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201

REVIEW

Use of diuretics in cardiovascular diseases: (1) heart failure

S U Shah, S Anjum, W A Littler
............................................................................................................................... Postgrad Med J 2004;80:201205. doi: 10.1136/pgmj.2003.010835

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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CLASSIFICATION AND MECHANISM OF ACTION

The commonly used classes of diuretics are loop, thiazide, and potassium sparing diuretics, and carbonic anhydrase inhibitors. Carbonic anhydrase inhibitors are rarely used in the management of hypertension or heart failure and hence will not be discussed in detail. This classification of diuretics is based on their site of action in the kidneys. This secondarily determines their potency and various biochemical effects (see table 1). Loop or high ceiling diuretics, including frusemide, bumetanide, and torseamide, reversibly inhibit the Na+K+2Cl2 symporter (cotransporter) situated at the luminal thick ascending limb of the loop of Henle. A second functional class of these drugs, typified by ethacrynic acid, is also effective only from the tubule lumen but exhibits a slower onset of action, and delayed and only partial reversibility. Loop diuretics therefore act by inhibiting the reabsorption of chloride, sodium, potassium, and hydrogen ions in the ascending loop of Henle.1 In comparison with thiazide diuretics, loop diuretics induce relatively more urine formation and relatively less loss of sodium and potassium (see table 2).2 The plasma half life of a typical loop diuretic, frusemide, is 1.5 hours; the duration of action is 46 hours. Diuresis starts within 1020 minutes of an intravenous dose and peaks 11.5 hours after an oral dose.3 The group often collectively referred to as thiazide diuretics are not all technically benzothiadiazine derivatives. Thiazides inhibit sodium and chloride reabsorption more distally. This cotransporter is insensitive to loop diuretics. More sodium reaches the distal tubules to

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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202 Shah, Anjum, Littler

Table 1 Classification and mechanism of action of diuretics

Diuretic Loop diuretics Frusemide Bumetanide Torasemide Principal site and mechanism of action Effects on urinary electrolytes Extrarenal effects Acute Increases venous capacitance Increases systemic vascular resistance Chronic; decreases cardiac preload Increases venous capacitance and glucose Increases LDL and triglycerides May be dose related Common or important side effects Hypokalaemia, hyponatraemia, hypomagnesaemia, hypocalcaemia, hyperuricaemia, hyperglycaemia, dehydration, blood dyscrasias, rashes, lipid abnormalities, ototoxicity

Thick ascending loop of Increases Na Henle, inhibition of and Cl NaK2KCl cotransporter

Thiazide related sulphonamide diuretics Bendrofluazide Hydrochlorothiazide Chlorthalidone Metolazone Indapamide

Distal tubule Inhibition of NaCl cotransport

Increases Na and Cl Increases K

Hypokalaemia, hyponatraemia, hypomagnesaemia, hypercalcaemia, hyperuricaemia, pancreatitis, rashes, increase in LDL and triglycerides (may be transient), impotence

Additional proximal tubular action Vasodilator

Additional effects include reducing Cl Milder

Potassium sparing diuretics Spironolactone Aldosterone antagonists, collecting duct Triamterene Inhibition of apical membrane Na conductance

Reduces K; increases Na and Cl Increases HCO

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

BIOCHEMICAL AND METABOLIC EFFECTS OF DIURETICS

Loop and thiazide diuretics may lead to deficiency of the main electrolytes, particularly potassium and sodium. Hypokalaemia and hyponatraemia to a lesser degree may secondarily cause other metabolic effects. The degree of potassium wastage and hypokalaemia is directly related to the dose of diuretic.18 Hypokalaemia may precipitate potentially hazardous ventricular ectopic activity and increase the risk of primary cardiac arrest, even in patients who are not on concomitant digitalis therapy and do not have myocardial irritability.19 Even mild hypokalaemia caused by these diuretics may result in leg cramps, polyuria, and muscle weakness.20 In some patients, concomitant diuretic induced magnesium deficiency prevents the restoration of intracellular potassium deficits.21 Hence, it is important that magnesium levels in patients with heart failure who are treated with diuretics are regularly checked and magnesium

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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Use of diuretics in cardiovascular diseases 203

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.

