Diuretic Agents

General

Diuretics are effective in relieving symptoms and edema in heart failure (HF) and hence, are currently considered to be the first-line treatment for HF. The four main classes of diuretics are: loop diuretics, thiazide diuretics, potassium sparing diuretics, and carbonic anhydrase inhibitors.

Loop diuretics are the most widely used diuretics for both outpatient therapy of chronic HF patients and in patients hospitalized for acute decompensated HF, followed by thiazide diuretics. Potassium sparing diuretics are used less often except for aldosterone antagonists, which are used for their mineralocorticoid receptor antagonistic actions rather than as a diuretic. Carbonic anhydrase inhibitors are rarely used in HF.

Acutely, diuretics act on the renal tubules to increase sodium urinary excretion leading to a reduction in central venous pressure, pulmonary congestion, and peripheral edema, with associated symptomatic relief and also improvement of patients’ general well-being. However, the physiologic effects of diuretics on the cardiovascular system in patients with HF are dependent on the volume status of the patients.

In the congested patient with HF, diuretics are extremely effective in relieving symptoms, reducing intracardiac pressures, and improving cardiac performance. However, in noncongested patients with HF, administration of diuretics may result in disparate vascular and hemodynamic effects.

In an elegant study by Ikram et al, they assessed the effects of acute furosemide in congested patients with left ventricular (LV) systolic dysfunction and subsequently assessed the effects of chronic furosemide in the same patients when they are noncongested. They reported that in congested patients, administration of furosemide resulted in diuresis and improved hemodynamics in the absence of major changes in the renin-angiotensin-aldosterone system (RAAS).

However, in noncongested patients, the diuretic and hemodynamic responses to furosemide declined, whereas the RAAS was activated.

Currently, with the exception of aldosterone antagonists, there are not any large randomized clinical trials of diuretic therapy with long-term follow-up in HF. Faris et al conducted a meta-analysis of diuretic treatment in chronic HF that included 14 trials (525 participants), 7 were placebo-controlled and 7 compared diuretics against other active therapies.

The authors analyzed the data for mortality and for worsening heart failure.

Mortality data, which was available in 3 of the placebo-controlled trials with 202 participants, demonstrated a lower mortality for participants treated with diuretics than for the placebo, odds ratio (OR) for death 0.24, 95% confidence interval (CI) 0.07 to 0.83; P = .02.

Hospitalization for worsening heart failure was reduced in those taking diuretics in two trials (169 participants), OR 0.07 (95% CI 0.01 to 0.52; P = .01).

The authors concluded that the available data from several small trials show that in patients with chronic HF, conventional diuretics appear to reduce the risk of death and worsening heart failure compared to a placebo. Compared to active control, diuretics appear to improve exercise capacity.

Differences between drugs within the class

Loop diuretics

Furosemide, torsemide, and bumetanide are the most commonly used loop diuretics in the management of HF. The rate of absorption and metabolism among loop diuretics are different.

Torsemide and bumetanide have a greater bioavailability (80% to 100%) and a more consistent rate of absorption in patients with heart failure than furosemide. Furosemide has a wider variability in the bioavailability in patients with HF, between 10% to 100%, suggesting altered absorption.

Furthermore, torsemide has a longer half-life in patients with HF, approximately 6 hours as compared to furosemide or bumetanide, which have a half-life of approximately 2 hours.

Recent studies have suggested that torsemide has antialdosterone actions and may have long-term clinical benefits over furosemide.

• Lopez et al conducted a small open-label trial, randomizing 26 patients with an ejection fraction of <50% or diastolic dysfunction with NYHA class II-IV heart failure symptoms to receive either torsemide 10 to 20 mg/day or furosemide 20 to 40 mg/day. There were significant decreases in serum markers for cardiac fibrosis and collagen type I synthesis in the torsemide group.

• Murray et al reported in an open-label, randomized trial of 234 patients with chronic HF, that patients treated with torsemide had a lower 1 year readmission rate for HF as compared to those treated with furosemide (17% versus 32%).

