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) . The loop diuretics are highly protein bound and therefore enter the tubule primarily by secretion in the proximal tubule, rather than by glomerular filtration .
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:
●No diuresis is seen with very low doses (ie, doses below the typical starting dose). (See 'Starting doses' below.)
●A progressively increasing diuresis is achieved at higher doses.
●However, a plateau is reached at which even higher plasma concentrations produce minimal further diuresis; this dose is called the maximum effective dose. This maximum effective dose is higher in patients with kidney impairment (ie, patients with reduced glomerular filtration rate [GFR] require higher loop diuretic doses to achieve the maximum effect). (See 'Maximum effective 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 .
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 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) . 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):
●A reduction in effective renal blood flow, which decreases the delivery of drug to the kidney
●Activation of the renin-angiotensin system and sympathetic nervous system, which enhance sodium reabsorption by the kidney (see "General principles of disorders of water balance (hyponatremia and hypernatremia) and sodium balance (hypovolemia and edema)", section on 'Regulation of effective arterial blood volume')
●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.
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).
MAJOR SIDE EFFECTS — 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".)
●Hypokalemia (see "Causes of hypokalemia in adults", section on 'Diuretics')
●Metabolic alkalosis (see "Causes of metabolic alkalosis", section on 'Loop or thiazide diuretics')
●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')
●Hyperuricemia (see "Diuretic-induced hyperuricemia and gout")
●Hyponatremia (primarily due to hypovolemia-induced release of antidiuretic hormone) (see "Diuretic-induced hyponatremia")
Hypersensitivity reactions — Furosemide, bumetanide, and torsemide, which are sulfonamides, can cause hypersensitivity reactions, usually manifested as a rash or rarely acute interstitial nephritis, similar to those produced by other sulfonamide drugs.
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.
Lack of allergic cross-reactivity with sulfonamide antimicrobials — A separate issue is the risk of an allergic reaction to the sulfonamide-based loop diuretics in patients with known sulfonamide antibiotic allergy. There is minimal evidence of allergic cross-reactivity between sulfonamide antimicrobials and non-antimicrobials such as loop diuretics. Allergic reactions that do occur appear to be related to a predisposition to allergic reactions rather than sulfonamide cross-reactivity . (See "Sulfonamide allergy in HIV-uninfected patients", section on 'Between sulfonamide antimicrobials and nonantimicrobials'.)
Ototoxicity — Loop diuretic-induced ototoxicity can lead to transient (usually lasting 30 minutes to 24 hours) or permanent deafness. Ototoxicity primarily occurs with high-dose intravenous therapy (eg, furosemide doses above 240 mg/hour) or at lower doses in patients with kidney function impairment or concurrent use of other ototoxins such as aminoglycosides. Ethacrynic acid, which is rarely used, may be more ototoxic in high doses than furosemide, torsemide, and bumetanide.
Mechanism — The development of hearing loss is thought to be related to the intrinsic mechanism of loop diuretic action. Transport in the loop of Henle that is mediated by a Na-K-2Cl cotransporter is inhibited by loop diuretics. (See "Mechanism of action of diuretics".)
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 .
Importance of dose and rate of administration — Ototoxicity is primarily seen in patients treated with high intravenous or oral doses of loop diuretics. In a review of 29 cases of deafness associated with furosemide therapy that were reported to the US Food and Drug Administration soon after the drug was approved, intravenous furosemide was administered in 17 patients. The average rate of furosemide infusion in these patients was above 4 mg/min (240 mg/hour), and total doses administered over one to nine days ranged, in most patients, from 200 mg to 21,600 mg . Therapy was usually more prolonged in the 12 patients treated with oral therapy (range 2 to 365 days), with doses ranging from 80 to 600 mg/day.
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 . 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 . 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 [13-15]. 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 . All five episodes 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) .
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●Basics topic (see "Patient education: Side effects from medicines (The Basics)")
SUMMARY AND RECOMMENDATIONS
●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.)
•However, a plateau is reached at which even higher plasma concentrations produce minimal further diuresis; this dose is called the maximum effective dose (table 1). In normal (ie, nonedematous) subjects, the maximum effect (above which no further diuresis occurs) is attained with 40 mg of furosemide given intravenously (approximately equivalent to 15 or 20 mg of torsemide and 1 mg of bumetanide). However, the maximum effective dose is higher in patients with heart failure, cirrhosis, nephrotic syndrome, or kidney function impairment. (See 'Maximum effective doses' above.)
•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:
•Those related to the diuresis and natriuresis (including hypokalemia, metabolic alkalosis, hypovolemia, and hyperuricemia). (See 'Diuresis related' above.)
•Hypersensitivity. Ethacrynic acid, a non-sulfonamide loop diuretic, can be used in patients who develop a hypersensitivity reaction to furosemide, bumetanide, torsemide. There is minimal evidence of allergic cross-reactivity between sulfonamide antimicrobials and non-antimicrobials. Thus, patients with a history of allergy to sulfonamide antimicrobial drugs would be expected to tolerate nonantimicrobial sulfonamides such as loop diuretics. (See 'Hypersensitivity reactions' above.)
•Loop diuretic-induced ototoxicity can lead to transient (usually lasting 30 minutes to 24 hours) or permanent deafness. Ototoxicity primarily occurs with high-dose intravenous therapy (eg, furosemide doses above 240 mg/hour) or at lower doses in patients with kidney function impairment or concurrent use of other ototoxins such as aminoglycosides. (See 'Ototoxicity' above.)