Loop diuretic

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Loop diuretic
Drug class
Loop diuretics.svg
Structure of the loop diuretics Furosemide, Azosemide, Bumetanide, Piretanide, Torasemide, Ethacrynic acid and Etozolin
Class identifiers
Synonyms High-ceiling diuretic [1]
Use congestive heart failure, nephrotic syndrome, cirrhosis, hypertension, edema [2]
ATC code C03C
Biological target Na-K-Cl cotransporter [3]
External links
MeSH D049994
Legal status
In Wikidata

Loop diuretics are pharmacological agents that primarily inhibit the Na-K-Cl cotransporter located on the luminal membrane of cells along the thick ascending limb of the loop of Henle. [4] They are often used for the treatment of hypertension and edema secondary to congestive heart failure, liver cirrhosis, or chronic kidney disease. While thiazide diuretics are more effective in patients with normal kidney function, loop diuretics are more effective in patients with impaired kidney function. [5]

Contents

Mechanism of action

Loop diuretics are 90% bonded to proteins and are secreted into the proximal convoluted tubule through organic anion transporter 1 (OAT-1), OAT-2, and ABCC4. Loop diuretics act on the Na+-K+-2Cl− symporter (NKCC2) in the thick ascending limb of the loop of Henle to inhibit sodium, chloride and potassium reabsorption. This is achieved by competing for the Cl− binding site. Loop diuretics also inhibit NKCC2 at macula densa, reducing sodium transported into macula densa cells. This stimulates the release of renin, which through renin–angiotensin system, increases fluid retention in the body, increases the perfusion of glomerulus, thus increasing glomerular filtration rate (GFR). At the same time, loop diuretics inhibit the tubuloglomerular feedback mechanism so that increase in salts at the lumen near macula densa does not trigger a response that reduces the GFR. [6]

Loop diuretics also inhibit magnesium and calcium reabsorption in the thick ascending limb. Absorption of magnesium and calcium are dependent upon the positive voltage at the luminal side and less positive voltage at the interstitial side with transepithelial voltage gradient of 10 mV. This causes the magnesium and calcium ions to be repelled from luminal side to interstitial side, promoting their absorption. The difference in voltage in both sides is set up by potassium recycling through renal outer medullary potassium channel. By inhibiting the potassium recycling, the voltage gradient is abolished and magnesium and calcium reabsorption are inhibited. [7] By disrupting the reabsorption of these ions, loop diuretics prevent the generation of a hypertonic renal medulla. Without such a concentrated medulla, water has less of an osmotic driving force to leave the collecting duct system, ultimately resulting in increased urine production. Loop diuretics cause a decrease in the renal blood flow by this mechanism. This diuresis leaves less water to be reabsorbed into the blood, resulting in a decrease in blood volume.[ citation needed ]

A secondary effect of loop diuretics is to increase the production of prostaglandins, which results in vasodilation and increased blood supply to the kidney. [8] [9] Prostaglandin-mediated vasodilation of preglomerular afferent arterioles increases the glomerular filtration rate (GFR) and facilitates diuresis. The collective effects of decreased blood volume and vasodilation help decrease blood pressure and ameliorate edema.[ citation needed ]

Pharmacokinetics

Loop diuretics are highly protein bound and therefore have a low volume of distribution. The protein bound nature of the loop diuretic molecules causes it to be secreted via several transporter molecules along the luminal wall of the proximal convoluted tubules to be able to exert its function.[ citation needed ]

Loop diuretics usually have a ceiling effect whereby doses greater than a certain maximum amount will not increase the clinical effect of the drug. Also, there is a threshold minimum concentration of loop diuretics that needs to be achieved at the thick ascending limb to enable the onset of abrupt diuresis. [10]

The availability of furosemide is highly variable, ranging from 10% to 90%. The biological half-life of furosemide is limited by absorption from the gastrointestinal tract into the bloodstream. The apparent half-life of its excretion is higher than the apparent half-life of absorption via the oral route. Therefore, furosemide taken intravenously is twice as potent as an equivalent dose taken orally. [6]

