Loop Diuretics

Loop diuretics are a group of diuretic medications primarily used to treat fluid overload in edematous conditions such as heart failure and cirrhosis. Loop diuretics also treat hypertension, but not as a 1st-line agent. The medication inhibits sodium reabsorption through the NKCC2 cotransporter in the thick ascending limb of the loop of Henle (TAL), leading to significant diuresis. Careful monitoring is important because loop diuretics result in increased excretion of sodium, potassium, chloride, calcium, magnesium, and water. In addition to electrolyte and fluid abnormalities, loop diuretics can lead to nephrotoxicity and ototoxicity.

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Overview

Definition

Loop diuretics are a group of medications primarily used to treat edema (and sometimes hypertension) by inhibiting sodium reabsorption through the NKCC2 cotransporter (as known as the Na+-K+-Cl cotransporter) in the thick ascending limb of the loop of Henle (TAL), which lead to significant diuresis.

Overview of antihypertensive agents

Table: Drugs used to treat hypertension
Location of actionClassSubclasses
Renal drugsDrugs affecting the RAAS
  • ACEis
  • ARBs
  • Direct renin inhibitors
Diuretics
  • Thiazide diuretics
  • Loop diuretics
  • Potassium-sparing diuretics
Extrarenal drugsDirect vasodilators
  • Calcium channel blockers
  • Potassium channel openers
  • Nitrodilators
  • Endothelin antagonists
Agents acting via the sympathetic nervous system
  • Drugs affecting CNS sympathetic outflow (e.g., clonidine)
  • Drugs affecting the ganglia (e.g., hexamethonium)
  • Drugs affecting the nerve terminals (e.g., guanethidine, reserpine)
  • Drugs affecting the α and β receptors

Drugs in the loop diuretic class

Drugs include: 

  • Furosemide (prototypical drug in the class)
  • Bumetanide
  • Torsemide
  • Ethacrynic acid

Chemistry and Pharmacodynamics

Chemical structure

  • All the loop diuretics are sulfonamides except ethacrynic acid.
  • Ethacrynic acid may be used in cases where patients have allergies to furosemide, bumetanide, and/or torsemide.
Chemical structure of furosemide

Chemical structure of furosemide

Image: “Furosemide” by Fvasconcellos. License: Public Domain

Mechanism of action

  • Blocks reabsorption of Na+, K+, and Cl through the inhibition of NKCC2 cotransporter in the TAL:
    • The channel is located on the apical side.
    • Reabsorbs 1 Na+, 1 K+, and 2 Cl from the tubule lumen into the cells
  • With the channel blocked → ↓ Na+ reabsorption
  • Water always follows Na+:
    • Water stays with Na+ in the tubules and is not reabsorbed.
    • The osmotic effect of Na+ results in diuresis.
Action of loop diuretics

Action of loop diuretics in the thick ascending limb of the loop of Henle (TAL)

Image by Lecturio. License: CC BY-NC-SA 4.0

Physiologic effects

  • ↑ Excretion of Na+, K+, Cl by blocking the NKCC2 cotransporter
  • Diuresis:
    • ↓ Blood volume → ↓ cardiac preload
    • Removes fluid from the body → improves edema
  • Inhibits the ability of the kidney to dilute or concentrate urine
  • ↑ Excretion of Ca2+ and Mg2+:
    • The interstitial fluid is relatively more negative compared to the tubular lumen.
    • The electrochemical gradient drives passive paracellular reabsorption of Ca2+ and Mg2+.
    • Blocking the NKCC2 transporter leads to ↓ reabsorption of Ca2+ and Mg2+ → ↑ excretion of Ca2+ and Mg2+
    • Patients have an increased risk of hypomagnesemia, hypocalcemia, and nephrolithiasis.
Passive paracellular reabsorption of magnesium and calcium

Passive paracellular reabsorption of magnesium and calcium in the thick ascending limb of the loop of Henle (TAL): driven by the voltage gradient between the tubular lumen (apical side) and the interstitial fluid (basolateral side)

