Pharmacology: Pharmacodynamics: Furosemide is a potent diuretic with a rapid action. Furosemide inhibits the reabsorption of electrolytes mainly in the thick ascending limb of the loop of Henle and also in the distal renal tubules. It may also have a direct effect in the proximal tubules. Excretion of sodium, chloride, potassium, hydrogen, calcium, magnesium, ammonium, bicarbonate, and possibly phosphate is increased; the chloride excretion exceeds that of sodium and there is an enhanced exchanged of sodium for potassium leading to greater excretion of potassium. The resulting low osmolality of the medulla inhibits the reabsorption of water by the kidney. There is possibility that furosemide may also act at a more proximal site.
In addition to its diuretic actions, furosemide has been shown to increase peripheral venous capacitance and reduce forearm blood flow. It also reduces renal vascular resistance with a resultant increase in renal blood flow the degree of which is proportional to the initial resistance.
Furosemide has been shown to increase plasma-renin activity plasma-noradrenaline concentrations, and plasma-arginine-vasopressin concentrations. Alterations in the renin-angiotensin-aldosterone system may play a part in the development of acute tolerance. Furosemide increases renal-prostaglandin concentrations but it is unknown whether this is due to increased synthesis or inhibition of degradation or both. Prostaglandins appear to mediate the diuretic/natriuretic action. The primary effects appear to be alterations in renal haemodynamics with subsequent increases in electrolyte and fluid excretion.
The diuretic response to furosemide is related to the concentration in the urine, not to that in the plasma. Furosemide is delivered to the renal tubules by a non-specific organic acid pump in the proximal tubules.
In some cases sodium intake may be sufficient to overcome the diuretic effect and limiting sodium intake could restore responsiveness.
Pharmacokinetics: Furosemide is fairly rapidly absorbed from the gastrointestinal tract; bioavailability has been reported to be about 60-70% but absorption is variable and erratic. The half life of furosemide is up to about 2 hours although it is prolonged in neonates and in patients with renal and hepatic impairment. Furosemide is up to 99% bound to plasma albumin and is mainly excreted in the urine, largely unchanged. There is also some excretion via the bile and non-renal elimination is considerably increased in renal impairment. Furosemide crosses the placental barrier and is distributed into breast milk. The clearance of furosemide is not increased by haemodialysis.
The efficacy of furosemide as a diuretic depends upon its reaching site of action, the renal tubules, unchanged. About one-half to two-thirds of an intravenous dose or one-quarter to one-third of an oral dose are excreted unchanged, the difference being largely due to the poor bioavailability from the oral route. The effect of furosemide is more closely related to its urinary excretion than to the plasma concentration. Urinary excretion may be reduced in renal impairment due to reduced renal blood flow and reduced tubular secretion.