Chapter 38 Introduction To Chemotherapeutic Drugs

1
Chapter 38 Introduction To
Chemotherapeutic Drugs
2
Brief History of Chemotherapeutic
Drugs

• 1910 Ehrlich Arsphnamine(???? )
  chemotherapy
• 1929 Fleming
• 1940 Florey and Chain Penicilin
• 1935 Domagk Prontosil(????)
• 1960s ß-Lactam antibiotics
• 1970s Fluoroquinolones
• 1980s New Macrolides

3
Paul Ehrlich
4
???????????.????????????????,?????1945??????????
?
???????????? ??????????
5
(No Transcript)
6
Domagk
7
Relationship between pathogen , chemotherapeutic
drugs and patients
host
Side effect
pathogenicity
process
immunity
Antimicrobial action
Antimicrobial agents
mycrobacterium
resistance
8
Several Terms related to Chemotherapy

• 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 )

9
Mechanism of action of the Antibacterial Agents

• Inhibiting the biosynthesis of the cell wall
• ß-lactam
• Increasing the permeability of the cytoplasmic
  membrane
• Aminoglycosides
• Imidazoles(miconazole, ketoconazole)
• Polymixins
• Amphotericin B/nystatin

10
(No Transcript)
11
Mechanism of action of Antimicrobial Agents

• Inhibition of protein synthesis
• Aminoglycosides
• Tetracyclines
• Chloramphenicol
• Macrolides
• Clindamycin

12
(No Transcript)
13
Mechanism of action of Antimicrobial Agents

• Interfering the metabolism of nucleotides and
  folic acid
• Rifampicin
• Quinolones
• Sulfonamides

14
(No Transcript)
15
Resistances of Bacteria

• Reasons
• Antibiotics abuse
• Classification
• Intrinsic resistance
• Acquired resistance

16
Antibiotics are routinely added to feed and water
to prevent disease and to promote growth in food
animals..
17
Mechanism of Bacterial Resistance

• Alteration of membrane permeability
• Production of Inactivating Enzyme
• ß-lactamase
• Adenylase, phosphorylase, acetyltransferase
• Alteration of target for the drugs
• Active efflux system
• Alteration of the metabolism route

18
(No Transcript)
19
Bacterial resistance to antimicrobial agents

• ESBLs extended spectrum ß-Lactamases(???ß-????)
• P.aeruginosa(??????)
• MRSA Methicillin resistant Staphylococcus
  aureus(?????????????)
• VRE Vancomycin resistant Enterococci(?????????)

20
Principles of antibacterial use

• Basic principles
• Diagnosis
• Rational use
• Newborn
• Pregnancy
• Elderly

21
Principles of antibacterial use

• Antimicrobial prophylaxis
• Surgical prophylaxis
• Infectious endocarditis
• Trauma, burn
• operation
• Nonsurgical prophylaxis
• Rheumatic fever
• Epidemic meningitis
• Malaria, Tuberculosis

22
Principles of antibacterial use

• Antimicrobial agents combination
• Drug categories
• 1.ß-Lactam antibiotics
• 2. Aminoglycosides
• 3. Tetracyclines, macrolide ,chloramphenicol
• 4. Sulfonamides
• 12 Synergism
• 13antagonism
• 23synergism or plus
• 34 plus

23
Synergetic mechanism of combination
antibacterial therapy

• 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

24
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

25
Principles of antibacterial use

• Misuse
• Virus infection
• Unknown fever
• Topical use
• Improper prophylaxis and combination

26
Chapter 39ß-Lactam Antibiotics
27
Classification

• Penicillins
• Cephalosporins
• Other ß-Lactam drugs
• Carbapenems(?????)
• Cephamycins(????)
• Oxacephalosporins (?????)
• Monolactums(??ß-????)
• ß-Lactamase inhibitors( ß-???????)

