Transcript Chemotherapeutic Agents Power Point

Chemotherapeutic
Agents
Antimicrobials and Antibiotics
Normal Microbiota
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Body Cavities
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Closed = free of microbes
Open = normal flora
Regions
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Skin
Mouth (teeth/gums)
GI
Genitourinary
 Upper = sterile
 Perineum
Bacterial Groups
Microbial Pathogenicity
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Cause of disease
Means
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Invasiveness
Toxigenesis
Stages
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Colonization
Adherence
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Nonspecific (dock)
Specific (anchor)
Invasion
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Enzymes
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Spread
Digest
Toxins
Definitions
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Chemotherapy
Antimicrobials
Antibiotics
Synthetic Drugs
Selective Toxicity
Paul Ehrlich
Antibiotic Development
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AB
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Natural Source
 Fungal molds
 Bacteria
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Bacillus
Actinomycetes
Chemotherapeutic
 Chemical
Semi-synthetic
 Hybrid
Drug Basics
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Classification
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Names (3+)
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Enzyme inhibition
Receptor interactions
Non-specific (i.e pH)
Modes of Action (MOA)
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Chemical
Brand/Trade
Generic
Sites of Action
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Chemtherapeutic
Pharmacodynamic
Miscellaneous
Pharmakokinetics
Stimulate/Depress/Kill
Effects
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Theruapeutic
Adverse
Antimicrobial Characteristics
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Toxicity
MOA
Spectrum
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BS (both GP and GN)
NS (GP or GN)
Limited spectrum
Target Tissue
Adverse Effects
Resistance
Route of Administration
Mechanism of Action (MOA)
Effectiveness of AB
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Route of Administration
Uptake
Clearance
Susceptibility
Dosage
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Exceed MIC
Therapeutic
Selective Toxicity
Adverse Drug Reactions (ADR)
AB and Sx
Other Drug Considerations
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Availability
Stability
Cost
MOA
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Cell Wall
Cell Membrane
DNA
Protein Synthesis
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30S
50S
Metabolites
Antimicrobial Resistance
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Natural (Inherent)
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Acquired
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G(-) LPS
Lack target or transport
Mutation
Horizontal transfer
Vertical
Horizontal
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Transformation
Transduction
Conjugation
Plasmids
R-Plasmid
AB resistance
“Super Bugs”
Kirby-Bauer Disk Diffusion
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MH agar
AB disks
MIC Table
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Zone diameter
Classified
 Susceptible
 Intermediate
 Resistant
Metabolite Inhibition
Sulfa Drugs
Sulfonamides
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Sulfa-; SulphaAntimetabolites
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Structural Analogs
Decrease folic acid
Bacteriostatic
Side Effects
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Allergic
KCS
PABA
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Competitive Enzyme
Inhibition
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PABA  Folic Acid
Folic Acid (B vitamin)
Synthesis of N bases
TMPS
actions as above
Trimethoprim inhibits conversion
of folic acid to its active form
Antimetabolite Action
TMPS
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BS
Block pathway of
synthesis for
tetrahydrofolic acid
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No DNA
No RNA
Competitive antagonism
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Sulfa first enzyme
Trimethoprim  3rd enzyme
Synergistic
Cell Wall Synthesis Inhibitors
Sir Alexander Fleming
Beta-Lactams
Penicillin Family
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Beta-lactams
Penicillium mold source
-cillin
MOA
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Inhibits PGC synthesis
Prevents cross-linking by
transpeptidase
Mimicks D-alanine at active
enzyme site
Bacteriocidal
G(+)
Adverse Rxn = allergies
Penicillin G, Penicillin V, Oxacillin,
Ampicillin, Cloxacillin, Ticarcillin,
Nafcillin, Dicloxacillin, Carbenicillin
Inhibition of Cell Wall Synthesis
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Prevent cross linking
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Binds to transpeptidases
 Add new monomers
 Reseal wall
Osmotic Lysis
Bacterial Resistance
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Penicillinase
 MRSA
 VRSA
Beta Lactamases
Cephalosporinases
Beta-Lactam Inhibition
Beta-Lactamase Inhibitors
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Clavulanic acid
Noncompetitive
inhibitor of penicillinase
Destroys enzyme
Carbapenems
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-penem
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Imipenem
Beta-lactam
BS
Cell wall synthesis
Cephalosporins
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Modified B-lactam ring (6)
Modified R groups
Sewer fungus source
Generations
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1st
2nd
3rd
4th
Cepha- or cefBroad Spectrum; Bacteriocidal
MOA
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Binds to transpeptidases
No cross linking of NAM-NAM
Prevents resealing
Weak  osmotic lysis
Cephalosporin Family
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1st
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2nd
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Cefaclor
Cefoxitin
3rd
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Cefalixin
Cephadroxil
Cefdinir
Deftibuten
4th
Glycopeptides
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Examples
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Vancomycin
Teichoplanin
MOA
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Bind to cell wall peptides
Block cross-linking of
transpeptidases
(Alanine-Alanine)
Blocks transglycolation
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NAM-NAG bond
Result
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Weak cell wall
Osmotic lysis
Bacteriocidal
GP
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VRSA has developed
Polypeptides
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Some can inhibit cell wall
synthesis
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Example
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Inhibit PGC subunit release
from carrier
Inhibits teichoic acid
synthesis
Bacitracin
NS: GP
Topic Use
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Skin
Ophthalmic
Bacitracin MOA
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Bactoprenol assembles
new monomers for the
cell wall in the PM
Bacitracin binds to
Bactoprenol in PM
Blocks
dephosphorylation
(must loose 2nd Phosphate)
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No monomers can
inserted into cell wall
Osmotic lysis
Inhibition of AFB
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MOA
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Disrupt cell wall synthesis
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Prevents replication
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Cycloserine
Clofazimine
