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Loop Diuretics: Dosing and Major Side Effects (Uptodate)
Loop Diuretics: Dosing and Major Side Effects (Uptodate)
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Feb 2023. | This topic last updated: Jan 24, 2023.
INTRODUCTION
Loop diuretics reduce sodium chloride reabsorption in the thick ascending limb of the loop of
Henle. This is achieved by inhibiting the Na-K-2Cl carrier in the luminal membrane in this
segment, thereby minimizing the entry of luminal sodium and chloride into the cell ( figure 1)
[1]. The loop diuretics are highly protein bound and therefore enter the tubule primarily by
secretion in the proximal tubule, rather than by glomerular filtration [1].
The most commonly used loop diuretics are furosemide, bumetanide, and torsemide, which are
sulfonamide derivatives. Ethacrynic acid is rarely used but is an alternative in patients who have
a hypersensitivity reaction to a typical loop diuretic. (See 'Hypersensitivity reactions' below.)
Intravenous loop diuretic treatment is commonly employed when urgent diuresis is needed or
when there is concern for poor gastrointestinal absorption. Continuous loop diuretic infusion is
sometimes prescribed rather than intermittent bolus therapy ( figure 2). However, if a
continuous infusion is used, it is important to begin with a bolus to assure that the patient is
diuretic responsive and to achieve therapeutic drug concentrations. These issues are discussed
elsewhere:
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DOSING
General principles — The effect of the loop diuretics is dose dependent, being determined
largely by the rate at which the diuretic is delivered to its site of action ( figure 3 and
table 1) [2,3]:
● No diuresis is seen with very low doses (ie, doses below the typical starting dose). (See
'Starting doses' below.)
● Doses higher than the maximum effective dose are sometimes used. However, dosing
should not exceed the maximal recommended daily dose because of increased risk for
toxicity (particularly ototoxicity, which may be irreversible). (See 'Maximal recommended
daily doses' below.)
All of the loop diuretics produce the same response if given at equipotent doses. When kidney
function is normal, a 40 mg dose of furosemide is approximately equal to 1 mg of bumetanide
and 20 mg of torsemide. In patients with impaired kidney function, the normal dose ratio of
furosemide-to-bumetanide falls from 40:1 to approximately 20:1 because of an increase in
extrarenal bumetanide clearance in such patients [4].
Bioavailability of oral torsemide and bumetanide is high; oral and intravenous doses of these
drugs are therefore roughly equipotent. By contrast, in normal subjects, the oral bioavailability
of furosemide is approximately 50 percent.
However, for several reasons, the response to an oral dose of furosemide is difficult to predict.
Plasma diuretic concentrations may be sustained above the diuretic threshold for a longer
period of time with oral administration, and therefore an oral dose may elicit the same
natriuresis as the same intravenous dose despite the lower bioavailability [3,5]. In addition,
there is substantial variability in the degree of bioavailability of oral furosemide (both between
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patients and within the same patient over time), making it difficult to predict the diuretic
response that will occur in individual patients from dose to dose.
Patients with generalized edema (due, for example, to heart failure, the nephrotic syndrome, or
kidney disease) are typically treated with daily therapy. At a given dose, net sodium loss occurs
for only one to two weeks before a new steady state is achieved; in this setting, sodium intake
and excretion are again equal as the effect of the diuretic is balanced by activation of
counterregulatory factors that promote sodium retention, such as the renin-angiotensin
system. However, selected patients with mild edema who are adherent with dietary sodium
restriction can be treated with intermittent therapy as needed. (See "General principles of
disorders of water balance (hyponatremia and hypernatremia) and sodium balance
(hypovolemia and edema)", section on 'The steady state' and "Time course of loop and thiazide
diuretic-induced electrolyte complications".)
Starting doses — Typical loop diuretic starting doses vary according to the cause of edema and
the presence of kidney function impairment ( table 1).
