2-Sulfonamides

Woods 1962 j gen microbial 29 687 being longest in

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Unformatted text preview: complex media (such as t he blood broth illustrated). It occurred, however, even if only t o the extent of one or two generations, in t he simplest medium sup7 Mechanism of Action of DHFR Inhibitors Dihydrofolate Trimethoprim Methotrexate Pyrimethamine -forms a tight non covalent complexex with DHFR Tight (noncovalent) binding to DHFR to form a stable E-I complex Sunday, March 31, 2013 8 Binding of trimethoprim to bacterial and mammalian dihydrofolate reductases Source of enzyme BACTERIAL Eschericha coli Staphylococcus aureus Proteus vulgaris MAMMALIAN Rat Rabbit Human Trimethoprim concentration required for 50% inhibition (nM) 5 15 5 260,000 370,000 300,000 60,000-fold difference in inhibition potency between the enzymes derived from human and E.coli species -this provides the ST which we desire Scholar and Pratt (2000) p. 223. Sunday, March 31, 2013 9 Synergism in antifolate therapy Control 109 Sulfa drug or TMP alone (1 μg/ml) (0.1 μg/ml) E. coli growth Cells/mL Sulfa drug plus TMP -in presence of both drugs there is more bacterial death 105 Time (hrs) Sunday, March 31, 2013 10 Effect of TMP and SMX alone and in combination on several pathogenic bacteria growing in vitro MIC MIC (μg/ml) SMX TMP Organism Alone Mixture Alone Mixture Staphylococcus aureus 3 0.3 1 0.015 Streptococcus pneumoniae 30 2 2 0.1 Haemophilus influenzae 10 0.3 1 0.015 Shigella sonnei 10 1 0.3 0.05 Proteus vulgaris 30 3 3 0.15 What is the pharmacological basis for the synergism? Reduces propensity for bacterial resistance Scholar and Pratt (2000) p. 224. Sunday, March 31, 2013 11 Effect of TMP and SMX alone and in combination on several pathogenic bacteria growing in vitro MIC MIC (μg/ml) SMX TMP Organism Alone Mixture Alone Mixture Staphylococcus aureus 3 0.3 1 0.015 Streptococcus pneumoniae 30 2 2 0.1 Haemophilus influenzae 10 0.3 1 0.015 Shigella sonnei 10 1 0.3 0.05 Proteus vulgaris 30 3 3 0.15 Scholar and Pratt (2000) p. 224. Sunday, March 31, 2013 12 What are the advantages of the SMX-TMP combinations? • Synergism • Lower doses required of each drug • Reduces (does not prevent) propensity for bacterial resistance Sunday, March 31, 2013 13 Mechanisms of resistance results from alterations in the cell wall causing • Affinity of sulfonamides for dihydropteroic acid synthase • • • Sulfonamide permeation into bacterial cell Sulfonamide efflux from bacterial cell Production of essential metabolite increase concentration of PABA = sulfonamide is ineffective Sunday, March 31, 2013 14 Sulfonamides Absorption / Fate / Excretion • • Absorbed rapidly / well from GI tract • PPC ≈ 2-6 hrs Bound to albumin; variable and related to (inactive) Hydrophobicity pKa At physiological pH • • Sunday, March 31, 2013 • • • High pKa → low protein binding Low pKa → high protein binding 15 Pharmacokinetics parameters of selected sulfonamides Drug Plasma t½ (hours) % Protein bound Level in CSF (%) Peak blood level (μg/ml) Sulfisoxazole 5-6 92 30-50 40-...
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