Originator
Sulfadiazine,Lederle,US ,1941
Definition
ChEBI: A sulfonamide consisting of pyrimidine with a 4-aminobenzenesulfonamido group at the 2-position.
Manufacturing Process
5.4 parts of 2-amino-pyrimidine were covered with 15 parts of anhydrous
pyridine. The reaction mixture was treated with 14 parts of pnitrobenzenesulfonyl
chloride and the whole heated briefly on the steam bath
and let stand 45 minutes at room temperature. To the reaction mixture were
added 80 parts of hot alcohol and the precipitate was filtered off and washed
with water. The solid was dissolved in dilute caustic solution and the solution
was filtered, cooled and acidified. The 2-(p-nitrobenzenesulfonamido)-
pyrimidine precipitated and was collected.
The crude 2-(p-nitrobenzenesulfonamido)-pyrimidine from the preceding step
was suspended in 130 parts alcohol and 1.5 parts of concentrated hydrochloric
acid were added. The suspension was then heated to reflux and 30 parts of
iron powder were added with mechanical stirring. The mixture was refluxed
and stirred for 24 hours with occasional addition of concentrated hydrochloric
acid. The reaction mixture was then made slightly basic and filtered hot and
the residues were extracted with several portions of boiling alcohol. The filtrate and wash solutions were combined and evaporated. The 2-
(sulfanilamido)-pyrimidine was recrystallized from boiling water with
decolorizing charcoal added, according to US Patent 2,410,793.
Brand name
Coco-Diazine (Lilly); Eskadiazine (SmithKline Beecham).
Therapeutic Function
Antibacterial
Antimicrobial activity
Sulfadiazine is somewhat more active than other sulphonamides.
General Description
Sulfadiazine’s plasma half-life is 17 hours. It is a white,odorless crystalline powder soluble in water to the extentof 1:8,100 at 37°C and 1:13,000 at 25°C, in human serumto the extent of 1:620 at 37°C, and sparingly soluble in alcoholand acetone. It is readily soluble in dilute mineralacids and bases. Its pKa is 6.3.
Pharmaceutical Applications
Sulfadiazine is almost insoluble in water and unstable on
exposure to light. It is administered orally or, as the sodium
salt, by intravenous injection. It is a component of several
multi-ingredient preparations. Its low solubility in urine led
to its general replacement by other compounds. The intravenous
solution is highly alkaline and should not be given by
any other route.
Biochem/physiol Actions
Sulfadiazine is a sulfonamide antibiotic that blocks the synthesis of dihydrofolic acid by inhibiting the enzyme dihydropteroate synthase. Sulfadiazine is a competitive inhibitor of bacterial para-aminobenzoic acid (PABA), which is required for bacterial synthesis of folic acid. It is active against Gram positive bacteria, Gram negative bacteria and Chlamydia. Mode of resistance is via the alteration of dihydropteroate synthase or alternative pathway for folic acid synthesis.
Clinical Use
Urinary tract infection
Nocardiasis
Chancroid
Toxoplasmosis (in combination with pyrimethamine)
Meningococcal infections
Prophylaxis of rheumatic fever
Synthesis
Sulfadiazine, N1
-2-pyrimidinylsulfanilamide (33.1.7), is synthesized by
reacting 4-acetylaminobenzenesulfonyl chloride with 2-aminopyrimidine, which gives an
acetanilide derivative (33.1.6). The subsequent hydrolysis of this product with a base leads
to the formation of the desired sulfadiazine.
Drug interactions
Potentially hazardous interactions with other drugs
Antibacterials: increased risk of crystalluria with
methenamine.
Anticoagulants: effect of coumarins enhanced;
metabolism of phenindione possibly inhibited.
Antiepileptics: antifolate effect and concentration of
phenytoin increased.
Antimalarials: increased risk of antifolate effect with
pyrimethamine.
Antipsychotics: avoid concomitant use with
clozapine (increased risk of agranulocytosis).
Ciclosporin: reduced levels of ciclosporin; increased
risk of nephrotoxicity.
Cytotoxics: increase risk of methotrexate toxicity
Metabolism
Sulfadiazine is metabolised in the liver to the acetylated
form, with elimination predominantly via the kidneys.
Urinary excretion of sulfadiazine and its acetyl derivative
is dependent on pH; when the urine is acidic about 30%
is excreted unchanged in both fast and slow acetylators,
whereas when the urine is alkaline about 75% is excreted
unchanged by slow acetylators.