However, patients with edema require higher doses to achieve a diuresis. As examples, starting
doses of furosemide are 20 mg once or twice daily in patients with heart failure and preserved
kidney function (10 mg of torsemide or 0.5 mg of bumetanide once or twice daily), and 40 mg
once or twice daily in patients with nephrotic syndrome and preserved GFR (20 mg of torsemide
or 1 mg of bumetanide once or twice daily). These higher starting doses compared with normal
subjects are required because edematous patients have varying degrees of decreased kidney
perfusion (which reduces drug delivery to the kidney) and increased activity of sodium-retaining
forces (such as the renin-angiotensin-aldosterone system) ( figure 3).
Maximum effective doses — The maximum effective diuretic dose is typically defined as the
dose that achieves the maximal peak rate of sodium excretion. This dose differs in patients with
heart failure, cirrhosis, nephrotic syndrome, and reduced GFR ( table 1).
In normal (ie, nonedematous) subjects, the maximum effect (above which no further diuresis
occurs) is attained with 40 mg given intravenously (approximately equivalent to 15 or 20 mg of
torsemide and 1 mg of bumetanide) [2]. However, the maximum effective dose is higher in
patients with heart failure, cirrhosis, nephrotic syndrome, or kidney function impairment due to
one or more of the following factors ( figure 3):
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● A reduction in effective renal blood flow, which decreases the delivery of drug to the
kidney
● A reduced GFR, which is associated with diminished secretion of loop diuretics by the
proximal tubule, resulting from the retention of competing anions in kidney failure
In chronic kidney disease, the upward dose adjustment varies inversely with the estimated GFR
[2,6]:
● In moderate chronic kidney disease (ie, estimated GFR >30 mL/min/1.73 m2), the
maximum effective dose is approximately 80 mg of intravenous furosemide, 2 to 3 mg of
bumetanide, or 20 to 50 mg of torsemide.
● In more severe chronic kidney disease (ie, estimated GFR <30 mL/min/1.73 m2), the
maximum effective dose is approximately 200 mg of intravenous furosemide, 8 to 10 mg
of bumetanide, or 50 to 100 mg of torsemide.
● In oliguric acute kidney injury, these doses may be adjusted upward to as much as 500 mg
of intravenous furosemide or equivalent doses of torsemide or bumetanide.
Maximal recommended daily doses — Although maximal effective doses are often sufficient
to achieve therapeutic success, higher doses are recommended in some guidelines to increase
natriuresis further. This is because net natriuresis is the product of both the maximal natriuretic
effect and the time of natriuresis.
As a hypothetical example, if the maximal natriuresis per unit time that is induced by a loop
diuretic is 20 percent of the filtered sodium load, giving a higher dose will not increase this
further (ie, this is the "maximum effective dose"). However, a higher dose of the diuretic, by
raising plasma concentrations, may prolong the period of time during which this maximum
effective dose acts upon the kidney, thereby providing an additional net natriuretic effect.
Thus, administering a dose that is above the maximum effective dose may be an effective
strategy to enhance natriuresis and has been incorporated into contemporary guidelines.
However, in order to avoid toxicity, the administered dose should not exceed the "maximal
recommended daily dose" ( table 1).
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There are three major types of side effects related to loop diuretic use: those related to the
diuresis and natriuresis, hypersensitivity reactions, and ototoxicity.
Diuresis related — A variety of fluid and electrolyte abnormalities can result from the diuresis
or from excessive diuresis. (See "Time course of loop and thiazide diuretic-induced electrolyte
complications".)
These include:
● Hypovolemia, hypotension, and azotemia (see "Etiology and diagnosis of prerenal disease
and acute tubular necrosis in acute kidney injury in adults", section on 'Causes of prerenal
disease')
Alternative loop diuretic therapy with ethacrynic acid — Ethacrynic acid, a non-
sulfonamide loop diuretic, can be used in patients who develop a hypersensitivity reaction to
furosemide, bumetanide, torsemide, or a sulfonamide-based thiazide diuretic. Ethacrynic acid is
rarely used in the absence of this indication because it may be more ototoxic than the
sulfonamide diuretics when given in high doses; in addition, it is relatively insoluble and
therefore cumbersome to administer intravenously.
