Chemotherapy (2)
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Transcript of Chemotherapy (2)
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Definition of ChemotherapyThe treatment of disease by means of
chemicals that have a specific toxic effect upon the disease-producing microorganisms or that selectively destroy cancerous tissue
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DefinitionsCompounds that are used to kill or inhibit
growth of microbial organisms are called ANTIMICROBIALS
Substances produced by some plants or microorganisms that can kill or inhibit growth of other organisms are called ANTIBIOTICS
ANTIBACTERIALS refer to substances that act against bacteria
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Modes of action of Antimicrobials
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Bactericidal vs Bacteriostatic antibiotics
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Antimicrobial targetsThe structures in microbes that are mainly
targeted by antimicrobials are Cell wallCell membraneCell proteinsCell nucleic acids
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Basic structure of Bacterial cell wall
Therefore it is a N-G-N-G chains that are crosslinked together by peptaglycine bridges
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Folic acid synthesis
ß-lactams & Glycopeptides (Vancomycin)
50 50 5030 30 30
DNA
mRNA
Ribosomes
PABA
DHFA
THFA
Cell wall synthesis
DNA gyrase
Quinolones
Protein synthesis inhibition
Protein synthesis inhibitionTetracyclines
Protein synthesis mistranslation
Macrolides & Lincomycins
DNA-directed RNA polymerase
Rifampin
Aminoglycosides
Sulfonamides
Trimethoprim
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Inhibitors of cell wall synthesis Β-lactam bactericidal drugs;
Examples Penicillin
AmoxicillinAmpicillinCephalosporins
Vancomycin
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Modes of action of cell wall inhibitorsΒ-lactam bactericidal drugsThey inhibit bacterial cell wall peptidoglycan
synthesis in growing bacteria. This leads to the death of the Bacteria
VancomycinThey kill Bacteria by interfering with
peptidoglycan polymerization (on gram positive bacteria only)
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Inhibitors of RNA synthesisExample
Rifampicin
Mode of actionThey kill bacteria by inhibiting RNA polymerase
Commonly used in G+ve bacteria especially Mycobacterium tuberculosis
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Inhibitors of DNA synthesisExamples
Fluoroquinolones
Polymixins (Polymixins B, colistin)
Sulphonamides
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Inhibitors of protein synthesisProkaryotic and
eukaryotic ribosomes are structurally different
Eukaryotes (80s ribosomes) contain 60s and 40s subunits
Prokaryotes (70s ribosomes) contain 50s and 30s subunits
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Inhibitors of protein synthesisExamples
AminoglycosidesTetracyclines PuromycinMacrolides
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BACTERIAL RESISTANCE TO ANTIBIOTICS
BACTERIAL RESISTANCE TO ANTIBIOTICS
Antibiotic resistance is a type of drug resistance where a susceptible microorganism is able to survive exposure to an antibiotic
Human factors that predispose antibiotic resistance- Under dosage- Frequent use of antibiotics- Undirected use of antibiotics- making poor quality drugs and counterfeit drugs
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Ability of Bacteria to express resistance to antibiotics
This basically happens due to structural and biochemical characteristics that can be due to - Inherent characteristics- Adaptive biochemical changes- Spontaneous genetics changes
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Mechanisms of Bacterial resistance to antibiotics
Inherent structural mechanismsInherent biochemical mechanismsAdaptive biochemical mechanisms
Inherent antibiotic resistance genesGenetic mutations
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Mechanisms of Bacterial resistance to antibiotics
Inherent structural mechanismSome bacteria have cell wall that prevents penetration of some bacteria
Example; Penicillin can not penetrate wall of G-ve bacteria because the wall has lipopolysaccharide layer that cover the site of peptidoglycan synthesis
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Mechanisms of Bacterial resistance to antibiotics
Inherent Biochemical mechanismsInactivation of drugs – Some bacteria can
inactivate drugs by chemically modifying themExample; Staphilococcus produce β-lactamase enzyme which hydrolyses β-lactam ring of drugs like penicillin
Decreased drug accumulation – some bacteria have proteins that actively pump out antibioticsExample; S. aureus has enhanced fluoroquinolone pumping capability
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Mechanisms of Bacterial resistance to antibiotics
Adaptive biochemical mechanismsAlteration of antibiotic target – Some
bacteria alter the stereochemistry of antibiotic targets hence antibiotic fails to bind
Example; Chloramphenicol action can be blocked by changes in bacterial 50s ribosomal unit that prevent it from binding
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Mechanisms of Bacterial resistance to antibiotics
Inherent bacterial resistance genesBacteria store genetic information in genes
within chromosomal DNA. Bacteria has also other extrachromosomal DNA
called PLASMIDSOf the most important genes in the plasmids,
are the one with information on Antibiotic resistance
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ANTIBACTERIAL RESISTANCE PLASMIDS (R-PLASMIDS)
They are collection of acquired foreign genetic elements that originated within other bacteria or fungi
R-plasmids are capable of combining with other plasmids, thus resistance to several antibiotics can reside on one plasmid
A bacterium may contain as many as 1,000 copies of a single plasmid
Bacteria are capable of transferring R-plamids from one cell to another through a process known as CONJUGATION
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Transfer of resistance through genetic materials
This can happen in three ways
1.Conjugation
2.Transposons
3.Bacteriophages
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Mechanisms of Bacterial resistance to antibiotics
Chromosaomal Genetic MutationsSpontaneous mutations in bacterial
chromosomes can lead to drug resistance
Basically chromosomal genetic mutations lead to the changes to structural or biochemical properties of a given bacteria and this can loose the susceptibility to a drug.