However, for torsemide and bumetanide, their oral bioavailability is consistently higher than 90%. Torsemide has a longer half life in heart failure patients (6 hours) than furosemide (2.7 hours). A 40 mg dose of furosemide is clinically equivalent to a 20 mg dose of torsemide and to a 1 mg dose of bumetanide. [6]

Clinical use

Loop diuretics are principally used in the following indications:

The 2012 KDIGO (Kidney Disease: Improving Global Outcomes) guidelines stated that diuretics should not be used to treat acute kidney injury, except for the management of volume overload. Diuretics has not shown any benefits of preventing or treating acute kidney injury. [16]

They are also sometimes used in the management of severe hypercalcemia in combination with adequate rehydration. [17]

Resistance

Diuretic resistance is defined as failure of diuretics to reduce fluid retention (can be measured by low urinary sodium) despite using the maximal dose of drugs. There are various causes for the resistance towards loop diuretics. After initial period of diuresis, there will be a period of "post-diuretic sodium retention" where the rate of sodium excretion does not reach as much as the initial diuresis period. Increase intake of sodium during this period will offset the amount of excreted sodium, and thus causing diuretic resistance. Prolonged usage of loop diuretics will also contributes to resistance through "braking phenomenon". This is the body physiological response to reduced extracellular fluid volume, where renin-angiotensin-aldosterone system will be activated which results in nephron remodelling. Nephron remodeling increases the number of distal convoluted cells, principle cells, and intercalated cells. These cells have sodium-chloride symporter at distal convoluted tubule, epithelial sodium channels, and chloride-bicarbonate exchanger pendrin. This will promote sodium reabsorption and fluid retention, causing diuretic resistance. Other factors includes gut edema which slows down the absorption of oral loop diuretics. Chronic kidney disease (CKD) reduces renal flow rate, reducing the delivery of diuretic molecules into the nephron, limiting sodium excretion and increasing sodium retention, causing diuretic resistance. Non-steroidal anti-inflammatory drug (NSAID) can compete with loop diuretics for organic ion transporters, thus preventing the diuretic molecules from being secreted into the proximal convoluted tubules. [6]

Those with diuretic resistance, cardiorenal syndrome, and severe right ventricular dysfunction may have better response to continuous diuretic infusion. Diuretic dosages is adjusted to produce 3 to 5 litres of urine per day. Thiazide (blockade of sodium-chloride symporter), amiloride (blockade of epithelial sodium channels) and carbonic anhydrase inhibitors (blockade of chloride-bicarbonate exchanger pendrin) has been suggested to complement the action of loop diuretics in resistance cases but limited evidence are available to support their use. [6]

Adverse effects

The most common adverse drug reactions (ADRs) are dose-related and arise from the effect of loop diuretics on diuresis and electrolyte balance.[ citation needed ]

Common ADRs include: hyponatremia, hypokalemia, hypomagnesemia, dehydration, hyperuricemia, gout, dizziness, postural hypotension, syncope. [17] The loss of magnesium as a result of loop diuretics has also been suggested as a possible cause of pseudogout (chondrocalcinosis). [18]

Infrequent ADRs include: dyslipidemia, increased serum creatinine concentration, hypocalcemia, rash. Metabolic alkalosis may also be seen with loop diuretic use.[ citation needed ]

Ototoxicity (damage to the inner ear) is a serious, but rare ADR associated with use of loop diuretics. This may be limited to tinnitus and vertigo, but may result in deafness in serious cases.[ citation needed ]

Loop diuretics may also precipitate kidney failure in patients concurrently taking an NSAID and an ACE inhibitor—the so-called "triple whammy" effect. [19]

Because furosemide, torsemide and bumetanide are technically sulfa drugs, there is a theoretical risk that patients sensitive to sulfonamides may be sensitive to these loop diuretics. This risk is stated on drug packaging inserts. However, the actual risk of crossreactivity is largely unknown and there are some sources that dispute the existence of such cross reactivity. [20] [21] In one study it was found that only 10% of patients with allergy to antibiotic sulfonamides were also allergic to diuretic sulfonamides, but it is unclear if this represents true cross reactivity or the nature of being prone to allergy. [22]