A secretory isoform of this cotransporter is present in the inner ear and plays an important role
in the composition of endolymph. A mouse model in which this transporter was inactivated led
to reduced endolymph secretion, structural damage to the inner ear, deafness, and imbalance
[8,9]. In humans, furosemide effects on vestibular potential have been used to diagnose
Meniere disease [10].
The risk of ototoxicity is also higher in patients with acute or chronic kidney disease and in
those taking other potential ototoxins such as an aminoglycoside antibiotic [11]. Specifically,
lower doses of loop diuretics (equivalent of 80 to 160 mg/hour [2 to 4 g/day] of furosemide)
may result in deafness among patients with acute kidney injury [12]. Similarly, deafness has
been reported with lower loop diuretic doses in patients concurrently treated with an
aminoglycoside.
The risk of ototoxicity may be lower with continuous intravenous infusion rather than bolus
therapy [13,14]. In a randomized, crossover trial, for example, 20 patients with severe heart
failure were treated with an 8 hour continuous infusion of high-dose furosemide (250 to 2000
mg, mean 690 mg) or the same dose given as a single intravenous bolus [13]. All five episodes
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of reversible hearing loss occurred with bolus therapy, which was associated with a significantly
higher maximum serum furosemide concentration (95 versus 24 mcg/mL with the continuous
infusion). Similar findings were noted in a subsequent meta-analysis of eight trials involving 254
patients with heart failure; continuous infusion was associated with a significantly lower rate of
ototoxicity, defined as hearing loss or tinnitus (relative risk 0.06, 95% CI 0.01-0.44) [14].
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Here are the patient education articles that are relevant to this topic. We encourage you to print
or e-mail these topics to your patients. (You can also locate patient education articles on a
variety of subjects by searching on "patient info" and the keyword(s) of interest.)
● Basics topic (see "Patient education: Side effects from medicines (The Basics)")
● The effect of the loop diuretics is dose dependent, being determined largely by the rate at
which the diuretic is delivered to its site of action ( figure 3 and table 1) (see 'General
principles' above):
• No diuresis is seen with very low doses (ie, doses below the typical starting dose)
( table 1). In normal subjects (ie, nonedematous individuals), a diuresis begins with
as little as 10 mg of furosemide (0.25 mg bumetanide or 5 mg torsemide). However,
patients with edema require larger doses to achieve a diuresis. A progressively
increasing diuresis is achieved at higher doses. (See 'Starting doses' above.)
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• Doses higher than the maximum effective dose are included in some evidence-based
guidelines because they lengthen the time above the diuretic threshold to increase net
natriuresis. However, dosing should not exceed the maximal recommended daily
dose because of increased risk for toxicity (particularly ototoxicity, which may be
irreversible) ( table 1). (See 'Maximal recommended daily doses' above.)
● All of the loop diuretics produce the same response if given at equipotent doses. When
kidney function is normal, a 40 mg dose of furosemide is approximately equal to 1 mg of
bumetanide and 20 mg of torsemide. In patients with impaired kidney function, the
normal dose ratio of furosemide-to-bumetanide falls from 40:1 to approximately 20:1
because of an increase in extrarenal bumetanide clearance in such patients. Bioavailability
of oral torsemide and bumetanide is high; oral and intravenous doses of these drugs are
therefore roughly equipotent. By contrast, the bioavailability of oral furosemide in normal
subjects is approximately 50 percent. (See 'General principles' above.)
● There are three major types of side effects related to loop diuretic use:
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REFERENCES
1. Ellison DH. Diuretic drugs and the treatment of edema: from clinic to bench and back
again. Am J Kidney Dis 1994; 23:623.
2. Brater DC, Voelker JR. Use of diuretics in patients with renal disease. In: Pharmacotherapy o
f Renal Disease and Hypertension (Contemporary Issues in Nephrology), Bennett WM, McC
arron DA (Eds), Churchill Livingstone, New York 1987. Vol 17.
3. Kaojarern S, Day B, Brater DC. The time course of delivery of furosemide into urine: an
independent determinant of overall response. Kidney Int 1982; 22:69.
