View source for Loop diuretic

{{Short description|Diuretics that act along the loop of Henle in the kidneys}}
{{Infobox drug class
| Name                = Loop diuretic
| Image               = Loop diuretics.svg
| ImageClass          = skin-invert-image
| Alt                 =
| Caption             = Structure of the loop diuretics Furosemide, Azosemide, Bumetanide, Piretanide, Torasemide, Ethacrynic acid and Etozolin
| Synonyms            = High-ceiling diuretic<ref>{{cite web |title=WHOCC - ATC/DDD Index |url=https://www.whocc.no/atc_ddd_index/?code=C03C&showdescription=yes |website=www.whocc.no |access-date=9 April 2022}}</ref>
<!-- Class identifiers -->
| Use                 = [[congestive heart failure]], [[nephrotic syndrome]], [[cirrhosis]], [[hypertension]], [[edema]]<ref>{{cite journal |last1=Huxel |first1=Chris |last2=Raja |first2=Avais |last3=Ollivierre-Lawrence |first3=Michelle D. |title=Loop Diuretics |url=https://pubmed.ncbi.nlm.nih.gov/31536262/ |website=StatPearls |publisher=StatPearls Publishing |access-date=9 April 2022 |date=2022|pmid=31536262 }}</ref>
| ATC_prefix          = C03C
| Mode_of_action      =
| Mechanism_of_action =
| Biological_target   = [[Na-K-Cl cotransporter]]<ref>{{cite book |last1=Khan |first1=M. Gabriel |title=Encyclopedia of Heart Diseases |chapter=Diuretics |chapter-url=https://doi.org/10.1016/B978-012406061-6/50053-9 |publisher=Academic Press |access-date=9 April 2022 |pages=313–318 |language=en |doi=10.1016/b978-012406061-6/50053-9 |date=1 January 2006|isbn=9780124060616 }}</ref>
| Chemical_class      =
<!-- Clinical data -->
| Drugs.com           = <!-- {{Drugs.com|drug-class|loop-diuretics}} -->
| Consumer_Reports    =
| medicinenet         =
| rxlist              =
<!-- External links -->
| MeshID              = D049994
}}
'''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]].<ref>{{cite journal |last1=Huxel |first1=Chris |last2=Raja |first2=Avais |last3=Ollivierre-Lawrence |first3=Michelle D. |title=Loop Diuretics |url=https://www.ncbi.nlm.nih.gov/books/NBK546656/ |website=StatPearls |publisher=StatPearls Publishing |access-date=13 April 2022 |date=2022|pmid=31536262 }}</ref> 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.<ref>{{cite journal|last=Wile|first=D|title=Diuretics: a review.|journal=Annals of Clinical Biochemistry|date=Sep 2012|volume=49|issue=Pt 5|pages=419–31|pmid=22783025|doi=10.1258/acb.2011.011281|doi-access=free}}</ref>

==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|Na<sup>+</sup>-K<sup>+</sup>-2Cl<sup>−</sup> 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<sup>−</sup> 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 (kidney)|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.<ref name="NEJM 2017">{{cite journal|last1=Ingelfinger|first1=Julie R|title=Diuretic Treatment in Heart Failure|journal=The New England Journal of Medicine|date=16 November 2017|volume=377|issue=20|pages=1964–1975|doi=10.1056/NEJMra1703100|pmid=29141174|pmc=5811193}}</ref>

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 [[ROMK|renal outer medullary potassium channel]]. By inhibiting the potassium recycling, the voltage gradient is abolished and magnesium and calcium reabsorption are inhibited.<ref>{{cite journal|last=Rose|first=BD|title=Diuretics.|journal=Kidney International|date=Feb 1991|volume=39|issue=2|pages=336–52|pmid=2002648|doi=10.1038/ki.1991.43|doi-access=free}}</ref>  By disrupting the reabsorption of these ions, loop diuretics prevent the generation of a [[Tonicity#Hypertonic solution|hypertonic]] [[renal medulla]]. Without such a concentrated medulla, water has less of an [[osmotic pressure|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.{{cn|date=August 2024}}

