Visual Reference  ·  Chapter 28 Module 4
Mineralocorticoids, Adrenal Insufficiency, CAH, and Cushing Syndrome
Mineralocorticoid receptor pharmacology · MR antagonist comparison · adrenal insufficiency replacement · Cushing syndrome drug targets
Mineralocorticoid Receptor Antagonists
Steroidal
Spironolactone
  • Off-target: Androgen receptor antagonism → gynecomastia and sexual side effects in men at >50–100 mg/day
  • Indications: HFrEF (RALES trial), primary hyperaldosteronism, cirrhotic ascites, resistant hypertension, acne/hirsutism in women
  • Once-daily dosing; active metabolite canrenone
Steroidal — Selective
Eplerenone
  • Selective: No androgen, progesterone, or glucocorticoid receptor cross-reactivity → no gynecomastia
  • 60x less potent than spironolactone at MR; twice-daily dosing
  • Indications: HFrEF (EMPHASIS-HF), post-MI left ventricular dysfunction (EPHESUS); preferred in men
Non-Steroidal
Finerenone
  • Selectivity: High MR selectivity; balanced heart/kidney tissue distribution; half-life 2–3 h
  • No gynecomastia; no androgen receptor effects
  • Indication: Diabetic kidney disease + type 2 diabetes + elevated albuminuria on maximum RAAS blockade (FIDELIO-DKD, FIGARO-DKD)
All MR Antagonists: Monitor Potassium
Hyperkalemia is the major dose-limiting adverse effect — especially with estimated GFR below 60 mL/min/1.73 m² or concurrent renin-angiotensin-aldosterone system blockade. Check potassium within 1 week of initiation and after any dose change.
Adrenal Insufficiency: Primary vs. Secondary
Primary (Addison Disease)
All Three Cortical Zones Destroyed
  • ACTH: elevated (loss of cortisol negative feedback) → hyperpigmentation (MSH co-secretion)
  • Deficiencies: glucocorticoid + mineralocorticoid + adrenal androgens
  • Replace: hydrocortisone 15–25 mg/day in divided doses + fludrocortisone 50–200 mcg/day
  • Monitor fludrocortisone: plasma renin activity (mid-normal), serum electrolytes, postural BP
Secondary (Pituitary/Hypothalamic)
Zona Glomerulosa Intact
  • ACTH: low or inappropriately normal; no hyperpigmentation
  • Deficiency: glucocorticoid only (aldosterone production preserved via RAAS)
  • Replace: hydrocortisone 15–25 mg/day in divided doses only — no fludrocortisone required
  • Most common cause in practice: glucocorticoid-induced HPA axis suppression
Adrenal Crisis: Immediate Treatment
Hydrocortisone 100 mg IV bolus → then 200 mg/day continuous infusion (or 50 mg IV every 6 h) + aggressive normal saline resuscitation. Draw cortisol + ACTH before dose if logistically possible — never delay treatment. Hemodynamic improvement within 30–60 min confirms diagnosis. All patients: sick-day rules + medical alert identification + emergency hydrocortisone kit.
Cushing Syndrome Pharmacotherapy by Drug Target
CYP11B1 Inhibitor
Metyrapone
  • Target: Blocks 11-deoxycortisol → cortisol (final step)
  • Adverse effects: Androgen excess (acne, hirsutism); mineralocorticoid precursor accumulation → hypertension, hypokalemia
  • Use: Rapid pre-op control; all etiologies; oral
Potent Selective CYP11B1 Inhibitor
Osilodrostat
  • Target: CYP11B1 (also modest CYP11B2 at high doses)
  • Adverse effects: Adrenal insufficiency (dose-dependent), androgen excess
  • Use: FDA-approved for Cushing disease; twice-daily oral; ~50–70% UFC normalization
Broad Steroidogenesis Inhibitor
Ketoconazole
  • Target: CYP17A1, CYP11A1, CYP11B1
  • Adverse effects: Hepatotoxicity (monitor LFTs monthly); potent CYP3A4 inhibitor → drug interactions
  • Use: Off-label in USA; approved in Europe
CYP11B1 Inhibitor — Parenteral Only
Etomidate
  • Target: CYP11B1 at sub-anesthetic IV infusion doses
  • Adverse effects: Sedation; adrenal insufficiency
  • Use: Only IV agent; ICU setting for acute severe hypercortisolism (ectopic ACTH)
Glucocorticoid Receptor Antagonist
Mifepristone
  • Target: Blocks glucocorticoid receptor (also progesterone receptor); cortisol and ACTH rise during therapy → UFC unreliable
  • Adverse effects: Hypokalemia; endometrial thickening in women
  • Use: FDA-approved for hyperglycemia in Cushing syndrome; monitor glycemic response, not UFC
Somatostatin Receptor Analog (SSTR1,2,3,5)
Pasireotide
  • Target: Suppresses ACTH secretion from corticotroph adenoma
  • Adverse effects: Hyperglycemia in ~70% (suppresses insulin + incretin secretion)
  • Use: Cushing disease only; ~25–30% UFC normalization; SC twice daily or IM monthly
Adrenocorticolytic Agent
Mitotane
Mechanism
DDT derivative; destroys adrenocortical mitochondria; inhibits CYP11A1. Dual antitumor + cortisol-lowering effect.
Adverse Effects
Prolonged adrenal insufficiency; neurological toxicity above 20 mg/L (ataxia, confusion). Glucocorticoid replacement at 2–3x normal dose required.
Clinical Use
Adrenocortical carcinoma only. Therapeutic drug monitoring: target 14–20 mg/L. Half-life 18–159 days.