Description
Torasemide is a novel loop diuretic launched in 1993 after a 12-year gap from the last
diuretic introduction. It is indicated for the treatment of hypertension and edema associated
with chronic congestive heart failure, renal disease and hepatic cirrhosis. Torasemide exerts
its major diuretic activity on the thick ascending limb of the Henle's loop to promote rapid and
marked excretion of water, Na+, Cl-, and to a lesser extent,K+ and Ca2+. Compared with other
loop diuretics such as furosemide, torasemide has a stronger antihypertensive action, a
higher bioavailability, a longer duration of action that is independent of the renal function, and
has no side effects such as paradoxical antidiuresis. The mechanism of its vasodilating effect
has been suggested to result from, at least in part, the competitive antagonism of the
thromboxane A2 receptor.
Chemical Properties
Crystalline Solid
Originator
Hafslund Nycomed
Germany; Italy (Norway)
Uses
Torasemide is a loop diuretic. Diuretics have been abused as performance-enhancing drugs and masking agents in doping in sports. Use of torsemide is effective for the treatment of edema associated with chronic renal failure. The pharmacology of torasemide is similar to that of frusemide,though torasemide has a longer duration of action with a plasma half-life of approximately 3.5 hours. It also causes a less marked loss of potassiumand calcium.
Definition
ChEBI: Torasemide is an N-sulfonylurea obtained by formal condensation of [(3-methylphenyl)amino]pyridine-3-sulfonic acid with the free amino group of N-isopropylurea. It is a potent loop diuretic used for the treatment of hypertension and edema in patients with congestive heart failure. It has a role as a loop diuretic and an antihypertensive agent. It is a N-sulfonylurea, an aminopyridine and a secondary amino compound. It is functionally related to a 4-aminopyridine.
Manufacturing Process
In a 100 ml three-necked flask equipped with magnetic stirrer, condenser,
thermometer and dropping funnel 3-sulfonylchloride-4-chloropyridine (10 g, 1
eq., 46.7 mmoles) was suspended in t-butyl-methyl ether (MTBE) (30 ml) at
room temperature. Ammonium hydroxide, 25% solution (13.5 ml, 2.13 eq.)
was dropped into the suspension in a rate such that the temperature is
allowed to increase to 22°-26°C, this temperature was maintained until all the
ammonium hydroxide was added. The suspension was then to cooled to room
temperature and was stirred for 1 h. The pH of the suspension was adjusted
to 80.1 by the addition of a few drops of ammonium hydroxide, 25% solution.
The suspension was filtered and washed with water (2 times 10 ml) and the
wet product (8 g) dried at 40°C, under the 1 mm Hg vacuum. 3-Sulfonamide-
4-chloropyridine was isolated in 74.4% yield, 6.7 g.
A mixture of 0.01 moles of 3-sulfonamido-4-chloropyridine, 0.02 mole of 3-
methylbenzylamine and 50 ml of dry ethanol was heated to reflux
temperature for 9 h. After distillation of the ethanol the residue was taken up
in an excess of diluted NaOH and the excess of amine was extracted by
means of ether.
The aqueous solution was then decolourized with charcoal and filtered, and
the filtrate was neutralized with acetic acid. The precipitated product was
separated and purified by crystallization from a mixture of water and acetone.The 3-sulfonamido-4-(3-methylbenzyl)amino-pyridine crystallized in the form
of beige coloured cristals having a melting point of 184°-186°C.
0.01 mole of 3-sulfonamido-4-(3-methylbenzyl)amino-pyridine was reacted
with 0.015 mole of isopropylisocyanate in the presence of 0.02 mole of
triethylamine and of 20 ml of dichloromethane, at room temperature for 20 h.
After evaporation under vacuum, the residue was taken up in an excess of
diluted Na2CO3, filtered off and acidified by means of acetic acid. After
precipitation of the product it was filtered and washed several times with ice
cold water. The 3-isopropylcarbamoylsulfonamido-4-(3-methylbenzyl)amino_x0002_pyridine (Torsemide) showing as a white powder, has a melting point of 147°-
149°C.
Brand name
Torasemide is INN and BAN;Unat;Toradiur.
Therapeutic Function
Diuretic
Biochem/physiol Actions
Torsemide is a loop diuretic of the pyridine-sulfonylurea class with antialdosteronergic properties and inhibitor of the Na+/K+/2Cl- carrier system.
Clinical Use
Loop diuretic:
Hypertension
Oedema
Drug interactions
Potentially hazardous interactions with other drugs
Analgesics: increased risk of nephrotoxicity with
NSAIDs; antagonism of diuretic effect with
NSAIDs.
Anti-arrhythmics: risk of cardiac toxicity with
anti-arrhythmics if hypokalaemia occurs; effects of
lidocaine and mexiletine antagonised.
Antibacterials: increased risk of ototoxicity with
aminoglycosides, polymyxins and vancomycin; avoid
concomitant use with lymecycline.
Antidepressants: increased risk of hypokalaemia with
reboxetine; enhanced hypotensive effect with MAOIs;
increased risk of postural hypotension with tricyclics.
Antiepileptics: increased risk of hyponatraemia with
carbamazepine.
Antifungals: increased risk of hypokalaemia with
amphotericin.
Antihypertensives: enhanced hypotensive effect;
increased risk of first dose hypotensive effect
with alpha-blockers; increased risk of ventricular
arrhythmias with sotalol if hypokalaemia occurs.
Antipsychotics: increased risk of ventricular
arrhythmias with amisulpride or pimozide (avoid
with pimozide) if hypokalaemia occurs; enhanced
hypotensive effect with phenothiazines.
Atomoxetine: hypokalaemia increases risk of
ventricular arrhythmias.
Cardiac glycosides: increased toxicity if hypokalaemia
occurs.
Cytotoxics: increased risk of ventricular arrhythmias
due to hypokalaemia with arsenic trioxide; increased
risk of nephrotoxicity and ototoxicity with platinum
compounds.
Lithium: risk of toxicity.
Metabolism
Torasemide is metabolised by the cytochrome P450 isoenzyme CYP2C9 to three inactive metabolites, M1, M3 and M5 by stepwise oxidation, hydroxylation or ring hydroxylation. The inactive metabolites are excreted in the urine.