Disrupt Waxy layer
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Mycolic acid and
Arabinogalactan
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Examples
 Isoniazid
 Ethambutal
Mycobacterium
Multidrug Therapies
TB resistance
Ribosomes
Protein Synthesis Steps
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Transcription
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DNA
mRNA
RNA polymerase
Translation
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Initiation
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Elongation
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mRNA
30S
50S
P site
A site
Translocation
Peptide bond formation
Termination
Protein Synthesis Inhibition
50S Inhibition
Chloramphenicol
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CHPC
BS
Synthetic
MOA
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Results
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Attaches to 50S ribosome
Interferes with peptide bonds
Inhibits protein synthesis
Side Effects
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Aplastic anemia
Can inhibit mitochondrial
protein synthesis
Macrolides
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-mycin (usually)
Actinomyces source
Examples
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MOA
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50S reversible binding
Inhibits elongation
Blocks translocation
Result
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Erythromycin
Azithromycin
Clarithromycin
Dithromycin
Inhibit protein synthesis
G(+) and select G(-) [resp]
Erythromycin
Macrolide MOA
Lincosamides
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Semisynthetic
Actinomyces source
Example
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Clindamycin
Lincomycin
G(+), some anaerobes
MOA
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Bind to 50S
Block elongation
Inhibits protein synthesis
Streptogramins
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Two Groups
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Examples
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A: nonpeptide
B: cyclic peptides
A: Dalfopristin
B: Quinupristin
MOA
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Group A
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Group B
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Distort ribosomes
Prevent tRNA binding
Block translocation
Results
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Inhibit protein synthesis
Synergistic if both groups used
30S Inhibition
Aminoglycosides
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-mycin (usually)
Streptomyces source
NS: G(-) but some have BS
Examples
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MOA
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Binds to 30S, irreversibly
Changes shape of 30S
50S can not bind
Interferes with initiation
Misreads mRNA codons
Wrong AA inserted by tRNA
Results
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Streptomycin
Gentamicin
Neomycin
Amikacin
Tobramycin
Inhibit protein synthesis by interfering with
translation
Side Effects
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Toxicity
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CN 8
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Kidney
Tetracyclines
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-cycline
Streptomyces source
BS
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Examples
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Bind to 30S subunit reversibly
Block tRNA attachment at A site
Inhibit codon-anticodon interaction
Result
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Tetracycline
Doxycycline (semi-synthetic)
Oxytetracycline
Tigecycline
Minocycline
MOA
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GN, GP
Rickettsial organisms
Inhibit protein synthesis
Side effects
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Affect bone development
Stain teeth in children
Tetracycline MOA
Tetracycline Resistance
Oxazolidinones
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New AB
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Example
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Prevents 30S-50S
assembly
Interferes with mRNA
Disrupts initiation
Results
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Linezolid
MOA
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-zolid
Inhibits translation
Use
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G(+)
MRSA / VRSA
Ribosome Inhibition Summary
Bacterial Resistance
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Pump out AB (efflux)
Methylate Ribosomes
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Obscure target
Block binding site
Modify AB so it can’t
bind to ribosome target
Nucleic Acid Inhibition
Quinolones
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Generations
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Examples
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Naldixic acid
MOA
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1st
2nd
3rd
4th
Block A subunit of DNA
gyrase
Results
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Bactericidal
GN
Fluroquinolones
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-floxacin
Second generation quinolone
Examples
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MOA
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Bind to DNA gyrase
Bind to Tropoisomerase IV
Result: Blocks DNA
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Levofloxacin
Norfloxacin
Repair
Replication
Transcription
Bacteriocidal
BS
DNA gyrase
Adverse Effects
Bacterial Resistance
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Modify DNA gyrase
Bacterial synthesis of
sort DNA segments to
trick quinolones
Metronidizole
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Activated by bacteria
Nicks in DNA to
fragment strand
Used in anaerobic
infections
Trade Name
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Flagyl
Rifampin
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Semi-synthetic
GN and Mycobacteria
Example
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MOA
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Rifampicin
Binds to RNA
polymerase
Results
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Prevents transcription
Plasma Membrane Disruption
Polypeptides
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Example
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MOA
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Polymixins
 Polymixin B
 Polymixin E (colistin)
Detergents
Replace Mg++ and Ca++
Damage phospholipids
Binds to Lipid A
Results
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Alter PM
Cell contents leak out
Antibiotic MOA Summary
Antifungals
Polyenes
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MOA
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Examples
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Inactivatate sterols
Changes membrane
permeability
Leakage of interacellular
components
Amphotericin
Nystatin
Results
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Antifungal
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-static
-cidal
Dose dependant
Fungal Cell Walls
Helminths
Protozoa
Pentamide
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MOA
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Binds to prokaryote DNA
Inhibits transcription and
translation
Antiprotozoal
Examples
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Pentamide
Pentam
Pneumopent
Antivirals
Antisense Nucleic Acids
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MOA
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Examples
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ssDNA or ssRNA
binds as complementary
strand to mRNA
Blocks translation
Fomivirsen
Use
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CMV
Questions?