Ethacrynic acid is the only medication of this class that is not a sulfonamide. It carries a greater risk of reversible or permanent hearing loss (ototoxicity), [23] and has a distinct complication of being associated with gastrointestinal toxicity. [24]

Examples

Loop DiureticRelative Potency [25]
Furosemide40 mg
Bumetanide1 mg
Ethacrynic Acid50 mg
Torasemide20 mg

Related Research Articles

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Diuresis is the excretion of urine, especially when excessive (polyuria). The term collectively denotes the physiologic processes underpinning increased urine production by the kidneys during maintenance of fluid balance.

<span class="mw-page-title-main">Furosemide</span> Loop diuretic medication

Furosemide, sold under the brand name Lasix among others, is a loop diuretic medication used to treat edema due to heart failure, liver scarring, or kidney disease. Furosemide may also be used for the treatment of high blood pressure. It can be taken intravenously or orally. When given intravenously, furosemide typically takes effect within five minutes; when taken orally, it typically metabolizes within an hour.

<span class="mw-page-title-main">Distal convoluted tubule</span> Feature of kidney anatomy

The distal convoluted tubule (DCT) is a portion of kidney nephron between the loop of Henle and the collecting tubule.

<span class="mw-page-title-main">Hydrochlorothiazide</span> Diuretic medication

Hydrochlorothiazide, sold under the brand name Hydrodiuril among others, is a diuretic medication used to treat hypertension and swelling due to fluid build-up. Other uses include treating diabetes insipidus and renal tubular acidosis and to decrease the risk of kidney stones in those with a high calcium level in the urine. Hydrochlorothiazide is taken by mouth and may be combined with other blood pressure medications as a single pill to increase effectiveness. Hydrochlorothiazide is a thiazide medication which inhibits reabsorption of sodium and chloride ions from the distal convoluted tubules of the kidneys, causing a natriuresis. This initially increases urine volume and lowers blood volume. It is believed to reduce peripheral vascular resistance.

Antihypertensives are a class of drugs that are used to treat hypertension. Antihypertensive therapy seeks to prevent the complications of high blood pressure, such as stroke, heart failure, kidney failure and myocardial infarction. Evidence suggests that reduction of the blood pressure by 5 mmHg can decrease the risk of stroke by 34% and of ischaemic heart disease by 21%, and can reduce the likelihood of dementia, heart failure, and mortality from cardiovascular disease. There are many classes of antihypertensives, which lower blood pressure by different means. Among the most important and most widely used medications are thiazide diuretics, calcium channel blockers, angiotensin-converting enzyme inhibitors (ACEis), angiotensin II receptor blockers or antagonists (ARBs), and beta blockers.

<span class="mw-page-title-main">Bumetanide</span> A loop diuretic

Bumetanide, sold under the brand name Bumex among others, is a medication used to treat swelling and high blood pressure. This includes swelling as a result of heart failure, liver failure, or kidney problems. It may work for swelling when other medications have not. For high blood pressure it is not a preferred treatment. It is taken by mouth, or by injection into a vein or muscle. Effects generally begin within an hour and last for about six hours.

<span class="mw-page-title-main">Amiloride</span> Medication

Amiloride, sold under the trade name Midamor among others, is a medication typically used with other medications to treat high blood pressure or swelling due to heart failure or cirrhosis of the liver. Amiloride is classified as a potassium-sparing diuretic. Amiloride is often used together with another diuretic, such as a thiazide or loop diuretic. It is taken by mouth. Onset of action is about two hours and it lasts for about a day.

