Diuretic

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Diuretics are "agents that promote the excretion of urine through their effects on kidney function."[1]

Physiology of sodium reabsorption in the kidney

Physiology of sodium reabsorption in the kidney
Location in nephron Proportion of total sodium reabsorption
accounted for
Membrane transport protein
Ion pump or ion channel
Diuretics that
act at this location
Proximal convulated tubule 40% Carbonic anhydrase
Sodium-hydrogen antiporter (Ion pump)
Carbonic anhydrase inhibitors
Late proximal tubule   Chloride-bicarbonate antiporter (Ion pump)  
Loop of Henle:
thin descending limb
0% Not applicable Osmotic diuretics
Loop of Henle:
thick ascending limb
('diluting segment')
25% Sodium potassium chloride symporter (Ion pump) Loop diuretics
Distal convulated tubule 10% Sodium chloride symporter (Ion pump) Thiazides
Collecting tubule 2-5% Mineralacorticoids receptors
Sodium channel (Ion channel)
Potassium-sparing diuretics

Classification

Carbonic anhydrase inhibitors

Carbonic anhydrase inhibitors are a "class of compounds that reduces the secretion of h+ ions by the proximal kidney tubule through inhibition of carbonic anhydrases."[2][3]

Osmotic diuretic

Osmotic diuretics are "compounds that increase urine volume by increasing the amount of osmotically active solute in the urine. Osmotic diuretics also increase the osmolarity of plasma."[4]

Loop diuretics

More formally called sodium potassium chloride symporter inhibitors, these are agents that inhibit sodium-potassium-chloride symporters in the thick ascending limb at the junction of the Loop of Henle and distal kidney tubules.[5]

A meta-analysis concluded that "administering furosemide as a continuous infusion for greater diuresis and reduction in total body weight in patients hospitalized with ADHF". [6]

Thiazides

Thiazides are "heterocyclic compounds with sulfur and nitrogen in the ring. This term commonly refers to the benzothiadiazines that inhibit sodium-potassium-chloride symporters."[7] Examples include hydrochlorothiazide and chlorthalidone.

Regarding effectiveness, a systematic review by the Cochrane Collaboration found:[8]

  • Chlorthalidone's reduces systolic and diagnostic blood pressure by 12.0/4 mmHg and the reduction is not dose related when tested at a range of doses from 12.5 mg to 75 mg/day.
  • Hydrochlorothiazide's effect is dose related and at a maximum dose of 50 mg/day, the reduction is 11 mmHg/5 mmHg.

Chlorthalidone may be the best choice based on the Multiple Risk Factor Intervention Trial[9] and other studies.[10][11][12] In the MRFIT trial, the clinics that predominantly used chlorthalidone reported lower mortality than the clinics using hydrochlorothiazide (5% versus 7%).

Regarding chlorthalidone versus calcium channel blockers:

  • "Thiazide-type diuretics are superior in preventing 1 or more major forms of CVD and are less expensive" according to a randomized controlled trial that compared to . [13]
  • "Similar antihypertensive efficacies, tolerabilities and cardiovascular event rates were observed with verapamil and with chlorthalidone" according to an unblinded randomized controlled trial[14]
  • "In elderly patients with isolated systolic hypertension, administration of lacidipine or chlorthalidone markedly reduced systolic blood pressure with no difference in the incidence of cardiovascular events and total mortality." according to an unblinded randomized controlled trial. [15]

Potassium-sparing diuretics

These work in the collecting duct and late distal convoluted tubule either by inhibiting mineralacorticoids receptors or by blocking the epithelial sodium channel.[16][17] Amiloride is beter tolerated than triamterene. Their ability to treat hypertension is doubtful.[18]

Vasopressin antagonists

Tolvaptan, a vasopressin antagonist, may be beneficial according to a randomized controlled trial.[19][20] Tolvaptan is a selective cell surface receptors V2 antagonist in the distal nephron which causes loss of free water.[21] Other vasopressin antagonists act mainly on V1a cell surface receptors.

Brain (B-type) natriuretic peptide

Nesiritide, a brain (B-type) natriuretic peptide, may help patients with decompensated congestive heart failure according to a randomized controlled trial.[22] Natriuretic peptide causes diuresis, vasodilitation, and suppression of the renin-angiotensin system and sympathetic nervous system.[22]

Medical uses

Diuretics may be used to treat hypertension, heart failure, and other illnesses.[23] Occasionally high doses or combinations of diuretics are needed.[23][24][25][26]

Adverse effects

Many diuretics, aimed at sodium and water retention, may reduce potassium to dangerous levels. In addition to monitoring, it may be necessary, for example, to combine thiazide diuretics with supplemental potassium or potassium-sparing diuretics.

