Folic acid synthesis inhibitors

Sulfonamide and trimethoprim

1. Folic Acid Synthesis Inhibitors Sameer Bhaila M. Optom Tilganga Institute of Medicine

2. Folic acid Is a water soluble vitamin Vitamin B9 Pteroyl -glutamate Biologically inactive form Needs to be converted into tetrahydrofolate for synthesis of amino acids, purines and pyrimidines (precursors of RNA and DNA) ,thymidine mono phosphate ( TMP ) and other compounds

3. Chemical Structure Folic acid consists of pteridine nucleus, para- aminobenzoic acid (PABA) and glutamate

4. Tetrahydrofolate Coenzymes containing folic acid - required for the synthesis of purines and pyrimidines (precursors of RNA and DNA) and other compounds

5. Tetrahydrofolate Vital for : Cellular growth and replication in bacteria and human Important in aiding rapid cell division growth such as in fetus, infancy and pregnancy Children and adults both require folic acid to produce healthy red blood cells and prevent anemia (megaloblastic anemia)

6. Folic Acid Antagonists In the absence of folic acid, bacterial cells cannot grow or divide.  FOLIC ACID ANTAGONISTS: 1. The sulfonamides (sulfa drugs) inhibit the synthesis of folic acid. 2. Trimethoprim/ Pyrimethamine - prevents the conversion of folic acid to its active, coenzyme form (tetrahydrofolic acid)

7. Mechanism of action

8. Folic Acid Synthesis Inhibitors

9. Sulfonamides The antimicrobial agent containing a sulfonamide (sulfanilamide, SO4NH2 ) group are called sulfonamides. Structurally related to p- aminobenzoic acid (PABA).

10. Classification 1. Orally absorbable agents Short acting(4-8hrs.)- Sulfadiazine, Sulfisoxazole, Sulfacytine , sulfamethizole Intermidiate acting(8-12hrs.)- Sulfamethaxazole , Sulfamoxole Long acting(7days)- Sulfadoxine , sulfamethopyrazine

11. Classification 2. Orally Non- absorbable agents Special purpose sulfonamides- Sulfasalazine Silver sulfadiazine Sulfacetamide Mafenide

12. Availabe Sulfonamides

13. Sulfacetamide Sulphacetamide sodium occurs as white or yellow-white crystals or a microcrystalline powder soluble in water S ulfacetamide have a bacteriostatic action

14. Sulfacetamide Inhibit the growth of most Gram-positive microorganisms and a variety of Gram-negative organisms, including some strains of Pseudomonas Suitable for topical application to the eye because of its acceptable pH and its solubility in aqueous solution

15. Mechanism of Action B asic structure of PABA is very similar to the sulfonamides Competes with PABA, causing inhibition of dihyropteroate synthase and formation of nonfunctional folic acid

16. Dihydrofolate reductase Dihydropteroate synthetase Inhibited by Trimethoprim

17. Mechanism of Action Some micro-organisms may utilize PREFORMED folic acid and thus not effected by these drugs – Sulfonamide Insensitive micro organisms. Mammalian cells are not affected as they require preformed Folic acid as they can not synthesize it. So they are comparable to sulfonamides – insensitive organisms.

18. Clinical Uses Have a wide spectrum uses, but use as individual agents is limited by resistance. Common uses include: N ocardial infections , S imple UT infections ( sulfisoxazole ), U lcerative colitis* (sulfasalazine), T rachoma ( sulfacetamide , topical), B urns (silver sulfadiazine, topical ), and Toxoplasmosis ( sulfadiazine)

19. Ocular Uses Toxoplasmic retinochoroiditis treated with trisuifapyrimidine (sulfadiazine + pyrimethamine ) In the past extensively used in blepharitis and blepharo -conjunctivitis

20. Resistance to sulfonamide Capable of developing resistance- Gonococci, meningococci, staph. aurius, E. coli & shigella

21. Resistance to sulfonamide As result of mutation or by plasmid mediated 1. Alteration in the nature of folic acid synthetase (decrease affinity). 2. Decreased bacterial permeability or active efflux of drug. 3. An appearance of alternative pathway for PABA synthesis.

22. Adverse effects Blood dyscrasias: Hemolytic and aplastic anemia Thrombocytopenia Agranulomatosis Hypersensitivity: Photosensitivity Exfoliative dermatitis Stevens-Johnson Syndrome. Drug fever

23. R enal toxicity: Kernicterus in neonates: Sulfonamides displace bilirubin from protein binding sites . Free bilirubin gets diposited -toxic encephalopathy Avoided in neonates & pregnancy (last trimester ) Gastro Intestinal: Nausea vomiting, diarrhea, pancreatitis

24. Ocular Side Effect Transient myopia ( several diopters) with or without astigmatism may be induced due to systemic sulfonamide use The mechanism is unknown Refractive status usually returns to normal when serum drug level decreases.

25. CONTRAINDICATIONS Pregnancy and lactating mother Newborn and infant (<2months) Patients on m ethenamine , t olbutamide , oral anticoagulants Patients with blood dyscrasias Patient taking oral hypoglycemic drugs

26. Trimethoprim/ Pyrimethamine 2,4 – diaminopyrimidines Inhibitor of bacterial dihydrofolate reductase Antibacterial spectrum similar to Sulfonamides Mostly compounded with sulfamethoxazole = co- trimoxazole

27. Powerful synergism exists between either of these drugs and sulfonamides Synergism results in a high degree of synergistic activity against a wide spectrum of micro-organism

28. Resistance, is via mutations in the gene that codes for the reductase . When used with sulfamethoxazole (TMP-SMX, cotrimoxazole ) The synergism and decreased emergence of resistance results the sequential blockade of folic acid synthesis T he combination is usually bactericidal.

29. Dihydrofolate reductase Inhibited by Trimethoprim

30. Clinical Uses W ide spectrum and many clinical uses: C omplicated UTI I n respiratory, ear, and sinus infections associated with H. influenme or M.catarrhalis ; B ackup drug for L. monocytogenes, Proteus mirabilis, S. typhi 0.1% trimethoprim and polymyxin B (10,000 units) a vailable as topical solution used in blepharitis and blepharoconjunctivitis

31. Adverse Effect Effects of folic acid deficiency ( megaloblastic anemia, leukopenia, thrombocytopenia granulocytopenia – especially in pregnant women and pts with a poor diets ) The blood disorders . can be reversed by the simultaneous administration of folic acid, which does not enter bacteria . Nausea , vomiting, skin rashes

32. Contraindication Patient with Megaloblastic anemia due to folic acid deficiency