungal
drugs, antiviral drugs)
Chemotherapy
Antibacterial drugs
Antibiotics
Antibacterial spectrum
Antibacterial activity
Minimal inhibitory concentration (MIC)
Minimal bactericidal concentration (MBC)
Bacteriostatic drugs
Bactericidal drugs
Chemotherapeutic index(CI)
Post-antibiotic effect ( PAE )
Mechanism of action of the
Antibacterial Agents
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Inhibiting the biosynthesis of the cell wall
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β-lactam
Increasing the permeability of the
cytoplasmic membrane
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Aminoglycosides
Imidazoles(miconazole, ketoconazole)
Polymixins
Amphotericin B/nystatin
Mechanism of action of
Antimicrobial Agents
 Inhibition
of protein synthesis
 Aminoglycosides
 Tetracyclines
 Chloramphenicol
 Macrolides
 Clindamycin
Mechanism of action of
Antimicrobial Agents
 Interfering
the metabolism of
nucleotides and folic acid
 Rifampicin
 Quinolones
 Sulfonamides
Resistances of Bacteria
 Reasons
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Antibiotics abuse
 Classification
 Intrinsic
resistance
 Acquired resistance
Antibiotics are routinely added to
feed and water to prevent disease
and to promote growth in food
animals..
Mechanism of Bacterial Resistance
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Alteration of membrane permeability
Production of Inactivating Enzyme
β-lactamase
 Adenylase, phosphorylase, acetyltransferase
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Alteration of target for the drugs
Active efflux system
Alteration of the metabolism route
Bacterial resistance to
antimicrobial agents
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ESBLs: extended spectrum β-Lactamases（超广谱
β-内酰胺酶）
P.aeruginosa（铜绿假单胞菌）
 MRSA: Methicillin resistant Staphylococcus
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aureus（耐甲氧西林的金黄色葡萄球菌）
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VRE: Vancomycin resistant Enterococci（耐
万古霉素的肠球菌）
Principles of antibacterial use
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Basic principles
 Diagnosis
 Rational
use
 Newborn
 Pregnancy
 Elderly
Principles of antibacterial use
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Antimicrobial prophylaxis
 Surgical
prophylaxis
 Infectious
endocarditis
 Trauma, burn
 operation
 Nonsurgical
 Rheumatic
prophylaxis
fever
 Epidemic meningitis
 Malaria, Tuberculosis
Principles of antibacterial use
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Antimicrobial agents combination
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Drug categories
1.β-Lactam antibiotics
2. Aminoglycosides
3. Tetracyclines, macrolide ,chloramphenicol
4. Sulfonamides
1+2: Synergism
1+3:antagonism
2+3:synergism or plus
3+4: plus
Synergetic mechanism of
combination antibacterial therapy
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Affect different component of the same
mechanism
Changing the permeability of the
cytoplasmic membrane or the cell wall
Inhibiting the inactiving enzyme of
antibacterial drugsInhibiting the different
resistant microbial population
Rationale for combination
antibacterial therapy
To Provide broad-spectrum empirical
therapy in seriously ill patients
 Serious infection that can not be controlled by
one drug
 To decrease the emergence of resistant strains
 To decrease dose-related toxicity
 Meningitis and osteomyelitis caused by
bacterial infection
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Principles of antibacterial use
 Misuse
 Virus
infection
 Unknown fever
 Topical use
 Improper prophylaxis and combination
Chapter 39
β-Lactam Antibiotics
Classification
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Penicillins
Cephalosporins
Other β-Lactam drugs
Carbapenems（碳青霉烯类）
 Cephamycins（头霉素类）
 Oxacephalosporins （氧头孢烯类）
 Monolactums（单环β-内酰胺类）
 β-Lactamase inhibitors（ β-内酰胺酶抑制剂）
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Mechanism of action
 Inhibition
of bacterial cell wall
synthesis
 Target:
PBPs(penicillin-binding
proteins)
 Cell-wall
autolytic enzyme
Mechanism of resistance
Inactivation of drug by β-lactamase
 Trapping mechanism
 Modification of PBPs
 Impaired penetration of drug to target
PBPs
 Active efflux system
 Absence of autolysins
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Penicillins
 History
 Basic
structure: 6-APA
 Classification
 Natural
penicillins
 Semisynthesized penicillins
