In this section, we describe folate antagonists and most of the slides are cited from: 1- Lippincott's Illustrated Pharmacology 2- KD Triphati Pharmacology 3- Basic Katzung Pharmacology

1. Folate Antagonists
Asst. Prof. Dr. Muhammad Haroon
MD, ECEA, MPH (JHSPH)
Head & Coordinator of MPH Program
Former Biochemistry Guest lecturer at SMS
medical college, India.
Email:mstanik2@jhu.edu

2. Introduction
l Enzymes involved in Purine and pyrimidine
synthesis require:
– Folate-derived cofactors
l Humans obtain folic acid from:
– The diet
l Bacteria are impermeable to:
– Folic acid
– Rely on their ability to synthesize folate de novo
Folate Antagonists2

3. Introduction Cont.…......
l In microorganisms:
– Sulfonamides (sulfa drugs) inhibit de novo synthesis of
folate
– Trimethoprim prevents converting Dihydrofolic acid to
Tetrahydrofolic acid
– Cotrimoxazole provides a synergistic combination
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4. Sulfonamides
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5. Introduction
l It is now:
– Seldom prescribed alone
l Common in developing countries due to:
– Low cost
– Efficacy
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6. Mechanism of Action
l In many microorganisms, dihydrofolic acid is
synthesized from:
– P -amino benzoic acid (PABA)
– Pteridine
– Glutamate
l Sulfonamides are synthetic analogs of :
– PABA
– Competitively inhibit dihydropteroate Synthetase
required for the synthesis of of dihydro-folic acid
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7. Mechanism of Action Cont.…......
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8. Anti-bacterial spectrum
l Enterobacteriaceae in the urinary tract
l Nocardia infections
l Toxoplasmosis
– Sulfadiazine in combination with Pyrimethamine
l Malaria
– Sulfadoxine in combination with Pyrimethamine
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9. Resistance
l Naturals:
– Bacteria that can obtain folate from their environment
l Acquired: (Mutations)
– Altered dihydropteroate synthetase
– Decreased cellular permeability
– Increase production of PABA
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10. Pharmacokinetics
l Absorption:
l Well absorbed After oral administration
– Exception is sulfasalazine
– Reserved for treatment of chronic inflammatory bowel
disease
– Local intestinal flora split sulfasalazine into
Sulfapyridine and 5-aminosalicylate
– 5-aminosalicylate exerting the anti-inflammatory effect
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11. Pharmacokinetics Cont.…......
l Absorption:
– Intravenous are for patients not able to take oral
l Only applied topically in burns:
– Creams of silver Sulfadiazine or Mafenide acetate are
effective in reducing burn-associated sepsis
– They prevent colonization of bacteria
– Silver sulfadiazine is preferred because:
– Mafenide produces pain
– Absorption may contribute to acid–base disturbances
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12. Pharmacokinetics Cont.…......
l Distribution:
– Bound to serum albumin in the circulation
– Distribute throughout the bodily fluids
– Penetrate well into cerebrospinal
– Pass the placental barrier and enter fetal tissues
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13. Pharmacokinetics Cont.…......
l Metabolism:
– Phase-2 (acetylation and conjugation)
– The acetylated product has toxic potential to precipitate at
neutral or acidic pH
– This causes Crystalluria (stone formation) in kidney
l Excretion:
– Renal elimination
– Dose adjustment in renal failure
– May be eliminated in breast milk
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14. Adverse effects
l Crystalluria:
– Requires adequate hydration and alkalization of urine
l Hypersensitivity:
– Rashes, Angioedema or Stevens-Johnson syndrome
l Hematopoietic disturbances:
– Hemolytic anemia in (G6PD) deficiency
– Granulocytopenia and Thrombocytopenia can also
occur.
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15. Additional Image
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16. Adverse effects Cont.…......
l Kernicterus:
– May occur in newborns
– Sulfa drugs displace bilirubin from binding sites on
serum albumin
l Warfarin toxicity:
– Sulfa drugs displace warfarin from binding sites on serum
albumin
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17. Contra Indications
l Pregnancy
l Newborns less than 2 months
l Kidney failure
l Liver failure
l Not given to patients receiving methenamine
– Easy crystallization
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18. Folate Antagonists18

