Cushing's Syndrome

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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

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