LOOP DIURETICS

• ACRONYMS AND DEFINITIONS

• AASLD - American Association for the Study of Liver Diseases
• AHA/ACC - American Heart Assoc / American College of Cardiology
• BP - Blood pressure
• BMD - Bone mineral density
• CrCl - Creatinine clearance
• DBP - Diastolic blood pressure
• EASL - European Association for the Study of the Liver
• GFR - Glomerular filtration rate
• HCTZ - Hydrochlorothiazide
• PI - Manufacturer's package insert
• PTH - Parathyroid hormone
• SBP - Systolic blood pressure

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• DRUGS IN CLASS

• Loop diuretics
• Furosemide (Lasix®)
• Bumetanide (Bumex®)
• Torsemide (Demadex®, Soaanz®)

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• MECHANISM OF ACTION

• General
• Diuretics cause the kidneys to produce more urine and therefore more fluid is removed from the body
• Fluid loss causes blood pressure to decrease and it reduces the workload on the heart
• Diuretics are used to treat a number of conditions where excess body fluid is a problem - heart failure, kidney failure, liver failure, etc.


• Specific
• The nephron is the fundamental working unit in the kidney. The "ascending Loop of Henle" is a part of the nephron where about 20% of freely filtered sodium is reabsorbed. Loop diuretics block sodium reabsorption through the Na-K-2Cl transporter in this segment, and sodium excretion is increased. Increased sodium excretion helps to promote fluid loss.
• Another mechanism by which loop diuretics promote fluid excretion is through their effect on osmolality. The medullary region of the kidney is hyperosmolar, and it promotes water reabsorption in the collecting ducts through osmosis. Medullary hyperosmolality is mostly a product of sodium, potassium, and chloride that is reabsorbed through the Na-K-2Cl transporter. When loop diuretics block this transporter, they lower the osmolality of the medullary region which decreases the osmotic reabsorption of free water in the collecting duct. Through this mechanism, loop diuretics promote the excretion of free water. This is in contrast to thiazide diuretics which do not promote free water excretion.


• Nephron and diuretics illustration - illustration of the nephron and how diuretics work

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• HYPERTENSION

• Overview
• Loop diuretics are not commonly used as first- or second-line agents to treat hypertension
• Other classes of blood pressure medications have more favorable side effect profiles and outcome data
• They are frequently used to treat hypertension in patients with conditions that cause fluid retention ( ex. heart failure, kidney disease, and liver failure)


• STUDY
  Blood pressure lowering efficacy of loop diuretics for primary hypertension, Cochrane meta-analysis (2009) [PubMed abstract]
• A Cochrane meta-analysis evaluated trials in which loop diuretics were used to treat hypertension
• The analysis only found 3 trials where furosemide had been compared to placebo in the treatment of hypertension (none were found for bumetanide and torsemide)
• Systolic blood pressure (SBP)
• In two trials comparing furosemide 40 mg a day to placebo, furosemide lowered SBP by an average of 5.80 mmHg more than placebo
• In one trial comparing furosemide 60 mg a day to placebo, furosemide lowered SBP by an average of 10 mmHg more than placebo [6]
• Diastolic blood pressure (DBP)
• In two trials comparing furosemide 40 mg a day to placebo, furosemide lowered DBP by an average of 3.53 mmHg more than placebo
• In one trial comparing furosemide 60 mg a day to placebo, furosemide lowered DBP by an average of 3.00 mmHg more than placebo [6]


• Summary
• Loop diuretics are not commonly used to treat patients with hypertension unless they also have heart, kidney, or liver failure
• Other medications have more outcome data and favorable side effect profiles than loop diuretics

