Loop diuretic

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Chemical structures of some loop diuretics.

Loop diuretics are diuretics that act at the ascending 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]

Mechanism of action[edit]

Loop diuretics act on the Na+-K+-2Cl- symporter (cotransporter) in the thick ascending limb of the loop of Henle to inhibit sodium and chloride reabsorption. This is achieved by competing for the Cl- binding site. Because magnesium and calcium reabsorption in the thick ascending limb is dependent on the positive lumen voltage gradient set up by potassium recycling through renal outer medullary potassium channel, loop diuretics also inhibit their reabsorption. By disrupting the reabsorption of these ions, loop diuretics prevent the generation of a hypertonic renal medulla.[2] 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.

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

Clinical use[edit]

Loop diuretics are principally used in the following indications:[3]

They are also sometimes used in the management of severe hypercalcemia in combination with adequate rehydration.[3]

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 fasten any recovery of renal function.[4]

Loop diuretic resistance[edit]

Renal insufficiency causes decreased bloodflow to the kidneys, which decreases the glomerular filtration rate (GFR) and reduces the ability of loop diuretics to reach their target organ, the loop of Henle. Similarly, non-steroidal anti-inflammatory drugs also decrease GFR with comparable results. In patients with reduced GFR, ceiling dosages of loop diuretics are increased proportional to the decrease in GFR. Simultaneous treatment with a thiazide diuretic such as hydrochlorothiazide (to inhibit sodium reabsorption at multiple sites in the nephron) is often successful. Newly emerging evidence shows that glucocorticoids may be use to reverse the loop diuretic resistance in heart failure.[5][6]

Patients with congestive heart failure tend to retain sodium, also necessitating an increase in dosage. The same is true for patients with increased sodium intake.

Adverse effects[edit]

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

Common ADRs include: hyponatremia, hypokalemia, hypomagnesemia, dehydration, hyperuricemia, gout, dizziness, postural hypotension, syncope.[3] The loss of magnesium as a result of loop diuretics also been suggested as a possible cause of pseudogout (chondrocalcinosis)[7]

Infrequent ADRs include: dyslipidemia, increased serum creatinine concentration, hypocalcemia, rash.

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 renal failure in patients concurrently taking an NSAID and an ACE inhibitor—the so-called "triple whammy" effect.[8]

Examples of loop diuretics[edit]

Loop DiureticRelative Potency
Ethacrynic Acid0.7



  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. ^ Rose, BD (Feb 1991). "Diuretics.". Kidney international 39 (2): 336–52. doi:10.1038/ki.1991.43. PMID 2002648. 
  3. ^ 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. 
  4. ^ 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. doi:10.1136/emj.2006.038513.  edit
  5. ^ Liu, C; Liu, G; Zhou, C; Ji, Z; Zhen, Y; Liu, K (September 2007). "Potent diuretic effects of prednisone in heart failure patients with refractory diuretic resistance.". The Canadian journal of cardiology 23 (11): 865–8. doi:10.1016/s0828-282x(07)70840-1. PMC 2651362. PMID 17876376. 
  6. ^ Massari, F; Mastropasqua, F; Iacoviello, M; Nuzzolese, V; Torres, D; Parrinello, G (March 2012). "The glucocorticoid in acute decompensated heart failure: Dr Jekyll or Mr Hyde?". The American journal of emergency medicine 30 (3): 517.e5–10. doi:10.1016/j.ajem.2011.01.023. PMID 21406321. 
  7. ^ 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
  8. ^ Thomas MC (February 2000). "Diuretics, ACE inhibitors and NSAIDs--the triple whammy". Med. J. Aust. 172 (4): 184–5. PMID 10772593. 
  9. ^ al.], ed. Laurence L. Brunton ... [et (2011). Goodman & Gilman's pharmacological basis of therapeutics. (12th ed. ed.). New York: McGraw-Hill. ISBN 978-0071624428. 

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