| Indication |
For the treatment of edema associated with congestive heart
failure, renal disease, or hepatic disease. Also for the treatment of
hypertension alone or in combination with other antihypertensive agents. |
| Pharmacodynamics |
Torasemide (INN) or torsemide (USAN) is a novel loop diuretic
belonging to pridine sulphonyl urea. It differs form other thiazide
diuretics in that a double ring system is incorporated into its
structure. Like thiazides, loop diuretics must be secreted into the
tubular fluid by proximal tubule cells. In the thick ascending loop Na+
and Cl- reabsorption is accomplished by a Na+/K+/2Cl-
symporter. The thick ascending limb has a high reabsorptive capacity
and is responsible for reabsorbing 25% of the filtered load of Na+. The loop diuretics act by blocking this symporter. Because of the large absorptive capacity and the amount of Na+
delivered to the ascending limb, loop diuretics have a profound
diuretic action. In addition, more distal nephron segments do not have
the reabsorptive capacity to compensate for this increased load. The
osmotic gradient for water reabsorption is also reduced resulting in an
increase in the amount of water excreted. |
| Mechanism of action |
Torasemide inhibits the Na+/K+/2Cl--carrier
system (via interference of the chloride binding site) in the lumen of
the thick ascending portion of the loop of Henle, resulting in a
decrease in reabsorption of sodium and chloride. This results in an
increase in the rate of delivery of tubular fluid and electrolytes to
the distal sites of hydrogen and potassium ion secretion, while plasma
volume contraction increases aldosterone production. The increased
delivery and high aldosterone levels promote sodium reabsorption at the
distal tubules, and By increasing the delivery of sodium to the distal
renal tubule, torasemide indirectly increases potassium excretion via
the sodium-potassium exchange mechanism. Torasemide's effects in other
segments of the nephron have not been demonstrated. Thus torasemide
increases the urinary excretion of sodium, chloride, and water, but it
does not significantly alter glomerular filtration rate, renal plasma
flow, or acid-base balance. Torasemide's effects as a antihypertensive
are due to its diuretic actions. By reducing extracellular and plasma
fluid volume, blood pressure is reduced temporarily, and cardiac output
also decreases. |
| Absorption |
Rapidly absorbed following oral administration. Absolute bioavailability is 80%. Food has no effect on absorption. |
| Volume of distribution |
- 12 to 15 L [normal adults or in patients with mild to moderate renal failure or congestive heart failure]
|
| Protein binding |
> 99% |
| Metabolism |
Metabolized via the hepatic CYP2C8 to 5 metabolites. The major
metabolite, M5, is pharmacologically inactive. There are 2 minor
metabolites, M1, possessing one-tenth the activity of torasemide, and
M3, equal in activity to torasemide. Overall, torasemide appears to
account for 80% of the total diuretic activity, while metabolites M1 and
M3 account for 9% and 11%, respectively. |
| Route of elimination |
Torsemide is cleared from the circulation by both hepatic
metabolism (approximately 80% of total clearance) and excretion into the
urine (approximately 20% of total clearance in patients with normal
renal function). |
| Half life |
3.5 hours |
| Clearance |
Not Available |
| Toxicity |
Symptoms of overdose include dehydration, hypovolemia,
hypotension, hyponatremia, hypokalemia, hypochloremic alkalosis, and
hemoconcentration. Oral LD50 in rat is 5 g/kg, and intravenous LD50 in rat is 500 mg/kg. |
