A 49-year-old man comes to his primary care provider for evaluation of gynecomastia, which the patient first noticed two weeks ago. The patient does not have breast tenderness or discharge. Past medical history is notable for hypertension and hyperlipidemia. Two months ago, the patient was started on a new antihypertensive agent that can lead to elevated serum potassium levels as a side effect. Family history is notable for breast cancer in his mother. The patient consumes around 3-4 beers per week and smokes one pack of cigarettes per day. Temperature is 37.1°C (98.8°F), blood pressure is 130/82 mmHg, and pulse is 76/min. Physical examination is notable for the findings below. Cardiovascular, pulmonary, and abdominal exams are noncontributory. Which of the following best describes the underlying cause of this patient’s symptoms? Image reproduced fromWikimedia Commons

Impaired binding of androgens to its receptors

Malignant proliferation of breast tissue

Impaired hepatic breakdown of estrogen

Impaired binding of androgens to its receptors

Reduced synthesis of dihydrotestosterone

Inhibition of cholesterol desmolase

Potassium sparing diuretics

Last updated: September 12, 2024

Foundational SciencesPharmacologyRenal and urinary systemDiuretics

Organ SystemsRenal and urinary systemPharmacologyDiuretics

USMLE® Step 1 ReviewRenal and urinary systemPharmacologyDiuretics

USMLE® Step 2 ReviewRenal and urinary systemBack to the Basic SciencesPharmacologyDiuretics

Definitions & Key takeaways

Potassium-sparing diuretics are a type of diuretic that helps eliminate excess sodium and water from the body while retaining potassium at the same time. Examples of potassium-sparing diuretics include spironolactone, amiloride, and triamterene. In combination with other diuretics, potassium-sparing diuretics can be used in the management of hypertension, while preventing hypokalemia. Common side effects of potassium-sparing diuretics include hyperkalemia and metabolic acidosis.

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Introduction0:00–0:34

Diuretics are medications that act on the kidneys to increase production of urine, and to eliminate water, certain metabolic wastes, and electrolytes from the body.

There are 5 main types of diuretics; carbonic anhydrase inhibitors, osmotic diuretics, thiazide and thiazide-like diuretics, loop diuretics,, and last but not least, potassium sparing diuretics - which is the only class of diuretic that retains potassium, rather than wasting it.

Now, the basic unit of the kidney is called a nephron, and each nephron is made up of a glomerulus, which filters the blood.

Physiology0:34–1:32

T. The filtered content then goes through the renal tubule, where excess waste, and molecules, such as ions and water, are removed or filtered through an exchange between the tubule and the peritubular capillaries.

So the renal tubule plays a huge role in secretion and reabsorption of fluid and ions - such as sodium, potassium, chloride, and magnesium - in order to maintain homeostasis - or the balance of fluid and ions in our body.

The renal tubule has a few segments of its own: the proximal convoluted tubule, the U-shaped loop of Henle, with a thin descending, a thin ascending limb, and a thick ascending limb, and finally, the distal convoluted tubule, which empties into the collecting duct, which collects the urine.

Different kinds of diuretics act on different segments of the renal tubule. Now, potassium sparing diuretics act on the cortical collecting tubules.

Mechanism of Action1:32–4:47

Here, there are principal cells and α-intercalated cells dispersed amongst the tubule cells. The principal cell has two pumps on the apical surface, an ATP-dependent potassium pump that pushes potassium into the tubule, and an epithelial sodium channel pump, called ENaC for short, that pulls sodium into the cell.

There’s also a Na/K ATPase pump on the basolateral surface that again moves 2 potassium ions into the cell for every 3 sodium ions out.

Now, the alpha intercalated cells mainly get rid of hydrogen ions from the blood, and they use two pumps on their apical surface for this.

First, they have a H+/ATPase which uses ATP to pump hydrogen into the tubule. Second, they have a hydrogen potassium ATPase (H+K+ATPase) which uses ATP to push 1 hydrogen into the tubule in exchange for 1 potassium.

Sodium and potassium levels in alpha intercalated cells are also controlled by Na/K ATPase pumps on the basolateral surface, which move two potassium ions into the cell and three sodium ions out of the cell.Now the reabsorption and secretion of these molecules in the distal convoluted tubule and collecting duct are hormonally regulated by aldosterone, a mineralocorticoid hormone made in the adrenal cortex.

In the principal cells, aldosterone diffuses across the basolateral membrane and binds to a mineralocorticoid receptor in the cytoplasm.

Then the aldosterone-receptor complex gets inside the nucleus of the cell where it triggers the increased synthesis of ENaCs, ATP-dependent potassium pumps, and the Na-K ATPase transporters.

Together, they work to increase sodium reabsorption into the blood and potassium secretion into the urine. In the alpha intercalated cells, Aldosterone increases the synthesis of hydrogen potassium ATPase to increase H+ secretion.

Now, potassium sparing diuretics come in two flavors according to their mechanism of action: first, we’ve got those that directly inhibit the aldosterone receptor like spironolactone and eplerenone, then we have medications that indirectly inhibit the effects of aldosterone by blocking the ENaC channels on the cell membrane, like amiloride and triamterene.

This decreases the level of sodium inside the principal cells which decreases the action of the Na+/K+ ATPase on the basolateral membrane.

However, at the end of the day, both categories have the same effect; first, they increase the excretion of sodium, and since water flows where the sodium goes, they also increase water loss through the urine.