A secondary effect of loop diuretics is to increase the production of [[prostaglandins]], which results in vasodilation and increased blood supply to the kidney.<ref>{{Cite journal | issn = 0031-6970 | volume = 55 | issue = 2 | pages = 117–124 | last = Liguori | first = A. |author2=A. Casini |author3=M. Di Loreto |author4=I. Andreini |author5=C. Napoli  | title = Loop diuretics enhance the secretion of prostacyclin in vitro, in healthy persons, and in patients with chronic heart failure | journal = European Journal of Clinical Pharmacology | date = 1999 | pmid = 10335906 | doi=10.1007/s002280050605| s2cid = 39588076 }}</ref><ref>{{Cite journal| issn = 0022-3565 | volume = 251 | issue = 3 | pages = 1155–1159 | last = Miyanoshita | first = A. |author2=M. Terada |author3=H. Endou  | title = Furosemide directly stimulates prostaglandin E2 production in the thick ascending limb of Henle's loop | journal = The Journal of Pharmacology and Experimental Therapeutics | date = 1989 | pmid = 2600809}}</ref> 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]].{{cn|date=August 2024}}

==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.{{cn|date=August 2024}}

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. <ref>{{cite journal | url=https://doi.org/10.1080/0886022X.2021.1906701 | doi=10.1080/0886022X.2021.1906701 | title=The furosemide stress test: Current use and future potential | date=2021 | last1=McMahon | first1=Blaithin A. | last2=Chawla | first2=Lakhmir S. | journal=Renal Failure | volume=43 | issue=1 | pages=830–839 | pmid=33971784 | pmc=8118439 }}</ref>

The availability of [[furosemide]] is highly variable, ranging from 10% to 90%. The [[biological half-life]] of furosemide is limited by [[Absorption (pharmacology)|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.<ref name="NEJM 2017"/>

However, for torsemide and bumetanide, their oral bioavailability is consistently higher than 90%. Torsemide has a longer half life in heart failure patients (6{{nbs}}hours) than furosemide (2.7{{nbs}}hours). A 40{{nbs}}mg dose of furosemide is clinically equivalent to a 20{{nbs}}mg dose of torsemide and to a 1{{nbs}}mg dose of bumetanide.<ref name="NEJM 2017"/>

==Clinical use==
Loop diuretics are principally used in the following indications:
* [[Heart failure]] - Giving 2.5 times of previous oral dose twice daily for those with [[acute decompensated heart failure]] is a reasonable strategy. However, daily assessment of clinical response is needed to adjust the subsequent doses.<ref name="NEJM 2017"/>
* [[Edema]] - Volume overload associated with liver [[cirrhosis]], [[heart failure]], or [[nephrotic syndrome]]<ref>{{cite journal|last1=O'Brien|first1=James G|last2=Chennubthotla|first2=Shobha A|title=Treatment of Edema|journal=American Family Physician|date=1 June 2005|volume=71|issue=11|pages=2111–2117|pmid=15952439 |url=https://www.aafp.org/afp/2005/0601/p2111.html|access-date=5 March 2018}}</ref>
* [[Cerebral edema]] - intravenous furosemide can be combined with [[mannitol]] to initiate rapid diuresis. However, the optimum duration of such treatment remains unknown. Frequent fluid status monitoring is required to prevent intravascular volume depletion which leads to reduced cerebral perfusion. A bolus intravenous dose of 10 or 20 mg of furosemide can be administered and then followed by intravenous bolus of 2 or 3% hypertonic saline to increase the serum sodium level.<ref>{{cite journal|last1=Ahmed|first1=Raslan|last2=Anish|first2=Bhardwaj|title=Medical management of cerebral edema|journal=Neurosurgical Focus|date=2007|volume=22|issue=5|pages=E12|pmid=17613230|doi=10.3171/foc.2007.22.5.13|doi-access=free}}</ref>
* [[Pulmonary edema]] - Slow intravenous bolus dose of 40 to 80 mg furosemide at 4 mg per minute is indicated for patients with fluid overload and pulmonary edema. Such dose can be repeated after 20 minutes. After the bolus, a continuous intravenous infusion can be given at 5 to 10 mg per hour. For those with underlying [[renal impairment]] or severe heart failure, up to 160 to 200 mg bolus dose can be given.<ref>{{cite journal|last1=Megan|first1=Purvey|last2=George|first2=Allen|title=Managing acute pulmonary oedema|journal=Australian Prescriber|date=April 2017|volume=40|issue=2|pages=59–63|doi=10.18773/austprescr.2017.013|pmid=28507398|pmc=5408000}}</ref>
* [[Hypertension]] - A systematic review by the Cochrane Hypertension group assessing the anti-hypertensive effects of loop diuretics found only a modest reduction in blood pressure when compared to placebo.<ref>{{cite journal | last1 = Musini | first1 = VM | last2 = Rezapour | first2 = P | last3 = Wright | first3 = JM | last4 = Bassett | first4 = K | last5 = Jauca | first5 = CD | year = 2015 | title = Blood pressure-lowering efficacy of loop diuretics for primary hypertension | journal = Cochrane Database of Systematic Reviews | volume = 2015 | issue = 5 | page = CD003825 | doi = 10.1002/14651858.CD003825.pub4 | pmid=26000442| pmc = 7156893 }}</ref> According to Joint National Committee (JNC-8) guidelines, the first line treatment of hypertension is [[thiazide]] diuretics. The use of loop diuretics is not mentioned in this guideline. Meanwhile, according to 2013 European Society of Cardiology (ESC) guidelines, a loop diuretic can only replace thiazide-type diuretics  if there is renal impairment ([[Creatinine]] of more than 1.5 mg/dL or estimated [[glomerular filtration rate]] (eGFR) of less 30 mL/min/1.73 m<sup>2</sup> due to lack of long term cardiovascular outcome data and appropriate dosing regimen of its use.<ref>{{cite journal|last1=Line|first1=Malha|last2=Samuel|first2=J Mann|title=Loop Diuretics in the Treatment of Hypertension|journal=Current Hypertension Reports|date=7 March 2016|volume=18|issue=27|pages=27|doi=10.1007/s11906-016-0636-7|pmid=26951244|s2cid=22999638 }}</ref>