• Torsemide in Congestive Heart Failure (TORIC) Study investigated the safety, tolerability, and efficacy of torsemide in 1377 CHF patients compared to furosemide or other diuretics in an open-label, nonrandomized, postmarketing surveillance trial. Torsemide was safe and well tolerated in CHF patients.

  Although not designed as a mortality study, TORIC suggests a lower mortality among CHF patients treated with torsemide compared to furosemide/other diuretics. A functional improvement and a lower incidence of abnormal serum potassium levels were also observed in patients receiving torsemide as compared to those receiving furosemide/other diuretics.

Thiazide diuretics

The most commonly used thiazide diuretics for the management of HF include hydrochlorothiazide and metolazone, which is a “thiazide-like” diuretic. Metolazone is an oral quinazoline diuretic that is a sulfonamide derivative of a thiazide diuretic with a similar site of action.

The bioavailability of metolazone is approximately 65% and its half-life is approximately 14 hours, which is considerably longer than hydrochlorothiazide (2 to 3 hours). Metolazone is around 10 times as potent as hydrochlorothiazide and remains effective even when the glomerular filtration rate is reduced. Thus, it is a useful adjunct to loop diuretics in patients with diuretic resistance or renal insufficiency.

Potassium-sparing diuretics

The potassium-sparing diuretics, amiloride and triamterene, have weak diuretic effects and, like the thiazide diuretics, are frequently used in combination with loop diuretics to enhance diuresis and to prevent hypokalemia. Mechanistically, the aldosterone antagonists, spironolactone, and eplerenone are different from amiloride and triamterene in that they work as mineralocorticoid receptor blockers, whereas amiloride and triamterene block the epithelial sodium channel.

The onset of the diuretic actions of spironolactone is slow, with a peak response at ≥ 48 hour after the first dose, which is related to the time needed for the active metabolites of spironolactone to reach steady-state levels in plasma and/or tissue. Eplerenone, a highly selective mineralocorticoid receptor blocker with reduced affinity for androgen and progesterone receptors, has fewer endocrine side effects than with spironolactone.

Spironolactone can trigger a natriuretic response when it is given to patients with heart failure, particularly if it is given in combination with a loop and/or a thiazide-type diuretic. In contrast, eplerenone has a mild diuretic effect, which may relate to its having a short half-life and no active metabolites.

The aldosterone antagonists are used in HF mainly for their neurohumoral actions and improvement in clinical outcomes as demonstrated in the RALES (Randomized Aldactone Evaluation Study), EPHESUS (Eplerenone Post-AMI Heart Failure Efficacy and Survival Study), and The Eplerenone in Mild Patients Hospitalization And Survival Study in Heart Failure (EMPHASIS-HF) trials.

Carbonic anhydrase inhibitor

Acetazolamide is the only carbonic anhydrase inhibitor with significant diuretic actions and is readily absorbed and undergoes renal elimination by tubular secretion. Acetazolamide has been used in HF patients with edema and metabolic alkalosis, where the increased proximal tubular reabsorption of sodium results in decreased distal sodium delivery, hence rendering loop diuretics ineffective.

Administration

A. Administration Of Diuretics in Chronic Heart Failure

Patients with early Stage C or New York Heart Association (NYHA) Class 2 HF with mild edema can be treated initially with a thiazide diuretic, sodium restriction (<2 g/day), and fluid restriction (<2 L/day). Hydrochlorothiazide (HCTZ) should be started at a dose of 25 mg/day, with titration to 50 to 100 mg/day as necessary.

Patients with more severe HF and fluid overload will require a loop diuretic. The dose of loop diuretics should be adjusted to the minimum dose to maintain a euvolemic state. Recommended dose of the common loop diuretics are as follows:

• Furosemide: Initial: 20 to 40 mg/day orally. Maintenance: 40 to 220 mg/day orally. Maximum: 600 mg/day orally.