19. Trimethoprim
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20. Introduction
l A potent inhibitor of:
– Bacterial dihydrofolate reductase:
l Antibacterial spectrum similar to:
– The sulfonamides
l Trimethoprim is most often compounded with:
– Sulfamethoxazole
– Producing the combination called Cotrimoxazole
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21. Mechanism of action
l The active form of folate is:
– The Tetra hydro derivative
l It is formed through:
– Reduction of dihydrofolic acid by dihydrofolate
reductase
– Inhibited by trimethoprim
l Bacterial enzyme have higher affinity for:
– The drugs
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22. Mechanism of action Cont.…......
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23. Anti-bacterial spectrum
l Similar to that of sulfonamides:
– 20- to 50-fold more potent than the sulfonamides
l Trimethoprim may be used alone in :
– UTIs*
– Bacterial prostatitis*
*fluoroquinolones are preferred
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24. Resistance
l Common Resistance mechanisms include:
– Altered dihydrofolate reductase {Gr (-)}
– Efflux pumps
– Decreased permeability
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25. Pharmacokinetics
l Administration:
– Oral
– The drug is a weak base
– Higher concentrations are achieved in the relatively
acidic prostatic and vaginal fluids
l Metabolism:
– Partial Metabolism (O –demethylation)
l Elimination:
– 60%-80% is renally excreted unchanged
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26. Adverse effects
l Can produce the effects of folic acid deficiency:
– Megaloblastic anemia
– Leukopenia
– Granulocytopenia
l Common in:
– Pregnant patients
– Those having very poor diets
l These blood disorders may be reversed:
– Simultaneous administration of folinic acid
– Folinic acid does not enter bacteria Folate Antagonists26

27. Cotrimoxazole
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28. Introduction
l Is a combination of:
– Trimethoprim with sulfamethoxazole
l Synergistic activity:
– Greater antimicrobial activity than equivalent quantities
of either drug used alone
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29. Introduction Cont.…......
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30. Mechanism of action
l Inhibits of two sequential steps in the synthesis of
tetrahydrofolic acid:
– Sulfamethoxazole inhibits the conversion of PABA into
dihydrofolic acid
– Trimethoprim prevents reduction of dihydrofolate to
tetrahydrofolate
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31. Mechanism of action Cont.…......
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32. Anti-Bacterial Spectrum
l Broader spectrum than the sulfa drugs alone
l It is effective in treating:
– UTIs
– Respiratory tract infections
– Pneumocystis jirovecii pneumonia (PCP)
– Toxoplasmosis
– Salmonella
– MRSA
l Drug of choice for infections caused by:
– Nocardia species
– Stenotrophomonas maltophilia Folate Antagonists32

33. Anti-Bacterial Spectrum Cont.…......
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34. Resistance
l Resistance to the Cotrimoxazole is less than:
– Resistance to either of the drugs alone
– Same resistance mechanisms
l Significant resistance occurs:
– E. coli
– MRSA
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35. Pharmacokinetics
l Administration:
– Oral
– IV: Patients with severe pneumonia caused by PCP
l Distribution:
– Both agents distribute throughout the body
– Crosses the blood brain barrier
l Elimination:
– Kidney
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36. Adverse effects
l Gastro-Intestinal:
– Nausea & Vomiting
– Glossitis & Stomatitis
l Dermatologic:
– Skin Rash
l Hematologic:
– Megaloblastic anemia
– Leukopenia
– Thrombocytopenia
– Hemolytic anemia (in G6PD deficiency)
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37. Adverse effects Cont.…......
l Drug Interaction:
– Warfarin
– Phenytoin
– Methotrexate
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38. Folate Antagonists38
Cotrimoxazole Preparations

39. References
l Katzung, B. G., Masters, S. B., & Trevor, A. J. (2015). Basic & clinical
pharmacology. New York: McGraw-Hill Medical
l Whalen, K., Finkel, R., & Panavelil, T. A. (2017). Pharmacology
(Seventh Edition.). Philadelphia: Wolters Kluwer
l Tripathi, K. (2008). Essentials of medical pharmacology (6th ed.). New
Delhi: Jaypee Brothers
l The images are retrieved from: www.google.com/images
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40. Thank You
40 Folate Antagonists