Chemotherapy (2)


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Chemotherapy (2)

  1. 1. 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
  2. 2. Definitions Compounds 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
  3. 3. Modes of action of Antimicrobials
  4. 4. Bactericidal vs Bacteriostatic antibiotics
  5. 5. Antimicrobial targetsThe structures in microbes that are mainly targeted by antimicrobials are  Cell wall  Cell membrane  Cell proteins  Cell nucleic acids
  6. 6. Basic structure of Bacterial cell wallTherefore it is a N-G-N-G chains thatare crosslinkedtogether bypeptaglycinebridges
  7. 7. DNA gyrase DNA-directed RNA polymerase Quinolones Cell wall synthesis Rifampin ß-lactams & Glycopeptides (Vancomycin) DNA THFA mRNATrimethoprim Protein Ribosomes synthesisFolic acid inhibitionsynthesis DHFA 50 50 50 Macrolides & 30 30 30 LincomycinsSulfonamides PABA Protein synthesis Protein synthesis inhibition mistranslation Tetracyclines Aminoglycosides
  8. 8. Inhibitors of cell wall synthesisΒ-lactam bactericidal drugs; Examples Penicillin Amoxicillin Ampicillin CephalosporinsVancomycin
  9. 9. Modes of action of cell wallinhibitorsΒ-lactam bactericidal drugsThey inhibit bacterial cell wall peptidoglycan synthesis in growing bacteria. This leads to the death of the BacteriaVancomycinThey kill Bacteria by interfering with peptidoglycan polymerization (on gram positive bacteria only)
  10. 10. Inhibitors of RNA synthesisExample RifampicinMode of action They kill bacteria by inhibiting RNA polymeraseCommonly used in G+ve bacteria especially Mycobacterium tuberculosis
  11. 11. Inhibitors of DNA synthesisExamples Fluoroquinolones Polymixins (Polymixins B, colistin) Sulphonamides
  12. 12. Inhibitors of protein synthesisProkaryotic and eukaryotic ribosomes are structurally differentEukaryotes (80s ribosomes) contain 60s and 40s subunitsProkaryotes (70s ribosomes) contain 50s and 30s subunits
  13. 13. Inhibitors of protein synthesisExamples Aminoglycosides Tetracyclines Puromycin Macrolides
  14. 14. BACTERIAL RESISTANCE TO ANTIBIOTICSAntibiotic resistance is a type of drug resistance where a susceptible microorganism is able to survive exposure to an antibioticHuman factors that predispose antibiotic resistance - Under dosage - Frequent use of antibiotics - Undirected use of antibiotics - making poor quality drugs and counterfeit drugs
  15. 15. Ability of Bacteria to express resistance to antibioticsThis basically happens due to structural and biochemical characteristics that can be due to - Inherent characteristics - Adaptive biochemical changes - Spontaneous genetics changes
  16. 16. Mechanisms of Bacterial resistance to antibiotics Inherent structural mechanisms Inherent biochemical mechanisms Adaptive biochemical mechanisms Inherent antibiotic resistance genes Genetic mutations
  17. 17. Mechanisms of Bacterial resistance to antibioticsInherent structural mechanism Some bacteria have cell wall that prevents penetration of some bacteriaExample; Penicillin can not penetrate wall of G-ve bacteria because the wall has lipopolysaccharide layer that cover the site of peptidoglycan synthesis
  18. 18. Mechanisms of Bacterial resistance to antibioticsInherent Biochemical mechanismsInactivation of drugs – Some bacteria can inactivate drugs by chemically modifying them Example; Staphilococcus produce β-lactamase enzyme which hydrolyses β-lactam ring of drugs like penicillinDecreased drug accumulation – some bacteria have proteins that actively pump out antibiotics Example; S. aureus has enhanced fluoroquinolone pumping capability
  19. 19. Mechanisms of Bacterial resistance to antibioticsAdaptive biochemical mechanismsAlteration of antibiotic target – Some bacteria alter the stereochemistry of antibiotic targets hence antibiotic fails to bindExample; Chloramphenicol action can be blocked by changes in bacterial 50s ribosomal unit that prevent it from binding
  20. 20. Mechanisms of Bacterial resistance to antibioticsInherent 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
  21. 21. 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
  22. 22. Transfer of resistance through genetic materialsThis can happen in three ways2. Conjugation4. Transposons6. Bacteriophages
  23. 23. Mechanisms of Bacterial resistance to antibioticsChromosaomal Genetic MutationsSpontaneous mutations in bacterial chromosomes can lead to drug resistanceBasically 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.
