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Diuretics and Heart Failure

  • Author: Eitan A Friedman, MD; Chief Editor: Karlheinz Peter, MD, PhD  more...
Updated: Apr 01, 2015


Congestive heart failure (CHF) is one of the most common chronic conditions in the United States, affecting an estimated 5.7 million people[1] and is the leading diagnosis for hospitalized patients. The most frequent presenting symptom for patients with CHF is dyspnea, which is often attributed to pulmonary edema and occurs in 93% of patients.[2] The second most frequent symptom is peripheral edema, occurring in 70%.[2] Naturally, one of the mainstays of therapy has been to target hypervolemia through the use of diuretics.

The therapeutic effects of diuretics have been known for centuries, and they were perhaps the first treatment available for CHF. As early as the 1600s, mercurial-based diuretics were used for the treatment of edema, termed dropsy. The 20th century saw the advent of carbonic anhydrase inhibitors, followed by thiazide diuretics, and finally loop diuretics. Currently, diuretics remain some of the most commonly prescribed drugs in the United States. Diuretics have proven to be an integral component to the treatment of acute and chronic heart failure, and their use has been extensively studied. Their efficacy in improving symptoms such as dyspnea and edema is clear; however, little data support a mortality benefit or an alteration in disease progression.

For many years, diuretics have been the cornerstone for treatment of both acute and chronic heart failure. Guidelines for the use of diuretics in both the inpatient and outpatient setting are largely based on expert opinion. Diuretics clearly improve hemodynamics and symptoms, although many studies have not been able to demonstrate a mortality benefit. In part, their effectiveness may be limited by adverse effects including electrolyte imbalances and neurohormonal activation. As new treatments for heart failure emerge, future research must address how diuretics fits into the armamentarium.


Knowledge of the pharmacology of diuretics is essential in understanding their function in the management of heart failure. The current available loop diuretics are furosemide, torsemide, bumetanide, and ethacrynic acid. They inhibit the Na-K-2Cl cotransporter in the thick ascending limb of the loop of Henle. By effectively inhibiting sodium reabsorption, they also reduce water reabsorption. The loop diuretics bind to the luminal surface of the transporter; thus, they must be secreted into the tubular lumen. As the glomerular filtration rate is reduced, luminal secretion is decreased, and less drug reaches the active site.[3]

Oral absorption of furosemide widely varies. Bumetanide and torsemide have greater bioavailability and more predictable pharmacokinetics. All of the loop diuretics except ethacrynic acid contain a sulfonamide group. Individuals who are allergic to sulfonamide antibiotics may be allergic to sulfonamide diuretics, although recent research suggests that the cross-reactivity is low.[4] Ethacrynic acid is rarely used other than in individuals with sulfa allergies.

Thiazide diuretics are most commonly used to treat hypertension, although they can be adjuncts in the management of heart failure. They inhibit the Na-Cl symporter in the distal convoluted tubule, leading to decreased sodium and water reabsorption. Spironolactone inhibits the aldosterone receptor in the cortical collecting duct, also limiting sodium and water reabsorption. Its diuretic effect is relatively weak, and its onset of action is slow.

Mechanism of action

The pulmonary and peripheral edema seen in CHF are the result of multiple physiologic disturbances. Decreased cardiac output leads to relative renal hypoperfusion that stimulates neurohormonal activation of the renin-angiotensin-aldosterone axis. Sodium and free water retention occur, resulting in an increase in both volume and pressure in capacitance vessels. Hydrostatic pressure elevation leads to fluid extravasation into peripheral tissues as well as the lungs.

The Frank-Starling law describes the mechanism whereby a normal heart under a physiologic range of filling pressures increases stroke volume proportionally with an increase in preload. In contrast, in acute decompensated heart failure, a myopathic heart subjected to very elevated filling pressures is not able to effectively increase stroke volume. Acute elevation of left ventricular preload (end-diastolic pressure) directly leads to elevated left atrial pressures and pulmonary edema. Diuretics reduce intravascular volume, leading to a decrease in central venous pressure, right and left heart filling pressures, and pulmonary vascular pressures. Venous capacitance increases, and intrapulmonary fluid returns to the circulation. The left ventricular volume is smaller, and cardiac output typically increases. In the setting of mitral regurgitation, the reduced left ventricular volume improves mitral leaflet coaptation and decreases the regurgitant volume.