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.<ref name="Claire 2013">{{cite journal|last1=Claire|first1=Annie|last2=Fredette|first2=Nadeau|last3=Bouchard|first3=Josée|title=Fluid Management and Use of Diuretics in Acute Kidney Injury|journal=Advances in Chronic Kidney Disease|date=January 2013|volume=20|issue=1|pages=45–55|doi=10.1053/j.ackd.2012.09.005|pmid=23265596}}</ref>

They are also sometimes used in the management of severe [[hypercalcemia]] in combination with adequate rehydration.<ref name="AMH2004"/>

== 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.<ref name="NEJM 2017"/>

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 inhibitor]]s (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.<ref name="NEJM 2017"/>

== 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.{{cn|date=August 2024}}

Common ADRs include: [[hyponatremia]], [[hypokalemia]], [[hypomagnesemia]], [[dehydration]], [[hyperuricemia]], [[gout]], [[dizziness]], [[postural hypotension]], [[Fainting|syncope]].<ref name="AMH2004">{{cite book |editor=Rossi S |title=Australian Medicines Handbook 2004 |edition=5th |isbn=978-0-9578521-4-3 |url=http://www.amh.net.au/ |year=2004 |publisher=Australian Medicines Handbook Pty Ltd |location=Adelaide, S.A. }}</ref> The loss of magnesium as a result of loop diuretics has also been suggested as a possible cause of pseudogout ([[chondrocalcinosis]]).<ref>{{cite journal | last1 = Rho | first1 = YH | last2 = Zhu | first2 = Y | last3 = Zhang | first3 = Y | last4 = Reginato | first4 = AM | last5 = Choi | first5 = HK | year = 2012 | title = Risk factors for pseudogout in the general population | journal = Rheumatology | volume = 51 | issue = 11| pages = 2070–2074 | doi = 10.1093/rheumatology/kes204| pmid = 22886340 |pmc=3475980 | doi-access = free }}</ref>

Infrequent ADRs include: [[dyslipidemia]], increased serum [[creatinine]] concentration, hypocalcemia, [[rash]]. [[Metabolic alkalosis]] may also be seen with loop diuretic use.{{cn|date=August 2024}}

[[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 (medical)|vertigo]], but may result in [[deafness]] in serious cases.{{cn|date=August 2024}}

