5. SULFONAMIDES- ANTIBIOTICS /FOLAT.pptx

ANTIBIOTICS

1. Antimicrobial agents that interfere with the synthesis of folate (Sulfonamides) 03/08/2021 1

2. SULFONAMIDES Landmark discovery in the 1930s by Domagk. Demonstrated drug was able to influence the course of a bacterial infection. The agent was Prontosil , a dye that proved to be an inactive prodrug but which is metabolised in vivo to give the active product, sulfanilamide . 03/08/2021 2

3. SULFONAMIDES Examples include; Short Acting: Sulfadiazine sulfadimidine Intermediate Acting: Sulfamethoxazole : Long Acting: S ulfametopyrazine , Others: Sulfasalazine ( poorly absorbed in the gastrointestinal tract). Sulfamethoxazole (in combination with trimethoprim as co- trimoxazole ). 03/08/2021 3

4. Mechanism of action Sulfonamides act by interfering with folate synthesis and thus with nucleotide synthesis. They are bacteriostatic. 03/08/2021 4

5. PTERIDINE + P-AMINOBENZOIC ACID DIHYDROPTEROIC ACID DIHYDROFOLIC ACID TETRAHYDROFOLIC ACID PURINES/PYRIMIDINES PRECURSORS Dihydropteroate synthetase DNA Dihydrofolate reductase Sulphonamides Trimethoprim Mechanism of action of sulphonamides sulphadiazine sulphamethoxazole cotrimoxazole 03/08/2021 5

6. Mechanism of action p - aminobenzoic acid (PABA), is essential for the synthesis of folic acid in bacteria. F olate is required for the synthesis of the precursors of DNA and RNA both in bacteria and mammals. Mammals obtain their folic acid in their diet whereas bacteria need to synthesize it. Sulfonamides compete with PABA for the enzyme dihydropteroate synthetase , and the effect of the sulfonamide may be overcome by adding excess PABA. 03/08/2021 6

7. Clinical uses of Sulfonamides Combined with trimethoprim (co-trimoxazole) for Pneumocystis carinii . Combined with pyrimethamine for drug-resistant malaria and for toxoplasmosis. A nti-inflammatory drug-sulfasalazine (sulfapyridine-aminosalicylate combination) i n inflammatory bowel disease. I nfected burns (silver sulfadiazine given topically). Some sexually transmitted infections (e.g. trachoma, chlamydia, chancroid). 03/08/2021 7

8. Clinical uses of Sulfonamides cont. Respiratory infections; confined to Nocardia infection. It is bacteriostatic rather than bactericidal . Their actions are negated by the presence of pus and the products of tissue breakdown since these contain thymidine and purines , which bacteria use to bypass the need for folic acid. Resistance is common and plasmid mediated and results from the synthesis of an enzyme insensitive to the drug. 03/08/2021 8

9. Pharmacokinetics Most sulfonamides are readily absorbed in the gastrointestinal tract. They are usually not given topically, mainly because of the risk of sensiti z ation and allergic reactions. The drugs pass into inflammatory exudates and cross the placental and blood-brain barriers. Metabolized mainly in the liver 03/08/2021 9

10. Side effects Nausea and vomiting H eadache and mental depression Cyanosis Hepatitis H ypersensitivity reactions (rashes, fever, anaphylactic reactions) B one marrow depression C rystalluria 03/08/2021 10

11. Trimethoprim R esembles the pteridine moiety of folate The similarity is close enough to confuse the relevant bacterial enzyme. Trimethoprim is chemically related to the antimalarial drug pyrimethamine ; both are folate antagonists . Bacterial dihydrofolate reductase is many times more sensitive to trimethoprim than is the equivalent enzyme in humans. Trimethoprim is active against most common bacterial pathogens, and acts by bacteriostatic means. It is given in combination with sulfamethoxazole ( co- trimoxazole ). 03/08/2021 11

12. Clinical uses of trimethoprim/co-trimoxazole U rinary tract and respiratory infections I nfection with Pneumocystis carinii , which causes pneumonia in patients with AIDS; co- trimoxazole is used in high dose. 03/08/2021 12

13. Pharmacokinetics A bsorbed in the GIT and widely distributed throughout the tissues and body fluids It reaches high concentrations in the lungs and kidneys and fairly high concentrations in the cerebrospinal fluid (CSF). Since trimethoprim is a weak base, its elimination by the kidney increases with decreasing urinary pH 03/08/2021 13

14. Side effects N ausea, vomiting B lood disorders S kin rashes Folate deficiency, with resultant megaloblastic anaemia (a toxic effect related to the pharmacological action of trimethoprim) And this can be prevented by giving folinic acid 03/08/2021 14

15. Thanks for your attention 03/08/2021 15