4. Voelker JR, Cartwright-Brown D, Anderson S, et al. Comparison of loop diuretics in patients
with chronic renal insufficiency. Kidney Int 1987; 32:572.
5. Ellison DH, Felker GM. Diuretic Treatment in Heart Failure. N Engl J Med 2017; 377:1964.
11. Gallagher KL, Jones JK. Furosemide-induced ototoxicity. Ann Intern Med 1979; 91:744.
12. Brown CB, Ogg CS, Cameron JS. High dose frusemide in acute renal failure: a controlled
trial. Clin Nephrol 1981; 15:90.
13. Dormans TP, van Meyel JJ, Gerlag PG, et al. Diuretic efficacy of high dose furosemide in
severe heart failure: bolus injection versus continuous infusion. J Am Coll Cardiol 1996;
28:376.
14. 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; :CD003178.
Topic 2310 Version 26.0
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GRAPHICS
Na: sodium; K: potassium; Cl: chloride; Ca: calcium; Mg: magnesium; NaCl: sodium
chloride; ROMK: renal outer medullary potassium channel.
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Patients may have a decreased response (ie, a decreased excretion of NaCl, shown in the y-axis)
over time (shown in the x-axis) despite using the same dose of a loop diuretic. This is due to
enhanced tubular sodium reabsorption in other parts of the nephron (other than the loop of
Henle) and is called the "braking phenomenon." Each bar in the figure represents the sodium
excreted during a 6-hour period. The horizontal dashed line represents the sodium intake. The
black bars represent the 6-hour sodium excretion immediately after diuretic administration.
Original figure modified for this publication. Wilcox CS, Mitch WE, Kelly RA, et al. Response of the kidney to furosemide.
I. Effects of salt intake and renal compensation. J Lab Clin Med 1983; 102:450. Illustration used with the permission of
Elsevier Inc. All rights reserved.
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Data from: Brater DC, Day B, Burdette A, et al. Kidney Int 1984; 26:183.
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Loop diuretic doses for adult patients with common causes of edema
* Refer to UpToDate topics on the maximum effective dose and major side effects of loop diuretics
for details.
Δ More aggressive regimens have been shown to be safe and effective for acute decompensated
heart failure. Refer to UpToDate topics on the use of diuretics in patients with heart failure for
details.
§ In most patients with cirrhosis, furosemide (or equivalent) should be combined with
spironolactone at a ratio of 40 mg furosemide to 100 mg of spironolactone; the dosing ratio should
be adjusted based upon the plasma potassium concentration. Refer to UpToDate topics on initial
therapy of ascites for details.
¥ Chronic kidney disease alone typically does not cause edema but complicates the treatment of
other edematous syndromes. In this situation, the presence of chronic kidney disease should guide
dosing. Refer to UpToDate topics on the maximum effective dose and major side effects of loop
diuretics for details.
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‡ Initial diuretic doses for patients with chronic kidney disease depend on its stage but are generally
higher than those given for patients with heart failure or cirrhosis.
† High doses of furosemide (500 mg) may be effective, but most authorities now avoid such high
doses and, instead, recommend a single trial with a lower starting dose.
References:
1. Writing Committee Members, Yancy CW, Jessup M, et al. 2013 ACCF/AHA guideline for the management of heart
failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice
guidelines. Circulation 2013; 128:e240.
2. Mullens W, Damman K, Harjola VP, et al. The use of diuretics in heart failure with congestion - a position statement
from the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2019; 21:137.
Courtesy of David H Ellison, MD, FASN, FAHA.
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Contributor Disclosures
D Craig Brater, MD No relevant financial relationship(s) with ineligible companies to disclose. David H
Ellison, MD, FASN, FAHA No relevant financial relationship(s) with ineligible companies to
disclose. Richard H Sterns, MD No relevant financial relationship(s) with ineligible companies to
disclose. Michael Emmett, MD No relevant financial relationship(s) with ineligible companies to
disclose. John P Forman, MD, MSc No relevant financial relationship(s) with ineligible companies to
disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must
conform to UpToDate standards of evidence.
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