HOW TO USE DIURETICS EFFECTIVELY IN HEART FAILURE (SEE TABLE 3)

Diuretics are the mainstay of therapy for symptomatic chronic heart failure but are now rarely used as monotherapy. Together with angiotensin converting enzyme inhibitors, b-blockers and digoxin, they improve patients symptoms and in most cases also improve their effort tolerance.32 In asymptomatic patients (New York Heart Association class I; NYHA I) with echocardiographic evidence of left ventricular systolic dysfunction, an angiotensin converting enzyme inhibitor rather than a diuretic should be used as a first line agent.32 However, in more symptomatic cases (NYHA IIIV) diuretics are usually needed in addition to other agents. Thiazide diuretics can be used in milder cases, particularly if there is no renal impairment. However, in more symptomatic patients (NYHA IIIIV) and in patients with renal impairment, loop diuretics are more useful owing to their relatively strong diuretic action and fewer side effects (see table 2). Thiazide diuretics are not effective in patients with renal failure (creatinine levels of more than 180 mmol/ l).5 In such patients, the dose of loop diuretics should be doubled for better diuresis. However, metolazone, which is a thiazide like diuretic, works efficiently in patients with renal failure owing to its additional action on the proximal tubule.33 In patients with substantial oedema, a combination of diuretics is much more useful than a higher dose of a single agent. Hence a combination of a high dose loop diuretic and a thiazide diuretic with or without a potassium sparing agent is much more potent than a high dose of either of these.34 This is due to the sequential blocking effect of these agents, thereby blocking all potential reabsorption sites for the glomerular filtrate. Metolazone is a very powerful agent and together with loop diuretics can cause a substantial loss of electrolytes and fluid. It is therefore advisable that metolazone therapy should be initiated in hospital, where daily renal profile and other parameters can be checked and the patient closely monitored. A smaller dose of 2.5 mg daily works in most patients and has fewer biochemical and haemodynamic effects. Once stable, patients on metolazone can be monitored in the community, with renal profile being measured perhaps once every fortnight and later less frequently. In patients with significant or generalised oedema (anasarca) there is usually a degree of intestinal oedema affecting the absorption of oral diuretics. In these cases, the loop diuretic torseamide has been shown to be better absorbed and hence more effective than frusemide.35

USE IN HEART FAILURE

Fluid retention is a consistent finding in almost all acute and most chronic heart failure patients. It manifests as pulmonary and peripheral oedema. Fluid retention impairs the transportation of oxygen, nutrients, and waste products, ultimately leading to organ failure.30 Diuretics have been used to improve pulmonary and peripheral symptoms and signs of congestion.31 There is, however, no specific long term mortality data available for the use of diuretics in heart failure. Diuretics can result in neuroendocrine activation, with potential long term consequences. However, no significant negative effects have so far been found. In patients with acute left heart failure, pulmonary oedema is the main abnormality and is usually treated with intravenous loop diuretics. The improvement in symptoms and the accompanying reduction in filling pressures occur even before diuresis is initiated and have been attributed to vasodilatation.15 However, the exact mechanism of these acute effects of diuretics is still not fully understood.

Box 1: How to minimise side effects

N N N N N N N N N N

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.

THE PHENOMENON OF DIURETIC RESISTANCE AND ITS MANAGEMENT

The effectiveness of potent loop diuretics can decrease with worsening heart failure, thereby causing diuretic resistence.36 Diuretics induce the loss of electrolytes and fluid, thereby stimulating several compensatory haemostatic mechanisms, which result in increased renal sodium retention by all nephron segments. If dietary salt intake is sufficiently high, a daily net negative sodium balance may not be achieved even with several daily intravenous doses of a loop diuretic.37 Hence, salt intake must be restricted in patients with heart failure to obtain a negative sodium balance. This also implies that short acting diuretics, particularly loop diuretics, must be administered at least twice a day to obtain consistent daily salt and water loss unless dietary sodium intake is severely restricted.36 Certain classes of drugs, particularly non-steroidal antiinflammatory drugs, can reduce renal function by various mechanisms. Renal prostaglandin production is required to compensate for circulating vasoconstrictor substances seen in

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204 Shah, Anjum, Littler

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

Box 2: Useful points

N N N N N N N N

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
.....................

