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Sulfonamides, trimethoprim and Quinolones

Sulfonamides, trimethoprim and Quinolones. By S. Bohlooli, PhD School of Medicine, Ardabil University of Medical Sciences. Antifolate drugs. Sulfonamides Trimethoprim Trimethoprim & Sulfamethoxazole mixture. Sulfonamides: chemistry. Inhibition of dihydropetroate synthase.

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Sulfonamides, trimethoprim and Quinolones

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  1. Sulfonamides, trimethoprim and Quinolones By S. Bohlooli, PhD School of Medicine, Ardabil University of Medical Sciences

  2. Antifolate drugs • Sulfonamides • Trimethoprim • Trimethoprim & Sulfamethoxazole mixture

  3. Sulfonamides: chemistry

  4. Inhibition of dihydropetroate synthase Sulfonamides: mechanism of action

  5. Sulfonamides: antimicrobial activity • Gram positive and negative bacteria • Nocardia, chlamydia trachomatis • Some protoza • Some enteric bacteria • Rickettisiae stimulated!

  6. Sulfonamides: resistance • Overproduction of PABA • Low affinity dihydropetroate synthase • Loss of permeability to sulfonamides

  7. Oral absorbable Short Medium Long Oral, nonabsorbable topical Serum protein bind 20 ~ 90% Excreted into urine Sulfonamides: pharmacokinetics

  8. Pharmacokinetic Properties of Some Sulfonamides and Trimethoprim

  9. Sulfonamides: clinical uses • Oral absorbable agents • Sulfisoxazole, sulfamethoxazole • To treat urinary tract infection • Sulfadiazine: toxoplasmosis • Sulfadoxine: long acting, in a combination for treatment of malaria • Oral nonabsorbable agents • Ulcerative colitis, enteritis, other inflammatory bowel disease • Topical agents • Sulfacetamide: ophthalemic • Mafenide & silver sulfadiazine: topically

  10. Sulfonamides: adverse reactions • Cross allergenic sulfonamide drugs: • Thiazide, furosemide, diazoxide, sulfonylurea hypoglycemic agents, and others • Fever, skin rashes, exfoliative dermatitis,photosensivity, urticaria, nausea, vomiting, diarrhea • Stevens-Johnson syndrom • Urinary tract disturbances • Crystalluria, hemturia, obstruction • Hematopoietic disturbance • Hemolytic or aplastic anemia • Granulocytopenia, thrombocytopenia, leukmoid reaction • Hemolysis in G-6PDH deficient patients • Kernicterus in newborn of mothers have taken near the end of pergnancy

  11. Trimethoprim: chemistry

  12. Trimethoprim: resistance • Reduced cell permeability • Overproduction of DHF reductase • Altered affinity of reductase

  13. Trimethoprim: pharmacokinetics • Usually given orally alone or in combination with sulfamethoxazole • Mainly excreted into urine • More antibacterial activity in prostatic and vaginal fluids

  14. Clinical use • Oral trimethoprim • Acute urinary infection • Oral trimethoprim-sulfamethoxazole • P jiroveci pneumonia, shigellosis, systemic salmonella infection, complicated urinary tract infection, • Active against many respiratory pathogens • Intravenous trimethoprim-sulfamethoxazole • Gram negative sepsis, pneumocystis pneumonia • Shigllosis, typhoid fever • Oral pryrimethamine with sulfanamide • With sulfadiazine in Leishmaniasis, toxoplasmosis • With sulfadoxine in malaria

  15. Adverse effects • Megaloblastic anemia • Leukopenia, granulocytopenia • Can be prevented by folinic acid • The AIDS patients have high frequency of unwanted reactions

  16. DNA gyrase inhibitors • Fluoroquinolones • Nalidixic acid and cinoxacin

  17. Fluoroquinolones: chemistry

  18. Fluoroquinolones: chemistry-2

  19. Fluoroquinolones: antibacterial activity • Block of bacterial DNA synthesis by • Inhibiting topoisomerase II, IV • Gram positive & negative bacteria • Mycoplasma & clamydia, legionella • Some mycobacteria • Anaerobic bacteria

  20. Fluoroquinolones: resistance • Change in permeability • Loss of affinity

  21. Fluoroquinolones: pharmacokinetics • Well absorbed after oral administration • Good distribution • Divalent cations impair absorption

  22. Pharmacokinetic Properties of Fluoroquinolones

  23. Fluoroquinolones: clinical uses • Urinary tract infection • Even with multi-drug resistant organisms • Bacterial diarrhea • Shigella, salmonella, toxigenic E. coli • Infections of soft tissues, bones and joints • Intra-abdominal and respiratory tract infections • Gonococcal infection • Chlamydial urethritis and cervicitis • Legionellosis • Tuberclusis and atypical mycobacterial infections

  24. Fluoroquinolones: adverse effects • Nausea, vomiting & diarrhea • Headache, dizziness, insomnia, skin rash, abnormal liver test • Acute hepatitis & hepatic failure: trovafloxacin • Photosensivity: lomefloxacin, pefloxacin • QT prolongation: sparfloxacin • Hyperglycemia or hypoglycemia • May damage growing cartilage: arthropathy • Tendinitis

  25. Nalidixic acid & cinoxacin • Excreted too rapidly • Useful for urinary tract infections

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