SULFONAMIDES

In the 1930s, Domagk first demonstrated that

prontosil, a dye and pro-drug, inactive in
vitro and metabolized in vivo to give the
active agent-Sulfanilamide.
E.g.
sulfonamides
are
sulfadiazine,
sulfadimidine, sulfamethoxazole (shortacting), sulfametopyrazine (long-acting).
Others are sulfasalazine (poorly absorbed in
the
gastrointestinal
tract)
and
sulfamethoxazole (given with trimethoprim,
the combination constitutes co-trimoxazole).
5/9/16

Mechanism of action
Sulfanilamide is a structural analogue of p-aminobenzoic
acid (PABA), which is essential for the synthesis of folic
acid in bacteria.
Folate is required for the synthesis of the precursors of
DNA and RNA both in bacteria and mammals
Mammals obtain their folic acid in their diet whereas
bacteria need to synthesize it.
Sulfonamides compete with PABA for the enzyme
dihydropteroate synthetase, and the effect of the
sulfonamide may be overcome by adding excess PABA.
Sulfonamides are bacteriostatic and act by interfering
with folate synthesis and thus with nucleotide synthesis.
Local anaesthetics, e.g. procaine, which are PABA esters,
can antagonize the antibacterial effect of these agents.
5/9/16

Clinical uses of Sulfonamides

Combined with trimethoprim (co-trimoxazole) for Pneumocystis
carinii.
Combined with pyrimethamine for drug-resistant malaria and for
toxoplasmosis.
Anti-inflammatory drug-sulfasalazine (sulfapyridineaminosalicylate combination) in inflammatory bowel disease.
Infected burns (silver sulfadiazine given topically).
Some sexually transmitted infections (e.g. trachoma, chlamydia,
chancroid).
Respiratory infections; confined to Nocardia infection.
It is bacteriostatic rather than bactericidal.
Their actions are negated by the presence of pus and the
products of tissue breakdown since these contain thymidine and
purines, which bacteria use to bypass the need for folic acid.
Resistance is common and plasmid mediated and results from
the synthesis of an enzyme insensitive to the drug.
5/9/16

Pharmacokinetics
Most sulfonamides are readily
absorbed in the gastrointestinal tract.
They are usually not given topically,
mainly because of the risk of
sensitization and allergic reactions.
The drugs pass into inflammatory
exudates and cross the placental and
blood-brain barriers.
Metabolized mainly in the liver by
acetylation
5/9/16

Side effects
Nausea and vomiting
Headache and mental depression
Cyanosis caused by
methaemoglobinaemia
Hepatitis
Hypersensitivity reactions (rashes,
fever, anaphylactic reactions)
Bone marrow depression
Crystalluria
5/9/16

Trimethoprim
Resembles the pteridine moiety of folate
The similarity is close enough to confuse the
relevant bacterial enzyme.
Trimethoprim is chemically related to the
antimalarial drug pyrimethamine; both are folate
antagonists.
Bacterial dihydrofolate reductase is many times
more sensitive to trimethoprim than is the
equivalent enzyme in humans.
Trimethoprim is active against most common
bacterial pathogens, and acts by bacteriostatic
means.
It is given in combination with sulfamethoxazole
(co-trimoxazole).
5/9/16

Clinical uses of trimethoprim/co-trimoxazole

Urinary tract and respiratory

infections
Infection with Pneumocystis carinii,
which causes pneumonia in patients
with AIDS; co-trimoxazole is used in
high dose.

5/9/16

Pharmacokinetics
Absorbed in the GIT and widely
distributed throughout the tissues
and body fluids
It reaches high concentrations in the
lungs and kidneys and fairly high
concentrations in the cerebrospinal
fluid (CSF).
Since trimethoprim is a weak base,
its elimination by the kidney
increases with decreasing urinary pH
5/9/16

Side effects

Nausea, vomiting
Blood disorders
Skin rashes
Folate deficiency, with resultant
megaloblastic anaemia-a toxic effect
related to the pharmacological action
of trimethoprim
And this can be prevented by giving
folinic acid
5/9/16