MIDTERMS

• Chemotherapy


  Treatment of disease by using chemical compounds
• Chemotherapy drug


  Originally employed against infectious organisms
• Quinine


  From tree bark was long used to treat malaria
• Paul Ehrlich


  • First to coin the term chemotherapy
  • One of the proponent of Gram staining
  • German physician
  • Proposed the term "selective toxicity" that would kill pathogens and not human cells
• Selective toxicity


  • Specific inhibition of some types of the cell but they will not harm other cells
  • The drug has the ability to injure the target cell or organism without injuring the not target or host cells
• Arsenicals


  For syphilis-infected rabbits
• Arsphenamine/Salvarsan®


  • For syphilis spirochetes
  • Also known as magic bullet or compound 606
• Alexander Fleming


  • Discovered penicillin (1896)
  • Observed that Penicillium fungus produced an antibiotic, penicillin, that killed S. aureus

  
• Gerard Domagk


  • Discovered Prontosil Red - for pathogenic streptococci and staphylococci in mice
  • Discovered sulfonamides or sulfa drugs (1939)

  
• Therapeutic dose


  The drug level required for clinical treatment of particular infection
• Toxic dose


  • The drug level which the agent becomes too toxic for the host
  • Dose that will exhibit adverse drug reaction
• Therapeutic index


  • The ratio of the toxic dose (TD50) to the therapeutic dose/effective dose (ED50)
  • The larger the therapeutic index, the better the chemotherapeutic agent
  • The higher the TI the safer the drug
• Side effects


  • Undesirable effects on the host and it may involve almost any organ system
  • Chemotherapeutic agents must be administered with care
  • It may vary on each individual
• Narrow spectrum drugs


  • Effective only against a limited variety of pathogens
  • Use on specific infection especially when the causative agent is known
• Narrow spectrum drugs


  • Will not kill as many normal biota as broad spectrum
  • Lesser ability to cause superinfections
  • Lesse bacterial resistance because it is targeted (deal with special bacteria)
• Broad spectrum drugs


  • Attack many different kinds of pathogens
  • Larger group of organism
• Agents on general microbial group


  • Antibacterial
  • Antifungal
  • Antiprotozoal
  • Antiviral

  
• Chemical therapeutic agents


  Can be synthesized by microorganisms or manufactured by chemical procedures independent of microbial activity
• Sources of chemical therapeutic agents


  • Molds
  • Fungi- penicillium cresogenum
  • Bacteria- streptomyces, bacillus species (bacitracin)

  
• Natural


  • Totally synthesized by one of a few bacteria or fungi
  • From living organisms

  
• Synthetic


  Drugs that are synthesize by chemical procedures in the laboratory
• Semisynthetic


  • Natural antibiotics that have been chemically modified by the addition of extra chemical groups to make them less susceptible to inactivation by pathogens
  • Parent compound are from natural

  
• Antibiotics


  • Substance produced by microorganisms that, in small amounts, inhibits another microorganism
  • Not all antimicrobials are antibiotics
  • Sources are living organisms (mold, fungi, and bacteria)

  
• Microorganisms and their antibiotics


  • B. subtilis - Bacitracin
  • B. polymyxa - Polymyxin
  • S. nodosus - Amphotericin B
  • S. venezuelae - Chloramphenicol
  • S. griseus - Streptomycin
  • Micromonospora purpurea - Gentamicin
  • Cephalosporium spp. - Cephalothin
  • Penicillium notatum - Penicillin

  
• Bactericidal


  Kills the target pathogen; its activity is concentration dependent and the agent may be only static at low levels

  
• Bacteriostatic


  • Inhibit growth; if agent is removed, the microorganisms will recover and grow again
  • Not effective if host's resistance is too low
  • Don't kill bacteria
• There are agents that are capable of killing some species, but are only bacteriostatic for others
• Chloramphenicol


  Inhibits growth of E. coli but kills Haemophilus influenzae
• All protein synthesis inhibitors and antimetabolites are "static" except aminoglycosides
• Antimetabolites


  Substances that inhibits chemicals on the body that is part of the normal metabolism of an organism
• Actions of antimicrobial drugs