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Selection of Antimicrobial agentsThis should consider four things;
Identity of the organism and susceptibility to a particular agent
The site of the infectionThe safety of the agent
Patient factors
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Chemotherapeutic spectraThe chemotherapeutic spectrum of a particular
drug refers to the range of species of microorganisms affected by the drug
There are1.Narrow spectrum drugs, eg Isoniazid 2.Extended spectrum drugs, eg Ampicillin3.Broad spectrum drug, eg Tetracycline and
chloramphenicol
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Combination of Antimicrobial drugs
Dynamics of combined antimicrobial action1.Indifference (2 + 3 = 3) 2.Antagonism (2 + 5 = 4) eg penicillin + tetracycline3.Synergism (2 + 2 = 5) eg Penicillin + Streptomycin
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Dynamics of drug combination
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ANTIBACTERIAL DRUGS
The following are the examples of the common Antibacterial groups
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SULFONAMIDESMode of action – interferes FOLATE synthesis by
inhibiting dihydropteroate synthetase, that incorporates PABA in making folate
Spectrum of Action – BroadPreparations - Sulfamethazine
- Sulfadimethoxine- Sulfathiazole- Sulfachlorpyridazine- Sulfasoxasole and
sulfamethaxazole- Sulfacetamide- Sulfasalazine
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Mode of action of Sulfonamides
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FluoroquinolonesMode of Action – inhibit DNA replication. They
are bactericidalPreparation – Enrofloxacin
- Ciprofloxacin
Spectrum of activity - Broad
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PenicillinsBelong to β-lactam bactricidal drugsMode of action – Inhibit cell wall synthesis
(bind transpeptidase enzyme involved in cross-linking of peptidoglycans)
Spectrum – act against G +ve aerobes and anaerobes
- Semisynthetic penicillins are effetcive against some G –ve bacteria
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PenicillinsPreparations (Natural Penicillins)
– Penicillin G, Penicillin C- Penicillin V- Penicillinase-stable penicillins (methicillin, Oxacillin, cloxacillin,
dicloxacillin)Broad spectrum Penicillins
- Ampicillin, amoxicillin and Hetacillin - Carbenicillin and Ticarcillin- Azlocillin, mezlocillin and Piperacillin
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Cephalosporins Modes of Action – Inhibit cell wall synthesis
(bactericidal)Preparations 1st Generation cephalosporins (G +ve aerobes)
- cephalexin, cefadroxil, cephaprin, cephalothin, cefazolin
2nd Generation cephalosporins (G +ve, plus some G –ve)- cefaclor, cefoxitin
3rd Generation cephalosporins (G +ve, G –ve, resistance to beta-lactamase, penetrate BBB)
- ceftiofur, moxalactam)
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AminoglycosidesMode of action – Interferes protein syhthesis
(Bactericidal)PreparationsNatural – Streptomycin and
dihydrostreptomycin- Neomycin
Extended-spectrum - Gentamycin and amikacin- Tobramycin- Kanamycin
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TetracyclinesMode of action – Inhibit Protein synthesis
(bond to 30s ribosome)Spectrum – BroadPreparations – Tetracycline
- Chlortetracycline- Oxytetracycline- Doxycycline
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Chloramphenicol Mode of action - Bind to 50s of ribosome Spectrum – it is a broad-spectrum antibiotic,
and it is effective against most anaerobic bacteria
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MacrolidesMode of action – Inhibit protein synthesis by
binding to 50s of ribosome
Spectrum – Effective against G +ve aerobes and anaerobes and Mycoplasma speices
Examples; - Erythromycin- Tylosin- Tilmicosin
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LincosamidesMode of action – Bind to 50s of ribosome to
inhibit protein synthesis
Spectrum – effective against G +ve aerobes and anaerobes, Toxoplasma species, Mycoplasma species
Examples - Lincomycin- Clindamycin
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Miscellaneous Anti-infectious agents
Metronidazole (Flagyl) – it disrupts DNA.- it is used in the treatment of bacterial
and protozoal infections (Amoeba, Giardia, Trichomonas)
Rifampicin – inhibits RNA synthesis- used in treatmet of Tuberculosis
Tiamulin – inhibits protein synthesisOthers – Bacitracin, Polymixin B.
