Pharmacology: Pharmacodynamics: Mechanism of Actions: Sulphonamides are broad spectrum, bacteriostatic anti infectives competitively inhibit a bacterial enzyme, dihydropteroate synthetase, that is responsible for incorporation of PABA into dehydrofolic acid, a cofactor for the synthesis of purines, thymidines and DNA.
Trimethoprim is a bacteriostatic lipophilic weak base structurally related to pyrimethamine, binds to and reversibly inhibits the bacterial enzyme dehydrofolate reductase, selectively blocking conversion of dehydrofolic acid. This depletes folates, and essential cofactor in the biosynthesis of nucleic acid and protein production. Bacterial dihydrofolate reductase is approximately 50000 and 60000 times more tightly bound by trimethoprim than the corresponding mammalian enzymes.
Exerts its effect at a step in the folate biosynthesis immediately subsequently to the one in which sulphonamides exerts their effect. When administered concurrently with sulphonamides, synergism occurs and is attributed to inhibition of tetrahydrofolate production at two sequential steps in its biosynthesis.
Pharmacokinetics: A combination which provides sequential and synergistic inhibition of bacterial folate synthesis. Sulphamethoxazole acts similarly to other sulphonamides while trimethoprim acts at a later step to inhibit the enzymatic reduction of dehydrofolic acid to tetrahydrofolic acid. The combination is active against many bacteria except anaerobes, Pseudomonas aeruginosa and many faecalis. It is also highly effective against protozoa and Pneumocystic carinii.
Absorption: Orally, sulphamethoxazole and trimethoprim are 90-100% absorbed.
Distribution: Sulphamethoxazole, widely distributed throughout the body tissues and fluids, including pleural, peritoneal, synovial and ocular fluid.
Trimethoprim, rapidly and widely distributed to various tissues and fluids, including kidneys, liver, spleen, bronchial secretion, saliva and prostatic tissues and fluids. It has also been demonstrated in bile, aqueous humor, bone marrow, and spongy but not compact bone, bowel mucosa, and seminal fluid. Both sulphamethoxazole and trimethoprim cross the placenta.
Protein binding: Sulphamethoxazole, approximately 66% in the plasma is protein bound.
Trimethoprim, approximately 50% in the plasma is protein bound.
Metabolism: Sulphamethoxazole - hepatic; primarily by acetylation to inactive metabolites which retain the toxicity of the parent compound. Some hepatic glucoronic conjugation may occur. Metabolism is increased with renal function impairment and decrease with hepatic failure.
Trimethoprim, hepatic; 10-20% metabolised to inactive metabolites.
Excretion: Sulphamethoxazole - renal by glomerular filtration, with some tubular secretion and re-absorption of both active drug and metabolites. Excretion is increased in alkaline urine. Small amounts are excreted in the feaces, breast milk, bile, and other body secretion.
Trimethoprim - renal; 40-60% excreted within 24 hours, of this amount 80-90% excreted unchanged and remainder excreted as inactive metabolites. Excretion increased in acid urine and decreased in alkaline urine.
Small amounts excreted in the faeces (approximately 4%) bile, and breast milk.
Toxicology: Cross Sensitivity: Patients intolerant of one sulphonamide may be intolerant of other sulphonamides also. Patient intolerant of frusemide, thiazide diuretics, sulphonylureas or carbonic anhydrase inhibitors may be intolerant of sulphonamides also.
Pregnancy/reproduction: Sulphonamides and trimethoprim cross the placenta. Although sulphonamides may displace bilirubin from protein binding sites in the foetal plasma, significant hyperbilirubinaemia does not usually occur in the neonate because of maternal hepatic conjugation of bilirubin.
Breast-feeding: Sulphonamides and trimethoprim are excreted in breast milk. However approximately 0.2% of the maternal dose of trimethoprim appears in breast milk. Although sulphonamides may displace bilirubin from protein binding sites of the foetal plasma, hyperbilirubinaemia does not usually occur except as a remote possibility during the first two week postpartum. Sulphonamides may cause haemolytic anaemia in glucose-6- phosphate dehydrogenase (G6PD) deficient neonates.