• Torsemide: Initial: 5 to 10 mg/day orally. Maintenance: 10 to 50 mg/day orally. Maximum: 200 mg/day orally.

• Bumetanide: Initial:0.5 to 1 mg/day orally. Maintenance: 1 to 5 mg/day orally. Maximum: 10 mg/day orally.

Diuretic resistance

The development of diuretic resistance, broadly defined as the progressive decline in renal diuretic response to loop diuretics, is common in patients with HF. There are several mechanisms responsible for the development of diuretic resistance and these include:

• Decreased bioavailability of the diuretic.

• Reduced secretion of the diuretic into the tubular lumen.

• Rebound retention of sodium.

• Hypertrophy of epithelial cells of the distal convoluted tubule.

• Activation of the renin-angiotensin-aldosterone system (RAAS).

• Associated renal insufficiency.

Management of diuretic resistance

1. Exclude noncompliance of dietary sodium restriction and the use of nonsteroidal antiinflammatory drugs (NSAIDs).

Sodium intake can be assessed from measurement of 24-hour salt excretion in the steady state. In subjects already receiving diuretic therapy, dietary non-compliance is suspected when daily salt excretion is high (>100 mmol/day) without concurrent weight loss. NSAIDs inhibit cyclooxygenase and decrease prostaglandin synthesis, resulting in a reduction of natriuretic response to loop diuretics.

2. Increase the dose and frequency of diuretic administration.

In patients with HF, dose-response curves for loop diuretics are shifted downward and rightward as compared to normal healthy controls. Furthermore, diminished renal blood flow and reduced activity of the organic anion transporter interfere with loop diuretic secretion into the luminal side of the renal tubules, the site of their biologic action.

Hence, increasing the dose may be an effective therapeutic strategy because it compensates for the changes in the pharmacokinetics and pharmacodynamics of loop diuretics that occur in patients with CHF.

Loop diuretics have a short half-life and hence, rebound sodium retention is an important mechanism contributing to diuretic resistance. More frequent administration of the diuretic (two to three times a day) may overcome the effect of postdiuretic salt retention by reducing the drug-free interval.

3. Using a different loop diuretic.

Furosemide has a wide variability in the bioavailability in patients with HF, between 10% and 100%, suggesting altered absorption. Torsemide and bumetanide have greater bioavailability (80% to 100%) and a more consistent rate of absorption in HF patients.

Torsemide has a longer half-life in patients with HF, approximately 6 hours, compared to furosemide or bumetanide, which have a half-life of approximately 2 hours. Hence, one should consider switching to torsemide or bumetanide if increasing the dose and frequency of furosemide does not overcome the diuretic resistance.

4. Combination diuretic therapy

The concept of combination of different classes of diuretics in patients who are resistant to loop diuretics is based on the ability of diuretics of different classes to affect sequential nephron blockade, thus generating an additive natriuretic response. The combination of thiazide and loop diuretics may be effective in establishing diuresis in patients resistant to high doses of loop diuretics.

Despite the fact that metolazone is commonly added in combination to loop diuretics, there is no physiologic advantage of one thiazide over another. Studies have demonstrated that the addition of 25 to 100 mg of hydrochlorothiazide or metolazone 2.5 to 10 mg were equally effective in establishing a diuresis when combined with loop diuretics.

Acetazolamide can be started at 250 to 375 mg once daily in the morning (5 mg/kg). If, after an initial response, the patient fails to continue to diurese, do not increase the dose but allow for kidney recovery by skipping medication for a day. Acetazolamide yields best diuretic results when given on alternate days, or for 2 days alternating with a day of rest.

B. Administration of Diuretics in Acute Decompensated Heart Failure

Dose of IV loop diuretic

There are currently no large scale randomized clinical trials to guide the initial dosing of IV loop diuretics in patients with acute decompensated HF. Dose determination is related to a number of factors, including renal function, maintenance dose, and previous response.

