2. FOLIC ACID
ANTAGONISTS
Coenzymes containing folic acid - required for the
synthesis of purines and pyrimidines (precursors of
RNA and DNA) and other compounds necessary for
cellular growth and replication.
•
In the absence of folic acid, cells cannot grow or
divide.
FOLIC ACID ANTAGONISTS:
1. The sulfonamides (sulfa drugs) inhibit the synthesis of
folic acid.
2. Trimethoprim - prevents the conversion of folic acid
to its active, coenzyme form (tetrahydrofolic acid)
2
3. SULFONAMIDES
The antimicrobial containing a sulfonamido
(sulfanilamide, SO4NH2) group are called sulfonamides.
NH2
SO4-NH
• Structurally related to p-aminobenzoic acid (PABA).
This group is also present in other non-antibacterial
compounds like
-Sulphonureas
-Benzothiazids
-Furosemide
-Acetazolamide
3
8. Mechanism of action
Folic acid - synthesized from PABA, pteridine,
and glutamate.
All sulfonamides are analogues of PABA. Because
of their structural similarity to PABA, SA compete
with this substrate for the bacterial enzyme,
dihydropteroate synthetase. They thus inhibit the
synthesis of bacterial folic acid.
All sulfa drugs are bacteriostatic.
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9. Resistance to sulfonamide
Capable of developing resistance-
Gonococci, meningococci, staph. aurius, E. coli &
shigella
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.
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10. Pharmacokinetics
Absorbed rapidly from the GIT (except topically used ).
Peak plasma levels are achieved in 2-6hrs.
widely distributed and pass through BBB as well as placental
barrier.
Metabolized as acetylated conjugates in liver.
Acetylated metabolites are inactive and low soluble in
acidic urine, leads to ppt. of crystaluria and renal toxicity.
Excreted through the glomerular filtration in urine.
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11. Individual sulfonamides:
1) Well absorbed orally, short-acting: Sulfadiazine,
Sulfadimidine, Sulfisoxazole, Sulfamethoxazole
2) Well absorbed orally, long-acting:
Sulfamethopyrazine
3) Poorly absorbed in GIT: Sulfasalazine
4) Used topically: Silver sulfadiazine
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12. Adverse effects
Blood
Hemolytic and aplastic
anemia (G6PD def.)
Thrombocytopenia
Hypersensitivity
Photosensitivity
Exfoliative dermatitis
Stevens-Johnsons.
Drug fever
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13. Crystalluria and renal toxicityAdequate intake of water
By making urine alkaline
Kernicterus in neonatesSulfonamides displace bilirubin from protein binding
sites. Free bilirubin gets diposited-toxic encephalopathy
Avoided in neonates & pregnancy (last trimester)
GI Nausea, vomiting, diarrhea, pancreatitis
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15. SULFASALAZINE
Poorly absorbed through GIT
Reserved for treatment of chronic inflammatory
bowel disease (e.g., Crohn disease or ulcerative
colitis).
Intestinal flora split sulfasalazine into
sulfapyridine and 5-aminosalicylate which exerts
the anti-inflammatory effect..
SILVER SULFADIAZINE
Effective in reducing burn-associated sepsis.
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16. - USES Lower respiratory tract infections
Bone and joint infections
Infectious diarrhea
Urinary tract infections
Skin infectionsBurn cases-silver sulfadiazine topically.
Sexually transmitted diseasesChancroids due to H. ducreyi
Lymphogranuloma venereum
Chloroquine resistant malaria
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17. TRIMETHOPRIM
Inhibitor of bacterial dihydrofolate
reductase.
Antibacterial spectrum similar to SA
• Mostly compounded with sulfamethoxazole
= co-trimoxazole.
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19. Mechanism of action
The active form of folate – tetrahydro derivative (formed
by reduction of dihydrofolate by dihydrofolate reductase).
• This enzymatic reaction is inhibited by trimethoprim ---• There occurs decreased availability of the tetrahydrofolate
coenzymes required for purine, pyrimidine, and amino
acid synthesis.
Other folate reductase inhibitors:
Pyrimethamine (used with SA in parasitic infections)
Methotrexate (in cancer chemotherapy).
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20. Antibacterial spectrum
Spectrum - similar to sulfamethoxazole
• Trimethoprim is 20- 50 fold more potent than SA.
Resistance
Presence of altered dihydrofolate reductase with
lower affinity for trimethoprim.
Overproduction of the enzyme
Decrease drug permeability.
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22. Pharmacokinetics
Similar to sulfamethoxazole.
But - it is a weak base - higher concentrations of
Trimethoprim in relatively acidic prostatic and
vaginal fluids.
It also penetrates the CSF.
It undergoes some O-demethylation, but mostly
excreted unchanged through the kidney.
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23. Adverse effects
Effects of folic acid deficiency (megaloblastic
anemia, leukopenia, granulocytopenia - especially
in pregnant women and pts with a poor diets)
The blood disorders . can be reversed by the
simultaneous administration of folinic acid, which
does not enter bacteria.
Nausea, vomiting, skin rashes
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24. CO-TRIMOXAZOLE
Trimethoprim – mostly compounded with
sulfamethoxazole.
This combination - co-trimoxazole - shows
greater antimicrobial activity than equivalent
quantities of either drug used alone.
Selected because of the similarity in the
pharmacokinetics of the two drugs.
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26. Mechanism of action
The synergistic antimicrobial activity of co-trimoxazole –
Inhibition of 2 sequential steps in the synthesis of
tetrahydrofolic acid.
Sulfamethoxazole inhibits the incorporation of PABA into
folic acid.
Trimethoprim prevents reduction of dihydrofolate to
tetrahydrofolate.
More potent activity than sulfamethoxazole or Trimethoprim
alone.
Doses of both drugs are 1/10 of those needed if drug were
used alone.
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27. Antibacterial spectrum
Broader spectrum than SA
Uses:
1.
Treating UTls
2.
Respiratory tract infections
3.
Pneumocystis pneumonia
4.
Ampicillin- or chloramphenicol-resistant
systemic salmonella infections.
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28. Pharmacokinetics
More lipid soluble than sulfamethoxazole - greater Vd.
Ratio: 20 parts sulfamethoxazole to 1 part trimethoprim –
according to some authors considered optimal for the
antibiotic effect.
Generally administered orally.
Trimethoprim concentrates in the relatively acidic milieu of
prostatic and vaginal fluids - the use of the trimethoprimsulfamethoxazole in infections at these sites.
Both parent drugs and their metabolites are excreted in the
urine
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29. Adverse effects
Dermatological: Reactions involving the skin are very common and
may be severe in the elderly.
GIT: N, V, glossitis, stomatitis - not unusual.
Hematological: Megaloblastic anemia, leukopenia, thrombocytopenia
May be reserved by administration of folinic acid (it protects the pts and
does not enter the microorganism).
Hemolytic anemia - in pts with G6PD deficiency due to the
sulfamethoxazole.
Pneumocystis pneumonia - frequently drug-induced fever, rashes, diarrhea,
and/or pancytopenia.
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