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

REFERENCES
1 Opie LH, Gersh BJ. Diuretics. In: Opie LH, Gersh BJ, eds. Drugs for the heart. 5th Ed. Philadelphia: WB Saunders, 2001:84106. 2 Reyes AJ, Taylor SH. Diuretics in cardiovascular therapy: the new clinicopharmacological bases that matter. Cardiovasc Drugs Ther 1999;13:37198. 3 Dikshit K, Vyden JK, Forrester JS, et al. Renal and extrarenal hemodynamic effects of furosemide in congestive heart failure after acute myocardial infarction. N Engl J Med 1973;288:108790. 4 Gamba G, Saltzberg SN, Lombardi M, et al. Primary structure and functional expression of a cDNA encoding the thiazide-sensitive, electroneutral sodiumchloride cotransporter. Proc Natl Acad Sci USA 1993;90:274953. 5 Brater DC. Diuretic therapy. N Engl J Med 1998;339:38795. 6 Brater DC. Pharmacology of diuretics. Am J Med Sci 2000;319:3850. 7 Canessa C, Schild L, Buell G, et al. Amiloride-sensitive epithelial Na+ channel is made of three homologous subunits. Nature 1994;367:4637.

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Use of diuretics in cardiovascular diseases 205

8 Daleau P, Turgeon J. Triamterene inhibits the delayed rectifier potassium current (KK) in guinea pig ventricular myocytes. Circ Res 1994;74:111420. 9 Wang L, Sheldon RS, Mitchell B, et al. Amiloridequinidine interaction: adverse outcomes. Clin Pharmacol Ther 1994;56:65967. 10 Marver D, Stewart J, Funder JW, et al. Renal aldosterone receptors: studies with (3H)aldosterone and the anti-mineralocorticoid (3H)spirolactone (SC26304). Proc Natl Acad Sci USA 1974;71:14315. 11 Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999;341:70917, 974. 12 Silke B. Hemodynamic impact of diuretic therapy in chronic heart failure. Cardiology 1994;84:11523. 13 Raftery EB. Hemodynamic effects of diuretics in heart failure. Br Heart J 1994;72(suppl 2):447S. 14 Greenberg S, McGowan C, Xie J, et al. Selective pulmonary and venous smooth muscle relaxation by furosemide: a comparison with morphine. J Pharmacol Exp Ther 1994;270:107785. 15 Wiemer G, Fink E, Linz W, et al. Furosemide enhances the release of endothelial kinins, nitric oxide and prostacyclin. J Pharmacol Exp Ther 1994;271:161115. 16 Pickkers P, Hughes AD, Frans G, et al. Thiazide-induced vasodilation in humans is mediated by potassium channel activation. Hypertension 1998;32:10716. 17 Kaplan NM. Diuretics as a basis of antihypertensive therapy. An overview. Drugs 2000;59(suppl 2):215. 18 Weir MR, Flack JM, Applegate WB. Tolerability, safety, and quality of life and hypertensive therapy: the case for low-dose diuretics. Am J Med 1996;101:8392S. 19 Siscovick DS, Raghunathan TE, Psaty BM, et al. Diuretic therapy for hypertension and the risk of primary cardiac arrest. N Engl J Med 1994;330:18527. 20 Kaplan NM, Carnegie A, Raskin P, et al. Potassium supplementation in hypertensive patients with diuretic-induced hypokalemia. N Engl J Med 1985;312:7469. 21 Dorup I, Skajaa K, Thybo NK. Oral magnesium supplementation restores the concentration of magnesium, potassium, and sodiumpotassium pumps in skeletal muscle of patients receiving diuretic treatment. J Intern Med 1993;233:11723. 22 Waller PC, Ramsay LE. Predicting acute gout in diuretic-treated hypertensive patients. J Hum Hypertens 1989;3:45761. 23 Lakshman MR, Reda DJ, Materson BJ, et al. Diuretics and beta blockers do not have adverse effects at 1 year on plasma lipid and lipoprotein profiles in men with hypertension. Arch Intern Med 1999;159:5518. 24 Hunter SJ, Harper R, Ennis CN, et al. Effects of combination therapy with an angiotensin converting enzyme inhibitor and thiazide diuretic on insulin action in essential hypertension. J Hypertens 1998;16:1039. 25 Gesek FA, Friedman PA. Mechanism of calcium transport stimulated by chlorothiazide in mouse distal convoluted tubule cells. J Clin Invest 1992;90:42938.

