After oral administration trimethoprim and sulfamethoxazole are rapidly and nearly completely absorbed.
Peak levels in the blood occur between 1-4 hours after ingestion and the level attained is dose related.
Tissue levels of trimethoprim are generally higher than corresponding plasma levels, the lungs and kidneys showing especially high concentrations.
Trimethoprim passes into amniotic fluid and foetal tissues reaching concentrations approximating those of maternal serum.
The half-life in healthy man is 8.6-17 hours in the presence of normal renal function. It is increased by a factor of 1.5 to 3.0 when the creatinine clearance is less than 10 ml/minute
There is no change in the half-life of active sulfamethoxazole with a reduction in renal function but there is prolongation of the half-life of the major, acetylated metabolite when the creatinine clearance is below 25 ml/minute.
The principal route of excretion of trimethoprim is renal and approximately 50% of the dose is excreted in the urine within 24 hours as unchanged drug
The principal route of excretion of sulfamethoxazole is renal; between 15% and 30% of the dose recovered in the urine is in the active form.
An estimated 10% to 30% of cotrimoxazole is renally excreted; however, the larger proportion undergoes hepatic excretion
Trimethoprim is a weak base with a pKa of 7.4 while Sulfamethoxazole is a weak acid with a pKa of 6.0
Approximately 50% of trimethoprim in the plasma is protein bound. Approximately 66% of sulfamethoxazole in the plasma is protein bound
Signs and symptoms of overdosage reported with sulfonamides include anorexia, colic, nausea, vomiting, dizziness, headache, drowsiness and unconsciousness. Pyrexia, hematuria and crystalluria may be noted. Blood dyscrasias and jaundice are potential late manifestations of overdosage.
Signs of acute overdosage with Trimethoprim (Co-Trimoxazole) include nausea, vomiting, dizziness, headache, mental depression, confusion and bone marrow depression and agranulocytosis (from interfering with the metabolism of folic acid).
Hypoglycemia (postulated that it binds to insulin cells and creates a state of insulin hypersecretion). Impaired renal function is recognized as a risk factor for hypoglycaemia
Slight elevations in liver function test results
Emesis or gastric lavage, followed by supportive care
Correct acidosis and hypoglycemia
Enhance elimination by forced oral fluids, and I.V. fluids
Treatment renal failure with hemodialysis. Hemodialysis, however, has limited ability to remove co-trimoxazole; Both trimethoprim and active sulfamethoxazole are moderately dialysable by haemodialysis
Transfuse appropriate blood products in severe hematologic toxicity
Seizures can be managed with diazepam.
Use folinic acid (leucovorin) to rescue bone marrow.
Electronic Medicines Compendium (EMC). Active ingredient:trimethoprim and sulfamethoxazole. https://www.medicines.org.uk/emc/product/267/smpc. Last updated on eMC: 31 Mar 2015