The National Heart, Lung, and Blood Institute Heart Failure Clinical Research Network conducted the Diuretic Optimization Strategies Evaluation (DOSE) trial, which was a prospective, randomized, double-blind, controlled clinical trial of various diuretic strategies for patients with acute decompensated heart failure.

Patients were randomly assigned in a 1:1:1:1 ratio to either a low-dose strategy (total intravenous furosemide dose equal to their total daily oral loop diuretic dose in furosemide equivalents) or a high-dose strategy (total daily intravenous furosemide dose 2.5 times their total daily oral loop diuretic dose in furosemide equivalents) and to administration of furosemide either by intravenous bolus every 12 hours or by continuous intravenous infusion.

In the comparison of the high-dose strategy with the low-dose strategy, there was a nonsignificant trend toward greater improvement in patients’ global assessment of symptoms in the high-dose group with no difference in plasma creatinine at 72 hours. The high-dose strategy was associated with greater diuresis and more favorable outcomes in some secondary measures but also with transient worsening of renal function.

Although worsening of renal function occurred more frequently with the high-dose strategy in the short term, there was no evidence at 60 days of worse clinical outcomes in the high-dose group than in the low-dose group.

Hence, based on the DOSE study, for patients who have been taking oral loop diuretics, it would be reasonable to start the IV loop diuretic at 2.5 times their daily oral loop diuretic dose in furosemide equivalents.

In patients who have not taken prior loop diuretic therapy, an initial IV furosemide dose of 20 to 40 mg is reasonable. Subsequently, the dose can be titrated up according to the urine output to a maximum intravenous dose of 80 to 100 mg of furosemide, 40 to 50 mg of torsemide, or 2 to 3 mg of bumetanide.

However, patients with an estimated glomerular filtration rate (GFR) <30 ml/min/1.73 m² may require higher maximum doses of up to 160 to 200 mg of furosemide, 80 to 100 mg of torsemide, or 6 to 8 mg of bumetanide.

Pharmacologic action

Pharmacologic actions of the different classes of diuretics

Loop diuretics

The loop diuretics commonly used for the management of HF include furosemide, torsemide, and bumetanide. They increase urinary sodium excretion by blocking the Na/K/2Cl transporter in the ascending limb of the loop of Henle located in the renal medulla.

Approximately one fourth of the filtered sodium load is reabsorbed in the ascending limb, and hence, the loop diuretics have potent natriuretic and diuretic actions. Loop diuretics are secreted from the blood by the organic anion transporters in proximal tubules and then delivered to their luminal site of action in the ascending limb. As such, the ability of loop diuretics to induce diuresis is directly related to renal blood flow and the efficacy of the organic anion transporters.

Thiazide diuretics

The most commonly used thiazide diuretics include hydrochlorothiazide and metolazone. Thiazide diuretics antagonize the NaCl transporter in the distal convoluted tubule.

Only 10% of the filtered sodium load is reabsorbed in the distal convoluted tubule. Hence, thiazide diuretics are less potent than loop diuretics.

Like the loop diuretics, thiazide diuretics are actively secreted by the organic anion transporters. Thiazide diuretics can be used in combination with loop diuretics to enhance natriuresis and diuresis by the dual inhibition of proximal and distal sodium reabsorption.

Potassium-sparing diuretics

Potassium-sparing diuretics include amiloride, triamterene, and aldosterone antagonists, which include spironolactone and eplerenone. Amiloride and triamterene act on the sodium channels on the luminal surface of the epithelial cells in both the distal tubule and collecting duct, resulting in a decrease in sodium and a decrease in potassium secretion.

However, with only 1% to 2% of the filtered sodium load reaching the distal tubule and collecting duct, these drugs have weak natriuretic and diuretic effects. They can be used in combination with loop diuretics to enhance diuresis and to prevent hypokalemia.

Spironolactone and eplerenone are aldosterone antagonists and they competitively inhibit the binding of aldosterone to the mineralocorticoid receptor on the epithelial cells in the distal tubule and collecting duct. Hence, mechanistically, the aldosterone antagonist antagonize mineralocorticoid receptors while amiloride and triamterene block the epithelial sodium channel, which may account for the improvement in clinical outcomes seen with aldosterone antagonists in patients with HF.

