Loop diuretics

Last updated on: 18.12.2020

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Loop diuretics selectively inhibit NaCl reabsorption in the thick ascending branch of the loop of Henle by inhibiting the Na+/K+/2Cl- symporter (co-transporter). Because of the high absorption capacity in this segment, loop diuretics are the most efficient diuretic agents. Loop diuretics have an approximately linear dose-response relationship over a wide dose range. This means that a stronger diuresis can be achieved with an increase in dose (ceiling effect).

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Loop diuretics can be classified according to their chemical structure into:

  • sulfonamide derivatives and
  • non-sulfonamide derivatives.

The sulfonamide derivatives include the active ingredients

  • Furosemide
  • Bumetanide
  • Piretanide (carrying a carboxy group on the central benzene ring)
  • Azosemide also a sulfonamide (carries no carboxy group on the central benzene ring).

Non-sulfonamide derivatives:

  • Torasemide (pyridinesulfonylurea derivative).
  • Etacrynic acid (halogenated phenoxyacetic acid, with attached ketone and methylene groups).
  • Etozolin.

Pharmacodynamics (Effect)
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In the kidney, metabolic end products are filtered out of the blood and excreted with the urine. Initially, about 180 to 200 litres of primary urine are produced daily, which is then concentrated in the subsequent system of tubules, loop of Henle and collecting tubes by reabsorption of water until only about 1 to 1.5 litres of final urine or secondary urine remain. Furthermore, important substances such as glucose, amino acids and electrolytes are reabsorbed.

Specifically, in the thick ascending part of Henle`s loop, the luminal Na+/K+-2CL--symporter takes care of Na+ reabsorption. This transporter utilizes the driving force of the electrochemical Na+ gradient and catalyzes an electroneutral uptake of 1Na+, 2CL-, and 1K+.

In this process, the uptake of Cl- and K+ occurs against prevailing gradients.

The uptaken Na+ leaves the cell via the basolateral side via the Na+/K+ pump.

The absorbed Cl- also diffuses on the basolateral side of the tubule cell through the Cl- channels there back into the lumen. Similarly, on the basolateral side of the tubule cell, the absorbed K+ diffuses back into the lumen through the luminal K+ channels.

This process of "channel-mediated diffusion of potassium ions" leads to hyperpolarization of the luminal membrane.

This creates a lumen-positive, transepithelial, electrochemical potential. As a result, cations such as potassium, calcium and magnesium ions are reabsorbed paracellularly. The luminal Na+, K+, 2CL- -symporter (cotransporter) of the tubule cells in the macula densa acts there as a sensor for the luminal NaCl concentration.

Loop diuretics are reversible inhibitors of luminal Na+, K+,2CL- -symporters in the thick ascending limb of the loop of Henle. By binding to the CL- -binding site of the transport protein, they inhibit its function. Sodium can no longer be reabsorbed. The NaCl excretion in the urine is massively increased. This leads to increased water excretion through osmosis.

Furthermore, negative membrane tension can no longer be built up as a result. Calcium and magnesium ions remain in the urine and are also lost to the body.

Loop diuretics also inhibit the Na+K+2Cl- symporters of the macula densa, resulting in an increase in the glomerular filtration rate (GFR). (see: glomerular feedback). After discontinuation of the drug, the organism tries to compensate for the loss of water and sodium ions. For this purpose, the physiological counter-regulatory mechanisms of the sympathico-adrenal and the RAAS (renin-angiotensin-aldosterone system) are activated. This reduces the glomerular filtration rate as well as the urine volume (postdiuretic sodium retention).

Loop diuretics are the diuretics with the highest maximum natriuretic effect (high-ceiling diuretics).

The natriuretic effect of loop diuretics is also responsible for their antihypertensive effect. They are rapidly eliminated. Furthermore, they lower the preload of the left heart. This is due to increased prostaglandin synthesis in the kidneys.

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Cardiac, hepatic and renal edema

Oliguria in advanced renal failure

Cardiac pulmonary edema

Chronic heart failure

Arterial hypertension

Severe hyponatremia (along with hypertonic NaCl solution)


Severe hyperkalemia

Forced diuresis in poisoning (drugs that are eliminated renally such as lithium, amphetamines)

Undesirable effects
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Due to the strong effect of loop diuretics, regular monitoring of the electrolyte concentration in the serum is necessary (exclusion of hypovolemia due to excessive drainage -dizziness, headache, tendency to collapse and orthostatic hypotension-). In severe cases, dehydration and exsiccosis may occur.

Increased excretion of potassium ions and protons may lead to hypokalemic metabolic alkalosis (administration of potassium and treatment of hypovolemia).

For further adverse reactions, see individual substances. Furthermore, long-term use often leads to decreased magnesium and calcium in the blood (hypomagnesemia and hypocalcemia, respectively).

At equivalent doses, loop diuretics cause less hypokalemia than thiazides.

With all loop diuretics, hearing impairment in the high frequencies up to deafness may occur due to inhibition of the Na+K+2Cl- symporter, as no potassium concentration gradient can be established (ototoxicity). This effect occurs depending on the dose and generally only during the treatment, only when using etacrynic acid the damage may be permanent.

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S. u. the individual substances

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See below the individual substances. If the use of loop diuretics is absolutely necessary despite existing contraindications, an exact balance, in particular of the electrolyte balance, is carried out.

Representatives of the sulfonamide diuretics must not be used, even in cases of known allergy to other sulfonamides.

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Furosemide is mainly excreted renally, piretanide and torasemide are eliminated metabolically and renally.

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  1. Fallahzadeh MA et al. (2017) Acetazolamide and Hydrochlorothiazide Followed by Furosemide Versus
  2. Furosemide and Hydrochlorothiazide Followed by Furosemide for the Treatment of
  3. Adults With Nephrotic Edema: A Randomized Trial. Am J Kidney Dis 69:420-427.
  4. Thestrup-Pedersen K (1987) Adverse reactions in the skin from anti-hypertensive drugs. Dan Med Bull 34 Suppl 1:3-5.

Incoming links (2)

Aldosteron-antagonists; Diuretics;

Last updated on: 18.12.2020