Glucocorticoids, Mineralocorticoids & Adrenocortical Antagonists: Cook

Question 1

Differentiate between glucocorticoids and mineralocorticoids and their mechanisms of action.

Answer 1

Both cortisol and aldosterone bind to the mineralcorticoid receptor with equal affinity. Cortisol is released into the blood at 100x rate of aldosterone, thus present in circulation at much higher concentration.

Differing effects of Adrenocortical Steroids:
• Regulate carbohydrate, protein and lipid
metabolism (cortisol). Cortisol has a permissive effect on lipolysis, allowing catecholamines to induce lipolysis at low doses.
• Maintain fluid and electrolyte balance
(aldosterone).

MOA:
Glucocorticoids: binding to nuclear receptors and either increase/decrease DNA transcription –>
changes in concentration of specific proteins.
• thus, most effects are delayed several hrs.

Mineralcorticoids: act on DCTs and CDs of kidney to increase reabsorption of Na+ and increase excretion of K+ and H+.

Question 2

Explain the regulatory mechanisms of the Hypothalamic Pituitary ADRENAL axis including mechanisms of feedback control that are important in adverse effects of these drugs.

Answer 2

Cortisol levels provide negative feedback on hypoth. and ant. pit.

Elevated BP/hyperosm provides feedback on hypoth.

Inflamm. cytokines (IL-1,2,6, TNF-a) stim. release of ACTH and CRH

By admin. glucocorticoids for a long period of time, you suppress CRH and ACTH release because body senses cortisol levels are chronically high, so tells hypoth./pit. to chill out. If you pull pt off steroids suddenly, they will effectively have an adrenal insuff. crisis. Hypoglycemia, HypoTN, hyponatremia, hyperkalemia, acidosis (?).

Question 3

Explain the importance of the enzyme 11β-hydroxysteroid dehydrogenase, type 2

Answer 3

The enzyme 11β-hydroxysteroid dehydrogenase, type 2
converts cortisol to cortisone in cells where aldosterone
is active (kidney, colon and salivary glands).
Cortisone does not bind to the mineralocorticoid
receptor, so cortisol cannot overwhelm aldosterone (given cortisol's much higher concentration in blood and equal affinity for the mineralcorticoid receptor).

Question 4

Discuss the problems with abruptly discontinuing glucocorticoid therapy.

Answer 4

Suppression of ACTH and TSH production from the
pituitary. Time of recovery from this suppression is
dependent on dose and time of therapy (Recovery can
take weeks to months).
Don’t stop therapy abruptly!!!

Question 5

Name the short half-life glucocorticoids.

Answer 5

Cortisol or hydrocortisone*
Cortisone acetate

*most used, clinically

Question 6

Name the intermediate half-life glucocorticoids.

Answer 6

prednisone
prednisolone
methylprednisolone*

*most used, clinically

Question 7

Name the long half-life glucocorticoids.

Answer 7

dexamethasone*
triamcinolone

*most used, clinically

Question 8

Describe the side effects of glucocorticoid therapy.

Answer 8

•Suppression of ACTH and TSH production from the
pituitary. Time of recovery from this suppression is
dependent on dose and time of therapy (Recovery can
take weeks to months). Don’t stop therapy abruptly!!!
• Glucocorticoid induced osteoporosis - especially in
children and postmenopausal women.
• Induces diabetes in pre-diabetic population.
• Increased incidence of peptic ulcers. Perforated ulcers
go undetected.
• CNS side effects - arousal and euphoria. Followed by
depression, sleep disturbances.

•IN MEN, glucocorticoids can suppress gonadotroph
secretion which can cause hypogonadism due to
decreased testosterone production.
• IN WOMEN, glucocorticoids can stop ovulation, or
cause dysmenorrhea or dysfunctional uterine bleeding.
• IN CHILDREN, glucocorticoids may impair linear
growth rate (decreased GH and inhibition of IGF-1
effects)

Question 9

List the mineralcorticoid drugs and their side effects.

Answer 9

Fludrocortisone – synthetic aldosterone
Spironolactone – Aldosterone antagonist (mineralocorticoid
receptor antagonist) So it also has anti-androgen effects
(gynecomastia) and can cause decreased spermatogenesis.
Eplerenone – similar to spironolactone but is much more specific for the mineralocorticoid receptor (has little or no antiandrogen effect)

• Excessive salt and water retention.
• Increased blood volume.
• Congestive heart failure.

Question 10

Explain how to evaluate for HPA axis suppression and how they are interpreted.

Answer 10

Stop GC for 24 hrs
Take a morning serum cortisol (before 0800)
10mcg/dl = Not impaired HPA axis
- therefore you can continue the pt on their current glucocorticoid tx on the day of surgery.

Question 11

Explain ACTH stimulation tests and how they are interpreted.

Answer 11

Measure serum cortisol 30 mins after 250mcg ACTH stimulation.
>18mcg/dl predicts adequate adrenal reserve during surgery with no need for glucocorticoid coverage perioperatively

Question 12

What is Mifepristone used for?

Answer 12

::Used in high doses to treat Cushing’s Syndrome.
::Binds with high affinity to GC receptor making functionally inactive GC-receptor complex in nucleus
-only for inoperable pts with ectopic ACTH secretion or adrenal carcinoma who have failed to respond to other tx.