Use of Diuretics in Cardiovascular Diseases: (1) Heart Failure S U Shah, S Anjum, W a Littler

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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, particularly 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

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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 diuretics may result in leg cramps, polyuria, and muscle (less than 0.125 mmol/l (0.5 mg/dl)) with thiazide use, at weakness.20 In some patients, concomitant diuretic induced least in part because increased calcium reabsorption accom- magnesium deficiency prevents the restoration of intracel- panies the increased sodium reabsorption in the proximal lular potassium deficits.21 Hence, it is important that tubule that is induced by contraction of the extracellular fluid magnesium levels in patients with heart failure who are volume.25 The rise is of little concern except in patients with treated with diuretics are regularly checked and magnesium 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) Na K Cl HCO Ca

Control 1 50 15 60 1 Variable Thiazide 3 150 25 150 25 0 Frusemide 8 140 10 155 1 + Triamterene 3 130 5 120 15 0 Amiloride 2 130 5 110 15 0

www.postgradmedj.com Use of diuretics in cardiovascular diseases 203 experience a much more marked rise. Conversely, the diuretic HOW TO USE DIURETICS EFFECTIVELY IN HEART induced positive calcium balance is associated with a FAILURE (SEE TABLE 3) reduction in the incidence of osteoporosis in the elderly.26 Diuretics are the mainstay of therapy for symptomatic An increase in the incidence of impotence has been noted chronic heart failure but are now rarely used as mono- in men taking thiazide diuretics.27 A significant increase in therapy. Together with angiotensin converting enzyme renal cell carcinoma among diuretic users was found in a inhibitors, b-blockers and digoxin, they improve patients’ search of nine case-control and three cohort studies.28 29 symptoms and in most cases also improve their effort Although the risk ratio was 1.55, the absolute incidence of tolerance.32 In asymptomatic patients (New York Heart renal cell carcinoma was only 0.065%, which was not Association class I; NYHA I) with echocardiographic evidence statistically significant. The overall positive effects of diuretic of left ventricular systolic dysfunction, an angiotensin use therefore far outweigh their hazards. converting enzyme inhibitor rather than a diuretic should be used as a first line agent.32 However, in more symptomatic USE IN HEART FAILURE cases (NYHA II–IV) diuretics are usually needed in addition Fluid retention is a consistent finding in almost all acute and to other agents. Thiazide diuretics can be used in milder most chronic heart failure patients. It manifests as pulmon- cases, particularly if there is no renal impairment. However, ary and peripheral oedema. Fluid retention impairs the in more symptomatic patients (NYHA III–IV) and in patients transportation of oxygen, nutrients, and waste products, with renal impairment, loop diuretics are more useful owing ultimately leading to organ failure.30 Diuretics have been used to their relatively strong diuretic action and fewer side effects to improve pulmonary and peripheral symptoms and signs of (see table 2). Thiazide diuretics are not effective in patients congestion.31 There is, however, no specific long term with renal failure (creatinine levels of more than 180 mmol/ mortality data available for the use of diuretics in heart l).5 In such patients, the dose of loop diuretics should be failure. Diuretics can result in neuroendocrine activation, doubled for better diuresis. However, metolazone, which is a with potential long term consequences. However, no sig- thiazide like diuretic, works efficiently in patients with renal nificant negative effects have so far been found. failure owing to its additional action on the