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Sulfonamides

صيدلانية نظري / د . فارس رابع صيدلة 23 / 4 / 2016. Sulfonamides. 4 th Year Pharmacy 2016. Antifolate drugs. Sulfonamides Trimethoprim Trimethoprim & Sulfamethoxazole mixture. Lead Compound. Notes Prontosil - red dye Antibacterial activity in vivo (1935) Inactive in vitro

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Sulfonamides

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  1. صيدلانية نظري / د . فارس رابع صيدلة 23 / 4 / 2016 Sulfonamides 4th Year Pharmacy 2016

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

  3. Lead Compound • Notes • Prontosil - red dye • Antibacterial activity in vivo (1935) • Inactive in vitro • Metabolised to active sulfonamide • Acts as a prodrug • Sulfanilamide - first synthetic antibacterial agent acting on a wide range of infections

  4. Sulfonamides: mechanism of action • Inhibition of dihydropetroate synthase

  5. para-Aminobenzoic acid Dihydropteroate synthetase Reversible inhibition Dihydropteroate Sulfonamides L-Glutamic acid Dihydrofolate Dihydrofolate reductase NADPH Trimethoprim _ _ Tetrahydrofolate (coenzyme F) Mechanism of action

  6. O O C S H H N N N R 2 2 O O van der Waals interactions Ionic bond Active site Active site H-Bond Mechanism of action Binding interactions

  7. Synthesis of Sulfa drugs

  8. N-Acetylation Sulfathiazole Insoluble metabolite Sulfonamides - Drug Metabolism • Notes • Sulfonamides are metabolised by N-acetylation • N-Acetylation increases hydrophobic character • Reduces aqueous solubility • May lead to toxic side effects

  9. Structure-Activity Relationships Aromatic para-Amino group Sulfonamide • para-Amino group is essential (R1=H) • para-Amido groups (R1=acyl) are allowed • inactive in vitro, but active in vivo • act as prodrugs • Aromatic ring is essential • para-Substitution is essential • Sulfonamide group is essential • Sulfonamide nitrogen must be primary or secondary • R2 can be varied

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

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

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

  13. Pharmacokinetic Properties of Some Sulfonamides and Trimethoprim

  14. Sulfonamides: chemistry

  15. 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 ( Burn )

  16. 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

  17. Trimethoprim: chemistry

  18. 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

  19. Adverse effects • Megaloblastic anemia • Leukopenia, granulocytopenia • Can be prevented by folinic acid • The AIDS patients have high frequency of unwanted reactions Sulfones ( Dapson) • Thought to inhibit dihydropteroate synthetase • Used in the treatment of leprosy

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