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
FOLIC ACID ANTAGONISTS:
1. The sulfonamides (sulfa drugs) inhibit the synthesis of
2. Trimethoprim - prevents the conversion of folic acid
to its active, coenzyme form (tetrahydrofolic acid)
The antimicrobial containing a sulfonamido
(sulfanilamide, SO4NH2) group are called sulfonamides.
• Structurally related to p-aminobenzoic acid (PABA).
This group is also present in other non-antibacterial
Mechanism of action
Folic acid - synthesized from PABA, pteridine,
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.
Resistance to sulfonamide
Capable of developing resistance-
Gonococci, meningococci, staph. aurius, E. coli &
As result of mutation or by plasmid mediated
1. Alteration in the nature of folic acid synthetase
2. Decreased bacterial permeability or active efflux of
3. An appearance of alternative pathway for PABA
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
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.
1) Well absorbed orally, short-acting: Sulfadiazine,
Sulfadimidine, Sulfisoxazole, Sulfamethoxazole
2) Well absorbed orally, long-acting:
3) Poorly absorbed in GIT: Sulfasalazine
4) Used topically: Silver sulfadiazine
Hemolytic and aplastic
anemia (G6PD def.)
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
Pregnancy (full term)
Newborn and infant (<2months)
Patients on Methenamine, Tolbutamide,
Poorly absorbed through GIT
Reserved for treatment of chronic inflammatory
bowel disease (e.g., Crohn disease or ulcerative
Intestinal flora split sulfasalazine into
sulfapyridine and 5-aminosalicylate which exerts
the anti-inflammatory effect..
Effective in reducing burn-associated sepsis.
- USES Lower respiratory tract infections
Bone and joint infections
Urinary tract infections
Skin infectionsBurn cases-silver sulfadiazine topically.
Sexually transmitted diseasesChancroids due to H. ducreyi
Chloroquine resistant malaria
Inhibitor of bacterial dihydrofolate
Antibacterial spectrum similar to SA
• Mostly compounded with sulfamethoxazole
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
Other folate reductase inhibitors:
Pyrimethamine (used with SA in parasitic infections)
Methotrexate (in cancer chemotherapy).
Spectrum - similar to sulfamethoxazole
• Trimethoprim is 20- 50 fold more potent than SA.
Presence of altered dihydrofolate reductase with
lower affinity for trimethoprim.
Overproduction of the enzyme
Decrease drug permeability.
Similar to sulfamethoxazole.
But - it is a weak base - higher concentrations of
Trimethoprim in relatively acidic prostatic and
It also penetrates the CSF.
It undergoes some O-demethylation, but mostly
excreted unchanged through the kidney.
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
Trimethoprim – mostly compounded with
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.
Mechanism of action
The synergistic antimicrobial activity of co-trimoxazole –
Inhibition of 2 sequential steps in the synthesis of
Sulfamethoxazole inhibits the incorporation of PABA into
Trimethoprim prevents reduction of dihydrofolate to
More potent activity than sulfamethoxazole or Trimethoprim
Doses of both drugs are 1/10 of those needed if drug were
Broader spectrum than SA
Respiratory tract infections
Ampicillin- or chloramphenicol-resistant
systemic salmonella infections.
More lipid soluble than sulfamethoxazole - greater Vd.
Ratio: 20 parts sulfamethoxazole to 1 part trimethoprim –
according to some authors considered optimal for the
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
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
Pneumocystis pneumonia - frequently drug-induced fever, rashes, diarrhea,