Cushing's Syndrome

Adapted from APhA Complete Review
Cushing's syndrome definition
Results from chronic glucocorticoid excess
(LOW incidence - 2-4 persons per million each year)
Types of Cushing's syndrome
Usually iatrogenic from tx with glucocorticoid drugs
Endogenous Cushing's is usually caused by overproduction of adrenocorticotropic hormone (ACTH) by pituitary gland adenomas
Clinical presentation of Cushing's syndrome
Obesity (moonface, neck, trunk, abdomen), hypertension, hirsutism, acne, amenorrhea, depression, thin skin, easy bruising, diabetes, osteopenia
Pathophysiology of Cushing's syndrome
The hypothalamus produces cortocotropin-releasing hormone --> stimulates the anterior pituitary gland to release ACTH. Circulating ACTH stimulates the adrenal cortex to produce cortisol.
Diagnosis of Cushing's syndrome
Based on s/sx of Cushing's
Deamethasone suppression test or 24-hour urine cortisol measurement may be used
Treatment principles of Cushing's syndrome
1. Minimize corticosteroid exposure
2. Pharmacotherapy aimed at reducing production of cortisol
Brand Nizoral
Generic ketoconazole (dosage 800 - 1200 mg qd)
Brand Cytadren
Generic aminoglutethimide
Brand lysodren
Generic mitotane
Brand metopirone
Generic Metyrapone
Ketoconazole Cushing's MoA
Inhibits P450-dependent enzymes and cortisol synthesis
Aminoglutethimide MoA
Inhibits conversion of cholesterol to pregnenolone --> blocks synthesis of adrenal steroids.
It induces P450 enzymes!
Mitotane MoA
Cytotoxic drugs that suppresses ACTH secretion and reduces synthesis of ACTH
Metyrapone MoA
Inhibits 11-hydroxylase activity thus blocking synthesis of cortisol.
Ketoconazole pt counseling
Notify MD if ab pain, yellow skin, plae stool
Space w/antacids by 2 hours
Take w/food
Ketoconazole adverse effects
N/V/HA, impotence, hepatotoxicity
Aminogltethimide AE's
Drowsiness, rash, weakness, hypotension, N, loss of appetite, hypothyroidism, blood dyscrasias
Metopirone AE's
N/V, dizziness, sedation
Mitotane AE's
N/V/D, tiredness
Major ketonazole drug interactions
Increases serum concentrations of cyclosporine, warfarin, cisapride, and triazolam.
Drugs that lower gastric acidity will lower ketoconazole absorption
Rifampin reduces ketoconazole levels
Aminoglutethimide drug interactions
May induce metabolism of warfarin
Monitoring parameters of mintotane
Cortisol levels