28
Mechanism of action

• Inhibition of bacterial cell wall synthesis
• Target PBPs(penicillin-binding proteins)
• Cell-wall autolytic enzyme

29
Mechanism of resistance

• Inactivation of drug by ß-lactamase
• Trapping mechanism
• Modification of PBPs
• Impaired penetration of drug to target PBPs
• Active efflux system
• Absence of autolysins

30
Penicillins

• History
• Basic structure 6-APA
• Classification
• Natural penicillins
• Semisynthesized penicillins

31
Penicillin G
32
Pharmacokinetics

• Absorption T1/20.5h1h
• Distribution
• Excretion probenecid
• 90 tubular secretion
• 10 glomerular filtration
• Benzathine benzyl penicillin
• Procaine benzyl penicillin

33
Penicillin G

• Antimicrobial activity
• Gram-positive cocci
• Streptococci ,pneumococci , staphylococci
• Gram-positive rods
• Bacillus anthracis, diphtheriae, clostridium
  tetani
• Gram-negative cocci
• Meningococci, diplococcus gonorrhoeae
• Spirochete
• ?????, leptospira

34
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

35
Adverse reactions

• Allergic reactions
• Common
• urticaria, fever, angioneurotic edema,
  eosinophilia, hemolytic anemia
• Severe anaphylactic shock
• Herxheimer reaction

36
Adverse reactions

• Allergic reactions
• Reasondegraded products of penicillin
• Prevention
• History of allergic reactions
• Skin test
• Epinephrine

37
Semi-synthesized penicillins

• Acid-resistant penicillins
• Penicillinase-resistant penicillins
• Extended-spectrum penicillins
• Extended-spectrum penicillins against
  P.aeruginosa
• Penicillins against gram-negative bacteria

38
Acid-resistant penicillins

• Drugs penicillin V, phenethicillin(????)
• Character
• Orally effective, not resist ß-Lactamase
• Lower potency than penicillin G
• Clinical uses moderate infections
• Adverse reactions allergic reaction

39
Penicillinase-resistant penicillins

• Drugsmethicillin(????)oxacillin(????),
  cloxacillin(????), dicloxacillin(????)flucloxacill
  in(????)
• Character acid-resistant/ penicillinase-resista
  nt / lower potency than penicillin G
• Clinical use
• Infection caused by penicillin-resistant
  staphylococci

40
Extended-spectrum penicillins

• Ampicillin, amoxicillin, pivampicillin
• Oral effective, susceptible to ß-Lactamase
• Broad spectrum G- / G ltpenicillin
• No effect on P.aeruginosa
• Clinical uses infection caused by gram-negative
  rods

41
Extended-spectrum penicillins

• Ampicillin
• Not completely absorbed , F low
• Effective on G-
• To G ltpenicillin
• Clinical use G- infection

42
Extended-spectrum penicillins

• Amoxycillin
• Absorbed well , F high
• G infection
• Meningitis
• Upper respiratory infection
• Urinary tract infection
• H.p infection

43
Extended-spectrum Penicillins against P.aeruginosa

• Carbenicillin, sulbencillin, ticarcillin,
• furbencillin, piperacillin, mezlocillin
• Character
• Wide spectrum and more activity on P.aeruginosa
• Not acid and ß-lactamase resistant
• Usually in combination with aminoglycosides

44
Extended-spectrum Penicillins against P.aeruginosa

• Carbenicillin
• High activity on G- and P.aeruginosa
• Concentration in CSF is low
• Mainly used to treat P.aeruginosa infection in
  burn patients
• Piperacillin
• Effective on anaerobes
• Concentration in CSF is high

45
Penicillins against gram-negative bacteria

• Mecillinam(???), temocillin(????) ,
  pivmecillinam(????)
• Narrow-spectrum mainly on G- rods
• ß-Lactamase resistant
• No effect on P.aeruginosa
• Treatment of infections caused by G- rods

46
(No Transcript)
47
(No Transcript)
48
Cephalosporins

• Chemistry 7-ACA
• Classification four generations
• First-generation cephalosporins
• Second- generation cephalosporins
• Third-generation cephalosporins
• Fourth- generation cephalosporins

49
(No Transcript)
50
First-generation cephalosporins

• Cefalothin ??????I
• Cefaloridine ??????II
• Cefaloglycin ??????III
• Cefalexin ??????IV
• Cefazolin ??????V
• Cefradine ??????VI
• Cefacetrile ??????VII
• Cefapirin ??????VIII
• Cefadroxil ?????