proximal In patients with acute left heart failure, pulmonary oedema tubule.33 is the main abnormality and is usually treated with In patients with substantial oedema, a combination of intravenous loop diuretics. The improvement in symptoms diuretics is much more useful than a higher dose of a single and the accompanying reduction in filling pressures occur agent. Hence a combination of a high dose loop diuretic and a even before diuresis is initiated and have been attributed to thiazide diuretic with or without a potassium sparing agent is vasodilatation.15 However, the exact mechanism of these much more potent than a high dose of either of these.34 This acute effects of diuretics is still not fully understood. 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 Box 1: How to minimise side effects 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 N Use the smallest possible doses and tailor individual daily renal profile and other parameters can be checked and therapy. the patient closely monitored. A smaller dose of 2.5 mg daily N Hypokalaemia can be avoided by using concomitant works in most patients and has fewer biochemical and angiotensin converting enzyme inhibitor, angiotensin haemodynamic effects. Once stable, patients on metolazone receptor blocker, b-blocker, or potassium sparing can be monitored in the community, with renal profile being agents. measured perhaps once every fortnight and later less N Combination of aminoglycosides and loop diuretics frequently. should be avoided because of the risk of ototoxicity. In patients with significant or generalised oedema (ana- N A low sodium diet (less than 2.4 g sodium) and fluid sarca) there is usually a degree of intestinal oedema affecting restriction (less than 1.5 l fluid) can reduce the need to the absorption of oral diuretics. In these cases, the loop use higher doses in advanced heart failure. diuretic torseamide has been shown to be better absorbed and hence more effective than frusemide.35 N Non-steroidal anti-inflammatory drugs blunt the effects of diuretics and angiotensin converting enzyme inhibitors, and should be avoided. THE PHENOMENON OF DIURETIC RESISTANCE AND N Xanthine oxidase inhibitors should be used in patients ITS MANAGEMENT with gout. The effectiveness of potent loop diuretics can decrease with N worsening heart failure, thereby causing ‘‘diuretic resis- Elderly patients should be commenced on a smaller tence’’.36 Diuretics induce the loss of electrolytes and fluid, dose and the dose slowly titrated to avoid many thereby stimulating several compensatory haemostatic complications. Mild diuretics, such as slow release mechanisms, which result in increased renal sodium reten- indapamide, are useful as antihypertensive agents tion by all nephron segments. If dietary salt intake is because of their excellent safety profile. sufficiently high, a daily net negative sodium balance may N In patients with advanced heart failure and low blood not be achieved even with several daily intravenous doses of a pressure, use a diuretic infusion rather than bolus loop diuretic.37 Hence, salt intake must be restricted in doses. patients with heart failure to obtain a negative sodium N In patients with hypertension, use a moderately long balance. This also implies that short acting diuretics, acting (12–18 hour) diuretic, such as hydrocholor- particularly loop diuretics, must be administered at least twice a day to obtain consistent daily salt and water loss othiazide, because longer acting drugs, such as 36 chlorthalidone, may increase potassium loss. unless dietary sodium intake is severely restricted. N Certain classes of drugs, particularly non-steroidal anti- Increase dietary potassium intake and restrict the inflammatory drugs, can reduce renal function by various concomitant use of laxatives. mechanisms. Renal prostaglandin production is required to compensate for circulating vasoconstrictor substances seen in