Penicillin G
Pharmacokinetics
Absorption
 Distribution
 Excretion
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T1/2=0.5h~1h
probenecid
 90%
tubular secretion
 10% glomerular filtration
Benzathine benzyl penicillin
 Procaine benzyl penicillin
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Penicillin G
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Antimicrobial activity
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Gram-positive cocci
 Streptococci
,pneumococci , staphylococci
Gram-positive
rods
 Bacillus
anthracis, diphtheriae,
clostridium tetani
Gram-negative
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cocci
Meningococci, diplococcus gonorrhoeae
Spirochete
 梅毒螺旋体,
leptospira
Clinical uses
First choice for the following infections
 Infection caused by streptococci,
pneumococci, meningococci etc
 Infection caused by spirochetes
 Infection caused by gram-positive rods
Adverse reactions
 Allergic
reactions
 Common:
urticaria, fever, angioneurotic edema,
eosinophilia, hemolytic anemia
 Severe: anaphylactic shock
 Herxheimer
reaction
Adverse reactions
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Allergic reactions
 Reason:degraded products of penicillin
 Prevention:
History of allergic reactions
 Skin test
 Epinephrine
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Semi-synthesized penicillins
Acid-resistant penicillins
 Penicillinase-resistant penicillins
 Extended-spectrum penicillins
 Extended-spectrum penicillins against
P.aeruginosa
 Penicillins against gram-negative
bacteria
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Acid-resistant penicillins
Drugs: penicillin V, phenethicillin(非奈西林）
 Character
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Orally effective, not resist β-Lactamase
Lower potency than penicillin G
• Clinical uses: moderate infections
• Adverse reactions: allergic reaction
Penicillinase-resistant
penicillins
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Drugs:methicillin(甲氧西林）oxacillin（苯唑西林）,
cloxacillin（氯唑西林）, dicloxacillin（双氯西林）
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flucloxacillin(氟氯西林)
Character: acid-resistant/ penicillinaseresistant / lower potency than penicillin G
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Clinical use
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Infection caused by penicillin-resistant
staphylococci
Extended-spectrum penicillins
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Ampicillin, amoxicillin, pivampicillin
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Oral effective, susceptible to β-Lactamase
 Broad
spectrum: G- / G+ <penicillin
 No effect on P.aeruginosa
 Clinical uses: infection caused by
gram-negative rods
Extended-spectrum penicillins
 Ampicillin
 Not
completely absorbed ,
 Effective on G To G+: <penicillin
 Clinical use: G- infection
F low
Extended-spectrum penicillins
 Amoxycillin
Absorbed well , F high
 G – infection
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 Meningitis
 Upper
respiratory infection
 Urinary tract infection
 H.p infection
Extended-spectrum Penicillins
against P.aeruginosa
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Carbenicillin, sulbencillin, ticarcillin,
furbencillin, piperacillin, mezlocillin
Character:
• Wide spectrum and more activity on P.aeruginosa
• Not acid and β-lactamase resistant
• Usually in combination with aminoglycosides
Extended-spectrum Penicillins
against P.aeruginosa
 Carbenicillin
activity on G- and P.aeruginosa
 Concentration in CSF is low
 Mainly used to treat P.aeruginosa
infection in burn patients
 High
 Piperacillin
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Effective on anaerobes
 Concentration
in CSF is high
Penicillins against gramnegative bacteria
Mecillinam（美西林）, temocillin（替莫西
林） , pivmecillinam（匹美西林）
 Narrow-spectrum: mainly on G- rods
 β-Lactamase resistant
 No effect on P.aeruginosa
 Treatment of infections caused by Grods
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Cephalosporins
 Chemistry:
7-ACA
 Classification: four generations
 First-generation
cephalosporins
 Second- generation cephalosporins
 Third-generation cephalosporins
 Fourth- generation cephalosporins
First-generation cephalosporins
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Cefalothin
Cefaloridine
Cefaloglycin
Cefalexin
Cefazolin
Cefradine
Cefacetrile
Cefapirin
Cefadroxil
头孢噻吩——先锋I
头孢噻啶——先锋II
头孢来星——先锋III
头孢氨苄——先锋IV
