Mineralocorticoids and Aldosterone

• Mineralocorticoids are steroid hormones produced by the adrenal cortex that regulate sodium reabsorption and potassium excretion in the kidneys.

Aldosterone

• The major natural mineralocorticoid in humans.
• Medications target mineralocorticoid actions with agonists and antagonists.
• Part of the renin-angiotensin-aldosterone system.
• Low blood pressure causes the kidney to release renin.
• Renin converts angiotensinogen into angiotensin I.
• Angiotensin-converting enzyme (ACE) converts angiotensin I into angiotensin II.
• Angiotensin II causes vasoconstriction and stimulates antidiuretic hormone release.
• It also triggers aldosterone secretion in the adrenal glands.
• Aldosterone affects principal and alpha-intercalated cells in the distal convoluted and collecting tubules.
• In principal cells, aldosterone binds to mineralocorticoid receptors, forming a complex.
• The complex enhances gene expression of epithelial sodium channels (ENaC) and sodium/potassium ion pumps.
• ENaC enables sodium to enter principal cells from the filtered urine.
• Sodium/potassium ion pumps drive sodium into the blood, increasing blood volume and pressure.
• These pumps also drive potassium into the tubule for excretion.

Impact on urine Ph

• Aldosterone stimulates proton pumps (H+-ATPase pumps) in alpha-intercalated cells.
• This causes more protons to get excreted into the urine, decreasing urine pH.
• Ion exchangers move bicarbonate into the extracellular space, increasing blood pH.

Mineralocorticoid-Receptor Agonists

• Used to treat conditions with lower than normal mineralocorticoid levels in the body.
• Primary adrenal insufficiency (Addison’s disease) is an example.
• Another example is congenital adrenal hyperplasia, where steroid production enzymes are deficient.
• Fludrocortisone is an oral agonist used to treat these conditions.
• It has a long duration of action (8-12 hours) and is used for replacement therapy after adrenalectomy.
• Can be used to treat low blood pressure, idiopathic orthostatic hypotension and septic shock.
• Fludrocortisone acts as a strong mineralocorticoid receptor agonist, also activating glucocorticoid receptors.
• Side effects can include fluid retention, hypertension, edema, hypokalemia, and hyperglycemia.
• High doses can lead to myopathy and adrenal suppression.
• Stimulation of glucocorticoid receptors can cause iatrogenic Cushing syndrome.
• Cushing syndrome symptoms include obesity (buffalo hump, truncal obesity, moon facies).
• It leads to hyperglycemia, diabetes, muscle weakness, skin stretch marks, hypertension, osteoporosis, and increased infection risk.

Mineralocorticoid-Receptor Antagonists

• Used to antagonize aldosterone effects and are typically taken orally.
• Medications include eplerenone and spironolactone.
• They compete with aldosterone for receptor sites in distal convoluted tubules.
• This increases sodium and water loss and decreases plasma volume, cardiac output, and blood pressure.
• They are potassium-sparing diuretics.
• Used to treat hypertension and edematous states.
• Reduces mortality after myocardial infarction due to reduced heart remodeling.
• Treats hyperaldosteronism (primary or secondary).
• Spironolactone can bind to androgen receptors and prevent testosterone binding.
• Useful in treating polycystic ovarian syndrome symptoms.

Side Effects of Antagonists

• Risk of hyperkalemia, especially in individuals with diabetes or renal impairment.
• High potassium levels can cause life-threatening arrhythmias.
• Should not be given with potassium supplements, ACE inhibitors, or ARBs.
• Can cause metabolic acidosis by blocking proton pump function in alpha-intercalated cells which lowers blood ph.
• Spironolactone can cause antiandrogenic side effects like gynecomastia and impotence.