Adrenal corticosteroid inhibitors

Introduction

Adrenal corticosteroid inhibitors are a group of pharmacological agents that suppress or block the synthesis or activity of adrenal corticosteroids, including glucocorticoids (cortisol) and mineralocorticoids (aldosterone). These drugs are primarily used in the treatment of Cushing’s syndrome, adrenal carcinoma, ectopic ACTH production, hyperaldosteronism, and as adjuvant therapy in certain cancers.

Because cortisol plays a central role in metabolism, stress response, and immune regulation, and aldosterone in fluid/electrolyte balance, inhibition of these pathways can have profound therapeutic and toxic effects.

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Mechanism of Action

Adrenal corticosteroid inhibitors work by one of three main mechanisms:

1. Inhibition of adrenal steroid biosynthesis enzymes

   • Blocking enzymes such as 11β-hydroxylase, 17α-hydroxylase, or cholesterol side-chain cleavage enzyme, reducing cortisol and/or aldosterone production.

2. Adrenolytic effect (adrenal cytotoxic drugs)

   • Direct destruction of adrenal cortical cells, lowering steroid production long term.

3. Receptor antagonism

   • Blocking glucocorticoid or mineralocorticoid receptors at the tissue level.

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Classification and Key Agents

1. Steroidogenesis Enzyme Inhibitors

Metyrapone

• Mechanism: Selectively inhibits 11β-hydroxylase (CYP11B1), blocking cortisol and corticosterone synthesis.

• Indications: Cushing’s syndrome, diagnostic test of HPA axis.

• Dose: Typically 250 mg orally every 6 hours, titrated up to 6 g/day in divided doses.

• Adverse effects: Hirsutism and acne (due to increased androgens), hypertension, electrolyte disturbances.

Ketoconazole

• Mechanism: Antifungal agent that also inhibits multiple CYP450 enzymes including 17α-hydroxylase and 11β-hydroxylase, reducing cortisol synthesis.

• Indications: Cushing’s syndrome (off-label), adrenal carcinoma adjunct.

• Dose: Usually 200–400 mg orally two to three times daily.

• Adverse effects: Hepatotoxicity, gynecomastia, gastrointestinal upset.

Etomidate

• Mechanism: At anesthetic doses it acts as a sedative-hypnotic; at lower continuous infusion doses it inhibits 11β-hydroxylase.

• Indications: Severe Cushing’s syndrome in critically ill patients when oral therapy is not possible.

• Dose: Continuous IV infusion, typically 0.03–0.1 mg/kg/h.

• Adverse effects: Sedation, nausea, myoclonus.

Aminoglutethimide (historical)

• Mechanism: Blocks conversion of cholesterol to pregnenolone (cholesterol side-chain cleavage), reducing synthesis of all adrenal steroids.

• Indications: Previously used for Cushing’s and hormone-dependent breast cancer; rarely used today.

• Dose: 250 mg orally 2–4 times daily.

• Adverse effects: Drowsiness, rash, hypothyroidism.

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2. Adrenolytic Agents

Mitotane

• Mechanism: Direct adrenolytic drug that destroys adrenocortical cells and alters peripheral metabolism of steroids.

• Indications: Adrenocortical carcinoma, severe Cushing’s syndrome refractory to other drugs.

• Dose: 2–6 g orally daily in divided doses; individualized titration required.

• Adverse effects: GI upset, neurotoxicity (ataxia, confusion), hyperlipidemia, adrenal insufficiency requiring replacement therapy.

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3. Glucocorticoid Receptor Antagonists

Mifepristone

• Mechanism: Potent glucocorticoid receptor antagonist (also progesterone receptor antagonist).

• Indications: Inoperable Cushing’s syndrome with hyperglycemia (especially in patients with type 2 diabetes).

• Dose: 300–1200 mg orally once daily, titrated to clinical effect.

• Adverse effects: Hypokalemia, hypertension (from unopposed mineralocorticoid effect), endometrial thickening in women.

• Note: Does not reduce cortisol levels—blocks effects at receptor level.

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Therapeutic Uses

1. Cushing’s Syndrome

   • Metyrapone, ketoconazole, mitotane, etomidate, and mifepristone are key drugs.

   • Used when surgery is not feasible, as bridging therapy, or in metastatic adrenal carcinoma.

2. Adrenocortical Carcinoma

   • Mitotane is the only drug with direct cytotoxic effect against adrenal cortex.

3. Diagnostic Testing

   • Metyrapone used to test pituitary ACTH reserve.

4. Other Uses

   • Ketoconazole and aminoglutethimide historically used in hormone-dependent cancers.

   • Mifepristone for hyperglycemia in Cushing’s.

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Adverse Effects and Risks

• Adrenal insufficiency: Excessive suppression can cause fatigue, hypotension, electrolyte disturbances—requires monitoring and sometimes corticosteroid replacement.

• Hepatotoxicity: Notably with ketoconazole.

• Electrolyte abnormalities: Metyrapone and mifepristone can cause hypokalemia.

• Androgen excess: With metyrapone, due to shunting of precursors into androgen pathways.

• Neurotoxicity: Mitotane at higher doses.

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Clinical Considerations

• Choice of agent depends on underlying condition, urgency, comorbidities, and whether oral or IV administration is required.

• Monitoring includes cortisol levels, liver function tests, electrolytes, and clinical symptoms of adrenal insufficiency.

• Combination therapy is sometimes used (e.g., metyrapone + ketoconazole) to achieve stronger blockade.

• Bridging therapy: In severe cases (e.g., adrenal crisis risk), etomidate IV infusion can be used in intensive care until definitive therapy is possible.