<span class="mw-page-title-main">Chlortalidone</span> Thiazide-like diuretic drug

Chlortalidone, also known as chlorthalidone, is a thiazide-like diuretic drug used to treat high blood pressure, swelling, diabetes insipidus, and renal tubular acidosis. Because chlortalidone is effective in most patients with high blood pressure, it is considered a preferred initial treatment. It is also used to prevent calcium-based kidney stones. It is taken by mouth. Effects generally begin within three hours and last for up to three days. Long-term treatment with chlortalidone is more effective than hydrochlorothiazide for prevention of heart attack or stroke.

<span class="mw-page-title-main">Thiazide</span> Class of chemical compounds

Thiazide refers to both a class of sulfur-containing organic molecules and a class of diuretics based on the chemical structure of benzothiadiazine. The thiazide drug class was discovered and developed at Merck and Co. in the 1950s. The first approved drug of this class, chlorothiazide, was marketed under the trade name Diuril beginning in 1958. In most countries, thiazides are the least expensive antihypertensive drugs available.

An osmotic diuretic is a type of diuretic that inhibits reabsorption of water and sodium (Na). They are pharmacologically inert substances that are given intravenously. They increase the osmolarity of blood and renal filtrate. This fluid eventually becomes urine.

<span class="mw-page-title-main">Gitelman syndrome</span> Genetic kidney disorder

Gitelman syndrome (GS) is an autosomal recessive kidney tubule disorder characterized by low blood levels of potassium and magnesium, decreased excretion of calcium in the urine, and elevated blood pH. It is the most frequent hereditary salt-losing tubulopathy. Gitelman syndrome is caused by disease-causing variants on both alleles of the SLC12A3 gene. The SLC12A3 gene encodes the thiazide-sensitive sodium-chloride cotransporter, which can be found in the distal convoluted tubule of the kidney.

<span class="mw-page-title-main">Potassium-sparing diuretic</span> Drugs that cause diuresis without causing potassium loss in the urine and leading to hyperkalemia

Potassium-sparing diuretics or antikaliuretics refer to drugs that cause diuresis without causing potassium loss in the urine. They are typically used as an adjunct in management of hypertension, cirrhosis, and congestive heart failure. The steroidal aldosterone antagonists can also be used for treatment of primary hyperaldosteronism. Spironolactone, a steroidal aldosterone antagonist, is also used in management of female hirsutism and acne from PCOS or other causes.

<span class="mw-page-title-main">Etacrynic acid</span> Chemical compound

Etacrynic acid (INN) or ethacrynic acid (USAN), trade name Edecrin, is a loop diuretic used to treat high blood pressure and the swelling caused by diseases like congestive heart failure, liver failure, and kidney failure. A con with ethacrynic acid compared to the other loop diuretic drugs such as furosemide is that it has a significantly steep dose-response curve, which means the drug's dosing is very important as small variance in dose can cause a significant difference in the biological response.

<span class="mw-page-title-main">Metolazone</span> Chemical compound

Metolazone is a thiazide-like diuretic marketed under the brand names Zytanix, Metoz, Zaroxolyn, and Mykrox. It is primarily used to treat congestive heart failure and high blood pressure. Metolazone indirectly decreases the amount of water reabsorbed into the bloodstream by the kidney, so that blood volume decreases and urine volume increases. This lowers blood pressure and prevents excess fluid accumulation in heart failure. Metolazone is sometimes used together with loop diuretics such as furosemide or bumetanide, but these highly effective combinations can lead to dehydration and electrolyte abnormalities.

<span class="mw-page-title-main">Bartter syndrome</span> Medical condition

Bartter syndrome (BS) is a rare inherited disease characterised by a defect in the thick ascending limb of the loop of Henle, which results in low potassium levels (hypokalemia), increased blood pH (alkalosis), and normal to low blood pressure. There are two types of Bartter syndrome: neonatal and classic. A closely associated disorder, Gitelman syndrome, is milder than both subtypes of Bartter syndrome.

In the physiology of the kidney, tubuloglomerular feedback (TGF) is a feedback system inside the kidneys. Within each nephron, information from the renal tubules is signaled to the glomerulus. Tubuloglomerular feedback is one of several mechanisms the kidney uses to regulate glomerular filtration rate (GFR). It involves the concept of purinergic signaling, in which an increased distal tubular sodium chloride concentration causes a basolateral release of adenosine from the macula densa cells. This initiates a cascade of events that ultimately brings GFR to an appropriate level.

