Folate Antagonists - Sulfonamides and Trimethoprime KFU PDF

FOLATE ANTAGONISTS (SULFONAMIDES & TRIMETHOPRIM) Dr. Sheryar Afzal College of veterinary Medicine King Faisal University  Sulfonamides and p-aminobenzoic acid Short-acting Sulfacetamide Sulfadiazine (Silver sulfadiazine for burns) (+pyrimethamine...

FOLATE ANTAGONISTS (SULFONAMIDES & TRIMETHOPRIM) Dr. Sheryar Afzal College of veterinary Medicine King Faisal University  Sulfonamides and p-aminobenzoic acid Short-acting Sulfacetamide Sulfadiazine (Silver sulfadiazine for burns) (+pyrimethamine for toxoplasmosis, 1st line) Sulfafurazole Sulfisomidine Intermediate-acting Sulfamethoxazole (with trimethoprim) Sulfamoxole Sulfanitran Long-acting (Days) Sulfadimethoxine Sulfamethoxypyridazine Sulfadoxine Sulfametoxydiazine Sulfonamides are Sulfadoxine (+ pyrimethamine for malaria disease, 2structural nd line) analogs Sulfametopyrazine of PABA! 5  6 Mechanism of action Humans obtain folic acid from the diet to synthesise tetrahydrofolic acid. In contrast, many bacteria have to synthesise the folate derivatives as the cell wall is impermeable to folic acid and other folates. Sulfonamides compete with PABA for bacteria enzyme dihydropteroate synthetase, thus inhibiting the synthesis of bacterial dihydrofolic acid and subsequent essential cofactors (human do not have this pathway). Trimethoprim inhibits dihydrofolate reductase, thus inhibiting the synthesis of the tetrahydrofolatic acid required for purine, pyrimidine, Cotrimoxazole and(trimethoprim amino acid synthesis. + [Trimethoprim has stronger towards sulfamethoxazole) bacterial dihydrofolate reductase than human (selectivity)]. Both are bacteriostatic !!  8 Antibacterial spectrum Sulfonamides are seldom prescribed alone. Sulfonamides inhibit nocardia infections and enterobacteriaceae in the urinary tract. Trimethoprim can be used alone to treat urinary and respiratory tract infections; prostatitis, shigellosis, invasive salmonella infections (20 to 50- fold more potent than sulfonamides). Cotrimoxazole: - broader spectrum than the sulfa drugs alone. - Treat UTIs and respiratory tract infections, Pneumocystis jirovecii pneumonia (PCP), toxoplasmosis, and ampicillin- or chloramphenicol-resistant salmonella infections. - Against community-acquired skin and soft tissue infections caused by MRSA. - It is the drug of choice for infections caused by susceptible Nocardia species and Stenotrophomonas maltophilia. Antibacterial spectrum  9 Resistance Sulfonamide resistance (plasmid transfer or random mutations): 1) Bacteria that can obtain folate from environment 2) Altered dihydropteroate synthestase (altered target) 3) ↓ drug permeability 4) ↑ PABA Trimethoprim resistance: 1) Altered dihydrofolate reductase (low affinity towards drug) 2) Efflux pumps 3) ↓ drug permeability Cotrimoxazole resistance: Less encountered. But resistance has been reported in E. coli and MRSA  16 Topical Agents Sodium sulfacetamide ophthalmic solution or ointment is effective in the treatment of bacterial conjunctivitis and as adjunctive therapy for trachoma. Mafenide acetate is used topically (but producing pain). Can be absorbed from burn sites, causing an increased risk of acid-base imbalance. Silver sulfadiazine is the drug of choice for burn wounds (less toxic).  16 Adverse effects Sulfonamides: 1) Crystalluria (nephrotoxicity): Adequate hydration and alkalinisation of urine can prevent the problem (↓ drug’s conc and promote drug’s ionisation). 2) Hypersensitivity: rashes, angioedema, Stevens- Johnson syndrome. 3) Hematopoietic disturbances: Haemolytic anaemia in glucose-6-phosphate dehydrogenase (G6PD) deficiency patients; Granulocytopenia, thrombocytopenia, agranulocytosis, aplastic anaemia, and other blood dyscrasias. 4) Kernicterus: occur in newborns. Sulfa drugs displace bilirubin from serum albumin. Bilirubin free to enter CNS (BBB is not fully developed in newborns). 5) Drug potentiation: ↑ serum level of warfarin and methotrexate (sulfa drugs displace the drugs from serum albumin)  9 Adverse effects Trimethoprim Folic acid deficiency: Megaloblastic anemia, leukopenia, granulocytopenia (especially in pregnant and poor diets patients). Note: Reversed by administration of folinic acid (10 mg), which does not enter bacteria. Cotrimoxazole (trimethoprim + sulfamethoxazole ) 1) Skin Rash (common) 2) Nausea and vomiting (most common) 3) Megaloblastic anemia, leukopenia, and thrombocytopenia may occur and have been fatal (Reversed by administration of folinic acid) 4) Hemolytic anemia in patients with G6PD deficiency 5) Drug potentiation: ↑ serum level of warfarin and methotrexate (sulfa drugs displace the drugs from  9 Pharmacokinetics Sulfonamides: - Well oral absorption excepts for sulfasalazine. Oral Sulfasalazine is reserved for chronic inflammatory bowel disease (e.g.: ulcerative colitis) as its metabolites (sulfapyridine and 5- aminosalicylate) exert anti-inflammatory effect. - Not applied topically (sensitization). However, creams of silver sulfadiazine/mafenide acetate reduce burn associated sepsis as these drugs prevent colonization of bacteria. IV form is given - Protein for patients who bound!! Distributed widely cannot swallow throughout the body fluid, including CSF even in the absence of inflammation. - Acetylated and conjugated in the liver. Metabolites have no antimicrobial activity but toxic at neutral/acidic pH (Causes crystalluria). - Eliminated by glomerular filtration and secretion.  Pharmacokinetics Trimethoprim: - Rapid oral absorption - Wide distribution including the CSF - Weak base (concentrate in acidic prostatic and vaginal fluids). - 60-80% is excreted unchanged via kidneys. Cotrimoxazole: - Oral (prefer) and IV (for severe pneumonia caused by PCP) - Wide distribution including the CSF - Both parent drugs and their metabolites are excreted in the urine.  12 Pharmacokinetic Properties of Some Sulfonamides and Trimethoprim 22