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Chemical structures of some loop diuretics.

Loop diuretics are diuretics that act at the ascending limb of the loop of Henle in the kidney. They are primarily used in medicine to treat hypertension and edema often due to congestive heart failure or renal insufficiency. While thiazide diuretics are more effective in patients with normal kidney function, loop diuretics are more effective in patients with impaired kidney function.[1]

Contents

Mechanism of actionEdit

Loop diuretics are 90% bounded to proteins and is 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 inhibits NKCC1 at macula densa, reducing the re-absorption of sodium, potassium, and chloride. The low electrolyte reabsorption level 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 inhibits the tubuloglomerular feedback mechanism so that increase in salts at the lumen near macula densa does not trigger a response that reduces the GFR.[2]

Loop diuretics also inhibits 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 are 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.[3] 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.

A secondary effect of loop diuretics is to increase the production of prostaglandins, which results in vasodilation and increased blood supply to the kidney.[4][5]

The collective effects of decreased blood volume and vasodilation decrease blood pressure and ameliorate oedema.

PharmacokineticsEdit

Loop diuretics is highly protein bound, therefore, its volume of distribution is limited. The protein bound nature of the loop diuretic molecules causes it to be secreted via several transporter molecules along luminal wall of the proximal convoluted tubules to be able to exert its function. The availability of furosemide is high variable from 10% to 90%. The biological half-life of furosemide is limited by absorption from gastrointestinal tract into the bloodstream. The apparent half-life of its excretion is higher than the apparent half-life of absorption via oral route. Therefore, intravenous dose of furosemide is twice as potent as the oral route.[2]

However, for torsemide and bumetanide, their oral bioavailability are consistently higher than 90%. Torsemide has longer half life in heart failure patients (6 hours) when compared to furosemide (2.7 hours). Loop diuretics usually has a "ceiling" effect where there is a maximum level of dosage where further increase in dosage will not increase the clinical effect of the drug. A dose of 40 mg of furosemide is equivalent to 20 mg of torsemide and 1 mg bumetamide.[2]

Clinical useEdit

Loop diuretics are principally used in the following indications:[6]

They are also sometimes used in the management of severe hypercalcemia in combination with adequate rehydration.[6]

On the other hand, in critically ill patients with acute renal failure, loop diuretics do not appear to reduce mortality, reduce length of intensive care unit or hospital stay, or hasten any recovery of renal function.[7]

A systematic review by the Cochrane Hypertension group assessing the anti-hypertensive effects of loop diuretics found only a modest reduction in blood pressure compared to placebo; the review highlights the need for more randomized control trials to be made available in order to construct a furnished assessment.[8]

ResistanceEdit

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 oedema 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.[2]

Those with diuretic resistance, cardiorenal syndrome, and severe right ventricular dysfunction may have better response to continuous duretic 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.[2]

Adverse effectsEdit

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

Common ADRs include: hyponatremia, hypokalemia, hypomagnesemia, dehydration, hyperuricemia, gout, dizziness, postural hypotension, syncope.[6] The loss of magnesium as a result of loop diuretics has also been suggested as a possible cause of pseudogout (chondrocalcinosis)[9]

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

Ototoxicity (damage to the 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.

Loop diuretics may also precipitate kidney failure in patients concurrently taking an NSAID and an ACE inhibitor—the so-called "triple whammy" effect.[10]

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.[11][12] 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.[13]

Ethacrynic acid is the only medication of this class that is not a sulfonamide. It has a distinct complication of being associated with gastrointestinal toxicity.[14]

Examples of loop diureticsEdit

Loop Diuretic Relative Potency[15]
Furosemide 40 mg
Bumetanide 1 mg
Ethacrynic Acid 50 mg
Torsemide 20 mg

ReferencesEdit

  1. ^ Wile, D (Sep 2012). "Diuretics: a review". Annals of Clinical Biochemistry. 49 (Pt 5): 419–31. doi:10.1258/acb.2011.011281. PMID 22783025. 
  2. ^ a b c d e f 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. 
  3. ^ Rose, BD (Feb 1991). "Diuretics". Kidney International. 39 (2): 336–52. doi:10.1038/ki.1991.43. PMID 2002648. 
  4. ^ 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. 
  5. ^ 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. 
  6. ^ a b c Rossi S, ed. (2004). Australian Medicines Handbook 2004 (5th ed.). Adelaide, S.A.: Australian Medicines Handbook Pty Ltd. ISBN 0-9578521-4-2. 
  7. ^ Davis, A. (2006). "The use of loop diuretics in acute renal failure in critically ill patients to reduce mortality, maintain renal function, or avoid the requirements for renal support". Emergency Medicine Journal. 23 (7): 569–70. doi:10.1136/emj.2006.038513. PMC 2579558 . PMID 16794108. 
  8. ^ 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 (5): CD003825. doi:10.1002/14651858.CD003825.pub4. PMID 26000442. 
  9. ^ Rho YH, Zhu Y, Zhang Y, Reginato AM, Choi HK. Risk factors for pseudogout in the general population. Rheumatology 2012;51:2070-2074 doi:10.1093/rheumatology/kes204
  10. ^ Thomas MC (February 2000). "Diuretics, ACE inhibitors and NSAIDs--the triple whammy". Med. J. Aust. 172 (4): 184–5. PMID 10772593. 
  11. ^ 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. 
  12. ^ 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. 
  13. ^ 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. 
  14. ^ 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. doi:10.1111/j.1749-6632.1966.tb41219.x. ISSN 1749-6632. Retrieved 2015-01-09. 
  15. ^ Goodman & Gilman's pharmacological basis of therapeutics. Goodman, Louis S. (Louis Sanford), 1906-2000., Brunton, Laurence L., Chabner, Bruce., Knollmann, Björn C. (12th ed.). New York: McGraw-Hill. 2011. ISBN 9780071624428. OCLC 498979404.  Unknown parameter |DUPLICATE_url= ignored (help)

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