Diuretics

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/bendrofluazide, chlorthalidone, 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/frusemide, bumetanide) 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 hospital setting for the treatment of cerebral oedema.
• Carbonic anhydrase inhibitors (acetazolamide) are used for the prophylaxis of mountain sickness (unlicensed) and glaucoma.

Hypertension¹

• Current 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 contraindication or a compelling indication for an alternative antihypertensive drug exists.
• This is supported by ALLHAT³ which showed that neither amlodipine nor lisinopril were significantly better than chlorthalidone, in preventing the primary outcome (coronary mortality and non-fatal MI) and doxazosin was significantly worse.³ A meta-analysis also showed reduced risk of stroke with diuretics compared to ACEI and reduced risk of heart failure compared with calcium channel blockers, ACEIs and beta-blockers.⁴

Acute left ventricular failure

(See Management of Heart Failure).
Furosemide (40-80 mg) given as a slow iv injection off-loads the pulmonary oedema causing the breathlessness associated with acute 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 myocardial infarct.

Chronic heart failure^5,6

• Use the lowest dose of diuretic necessary to relieve fluid overload and breathlessness and adjust following the addition of other heart failure therapies.⁵ Tolerance to long-term loop diuretics may develop.⁷ Patients on long-term treatment may be able to adjust their own dose according to clinical status.
• Thiazides can be as effective 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 (NHYA grades III-IV) who are already on an ACE Inhibitor and a loop diuretic. The RALES study showed that 25 mg Spironolactone daily in this group reduced mortality and hospitalisation.⁸
• NICE guidance suggests that those with heart failure who continue to have moderate to severe impairment despite otherwise optimal therapy (ACEI, beta-blocker, diuretic) should be considered for treatment with spironolactone and should be reviewed by a specialist.⁵

Liver failure and ascites^7,9

• 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.

Note, diuretics are sometimes abused by sportsmen and women who need to lose weight rapidly to make a weight class e.g. in boxing or horse racing.¹⁰

• Thiazide and loop diuretic - indicated in refractory heart failure where there is an inadequate response to loop diuretic alone. This may need initiation in secondary care to ensure adequate monitoring of clinical status, electrolytes and fluid balance.
• 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. This combination (with an ACEI) improves outcome in heart failure.¹¹ No effect has been shown with potassium sparing diuretics in place of spironolactone. Beware hyperkalaemia with the use of an ACEI and spironolactone.

Combination products e.g. co-amilofruse (furosemide and amiloride) - may be indicated where a patient is stable on a fixed dose of loop/thiazide and potassium sparing diuretics and 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 ACEI which has a potassium sparing effect.

Potassium loss

• Hypokalaemia can occur with loop or thiazide diuretics.⁷ 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 those with:
  • Patients with pre-existing hypokalaemia.
  • Where hypokalaemia could have serious consequences (e.g. those on digoxin and other anti-arrhythmic drugs, patients with severe IHD).
  • Where concomitant medication is likely to further lower potassium (e.g. steroids, potent laxatives).
• Potassium-sparing diuretics are not particularly potent and loop diuretics are a better choice for the treatment of cardiac oedema.
• 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 hyponatraemia 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 a higher fasting glucose levels and rates of developing diabetes than amlodipine or lisinopril.¹² However, evidence that their use translates into worse cardiovascular and overall outcomes is lacking, even among older adults with metabolic syndrome.¹³ Further research is needed to assess the risk of their use amongst younger pre-diabetics.¹⁴

Hypotension⁷

• Acute hypotension may be induced where aggressive diuresis has been undertaken, particularly with a loop diuretic or combination therapy. The diuresis associated with diuretics is dose-related. Ensure a patient is not hypovolaemic before starting diuretics since diuresis occurs from the intravascular space. 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.⁷
• 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.

Prior treatment with diuretics increases the risk of first-dose hypotension when starting ACEI. Stop the diuretic for 2 days (where possible) before starting an ACEI and give the first dose with the patient lying down.

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 (e.g. NSAIDs). 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.

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 pre-term birth, but there were confounding factors.¹⁵ Methyl-dopa 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.

• Check electrolytes prior to starting treatment and correct any pre-existing hypokalaemia.^1,6
• Check BP and fluid status - avoid diuresis where evidence of hypovolaemia.
• Check blood glucose and lipids - pre-existing glucose intolerance or hyperlipidaemia may be worsened by thiazides or loop diuretics.

• Thiazides in the low dose used to treat hypertension are unlikely to cause major electrolyte disturbance. However, BP and electrolytes should be checked within 4-6 weeks of commencing therapy.¹ If BP is not adequately controlled by a low dose of thiazide, an additional anti-hypertensive agent should be considered rather than increasing the dose. If BP is stable and electrolytes are normal, annual monitoring (BP, U&Es, lipids and fasting blood sugar) should suffice unless the patient's clinical condition changes or interacting drugs are added.¹
• Repeat serum electrolytes within a week of starting a loop diuretic or spironolactone⁵ and clinically review patient. Titrate dose of diuretic to clinical effect and check U&Es on a weekly basis until treatment is stable.⁶ The frequency of bloods and clinical reviews should be based on the patient's condition, potency of the diuretic and risk of complications.⁵ Once stable, six-monthly should suffice unless there is any change in therapy, intercurrent illness or worsening renal impairment.⁵
• If hyperkalaemia develops on spironolactone, halve dose and recheck U&Es.⁵
• 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.⁷
• 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.

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

• Explain indication for use of diuretic (or “water table”).
• 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. Please tell the doctor/nurse if you experience difficulty getting to the toilet in time or if your sleep or day-time activities are being upset.
• Side-effects such as impotence should be mentioned since patients may not volunteer these themselves.
• Advise that some OTC medications such as NSAIDs may interact with their diuretic and patients should check with pharmacists/their doctor before taking additional medicines.