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
Folic Acid
Antagonists
Sulfonamides
Trimethoprim
Co-
trimoxazole

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
Sulfonamide
Oral
Sulfisoxazole
Sulfamethoxazole
Sulfadiazine
Topical
Sulfacetamide
Sulfisoxazole

13. Sulfacetamide
• Sulphacetamide sodium occurs as white or yellow-
white crystals or a microcrystalline powder soluble in
water
• Sulfacetamide 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
• Basic 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
Trimethopri
m

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:
1. Nocardial infections ,
2. Simple UT infections (sulfisoxazole),
3. Ulcerative colitis* (sulfasalazine),
4. Trachoma (sulfacetamide, topical),
5. Burns (silver sulfadiazine, topical), and
6. 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:
1. Hemolytic and aplastic anemia
2. Thrombocytopenia
3. Agranulomatosis
• Hypersensitivity:
1. Photosensitivity
2. Exfoliative dermatitis
3. Stevens-Johnson Syndrome.
4. Drug fever

23. • Renal toxicity:
• Kernicterus in neonates:
1. Sulfonamides displace bilirubin from protein binding
sites.
2. Free bilirubin gets diposited-toxic encephalopathy
3. 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 methenamine, tolbutamide, 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
• The combination is usually bactericidal.

29. Dihydrofolate
reductase
Inhibited by
Trimethopri
m

30. Clinical Uses
• Wide spectrum and many clinical uses:
1. Complicated UTI
2. In respiratory, ear, and sinus infections associated
with H. influenme or M.catarrhalis;
3. Backup drug for L. monocytogenes, Proteus
mirabilis, S. typhi
4. 0.1% trimethoprim and polymyxin B (10,000 units)
available 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