Furosemide (frusemide). A pharmacokinetic/pharmacodynamic review (Part I)

Abstract

Furosemide (frusemide) is a potent loop diuretic used in the treatment of oedematous states associated with cardiac, renal and hepatic failure, and for the treatment of hypertension. Therapy is frequently complicated by apparently erratic systemic availability from the oral route and from unpredictable responses to a given dosage. The exact mechanism of action is not fully understood, but furosemide is believed to act at the luminal surface of the ascending limb of the loop of Henle by inhibiting the active reabsorption of chloride. The response to a given dosage is modulated by the fluid and electrolyte balance of the individual. Acute and delayed tolerance has been demonstrated both in animals and in man, and is postulated to be due to the intervention of homeostatic mechanisms influencing fluid and electrolyte balances. Furosemide is delivered to its site of action by active secretion via the nonspecific organic acid pump. Comparisons between the observed diuresis/saluresis and plasma furosemide concentrations, urinary excretion rates and renal clearance found either negative or no correlations with plasma drug concentration but significant correlations with urine measurements. Response is related to the concentration of the drug in urine rather than in plasma. The most common adverse reactions attributable to furosemide therapy are essentially extensions of the therapeutic effects (i.e. fluid and electrolyte disturbances). The pharmacokinetic behaviour of furosemide is marked by a large degree of variability, derived from differences within and between both subjects and study protocols. Part of this variability can be attributed to differences in organ function, which is important in view of the types of patients treated with furosemide. On the other hand, a large proportion remains as inter- and intrasubject variation. The bioavailability of furosemide from oral dosage forms is highly variable. The poor bioavailability has been hypothesized to be due to the poor solubility of the compound, site-specific absorption, presystemic metabolism and/or other unknown mechanisms. Furosemide is highly bound to plasma proteins, almost exclusively to albumin. Although the drug is insoluble in water and favours partitioning into fatty tissue, the high degree of plasma protein binding restricts the apparent volume of distribution at steady-state to values within a multiple of 2 to 5 times the plasma volume. Furosemide has two documented metabolites--furosemide glucuronide and saluamine (CSA). The first is an accepted metabolic product, whereas the status of CSA as a metabolite is highly controversial.(ABSTRACT TRUNCATED AT 400 WORDS)