Next, they decrease the excretion of hydrogen and potassium, hence the name, potassium sparing. Ok, so the major indication for diuretics is for the management of hypertension and edematous states.

Indications4:47–7:15

These medications increase sodium and water loss through the urine, which leads to decreased plasma volume and cardiac output, resulting in lower blood pressure.

This also treats edematous states like pulmonary edema or ascites where fluid builds up in the extracellular space. Potassium sparing diuretics are usually pretty weak, so they are used in combination with other diuretics, like loop or thiazides that would normally cause renal potassium wasting and hypokalemia.

The addition of a potassium sparing diuretic increases the reabsorption of potassium in the final stretches of the renal tubule, and therefore reduces potassium loss.

Aldosterone receptor antagonists like spironolactone and eplerenone are also useful in hyperaldosteronism. Hyperaldosteronism can be primary, meaning too much aldosterone is secreted by the adrenal cortex itself; like with Conn syndrome, or when a tumor secretes too much ACTH, which then tells the adrenal cortex to make too much aldosterone.

Hyperaldosteronism can also be secondary, when high levels of aldosterone result from the activation of the renin-angiotensin-aldosterone system.

This is typically due to low plasma volume, because too much fluid “escapes” to the extracellular space, leading to edema.Also, aldosterone receptor antagonists have been proven to reduce mortality after a myocardial infarction, presumably because they reduce the rate of remodelling in the heart.

Finally, spironolactone can also bind to androgen receptors and prevent testosterone from binding. This makes it useful for blunting the effects of testosterone in the body, like in polycystic ovarian syndrome, where there are many cysts on the ovaries that secrete excess testosterone.

This can result in symptoms like infertility, hair loss, acne, and hirsutism, or unwanted facial hair growth in women. ENaC channel blockers like amiloride are useful in a condition called Liddle’s syndrome - a rare genetic disease where the ENaC channels are continuously activated and cause sodium retention and renal potassium wasting.

Ok, now as far as side effects go, since these diuretics spare potassium, there’s a risk for too much potassium building up in the blood, or hyperkalemia, which can lead to arrhythmias.

Side Effects7:15–8:13

Because of this, these medications should be used cautiously under close monitoring with potassium supplements or other medications that could increase potassium like ACE inhibitors or ARBs, since they also increase hydrogen retention.

A buildup of hydrogen ions in the blood might lower blood pH and cause metabolic acidosis. Very rarely, spironolactone may cause antiandrogenic side effects like gynecomastia, or the development of breasts in men, and impotence.

Finally, triamterene in particular may form kidney stones due to its low solubility, and may induce acute renal failure when associated with indomethacin, an NSAID.Now, we want to make a simple and fun mnemonic that’ll help you efficiently memorize and retain all these pharm facts!

Memory Palace8:13–10:21

So let’s have a scene at the beach. We have two groups of potassium sparing diuretics; the ones targeting aldosterone, represented by an albatross, and the ones targeting ENaC, represented by a salt shaker reenacting Shakespeare.

The aldosterone antagonists include a sea snail with a spiral on its shell for spironolactone, and there’s a plier clamped on its shell for eplerenone.

Let’s have the snail make fun of the albatross since it’s an aldosterone antagonist. For the drugs targeting ENaC, let’s have Amelia Earhart represent amiodarone, carrying a trident with marine fish stuck to one end, representing triamterene.

She’s trying to get some salt on the seafood so she’s poking the saltshaker with the trident. For indications, we’ll wrap a blood pressure cuff for hypertension, around a water balloon for edema, and have them float in the ocean.

Since the aldosterone antagonists can treat symptoms caused by excess androgen, let’s give the snail a giant mustache to represent hirsutism.

Next, let’s have the snail crash through a heart shaped wall to help you remember it prevents cardiac remodeling after a MI.

Finally, let’s have Amelia Earhart carry a ladle in her other hand since it’s used to treat Liddle’s syndrome. For the main side effects of potassium sparing diuretics, we’ll stick a large banana for hyperkalemia in the sand, and it’s got a sticker of a heart with an EKG tracing on it for arrhythmias.

Next to the banana is a can of soda for metabolic acidosis. Let’s also put a bra on the snail with the pliers since aldosterone antagonists cause anti androgenic side effects, like gynecomastia in men.

Next, let’s put a large kidney stone at the tip of the triamterene trident. All right, as a quick recap...potassium sparing diuretics are the only class of diuretic that help eliminate excess sodium and water from the body, while retaining potassium at the same time.

Review10:21–11:30

There’s four of them, and they act in two different ways: spironolactone and eplerenone blocks the aldosterone receptors on the collecting tubule principal cells, cancelling out its physiological effects, while amiloride and triamterene block the epithelial sodium channels.

In combination with other diuretics, potassium sparing diuretics can be used in the management of hypertension to prevent hypokalemia.

Particularly, aldosterone receptor blockers are indicated in primary and secondary hyperaldosteronism - like Conn’s syndrome and heart failure or hepatic cirrhosis and nephrotic syndrome, respectively.

They are also indicated for use after a myocardial infarction. Particularly, sodium channel blockers like amiloride may be useful in Liddle’s syndrome.

Common side effects of potassium sparing diuretics include hyperkalemia and metabolic acidosis. But wait, there's more: Here's a mind map with all of the mnemonics from the video.