Carbonic anhydrase inhibitors

Acetazolamide is a carbonic anhydrase inhibitor that prevents bicarbonate reabsorption in the proximal tubules of the kidneys leading to a decrease in sodium reabsorption. Even though two thirds of the filtered sodium is reabsorbed in the proximal tubules, acetazolamide has modest natriuretic and diuretic actions as the increase in sodium reabsorption in distal tubule offsets proximal sodium losses.

Acetazolamide can be used to correct metabolic alkalosis that may result with the use of loop diuretics. Acetazolamide, when given together with a loop diuretic and spironolactone, may result in synergistic diuretic response effecting sequential nephron blockade of sodium reabsorption.

Patients with acute decompensated HF require intravenous (IV) doses of loop diuretics to provide rapid relief of pulmonary edema and fluid overload.

IV bolus versus continuous infusion

The method of administration of intravenous loop diuretic in patients with acute decompensated heart failure may have an effect on diuresis. From a pharmacodynamic stand point, with intermittent bolus dosing, the concentration of diuresis peaks above the threshold needed for diuresis and then rapidly declines below the threshold, accounting for the initial peak in diuresis followed by a decline to baseline.

With the administration of an initial loading dose followed by continuous infusion, concentration stays above the diuresis threshold for a longer period of time and gradually declines, and may result in more effective diuresis. A meta-analysis of multiple small studies reported that continuous infusion was associated with greater urine output, shorter length of hospital stay, less impairment of renal function, and lower mortality when compared with intermittent bolus dosing.

In the DOSE study, there was no significant difference in efficacy or safety endpoints for bolus administration every 12 hours versus continuous infusion. Based on currently available data, either IV bolus or continuous infusion of loop diuretic is a reasonable approach for patients with acute decompensated HF. It is important, however, to monitor the urine output in response and adjust the dose and/or frequency of administration accordingly.

Combination diuretic therapy

In patients refractory to IV loop diuretics, consider the addition of a thiazide or thiazide-like diuretic, such as metolazone. In some patients, the addition of a potassium-sparing diuretic such as amiloride (5 to 10 mg orally) and triamterene (50 to 100 mg orally) that acts on the distal nephron sites may increase sodium excretion. In patients with metabolic alkalosis, acetazolamide, IV 250 to 500 mg can be given in addition to IV loop diuretic.

Undesirable effects

Diuretic-related adverse events

Overdiuresis and hypotension

Patients that are diuretic naive should be monitored closely for overdiuresis and hypotension especially, with IV diuretic administration. Diuretics should be started at a low dose and titrated upwards according to the response to the initial dose.

Worsening renal function

Overdiuresis may lead to the activation of RAAS and hemodynamic changes resulting in worsening renal function with

increased plasma creatinine and blood urea nitrogen (BUN).

Hyponatremia

Hyponatremia is more likely with thiazide diuretics than with loop diuretics. Management of mild hyponatremia includes withholding the diuretic that caused the hyponatremia, restricting free water intake and/or correcting hypokalemia if present.

Vasopressin receptor antagonists, conivaptan or tolvaptan, can be used to treat hyponatremia if the conservative management does not result in resolution of the hyponatremia.

Hypokalemia

Hypokalemia is common with both loop and thiazide diuretics. The use of potassium supplements or addition of aldosterone antagonists will prevent hypokalemia.

Hyperkalemia

Potassium-sparing diuretics (such as triamterene and amiloride) and aldosterone-receptor antagonists (such as spironolactone and eplerenone) may cause hyperkalemia, especially in patients with renal insufficiency. Hence, patients on potassium-sparing diuretics or aldosterone antagonists need to have their renal function and potassium monitored regularly, especially those with renal insufficiency.

