department of pharmacology & therapeutics faculty of medicine...
TRANSCRIPT
D S HIDAYAT
Department of Pharmacology & TherapeuticsFaculty of Medicine
U i it S t UtUniversitas Sumatera Utara
Basic Principles of Resistance
OUTLINES OF DISCUSSIONOUTLINES OF DISCUSSIONOUTLINES OF DISCUSSIONOUTLINES OF DISCUSSION
Mechanism of selective targeting
Pathogens, Cancer biology and Drug classes
Antineoplastic drug classes:
Mechanisms of drug resistance:
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Basic Principles of Resistance
I. Mechanism of selective targeting:
- Unique target- Selective inhibition of similar target- Common target
II. Pathogens, Cancer biology & Drug classesSites of action of antibacterial drug classes- Sites of action of antibacterial drug classes
- Stages of the viral life cycle targeted by antiviral drug classesantiviral drug classes
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Basic Principles of Resistance
III. Antineoplastic drug classes:
IV. Mechanisms of drug resistance:
G ti f d i tGenetic causes of drug resistance: - Reduced intracellular drug concentr.- Altered targeted- Insensitivity to apoptosis
Non-genetic causes of treatment failure
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Mechanism of selective targeting
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The goal of antimicrobial & antineoplasticantineoplastic
Selective toxicity
Inhibiting pathway/targets critical for pathogen (Inhibiting pathway/targets critical for pathogen ( bakteri, virus & jamur ) /cancer cell survival,
at concentration of drugat concentration of drug lower than required
to affect host pathwayto affect host pathway
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Drug Selectivity
Attacking target unique to the pathogen/ g g q p gcancer cell that not present in the host
Att ki t t i th th /Attacking targets in the pathogen/ cancer cell that are similar but not identicalthose in the hostthose in the host
Attacking targets in the pathogen/ g g p gcancer cell that are shared by the host, but that vary in importance between pathogen and host (impart selectivity)
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Drugs exhibit <<< toxicity to the host
target unique differences
D hibit t i it t th h tDrugs exhibit >>> toxicity to the host
t t thtarget common pathway
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Therapeutic index / Therapeutic windowTherapeutic index / Therapeutic window
Indication of how selective drugs in producing the desired effects
Toxic dose
Therapeutic dose
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Highly selective drug ( i illi )
g y g(penicillin)
High therapeutic index/f fMargin of safety >>>
Prescribed safelyPrescribed safely (Large difference between
therapeutic & toxic concentration)therapeutic & toxic concentration)RZH, Faculty of Medicine, USU, Medan.
Less selective drug ( th t t )
g(methotrexate)
Low therapeutic index/f fMargin of safety <<<
Prescribed carefullyPrescribed carefully (Very small difference between
therapeutic & toxic concentration)therapeutic & toxic concentration)RZH, Faculty of Medicine, USU, Medan.
Unique drug targetsU que d ug ta gets
Drug targets, genetic or biochemical pathway that is unique to pathogenpathway that is unique to pathogen
Bacterial cell wall synthesis inhibitor(peptidoglycan cell wall)
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Unique drug targetsUnique drug targets
Metabolic pathway, enzymes, t t d d d tmutated genes and gene product
(present in the pathogen/cancer cell, but lacking in the host)
Bacterial cell wall synthesis inhibitor(peptidogl can cell all)(peptidoglycan cell wall)
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Selective inhibition of similar targetg
Drug targets protein isoform that is unique to pathogenpathogen
Inhibitors of the enzyme dihydrofolate reductase (DHFR)
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Common targetsCommon targets
Drug targets, metabolic requirementthat is specific to pathogen
5-fluorouracil
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Pathogens, Cancer Cell Biology,and Drug Classesa d ug C asses
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Sites of action ofSites of action of antimicrobial drug classes
Sites of action of antimicrobial drug classesantimicrobial drug classes
Inhibit specific enzymes involved in bacterial DNA synthesis & integrity
Inhibit transcription and translation(inhibit bacterial(inhibit bacterial:
DNA-dependent RNA polymerase, 30 S ribosomal subunit,
Inhibit specific steps in bacterial
,50 S ribosomal subunit)
Inhibit specific steps in bacterial cell wall synthesis
