Pharmacology: Pharmacodynamics: Mechanism of Action: It appears to act primarily by inhibiting active reabsorption of chloride ions in the ascending limb of the loop of Henle. Urinary 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 exchange 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 a possibility that furosemide may also act at a more proximal site.
Pharmacokinetics: Furosemide is highly bound to plasma proteins, almost exclusively to albumin. The proportion of free (unbound) furosemide is higher in patients with heart disease, renal impairment, and cirrhosis of the liver. Patients with liver disease also have an increased apparent volume of distribution which is proportionally greater than the observed decrease in protein binding. Patients with nephrotic syndrome have significant proteinuria and secondary hypoalbuminaemia. This results in reduced protein binding in the blood, particularly at higher blood concentrations, and binding to proteins present in the urine, which may account for the resistance to furosemide therapy reported in these patients. A glucuronide metabolite of furosemide is produced in varying amounts. The site of metabolism is unknown at present. There is debate over another potential metabolite, 4-chloro-5-sulfamoyl anthranilic acid (CSA). It has been argued that it is an artifact produced during the extraction procedures although there is some evidence to refute this. A half-life for furosemide in healthy subjects has generally been reported in the range of 30 to 120 minutes. In patients with endstage renal disease the average half-life is 9.7 hours. The half-life may be slightly longer in patients with hepatic dysfunction and a range of 50 to 327 minutes has been reported in patients with heart failure. In severe multi-organ failure the half-life may range from 20 to 24 hours. Furosemide clearance is influenced by age, underlying disease state, and drug interactions. Clearance reduces with increasing age, probably due to declining renal function. Renal impairment in renal or cardiac disease reduces renal clearance, although this may be compensated for by increases in non-renal clearance. Hepatic impairment has little impact on clearance. Renal and nonrenal clearance may be reduced by probenecid and indometacin.
The effectiveness of furosemide as a diuretic depends upon it reaching its site of action, the renal tubules, unchanged. About one-half to two-thirds of an intravenous 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.