26 Morton DJ, Barrett-Connor EL, Edelstein SL. Thiazides and bone mineral density in elderly men and women. Am J Epidemiol 1994;139:110715. 27 Grimm RH Jr, Grandits GA, Prineas RJ, et al. Long-term effects on sexual function of five antihypertensive drugs and nutritional hygienic treatment in hypertensive men and women. Hypertension 1997;29:814. 28 Lee I-M, Hennekens CH. Diuretics and renal cell carcinoma. Am J Cardiol 1999;83:1094. 29 Grossman E, Messerli FH, Goldbourt U. Does diuretic therapy increase the risk of renal cell carcinoma? Am J Cardiol 1999;83:10903. 30 Winawer J, Abassi Z, Green J, et al. Control of extracellular fluid volume and the pathophysiology of edema formation. In: Brenner BM, Rector FC, eds. Brenner and Rectors the kidney. 6th Ed. Philadelphia: WB Saunders, 2000:22065. 31 Schrier RW, Martin PY. Recent advances in the understanding of water metabolism in heart failure. Adv Exp Med Biol 1998;449:41526. 32 Packer M, Cohn JN. Consensus recommendations for the management of chronic heart failure. Am J Cardiol 1999;83(2A):138A. 33 Kiyingi A, Field MJ, Pawsey CC, et al. Metolazone in treatment of severe refractory congestive cardiac failure. Lancet 1990;335:2931. 34 Dormans TPJ, Gerlag PGG. Combination of high-dose furosemide and hydrochlorothiazide in the treatment of refractory congestive heart failure. Eur Heart J 1996;17:186774. 35 Vargo D, Kramer WG, Black RK, et al. The pharmacodynamics of torsemide in patients with congestive heart failure. Clin Pharmacol Ther 1994;56:4854. 36 Brater DC. Diuretic resistance: mechanisms and therapeutic strategies. Cardiology 1994;84(suppl 2):5767. 37 Gradual NA, Galloe AM, Garred P. Effects of sodium restriction on blood pressure, renin, aldosterone, catecholamines, cholesterols, and triglyceride. JAMA 1998;279:138391. 38 Dzau VJ, Packer M, Lilly LS, et al. Prostaglandins in severe congestive heart failure. Relation to activation of the renin-angiotensin system and hyponatremia. N Engl J Med 1984;310:34752. 39 Morsing P, Velazquez H, Wright FS, et al. Adaptation of distal convoluted tubule of rats. II. Effects of chronic thiazide infusion. Am J Physiol 1991;261:F13743. 40 Good JM, Brady AJB, Noormohamed FH, et al. Effect of intense angiotensin II suppression on the diuretic response to furosemide during chronic ACE inhibition. Circulation 1994;90:2204. 41 Lahav M, Regev A, Raanani P, et al. Intermittent administration of furosemide vs continuous infusion preceded by a loading dose for congestive heart failure. Chest 1992;102:72531. 42 Ellison DH. The physiologic basis of diuretic synergism: its role in treating diuretic resistance. Ann Intern Med 1991;114:88694. 43 Wingo CS, Cain BD. The renal H-K-ATPase: physiological significance and role in potassium homeostasis. Annu Rev Physiol 1993;55:32347. 44 Weber KT, Villarreal D. Aldosterone and antialdosterone therapy in congestive heart failure (abstract). Am J Cardiol 1993;71:311A. 45 Bigger JT Jr. Diuretic therapy, hypertension, and cardiac arrest. N Engl J Med 1994;330:1899900.

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Use of diuretics in cardiovascular diseases: (1) heart failure

S U Shah, S Anjum and W A Littler Postgrad Med J 2004 80: 201-205

doi: 10.1136/pgmj.2003.010835

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