Image by Lecturio. License: CC BY-NC-SA 4.0

Pharmacokinetics

  • Absorption:
    • Absorption varies among agents
    • Can be absorbed orally (slightly slower onset of action) or intravenously (faster)
    • Bioavailability: bumetanide and torsemide > furosemide
  • Distribution:
    • Highly protein-bound → no renal filtration
    • Renal excretion in the proximal tubule via organic anion transport (OAT) pumps
  • Metabolism:
    • Bumetanide and torsemide: mostly inactivated in the liver by cytochrome P450 (CYP450)
    • Furosemide: minimal hepatic metabolism
  • Excretion:
    • Mostly renal excretion as an unchanged drug
    • Half-life range: 1–4 hours
Table: Pharmacokinetics of loop diuretics
DrugAbsorptionDistributionMetabolismExcretion
Furosemide (Lasix®)
  • Peak effect:
    • Oral: 1–2 hours
    • IV: 30 minutes
  • Bioavailability: 50%
Protein binding: 95%Minimal hepatic metabolism
  • Urine (some fecal)
  • Half-life:
    • Normal renal function: 0.5–2 hours
    • ESRD: 9 hours
Bumetanide (Bumex®)
  • Peak effect:
    • Oral: 1–2 hours
    • IV: 30 minutes
  • Bioavailability: 60%–90%
  • Vd: 9–25 L
  • Protein binding: 95%
Partial hepatic metabolism
  • Urine
  • Feces (2%)
  • Half-life: 60–90 minutes
Torsemide (Demadex®)
  • Peak effect: 1–2 hours
  • Bioavailability: 80%
  • Vd: 12–15 L
  • Protein binding: > 99%
Hepatic (80%) via CYP2C9
  • Urine
  • Half-life: 3.5 hours
Ethacrynic acid (Edecrin®)Peak effect:
  • Oral: 2 hours
  • IV: 30 minutes
Protein binding: > 90%Hepatic (40%) via active cysteine conjugate
  • Feces and urine
  • Half-life: 2–4 hours
ESRD: end-stage renal disease

Indications, Contraindications, and Adverse Effects

Indications

  • Edema: 
    • Includes:
      • Peripheral edema
      • Pulmonary edema
      • Generalized edema
      • Ascites
    • Resulting from:
      • Heart failure (used for symptomatic management; no mortality benefit)
      • Hepatic disease/cirrhosis
      • Renal disease, including nephrotic syndrome
  • Hypertension: 
    • Not 1st-line agents
    • Typically used in combination with other agents
    • Most commonly used in heart failure patients with hypertension presenting with fluid overload

Contraindications

  • Anuria
  • Allergy to sulfa drugs (except ethacrynic acid)
  • Hepatic coma
  • Severe electrolyte depletion
  • Ethacrynic acid in infants

Significant adverse effects and toxicity

  • Nephrotoxicity
  • Ototoxicity
  • Fluid and electrolyte loss, which may predispose to:
    • Cardiac arrhythmias 
    • Orthostatic hypotension
    • Dehydration
    • Dizziness/vertigo/syncope
    • Headaches
    • GI symptoms (abdominal cramps, nausea, constipation, diarrhea)
    • Muscle cramps
  • Photosensitivity

Mnemonic:

To recall the adverse effects of loop diuretics, remember “Ohh Daang”:

  • Ototoxicity
  • Hypokalemia
  • Hypomagnesemia
  • Dehydration
  • Allergy (sulfa)
  • Alkalosis (metabolic)
  • Nephritis (interstitial)
  • Gout

Precautions

Loop diuretics should be used with caution in the following situations:

  • In electrolyte, fluid, or acid-base abnormalities, loop diuretics can cause:
    • Hypokalemia (↓ K+)
    • Hyponatremia (↓ Na+)
    • Hypocalcemia (↓ Ca2+) (thiazides tend to cause hypercalcemia)
    • Hypomagnesemia (↓ Mg2+)
    • Metabolic alkalosis
    • Prerenal azotemia
    • Hypovolemia
  • Taken with another medication increasing the risk for hypokalemia:
    • Corticosteroids
    • Certain antipsychotics drugs
    • Amphotericin B
  • Taken with another medication increasing the risk for nephrotoxicity and/or ototoxicity:
    • Aminoglycosides 
    • Probenecid
  • Certain medical conditions:
    • Hyperuricemia/gout (may precipitate gout)
    • Systemic lupus erythematosus (SLE) (may cause a flare)
    • Kidney and/or liver disease
    • QT prolongation (may worsen secondary to diuretic-induced hypokalemia)
    • Pregnancy and lactation

Comparison of Medications

Thiazide diuretics, potassium-sparing diuretics, carbonic anhydrase inhibitors, and osmotic diuretics are also common diuretics.