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• HEART FAILURE

• Overview
• Loop diuretics are the preferred diuretic in most patients with heart failure
• In patients with mild heart failure who do not have significant fluid retention, thiazide diuretics may be used
• Loop diuretics are used acutely to remove large volumes of fluid in patients with decompensated heart failure
• Loop diuretics are used chronically in heart failure to prevent fluid retention and buildup
• Despite their almost universal use in patients with heart failure, there have been no long-term studies that have evaluated the effects of loop diuretics on significant clinical outcomes [19]
• Compared to thiazide diuretics, loop diuretics have the following characteristics:
• Loop diuretics increase sodium excretion by 20 - 25% compared to 5 - 10% for thiazide diuretics
• Loop diuretics maintain their effectiveness once the CrCl falls below 30 - 40 ml/min, where thiazides tend to become ineffective


• AHA recommendations
• The AHA/ACC recommends diuretics and salt restriction in the following heart failure patients:
• Patients with current or prior symptoms of heart failure
• Patients with a reduced ejection fraction who have evidence of fluid retention
• Loop diuretics are the preferred diuretics in most patients, however, thiazide diuretics may be preferred in hypertensive patients with mild fluid retention [19]

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• CHRONIC KIDNEY DISEASE

• Overview
• Patients with chronic kidney disease tend to retain sodium and fluid, and this causes their blood pressure to rise
• Loop and thiazide diuretics help to alleviate this effect
• Thiazide diuretics tend to become less effective as kidney function decreases where loop diuretics tend to maintain their effectiveness


• National Kidney Foundation recommendations
• Thiazide diuretics can be used in patients with a GFR > 30 ml/min
• Loop diuretics can be used in all patients with chronic kidney disease, and should be used in patients with a GFR < 30 ml/min
• Potassium-sparing diuretics should be used with great caution because of their potential to raise potassium levels [90]

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• LIVER FAILURE (CIRRHOSIS)

• Loop diuretics are often combined with aldosterone antagonists to treat fluid retention in cirrhosis. See cirrhosis treatment recommendations for more.

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• TOLERANCE TO LOOP DIURETICS

• Over time, the kidneys can adapt to chronic loop diuretic therapy and their effectiveness can wane
• Strategies that may help overcome tolerance include:
• Increasing the dose of diuretic
• Increasing the frequency of the dosing
• Restricting dietary sodium intake
• Adding a thiazide diuretic (see combination therapy below) [19]

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• COMBINING THIAZIDE AND LOOP DIURETICS

• Overview
• Over time, the effectiveness of loop diuretics can wane as the kidneys adapt to chronic diuretic therapy
• Patients with obvious fluid overload who do not respond to optimal doses of loop diuretics may benefit from the addition of a thiazide diuretic


• Effectiveness
• In studies, combination therapy has yielded a significant diuretic response in > 90% of patients
• Fluid loss (measured as weight loss) of 1 kg a day is common, but 3 - 5 kg loss over 24 hours has been seen


• Adverse effects
• Low potassium (hypokalemia) is a major concern with combination diuretic therapy
• Serum potassium reductions of 0.4 - 0.8 meq/L are common even with potassium supplements
• Increases in serum creatinine, sodium loss (hyponatremia), and dehydration are also a concern


• Thiazide choice
• Metolazone has been studied the most in combination therapy, but other thiazides (HCTZ, chlorothiazide) have also been shown to be effective [20]
• A small study (N=60) published in 2020 compared the effects of oral metolazone, IV chlorothiazide, or tolvaptan when added to high-dose furosemide in heart failure patients with diuretic resistance. All 3 therapies achieved similar weight loss at 48 hours. [PMID 31838029]


• Recommended dosing
• Metolazone 2.5 - 10 mg once a day, or 2.5 - 10 mg two to three times a week
• HCTZ 25 - 100 mg once a day
• Intravenous chlorothiazide 500 - 1000 mg given once or twice a day or intermittently [19,20]


• Summary
• When optimal doses of loop diuretics become ineffective, adding a thiazide diuretic can have a profound effect
• Electrolytes and fluid balance must be monitored closely when loop diuretics are combined with thiazides

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• SIDE EFFECTS

• Potassium loss
• Loop diuretics block potassium reabsorption from the renal tubule and this causes potassium to be lost in the urine
• The overall magnitude of this effect is not well defined. A small review that looked at potassium loss with diuretics is summarized below.


