Pharmacotherapeutic group: High-ceiling diuretic. ATC Code: C03CA01.
Pharmacology: Pharmacodynamics: Mechanism of action: Furosemide Kabi is a strong diuretic agent of fast action. From a pharmacological point of view, Furosemide inhibits the co-transport system (re-absorption) of the following electrolytes Na+, K+ and 2Cl-, located on the luminal's cell membrane on the ascending limb of the loop of Henle. Consequently, Furosemide's efficiency depends on the drug reaching the tubular lumen through an anionic transport mechanism. The diuretic effect results on the inhibition of sodium chloride reabsorption in this segment of the loop of Henle. As a result, the fraction of excreted sodium may ascend to 35% of sodium's glomerular filtration. The secondary effects of increased elimination of sodium are: increase of urinary excretion and increase of potassium distal secretion at the distal tube. Excretion of calcium and magnesium salts are also increased.
Furosemide inhibits the feedback mechanism in the dense macula and induces dose-dependent stimulation of the renin-angiotensin-aldosterone system.
In case of heart failure, furosemide induces an acute reduction of cardiac pre-load (through the enlargement of the blood vessels capacity). This early vascular effect seems to be mediated by prostaglandins and assumes an adequate renal function with activation of the renin-angiotensin system and an intact synthesis of prostaglandins. Due to its natriuretic effect, furosemide reduces the vascular reactivity to catecholamine that is enlarged in hypertensive patients.
The antihypertensive effect of furosemide is attributed to the increase in sodium excretion, to the reduction of blood volume and to the vascular smooth muscle response to vasoconstriction stimulation.
Pharmacodynamic effects: The diuretic effect of furosemide is established within 15 minutes of an intravenous administration and within 1 hour of an oral administration.
A dose-dependent increase in diuresis and natriuresis was found in healthy individuals to whom furosemide was administered (doses between 10 and 100 mg). The duration of action in healthy individuals after the administration of an intravenous 20 mg dose of furosemide is approximately 3 hours and 3 to 6 hours, when an oral 40 mg dose is given.
In ill patients, the relation between tubular concentration of free furosemide and bound furosemide (determined through the urine excretion rate) and it's natriuretic effect is translated in a sigmoid graphic, with a minimum effective excretion rate of approximately 10 micrograms per minute. Consequently, a continuous infusion of furosemide is more effective than repeated bolus injections. Above a certain bolus administration dose, the drugs effects do not significantly increase. The efficacy of furosemide is decreased in cases of reduced tubular secretion or in cases of intra-tube binding of the drug to albumin.
Pharmacokinetics: Distribution: Furosemide distribution volume is 0.1 to 1.2 litres per kg of body weight. The distribution volume may be increased depending on the concomitant illness.
Protein binding (mostly to albumin) is higher than 98 %.
Furosemide is excreted in breast milk. It crosses the placental barrier transferring itself slowly to the foetus. Furosemide achieves similar concentrations in the mother, foetus or newborn.
Elimination: Furosemide is mostly eliminated as the non-conjugated form, mainly through secretion at the proximal tube. After intravenous administration, 60 to 70 % of furosemide is eliminated by this manner. The glucuronic metabolite of furosemide represents 10 % to 20 % of the recovered substances in the urine. The remaining dose is eliminated in the faeces, probably after biliary secretion. After intravenous administration, the plasma half-life of furosemide ranges from 1 to 1.5 hours.
Renal Impairment: In case of renal impairment, furosemide's elimination is slower and its half-life is increased. The terminal half-life may achieve 24 hours in patients with renal impairment.
In case of nephrotic syndrome, the lower concentration of plasmatic proteins leads to higher concentrations of non-conjugated furosemide (free). On the other hand, the efficiency of furosemide is reduced in these patients, due to intratubular albumin binding and to reduced tubular secretion.
Furosemide suffers low dialysis in patients undergoing hemodialysis, peritoneal dialysis or CAPD (Chronic Ambulatory Peritoneal Dialysis).
Hepatic Impairment: In case of hepatic impairment, furosemide's half-life increases 30 to 90%, mainly due to the higher distribution volume. Biliary elimination might be reduced (up to 50%). In this group of patients, there is a wider variability of the pharmacokinetic parameters.
Congestive Heart Failure, severe hypertension, elderly: Furosemides elimination is slower due to reduced renal function in patients with congestive heart failure, severe hypertension or in elderly.
Premature infants and new-born: Depending on the maturity of the kidney, elimination of furosemide may be slow. In case of children with insufficient capacity of glucuronidation, the metabolism of the drug is also reduced. In term neonates the half-life is generally less than 12 hours. In children with 2 or more months of age, terminal clearance is identical to adults.
Toxicology: Preclinical safety data: Acute oral toxicity was low in all species tested. Chronic toxicity studies in the rat and dog led to renal alterations (among others fibrous degeneration and renal calcification).
In vitro and in vivo tests of genetic toxicology did not reveal any clinically relevant evidence of a genotoxic potential of furosemide.
Long-term studies in mice and rats did not yield any relevant evidence of a tumorigenic potential.
In studies of reproductive toxicology in foetal rats, a reduced number of differentiated glomeruli, skeletal anomalies of the scapulae, humerus and ribs (induced by hypokalaemia), as well as hydronephrosis occurred in foetal mice and rabbits after administration of high doses.
The results of a mouse study and one of the three rabbit studies showed an increased incidence and severity of hydronephrosis (distention of the renal pelvis and, in some cases, of the ureters) in foetuses derived from the treated dams as compared with the incidence in foetuses from the control group.
Preterm rabbits given furosemide had a higher incidence of intraventricular haemorrhage than saline-treated littermates, possibly due to furosemide-induced intracranial hypotension.