  24. 24. Selection of Antimicrobial agentsThis should consider four things; Identity of the organism and susceptibility to a particular agent The site of the infection The safety of the agent Patient factors
  25. 25. Chemotherapeutic spectraThe chemotherapeutic spectrum of a particular drug refers to the range of species of microorganisms affected by the drugThere are3. Narrow spectrum drugs, eg Isoniazid4. Extended spectrum drugs, eg Ampicillin5. Broad spectrum drug, eg Tetracycline and chloramphenicol
  26. 26. Combination of Antimicrobial drugsDynamics of combined antimicrobial action2. Indifference (2 + 3 = 3)3. Antagonism (2 + 5 = 4) eg penicillin + tetracycline4. Synergism (2 + 2 = 5) eg Penicillin + Streptomycin
  27. 27. Dynamics of drug combination
  28. 28. ANTIBACTERIAL DRUGSThe following are the examples of the common Antibacterial groups
  29. 29. SULFONAMIDESMode of action – interferes FOLATE synthesis by inhibiting dihydropteroate synthetase, that incorporates PABA in making folateSpectrum of Action – BroadPreparations - Sulfamethazine - Sulfadimethoxine - Sulfathiazole - Sulfachlorpyridazine - Sulfasoxasole and sulfamethaxazole - Sulfacetamide - Sulfasalazine
  30. 30. Mode of action of Sulfonamides
  31. 31. FluoroquinolonesMode of Action – inhibit DNA replication. They are bactericidalPreparation – Enrofloxacin - CiprofloxacinSpectrum of activity - Broad
  32. 32. 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
  33. 33. 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
  34. 34. CephalosporinsModes of Action – Inhibit cell wall synthesis (bactericidal)Preparations1st Generation cephalosporins (G +ve aerobes) - cephalexin, cefadroxil, cephaprin, cephalothin, cefazolin2nd Generation cephalosporins (G +ve, plus some G –ve) - cefaclor, cefoxitin3rd Generation cephalosporins (G +ve, G –ve, resistance to beta-lactamase, penetrate BBB) - ceftiofur, moxalactam)
  35. 35. AminoglycosidesMode of action – Interferes protein syhthesis (Bactericidal)PreparationsNatural – Streptomycin and dihydrostreptomycin - NeomycinExtended-spectrum - Gentamycin and amikacin - Tobramycin - Kanamycin
  36. 36. TetracyclinesMode of action – Inhibit Protein synthesis (bond to 30s ribosome)Spectrum – BroadPreparations – Tetracycline - Chlortetracycline - Oxytetracycline - Doxycycline
  37. 37. ChloramphenicolMode of action - Bind to 50s of ribosomeSpectrum – it is a broad-spectrum antibiotic, and it is effective against most anaerobic bacteria
  38. 38. MacrolidesMode of action – Inhibit protein synthesis by binding to 50s of ribosomeSpectrum – Effective against G +ve aerobes and anaerobes and Mycoplasma speicesExamples; - Erythromycin - Tylosin - Tilmicosin
  39. 39. LincosamidesMode of action – Bind to 50s of ribosome to inhibit protein synthesisSpectrum – effective against G +ve aerobes and anaerobes, Toxoplasma species, Mycoplasma speciesExamples - Lincomycin - Clindamycin
  40. 40. Miscellaneous Anti-infectious agentsMetronidazole (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 TuberculosisTiamulin – inhibits protein synthesisOthers – Bacitracin, Polymixin B.
  41. 41. 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 structureHowever there have been several drugs for viral infections with varying mechanisms and effectiveness
  42. 42. Mechanisms of action of antiviral drugsInhibition of Penetration to host cell - Amantidin – Inhibits uncoating - Gammaglobulins – “neutralize” the virus
  43. 43. Mechanisms of action of antiviral drugsInhibition of nucleic acids Inhibitors of viral DNA polymerase – Acyclovir, Vidarabine, Foscarnet Interference with viral DNA synthesis – Gancyclovir, ribavirin Inhibitors of Reverse transcriptase – Zidovudine, Zalcitabine, Didanosine
  44. 44. Mechanisms of action of antiviral drugsNeuramidase inhibitors - Zanamivir - OseltamivirImmunomodulators - Interferons - Pavilizumab - Imiquimod
  45. 45. Treatment of HIV and AIDS (ARVs)
  46. 46. Treatment of HIV and AIDS (ARVs)ARV Drugs Reverse transcriptase inhibitors Protease inhibitors Fusion inhibitors
  47. 47. Treatment of HIV and AIDS (ARVs)
  48. 48. Treatment of HIV and AIDS (ARVs)Protease Inhibitors
  49. 49. Treatment of HIV and AIDS (ARVs)
  50. 50. Treatment of HIV and AIDS (ARVs)
  51. 51. ANTIFUNGAL DRUGSGRISEOFULVINMode of action; It binds to microtubules to inhibit spindle formation and mitosis. FungistaticKETOCONAZOLEMode of action; Inhibits synthesis of ergosterol in fungal cytoplasmic membranes by blocking cytochrome P-450 enzymes
  52. 52. 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
  53. 53. ANTIPROTOZOAL DRUGS Anticoccidial drugs Antitrypanosomal drugs Antitheilerial drugs Antibabesial drugs Anti-anaplasmal drugs Anti-Giardial drugs
  54. 54. Anticoccidial drugs Amprolium – block thiamine receptors Sulfonamides (s/methoxine, s/quinoxaline) – Inhibit folate synthesis Halofuginone Sodium inophores (monensin, salinomycin, lasalocid) – increase intracellular Na+ to impair Mit. functions Decoquinate – inhibit DNA synthesis Apronicid – interfere purine metabolism
  55. 55. Antitrypanosomal drugsHuman African Tripanosomosis (HAT)First stage drugs - Pentamidine - SuraminSecond stage drugs - Melasoprol - Eflornithine
  56. 56. Antitrypanosomal drugsLivestock trypanosomosisDiminazene (Berenil®, Veriben®) - bind to kinetoplast and nucleusPhenanthridinium compounds (Isometamedium, Homidium) - inhibit DNA and RNA synthesisSuraminMelarsomineQuinapyramine
  57. 57. Antitheilerial drugs Halofuginone – destroys parasitized erythrocytes Parvaquone – Interferes with electron transport in mitochondria Buparvaquone - Interferes with electron transport in mitochondria
  58. 58. Antibabesial drugs Imidocarb (Imizol®) – for therapeutic and prophylaxis Diminazine aceturate (Berenil®)
  59. 59. Antianaplasmal drugs Tetracycline Imidocarb Dithiosemicarbazones
  60. 60. Anti-Giardial drugs Metronidazole (Flagyl) Tinidazole (Fasigyn) Nitazoxanide
  61. 61. ANTIHELMINTHIC DRUGSThere are three major groups of helminthsNematodes (Antinematodal)Cestodes (Anticestodal)Trematodes (Antitrematodal drugs)