• STUDY
  Hypokalemia and diuretics: an analysis of publications, BMJ (1980) [PubMed abstract]
  • A review from the BMJ looked at trials involving furosemide that measured changes in potassium levels
  • Out of 11 studies involving 181 patients, the following effect of furosemide on potassium levels was seen:
  • At an average dose of 75 mg, furosemide caused an average decrease in potassium levels of 0.30 meq/L [35]
  
  
• Summary
• Loop diuretics cause potassium loss. The degree of potassium loss will vary greatly among patients, and will be affected by factors such as kidney function, other medications taken, diuretic dose, diet, and medical conditions. In practice, loop diuretics are often prescribed with potassium supplements. See hypokalemia for more.
• Potassium levels should be checked frequently when starting a loop diuretic or during dose adjustments. In chronic, stable therapy, potassium levels should be checked periodically.

• Increased urination
• The primary effect of loop diuretics is to promote fluid loss, and therefore, they also increase urination

• Low sodium (hyponatremia)
• Because loop diuretics promote sodium excretion, they can cause hyponatremia. The risk of hyponatremia from loop diuretics is lower than that of thiazide diuretics because loop diuretics also promote the excretion of free water where thiazide diuretics do not. Patient-specific factors that affect hyponatremia risk include dietary sodium intake, diuretic dose, concomitant medications, and comorbid medical conditions. See hyponatremia for more.
• Patients on chronic loop diuretic therapy should have their sodium levels checked periodically

• Increased uric acid (gout risk)
• Loop diuretics cause the kidneys to retain uric acid which can lead to higher blood uric acid levels. High uric acid levels can precipitate or worsen gout, an inflammatory joint disease.
• A number of case-control and cohort studies have found that the risk of gout is elevated in patients who take loop diuretics [39]
• The effect size of loop diuretics on uric acid levels is not well-defined. A study presented in the Demadex® PI found that the average uric acid level increased by 1.2 mg/dl in hypertensive patients taking Demadex® 10 mg/day for 6 weeks. [36]
• Summary
• If possible, patients with uncontrolled gout may want to avoid loop diuretics
• If loop diuretics are necessary, then uric acid levels should be monitored closely and treated appropriately

• Calcium loss (hypocalcemia)
• Loop diuretics promote calcium excretion, and this can lower serum calcium levels. A few small studies that looked at the magnitude of this effect are presented below.


• Studies
• Randomized trial
• In a randomized trial where participants took bumetanide or placebo for a year (see bone loss study below), urinary calcium excretion was increased by 44% from baseline in bumetanide-treated patients and by 26% in placebo-treated patients. Plasma calcium levels were not affected by bumetanide.
• Participants in both groups took calcium supplements and vitamin D throughout the trial [44]
• Cross-sectional study
• A cross-sectional study looked at the association of loop diuretic use and calcium levels
• Compared to nonusers, loop diuretic users had slightly lower average blood calcium levels (9.11 mg/dl vs 9.21 mg/dl) [102]
• Torsemide PI
• The Torsemide PI cites one study in heart failure patients that showed an average decrease in calcium levels of 0.10 mg/dl after one year of torsemide therapy [36]


• Summary
• Loop diuretics increase calcium excretion in the kidneys. To compensate for the loss, PTH levels rise and calcium is sequestered from bones (see calcium homeostasis). In long-term use, this may adversely affect bone health.

• Parathyroid hormone (PTH) levels
• Loop diuretics promote calcium excretion in the kidneys, and this causes serum calcium levels to fall. Decreasing calcium levels stimulate PTH release from the parathyroid gland. PTH promotes calcium retention in the kidneys, calcium absorption from the intestines, and calcium resorption from bones. See calcium regulation for more.
• The two small studies presented below looked at the effects of loop diuretics on PTH levels


