LOOP DIURETICS

































Potassium loss
Overview
  • 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 effects 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
  • 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

Low sodium (hyponatremia)

Increased uric acid (gout risk)
Overview
  • 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)
Overview
  • Loop diuretics cause the kidneys to excrete calcium
  • Urinary loss of calcium can affect blood levels of calcium
Studies
  • Randomized trial
    • In a randomized trial where participants took bumetanide or placebo for a year (see bone loss 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. In long-term use, this may adversely affect bone health.

Parathyroid hormone (PTH) levels
Overview
  • Parathyroid hormone is a hormone that increases blood levels of calcium by stimulating calcium release from bones and by promoting calcium reabsorption from the kidneys and intestines
  • Because loop diuretics cause calcium loss in the urine, parathyroid hormone excretion is often increased to counteract this effect
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



Overview
  • Loop diuretics cause the kidneys to excrete (lose) calcium
  • Calcium loss can increase the risk of bone loss and osteoporosis
  • We found several studies that evaluated the effects of loop diuretics on bone health
Bumetanide vs Placebo for BMD changes in women with Osteopenia, J of Bone and Mineral Res (2006) [PubMed abstract]
  • The trial enrolled 87 postmenopausal women with osteopenia
Main inclusion criteria
  • > 50 years old
  • > 12 months since last menses
  • Osteopenia at lumbar spine or total hip
Main exclusion criteria
  • Hypo- or hyperthyroidism within last 5 years
  • Diuretic treatment within last 3 months
  • Received treatment with corticosteroids, anticonvulsants, NSAIDs, bisphosphonates, estrogen, or raloxifene in last 2 years
Baseline characteristics
  • Average age 66 years
  • Median T-score lumbar spine -1.7
  • Median T-score total hip -1.4
  • Taking calcium supplements ∼ 41%
Randomized treatment groups
  • Group 1 (46 patients) - Bumetanide 2 mg once daily
  • Group 2 (41 patients) - Placebo once daily
  • All patients took calcium 800 mg + cholecalciferol 10 mcg throughout the study
  • Bumetanide 2 mg is considered equivalent to furosemide 80 mg
Primary outcome: Percentage change at week 52 from baseline in BMD at the lumbar spine and total hip
Results

Duration: 52 weeks
Outcome Bumetanide Placebo Comparisons
Primary outcome (lumbar spine) -0.69% +0.26% p=0.08
Primary outcome (total hip) -1.61% +0.32% p=0.003
Plasma PTH levels (% change) +5.6% -3.0% p=0.003
Urinary calcium excretion (% change) +44% +26% p<0.01

Findings: Treatment with loop diuretics affects bone turnover and decreases BMD. Further studies may reveal whether loop diuretics should be considered as a risk factor for fracture.
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
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 or 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


Kidney stones

Low magnesium (hypomagnesemia)
Overview
  • Loop diuretics cause the kidneys to excrete (lose) magnesium
  • Low magnesium levels may be a particular concern in heart failure patients since they have been associated with heart arrhythmias
  • A handful of cohort studies have come to differing conclusions on the long-term effects of low magnesium levels in heart failure patients [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 caused by loop diuretics is unclear
  • Currently, there is no conclusive evidence that routine monitoring of magnesium levels is beneficial

Photosensitivity

Cholesterol (lipid parameters)

Elevated blood sugars / diabetes risk

Hearing loss / tinnitus






Kidney disease

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
Overview
  • Loop and thiazide diuretics contain a sulfonamide group in their structure
  • The sulfonamide group is different from the one that is found in sulfa-based antibiotics
  • Patients with a history of allergy to sulfa-based antibiotics may be at a slightly increased risk of an allergic reaction to thiazide and loop diuretics
  • A study that looked at the potential cross-reactivity is summarized 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 thiazide and 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
    • In addition, 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 [84]
Summary
  • Loop and thiazide diuretics may be prescribed to patients with a history of sulfa-based antibiotic allergy
  • Patients should be aware that a cross-sensitivity reaction may occur with a risk of around 10%
  • Patients with a history of severe reactions to sulfa-based antibiotics should avoid nonantibiotic sulfonamides if they can. If not, then the initial dosing should be done under medical supervision.

Gout

Prolonged QT interval

Osteoporosis

Kidney stones



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



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