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Antimicrobial which inhibit specific enzymes involved in
b i l DNA h i & i ibacterial DNA synthesis & integrity
Sulfonamida & trimethoprim
Formation or use of folate compoundFormation or use of folate compound that are necessary for nucleotide synthesis
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Antimicrobial which inhibit specific enzymes involved in
b i l DNA h i & i ibacterial DNA synthesis & integrity
QuinoloneQuinolone
Bacterial type II isomeraseBacterial type II isomerase
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Antimicrobial which inhibit transcription & translationtranscription & translation
Rifampin
Bacterial DNA-dependent RNA polymeraseBacterial DNA-dependent RNA polymerase
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Antimicrobial which inhibit transcription & translationtranscription & translation
Aminoglycosides,spectinomycin & tetracyclinestetracyclines
Bacterial 30S ribosomal subunit
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Antimicrobial which inhibit transcription & translationtranscription & translation
Macrolides, chloramphenicol,lincosamides streptograminslincosamides, streptogramins,
oxazolidinones
Bacterial 50S ribosomal subunit
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Antimicrobial which inhibit specific steps in bacterial p p
cell wall synthesis
Fosfomycin, cycloseriney , y
E l t i tid lEarly steps in peptidoglycan monomer synthesis
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Antimicrobial which inhibit specific steps in bacterial p p
cell wall synthesis
VancomycinVancomycin
Polymerization of peptidoglycanPolymerization of peptidoglycan (bind peptidoglycan intermediate)
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Antimicrobial which inhibit specific steps in bacterial p p
cell wall synthesis
Penicillins, cephalosporins, monobactams, carbapenemcarbapenem
Peptidoglycan crosslinkingPeptidoglycan crosslinking
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Antimicrobial which inhibit specific steps in bacterial p p
cell wall synthesis
Ethambutol, pyrazinamide, isoniazid
Process necessary for synthesis of cell wall &Process necessary for synthesis of cell wall & outer membrane of M.tuberculosis
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Bacteriostatic
D th t i hibit th th f thDrugs that inhibit the growth of pathogen without causing cell death(f i h )(for immunocompetent host)
These drugs target metabolic pathway that necessary for bacterial growth
but not for bacterial survivalbut not for bacterial survival
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Bactericidal
Drugs that kill bacteria(for immunocompromised hosts)
These drugs target metabolic pathway that necessary for bacterial growththat necessary for bacterial growth
but not for bacterial survival
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Bacteriostatic + bactericidal
Antagonistic effectsg
Th b t i t ti d t t liThe bacteriostatic drug tetracycline inhibits protein synthesis, antagonizes the
effect of cell wall synthesis inhibitor (penicillin), which requires bacterial(penicillin), which requires bacterial
growth to be effective
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Combination of two bactericidal
Synergistic effectsSynergistic effects
Penicillin + aminoglycoside (Inhibition of bacterial cell wall synthesis by ( y y
penicillin allow increased entry of aminoglycoside)allow increased entry of aminoglycoside)
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Stages of the viral glife cycle targeted by
antiviral drugsantiviral drugs
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The stages of the viral life cycletargeted by antiviral drugstargeted by antiviral drugs
1.Attachment and entry1.Attachment and entry
2.Virus become uncoated
3.Genome replication
4.Viral genes are transcribed (RNA synthesis)g ( y )
5.Virally coded RNA is translated into protein on host cell ribosomeshost cell ribosomes
6.Virion form (viral particle), which release from the host cellthe host cell
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The stages of the viral life cycletargeted by antiviral drugstargeted by antiviral drugs
1. Fusion inhibitors (enfuvirtide)
2. Inhibit virus uncoating (ion channel blocker: amantadine, rimantadine)rimantadine)
3. Inhibit viral genome replicationg p(polymerase inhibitor: acyclovir;reverse transcriptase: zidovudine &efavirenz)
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efavirenz)
The stages of the viral life cycletargeted by antiviral drugstargeted by antiviral drugs