头孢唑啉——先锋V
头孢拉定——先锋VI
头孢乙氰——先锋VII
头孢匹林——先锋VIII
头孢羟氨苄
First-generation cephalosporins
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Common characters:
 Activity on
gram-positive bacteria:
first>second>third
 Activity on gram-negative bacteria:
first<second<third
 No effect on P. aeruginosa and anaerobes
 Stability to β-Lactamase produced by gramnegative rods: first<second<third
 Stable to β-Lactamase produced by gram-positive
bacteria
 Renal toxicity: first>second>third
First-generation
cephalosporins
 Clinical
uses
• Penicillin-resistant staphylococcal
infection
• Minor to moderate infections caused by
sensitive bacteria
Second-generation
cephalosporins
 Drugs
Cefamandole（头孢孟多）,
Cefuroxime（头孢呋辛）
Cefaclor（头孢克洛，希刻劳）
Second-generation
cephalosporins
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Common characters
More active on gram-negative bacteria
 Less active on gram-positive bacteria
 More stable to β-Lactamase produced by
gram-negative rods
 Some are effective on anaerobes
 No effect on P. aeruginosa
 Less renal toxicity
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Second-generation
cephalosporins
 Clinical
uses
• Gram-negative bacteria infections：
first choice
• Anaerobic infections
Third-generation
cephalosporins
Ceftriaxone （头孢曲松，罗氏芬）
 Ceftazidime （头孢他定）
 Cefoperazone (头孢哌酮）
 Cefotaxime
(头孢噻圬）
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Third-generation
cephalosporins
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Common characters
• Much more active on gram-negative bacteria
• To gram-positive bacteria: third<second<first
• Stable to extended β-Lactamase produced by
gram-negative bacteria
• Effective on anaerobes and P.aeruginosa
• No renal toxicity
• Penetrating body fluids and tissues well
Third-generation
cephalosporins
 Clinical
uses
a wide variety of serious infections
caused by organisms that are
resistant to most other drugs
Fourth- generation
cephalosporins
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Cefpirome（头孢匹罗）,cefepime（头孢吡圬）,
cefclidin（头孢利定）
Character:
• Enhanced antimicrobial activity and broader
spectrum
• Stable to most β-lactamase
• More activity on gram-positive cocci
Clinical uses:
• infections caused by organisms that are resistant
to third-generation cephalosporins
一、二、三代头孢作用比较
一代
二代
三代
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+
+
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绿脓杆菌
-
-
有效
厌氧菌
-
有效
有效
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+
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-
G+
G
-
对-内酰胺 G+ +++
酶稳定性 G- ++
肾毒性
Side effect of cephalosporins
Allergic effect
 Gastrointestinal reactions
 Renal toxicity
 Other : bleeding
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Disulfiram-like effect(双硫仑反应）
Other β-Lactam drugs
Carbapenems（碳青霉烯类）
The most important antimicrobial agents
in 1990’s
 Wide spectrum and high activity
 Resistant to most β-Lactamase
(including ESBLs and cephalosporinase)
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Carbapenems
 Thienamycin（硫霉素）
Imipenem（亚胺培南）
 Imipenem-cilastatin:tienam（泰能）
 Meropenem（美罗培南）
 Panipenem（帕尼培南）
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Imipenem-cilastatin:tienam
 Susceptible
to acid
iv
 Treatment of severe infections
 Contradications:
 CNS
disorder
 Baby less than 3 months
 Renal dysfunction
Cephamycins （头霉素类）
Cefoxitin（头孢西丁）
 Similar to second-generation cephalosporins
 More activity on anaerobes
 β-Lactamase resistant
 High concentration in CSF
 Treatment of mixed anaerobic and aerobic
infections
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Oxacephalosporin（氧头孢烯类）
Latamoxef（拉氧头孢）, Flomoxef（氟
氧头孢）
 Higher activity on anaerobes (especially
Bacteroids fragilis) than third-generation
cephalosporins
 Well resistant to manyβ-Lactamase
 Adverse reactions: PLT / disulfiram-like
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effect
Monobactams
Aztreonam（氨曲南）, carumonam（卡芦莫南）
 No effect on gram-positive bacteria and
anaerobes
 High activity on gram-negative bacteria
 No cross-allergic reaction with penicillin
 Penicillin-allergic patients tolerate well
 Low toxicity
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β-Lactamase inhibitors
 Clavulanic
acid
 Sulbactam
 tazobactam
β-Lactamase inhibitors
Weak antimicrobial action
 Protect β-lactams from inactivation
by β-lactamase
 Synergism
 Compound preparation (复方制剂）
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