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REVIEW
Diuretics are used extensively in hospitals and in community medical practice for the management of cardiovascular diseases. They are used frequently as the first line treatment for mild to moderate hypertension and are an integral part of the management of symptomatic heart failure. Although diuretics have been used for several decades, there is still some ambiguity and confusion regarding the optimal way of using these common drugs. In this paper, the classes and action of diuretics are reviewed, and the various indications, optimal doses, and recommendations on the effective use of these agents are discussed.
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See end of article for authors affiliations ....................... Correspondence to: Dr Saeed Ullah Shah, 17 South Street, Harborne, Birmingham B17 0DB, UK; saeedshah@miranshah. freeserve.co.uk Submitted 7 June 2003 Accepted 29 August 2003 .......................
stimulate the exchange with potassium, particularly in the presence of an activated renin angiotensinaldosterone system.4 Thiazides may also increase the active excretion of potassium in the distal renal tubule. Thiazides are rapidly absorbed from the gastrointestinal tract, producing diuresis within 12 hours, which typically lasts for 612 hours. Their potency is midway between loop and potassium sparing agents, which act mainly on the distal tubules. Metolazone, which is a thiazide-like diuretic, seems to affect the proximal tubule in addition to its more distal effect.5 It is therefore effective even in renal failure, whereas other thiazide diuretics, owing to their distal and hence less 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 retain magnesium. Amiloride and triamterene inhibit the sodium proton exchanger, which is concerned with sodium reabsorption in the distal tubules and collecting tubules.7 Thereby potassium loss is indirectly decreased. They are relatively weak diuretics, which are often used in combination with thiazides and loop diuretics.8 An advantage of such combination is that the loss of sodium is achieved without a major loss of potassium and magnesium. Both amiloride and triamterene affect cardiac repolarisation, possibly by inhibiting delayed rectifier K+ currents (IK), and may exaggerate the prolonged repolarisation observed with SinghVaughan Williams class IA antiarrhythmics.8 9 Spironolactone and its active metabolites canrenone and potassium canrenoate competitively inhibit the binding of aldosterone to mineralocorticoid or type I receptors in many tissues, including epithelial cells of the distal convoluted tubule and collecting duct.10 Spironolactone is more powerful then other potassium sparing diuretics. One daily dose is usually adequate for diuresis. Recently, spironolactone has been shown to decrease mortality markedly in subjects with advanced heart failure.11 Diuretics have also been shown to exert some extrarenal effects. Both loop and thiazide diuretics can induce vasodilatation when used acutely.1214 Frusemide has been shown to relax precontracted pulmonary venous rings by directly affecting smooth muscle cells.14 Interestingly, this effect is apparent only in pulmonary venous and not in arterial vascular tissue and was apparent in these in vitro studies only at drug concentrations achievable transiently after bolus infusions. This vasodilatory
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Hypokalaemia, hyponatraemia, hypomagnesaemia, hypercalcaemia, hyperuricaemia, pancreatitis, rashes, increase in LDL and triglycerides (may be transient), impotence
Potassium sparing diuretics Spironolactone Aldosterone antagonists, collecting duct Triamterene Inhibition of apical membrane Na conductance
Antiandrogenic
Hyperkalaemia
effect is sustainable with long term use, although it is influenced by other factors, such as dosage, route, and concomitant use of other medications. All these rapid haemodynamic changes are attenuated in patients with chronic congestive heart failure.12 The vasodilatory effect of these two classes of diuretics is probably related to the loss of sodium and water from the vessel wall.13 At least some of this vasodilatory action is mediated through the release of prostacyclin and endothelin derived relaxing factor.15 The mechanism responsible for the lowered peripheral resistance may also involve potassium channel activation.16 17