Hydrochlorothiazide at doses above 25 mg per day may be associated with sudden cardiac death.[27] This risk may be reduced by adding a potassium-sparing diuretic.[27]

References

  1. Anonymous (2015), Diuretic (English). Medical Subject Headings. U.S. National Library of Medicine.
  2. Anonymous (2015), Carbonic anhydrase inhibitors (English). Medical Subject Headings. U.S. National Library of Medicine.
  3. Katzung, Bertram G. (2001). “Diuretic Agents”, Basic & Clinical Pharmacology. New York: Lange Medical Books/McGraw-Hill, 249. ISBN 0-8385-0598-8. 
  4. Anonymous (2015), Osmotic diuretics (English). Medical Subject Headings. U.S. National Library of Medicine.
  5. Anonymous (2015), Sodium Potassium Chloride Symporter Inhibitors (English). Medical Subject Headings. U.S. National Library of Medicine.
  6. Amer M, Adomaityte J, Qayyum R (2012). "Continuous infusion versus intermittent bolus furosemide in ADHF: an updated meta-analysis of randomized control trials.". J Hosp Med 7 (3): 270-5. DOI:10.1002/jhm.991. PMID 22125127. Research Blogging.
  7. Anonymous (2015), Thiazides (English). Medical Subject Headings. U.S. National Library of Medicine.
  8. Musini VM, Nazer M, Bassett K, Wright JM (2014). "Blood pressure-lowering efficacy of monotherapy with thiazide diuretics for primary hypertension.". Cochrane Database Syst Rev 5: CD003824. DOI:10.1002/14651858.CD003824.pub2. PMID 24869750. Research Blogging.
  9. (November 1990) "Mortality after 10 1/2 years for hypertensive participants in the Multiple Risk Factor Intervention Trial". Circulation 82 (5): 1616–28. PMID 2225366[e]
  10. Ernst ME, Carter BL, Goerdt CJ, et al (March 2006). "Comparative antihypertensive effects of hydrochlorothiazide and chlorthalidone on ambulatory and office blood pressure". Hypertension 47 (3): 352–8. DOI:10.1161/01.HYP.0000203309.07140.d3. PMID 16432050. Research Blogging.
  11. Carter BL, Ernst ME, Cohen JD (January 2004). "Hydrochlorothiazide versus chlorthalidone: evidence supporting their interchangeability". Hypertension 43 (1): 4–9. DOI:10.1161/01.HYP.0000103632.19915.0E. PMID 14638621. Research Blogging.
  12. (January 2009) "Drugs for hypertension". Treat Guidel Med Lett 7 (77): 1–10. PMID 19107095[e]
  13. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (2002). "Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).". JAMA 288 (23): 2981-97. PMID 12479763[e] Review in: ACP J Club. 2003 Jul-Aug;139(1):7
  14. Rosei EA, Dal Palù C, Leonetti G, Magnani B, Pessina A, Zanchetti A (1997). "Clinical results of the Verapamil inHypertension and Atherosclerosis Study. VHAS Investigators.". J Hypertens 15 (11): 1337-44. PMID 9383184[e]
  15. Malacco E, Mancia G, Rappelli A, Menotti A, Zuccaro MS, Coppini A et al. (2003). "Treatment of isolated systolic hypertension: the SHELL study results.". Blood Press 12 (3): 160-7. PMID 12875478[e]
  16. Anonymous (2015), Sodium channel blockers (English). Medical Subject Headings. U.S. National Library of Medicine.
  17. Katzung, Bertram G. (2001). “Diuretic Agents”, Basic & Clinical Pharmacology. New York: Lange Medical Books/McGraw-Hill, 256. ISBN 0-8385-0598-8. 
  18. Heran BS, Chen JM, Wang JJ, Wright JM (2012). "Blood pressure lowering efficacy of potassium-sparing diuretics (that block the epithelial sodium channel) for primary hypertension.". Cochrane Database Syst Rev 11: CD008167. DOI:10.1002/14651858.CD008167.pub3. PMID 23152254. Research Blogging.
  19. Gheorghiade M et al. Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: the EVEREST Clinical Status Trials. JAMA 2007;297:1332-43. Epub 2007 Mar 25. PMID 17384438
  20. Konstam MA et al. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial. JAMA 2007;297:1319-31. Epub 2007 Mar 25. PMID 17384437
  21. Goldsmith SR, Gheorghiade M. Vasopressin antagonism in heart failure. J Am Coll Cardiol. 2005;46:1785-91. PMID 16286160
  22. 22.0 22.1 Colucci WS, et al. Intravenous nesiritide, a natriuretic peptide, in the treatment of decompensated congestive heart failure. Nesiritide Study Group. N Engl J Med. 2000 Jul 27;343(4):246-53. Erratum in: N Engl J Med 2000 Nov 16;343(20):1504. N Engl J Med 2000;343:896. PMID 10911006
  23. 23.0 23.1 Brater DC (August 1998). "Diuretic therapy". N. Engl. J. Med. 339 (6): 387–95. PMID 9691107[e]
  24. Wollam GL, Tarazi RC, Bravo EL, Dustan HP (June 1982). "Diuretic potency of combined hydrochlorothiazide and furosemide therapy in patients with azotemia". Am. J. Med. 72 (6): 929–38. PMID 7046434[e]
  25. Fliser D, Schröter M, Neubeck M, Ritz E (August 1994). "Coadministration of thiazides increases the efficacy of loop diuretics even in patients with advanced renal failure". Kidney Int. 46 (2): 482–8. PMID 7967362[e]
  26. Knauf H, Mutschler E (September 1995). "Diuretic effectiveness of hydrochlorothiazide and furosemide alone and in combination in chronic renal failure". J. Cardiovasc. Pharmacol. 26 (3): 394–400. PMID 8583780[e]
  27. 27.0 27.1 Siscovick DS, Raghunathan TE, Psaty BM, et al (June 1994). "Diuretic therapy for hypertension and the risk of primary cardiac arrest". N. Engl. J. Med. 330 (26): 1852–7. PMID 8196728[e]