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

Sulfonamides: mechanism of action Inhibition of dihydropetroate synthase

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

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

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

Pharmacokinetic Properties of Some Sulfonamides and Trimethoprim

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

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

Trimethoprim: chemistry

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

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

Clinical use Oral trimethoprim Oral trimethoprim-sulfamethoxazole 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

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

DNA gyrase inhibitors Fluoroquinolones Nalidixic acid and cinoxacin

Fluoroquinolones: chemistry

Fluoroquinolones: chemistry-2

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

Fluoroquinolones: resistance Change in permeability Loss of affinity

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

Pharmacokinetic Properties of Fluoroquinolones

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

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

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