Antimicrobial Drugs I Dental Pharmacology (PHCL 5-103) April 3, 2008

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					                       Antimicrobial Drugs I

               Dental Pharmacology (PHCL 5-103)

                             April 3, 2008

                                            Hiroshi Hiasa, Ph.D.
                                            Office: 3-117 NHH
                                            Tel. 626-3101

Pathogens (infectious agents)
   Biological agents that cause disease or illness to its host

 1. Bacteria

 2. Fungi

 3. Protozoans
    - malaria

 4. Virus

  1. Principles of antimicrobial agents
   A. Selective Toxicity
   (1) Selective toxicity
         Bacterial pathogens (prokaryotic cells) are different from their
         human hosts (eukaryotic cells).
   (2) Drug targets
         a. process unique to prokaryotic cells
            - cell wall synthesis.
         b. process that occurs in both, yet exploits metabolic
            - folic acid metabolism
         c. process that occurs in both, yet specific for bacterial
            - protein synthesis and nucleic acids synthesis
   (3) Therapeutic index (TI)
         TI = LD50/ED50
            LD: lethal dose, ED: effective dose
            TI = 1: equally toxic to the pathogen and to human

 (4) Basis of selective toxicity - five categories

     a. Inhibition of cell wall synthesis
     b. Disruption of cell membrane
     c. Inhibition of protein synthesis
     d. Inhibition of nucleic acids synthesis
     e. Inhibition of folic acid metabolism

 Need to identify other essential processes
   Genome Projects - more than 600 complete
                        microbial genomes
     New therapeutic targets?
     New drugs??

a. Inhibition of cell wall (peptidoglycan) synthesis

 b. Disruption of cell membrane

c. Inhibition of protein synthesis (ribosome)
        aminoglycosides, chloramphenicol, erythromycin

d. Inhibition of nucleic acids synthesis
    (i) DNA replication (topoisomerases)

(ii) Inhibition of transcription (RNA polymerase)

   e. Inhibition of folic acid synthesis
           sulfonamides, trimethoprim
                  Human                  Bacteria

                  Folate                 PABA
        Dietary                                    Dihydropteroate
        Intake                                       Synthetase            Sulfonamides

             Dihydrofolic             Dihydrofolic
                Acid                     Acid
Dihydrofolic Acid                                Dihydrofolic Acid
  Reductase                                        Reductase               Trimethoprim

          Folic Acid (THFA)         Folic Acid (THFA)

  B. Cytotoxicity
    (1) Toxicity
        a. Bactericidal drugs
            - directly kill bacterial cells
        b. Bacteriostatic drugs
            - inhibit bacterial reproduction/growth
              (do not kill)
                 Host’s immune system must attack and
                 kill bacterial cells
    (2) Spectrum
        a. Narrow spectrum
            - effective against limited types of bacteria
        b. Broad spectrum
            - effective against various types of bacteria

  (3) Gram-positive and Gram-negative bacteria

                    Gram-positive                         Gram-negative
                                     Outer membrane
                                                                          Periplasmic space
                                     Plasma membrane

C. Drug Resistance
      A major issue in medicine today
      Need of novel drugs

(1) Natural (Inherent) resistance
     Pseudomonas aeruginosa is
     resistant to penicillin G

(2) Acquired resistance
   a. Genomic mutation

  b. Plasmid
     - transfer of a drug
       resistance gene(s)
      such as penicillinase

  Plasmid Conjugation (natural biological process)
     Transfer of drug resistance between bacteria
     even in the absence of the drug treatment

Hospital Infections
  Pathogens in the hospital setting are often (multi)drug

  (3) Molecular mechanisms of drug resistance
   a. Inactivation of the antibiotics
   b. Mutations in the drug target
   c. Membrane permeability

      Efflux pumps
        multidrug resistance

 2. Use of antimicrobial agents
        - somewhat different in dental practice
    (1) Formulate a clinical diagnosis of microbial
    (2) Obtain specimens for microbial evaluation
    (3) Formulate a microbiological diagnosis
    (4) Initiate treatment
  A. Method of drug delivery
        oral, IV, Topical

  B. Duration of treatment
      a. Treatment should extend at least 2 days beyond
         resolution of symptoms
            Bacteriostatic drugs
      b. Compliance of patient

  C. Drug interactions
        a. Antibiotic - antibiotic

         b. Antibiotic - other
                Immunosuppressive drugs
                Cytotoxic drugs
                Birth control pills

D. General adverse reactions to microbial agents

(1) Allergic reaction
    Mild- rash
    Severe- anaphylaxis and death

(2) Superinfection
    Results from killing of normal
        Minimize with narrow
        spectrum antibiotic
        (first choice of drug)

(3) GI complaints
       Mild diarrhea, nausea, vomiting
       Severe - pseudomembranous colitis (PMC)

(4) In case of Pregnancy
        Risk of teratogenicity
        Effect on fetal tooth formation - ex. tetracyclines

(5) Development of (multi)drug resistant pathogens
      Serious infections in hospital setting
          Infections in hospital setting are more difficult
          to treat than community infections due to
          (multi)drug-resistant pathogens in hospital