Hypomagnesemia

Both thiazide and loop diuretics increase urinary magnesium excretion which may lead to hypomagnesemia.

Hypercalcemia

Thiazide diuretics can result in hypercalcemia, secondary to increased calcium reabsorption in the distal tubule. People with hyperparathyroidism or vitamin D treated hypoparathyroidism and those people with immobilization hypercalcemia are most susceptible.

Metabolic alkalosis

Metabolic alkalosis can occur with high-dose diuretic therapy secondary to contraction of the extracellular fluid space caused by urinary losses of a relatively bicarbonate free fluid. Diuretic-induced metabolic alkalosis can be managed with acetazolamide, a carbonic anhydrase inhibitor.

Hyperuricemia

The concentration of serum uric acid can be increased with the use of thiazide diuretics. Hyperuricemia as a result of diuretic therapy is dose-dependent and may result in gout.

Allergic reactions to loop diuretics

Therapy with a thiazide or furosemide may result in photosensitive dermatitis. Patients who are allergic to sulfonamide drugs may have cross-sensitivity with all diuretics except ethacrynic acid.

Rarely, severe necrotizing pancreatitis or acute allergic interstitial nephritis may occur. Ethacrynic acid is chemically dissimilar from the other loop diuretics and can be safely substituted in patients with allergic reaction to loop diuretics.

Ototoxicity

Loop diuretics associated ototoxicity is usually reversible, although permanent deafness has been reported with ethacrynic acid. Ototoxicity is related to the rate of infusion and the peak serum concentrations of the loop diuretic. Patients with renal failure and those receiving concomitant aminoglycoside therapy are at greatest risk of developing ototoxicity.

Pancreatitis

Acute pancreatitis has been reported after exposure to thiazide diuretics. However, this is rare.

What's the Evidence?

Brater, DC. “Diuretic therapy”. N Engl J Med. vol. 339. 1998. pp. 387(A detailed general review of diuretics.)

Ellison, DH. “Diuretic therapy and resistance in congestive heart failure”. Cardiology.. vol. 96. 2001. pp. 132-143. (Review of the mechanisms of diuretic resistance in heart failure.)

Loon, NR, Wilcox, CS, Unwin, RJ. “Mechanism of impaired natriuretic response to furosemide during prolonged therapy”. Kidney Int. vol. 36. 1989. pp. 682-89. (Review of the mechanisms of diuretic resistance in heart failure.)

Kaissling, B, Bachmann, S, Kriz, W. “Structural adaptation of the distal convoluted tubule to prolonged furosemide treatment”. Am J Physiol. vol. 248. 1985. pp. F374-81. (Describes the mechanism for diuretic resistance.)

Pitt, B, Zannad, F, Remme, WJ. “The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators”. N Engl J Med. vol. 341. 1999. pp. 709-17. (Describes the RALES study.)

Allen, LA. “Continuous versus bolus dosing of furosemide for patients hospitalized for heart failure”. Am J Cardiol. vol. 105. 2010. pp. 1794-97. (Compares continous versus bolus dosing of furosemide.)

Felker, GM. “Diuretic strategies in patients with acute decompensated heart failure”. N Engl J Med. vol. 364. 2011. pp. 797-805. (Compares high dose versus low dose lasix in acute heart failure.)

Faris, R, Flather, MD, Purcell, H. “Diuretics for heart failure”. Cochrane Database Syst Rev. 2006. pp. CD003838(Review of Diuretics for Heart Failure.)

Cosin, J, Diez, J. “TORIC investigators. Torsemide in chronic heart failure: results of the TORIC study”. Eur J Heart Fail. vol. 4. 2002. pp. 507(Describes the TORIC study.)

Salvador, DR, Rey, NR, Ramos, GC, Punzalan, FE. “Continuous infusion versus bolus injection of loop diuretics in congestive heart failure”. Cochrane Database Syst Rev. 2005. pp. CD003178(Meta-analysis of continuous infusion versus bolus injection of loop diuretics in congestive heart failure.)

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