corrected if necessary. Magnesium deficiency may also be responsible for some of the arrhythmias ascribed to hypokalaemia.21 Most diuretics decrease urate excretion with the risk of increasing levels of uric acid in the blood, causing gout in predisposed patients. The serum level of uric acid is elevated in as many as one third of untreated hypertensive patients. With long term high dose diuretic therapy, hyperuricaemia appears in another third of patients, probably because of increased proximal tubular reabsorption accompanying 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 family history of this condition.22 Serum cholesterol levels often rise after diuretic therapy, but after one year no adverse effects were noted in those who responded to smaller doses.23 High doses of diuretics may impair glucose tolerance and precipitate diabetes mellitus, probably because they increase insulin resistance and therefore induce hyperinsulinaemia.24 The mechanism by which diuretics increase insulin resistance is uncertain. However, it is probably related to their lowering of potassium levels1 (thiazides more so than loop diuretics owing to their longer action). There is usually a slight increase in serum calcium levels (less than 0.125 mmol/l (0.5 mg/dl)) with thiazide use, at least in part because increased calcium reabsorption accompanies the increased sodium reabsorption in the proximal tubule that is induced by contraction of the extracellular fluid volume.25 The rise is of little concern except in patients with previously unrecognised hyperparathyroidism, who may
Table 2 Relative potency of various diuretics, and effects on loss of fluid and electrolytes (in mmol/l) (modified from Drugs for the heart1)
Volume (ml/min) Control Thiazide Frusemide Triamterene Amiloride 1 3 8 3 2 Na 50 150 140 130 130 K 15 25 10 5 5 Cl 60 150 155 120 110 HCO 1 25 1 15 15 Ca Variable 0 + 0 0
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experience a much more marked rise. Conversely, the diuretic induced positive calcium balance is associated with a reduction in the incidence of osteoporosis in the elderly.26 An increase in the incidence of impotence has been noted in men taking thiazide diuretics.27 A significant increase in renal cell carcinoma among diuretic users was found in a search of nine case-control and three cohort studies.28 29 Although the risk ratio was 1.55, the absolute incidence of renal cell carcinoma was only 0.065%, which was not statistically significant. The overall positive effects of diuretic use therefore far outweigh their hazards.
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Use the smallest possible doses and tailor individual therapy. Hypokalaemia can be avoided by using concomitant angiotensin converting enzyme inhibitor, angiotensin receptor blocker, b-blocker, or potassium sparing agents. Combination of aminoglycosides and loop diuretics should be avoided because of the risk of ototoxicity. A low sodium diet (less than 2.4 g sodium) and fluid restriction (less than 1.5 l fluid) can reduce the need to use higher doses in advanced heart failure. Non-steroidal anti-inflammatory drugs blunt the effects of diuretics and angiotensin converting enzyme inhibitors, and should be avoided. Xanthine oxidase inhibitors should be used in patients with gout. Elderly patients should be commenced on a smaller dose and the dose slowly titrated to avoid many complications. Mild diuretics, such as slow release indapamide, are useful as antihypertensive agents because of their excellent safety profile. In patients with advanced heart failure and low blood pressure, use a diuretic infusion rather than bolus doses. In patients with hypertension, use a moderately long acting (1218 hour) diuretic, such as hydrocholorothiazide, because longer acting drugs, such as chlorthalidone, may increase potassium loss. Increase dietary potassium intake and restrict the concomitant use of laxatives.
