Dr.

RAGHU PRASADA M S
MBBS,MD
ASSISTANT PROFESSOR
DEPT. OF PHARMACOLOGY
SSIMS & RC.

1
They inhibit the folic acid synthesis
p-Aminobenzoic acid (PABA)
Dihydropteroate synthase Sulfonamides (compete with PABA)
Dihydrofolic acid
Dihydrofolate reductase Trimethoprim, pyrimethamine
Tetrahydrofolic acid

Purines

DNA
generic name for derivatives of para-
aminobenzene sulfonamide
(sulfanilamide)
Analogues of PABA
Broad spectrum
Competitive inhibitors of dihydropteroate
synthase – needed for folic acid synthesis
Baceticidal in urine
Gerhard Domagk gets a Nobel for Medicine,
1939.
Orally absorbable agents
Short acting agents T1/2-6-9 hrs-SULFACYTINE,
SULFADIAZINE, SULFIZOXAZOLE and SULFAMETHIZOLE
Intermediate acting-T1/2-10-12hrs-SULFAMETHOXAZOLE
SULFAMOXOLE
Long acting-SULFADOXINE
Orally non-absorbable-SULFASALAZINE, BALASALAZINE,
OLASALAZINE
Topical agents- SILVER SULFADIAZINE, MAFENIDE,
SULFACITAMIDE
• 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.
 Gram-positive and gram negative.
 Nocardia, chlamydia trachomatis, some protozoa.
Invitro-Streptococcus pyogenes, Streptococcus
pneumoniae, Haemophilus influenzae, Haemophilus
ducreyi, Nocardia, Actinomyces,
Absorbed from the stomach and small intestine
→distributed widely to tissues and body fluids CNS,
CSF, placenta, fetus
Hepatic metabolism → acetylated or glucuronidated
and excreted in the urine

Rate of excretion increases in alkaline urine.

 Altered affinity of enzyme for drug
Decreased permeability or active efflux
New pathway of folic acid synthesis
Production of a mutated dihydropteroate synthetase that has
reduced affinity for binding of sulfonamides. Resistance is
transmitted among Gram-negative bacteria by plasmids.
Resistance in Staphylococcus aureus occurs as a result of
excessive synthesis of PABA. Some resistant bacteria have
reduced uptake of sulfonamides.
Bacteria which utilize exogenous folic acid are resistant to
sulfonamides.
A rapidly increasing problem. However, it is lower with
the combination compared to agents used alone.
In a survey of children in Memphis Tennessee 29%
isolates were penicillin resistant, and 25% of these
were resistant to TMP-SMZ.
Emergence of TMP-SMZ resistant S.aureus and
Enterobacteriaceae is a serious problem in AIDS
patients!
Mechanism of action:
Sequential blocking of purine synthesis (synergism).
Trimethoprim inhibits dihydrofolate reductase enzyme
so inhibits tetrahydrofolic acid synthesis
The combination is bactericidal
 PABA + Pteridine

SULFONAMIDE
Dihydropteroate
Synthetase
DIHYDROPTEROIC ACID

Dihydrofolate Synthetase
DIHYROFOLIC ACID

Dihydrofolate Reductase TRIMETHOPRIM

TETRAHYDROFOLIC ACID
Synergism
Trimethoprim is a selective inhibitor of bacterial
dihydrofolate reducate that prevents formation of the
active tetrahydro form of folic acid.
It is a weak base and is trapped in acidic environments,
reaching high concentrations in prostatic and vaginal
fluids.
A large fraction of trimethoprim is excreted unchanged in
the urine.
The half-life of this drug is similar to that of
sulfamethoxazole (10—12 h).
A.TOPICAL
1. Opthalmology- ocular infections
Sulfacetamide 10- 30%
2. Ulcerative colitis
Sulfasalazine ( sulfapyridine+ 5- amino salicylate )-(
orally, not absorbed )
3. Infected burns
Mafenide acetate ( sulfamylon cream )
Silver sulfadiazine
Effective against p.aeruginosa
Less effective against staphyllococci
B. ORAL
Pneumocystis carinii pneumonia
2. Nocardiosis
3. Toxoplasmosis
4. UTIs – limited cases
5. RTIs ( H. influenza; S. pneumonia )
6. Acute otitis media in children- L. cases
7. Prostatitis
8. Shigellosis
9. Falciparum malaria ( sulfadoxine+ pyrimethamine )
10. Rheumatoid arthritis-sulfasalazine
11. Ulcerative colitis-sulfasalzine
2. Trimethoprim-sulfamethoxazole (TMP-SMX)
is effective against P jiroveci pneumonia, shigellosis,
systemic salmonella infections, uti, prostatitis,
respiratory pathogens pneumococcus, H.influenzae
and Moraxella catarrhalis
TMP-SMX is also the drug of choice in nocardiosis, a
possible backup drug for cholera, typhoid fever, and
shigellosis, and has been used in the treatment of
infections caused by methicillin-resistant staphylococci
and Listeria monocytogenes.
Hypersensitivity reactions
N.V.D.
Crystalluria, hematuria, renal obstruction.
Allergic nephritis
Haemolytic anaemia, aplastic anaemia,
thrombocytopenia.
Megaloblastic anemia , leukopenia & granulocytopenia
( can be prevented by administration of folic acid )
Kernicterus in new born
Trimethoprim
Trimethoprim may cause the predictable adverse
effects of an antifolate drug, including megaloblastic
anemia, leukopenia, and granulocytopenia.
These effects are usually ameliorated by supplementary
folinic acid.
The combination of TMP-SMX may cause any of the
adverse effects associated with the sulfonamides.
AIDS patients given-SMX have a high incidence of
adverse effects, including fever, rashes, leukopenia
Competition with warfarin, hypoglycemic drugs
sulfonylureas, phenytoin and methoteraxate for
plasma protein binding transiently increases the
plasma levels of these drugs
Sulfonamides can displace bilirubin from plasma
proteins, with the risk of kernicterus in the neonate if
use in the third trimester of pregnancy