201 REVIEW Use of diuretics in cardiovascular diseases: (1) heart failure S U Shah, S Anjum, W A Littler ............................................................................................................................... Postgrad Med J 2004;80:201–205. doi: 10.1136/pgmj.2003.010835 Diuretics are used extensively in hospitals and in stimulate the exchange with potassium, particu- larly in the presence of an activated renin– community medical practice for the management of angiotensin–aldosterone system.4 Thiazides may cardiovascular diseases. They are used frequently as the also increase the active excretion of potassium in first line treatment for mild to moderate hypertension and the distal renal tubule. Thiazides are rapidly absorbed from the gastrointestinal tract, produ- are an integral part of the management of symptomatic cing diuresis within 1–2 hours, which typically heart failure. Although diuretics have been used for several lasts for 6–12 hours. Their potency is midway decades, there is still some ambiguity and confusion between loop and potassium sparing agents, which act mainly on the distal tubules. regarding the optimal way of using these common drugs. Metolazone, which is a thiazide-like diuretic, In this paper, the classes and action of diuretics are seems to affect the proximal tubule in addition to reviewed, and the various indications, optimal doses, and its more distal effect.5 It is therefore effective even in renal failure, whereas other thiazide recommendations on the effective use of these agents are diuretics, owing to their distal and hence less discussed. potent action, are of limited or no use. ........................................................................... Indapamide has been shown to have mainly vasodilatory effects in smaller doses, and it works as a weak diuretic in relatively larger doses.6 Potassium sparing diuretics also generally CLASSIFICATION AND MECHANISM OF retain magnesium. Amiloride and triamterene ACTION inhibit the sodium proton exchanger, which is The commonly used classes of diuretics are loop, concerned with sodium reabsorption in the distal thiazide, and potassium sparing diuretics, and tubules and collecting tubules.7 Thereby potas- carbonic anhydrase inhibitors. Carbonic anhy- sium loss is indirectly decreased. They are drase inhibitors are rarely used in the manage- relatively weak diuretics, which are often used ment of hypertension or heart failure and hence in combination with thiazides and loop diure- will not be discussed in detail. This classification tics.8 An advantage of such combination is that of diuretics is based on their site of action in the the loss of sodium is achieved without a major kidneys. This secondarily determines their loss of potassium and magnesium. Both amilor- potency and various biochemical effects (see ide and triamterene affect cardiac repolarisation, + table 1). possibly by inhibiting delayed rectifier K cur- Loop or high ceiling diuretics, including rents (IK), and may exaggerate the prolonged frusemide, bumetanide, and torseamide, rever- repolarisation observed with Singh–Vaughan sibly inhibit the Na+–K+–2Cl2 symporter (cotran- Williams class IA antiarrhythmics.89 sporter) situated at the luminal thick ascending Spironolactone and its active metabolites limb of the loop of Henle. A second functional canrenone and potassium canrenoate competi- class of these drugs, typified by ethacrynic acid, tively inhibit the binding of aldosterone to is also effective only from the tubule lumen but mineralocorticoid or type I receptors in many exhibits a slower onset of action, and delayed tissues, including epithelial cells of the distal and only partial reversibility. Loop diuretics convoluted tubule and collecting duct.10 therefore act by inhibiting the reabsorption of Spironolactone is more powerful then other chloride, sodium, potassium, and hydrogen ions potassium sparing diuretics. One daily dose is in the ascending loop of Henle.1 In comparison usually adequate for diuresis. Recently, spirono- with thiazide diuretics, loop diuretics induce lactone has been shown to decrease mortality relatively more urine formation and relatively markedly in subjects with advanced heart fail- less loss of sodium and potassium (see table 2).2 ure.11 See end of article for Diuretics have also been shown to exert some authors’ affiliations The plasma half life of a typical loop diuretic, ....................... frusemide, is 1.5 hours; the duration of action is extrarenal effects. Both loop and thiazide diure- 4–6 hours. Diuresis starts within 10–20 minutes tics can induce vasodilatation when used Correspondence to: of an intravenous dose and peaks 1–1.5 hours acutely.12–14 Frusemide has been shown to relax Dr Saeed Ullah Shah, 