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Table 3 Commonly used diuretics, recommended doses, and their durations of action
Diuretic Bendrofluazide Hydrochlorthiazide Indapamide Metolazone Frusemide Bumetanide Torasemide Spironolactone Amiloride Triamterene Dosage in hypertension 1.252.5 mg once daily 12.525 mg once daily 1.252.5 mg once daily 2.55.0 mg once daily 1040 mg twice daily Not licensed for the treatment of hypertension 510 mg once daily 25100 mg once daily 2.510 mg once daily 50150 mg once daily or twice daily Dosage in heart failure 510 mg once daily 25200 mg once daily 2.55 mg once daily 2.520 mg once daily 20320 mg once daily or twice daily, up to 2000 mg orally or intravenously 0.55 mg once daily or twice daily 1020 mg once daily, up to 200 mg daily 12.550 mg once daily 2.520 mg once daily 25200 mg once daily Duration of action (hours) 612 612 1636 1825 45 45 68 72120 624 812
patients with heart failure. All non-steroidal anti-inflammatory drugs, including aspirin, can diminish diuretic efficacy by decreasing the renal synthesis of these vasodilator substances.38 The concomitant use of vasodilators is a common cause of diuretic resistance. In addition, all vasodilators commonly used as afterload reducing agents in patients with heart failure dilate a number of central and peripheral vascular beds. Therefore, renal blood flow may be reduced despite an increase in cardiac output, thus causing a decline in the effectiveness of the diuretic action. Vasodilator therapy may also lower renal perfusion pressure below that necessary to maintain normal autoregulation and glomerular filtration in patients with renal artery stenosis caused by atherosclerotic disease. Diuretic resistance should be distinguished from diuretic adaptation or the braking phenomenon observed even in normal subjects given multiple doses of a short acting loop diuretic. This effect is now known to be due largely to compensatory hypertrophy of the tubular epithelium distal to the site of action of the Na+K+2Cl2 cotransporter inhibitor, which increases the solute resorptive capacity of the kidney, as well as other adaptive mechanisms.39 Chronic and perhaps even acute treatment with loop diuretics causes rapid (roughly 60 minutes) upregulation of the thiazide sensitive
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Use angiotensin converting enzyme inhibitors rather than diuretics as the first line therapy in asymptomatic patients with left ventricular systolic dysfunction. Thiazide diuretics are generally not useful in patients with renal failure. Metolazone (a thiazide like diuretic) is effective in smaller doses, and larger doses should be avoided if possible. It can be used in patients with renal failure. Use larger doses (twice the normal dose) of loop diuretics in patients with renal failure. In resistant cases, use a combination of loop and thiazide diuretics with or without potassium sparing agents. Consider using either bolus or continuous intravenous loop diuretics in resistant cases. Potassium sparing diuretics should be used instead of potassium supplements in patients with hypokalaemia caused by diuresis. Use spironolactone in smaller doses mainly for its antialdosterone effect.
Na+Cl2 cotransporter in the distal tubule.39 In addition, many patients with heart failure also have some degree of renal impairment, which shifts the diuretic concentration effect relationship downward and to the right. Diuretic resistance may be prevented by the use of renninangiotensin system inhibitors. These agents can uniquely augment the effectiveness of diuretics by mechanisms that are independent of their ability to reduce systemic vascular resistance.40 Diuretic resistance can also be managed by increasing the frequency of loop diuretic dosing or by switching to a continuous intravenous infusion.41 Concomitant administration of a more distally acting diureticfor example, a thiazide or thiazide like diuretic, such as intravenous chlorothiazide, oral bendrofluazide, or oral metolazonewill usually also result in substantial natriuresis.42 This combination should, however, be used cautiously and with careful monitoring of renal function and serum levels of potassium and sodium, especially in outpatients. Potassium sparing diuretics may also be able to increase the effectiveness of more proximally acting diuretics. These agents reduce the oral potassium requirement and maintain serum potassium levels well inside the normal range. Hence, most subjects receiving large doses of loop diuretics or loop diuretics plus thiazides benefit from a potassium sparing diuretic. If tolerated, spironolactone should be the potassium sparing diuretic used because of its mortality reducing effects.11 Observational studies suggest that potassium sparing diuretics reduce the incidence of serious ventricular arrhythmias in patients with heart failure (particularly those who are on digoxin) and hypertension (particularly in patients with left ventricular hypertrophy).4345
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Authors affiliations
S U Shah, University of Birmingham, Birmingham, UK S Anjum, Glan Clwyd Hospital, Rhyl, Denbighshire, UK W A Littler, University Hospital Birmingham, Birmingham, UK
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doi: 10.1136/pgmj.2003.010835
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