Sulfamethazine

Absorption

Rapidly absorbed following oral administration.

Toxicity

Sulfamethazine may cause nausea, vomiting, diarrhea and hypersensitivity reactions. Hematologic effects such as anemia, agranulocytosis, thrombocytopenia and hemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency may also occur. Sulfamethoxazole may displace bilirubin from albumin binding sites causing jaundice or kernicterus in newborns.

Description

Sulfamethazine is an antibacterial sulfonamide. Like other sulfonamides, sulfamethazine is bacteriostatic, competitively inhibiting dihydropteroate synthase to block folate synthesis and inhibit growth and multiplication. Sulfamethazine is metabolized by cytochrome P450 isoforms and arylamine N-acetyltransferase 2 in a sex-dependent manner.

Description

Sulfamethazine (or sulfadimidine) is an antibiotic in the sulfonamide class that has been marketed under numerous trade names. Its synthesis was first reported by W. T. Caldwell and co-workers in 1941.
Many sulfonamide drugs cause neurological side effects, including headaches and insomnia, but sulfamethazine does not. K. Johnsson and colleagues at ETH Lausanne (Switzerland) recently showed that the side effects are caused by disruption of the enzyme sepiapterin reductase. Sulfamethazine does not fit into the enzyme''s active site and therefore cannot cause the side effects.

Chemical properties

White to Off-Solid

Originator

Cremomethazine,MSD,US,1947

The Uses of Sulfamethazine

Sulfamethazine is an antibacterial.This compound is a contaminant of emerging concern (CECs).

What are the applications of Application

Sulfamethazine is a sulfonamide antibacterial

Indications

For the treatment bacterial infections causing bronchitis, prostatitis and urinary tract infections.

Background

A sulfanilamide anti-infective agent. It has a spectrum of antimicrobial action similar to other sulfonamides.

Definition

ChEBI: A sulfonamide consisting of pyrimidine with methyl substituents at the 4- and 6-positions and a 4-aminobenzenesulfonamido group at the 2-position.

Manufacturing Process

A flask heated in an oil bath is filled with 600 ml water and 60 g (1 mol) glacial acetic acid (or an equivalent quantity of diluted acetic acid). While stirring 235 g (1.1 mols) anhydrous p-aminobenzenesulfonamidoguanidine (or an equivalent quantity of a nonanhydrous product) and 122 g (1 mol) sodium acetylacetonate 100% purity (or an equivalent quantity of product of a lower purity) are introduced into the flask while stirring.
The temperature of the reaction mixture is brought to 102°C to 103°C, the mixture is further stirred at this temperature during 24 hours. The pH value of the mixture, which should range between 5 and 6 is checked during the reaction.
On expiry of the reaction period heating is cut off, the mass being cooled or allowed to cool down to 60°C.
Filtering under suction is effected, the solids on the filter being washed with 100 ml water at 80°C.
After drying of the product on the filter 256 g of 2-paminobenzenesulfonamido- 4,6-dimethylpyrimidine, melting point 196°C to 197°C, purity 99.5% are obtained. The output is 92% of the theory calculated with respect to the sodium acetylacetonate employed.

brand name

Calfspan Tablets [Veterinary] (Fort Dodge Animal Health); Sulka S Boluses [Veterinary] (Fort Dodge Animal Health); SulfaSURE SR Bolus [Veterinary] (Boehringer Ingelheim Animal Health);Crermomethazine;Deladine;Dimezathine;Hava-span;Intradin;Neotrizine;Rigesol;Rivodin;S-dimidine;Spanbolet;Sulka-s;Sulphamezathine;Sulphfmezatine;Superseptyl;Sustain iii;Tersulpha;Trisulfaminic;Trisulfaminie.

Therapeutic Function

Antimicrobial

World Health Organization (WHO)

Sulfadimidine, a sulfonamide anti-infective agent, was introduced in 1942 for the treatment of bacterial infections. The importance of sulfonamides has subsequently decreased as a result of increasing resistance and their replacement by antibiotics which are generally more active and less toxic. The sulfonamides are known to cause serious adverse effects such as renal toxicity, sometimes fatal exfoliative dermatitis and erythema multiforma and dangerous adverse reactions affecting blood formation such as agranulocytosis and haemolytic or aplastic anaemia. Sulfadimidine is still used in some countries as a injectable or oral antimicrobial for susceptible infections.

