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

Antifolate drugs Sulfonamides Trimethoprim Trimethoprim & Sulfamethoxazole mixture

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

Sulfonamides: mechanism of action Inhibition of dihydropetroate synthase

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

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

Synthesis of Sulfa drugs

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

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

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: chemistry

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 )

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

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 Sulfones ( Dapson) 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