Table: Comparison of diuretics
MedicationMechanismPhysiologic effectIndication
Thiazide diuretic: Hydrochlorothiazide↓ Reabsorption of NaCl in the DCT through the inhibition of Na+/Cl cotransporter
  • ↓ Blood pressure
  • ↓ Edema
  • Hypertension
  • Edema
Loop diuretic: FurosemideInhibits the luminal Na+/K+/Cl cotransporter in the thick ascending limb of the loop of Henle
  • ↓ Edema
  • ↓ Blood pressure
  • Edema/ascites
  • CHF
  • Hypertension
Potassium-sparing diuretic: Spironolactone
  • ↓ Reabsorption of Na through the ENaC channels in the CD
  • Inhibition of aldosterone receptors in the CD
  • ↓ Blood pressure
  • ↓ Edema
  • Does not cause ↑ excretion of K+
  • Anti-androgenic effects
  • CHF
  • Edema/ascites
  • Hypertension
  • Hirsutism in females
  • Primary hyperaldosteronism
Carbonic anhydrase inhibitor: AcetazolamideInhibits both the hydration of CO2 in the PCT epithelial cells and the dehydration of H2CO3 in the PCT lumen; results in ↑ HCO3 and Na+ excretion
  • ↑ Urinary excretion of HCO3 → metabolic acidosis
  • ↓ Intraocular pressure
  • Edema in patients with metabolic alkalosis
  • Altitude sickness
  • ↑ Intraocular pressure
  • Off label: normal pressure hydrocephalus
Osmotic diuretics: Mannitol↑ Osmotic pressure in the glomerular filtrate → ↑ tubular fluid and prevents water reabsorption
  • ↓ Free water
  • ↓ Cerebral blood volume
  • Increased intracranial pressure
  • Increased intraocular pressure
PCT: proximal convoluted tubule
DCT: distal convoluted tubule
CHF: congestive heart failure
Diuretics

The sites of action within the nephron for the diuretic drug classes

Image by Lecturio. License: CC BY-NC-SA 4.0

References

  1. The American Society of Health-System Pharmacists. (2021). Furosemide. Retrieved February 18, 2021, from https://www.drugs.com/monograph/furosemide.html#
  2.  Fischer, J., Ganellin, C.R. (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 458.
  3. World Health Organization. (2019). World Health Organization model list of essential medicines: 21st list 2019. http://apps.who.int/iris/handle/10665/325771
  4. Kane, S.P. (2020). Furosemide. Retrieved February 18, 2021, from https://clincalc.com/DrugStats/Drugs/Furosemide
  5. King, K.C. Goldstein, S. (2021). Congestive Heart Failure And Pulmonary Edema. StatPearls, Treasure Island (FL): StatPearls Publishing. Retrieved May 8, 2021, from https://pubmed.ncbi.nlm.nih.gov/32119444/
  6. Felker, G.M., et al. (2011). Diuretic strategies in patients with acute decompensated heart failure. N Engl J Med. 364(9), 797–805. https://pubmed.ncbi.nlm.nih.gov/21366472/
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  8. Whelton, P.K., et al. (2018). 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 71(6), e13–e115. https://pubmed.ncbi.nlm.nih.gov/29133356/
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  11. Shankar, S.S., Brater, D.C. (2003). Loop diuretics: from the Na-K-2Cl transporter to clinical use. Am J Physiol Renal Physiol. 284(1), F11–21. https://pubmed.ncbi.nlm.nih.gov/12473535/
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  15. Mann, J.F. (2020). Choice of drug therapy in primary (essential) hypertension. In Forman, J.P. (Ed.), UpToDate. Retrieved June 14, 2021, from https://www.uptodate.com/contents/choice-of-drug-therapy-in-primary-essential-hypertension 
  16. Brater, D.C., Ellison, D.H. (2019). Loop diuretics: Dosing and major side effects. In Forman, J.P. (Ed.), UpToDate. Retrieved June 15, 2021, from https://www.uptodate.com/contents/loop-diuretics-dosing-and-major-side-effects 
  17.  UpToDate Lexicomp Drug Topic Pages. Furosemide; Bumetanide; Torsemide; Ethacrynic acid. Retrieved June 15, 2021, from
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    2. https://www.uptodate.com/contents/bumetanide-drug-information
    3. https://www.uptodate.com/contents/torsemide-torasemide-drug-information 
    4. https://www.uptodate.com/contents/ethacrynic-acid-drug-information 
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