• Studies
• Randomized controlled trial
• In a randomized trial where participants took bumetanide or placebo for a year (see bone loss study below), parathyroid levels were higher in the bumetanide group
• Placebo group had a decrease in PTH levels of 3% where PTH levels were increased by 5.6% in the bumetanide group
• Both groups received calcium and vitamin D supplements throughout the study [44]
• Cross-sectional study
• A cross-sectional study looked at the association of loop diuretic use and PTH levels in 3616 patients with chronic kidney disease
• Compared to nonusers, loop diuretic users had higher average levels of PTH (67.9 pg/ml vs 52.8 pg/ml, p<0.001)
• Compared to nonusers, loop diuretic users had a higher risk for secondary hyperparathyroidism (odds ratio 2.1, 95%CI [1.7 - 2.6]) [102]


• Summary
• Loop diuretics cause calcium loss and the body compensates for this by increasing parathyroid hormone secretion

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• SIDE EFFECTS | Bone loss

• Overview
• Loop diuretics cause the kidneys to excrete calcium, and this in turn stimulates PTH release. PTH promotes the mobilization of calcium from bones through bone resorption. In long-term use, this can have a detrimental effect on bone health.
• A randomized controlled trial and two observational studies that looked at the effects of loop diuretics on bone health are detailed below

• STUDY
  Loop diuretic use and increased rates of hip bone loss in older men, Arch Intern Med (2008) [PubMed abstract]
• This cohort study compared changes in bone mineral density (BMD) between men who took loop diuretics continuously (N=84) or intermittently (N=181) to nonusers (N=3004). Average follow-up was 4.6 years.
• Men who took loop diuretics continuously had twice the annual decline in bone mineral density at the hip as those who did not take loop diuretics
• Continuous users - average decrease of 0.78% hip BMD annually
• Intermittent users - average decrease of 0.58% hip BMD annually
• Nonusers - average decrease of 0.33% hip BMD annually
• Findings were similar for change in BMD at the femoral neck and trochanter

• STUDY
  Loop diuretic use and fracture in postmenopausal women: findings from the Women's Health Initiative, Arch Intern Med (2009) [PubMed abstract]
• This cohort study looked at the risk of fracture and BMD changes in women who took loop diuretics (N=3411) compared to nonusers (N=130,444). Average follow-up was 7.7 years.
• The following results were seen:
• There was no significant difference between loop diuretic users and nonusers for risk of hip fractures, vertebral fractures, or lower arm and wrist fractures
• An increased risk was found for other clinical fractures (HR 1.16 95%CI [1.01-133]) and total fractures (HR 1.16 95%CI [1.03-1.31]) with more than 3 years' use of loop diuretics
• There was no significant difference in BMD changes between loop diuretic users and nonusers

• Summary
• Loop diuretics promote calcium excretion and this appears to increase the risk of bone loss. Patients with osteoporosis and those who are at high risk for osteoporosis may want to avoid loop diuretics, although in many cases, this will not be an option
• Theoretically, calcium supplements may help attenuate this effect, but this has not proven in a clinical trial

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• Kidney stones
• Because loop diuretics promote calcium excretion into the urine, they could theoretically be associated with kidney stone formation
• In sick newborns that need furosemide, this is a known issue. In other patients, the risk is not well-defined. See kidney stones for more.

• Low magnesium (hypomagnesemia)
• Loop diuretics promote magnesium excretion in the kidneys, and this can lead to hypomagnesemia. Hypomagnesemia increases the risk of heart arrhythmias (see magnesium for more). Patients with heart failure are at increased risk of arrhythmias, and many of them are prescribed loop diuretics, so there is concern that hypomagnesemia may worsen outcomes in these patients. Studies that have looked at the long-term effects of hypomagnesemia in heart failure patients have come to differing conclusions. [47]
• AHA recommendations
• The AHA/ACC recommends that magnesium levels be checked on hospitalized heart failure patients, but makes no recommendation for outpatient or chronic care [19]
• Summary
• The clinical significance of magnesium loss from loop diuretics is unclear. Currently, there is no conclusive evidence that routine monitoring of magnesium levels is beneficial. The addition of an ENaC inhibitor can help to attenuate the loss of magnesium that is induced by loop diuretics (see magnesium retention with ENaC inhibitors for more).

