Diuretics increase urine excretion and are commonly called “water tablets”. In general, they inhibit electrolyte reabsorption from the lumen of the nephron, increasing osmolarity and enhancing water excretion.

Diuretics have different clinical uses depending on their sites and mechanisms of action. The sub-classes of diuretics:

• Thiazides (bendroflumethiazide, chlortalidone, metolazone) are used mainly in low dose in the treatment of hypertension but also, in combination with loop diuretics, to treat severe heart failure.
• Loop diuretics (furosemide, bumetanide, torasemide) are widely used for the symptomatic treatment of heart failure.
• Potassium-sparing diuretics (amiloride, triamterene) are weak diuretics, most often prescribed in combination with thiazides or loop diuretics to prevent hypokalaemia.
• Aldosterone antagonists (spironolactone, eplerenone) are used in the treatment of the oedema of liver failure, malignant ascites, nephrotic syndrome and heart failure.
• Osmotic diuretics (mannitol) are used in a hospital setting for the treatment of cerebral oedema.
• Carbonic anhydrase inhibitors (acetazolamide) are used for the prophylaxis of mountain sickness (unlicensed) and glaucoma.

Main indications

Hypertension¹

(See separate article Management of Hypertension.)

• Current National Institute for Clinical Excellence (NICE) and Joint British Societies' guidelines² recommend thiazides (or calcium channel blockers) as first-line choice for treatment of uncomplicated hypertension:
  • In those over 55 years.
  • In those of black African or Caribbean descent.
  • Where no contra-indication or a compelling indication for an alternative antihypertensive drug exists.
• This is supported by the Antihypertensive and Lipid-lowering Treatment to Prevent Heart Attack Trial (ALLHAT)³ which showed that neither amlodipine nor lisinopril were significantly better than chlortalidone in preventing the primary outcome (coronary mortality and non-fatal myocardial infarction (MI)) and that doxazosin was significantly worse.³ A meta-analysis also showed reduced risk of stroke with diuretics compared to angiotensin-converting enzyme (ACE) inhibitors, and reduced risk of heart failure compared with calcium channel blockers, ACE inhibitors and beta blockers.⁴
• The use of indapamide (+/- perindopril) in those aged over eighty, to achieve target blood pressure below 150/80, reduced all-cause mortality, heart failure and stroke with few adverse effects, providing evidence of the benefits of treating hypertension in the elderly.⁵

Acute left ventricular failure

(See separate article Heart Failure Management.)

• Furosemide (40-80 mg) given as a slow IV injection offloads the pulmonary oedema causing the breathlessness associated with acute left ventricular heart failure (LVF). Higher doses may be necessary if the patient has been taking large doses over the longer term. The rapid initial action is due to pulmonary vasodilation rather than the later diuretic effect.
• Eplerenone is licensed for use as an adjunct in LVF following MI.

Chronic heart failure^6,7

• Use the lowest dose of diuretic necessary to relieve fluid overload and breathlessness and adjust following the addition of other heart failure therapies.⁶ Tolerance to long-term loop diuretics may develop.⁸ Patients on long-term treatment may be able to adjust their own dose according to clinical status.
• Thiazides can be as effective in treating oedema in those with mild heart failure with preserved renal function although, generally, loop diuretics are the preferred, more potent option.
• Loop diuretics reduce symptoms but have not been shown to reduce mortality.
• Spironolactone should be considered for those with moderate-to-severe heart failure (New York Heart Association grades III-IV) who are already on an ACE inhibitor and a loop diuretic. The Randomized Aldactone Evaluation Study (RALES) showed that 25 mg spironolactone daily in this group reduced mortality and hospitalisation.⁹ However, the risk of hyperkalaemia with the combined use of an ACE inhibitor and spironolactone requires careful monitoring.
• NICE guidance suggests that those with heart failure, who continue to have moderate-to-severe impairment despite otherwise optimal therapy (ACE inhibitor, beta blocker, diuretic), should be considered for treatment with spironolactone and should be reviewed by a specialist.⁶

Liver failure and ascites⁸

(See separate article Ascites.)