Antimicrobial activity

This drug is used for pneumococcal, staphylococcal, and streptococcal infections as well as for sepsis, gonorrhea, and other infectious diseases. Synonyms of this drug are sulfadiamezin and sulfadimidin.

General Description

Odorless sticky, white or creamy-white crystalline powder. Slightly bitter taste. An antibacterial.

General Description

Sulfamethazine’splasma half-life is 7 hours. This compound is similar inchemical properties to sulfamerazine and sulfadiazine butdoes have greater water solubility than either. Its pKa is 7.2.Because it is more soluble in acid urine than sulfamerazineis, the possibility of kidney damage from use of the drug isdecreased. The human body appears to handle the drugunpredictably; hence, there is some disfavor to its use in thiscountry except in combination sulfa therapy (in trisulfapyrimidines,USP) and in veterinary medicine.

Air & Water Reactions

Water solubility increases rapidly with increasing pH [Merck]. Insoluble in water.

Reactivity Profile

Sulfamethazine is sensitive to light and may also be sensitive to heat. The presence of oxygen and moisture may accelerate the effects of heat and light .

Fire Hazard

Flash point data for Sulfamethazine are not available; however, Sulfamethazine is probably combustible.

Pharmaceutical Applications

2-Sulfanilamido-4,6-methylpyrimidine (syn: sulphamethazine, sulfamezathine). A water-soluble compound, unstable on exposure to light. It is usually administered by mouth and is a component of some triple sulfonamide combinations.
The spectrum is typical of the group, but sulfadimidine exhibits relatively low potency. It is well absorbed after oral administration. It is extensively metabolized, predominantly by acetylation. The mean plasma half-life (1.5–5 h) varies with acetylator status.
In addition to side effects common to the group, a serious interaction between ciclosporin (cyclosporin A) and sulfadimidine, leading to reduced ciclosporin levels, has been reported.

Biochem/physiol Actions

Sulfamethazine is an antimicrobial sulfur drug that blocks the synthesis of dihydrofolic acid by inhibiting the enzyme dihydropteroate synthase. Sulfamethazine is a competitive inhibitor of bacterial para-aminobenzoic acid (PABA), which is required for bacterial synthesis of folic acid. It induces CYP3A4 expression and is acetylated by N-acetyltransferase. It exhibits sex dependent pharmacokinetics, metabolized by the male specific isoform CYP2C11. Sulfamethazine is bacteriostatic.

Pharmacokinetics

Sulfamethazine is a sulfonamide drug that inhibits bacterial synthesis of dihydrofolic acid by competing with para-aminobenzoic acid (PABA) for binding to dihydropteroate synthetase (dihydrofolate synthetase). Sulfamethazine is bacteriostatic in nature. Inhibition of dihydrofolic acid synthesis decreases the synthesis of bacterial nucleotides and DNA.

Safety Profile

Moderately toxic by intravenous and intraperitoneal routes. Experimental teratogenic and reproductive effects. Questionable carcinogen with experimental tumorigenic data. When heated to decomposition it emits very toxic fumes of SOx and NOx.

Synthesis

Sulfamethazine, N1 -(4,6-dimethyl-2-pyrimidinyl)sulfanilamide (33.1.13), is also synthesized in the aforementioned manner by reacting 4-acetylaminobenzenesulfonyl chloride with 2-amino-4,6-dimethylpyrimidine, which is in turn synthesized by condensing acetylacetone with guanidine followed by hydrolysis of the acetylamino group using a base.

Metabolism

Not Available

Purification Methods

Crystallise it from dioxane or aqueous dioxane. [Caldwell et al. J Am Chem Soc 63 2188 1941, Roblin et al. J Am Chem Soc 64 567 1942, Beilstein 25 III/IV 2215.]