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Table 3 Commonly used diuretics, recommended doses, and their durations of action

Duration of action Diuretic Dosage in hypertension Dosage in heart failure (hours)

Bendrofluazide 1.25–2.5 mg once daily 5–10 mg once daily 6–12 Hydrochlorthiazide 12.5–25 mg once daily 25–200 mg once daily 6–12 Indapamide 1.25–2.5 mg once daily 2.5–5 mg once daily 16–36 Metolazone 2.5–5.0 mg once daily 2.5–20 mg once daily 18–25 Frusemide 10–40 mg twice daily 20–320 mg once daily or twice daily, up to 4–5 2000 mg orally or intravenously Bumetanide Not licensed for the treatment of 0.5–5 mg once daily or twice daily 4–5 hypertension Torasemide 5–10 mg once daily 10–20 mg once daily, up to 200 mg daily 6–8 Spironolactone 25–100 mg once daily 12.5–50 mg once daily 72–120 Amiloride 2.5–10 mg once daily 2.5–20 mg once daily 6–24 Triamterene 50–150 mg once daily or twice daily 25–200 mg once daily 8–12

patients with heart failure. All non-steroidal anti-inflamma- Na+–Cl2 cotransporter in the distal tubule.39 In addition, tory drugs, including aspirin, can diminish diuretic efficacy many patients with heart failure also have some degree of by decreasing the renal synthesis of these vasodilator renal impairment, which shifts the diuretic concentration– substances.38 The concomitant use of vasodilators is a effect relationship downward and to the right. common cause of diuretic resistance. In addition, all Diuretic resistance may be prevented by the use of rennin- vasodilators commonly used as afterload reducing agents in angiotensin system inhibitors. These agents can uniquely patients with heart failure dilate a number of central and augment the effectiveness of diuretics by mechanisms that peripheral vascular beds. Therefore, renal blood flow may be are independent of their ability to reduce systemic vascular reduced despite an increase in cardiac output, thus causing a resistance.40 Diuretic resistance can also be managed by decline in the effectiveness of the diuretic action. Vasodilator increasing the frequency of loop diuretic dosing or by therapy may also lower renal perfusion pressure below that switching to a continuous intravenous infusion.41 necessary to maintain normal autoregulation and glomerular Concomitant administration of a more distally acting filtration in patients with renal artery stenosis caused by diuretic—for example, a thiazide or thiazide like diuretic, atherosclerotic disease. such as intravenous chlorothiazide, oral bendrofluazide, or Diuretic resistance should be distinguished from ‘‘diuretic oral metolazone—will usually also result in substantial 42 adaptation’’ or the ‘‘braking’’ phenomenon observed even in natriuresis. This combination should, however, be used normal subjects given multiple doses of a short acting loop cautiously and with careful monitoring of renal function and diuretic. This effect is now known to be due largely to serum levels of potassium and sodium, especially in out- compensatory hypertrophy of the tubular epithelium distal to patients. the site of action of the Na+–K+–2Cl2 cotransporter inhibitor, Potassium sparing diuretics may also be able to increase which increases the solute resorptive capacity of the kidney, the effectiveness of more proximally acting diuretics. These as well as other adaptive mechanisms.39 Chronic and perhaps agents reduce the oral potassium requirement and maintain even acute treatment with loop diuretics causes rapid serum potassium levels well inside the normal range. Hence, (roughly 60 minutes) upregulation of the thiazide sensitive 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 Box 2: Useful points sparing diuretic used because of its mortality reducing effects.11 Observational studies suggest that potassium sparing diuretics reduce the incidence of serious ventricular N Use angiotensin converting enzyme inhibitors rather arrhythmias in patients with heart failure (particularly those than diuretics as the first line therapy in asymptomatic who are on digoxin) and hypertension (particularly in patients with left ventricular systolic dysfunction. patients with left ventricular hypertrophy).43–45 N Thiazide diuretics are generally not useful in patients with renal failure...... N Metolazone (a thiazide like diuretic) is effective in Authors’ affiliations smaller doses, and larger doses should be avoided if S U Shah, University of Birmingham, Birmingham, UK S Anjum, Glan Clwyd Hospital, Rhyl, Denbighshire, UK possible. It can be used in patients with renal failure. W A Littler, University Hospital Birmingham, Birmingham, UK N Use larger doses (twice the normal dose) of loop diuretics in patients with renal failure. N REFERENCES In resistant cases, use a combination of loop and 1 Opie LH, Gersh BJ. Diuretics. In: Opie LH, Gersh BJ, eds. Drugs for the heart. thiazide diuretics with or without potassium sparing 5th Ed. Philadelphia: WB Saunders, 2001:84–106. agents. 2 Reyes AJ, Taylor SH. Diuretics in cardiovascular therapy: the new clinicopharmacological bases that matter. Cardiovasc Drugs Ther N Consider using either bolus or continuous intravenous 1999;13:371–98. loop diuretics in resistant cases. 3 Dikshit K, Vyden JK, Forrester JS, et al. 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