  • Inhibition of cell wall synthesis
  • Inhibition of protein synthesis
  • Injury to plasma membrane
  • Inhibition of nucleic acid synthesis
  • Antimetabolites

  
• Inhibiting cell wall synthesis


  • Penicillin targets gram positive bacteria
  • Penicillin and certain other antibiotics prevent the synthesis of intact peptidoglycan; consequently, the cell wall is greatly weakened, and the cell undergoes lysis

  
• Inhibiting protein synthesis


  • Eukaryotic cells have 80S ribosomes; prokaryotic cells have 70S ribosomes
  • The difference in ribosomal structure accounts for the selective toxicity of antibiotics that affect protein synthesis
  • Mitochondria also contain 70S ribosomes similar to those of bacteria, so antibiotics targeting the 70S ribosomes can have adverse effects on the cells of the host
• Inhibiting plasma membrane


  • Antifungal drugs, such as amphotericin B, miconazole, and ketoconazole, combine with sterols in the fungal plasma membrane to disrupt the membrane
  • Certain antibiotics, especially polypeptide antibiotics, bring about changes in the permeability of the plasma membrane, resulting in the loss of important metabolites from the microbial cell
  • Bacterial plasma membranes generally lack sterols, so these antibiotics do not act on bacteria
• Inhibiting nucleic acid synthesis


  • A number of antibiotics interfere with the processes of DNA replication and transcription in microorganisms
  • Some drugs with this mode of action have an extremely limited usefulness because they interfere with mammalian DNA and RNA as well
• Inhibiting the synthesis of essential metabolites


  • An example is the relationship between the antimetabolite sulfanilamide (a sulfa drug) and Para Aminobenzoic Acid (PABA)
  • PABA is the substrate for an enzymatic reaction leading to the synthesis of folic acid, a vitamin that functions as a coenzyme for the synthesis of the purine and pyrimidine bases of nucleic acids and many amino acids
• Purine and pyrimidine


  Nitrogenous bases in our nucleic acid (RNA and DNA)
• Chemical structures of antibacterial agents


  • Beta Lactams
  • Fusidic Acid
  • Glycopeptides
  • Sulfonamides
  • Aminoglycosides
  • Trimethoprim
  • Tetracyclines
  • Quinolones
  • Chloramphenicol
  • Rifampicin
  • Macrolides
  • Lincosamides

  
• Beta-lactam ring


  3 carbon and a nitrogen
• Properties of some common antibacterial drugs

  • Ampicillin - Cidal, broad gram positive and some gram negative, allergic responses
  • Bacitracin - Cidal, narrow gram positive, renal injury if injected
  • Carbenicillin - Cidal, broad gram positive and many gram negative, allergic responses
  • Cephalosporins - Cidal, broad gram positive and some gram negative, allergic responses, thrombophlebitis, renal injury
  • Chloramphenicol - Static, broad gram positive and gram negative, rickettsia and chlamydia, bone marrow dysfunction, allergic reactions
  • Ciprofloxacin - Cidal, broad gram positive and gram negative, GIT upset, allergic reactions
  • Clindamycin - Static, narrow gram positive, anaerobes, diarrhea
  • Dapsone - Static, narrow (mycobacteria), anemia, allergic responses
  • Erythromycin - Static, broad gram positive and some gram negative, GIT upset, hepatic injury
  • Gentamicin - Cidal, narrow gram negative, allergic responses, nausea, loss of hearing, renal damage
  • Isoniazid - Static and Cidal, narrow (mycobacteria), allergic reactions, GIT upset, hepatic injury
  • Methicillin - Cidal, narrow gram positive, allergic reactions, renal toxicity, anemia
  • Penicillin - Cidal, narrow gram positive, allergic reactions, nausea, vomiting
  • Polymyxin B - Cidal, narrow gram negative, renal damage, neurotoxic reactions
  • Rifampin - Static, broad gram positive, mycobacteria, hepatic injury nausea, allergic responses
  • Streptomycin - Cidal, narrow gram positive, allergic reactions, renal toxicity, anemia