Sulfonamides trimethoprim and Quinolones By S Bohlooli Ph

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

Antifolate drugs n n n Sulfonamides Trimethoprim & Sulfamethoxazole mixture

Sulfonamides: chemistry

Sulfonamides: mechanism of action n Inhibition of dihydropetroate synthase

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

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

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

Pharmacokinetic Properties of Some Sulfonamides and Trimethoprim

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

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

Trimethoprim: chemistry

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

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

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

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

DNA gyrase inhibitors n n Fluoroquinolones Nalidixic acid and cinoxacin

Fluoroquinolones: chemistry

Fluoroquinolones: chemistry-2

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

Fluoroquinolones: resistance n n Change in permeability Loss of affinity

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

Pharmacokinetic Properties of Fluoroquinolones

Fluoroquinolones: clinical uses n Urinary tract infection n n Bacterial diarrhea n n n n Even with multi-drug resistant organisms 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 n n n n 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 n n Excreted too rapidly Useful for urinary tract infections