• Photosensitivity
• Loop diuretics may cause the skin to become more sensitive to the sun and reactions may occur
• Limiting sun exposure and using sunscreen can help prevent reactions [85]

• Cholesterol (lipid parameters)
• Loop diuretics appear to cause a small, acute increase in total cholesterol, LDL cholesterol, and triglycerides [49,50,36]
• This effect may be related to hemoconcentration (increased concentration of blood products due to free water loss)
• In chronic therapy, loop diuretics do not appear to have a significant effect on lipid parameters [36]

• Elevated blood sugars / diabetes risk
• The effect of loop diuretics on blood sugar levels and diabetes risk is not well-defined
• Studies evaluating an effect have been mixed and inconsistent
• In long-term therapy, the effect does not appear to be significant [36, 52, 56, 57]

• Hearing loss / tinnitus
• In rare cases, loop diuretics have been associated with hearing loss and tinnitus (ringing in ears)
• Factors that may increase the risk include:
• Very high doses
• Severe kidney disease
• Intravenous (IV) dosing
• Low protein levels (hypoproteinemia)
• When given with certain medications - aminoglycoside antibiotics, cisplatin, ethacrynic acid, salicylates [56,57]

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• CONTRAINDICATIONS

• Bumetanide (Bumex®)
• Hypersensitivity to bumetanide
• Anuria (no urine output)
• Hepatic coma
• Severe electrolyte depletion


• Furosemide (Lasix®)
• Hypersensitivity to furosemide
• Anuria (no urine output)


• Torsemide (Demadex®)
• Hypersensitivity to torsemide
• Hypersensitivity to sulfonylureas (see sulfa allergy below)
• Anuria (no urine output)
• Hepatic coma
• Severe electrolyte depletion

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• PRECAUTIONS

• Kidney disease
• Patients with significant kidney disease need diuretics to help increase fluid elimination
• Loop diuretics are the most effective class of diuretics for eliminating fluid
• Loop diuretics maintain their effectiveness once the CrCl falls below 30 ml/min, where thiazide diuretics do not

• Liver disease
• Cirrhosis (Child-Pugh C)
• Patients with cirrhosis often need diuretics to control fluid retention
• Loop diuretics and spironolactone are preferred in these patients
• See liver failure above
• Mild to moderate liver disease (Child-Pugh A/B)
• Dosage adjustments are not typically needed

• Sulfa allergy
• Loop diuretics contain a sulfonamide group in their structure, but it is different from the one found in sulfa-based antibiotics. Patients with a history of sulfa-based antibiotic allergy have a small risk of having an allergic reaction to loop diuretics. A cohort study that examined the issue is detailed below.


• STUDY
  Cross-reactivity between sulfa-based antibiotics and sulfonamide nonantibiotics, NEJM (2003) [PubMed abstract]
• A cohort study in the NEJM looked at the risk of an allergic reaction to nonantibiotic sulfonamides in patients who had a previous reaction to a sulfa-based antibiotic
• The study found the following:
• Patients with a history of sulfa-based antibiotic allergy who subsequently took nonantibiotic sulfonamides (including loop diuretics) had a 10% risk of having a reaction to the nonantibiotic sulfonamide
• In patients without a history of allergic reaction to a sulfa-based antibiotic, 1.6% had a reaction to a nonantibiotic sulfonamide
• Patients with a history of sulfa-based antibiotic allergy had a 14% chance of having a reaction to a penicillin antibiotic. This finding led researchers to conclude that a history of allergic reactions, in general, may be more predictive of a reaction than reactions to any specific medication [15]


• Summary
• Patients with a history of sulfa-based antibiotic allergy have about a 10% chance of reacting to a loop diuretic. Patients with a history of severe reaction to sulfa-based antibiotics should avoid nonantibiotic sulfonamides if possible. If not, the initial dosing should be done under medical supervision.

