Folate antagonists

1. FOLATE ANTAGONISTS
By.Dr Ishfaq Ahmad

2. ANTIFOLATE DRUGS
CLASSIFICATION AND PHARMACOKINETICS
Sulfonamides
The sulfonamides have a common chemical nucleus
resembling p-aminobenzoic acid (PABA).

3. SULFONAMIDES
ORALLY ABSORBABLE
short acting  sulfisoxazole,
intermediate acting  sulfamethoxazole,
long
acting  sulfadoxine
ORALLY NONABSORBABLE
Sulfaguanidine, sulfasalazine
weakly absorbed after oral
administeration ,used for enteric fever
TOPICAL Sulfadiazine is used in burns
topically,
Sulfacetamide in ophthalmic
preparations

4. ANTIFOLATE DRUGS
MECHANISMS OF ACTION
1. Sulfonamides
• The sulfonamides are bacteriostatic
inhibitors of folic acid synthesis.
• As antimetabolites of PABA, they are
competitive inhibitors of dihydropteroate
synthase.
• The selective toxicity of sulfonamides
results from the inability of mammalian cells
to synthesize folic acid; they must use
preformed folic acid that is present in the
diet.

5. ANTIMETOBOLITE ANTIBIOTICS
They inhibit the folic acid synthesis
p-Aminobenzoic acid (PABA)‫‏‬
Dihydrofolic acid
Tetrahydrofolic acid
Purines
DNA
Dihydropteroate synthase
Dihydrofolate reductase
Sulfonamides (compete with PABA)‫‏‬
Trimethoprim, pyrimethamine

7. ANTI-BACTERIAL SPECTRUM
Against enterobacter species in UTIs
Nocardia species
Sulfadiazine + pyrimethamine= used
for toxoplasmosis
Sulfadoxine + pyrimethamine = as
anti-malarial drug

8. RESISTANCE
 Bacteria that obtain folate from
environment
 Resistance may be due to plasmid
transfer or mutation
 These involves following processes
1.Altered dihydropteroate synthetase
2. Decreased permeability
3.Enhanced production of PABA

9. PHARMACOKINETICS
 Well absorbed orally
 sulfasalazine is used as suppository for
treatment of ulcerative colitis
 IV preparation are also available
 Usually not applied topically due to risk of
allergic reaction
 But in burn units, creams of silver sulfadiazine
or mafenide acetate used to inhibit sepsis

10. DISTRIBUTION
 Bound to serum albumin, depends on pKa
value of drug
 Smaller pKa, greater the binding
 Distribute throughout the body including CSF
 Also cross placental barrier
 METABOLISM
 Acetylated and conjugated in liver
 Acetylated product is devoid of activity

11. EXCRETION
 Through glomerular filtration
 dose adjustment in renally compromised
patients
ADRs
 Crystalluria/ stone formation in kidney that can
be prevented by adequate hydration and
alkalinization of urine
 Hypersensitivity; rashes, angioedema or stevens-
johnson syndrome

12.  Hematopoietic disturbances:
1. Hemolytic anemia
2. granulocytopenia
3. Aplastic anemia
4. Blood dyscrasias
 Kernicterus
 Billirubin in CNS of newborns as sulfa drugs
displace them from serum albumin

14.  Drug potentiation; warfarin and
methotrexate levels increased due to
displacement
 Contraindication
 Due to kernicterus, should be avoided in
newborns and pregnant women

15. TRIMETHOPRIM
 Anti-bacterial spectrum similar to sulfonamides
 Mostly used in combination with
sulfamethoxazole
 20-50 folds more potent than sulfa drugs
 MOA
 Through inhibition of dihydrofolate reductase
leading to decreased availability of
tetrahydrofolate cofactor necessary for purine,
pyrimidine synthesis

16. RESISTANCE
 Altered dihydrofolate reductase
 Efflux pump
 Decreased permeability

17. PHARMACOKINETICS
 Absorbed after oral administration
 Widely distributed into body fluids and
tissues
 Also penetration into CSF
 Undergoes O-demethylation metabolism
 60-80 % excreted unchanged in urine

18. ADRS
 Folic acid deficiency which includes
megaloblastic anemia, leukopenia and
granulocytopenia
 But these disorder can be reversed through
adminitration of folinic acid which cant enter in
bacteris

19. COTRIMOXAZOLE
 The combination of trimethoprim
with sulfamethoxazole, called
cotrimoxazole
 shows greater antimicrobial
activity than equivalent quantities of
either drug used alone
 combination was selected because of
the similarity in the half-lives and
synergistic activity of the two
drugs.

21. MECHANISM OF ACTION
 inhibition of two sequential steps in
the synthesis of tetrahydrofolic
acid
 Sulfamethoxazole inhibits the
incorporation of PABA into
dihydrofolic acid precursors,
 Trimethoprim prevents reduction of
dihydrofolate to tetrahydrofolate

22. ANTIBACTERIAL SPECTRUM
 Broader spectrum of antibacterial
action than the sulfa drugs
 effective in treating following
infections
 UTIs
 RTIs
 Pneumocystis jiroveci pneumonia
and ampicillin-
 chloramphenicol-resistant systemic
salmonella infections.

23.  MRSA so can be used for skin and soft
tissue infections
 Also activity against Nocardia species

24. RESISTANCE
Resistance is less frequently
encountered than resistance to
either of the drugs alone
 because simultaneous
resistance to both drugs is
required.

25. PHARMACOKINETICS
 Administration of one part trimethoprim
to five parts of the sulfa drug
 generally administered orally
 Intravenous administration to
patients with severe pneumonia caused
by P. jiroveci.
 Both agents distribute throughout the
body.

26. Trimethoprim concentrates in the
relatively acidic environment
Crosses BBB
Both drugs and metabolites
excreted in urine

27. ADVERSE DRUG REACTIONS
Dermatologic: Reactions involving the
skin are very common
Gastrointestinal: Nausea, vomiting, as
well as glossitis and stomatitis are not
unusual.
Hematologic: Megaloblastic anemia,
leukopenia, and thrombocytopenia
All these effects may be reversed by the
concurrent administration of folinic acid

28. Patients infected with human
immunodeficiency virus:
 Immuno-compromised patients with
P. jiroveci pneumonia frequently show
drug-induced fever, rashes,
diarrhea, and/or pancytopenia.
Drug interactions:
 Prolonged prothrombin time in
combination with warfarin

29. The plasma half-life of phenytoin may
be increased due to an inhibition of
its metabolism.
Methotrexate levels may rise due to
displacement from albumin-binding
sites by sulfamethoxazole.