<span class="mw-page-title-main">Xipamide</span> Chemical compound used as a diuretic

Xipamide is a sulfonamide diuretic drug marketed by Eli Lilly under the trade names Aquaphor and Aquaphoril. It is used for the treatment of oedema and hypertension.

<span class="mw-page-title-main">Acute decompensated heart failure</span> Medical condition

Acute decompensated heart failure (ADHF) is a sudden worsening of the signs and symptoms of heart failure, which typically includes difficulty breathing (dyspnea), leg or feet swelling, and fatigue. ADHF is a common and potentially serious cause of acute respiratory distress. The condition is caused by severe congestion of multiple organs by fluid that is inadequately circulated by the failing heart. An attack of decompensation can be caused by underlying medical illness, such as myocardial infarction, an abnormal heart rhythm, infection, or thyroid disease.

<span class="mw-page-title-main">Diuretic</span> Substance that promotes the production of urine

A diuretic is any substance that promotes diuresis, the increased production of urine. This includes forced diuresis. A diuretic tablet is sometimes colloquially called a water tablet. There are several categories of diuretics. All diuretics increase the excretion of water from the body, through the kidneys. There exist several classes of diuretic, and each works in a distinct way. Alternatively, an antidiuretic, such as vasopressin, is an agent or drug which reduces the excretion of water in urine.

