DBL Sulfamethoxazole & Trimethoprim Mechanism of Action

Pharmacology: Pharmacodynamics: Mechanism of action: Sulfamethoxazole/trimethoprim interferes with the bacterial synthesis of tetrahydrofolic acid, an essential stage in the production of thymidine, purines and subsequently nucleic acids. Sulfamethoxazole inhibits the formation of dihydrofolic acid from p-aminobenzoic acid; trimethoprim inhibits the action of the enzyme dihydrofolate reductase, thus preventing the synthesis of tetrahydrofolic acid from dihydrofolic acid. Thus the combination of trimethoprim and sulfamethoxazole blocks two consecutive steps within the bacterial metabolic pathway of the biosynthesis of nucleic acids and proteins.
Sulfamethoxazole/trimethoprim usually shows in vitro activity against the following gram-negative and gram-positive organisms, e.g. E. coli, Neisseria, Salmonella, Klebsiella-Enterobacter, Shigella, Vibrio cholerae, Bordetella pertussis, Streptococcus, Staphylococcus, Pneumococcus, Haemophilus influenzae and Proteus.
Sulfamethoxazole/trimethoprim is also active against the protozoan Pneumocystis carinii. However, Mycobacterium tuberculosis, Treponema pallidum, Mycoplasma and Pseudomonas aeruginosa are frequently resistant to sulfamethoxazole/trimethoprim.
Clinical trials: No data available.
Pharmacokinetics: Absorption: Concentrations of at least 0.5 microgram/mL trimethoprim and 20 microgram/mL sulfamethoxazole are reached within 30 minutes after the start of an infusion and are maintained for at least 12 hours. Mean peak steady state serum concentrations of approximately 9 and 105 microgram/mL of trimethoprim and sulfamethoxazole, respectively, are reached after intravenous (IV) infusion of 160 mg trimethoprim and 800 mg sulfamethoxazole every 8 hours in adults with normal renal function. Steady state trough concentrations reached with this intravenous (IV) dose are approximately 6 microgram/mL of trimethoprim and 70 microgram/mL of sulfamethoxazole. The administration of a trimethoprim/sulfamethoxazole ratio of 1:5 achieves trimethoprim/sulfamethoxazole concentrations in the blood of about 1:20.
Distribution: Sulfamethoxazole/trimethoprim is widely distributed into body tissues. Sulfamethoxazole is distributed mainly in the extracellular body fluids while trimethoprim, which has lipophilic properties, concentrates in the tissues. Approximately 44% of trimethoprim and 70% of sulfamethoxazole are protein bound in the blood.
Metabolism: Sulfamethoxazole/trimethoprim is metabolised in the liver. Trimethoprim is metabolised to oxide and hydroxylated metabolites, while sulfamethoxazole is acetylated and conjugated with glucuronic acid.
Excretion: Sulfamethoxazole/trimethoprim is rapidly excreted in the urine.
Toxicology: Preclinical Safety Data: Genotoxicity: No data available.
Carcinogenicity: No data available.