• Spironolactone is particularly useful for the secondary hyperaldosteronism associated with hepatic cirrhosis and is the diuretic of choice to control resultant ascites and oedema. Treatment must be stopped if encephalopathy develops.
• Spironolactone can also be used to treat malignant ascites.

Combination therapy

• Thiazide and loop diuretic - indicated in refractory heart failure where there is an inadequate response to loop diuretic alone. This combination can cause dramatic diuresis with resultant dehydration, hypovolaemia, hyponatremia and hypokalaemia. In the past, it has tended to be initiated in hospital but Clinical Knowledge Summaries' guidance suggests that it may be done in primary care under specialist supervision.⁷ Dose titration should be gradual with adequate clinical and biochemical monitoring. Heart failure specialist nurses may be helpful in this situation.
• Potassium-sparing diuretic and thiazides - the addition of a potassium-sparing diuretic may be useful in those who develop hypokalaemia on thiazide therapy.
• Potassium-sparing diuretic and loop diuretic - a potassium-sparing diuretic can again be added to those who develop, or are at high risk of, developing hypokalaemia.
• Spironolactone and loop diuretic - spironolactone can be used as a potassium-sparing diuretic for patients on loop diuretics at risk of hypokalaemia.

Combination products, for example co-amilofruse (furosemide and amiloride), may be indicated where a patient is stable on a fixed dose of loop/thiazide and potassium-sparing diuretics where a single preparation may aid compliance. However, combination products are less flexible - changing the dose of one component will alter the dose of the other component without necessarily producing the most optimal therapeutic response. Also, routine prescribing of combination products is poor practice: amiloride is frequently not required since as many heart failure patients will also be on an ACE inhibitor which has a potassium-sparing effect.

Common problems

Potassium loss

• Hypokalaemia can occur with loop or thiazide diuretics.⁸ The risk of hypokalaemia is related to duration of action as well as potency, so is actually greater with an equipotent dose of thiazide compared to loop diuretic.
• Avoid loop diuretics and thiazides (or consider prophylactic use of a potassium-sparing diuretic) in:
  • Patients with pre-existing hypokalaemia.
  • Where hypokalaemia could have serious consequences (e.g. those on digoxin and other anti-arrhythmic drugs, patients with severe ischaemic heart disease).
  • Where concomitant medication is likely to lower potassium further (e.g. steroids, potent laxatives).
• Potassium-sparing diuretics are not particularly potent and should generally be avoided in heart failure patients where loop diuretics are more efficacious and patients are likely also to be taking ACE inhibitors.
• Spironolactone can be used as a potassium-sparing diuretic in cardiac failure.
• Only prescribe potassium-sparing diuretics where a patient has, or is at risk of, hypokalaemia. They offer a more effective alternative to potassium supplements. However, they are not a guarantee against hypokalaemia, so monitoring is still mandatory.
• Hypokalaemia in liver failure can precipitate encephalopathy, particularly in alcoholic cirrhosis.

Additional electrolyte disturbances such as hyponatremia and hypomagnesaemia may occur, particularly at higher doses of diuretic therapy, due to increased renal excretion. Hyperuricaemia and metabolic alkalosis are also risks.

Metabolic disturbance

Hyperglycaemia and increased insulin resistance are associated with thiazide diuretic use: ALLHAT showed that use of chlortalidone was associated with higher fasting glucose levels and rates of developing diabetes than amlodipine or lisinopril.¹⁰ Despite this, re-analysis of ALLHAT data and further studies have not shown any evidence of worse cardiovascular outcomes. ¹¹

Hypotension⁸

Acute hypotension may be induced where aggressive diuresis has been undertaken, particularly with a loop diuretic or combination therapy:

• Ensure a patient is not hypovolaemic before starting diuretics, since diuresis occurs from the intravascular space.
• The diuresis associated with diuretics is dose-related. Excessive doses of diuretics can cause hypotension and dehydration without relieving oedema (which is still in the extravascular space).
• The usual maximum target rate of fluid loss is 1 litre per day.
• Previous treatment with diuretics increases the risk of first-dose hypotension when starting ACE inhibitors. Stop the diuretic for 2 days (where possible) before starting an ACE inhibitor and give the first dose with the patient lying down.

