PubMed · 7014175
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A A Lawson. 1981. Potassium replacement: when is it necessary?. https://doi.org/10.2165/00003495-198121050-00003
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A thorough understanding of the clinical pharmacology of diuretic agents, particularly loop diuretics, is crucial in patients with abnormal (and those with normal) renal function. Renal insufficiency represents a pathophysiological state characterised by diuretic resistance. Diuretic resistance is defined as a diminished pharmacological response, or diminished natriuresis, to a given dose of a diuretic. The phenomenon of diuretic resistance is demonstrated by a shift in the dose-response curve relating urinary diuretic excretion rates (dose) with sodium excretion (response). Pharmacokinetic factors underlie the diuretic resistance observed in patients with renal failure. Diminished renal blood flow and sodium filtration, accumulation of organic acids that inhibit tubular secretion of the diuretic, and inadequate cumulative sodium excretion to meet patients' needs contribute to the diuretic-resistant state. In contrast, the pharmacological response of remnant (i.e. remaining) nephrons to diuretic agents remains intact. The time course of delivery of diuretics to their intraluminal site of action is an independent determinant of natriuretic response. An administration regimen that continuously maintains effective rates of excretion of diuretics into the urine would be expected to cause a greater overall natriuretic effect than the same amount of diuretic administered in intermittent doses. Thus, diuretic administration strategies that take account of the altered pharmacological responses in patients with renal failure are necessary to provide effective and safe treatment. Additionally, such strategies warrant revision by the prescribing physician as renal function changes over time.
Torasemide is a new loop diuretic that differs from others in this class in that only 20% of the drug is excreted unchanged in the urine with the remaining 80% being eliminated by hepatic metabolism. The large component of nonrenal clearance would predict that torasemide would have only minimal accumulation and prolongation of half-life in patients with renal insufficiency, and this proves to be the case. In contrast, in patients with liver disease, impairment of hepatic elimination causes accumulation of torasemide in plasma with prolongation of half-life. In addition, in cirrhosis, there is increased elimination of unchanged drug into the urine compared to healthy controls. In patients with renal insufficiency, response to remaining nephrons is normal as has been observed with other loop diuretics. In patients with cirrhosis and in those with congestive heart failure, response is diminished, again as has been observed with other loop diuretics. Interestingly, in patients with cirrhosis, the increased delivery of drug into the urine is sufficient to compensate for the decreased pharmacodynamics of response so that overall response is similar to that which occurs in health subjects.
An important role for diuretics in the treatment of hypertension is assured on the basis of the latest randomized, prospective trials. Although thiazide diuretics have been the mainstay of treatment thus far, they continue to engender debate because of putative, undesirable side effects. Older loop diuretics, such as furosemide, did not establish themselves in the treatment of essential hypertension because of an inferior efficacy profile compared with that of thiazides. Torasemide is a new loop diuretic that is efficacious at low once-daily doses in the treatment of essential hypertension. The drug compares favorably with hydrochlorothiazide and indapamide. Its mechanism of action may not be entirely based on elimination of salt and water from the body. Torasemide exhibits a favorable side-effect profile, particularly because it does not engender hypokalemia, increases in blood sugar, or serum lipid values. When the additional costs of potassium supplements or potassium-retaining medication are considered, torasemide treatment also compares favorably in terms of health-care economics. Torasemide represents a reasonable alternative to conventional diuretic management in patients with essential hypertension.