User:PharmD2026/Potassium-sparing diuretic

Mechanism of action
Normally, sodium is reabsorbed in the collecting tubules of a renal nephron. This occurs via epithelial sodium channels or ENaCs, located on the luminal surface of principal cells that line the collecting tubules. Positively-charged Na+ entering the cells during reabsorption leads to an electronegative luminal environment causing the secretion of potassium (K+) into the lumen/ urine in exchange. Sodium reabsorption also causes water retention.

When the kidneys detect low blood pressure, the renin–angiotensin–aldosterone system (RAAS) is activated and eventually, aldosterone is secreted. Aldosterone binds to aldosterone receptors (mineralocorticoid receptors) increasing sodium reabsorption in an effort to increase blood pressure and improve fluid status in the body. When excessive sodium reabsorption occurs, there is an increasing loss of K+ in the urine and can lead to clinically significant decreases, termed hypokalemia. Increased sodium reabsorption also increases water retention.

Potassium-sparing diuretics act to prevent sodium reabsorption in the collecting tubule by either binding ENaCs (amiloride, triamterene) or by inhibiting aldosterone receptors (spironolactone, eplerenone). This prevents excessive excretion of K+ in urine and decreased retention of water, preventing hypokalemia.

- Understanding of aldosterone focused on its effects on Na & water retention & K+ excretion, which are mediated by the binding of aldosterone to the mineralocorticoid receptor in kidneys

- Normally, activation of mineralocorticoid receptors via aldosterone causes increased Na reabsorption from distal tubule & collecting duct in exchange for increased K+ secretion. Spironolactone inhibits mineralocorticoid receptors, which leads to less activated Na channels at luminal membrane, & less Na-K ATPase pumps at interstitial space membrane. This results in secretion of Na, decreased blood volume, & reabsorption of K+.

- The main aldosterone receptor antagonist MOA for HTN is the blocking of mineralocorticoid receptor in the kidney's distal tubule, preventing upregulation of the epithelial Na channel & Na/K ATPase pump. This results in increased urine production, K+ reabsorption, & overall decrease in volume.

Adverse effects
Due to its activity as an androgen receptor antagonist and progesterone receptor agonist, spironolactone causes adverse effects, including gynecomastia or decreased libido in males and menstrual abnormalities in females. '''Spironolactone also causes hyperkalemia and renal insufficiency. '''

- Spironolactone is associated w/ risk of sexual side effects that are dose & duration dependent

- Both eplerenone & spironolactone are associated w/ increased serum K+ levels - pts w/ renal dysfunction or HF are at greater risk of hyperkalemia

- Spironolactone also acts as an antagonist at the androgen receptor & as an agonist at progesterone receptors, leading to gynecomastia or loss of libido in male pts, & menstrual irregularities in women

- Spironolactone also causes acute renal insufficiency

Drug Interactions
Spironolactone interacts with the following medications:

- ACE inhibitors and/or ARBs: increases hyperkalemia risk

- Alcohol: risk of orthostatic hypotension

- Barbiturates: risk of orthostatic hypotension

- Narcotics: risk of orthostatic hypotension

- NSAIDs: increases hyperkalemia risk and decreases diuretic effect of K-sparing diuretics

- Digoxin: increases digoxin plasma concentrations, leading to increased toxicity

- Spironolactone has increased risk of hyperkalemia w/ concomitant use w/ ACEi or ARBs

- Alcohol, barbiturates, & narcotics have the potential to result in orthostatic hypotension w/ concurrent spironolactone use

- NSAIDs can reduce the diuretic & antihypertensive effects of potassium-sparing diuretics, & combination has been associated w/ severe hyperkalemia

- Combining w/ potassium supplements increases risk for hyperkalemia

- Spironolactone can increase half life of digoxin, which can result in increased serum digoxin conc & subsequent digitalis toxicity

Other diuretics
While not classically considered potassium-sparing diuretics, ACE inhibitors (ACEis) and angiotensin receptor blockers (ARBs) are anti-hypertensive drugs with diuretic effects that decrease renal excretion of potassium. They work by inhibiting either the production (ACEis) or effects (ARBs) of angiotensin 2. This results in a decrease in aldosterone release, which causes potassium-sparing-diuretic-like effects similar to those of the aldosterone antagonists, spironolactone, and eplerenone.

'''**May remove this section as b/c not really related to K-sparing diuretics. ACEi/ARBs are completely different class of anti-hypertensives, so not necessary to mention them in this specific article!'''