Resistance to loop diuretics is often encountered clinically. Studies in healthy subjects have shown that overall response to loop diuretics depends upon the interplay between the total amount of drug reaching the urine, the time course of its entry into urine and the pharmacodynamics of response to diuretic in the urine. The mechanism by which diuretic resistance occurs has been elucidated in several clinical conditions. Treatment with inhibitors of prostaglandin synthesis has no effect on diuretic appearance in urine but blunts response by blocking the increase in renal blood flow produced by loop diuretics. In the elderly and in patients with moderate renal insufficiency, the mechanism of resistance appears to be purely pharmacokinetic, involving altered access of diuretic into the urine. In contrast, patients with nephrotic syndrome and hepatic cirrhosis manifest a purely pharmacodynamic form of resistance: in nephrosis, diuretic may bind to protein in the urine; in cirrhosis the mechanism of resistance is unclear. Lastly, in patients with congestive heart failure, with intravenous administration, resistance represents a pharmacodynamic phenomenon. With oral administration, however, the time course but not the extent of absorption is altered; consequently, in this setting, both pharmacokinetic and pharmacodynamic changes may contribute to the subnormal response. Strategies for overcoming resistance to loop diuretics in patients receiving NSAIDs or those with renal disease, hepatic cirrhosis or congestive heart failure include one or more of: increasing the dose size; administering frequent 'small' (but effective) doses; continuous intravenous infusion of the diuretic; or concomitant administration of another diuretic such as metolazone or hydrochlorothiazide.

Patients with congestive heart failure (CHF) represent one of the largest groups in which loop diuretics are a mainstay of treatment. Their proper use requires an understanding of the mechanisms of response to diuretics in such patients. Over the past few years information has increased concerning the pharmacokinetics and pharmacodynamics of loop diuretics in various diseases but particularly CHF. These data have in turn allowed a more rational design of therapeutic regimens. This review discusses our current understanding of mechanisms of resistance to loop diuretics in patients with CHF and shows how such understanding dictates therapeutic strategy. The delayed absorption results in lower peak concentrations of drug at the urinary site of action (fig 1). As such, relatively higher oral doses might have to be given to such patients to attain concentrations necessary to reach the steep portion of the dose-response curve. Due to the unpredictability in an individual patient of the duration of delay in absorption, it is usually easiest to avoid this problem of absorption altogether by simply giving loop diuretics intravenously to patients with CHF until they attain dry weight. If this strategy is used, oral dosing is then begun when the patient has reached a clinical condition in which optimal absorption for that patient occurs.

Torasemide is a lipophilic anilinopyridine sulphonylurea derivative that acts as a high ceiling loop diuretic and has been used for the treatment of both acute and chronic congestive heart failure (CHF) and hypertension. Torasemide is similar to other loop diuretics in terms of its mechanism of diuretic action; namely, blockade of Na+/K+/2Cl- cotransport in the thick ascending limb of the loop of Henle. It has high bioavailability (> 80%), as does bumetanide, but a longer elimination half-life (3 to 4 hours) than either bumetanide or furosemide (frusemide). In the treatment of chronic CHF, oral torasemide (5 to 20 mg/day) has been shown to be an effective diuretic. Patients treated with torasemide for up to 1 year have reduced bodyweight, improved pulmonary haemodynamics, and decreased CHF severity. Intravenous torasemide (20 to 60mg as a single dose) has been shown to be as effective as furosemide in the treatment of acute CHF, and resulted in significant diuresis, bodyweight loss, and improved pulmonary haemodynamics and exercise performance. 'Non-diuretic' dosages (2.5 to 5 mg/day) of oral torasemide have been used to treat essential hypertension, both as monotherapy and in combination with other antihypertensive agents. When used in these dosages, torasemide lowered diastolic blood pressure (DBP) to below 90mm Hg in 8 to 12 weeks in 70 to 80% of patients. With dose doubling, this level of efficacy occurred in more than 90% of hypertensive patients. Clinical trials have established that blood pressure can be maintained at this level for at least 1 year with low dose torasemide. Torasemide is well tolerated in dosages up to 20 mg/day for at least 1 year. The most commonly reported adverse effects are those associated with loop diuretics in general. These include transient hypokalaemia, hyperuricaemia, dizziness, headache, gastrointestinal disturbances, orthostatic hypotension and fatigue. Adverse effects are comparable with those of other diuretics and rarely necessitate drug withdrawal.