4. Inhibit viral maturation : proteaseinhibitor (anti HIV drugs : saquinavir &ritonavir)
5. Block the relase of virus particles from5. Block the relase of virus particles from the host cell: neuramidase inhibitors
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Antineoplastic drug classes
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Antineoplastic drug classes
1.Chemoterapeutic agents interfere cell p gproliferation & rely on rapid cell cycling and/or promotion of apoptosis
2. Interfere the cell cycle in the particular phase (cell cycle spesific)phase (cell-cycle spesific) (phase M, S1, S2, G)
3. Independently of the cell cycle at a particular phase (cell cycle non-
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p p ( yspecific)
The cell cycle (4 phases)
1.M phase (M): mitosis phasep ( ) p
2. Gap 1 phase (G1): active metabolism inth b f DNA th ithe absence of DNA synthesis
3. Synthesis phase (S): DNA replication3. Synthesis phase (S): DNA replication of the cells
G 2 (G2) f S4. Gap 2 phase (G2): after completion S phase (the cell prepares for mitosis
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during the Gap 2 phase)
Cell-cycle specificity of antineoplastic drugantineoplastic drug
1.Inhibitors of microtubule function: M phase
2. Glucocorticoid : G1 phase
3. Antimetabolite & folate pathway inhibitors : S phase
4 Antitumor antibiotics: G1 phase
inhibitors : S phase
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4. Antitumor antibiotics: G1 phase
Mechanism of drug resistanceg
1 G ti1.Genetic
2.Non Genetic2.Non Genetic
Genetic causes of drug resistance
The mechanism of genetic drug resistancedrug resistance
1.Reduced intracellular concentration of drugdrug
2. Altered drug target
3. Insensitivity to apoptosis
4. Bypass metabolic requirement fortarget
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target
I. Reduced intracellular concentration of drugof drug
1. In activate drug
2. Prevent uptake activate drug
3. Promote effIuxs activate drugg
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Reduced intracellular concentration of drugof drug
1. In activate drug
Antimicrobial: inactivation of ß-lactam antibioticsinactivation of ß lactam antibiotics by ß-lactamase
A i l iAntineoplastic: inactivation of antimetabolites
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by de-aminase
Reduced intracellular concentration of drugof drug
2. Prevent uptake of drugAntimicrobial:
prevention of aminoglycoside t b lt d ientry by altered porins
Antineoplastic:Antineoplastic: decreased methotrexate entry byexpression of reduced folate
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expression of reduced folatecarrier
Reduced intracellular concentration of drugof drug
3. Promote efflux of drugAntimicrobial:
efflux of multiple drugs by MDR membrane efflux pump
Antineoplastic:Antineoplastic: efflux of multiple drugs by p170 membrane efflux pump
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membrane efflux pump
ii. Altered drug targetii. Altered drug target
Antimicrobial: i f lt d tid lexpression of altered peptidoglycan
that no longer binds vancomycin
Antineoplastic:Antineoplastic: expression of mutant DHFR that no longer bind methotrexate
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longer bind methotrexate
III. Insensitivity to apoptosisIII. Insensitivity to apoptosis
Antineoplastic: ploss of active p53
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IV. Bypass metabolic requirement for targetyp q g
Antimicrobial: inhibition of thymidylate synthaseinhibition of thymidylate synthase bypassed by exogenous thymidine
Antineoplastic: loss of estrogen receptor-dependentloss of estrogen receptor dependentgrowth results in tamoxifen resistance
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resistance
Non-genetic gcauses of
therapeutic failurep
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Non-genetic causes of therapeutic failureg p
The excessive overpriscription of antibiotics that are not indicatedantibiotics that are not indicated
for the clinical situation
Resistance involve pharmacologic and anatomical drug barriersanatomical drug barriers(the wall of abscess or the blood brain barrier)
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the blood brain barrier)
Non-genetic causes of therapeutic failureg p
Poor patient compliance(erratic drug availability found in parts of the(erratic drug availability found in parts of the
developing world)
International travel promotes a global disease community ensuring MDRdisease community, ensuring MDR
tuberculosis in all over the world
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