Diuretics

Diuretics are a group of drugs that act on the kidney to increase the excretion of sodium chloride and water. They are most commonly used to reduce oedema in congestive cardiac failure, some renal diseases and hepatic cirrhosis. Some diuretics, most notably the thiazide diuretic class, can also be used to manage hypertension.

Most diuretics work by reducing the reabsorption of electrolytes by the tubules. The resultant increased electrolyte excretion is accompanied by an increase in water excretion.

The following table summarises the mechanism of action of the different types of diuretic:

Diuretic	Mechanism of action
Loop diuretics, e.g. furosemide, bumetanide	Act on the Na.K.2Cl co-transporters in the ascending loop of Henlé to inhibit sodium, chloride and potassium reabsorption.
Thiazide diuretics, e.g. bendroflumethiazide, hydrochlorothiazide	Act on the Na.Cl co-transporter in the distal convoluted tubule to inhibit sodium and chloride reabsorption.
Osmotic diuretics, e.g. mannitol	Increases the osmolality of the glomerular filtrate and tubular fluid, increasing urinary volume by an osmotic effect.
Aldosterone antagonists, e.g. spironolactone	Acts in the distal convoluted tubule as a competitive aldosterone antagonist resulting in inhibition of sodium reabsorption and increasing potassium reabsorption.
Carbonic anhydrase inhibitors, e.g. acetazolamide	Inhibits the enzyme carbonic anhydrase preventing the conversion of bicarbonate and hydrogen ions into carbonic acid. This reduces the availability of hydrogen ions and causes sodium and bicarbonate to remain in the renal tubule resulting in diuresis.

Loop diuretics

Loop diuretics are powerful diuretics used to reduce oedema associated with congestive cardiac failure, liver cirrhosis and renal disease. They also have a limited role in the management of resistant hypertension. The two most commonly used loop diuretics are furosemide and bumetanide.

Both furosemide and bumetanide act within 1 hour of oral administration, and diuresis is complete within 6 hours so that, if necessary, they can be given twice in one day without interfering with sleep. Following intravenous administration, furosemide has a peak effect within 30 minutes. The diuresis associated with these drugs is dose-related.

They act on the Na.K.2Cl co-transporters in the ascending loop of Henlé to inhibit sodium, chloride and potassium reabsorption. This prevents the generation of a hypertonic renal medulla and reduces the osmotic gradient that forces water to leave the collecting duct system.

Furosemide can be administered orally or intravenously. The doses for furosemide are as follows:

Orally 20-40 mg daily, increased to 120 mg in resistant oedema
Intravenously 20-50 mg, increased in steps of 20 mg every 2 hours if required, doses greater than 50 mg given by intravenous infusion only; maximum 1.5 g per day.

Bumetanide is administered orally. The doses for bumetanide are as follows:

Adults – 1 mg, dose to be taken in the morning, then 1 mg after 6–8 hours if required.
Elderly – 500 micrograms daily; this lower dose may be sufficient in elderly patients.
Severe oedema – Initially 5 mg daily, increased in steps of 5 mg every 12–24 hours, adjusted according to response.

Bumetanide is 40 times more potent than furosemide, and a dose of 1 mg is roughly equivalent to 40 mg of furosemide.

Bumetanide is mainly used in patients with heart failure in whom high doses of furosemide are ineffective. The main difference between bumetanide and furosemide is in bioavailability and pharmacodynamic potency. Furosemide is incompletely absorbed in the intestine and has a bioavailability of 40-50%. In contrast, bumetanide is almost completely absorbed in the intestine and has a bioavailability of approximately 80%. For this reason, it is commonly used in patients with gut oedema when it has better bioavailability than furosemide.

The following are contra-indications to the use of loop diuretics:

Anuria
Comatose and precomatose states associated with liver cirrhosis
Renal failure due to nephrotoxic or hepatotoxic drugs
Severe hypokalaemia
Severe hyponatraemia

The following are cautions to the use of loop diuretics:

Can exacerbate diabetes (but hyperglycaemia less likely than with thiazides)
Can exacerbate gout
Hypotension should be corrected before initiation of treatment
Hypovolaemia should be corrected before initiation of treatment
Urinary retention can occur in prostatic hyperplasia
Lower initial doses may be necessary in the elderly because they are particularly susceptible to the side-effects

Common side-effects of loop diuretics include:

Dizziness
Electrolyte imbalance
Fatigue
Headache
Metabolic alkalosis
Muscle spasms
Nausea

Thiazide diuretics

Thiazides are moderately potent diuretics that are widely used in the treatment of heart failure and hypertension. They act on the Na.Cl co-transporter in the distal convoluted tubule to inhibit sodium and chloride reabsorption. Bendroflumethiazide is the most widely used thiazide diuretic.