51
First-generation cephalosporins

• Common characters
• Activity on gram-positive bacteria
  firstgtsecondgtthird
• Activity on gram-negative bacteria
  firstltsecondltthird
• No effect on P. aeruginosa and anaerobes
• Stability to ß-Lactamase produced by
  gram-negative rods firstltsecondltthird
• Stable to ß-Lactamase produced by gram-positive
  bacteria
• Renal toxicity firstgtsecondgtthird

52
First-generation cephalosporins

• Clinical uses
• Penicillin-resistant staphylococcal infection
• Minor to moderate infections caused by sensitive
  bacteria

53
Second-generation cephalosporins

• Drugs
• Cefamandole(????), Cefuroxime(????)
• Cefaclor(????,???)

54
Second-generation cephalosporins

• Common characters
• More active on gram-negative bacteria
• Less active on gram-positive bacteria
• More stable to ß-Lactamase produced by
  gram-negative rods
• Some are effective on anaerobes
• No effect on P. aeruginosa
• Less renal toxicity

55
Second-generation cephalosporins

• Clinical uses
• Gram-negative bacteria infectionsfirst choice
• Anaerobic infections

56
Third-generation cephalosporins

• Ceftriaxone (????,???)
• Ceftazidime (????)
• Cefoperazone (????)
• Cefotaxime (????)

57
Third-generation cephalosporins

• Common characters
• Much more active on gram-negative bacteria
• To gram-positive bacteria thirdltsecondltfirst
• Stable to extended ß-Lactamase produced by
  gram-negative bacteria
• Effective on anaerobes and P.aeruginosa
• No renal toxicity
• Penetrating body fluids and tissues well

58
Third-generation cephalosporins

• Clinical uses
• a wide variety of serious infections caused
  by organisms that are resistant to most other
  drugs

59
Fourth- generation cephalosporins

• Cefpirome(????),cefepime(????), cefclidin(????)
• Character
• Enhanced antimicrobial activity and broader
  spectrum
• Stable to most ß-lactamase
• More activity on gram-positive cocci
• Clinical uses
• infections caused by organisms that are resistant
  to third-generation cephalosporins

60
????????????
?? ?? ??
G
G-
???? - - ??
??? - ?? ??
??-??????? G G- -
??? -
61
Side effect of cephalosporins

• Allergic effect
• Gastrointestinal reactions
• Renal toxicity
• Other bleeding
• Disulfiram-like
  effect(?????)

62

Other ß-Lactam drugs
63
Carbapenems(?????)

• The most important antimicrobial agents in 1990s
• Wide spectrum and high activity
• Resistant to most ß-Lactamase
• (including ESBLs and cephalosporinase)

64
Carbapenems

• Thienamycin(???)
• Imipenem(????)
• Imipenem-cilastatintienam(??)
• Meropenem(????)
• Panipenem(????)

65
Imipenem-cilastatintienam

• Susceptible to acid iv
• Treatment of severe infections
• Contradications
• CNS disorder
• Baby less than 3 months
• Renal dysfunction

66
Cephamycins (????)

• Cefoxitin(????)
• Similar to second-generation cephalosporins
• More activity on anaerobes
• ß-Lactamase resistant
• High concentration in CSF
• Treatment of mixed anaerobic and aerobic
  infections

67
Oxacephalosporin(?????)

• Latamoxef(????), Flomoxef(????)
• Higher activity on anaerobes (especially
  Bacteroids fragilis) than third-generation
  cephalosporins
• Well resistant to manyß-Lactamase
• Adverse reactions PLT / disulfiram-like effect

68
Monobactams

• Aztreonam(???), carumonam(????)
• 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
  

69
ß-Lactamase inhibitors

• Clavulanic acid
• Sulbactam
• tazobactam

70
ß-Lactamase inhibitors

• Weak antimicrobial action
• Protect ß-lactams from inactivation by
  ß-lactamase
• Synergism
• Compound preparation (????)

71
(No Transcript)
72
The end
73
Thank you
74
(No Transcript)
75
(No Transcript)
76
(No Transcript)
77
flory
chain
florey
78
(No Transcript)
79
(No Transcript)
80
(No Transcript)
81
(No Transcript)
82
(No Transcript)
83
(No Transcript)
84
(No Transcript)
85
(No Transcript)