Technical Considerations

Complication Prevention

Diuretic resistance explains why some patients require high doses of diuretics or have a decreased response to diuretics over time. Several mechanisms contribute to diuretic resistance. The “braking phenomenon” refers to a short-term resistance following a bolus dose and may be related to neurohormonal activation that acts to preserve intravascular volume.[3] A longer term resistance may be due to compensatory hypertrophy of the distal convoluted tubule, which avidly reabsorbs sodium and counteracts the natriuretic effects of loop diuretics. Additionally, as the GFR decreases, a higher dose of diuretic is necessary to achieve therapeutic effect. Finally, GI absorption and subsequent bioavailability of oral diuretics may be impaired in heart failure due to bowel wall edema.



The efficacy of diuretics in improving symptoms of heart failure such as dyspnea and edema has long been documented. However, numerous studies examining the effects of diuretics on clinical outcomes in heart failure patients have generally been disappointing. Several studies have uncovered a correlation of diuretic dose with renal dysfunction, sudden death, hospital length of stay, and overall mortality.[5, 6, 7] However, diuretic dose itself is a marker of heart failure and renal failure severity and may not contribute directly to poor outcomes.

Diuretic use in the heart failure patient does carry certain risks. Various electrolyte abnormalities can occur. Inhibition of the Na-K-2Cl channel leads to increased sodium delivery to the distal tubule and cortical collecting duct. Via the ENaC channel (Na-K antiporter), distal sodium is reabsorbed at the expense of potassium loss, resulting in hypokalemia. Hypomagnesemia can occur as well, potentiating the hypokalemia. This imbalance may contribute to arrhythmias.

Chloride losses can lead to a hypochloremic metabolic alkalosis. Significant alkalosis can decrease respiratory drive in a patient with respiratory failure. Hyponatremia can also occur with diuretics, more commonly with thiazide than loop diuretics, and especially if large amounts of free water are ingested. Although hyponatremia itself is rarely symptomatic, its occurrence is a marker of poor prognosis.

Diuretic use does can lead to worsening renal function. Whether higher diuretic doses directly lead to the development of renal failure (cardio-renal syndrome) or are simply a marker for patients at risk is debatable. Newer data suggest that renal failure is more closely associated with elevation of central venous pressure than relative intravascular volume depletion from high dose diuretics.[8]

Because diuretics acutely decrease left ventricular preload, they can lead to a reflex neurohormonal stimulation of the sympathetic nervous system (SNS) and renin-angiotensin-aldosterone axis.[9] Numerous studies have determined that activation of these pathways contributes to the pathophysiology of heart failure, thus potentially undermining the benefits of diuretic use. This mechanism may also explain why various studies have failed to show a mortality benefit from diuretics use. Concurrent treatment with neurohormonal blockade (ie, vasodilators, beta blockers, renin-angiotensin-aldosterone system antagonists) may improve outcomes, although this has not been systematically studied.

A study sought to determine the use of intravenous fluids in the early care of patients with acute decompensated heart failure (HF) who are treated with loop diuretics. The study found that among 131,430 hospitalizations for HF, 13,806 (11%) were in patients treated with intravenous fluids during the first 2 days. The study concluded that many patients who are hospitalized with HF and receive diuretics also receive intravenous fluids during their early inpatient care, and the proportion varies among hospitals. Such practice is associated with worse outcomes and warrants further investigation.[10, 11]

Contributor Information and Disclosures

Eitan A Friedman, MD Fellow, Cardiovascular Medicine, Vanderbilt University Medical Center

Eitan A Friedman, MD is a member of the following medical societies: American College of Cardiology, American College of Physicians, American Medical Student Association/Foundation

Disclosure: Nothing to disclose.

Chief Editor

Karlheinz Peter, MD, PhD Professor of Medicine, Monash University; Head of Centre of Thrombosis and Myocardial Infarction, Head of Division of Atherothrombosis and Vascular Biology, Associate Director, Baker Heart Research Institute; Interventional Cardiologist, The Alfred Hospital, Australia

Karlheinz Peter, MD, PhD is a member of the following medical societies: American Heart Association, German Cardiac Society, Cardiac Society of Australia and New Zealand

Disclosure: Nothing to disclose.

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