Postural hypotension is common with both thiazides and loop diuretics and most likely in elderly patients. If possible, withdraw offending drugs or reduce dose. Advise the patient to stand up slowly and in stages. Compression stockings may assist if venous insufficiency contributes.

Renal failure

• At high doses, diuretics may cause a pre-renal uraemia.
• Renal toxicity with diuretics occurs frequently, especially amongst the elderly, via diminished renal excretion, altered plasma protein binding and interactions with other drugs such as non-steroidal anti-inflammatory drugs. Remember that renal function may diminish over time or with concurrent illness.
• High doses of furosemide may be required in moderate-to-severe renal impairment.
• Patients with renal insufficiency are at risk of hyperkalaemia, so potassium-sparing diuretics are not usually indicated.
• Patients with heart failure and concomitant severely impaired renal function often require very large doses of diuretics -specialist help is recommended.

Contra-indications and cautions

See individual drug monographs for full list. In general:

• Renal impairment - there is an increased risk of hyperkalaemia with potassium-sparing diuretics and spironolactone. Thiazides are ineffective with increasing severity of impairment.
• Severe liver disease - thiazides and loop diuretics should be used with extreme caution, as hypokalaemia may precipitate hepatic coma. High doses of spironolactone are sometimes necessary in the treatment of cirrhosis - seek specialist help.
• Elderly - use lower initial doses since the elderly are particularly susceptible to diuretic side-effects. Adjust dose according to renal function. Avoid long-term use of diuretics to shift gravitational oedema - increasing muscle pump activity, raising the legs at rest and use of support stockings are more appropriate.
• Pregnancy - there is a risk of volume depletion and fetal/neonatal toxicity associated with diuretics. One study suggested that women using loop diuretics during pregnancy gave birth to heavier infants and had a higher risk of preterm birth, but there were confounding factors.¹² Methyldopa and beta blockers are used to treat hypertension in pregnancy and thiazides should be avoided.
• Gout - both thiazides and loop diuretics can precipitate or worsen pre-existing gout. If a diuretic is unavoidable, consider prophylaxis with allopurinol.

Initiating diuretics

• Check electrolytes and renal function prior to starting treatment and correct any pre-existing hypokalaemia.
• Check blood pressure and fluid status - avoid diuresis where there is evidence of hypovolaemia.
• Check blood glucose and lipids - pre-existing glucose intolerance or hyperlipidaemia may be worsened by thiazides or loop diuretics.

Monitoring diuretics

• Thiazides in the low dose used to treat hypertension are unlikely to cause major electrolyte disturbance:¹
  • Recheck blood pressure, renal function and electrolytes within 4-6 weeks of commencing therapy.
  • If blood pressure is not adequately controlled by a low dose of thiazide, an additional antihypertensive agent should be considered rather than increasing the dose.
  • Where blood pressure, renal function and electrolytes are satisfactory, review every 6-12 months unless the patient's clinical condition changes or interacting drugs are added.
• With loop diuretics:⁷
  • Recheck renal function and electrolytes 1-2 weeks after commencing therapy and after increasing the dose. This should be done earlier (within 5-7 days) if there is pre-existing renal impairment or where the patient is already receiving an ACE inhibitor (or AGT2 receptor antagonist) or aldosterone antagonist.
  • Once stable, six-monthly should suffice unless there is any change in therapy, intercurrent illness or worsening renal impairment. However, more frequent monitoring is still advised in those at higher risk.⁶
• With combined loop and thiazide diuretics:⁷
  • Check renal function and electrolytes within 5 days of starting then every 5-14 days, depending on an individual's stability.
  • Monitor weight and hydration status and, where diuresis is extensive, consider earlier testing of renal function.
  • Once stable, six-monthly checks may suffice unless there is any change in therapy, intercurrent illness or worsening renal impairment.
• With spironolactone:⁷
  • Check renal function and electrolytes at 1, 4, 8, and 12 weeks. Thereafter at 6, 9, and 12 months and then on a six-monthly basis.
  • If hyperkalaemia occurs (between 5.5 mmol/L and 5.9 mmol/L) or serum creatinine rises to ≥220 micromol/L on spironolactone, halve the dose to 25 mg on alternate days and recheck U&Es frequently.
  • A potassium ≥6.0 mmol/L or a creatinine level >310 micromol/L, should prompt the immediate stopping of spironolactone and the seeking of specialist advice.
  • Eplerenone should be monitored in the same way as spironolactone.
• Daily weights can help monitor fluid loss with cardiac oedema or ascites. With ascites, aim for a weight reduction of no more than 0.5 kg/day.⁸
• Compliance - many patients find that diuresis interferes with their daily activity. Discuss with the patient to find the most convenient time to take their diuretic - it may not necessarily be first thing in the morning.