• Gout
• Loop diuretics can increase uric acid levels
• Patients with uncontrolled gout should avoid loop diuretics if possible. Patients with gout who need loop diuretics should monitor uric acid levels and treat appropriately.
• See uric acid above

• Prolonged QT interval
• Loop diuretics may cause hypokalemia which can increase the risk of Torsades de pointes in patients with prolonged QT interval
• Loop diuretics should be avoided if possible in patients with congenital long QT syndrome

• Osteoporosis
• Loop diuretics promote calcium loss which in turn can lead to bone loss (see bone loss above)
• Patients with osteoporosis should avoid loop diuretics if possible. If loop diuretics are necessary, bone density should be monitored.

• Kidney stones
• Loop diuretics increase the excretion of calcium into the urine. This may increase the risk of kidney stone formation.
• Patients with a history of kidney stones should avoid loop diuretics if possible

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• DRUG INTERACTIONS

• NOTE: Drug interactions presented here are NOT all-inclusive. Other interactions may exist. The interactions presented here are meant to encompass commonly prescribed medications and/or interactions that are well-documented. Always consult your physician or pharmacist before taking medications concurrently. CLICK HERE for more information on drug interactions.


• All loop diuretics
• Aminoglycoside antibiotics (gentamicin, etc) - Loop diuretics and aminoglycoside antibiotics both have the potential to cause ototoxicity (hearing loss). The risk may be increased when they are taken together.
• Bile Acid Sequestrants (Questran®, Welchol®, etc) - Bile acid sequestrants may decrease the absorption of loop diuretics. Loop diuretics should be taken one hour before or 4 hours after bile acid sequestrants.
• Cisplatin - Loop diuretics and cisplatin both have the potential to cause ototoxicity (hearing loss). The risk may be increased when they are taken together. Loop diuretics may also increase the risk of kidney damage from cisplatin.
• Cyclosporine - Loop diuretics and cyclosporine both increase the risk of gout. When taken together, the risk may be compounded.
• Ethacrynic acid - Loop diuretics and ethacrynic acid both have the potential to cause ototoxicity (hearing loss). The risk may be increased when they are taken together.
• Lithium - Loop diuretics may reduce the clearance of lithium. Loop diuretics should not be taken with lithium if possible. Lithium levels should be monitored closely in patients taking loop diuretics.
• Methotrexate - Loop diuretics may increase blood levels of methotrexate and vice versa.
• NSAIDS (Advil®, ibuprofen, naprosyn, etc.) - NSAIDS can block the therapeutic effect of all diuretics. Patients should monitor for decreased effectiveness of diuretics when taking NSAIDS for extended periods.
• Probenecid - Probenecid may inhibit the action of loop diuretics
• Salicylates (Aspirin, etc.) - In patients receiving high doses of salicylates, loop diuretics may block their clearance and increase the risk of salicylate toxicity.
• Thyroid hormone (Synthroid®, levothyroxine, etc.) - high doses of furosemide (> 80 mg) may inhibit binding of thyroid hormone to thyroxine-binding globulin (TBG). This can increase free levels of thyroid hormone and subsequently lead to a decrease in total (free and bound) thyroid.


• Furosemide
• Sucralfate (Carafate®) - Sucralfate may inhibit the effects of furosemide. Intake should be separated by 2 hours.
• Cephalosporin antibiotics (Keflex®, Rocephin®, etc) - Furosemide may potentiate the risk of cephalosporin-induced kidney damage
• Phenytoin (Dilantin®) - Phenytoin may inhibit the diuretic effect of furosemide

• Metabolism and clearance
• Furosemide
• Furosemide does not undergo extensive liver metabolism
• Bumetanide
• The liver metabolism of bumetanide is not well-defined
• Torsemide
• CYP2C9 - substrate
• CYP2C8 - substrate

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• PHARMACOKINETICS

Drug	Peak effect	Duration of effect
Furosemide	1 - 2 hours	6 - 8 hours
Bumetanide	1 - 2 hours	4 - 6 hours
Torsemide	1 - 2 hours	6 - 8 hours

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• DOSING

• Loop diuretic dosing chart

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• LONG-TERM SAFETY

• Loop diuretics have been in use since the 1960s. They have been prescribed to millions of people.
• Loop diuretics have been proven safe when prescribed appropriately

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