We begin with the kidney – a small bean-shaped organ which weighs, on average, around 130-170 grams in males and 120-150 grams in females. There’s an asymmetry between the left and right kidney, with the right kidney perched marginally lower than its left equivalent – not least due to the location of the liver. It’s this organ which is responsible for regulating plasma electrolyte concentrations and fluid balance. It’s also imperative in the regulation of acid-base balance, elimination of waste, and conservation of essential nutrients. And it’s this organ which responds to diuretics – a diuretic being a substance that promotes urinary loss. Here, we take you through the pharmacology of diuretics – drugs which have become invaluable tools in the treatment of conditions such as hypertension, heart failure, and cirrhosis.
Pharmacology of Diuretics
A diuretic is a substance which promotes the elimination of water from the body. In contrast, an antidiuretic – such as vasopressin – promotes the retention of water in the body. In terms of diuretics, there are many, distinct classes. They include, but are not limited to:
- Carbonic anhydrase inhibitors
- Osmotic diuretics
- Loop diuretics
- Thiazide and thiazide-like diuretics
- Potassium-sparing diuretics
Another class – known as calcium-sparing diuretics – also exists, though this class typically refers to thiazides and potassium-sparing diuretics (which decrease calcium loss in comparison to other diuretic classes). A visual of all of the above classes may be found below. First though, we must delve into the pharmacology of diuretics – looking at how and why they work, and why one class is more advantageous in a given clinical setting than another. We begin at once with the carbonic anhydrase inhibitors.
Carbonic Anhydrase Inhibitors
Carbonic anhydrase inhibitors include the distinguished, if not isolated, member of acetazolamide. Carbonic anhydrase inhibitors work by interfering with Na+ reabsorption in the proximal tubule – reabsorption which also comes with H+ loss. In other words, by inhibiting carbonic anhydrase ions such as bicarbonate, sodium, and chloride are excreted – and with their excretion follows water. Acetazolamide is commonly used in the treatment of conditions such as:
- Drug-induced edema
- Mountain sickness
- Heart failure-induced edema
Acetazolamide is well absorbed from the gut and is eliminated unchanged through the kidney. It has a half-life of approximately 3-5 hours.
Osmotic diuretics increase osmolality – by expanding extracellular fluid and plasma volume. As a result, osmotic diuretics – such as mannitol – increase blood flow to the kidneys. It limits passive tubular reabsorption of water by exerting its osmotic effect in the proximal renal tubule and descending limb of the loop of Henle. It is administered by intravenous infusion and excreted unchanged in the glomerulus. It has a short half-life of just two hours – a half-life which rapidly rises in patients with kidney disease.
Loop diuretics – such as bumetanide and furosemide – have to be secreted into the proximal kidney tubule by the tubular anion transport mechanism, in order to gain access to their site of action. The degree of diuresis, and indeed natriuresis, wholly depends on the rate of drug delivery to the site of action via this route. Loop diuretics inhibit chloride reabsorption in the following way – by binding to the Na+/K+/Cl- cotransporter complex at the luminal border of the thick ascending limb of the loop of Henle.
Inhibiting chloride reabsorption has the effect of reducing the electrochemical gradient across the cell which, in turn, reduces sodium reabsorption from the tubular fluid. In other words, loop diuretics compete for the chloride binding site on the cotransporter. This leads to an inhibition of sodium, chloride, and potassium reabsorption and consequent water loss. Loop diuretics are also known as high-ceiling diuretics for producing substantial diuresis – as much as 20 percent of the filtered amount. Other loop diuretics include torsemide and ethacrynic acid.
In terms of the pharmacology of diuretics, loop diuretics exhibit profoundly erratic inter-individual absorption. Furosemide is less completely absorbed than bumetanide – and the latter is also associated with less variation. Loop diuretics are highly protein bound. Natriuesis and diuresis commence approximately 30 minutes post-administration of the drug, though intravenous administration produces a considerably more rapid response – with onset in a matter of minutes, and its effects lasting for around 2-3 hours.
Adverse effects of loop diuretics include:
- Intravascular volume depletion and renal impairment
- Hyponatremia, hypokalemia, hypomagnesemia
- Increased calcium excretion
Thiazide and Thiazide-like Diuretics
Thiazide and thiazide-like diuretics act at the distal convoluted tubule – inhibiting the sodium-chloride symporter. This leads directly to water loss. The onset of diuresis is much slower than that seen with loop diuretics, and they also have a considerably lower efficacy – achieving a maximum natriuresis of approximately 5-8 percent, but thiazide diuretics do have a longer duration of action compared to loop diuretics. And unlike loop diuretics, thiazide diuretics reduce urinary calcium loss by inhibiting calcium transport in the proximal and distal tubules. Examples of thiazide diuretics include bendoflumethiazide, chlortalidone, and metolazone.
Thiazide and their ‘like-equivalents’ are well absorbed drugs – and the vast majority are extensively metabolised via hepatic means. They are highly protein bound and have variably half-lives – ranging from 4 to 90 hours. Unwanted effects include hypokalemia, salt and water depletion, hyperuricemia, glucose intolerance (dose related), hyperlipidemia, impotence, and nocturia (note the similarity of many adverse effects among diuretics).
The last class in our analysis of the pharmacology of diuretics is the potassium-sparing diuretics. Examples include amiloride, eplerenone, spironolactone, and triamterene. As their name suggests, potassium-sparing diuretics promote potassium retention. There are two main classes:
- Aldosterone antagonists – of which spironolactone and eplerenone are members.
- Epithelial sodium channel (ENaC) blockers – amiloride and triamterene.
Aldosterone typically functions to pepper sodium channels to the collecting duct and distal tubule. Drugs such as spironolactone therefore inhibit sodium reabsorption – leading to water loss. ENaC channels are primarily found in the distal tubule (though they are also found elsewhere, such as the lung). By blocking ENaC channels, amiloride and triamterene inhibit sodium reabsorption, thereby increasing water loss. Aldosterone antagonists work most effectively in hyperaldosteronism – when more aldosterone is available to antagonise.
Potassium-sparing diuretics are administered orally. Spironolactone is metabolised in the gut to canrenone – an intermediate responsible for a considerable amount of diuretic effect. The half-life of spironolactone is only 1 hour, in contrast to canrenone which labours around the 18-20 hour mark. The onset of action, compared to loop diuretics and others, is quite slow – taking around one day to commence and 3-4 days to reach maximum effect. Eplerenone has a half-life of around 4-6 hours and also has slow onset of action. The onset of amiloride and triameterene is, in contrast, quite rapid.
Spironolactone is associated with an anti-androgen effect, due to its propensity for androgen receptors – inhibiting dihydrotestosterone from binding. This may cause gynecomastia and impotence in men. Potassium-sparing diuretics are also associated with hyperkalemia, hyponatremia, and gastrointestinal disturbances.
Test your knowledge of the pharmacology of diuretics with this quiz - ten questions which cover the whole spectrum of material covered in this article.