PharmacologyTier 1Medical Sciences concept

Cortisol synthesis/action inhibitor drugs (metyrapone, ketoconazole, mifepristone, pasireotide)

Core concept

Drugs used to control hypercortisolism (Cushing's syndrome, esp. ectopic ACTH or inoperable adrenal/pituitary disease) by different mechanisms along the steroidogenesis pathway or receptor
Steroidogenesis inhibitors: metyrapone, ketoconazole
Glucocorticoid receptor antagonist: mifepristone
Somatostatin analogue (pituitary-directed): pasireotide

Drug	Mechanism	Key point
Metyrapone	Inhibits 11-beta-hydroxylase (final step to cortisol)	Precursor (11-deoxycortisol) accumulates -- used diagnostically (metyrapone test) too
Ketoconazole	Inhibits multiple CYP steroidogenic enzymes (broad)	Hepatotoxicity limits use; also inhibits testosterone synthesis
Mifepristone	Glucocorticoid receptor antagonist (blocks action, not synthesis)	Cortisol levels stay high/rise -- cannot monitor response with serum cortisol
Pasireotide	Somatostatin analogue -> dec ACTH secretion from pituitary	Causes hyperglycaemia (inhibits insulin/incretin secretion)

Used as medical bridge or adjunct when surgery not curative/possible (e.g. occult ectopic ACTH source, metastatic adrenal cancer)
Mifepristone trap: because it blocks the receptor rather than lowering cortisol, ACTH and cortisol levels rise further -- monitor clinically (glucose, BP, symptoms), not with cortisol assays
Ketoconazole requires LFT monitoring; metyrapone can worsen hypertension/hypokalaemia via precursor mineralocorticoid activity

Contrast with drugs causing iatrogenic Cushing's (exogenous steroids) -- opposite clinical problem
Metyrapone test (diagnostic use) exploits the same enzyme block to test pituitary ACTH reserve
Pasireotide's hyperglycaemia mechanism parallels other somatostatin analogues (octreotide) used in acromegaly/carcinoid

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