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.

Last updated: July 10, 2023

CONTENTS

Overview
Chemistry and Pharmacodynamics
Pharmacokinetics
Indications, Contraindications, and Adverse Effects
Comparison of Medications
References

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 Class Subclasses

action

Renal drugs Drugs affecting the RAAS ACEis

ARBs
Direct renin inhibitors

Diuretics Thiazide diuretics

Loop diuretics
Potassium-sparing diuretics

Extrarenal Direct vasodilators Calcium channel blockers

drugs Potassium channel openers
Nitrodilators
Endothelin antagonists

Agents acting via the Drugs affecting CNS sympathetic

sympathetic nervous outflow (e.g., clonidine)
system 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

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 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 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

Drug Absorption Distribution Metabolism Excretion

Furosemide Peak effect: Protein Minimal Urine

(Lasix®) Oral: 1–2 binding: hepatic (some
hours 95% metabolism fecal)
IV: 30 Half-life:
minutes Normal
Bioavailability: renal
50% function:
0.5–2
hours
ESRD: 9
hours

Bumetanide Peak effect: Vd: 9–25 Partial Urine

(Bumex®) Oral: 1–2 L hepatic Feces (2%)
hours Protein metabolism Half-life:
IV: 30 binding: 60–90
minutes 95% minutes
Bioavailability:
60%–90%

Torsemide Peak effect: Vd: 12–15 Hepatic Urine

(Demadex®) 1–2 hours L (80%) via Half-life:
Bioavailability: Protein CYP2C9 3.5 hours
80% binding:
> 99%

Ethacrynic Peak effect: Protein Hepatic Feces and

acid Oral: 2 hours binding: > (40%) via urine
(Edecrin®) IV: 30 90% active Half-life:
minutes cysteine 2–4 hours
conjugate

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

Medication Mechanism Physiologic Indication

effect
Medication Mechanism Physiologic Indication
effect

Thiazide diuretic: ↓ Reabsorption ↓ Blood Hypertension

Hydrochlorothiazide of NaCl in the pressure Edema
DCT through ↓ Edema
the inhibition of
Na+/Cl-
cotransporter

Loop diuretic: Inhibits the ↓ Edema Edema/ascites

Furosemide luminal ↓ Blood HF
Na+/K+/Cl- pressure Hypertension
cotransporter in
the thick
ascending limb
of the loop of
Henle

Potassium-sparing ↓ ↓ Blood HF
diuretic: Reabsorption pressure Edema/ascites
Spironolactone of Na ↓ Edema Hypertension
through the Does not Hirsutism in
ENaC cause ↑ females
channels in excretion Primary
the CD of K+ hyperaldosteronism
Inhibition of Anti-
aldosterone androgenic
receptors in effects
the CD

Carbonic anhydrase Inhibits both ↑ Urinary Edema in patients

inhibitor: the hydration of excretion with metabolic
Acetazolamide CO2 in the PCT of HCO3– alkalosis
epithelial cells → Altitude sickness
and the metabolic ↑ Intraocular
dehydration of acidosis pressure
H2CO3 in the ↓ Off label: normal
PCT lumen; Intraocular pressure
hydrocephalus
results in ↑ pressure
HCO3– and Na+
excretion
 Medication Mechanism Physiologic Indication
effect

Osmotic diuretics: ↑ Osmotic ↓ Free Increased

Mannitol pressure in the water intracranial
glomerular ↓ Cerebral pressure
filtrate → ↑ blood Increased
tubular fluid volume intraocular
and prevents pressure
water
reabsorption

PCT: proximal convoluted tubule

DCT: distal convoluted tubule
HF: heart failure

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

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

References
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