Referral criteria

• Inadequate response to therapy
• Poor tolerance of drugs
• Deteriorating renal function

Patient advice

• Explain indication for use of diuretic (or “water tablet“).
• Explain frequency of initial monitoring and how blood tests/reviews will be arranged and followed up.
• Diuretics usually make people need to pass urine more frequently. Enquire about difficulties getting to the toilet in time and disruption to sleep or day-time activities.
• Patients can be educated to increase diuretic doses, for example, if they have worsening symptoms of heart failure, or can be educated to adjust dose timing to suit their daily needs.
• Side-effects such as impotence should be mentioned, since patients may not volunteer these themselves.
• Advise that some over-the-counter medications, such as NSAIDs, may interact with their diuretic and that patients should check with pharmacists/their doctor before taking additional medicines.
• Advise avoiding the use of salt substitutes, that are high in potassium, with aldosterone antagonists or potassium-sparing diuretics.

Document references

1. Hypertension, Clinical Knowledge Summaries (July 2009)
2. Hypertension: management of hypertension in adults in primary care, NICE Clinical guideline (June 2006)
3. No authors listed; 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. 2002 Dec 18;288(23):2981-97. [abstract]
4. Psaty BM, Lumley T, Furberg CD, et al; Health outcomes associated with various antihypertensive therapies used as first-line agents: a network meta-analysis.; JAMA. 2003 May 21;289(19):2534-44. [abstract]
5. Beckett NS, Peters R, Fletcher AE, et al; Treatment of hypertension in patients 80 years of age or older. N Engl J Med. 2008 May 1;358(18):1887-98. Epub 2008 Mar 31. [abstract]
6. Management of chronic heart failure in adults in primary and secondary care, NICE (July 2003)
7. Heart failure - chronic, Clinical Knowledge Summaries (June 2009)
8. Richards D, Aronson J Oxford Handbook of Practical Drug Therapy. OUP; ISBN 0-19-853007-2
9. Pitt B, Zannad F, Remme WJ, et al; The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators.; N Engl J Med. 1999 Sep 2;341(10):709-17. [abstract]
10. Barzilay JI, Davis BR, Cutler JA, et al; Fasting glucose levels and incident diabetes mellitus in older nondiabetic adults randomized to receive 3 different classes of antihypertensive treatment: a report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Arch Intern Med. 2006 Nov 13;166(20):2191-201. [abstract]
11. Wright JT Jr, Probstfield JL, Cushman WC, et al; ALLHAT findings revisited in the context of subsequent analyses, other trials, and meta-analyses. Arch Intern Med. 2009 May 11;169(9):832-42. [abstract]
12. Olesen C, de Vries CS, Thrane N, et al; Effect of diuretics on fetal growth: A drug effect or confounding by indication? Pooled Danish and Scottish cohort data. Br J Clin Pharmacol. 2001 Feb;51(2):153-7. [abstract]
13. British National Formulary

Acknowledgements