Dewitt: Adrenal

Question 1

Corticosteroids: Agonists and Antagonists

Answer 1

• Agonists:
  
  • Glucocorticoids
    
    • prednisode
  • Mineralcorticoids
    
    • fludrocortisone
• Antagnoists:
  
  • Synthesis inhibitors:
    
    • Ketoconazole
  • Receptor Antagonists:
    
    • Glucocorticoid antagonists:
      
      • mifepristone
    • Mineralocorticoid antagonists:
      
      • apironolactone

Question 2

Adrenal Hormone Pathway

Answer 2

• Negative feedback: Androgens, glucocorticoids, mineralocorticoids

Question 3

What zone of the adrenal gland does mineralocorticoids, glucocorticoids, and androgens come from?

Answer 3

• Mineralocorticoids:
  
  • zona glomerulosa (outer)
    
    • Major: Aldosterone
    • minor=deoxycorticosterone
• Glucocorticoids:
  
  • zona fasciculata
    
    • major=cortisol
• Androgens
  
  • Zona reticularis (inner)

Question 4

Clinical Presentation of Low mineralocorticoids

Answer 4

• Addison’s Disease=chronic adrenal insufficiency
  
  • low aldosterone
    
    • low blood pressure
    • salt craving

Question 5

Pharmacological management of Low mineralocorticosteroid?

Answer 5

• cosyntropin/ACTH
• Fludrocortisone

Question 6

Cosyntropin

Answer 6

• Low mineralocorticoids or glucocorticoids
• diagnose if adrenal insufficiency is:
  
  • primary-adrenal
  • Secondary=pituitary
  • Tertiary=Hypothalamus

Question 7

Fludorocortisone

Answer 7

• Low mineralocorticosteroid (Addison’s Disease)
• Synthetic corticosteroid
• Mechanism=cortisol Agonist (w/salt retaining activity)
• most widely used mineralocorticoid
  
  • Long duration of action
  • potent corticosteroid
  • High salt-retaining activity
  • Glucocorticoid activity
    
    • low doses-no anti-inflammatory or anti-growth effects

Question 8

Desoxycorticosterone acetate

Answer 8

• Salt retaining agent w/no anti-inflammatory
• Not in US

Question 9

Clinical Presentaiton of High mineralocorticoids

Answer 9

• Cushing Syndrome or Primary Aldosteronism
  
  • adrenal hypersecretion
    
    • High aldosterone
  • hypertension/edema

Question 10

Pharmacological management of High Mineralocorticoids?

Answer 10

• Aldosterone Antagonist
  
  • Spironolactone
  • Eplerenone
  • Drospirenone

Question 11

Spironolactone

Answer 11

• High Mineralocorticoids (aldosterone)
• Aldosterone antagonist:
  
  • does not reduce aldosterone production
  • also:
    
    • androgen antagonist
    • progesterone agonist
• used to tx primary aldosteronism or higher doses to diagnose aldosteronism
• Side effects:
  
  • breast tenderness
  • irregular menstrual cycles
  • impotence
  • decreased libido
  • gynecomastia in men

Question 12

Eplerenone

Answer 12

• Aldosterone Antagonist
• more selective than spironolactone
  
  • Not a androgen antagonist

Question 13

Drospirenone

Answer 13

• Progestin
• Aldosterone antagonist

Question 14

Pharmacological management of low glucocorticoids

Answer 14

• Hydrocortisone
  
  • may need fludrocortisone depending on degree of adrenal insufficiency

Question 15

Hydrocortisone

Answer 15

• cortisol agonists
• most common glucocorticoid for low glucocorticoid
• some salt retaining activity
  
  • but may need fludrocortisone depending on degree of adrenal insufficiency (in primary insufficiency)
• Given in large amounts (IV) for:
  
  • acute adrenal insufficiency
  • congenital adrenal hyperplasia
    
    • (Fludrocortison given for low mineralocorticoid production)

Question 16

Dexamethasone

Answer 16

• Synthetic Cortisol
• Pregnancies at high risk for congenital adrenal hyperplasia
• protect fetus

Question 17

Pharmacological management of high glucocorticoids

Answer 17

• Synthesis inihibitors:
  
  • Aminoglutethimide
  • Ketoconazole
  • Etomidate
  • Metyrapone
• Mifepristone
• Mitotane

Question 18

Synthesis of glucocorticoids

Answer 18

• multistep rpcoess
• many adrenal hormones share common pathways/starting products

Question 19

Aminoglutethimide

Answer 19

• High Glucocorticoids
• Mechanism: Cortisol Synthesis Inhibitors
• Blocks conversion of Cholesterol to prenenolone
  
  • reduces synthesis of all hormon active steroids
• Tx: Cushing’s Syndrome

Question 20

Ketoconazole

Answer 20

• Antifungal Agent
• Mechanism=Cortisol synthesis inhibitors
• inhibits cholesterol side chain cleavage
• Tx: Cushing’s Syndrome
• Side effect:
  
  • hepatotoxicity

Question 21

Etomidate

Answer 21

• Mechanism: Cortisol Synthesis Inhibitors
• Inhibits adrenal steroidogenesis
• ONLY parenteral agent for Cushings Syndrome

Question 22

Metyrapone

Answer 22

• Mechanism: Cortisol Synthesis Inhibitors:
• Selective inhibitor of specific enzyme in cortisol synthesis pathway
• Tx: Cushing’s Syndrome
• No longer in US except on compassionate basis

Question 23

Mifepristone (RU-486)

Answer 23

• Mechanism: Cortisol Antagonist
• Glucocorticoid Antagonist
• can cause generalized glucocorticoid resistance
• Tx: Only inoperable ectopic ACTH secretion or adrenal carcinoma
  
  • failed to respond to other agents
  • Due to:
    
    • long Half life
    • Widespread receptor antagonism

Question 24

Mitotane

Answer 24

• Mechanism: Cytotoxic to adrenal cortex
  
  • nonselective cytotoxic on adrenal cortex to reduce tumors
• Removed from US market
  
  • available on compassinate basis