Adrenal Pharmacology

Question 1

Physiologic and Pharm dosing effects of cortisol

Answer 1

Phys:
Carb: increases gluconeogenesis, increases blood glucose (increases insulin)
Excess: diabetes like state

Protein: decreases protein synthesis leads to increased aa to glucose
Excess: muscle wasting, skin CT atrophy

Fat: increases lipolysis (peripherally), increases FA
Excess: increases lipogenesis (centrally via insulin action), centripetal obesity (moon facies, buffalo hump)

Question 2

Aldosterone phys vs pharm doses

Answer 2

increases Na reabsorption at kidney, increases blood volume and BP (loosely coupled to K and H secretion)
Excess: fluid retention, hypertension, hypokalemia

Question 3

Glucocorticoids (pharm effects)

Answer 3

anti-inflammatory, immunosuppressive

• vacular: reduced vasodilation, decreased fluid exudation
• Effects on cellular events: decrease in accumulation and activation of inflammatory and immune cells

Effects on inflammatory and immune mediators: decrease in synthesis

Upside: GCs suppress chronic inflammation and autoimmune reactions

Downside: GCs also decrease healing and diminish immunoprotection

Question 4

Metabolism of glucocorticoids

Answer 4

11beta-hydroxysteroid dehydrogenase (11betaHSD)
Liver: 11betaHSD1 can convert cortisone back to cortisol– activating
Kidney: 11beta HSD2 converts cortisol to cortisone– inactivating (less MC activity at kidney)
Fetus: 11 beta HSD2 protects fetus from effects of maternal steroids

Question 5

Characteristics of adrenocorticoid agents

Answer 5

Dexamethasone has highest anti-inflammatory potential

Fludrocortisone ahs highest salt retaining potential

Question 6

Q: adverse effects of pharmacologic doses unlikely to be seen with dexamethasone but possible with prednisone

Answer 6

• elevated BP

- hypokalemia

Question 7

Ex of when you’d need physiologic replacement regimen

Answer 7

Addison’s disease

-use agent with both GC and MC actions like cortisol or add fludrocortisone)

Question 8

For pharm doses for anti-inflamm or immunosuppressive actions

Answer 8

• desirable to select an agent with minimal or no MC activity (dexamethasone)
• not possible to avoid GC metabolic side effects with the anti-inflammatory GCs currently available.

Question 9

Activation of prednisone

Answer 9

-inactive until hepatic conversion to prednisolone (NO topical activity or parenteral activity)

Question 10

Adrenocortical Insufficiency: chronic

Answer 10

Chronic (Addison’s disease)

• oral hydrocortisone (15-25 mg/day in 2-3 divided doses- roughly mimics the normal diurnal rhythm)
• long-acting agents provide smoother physiologic effect given daily (Dexamethasone, prednisone)
• temporary dosage increase w/ illness or surgery
• Fludrocortisone can be added if need increased salt retaining activity
• DHEA supplementation may be needed in some women (mood and well being)

Question 11

Acute adrenocortical insufficiency

Answer 11

• adrenal crisis: electrolyte abnormalities (decreased Na, Increased K) and plasma volume depletion
• Volume replenishment with NS or D5NS
• large amounts of IV hydrocortisone if previous dx
• without dx: dexamethasone
• additional MC action greater than hydrocortisone not needed unless hyperkalemic (K greater than 6 meq/L)

Question 12

Adrenocortical hyperfunction: Cushing’s Syndrome (hypercortisolism) tx

Answer 12

• Surgery is tx of choice
• Pharm: reserved for adjunctive therapy in refractory or inoperable cases, can include:
• Synthesis inhibitors:
  early: miotante, *ketoconazole, aminoglutethimide, trilostane
  late: metyrapone
• Glucocorticoid receptor antagonist: Mifepristone (RU-486)