17 3 South Street, Harborne, after an oral dose. precontracted pulmonary venous rings by Birmingham B17 0DB, UK; The group often collectively referred to as directly affecting smooth muscle cells.14 saeedshah@miranshah. ‘‘thiazide’’ diuretics are not all technically ben- Interestingly, this effect is apparent only in freeserve.co.uk zothiadiazine derivatives. Thiazides inhibit pulmonary venous and not in arterial vascular Submitted 7 June 2003 sodium and chloride reabsorption more distally. tissue and was apparent in these in vitro studies Accepted 29 August 2003 This cotransporter is insensitive to loop diuretics. only at drug concentrations achievable transi- ....................... More sodium reaches the distal tubules to ently after bolus infusions. This vasodilatory www.postgradmedj.com 202 Shah,Anjum,Littler Table 1 Classification and mechanism of action of diuretics Principal site and Effects on urinary Diuretic mechanism of action electrolytes Extrarenal effects Common or important side effects Loop diuretics Thick ascending loop of Increases Na Acute Hypokalaemia, hyponatraemia, Frusemide Henle, inhibition of and Cl Increases venous capacitance hypomagnesaemia, hypocalcaemia, Bumetanide Na–K–2KCl cotransporter Increases systemic vascular hyperuricaemia, hyperglycaemia, dehydration, Torasemide resistance blood dyscrasias, rashes, lipid abnormalities, Chronic; decreases cardiac ototoxicity preload Thiazide related Distal tubule Increases Na Increases venous capacitance Hypokalaemia, hyponatraemia, sulphonamide diuretics Inhibition of NaCl and Cl and glucose hypomagnesaemia, hypercalcaemia, Bendrofluazide cotransport Increases K Increases LDL and triglycerides hyperuricaemia, pancreatitis, rashes, increase in Hydrochlorothiazide May be dose related LDL and triglycerides (may be transient), Chlorthalidone impotence Metolazone Additional proximal Additional effects tubular action include reducing Cl Indapamide Vasodilator Milder Potassium sparing diuretics Spironolactone Aldosterone antagonists, Reduces K; Antiandrogenic Hyperkalaemia collecting duct increases Na and Cl Triamterene Inhibition of apical Increases HCO membrane Na conductance effect is sustainable with long term use, although it is corrected if necessary. Magnesium deficiency may also be influenced by other factors, such as dosage, route, and responsible for some of the arrhythmias ascribed to hypoka- concomitant use of other medications. All these rapid laemia.21 haemodynamic changes are attenuated in patients with Most diuretics decrease urate excretion with the risk of chronic congestive heart failure.12 The vasodilatory effect of increasing levels of uric acid in the blood, causing gout in these two classes of diuretics is probably related to the loss of predisposed patients. The serum level of uric acid is elevated sodium and water from the vessel wall.13 At least some of this in as many as one third of untreated hypertensive patients. vasodilatory action is mediated through the release of With long term high dose diuretic therapy, hyperuricaemia prostacyclin and endothelin derived relaxing factor.15 The appears in another third of patients, probably because of mechanism responsible for the lowered peripheral resistance increased proximal tubular reabsorption accompanying may also involve potassium channel activation.16 17 volume contraction.22 Diuretic induced hyperuricaemia may precipitate acute gout, most frequently in those who are obese and consume large amounts of alcohol or who have a BIOCHEMICAL AND METABOLIC EFFECTS OF family history of this condition.22 DIURETICS Serum cholesterol levels often rise after diuretic therapy, Loop and thiazide diuretics may lead to deficiency of the but after one year no adverse effects were noted in those who main electrolytes, particularly potassium and sodium. responded to smaller doses.23 High doses of diuretics may Hypokalaemia and hyponatraemia to a lesser degree may impair glucose tolerance and precipitate diabetes mellitus, secondarily cause other metabolic effects. The degree of probably because they increase insulin resistance and there- potassium wastage and hypokalaemia is directly related to fore induce hyperinsulinaemia.24 The mechanism by which the dose of diuretic.18 Hypokalaemia may precipitate poten- diuretics increase insulin resistance is uncertain. However, it tially hazardous ventricular ectopic activity and increase the is probably related to their lowering of potassium levels1 risk of primary cardiac arrest, even in patients who are not on (thiazides more so than loop diuretics owing to their longer concomitant digitalis therapy and do not have myocardial action). irritability.19 Even mild hypokalaemia caused by these There is usually a slight increase in serum calcium levels