Mineralocorticoids and mineralocorticoid antagonists Notes

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Mineralocorticoids and mineralocorticoid antagonists

NOTES NOTES MINERALOCORTICOIDS & MINERALOCORTICOID ANTAGONISTS Figure 1.1 Mineralocorticoid-receptor agonist, corticosteroid: mechanism of action. WHAT ARE THEY? Basic information ▪ Drugs used to ↑/↓ mineralocorticoid activity Key points ▪ “Aldosterone receptor” used interchangeably with “mineralocorticoid receptor” CLASSIFICATION MINERALOCORTICOID-RECEPTOR AGONIST, CORTICOSTEROID ▪ Fludrocortisone (Florinef): PO Mechanism of action ▪ Bind to mineralocorticoid receptors in target cells’ cytoplasm (esp. principal cells of distal convoluted tubule/collecting tubule) → enter nucleus; ↑ expression of Na/K ATPase, epithelial Na channel (ENaC) → ↑ Na+ and water reabsorption; ↑ K+ loss in distal convoluted tubules ▪ Moderate activation of glucocorticoid OSMOSIS.ORG 1
receptors Common indications ▪ Mineralocorticoid replacement therapy (e.g. post-adrenalectomy; congenital adrenal hyperplasia; Addison disease; idiopathic orthostatic hypotension; septic shock unresponsive to volume resuscitation/ vasopressors) MINERALOCORTICOID-RECEPTOR ANTAGONISTS; POTASSIUMSPARING DIURETICS ▪ Eplerenone (Inspra): PO ▪ Spironolactone (Aldactone): PO Mechanism of action ▪ Compete with aldosterone for receptor sites in distal convoluted tubules → ↓ loss of K+, H+; ↑ loss of Na+, water → ↓ blood pressure, ↓ myocardial and vascular fibrosis Common indications ▪ Edematous states; hypertension, heart failure; primary aldosteronism ▪ Spironolactone: ↓ effects of testosterone (e.g. polycystic ovarian syndrome, acne vulgaris in female individuals) CLINICAL CONCERNS ADVERSE EFFECTS Drug-specific adverse effects ▪ Mineralocorticoid-receptor agonists ▫ Fluid retention, edema, hypertension, hypokalemia, hyperglycemia ▫ Hyperpigmentation ▫ Myopathy (high doses) ▫ Adrenal/hypothalamic-pituitary-adrenal (HPA) axis suppression (high doses for prolonged period) ▫ Stimulation of glucocorticoid receptors → iatrogenic Cushing syndrome (buffalo hump, truncal obesity, moon facies, hyperglycemia, diabetes, hypertension, osteoporosis, ↑ infection risk) ▪ Mineralocorticoid-receptor antagonists ▫ Antiandrogenic side effects (e.g. gynecomastia, impotence) ▫ Hyperkalemia (associated with life- 2 OSMOSIS.ORG threatening arrhythmia), hyponatremia; rashes ▫ ↓ excretion of H+ → ↑ H+ concentration in blood; ↓ pH → metabolic acidosis DISEASE-RELATED CONCERNS ▪ Mineralocorticoid-receptor agonists ▫ Cardiovascular disease: fluid retention, electrolyte disturbances, hypertension ▫ Diabetes: hyperglycemia ▫ Gastrointestinal disease: ↑ risk of ulceration, perforation ▫ Ocular disease: ↑ risk of cataracts; ↑ intraocular pressure, open-angle glaucoma ▫ Osteoporosis: ↑ risk of bone loss, fractures (high-dose/long-term use) ▪ Mineralocorticoid-receptor antagonists ▫ Diabetes/renal impairment: ↑ hyperkalemia risk ▫ Hepatic impairment: electrolyte imbalance → ↑ hepatic coma risk ADMINISTRATION Administration issues ▪ Mineralocorticoid: withdrawal (discontinue slowly) ▪ Spironolactone: suspension not therapeutically equivalent to tablets; shake well before administration Dietary ▪ Grapefruit juice: ↑ eplerenone serum levels ▪ Food: ↑ bioavailability of spironolactone, administer consistently with/without food PREGNANCY/BREASTFEEDING IMPLICATIONS ▪ Fludrocortisone: use during pregnancy may → hypoadrenalism in newborns ▪ Spironolactone/eplerenone: avoid during pregnancy, particularly first trimester (antiandrogenic effects) CONTRAINDICATIONS ▪ Eplerenone ▫ Serum potassium > 5.5mEq/L at initiation; CrCl ≤ 30mL/min ▫ Concomitant use: strong CYP3A4
Endocrine Mineralocorticoids & Mineralocorticoid Antagonists inhibitor ▪ Fludrocortisone ▫ Systemic fungal infections ▪ Spironolactone ▫ Hyperkalemia, Addison disease ▫ Concomitant use: eplerenone PATIENT EDUCATION ▪ Mineralocorticoid antagonists: avoid potassium supplements, potassiumcontaining salt substitutes, potassium-rich diets, ↑ K+ drugs (e.g. NSAIDS) Figure 1.2 Mineralocorticoid-receptor antagonists; potassium-sparing diuretics: mechanism of action. Figure 1.3 Mineralocorticoids and mineralocorticoid antagonists: pharmacokinetic interactions. OSMOSIS.ORG 3
Figure 1.4 Mineralocorticoids and mineralocorticoid antagonists: common drug-drug interactions. (1) Figure 1.5 Mineralocorticoids and mineralocorticoid antagonists: general adult dosing guidelines. *Dose and dosing interval varies depending on individual patient characteristics 4 OSMOSIS.ORG
Endocrine Mineralocorticoids & Mineralocorticoid Antagonists Figure 1.6 Mineralocorticoids and mineralocorticoid antagonists: common drug-drug interactions. (2) OSMOSIS.ORG 5

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