Class of Diuretics
Loop diuretics, reversibly, inhibit the Na+⁄2Cl-⁄K+ co-transporter of the thick ascending loop of Henle where one-third of filtered sodium is reabsorbed. This causes decreased sodium and chloride reabsorption and increased diuresis.5
Loop diuretics also enhance the synthesis of prostaglandins, which cause renal and venous dilatation. This explains some of the cardiac effects, such as reduction in pulmonary wedge pressure.6 However, it is important to recognise that the diuretic actions of loop diuretics may be decreased by the concomitant use of non-steroidal anti-inflammatory drugs (NSAIDs), possibly because this inhibits renal prostaglandin synthesis. Loop diuretics include furosemide, bumetanide, torsemide and ethacrynic acid.
While the bioavailability of oral furosemide ranges from 40 to 80 %, the bioavailability of torasemide and bumetanide exceeds 80 %; so these two molecules may be more effective in treating patients suffering from HF.7
A well-known consequence of loop diuretic therapy is depletion of other electrolytes, such as potassium, magnesium, calcium and chloride (see Table 1).
Thiazide Diuretics and Metolazone
Benzothiazide diuretics inhibit the sodium–chloride transporter at the distal portion of the ascending limb and the first part of the distal tubule. They prevent maximal dilution of urine, thus increasing free water clearance and excretion of sodium and chloride through the renal tubular epithelium. The increased delivery of sodium to the collecting ducts enhances the exchange of sodium with potassium and, as a result, potassium depletion.
They are less effective in patients with reduced glomerular filtration, because they exert their diuretic effects from the luminal side of the nephron. Although they are less potent than loop diuretics, they may work in synergy with them when a sequential segmental nephron blockade is achieved.
Thiazides also decrease peripheral vascular resistance by a mechanism which is, at present, not well understood, resulting in a decrease of blood pressure.8
Metolazone is not a thiazide but acts in a similar way. Metolazone is more potent than hydrochlorothiazide and retains its effectiveness even when there is severe glomerular filtration rate (GFR) reduction.
The potassium-sparing diuretics used for treating HF are the aldosterone receptor antagonists spironolactone and eplerenone. They act at the cortical collecting duct, in particular by reducing the absorption of sodium and water and increasing the excretion of hydrogen ions and potassium, and their action is mediated by the antagonism of the actions of mineral corticoids. Only 3 % of filtered sodium is reabsorbed at the collecting duct, so this class of drugs does not have an appreciable diuretic effect. However they are often used in association with other more effective diuretics to correct or prevent potassium deficiency. They are also significantly efficacious in reducing the deleterious effects of aldosterone on the cardiovascular system. Spironolactone is a non-selective aldosterone receptor antagonist, and thus endocrine-related adverse effects (such as gynecomastia) are relatively common when it is used. Eplerone has greater selectivity on the mineral corticoid receptor, and has fewer side effects.9