References

  1. ↑ "WHOCC - ATC/DDD Index". www.whocc.no. Retrieved 9 April 2022.
  2. ↑ Huxel, Chris; Raja, Avais; Ollivierre-Lawrence, Michelle D. (2022). "Loop Diuretics". StatPearls. StatPearls Publishing. PMID   31536262 . Retrieved 9 April 2022.
  3. ↑ Khan, M. Gabriel (1 January 2006). "Diuretics". Encyclopedia of Heart Diseases. Academic Press. pp. 313–318. doi:10.1016/b978-012406061-6/50053-9. ISBN   9780124060616 . Retrieved 9 April 2022.
  4. ↑ Huxel, Chris; Raja, Avais; Ollivierre-Lawrence, Michelle D. (2022). "Loop Diuretics". StatPearls. StatPearls Publishing. PMID   31536262 . Retrieved 13 April 2022.
  5. ↑ Wile, D (Sep 2012). "Diuretics: a review". Annals of Clinical Biochemistry. 49 (Pt 5): 419–31. doi: 10.1258/acb.2011.011281 . PMID   22783025.
  6. 1 2 3 4 5 6 Ingelfinger, Julie R (16 November 2017). "Diuretic Treatment in Heart Failure". The New England Journal of Medicine. 377 (20): 1964–1975. doi:10.1056/NEJMra1703100. PMC   5811193 . PMID   29141174.
  7. ↑ Rose, BD (Feb 1991). "Diuretics". Kidney International. 39 (2): 336–52. doi: 10.1038/ki.1991.43 . PMID   2002648.
  8. ↑ Liguori, A.; A. Casini; M. Di Loreto; I. Andreini; C. Napoli (1999). "Loop diuretics enhance the secretion of prostacyclin in vitro, in healthy persons, and in patients with chronic heart failure". European Journal of Clinical Pharmacology. 55 (2): 117–124. doi:10.1007/s002280050605. ISSN   0031-6970. PMID   10335906. S2CID   39588076.
  9. ↑ Miyanoshita, A.; M. Terada; H. Endou (1989). "Furosemide directly stimulates prostaglandin E2 production in the thick ascending limb of Henle's loop". The Journal of Pharmacology and Experimental Therapeutics. 251 (3): 1155–1159. ISSN   0022-3565. PMID   2600809.
  10. ↑ McMahon, Blaithin A.; Chawla, Lakhmir S. (2021). "The furosemide stress test: Current use and future potential". Renal Failure. 43 (1): 830–839. doi:10.1080/0886022X.2021.1906701. PMC   8118439 . PMID   33971784.
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  12. ↑ Ahmed, Raslan; Anish, Bhardwaj (2007). "Medical management of cerebral edema". Neurosurgical Focus. 22 (5): E12. doi: 10.3171/foc.2007.22.5.13 . PMID   17613230.
  13. ↑ Megan, Purvey; George, Allen (April 2017). "Managing acute pulmonary oedema". Australian Prescriber. 40 (2): 59–63. doi:10.18773/austprescr.2017.013. PMC   5408000 . PMID   28507398.
  14. ↑ Musini, VM; Rezapour, P; Wright, JM; Bassett, K; Jauca, CD (2015). "Blood pressure-lowering efficacy of loop diuretics for primary hypertension". Cochrane Database of Systematic Reviews. 2015 (5): CD003825. doi:10.1002/14651858.CD003825.pub4. PMC   7156893 . PMID   26000442.
  15. ↑ Line, Malha; Samuel, J Mann (7 March 2016). "Loop Diuretics in the Treatment of Hypertension". Current Hypertension Reports. 18 (27): 27. doi:10.1007/s11906-016-0636-7. PMID   26951244. S2CID   22999638.
  16. ↑ Claire, Annie; Fredette, Nadeau; Bouchard, Josée (January 2013). "Fluid Management and Use of Diuretics in Acute Kidney Injury". Advances in Chronic Kidney Disease. 20 (1): 45–55. doi:10.1053/j.ackd.2012.09.005. PMID   23265596.
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  19. ↑ Thomas MC (February 2000). "Diuretics, ACE inhibitors and NSAIDs--the triple whammy". Med. J. Aust. 172 (4): 184–5. doi:10.5694/j.1326-5377.2000.tb125548.x. PMID   10772593. S2CID   37558579.
  20. ↑ Phipatanakul, Wanda; N. Franklin Adkinson (2000). "Cross-Reactivity Between Sulfonamides and Loop or Thiazide Diuretics: Is it a Theoretical or Actual Risk?". Allergy & Clinical Immunology International. 12 (1): 26–28. doi:10.1027/0838-1925.12.1.26. ISSN   1097-1424. PMC   3365608 . PMID   22661885.
  21. ↑ Rachoin, Jean-Sebastien; Elizabeth A. Cerceo (2011). "Four nephrology myths debunked". Journal of Hospital Medicine. 6 (5): –1–5. doi:10.1002/jhm.703. ISSN   1553-5606. PMID   21661096.
  22. ↑ Strom, Brian L.; Rita Schinnar; Andrea J. Apter; David J. Margolis; Ebbing Lautenbach; Sean Hennessy; Warren B. Bilker; Dan Pettitt (2003-10-23). "Absence of cross-reactivity between sulfonamide antibiotics and sulfonamide nonantibiotics". The New England Journal of Medicine. 349 (17): 1628–1635. doi: 10.1056/NEJMoa022963 . ISSN   1533-4406. PMID   14573734.
  23. ↑ Bosher SK (1980). "The nature of the ototoxic actions of ethacrynic acid upon the mammalian endolymph system. I. Functional aspects". Acta Oto-Laryngologica. 89 (5–6): 407–18. doi:10.3109/00016488009127156. PMID   7446061.
  24. ↑ Laragh, John H.; Paul J. Cannon; William B. Stason; Henry O. Heinemann (1966). "Physiologic and Clinical Observations on Furosemide and Ethacrynic Acid*". Annals of the New York Academy of Sciences. 139 (2): 453–465. Bibcode:1966NYASA.139..453L. doi:10.1111/j.1749-6632.1966.tb41219.x. ISSN   1749-6632. PMID   5339515. S2CID   6942431.
  25. ↑ Brunton, Laurence; Knollmann, Bjorn (2023). Goodman & Gilman's the pharmacological basis of therapeutics (Fourteenth ed.). New York Chicago San Francisco: McGraw Hill. ISBN   978-1264258079.
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