Adrenal hormone synthesis inhibitors Notes

NOTES NOTES ADRENAL HORMONE SYNTHESIS INHIBITORS Figure 1.1 Ketoconazole: mechanism of action. WHAT ARE THEY? Basic information ▪ Drugs that inhibit one or more enzymes in adrenocortical hormone synthetic pathway (especially cortisol) Mechanism of action ▪ Ketoconazole ▫ Inhibits cholesterol desmolase → blocks cholesterol–pregnenolone conversion → ↓ synthesis of all adrenal hormones ▫ Inhibits 17, 20-lyase: blocks 17-hydroxypregnenolone → dehydroepiandrosterone and 17-hydroxyprogesterone– androstenedione conversion → ↓ synthesis of androgens ▫ Inhibits 17α-hydroxylase: blocks pregnenolone–17-hydroxypregnenolone conversion; progesterone–17hydroxyprogesterone conversion → ↓ cortisol synthesis ▪ Aminoglutethimide: inhibits cholesterol desmolase → blocks cholesterol– OSMOSIS.ORG 1

pregnenolone conversion → ↓ synthesis of all adrenal hormones ▪ MetyraPONE: inhibits 11β-hydroxylase → blocks 11-deoxycortisol–cortisol conversion; does not block androgen synthesis ▪ Mitotane: selectively destroys adrenocortical cells by inhibiting mitochondria ▪ Etomidate: inhibits 11-β hydroxylase → Figure 1.2 MetyraPONE: mechanism of action. Figure 1.3 Mitotane: mechanism of action. 2 OSMOSIS.ORG blocks 11-deoxycortisol–cortisol conversion Key Points ▪ Etomidate: only IV medication available for severe Cushing’s syndrome treatment ▪ Aminoglutethimide (Cytadren): discontinued from US, Canadian markets ▪ Ketoconazole: potent CYP3A4 inhibitor ▪ Mitotane: potent CYP3A4 inducer

Endocrine Adrenal Hormone Synthesis Inhibitors Figure 1.4 Etomidate: mechanism of action. Figure 1.5 Adrenal hormone synthesis pathway. OSMOSIS.ORG 3

TYPES ▪ Ketoconazole: PO ▫ Primarily used as antifungal (imidazole); first-line choice for Cushing’s syndrome ▪ Aminoglutethimide ▪ MetyraPONE (Metopirone): PO ▪ Mitotane (Lysodren): PO ▪ Etomidate (Amidate): IV ▫ Primarily used as anesthetic Common indications ▪ Cushing’s syndrome Drug-specific indications ▪ Ketoconazole ▫ Adrenocortical carcinoma; breast, prostate cancer ▫ Polycystic ovary syndrome (↓ androgenic symptoms) ▪ Mitotane ▫ Adrenocortical carcinoma ▫ Post-treatment: start synthetic corticosteroid replacement therapy (due to adrenocortical cell destruction) ▪ MetyraPONE ▫ MetyraPONE stimulation test: evaluation of hypothalamic-pituitaryadrenal axis ▫ Normal response: ↑ ACTH; ↑ 11-deoxycortisol (↓ cortisol → ↓ negative feedback at hypothalamus, anterior pituitary → ↑ production of CRH, ACTH → stimulation of adrenal glands → ↑ 11-deoxycortisol) ▫ 1° adrenal insufficiency: ↑ ACTH; ↓ 11-deoxycortisol (↓ cortisol → ↓ negative feedback at hypothalamus, anterior pituitary → ↑ production of CRH, ACTH → stimulation of adrenal glands → ↓ 11-deoxycortisol due to adrenal insufficiency) ▫ 2°/3° adrenal insufficiency: ↓ ACTH; ↓ 11-deoxycortisol (↓ cortisol → ↓ negative feedback at hypothalamus, anterior pituitary → ↓ production of CRH/ACTH due to hypothalamic/ pituitary insufficiency → ↓ stimulation of adrenal gland → ↓ 11-deoxycortisol) 4 OSMOSIS.ORG CLINICAL CONCERNS ADVERSE EFFECTS Drug-specific adverse effects ▪ Ketoconazole ▫ Nausea, vomiting; sedation; ↓ libido ▫ Boxed warnings: hepatotoxicity ▪ Aminoglutethimide ▫ Skin rash; neurological symptoms (blurred vision, sedation) ▪ MetyraPONE ▫ Nausea, vomiting, edema ▫ Biologically female: acne, hirsutism ▪ Mitotane ▫ Diarrhea, nausea, vomiting; hypercholesterolemia; ↓ WBCs; skin rash ▪ Etomidate ▫ Injection site: myoclonus, pain ▫ Prolonged administration → adrenal suppression DISEASE-RELATED CONCERNS ▪ Metyrapone ▫ Acute adrenal insufficiency: in individuals with ↓ adrenal secretory capacity Dietary ▪ Alcohol: ketoconazole ↑ adverse/toxic effects of alcohol due to CYP450 inhibition PREGNANCY/BREASTFEEDING IMPLICATIONS ▪ Ketoconazole: teratogenic effects ▪ MetyraPONE: only medication recommended for pregnant people with Cushing’s syndrome, breastfeeding not recommended ▪ Mitotane: not recommended during pregnancy, breastfeeding

Endocrine Adrenal Hormone Synthesis Inhibitors Figure 1.6 MetyraPONE stimulation test: evaluation of hypothalamic-pituitary-adrenal axis. OSMOSIS.ORG 5

Figure 1.7 Adrenal hormone synthesis inhibitors: common drug-drug interactions. Figure 1.8 Adrenal hormone synthesis inhibitors: pharmacokinetic interactions. 6 OSMOSIS.ORG

Endocrine Adrenal Hormone Synthesis Inhibitors Figure 1.9 Adrenal hormone synthesis inhibitors: general adult dosing guidelines. *Dose and dosing interval varies depending on individual characteristics. OSMOSIS.ORG 7