Furosemide

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Furosemide is usually administered intravenously (0.1-1 mg kg~l) or orally (0.75-3 mg kg~l). It is well absorbed orally and about 60% of the dose reaches the central circulation within a short period, with the peak effect after 1-1.5 h. Intravenous furosemide is usually started as a slow 20-40 mg injection in adults, but higher doses or even an infusion may be required in the case of elderly patients with renal failure or severe congestive cardiac failure. Approximately 90% of the drug is bound to plasma proteins and its volume of distribution is relatively low. Metabolism and excretion into the gastrointestinal tract contribute to about 30% of the elimination of a dose of furosemide. The rest is excreted unchanged through glomerular filtration and tubular secretion. Impaired renal function affects the elimination process, but liver disease does not seem to influence this. The elimination half-life of furosemide is 1-1.5 h.

Loop diuretics act primarily on the medullary part of the ascending limb of the loop of Henle. After initial glomerular filtration and proximal tubular secretion, furosemide inhibits the active reabsorption of chloride in the thick portion of the ascending limb. This leads to chloride, sodium, potassium and hydrogen ions remaining in the tubule to maintain electrical neutrality, and their increased excretion in the urine. The extent of the following diuresis is determined by the concentration of furosemide active in this part of the tubule. Because the ascending limb plays an important role in the reabsorption of sodium chloride in the kidney, furosemide results in a marked diuretic response. The decrease in sodium chloride reabsorption leads to a reduced urine-concentrating ability of the normally hypertonic medullary interstitium.

Furosemide increases renal artery blood flow if the intravascular fluid volume is maintained. It causes redistribution so that flow to the outer part of the cortex remains unchanged while inner cortex and medullary flow is increased. It leads to an improved renal tissue oxygen tension. This effect, together with the increased release of renin and the activation of the angiotensin-aldosterone axis, is mediated via prostaglandins. A particular advantage of loop diuretics is the high ceiling effect (i.e. increasing doses lead to increasing diuresis).

In case of acute pulmonary oedema or other oedematous states of fluid overload due to cardiac, renal or liver failure, furosemide is the diuretic of choice. It reduces the intravascular fluid volume by promoting a rapid, powerful diuresis even in the presence of a low GFR. The pulmonary vascular bed and capacitance vessels are dilated by fiirosemide, and often a relief of dyspnoea and a reduction in pulmonary pressures may take place before the diuretic effect has occurred. In hypertensive patients, the vasodilatation and preload reduction lead to a decrease in arterial pressure.

The use of fiirosemide for prophylactic protection of the kidney against ischaemic injury and in the treatment of acute renal failure is controversial. In common with mannitol, fiirosemide has been shown in animal studies to help protect the kidney against ischaemic damage. Human studies, however, failed to support this. Loop diuretics, if administered early in the course of ischaemic acute renal failure, may change an oliguric into a non-oliguric state. Although non-oliguric acute renal failure is generally associated with a lower mortality rate, there is little evidence that this conversion changes the outcome. Furosemide should never be used, however, to treat oliguria caused by a decreased intravascular fluid volume or dehydration, because the following diuresis could exaggerate hypovolemia and renal ischaemic injury. It is important to restore the intravascular volume status first before any pharmacological intervention.

A raised intracranial pressure is often treated with furosemide. It mobilizes the oedema fluid, decreases cerebrospinal fluid production and lowers the intracranial pressure without changing the plasma osmolarity. In contrast to mannitol, a disrupted blood-brain barrier does not influence the effect of furosemide on the intracranial pressure.

Excessive doses of furosemide often lead to fluid or electrolyte abnormalities. Severe hypokalaemia may precipitate dangerous cardiac arrhythmias, especially in the presence of high concentrations of digitalis. It may also enhance the effect of non-depolarizing muscle relaxants. Hypovolaemia, dehydration and the consequent haemoconcentration may lead to changes in blood viscosity. Hyperuricaemia and prerenal uraemia may develop and may precipitate an acute gout attack in a patient with pre-existing gout.

Furosemide may cause high concentrations of aminoglycosides and cephalosporins in the kidneys and this may enhance their nephrotoxic effect. Prolonged high blood concentrations of furosemide may cause transient or permanent deafness because of changes in the endolymph electrolyte composition. Patients allergic to other sulphonamide drugs may have a cross-sensitivity, although idiosyncratic reactions are rare.

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