Loop diuretics may also precipitate kidney failure in patients concurrently taking an [[NSAID]] and an [[ACE inhibitor]]—the so-called "triple whammy" effect.<ref>{{cite journal |author=Thomas MC |title=Diuretics, ACE inhibitors and NSAIDs--the triple whammy |journal=Med. J. Aust. |volume=172 |issue=4 |pages=184–5 |date=February 2000 |pmid=10772593 |doi= 10.5694/j.1326-5377.2000.tb125548.x|s2cid=37558579 }}</ref>

Because furosemide, [[torsemide]] and [[bumetanide]] are technically [[sulfa]] drugs, there is a theoretical risk that patients sensitive to [[Sulfonamide (medicine)|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.<ref>{{Cite journal | issn = 1097-1424| volume = 12| issue = 1| pages = 26–28| last = Phipatanakul| first = Wanda|author2=N. Franklin Adkinson | title = Cross-Reactivity Between Sulfonamides and Loop or Thiazide Diuretics: Is it a Theoretical or Actual Risk?| journal = Allergy & Clinical Immunology International
| date = 2000| pmid = 22661885| pmc = 3365608| doi=10.1027/0838-1925.12.1.26
}}</ref><ref>{{Cite journal| doi = 10.1002/jhm.703| issn = 1553-5606| volume = 6| issue = 5| pages = –1–5| last = Rachoin| first = Jean-Sebastien|author2=Elizabeth A. Cerceo | title = Four nephrology myths debunked| journal = Journal of Hospital Medicine | date = 2011 | pmid = 21661096}}</ref>  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.<ref>{{Cite journal | doi = 10.1056/NEJMoa022963 | issn = 1533-4406 | volume = 349 | issue = 17 | pages = 1628–1635 | last = Strom | first = Brian L. |author2=Rita Schinnar |author3=Andrea J. Apter |author4=David J. Margolis |author5=Ebbing Lautenbach |author6=Sean Hennessy |author7=Warren B. Bilker |author8=Dan Pettitt  | title = Absence of cross-reactivity between sulfonamide antibiotics and sulfonamide nonantibiotics | journal = The New England Journal of Medicine | date = 2003-10-23 | pmid = 14573734 | doi-access = free }}</ref>

[[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),<ref name="pmid7446061">{{cite journal | vauthors = Bosher SK | title = The nature of the ototoxic actions of ethacrynic acid upon the mammalian endolymph system. I. Functional aspects | journal = Acta Oto-Laryngologica | volume = 89 | issue = 5–6 | pages = 407–18 | year = 1980 | pmid = 7446061 | doi = 10.3109/00016488009127156 }}</ref> and has a distinct complication of being associated with gastrointestinal toxicity.<ref>{{Cite journal| doi = 10.1111/j.1749-6632.1966.tb41219.x| issn = 1749-6632| volume = 139| issue = 2
| pages = 453–465| last = Laragh| first = John H.|author2=Paul J. Cannon |author3=William B. Stason |author4=Henry O. Heinemann | title = Physiologic and Clinical Observations on Furosemide and Ethacrynic Acid*| journal = Annals of the New York Academy of Sciences| date = 1966| pmid = 5339515| bibcode = 1966NYASA.139..453L| s2cid = 6942431}}</ref>

== Examples ==
* [[Furosemide]]
* [[Bumetanide]]
* [[Ethacrynic acid]]
* [[Torasemide]]
{| class="wikitable"
|-
! Loop Diuretic !! Relative Potency<ref>{{cite book |last1=Brunton |first1=Laurence |last2=Knollmann |first2=Bjorn |title=Goodman & Gilman's the pharmacological basis of therapeutics |date=2023 |publisher=McGraw Hill |location=New York Chicago San Francisco |isbn=978-1264258079 |edition=Fourteenth}}</ref>
|-
| Furosemide ||  40&nbsp;mg
|-
| Torasemide ||  20&nbsp;mg
|-
| Ethacrynic Acid ||  50&nbsp;mg
|-
| Bumetanide ||  1&nbsp;mg
|}

==References==
{{reflist}}

== External links ==
* [http://www.fpnotebook.com/cv/pharm/lpdrtc.htm Loop Diuretic], from the Family Practice Notebook

{{Diuretics}}

[[Category:Loop diuretics| ]]