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ANTIVIRAL DRUGSTreatment of viral diseases is difficult because
- Viruses do not have many metabolic processes
- Viruses incorporate into the host cell and uses the host cell machinery for replication
- Most viruses undergo continuous spontaneous mutation, leading to the changing of structure
However there have been several drugs for viral infections with varying mechanisms and effectiveness
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Mechanisms of action of antiviral drugs
Inhibition of Penetration to host cell - Amantidin – Inhibits uncoating
- Gammaglobulins – “neutralize” the virus
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Mechanisms of action of antiviral drugs
Inhibition of nucleic acidsInhibitors of viral DNA polymerase – Acyclovir, Vidarabine, Foscarnet
Interference with viral DNA synthesis – Gancyclovir, ribavirin
Inhibitors of Reverse transcriptase – Zidovudine, Zalcitabine, Didanosine
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Mechanisms of action of antiviral drugs
Neuramidase inhibitors - Zanamivir - Oseltamivir
Immunomodulators - Interferons - Pavilizumab - Imiquimod
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Treatment of HIV and AIDS (ARVs)
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Treatment of HIV and AIDS (ARVs)ARV Drugs Reverse transcriptase inhibitors Protease inhibitors Fusion inhibitors
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Treatment of HIV and AIDS (ARVs)
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Treatment of HIV and AIDS (ARVs)Protease Inhibitors
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Treatment of HIV and AIDS (ARVs)
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Treatment of HIV and AIDS (ARVs)
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ANTIFUNGAL DRUGSGRISEOFULVIN Mode of action; It binds to microtubules to
inhibit spindle formation and mitosis. Fungistatic
KETOCONAZOLEMode of action; Inhibits synthesis of ergosterol
in fungal cytoplasmic membranes by blocking cytochrome P-450 enzymes
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ANTIFUNGAL DRUGSAMPHOTERICIN BMode of action; Binds to ergosterol of cell
membranes and result to leakage of cell contents. Fungicidal.
FLUCYTOSINEMode of action; Inhibits thymidylate
synthetase, thereby inhibiting DNA and RNA synthesis
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ANTIPROTOZOAL DRUGSAnticoccidial drugsAntitrypanosomal drugsAntitheilerial drugsAntibabesial drugsAnti-anaplasmal drugsAnti-Giardial drugs
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Anticoccidial drugsAmprolium – block thiamine receptorsSulfonamides (s/methoxine, s/quinoxaline) –
Inhibit folate synthesisHalofuginone Sodium inophores (monensin, salinomycin,
lasalocid) – increase intracellular Na+ to impair Mit. functions
Decoquinate – inhibit DNA synthesisApronicid – interfere purine metabolism
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Antitrypanosomal drugsHuman African Tripanosomosis (HAT)First stage drugs
- Pentamidine- Suramin
Second stage drugs- Melasoprol- Eflornithine
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Antitrypanosomal drugsLivestock trypanosomosisDiminazene (Berenil®, Veriben®)
- bind to kinetoplast and nucleusPhenanthridinium compounds
(Isometamedium, Homidium)- inhibit DNA and RNA synthesis
SuraminMelarsomineQuinapyramine
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Antitheilerial drugsHalofuginone – destroys parasitized
erythrocytesParvaquone – Interferes with electron
transport in mitochondriaBuparvaquone - Interferes with electron
transport in mitochondria
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Antibabesial drugsImidocarb (Imizol®) – for therapeutic and
prophylaxis
Diminazine aceturate (Berenil®)
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Antianaplasmal drugsTetracyclineImidocarbDithiosemicarbazones
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Anti-Giardial drugsMetronidazole (Flagyl)Tinidazole (Fasigyn)Nitazoxanide
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ANTIHELMINTHIC DRUGSThere are three major groups of helminths Nematodes (Antinematodal)Cestodes (Anticestodal)Trematodes (Antitrematodal drugs)