Thiazide diuretics act within 1 to 2 hours of oral administration, and most have a duration of action of 12 to 24 hour. They are usually administered early in the day so that the diuresis does not interfere with sleep.

The following are contra-indications to the use of thiazide diuretics:

Addison’s disease
Hypercalcaemia
Hyponatraemia
Refractory hypokalaemia
Symptomatic hyperuricaemia

The following are cautions to the use of thiazide diuretics:

Diabetes
Gout
Risk of hypokalaemia
Systemic lupus erythematosus

Common side-effects of thiazide diuretics include:

Constipation
Diarrhoea
Dizziness
Dry mouth
Electrolyte imbalance
Erectile dysfunction
Fatigue
Headache
Hyperglycaemia
Hyperuricaemia
Hypochloraemic alkalosis
Nausea
Postural hypotension
Skin reactions

The two most common electrolyte disturbances seen in patients taken thiazide diuretics are hyponatraemia (seen in approximately 13.7% of patients taking them) and hypokalaemia (seen in approximately 8.5% of patients taking them). The following study provides a useful overview of this topic:

Thiazide diuretic prescription and electrolyte abnormalities in primary care

Osmotic diuretics

Osmotic diuretics are most commonly used to treat cerebral oedema and raised intracranial pressure. Mannitol is the most widely used osmotic diuretic.

Mannitol is a low molecular weight compound and is, therefore, freely filtered at the glomerulus and is not reabsorbed. It, therefore, increases the osmolality of the glomerular filtrate and tubular fluid, increasing urinary volume by an osmotic effect. It also does not cross the blood-brain-barrier (BBB). This decreases the volume of CSF by:

Decreasing the rate of CSF formation, and;
Withdrawing extracellular fluid from the brain across the BBB

The recommended dose of mannitol for the reduction of CSF pressure/cerebral oedema is 0.25-2g/kg as an intravenous infusion over 30-60 minutes. This can be repeated 1-2 times after 4-8 hours if needed.

Other uses of mannitol include:

Short-term management of glaucoma
Treatment of rhabdomyolysis
Preserve renal function in peri-operative jaundiced patients
To initiate diuresis in transplanted kidneys
Bowel preparation prior to colorectal procedures

The following are contra-indications to the use of mannitol:

Anuria
Intracranial bleeding (except during craniotomy)
Severe cardiac failure
Severe dehydration
Severe pulmonary oedema

Common side-effects of mannitol include:

Cough
Extravasation causing inflammation and thrombophlebitis
Headache
Vomiting

Aldosterone antagonists

Aldosterone antagonists are ‘potassium-sparing’ diuretics used in the treatment of oedema and ascites caused by liver cirrhosis and heart failure, in the management of Conn’s syndrome, and also in the treatment of resistant hypertension. They are not usually used in the routine treatment of hypertension unless hypokalaemia develops. Spironolactone is the most widely used aldosterone antagonists.

Spironolactone acts as a competitive antagonist of aldosterone in the distal convoluted tubule. It, therefore, inhibits sodium reabsorption and increases potassium reabsorption and increases the urinary excretion of sodium and water.

The following are contra-indications to the use of spironolactone:

Addison’s disease
Anuria
Hyperkalaemia

The predominant side effect of spironolactone is hyperkalaemia, especially in the presence of renal impairment. In severe cases, hyperkalaemia can be life-threatening.

Other potential side effects include:

Acute kidney injury
Agranulocytosis
Alopecia
Breast pain
Confusion
Dizziness
Gastrointestinal disturbance
Gynaecomastia
Hepatic function abnormalities
Hyperkalaemia
Hypochloraemic alkalosis
Leg cramps
Leucopenia
Libido disorders
Menstrual disorders
Nausea
Severe cutaneous adverse reactions (SCARs)
Thrombocytopenia

Carbonic anhydrase inhibitors

Carbonic anhydrase inhibitors are weak diuretics that are rarely used for their diuretic effects. Acetazolamide is the most widely used carbonic anhydrase inhibitors.

Acetazolamide is a reversible, non-competitive inhibitor of carbonic anhydrase situated with cell cytosol and on the brush border of the proximal convoluted tubule. Carbonic anhydrase catalyses the conversion of bicarbonate and hydrogen ions into carbonic acid and then carbonic acid to carbon dioxide and water. Acetazolamide, therefore, decreases the availability of hydrogen ions and therefore, sodium and bicarbonate ions remain in the renal tubule, resulting in a diuresis.

Acetazolamide is commonly used to reduce intraocular pressure in glaucoma and can be used to alkalinise the urine in salicylate poisoning.

The following are contra-indications to the use of acetazolamide: