corticosteroid drugs

Question 1

What is the main mineralocorticoid and the main glucocorticoid?
which one is released at a faster rate?

Answer 1

mineralocorticoid = aldosterone

glucocorticoid = cortisol

-cortisol is released at a rate 100X greater

Question 2

is aldosterone or cortisol presnet in circulation at a higher level?

Answer 2

• cortisol

Question 3

which enzyme converts cortisol to cortisone in cells where aldosterone is active (kidney, colon, salivary glands)?

Answer 3

• 11beta-hydroxysteroid dehydrogenase, type 2
• cortisone doesnt bind mineralocorticoid receptor, so cortisol cannot overwhelm aldosterone even though both aldosterone and cortisol bind to mineralocorticoid receptor with equal affinity

Question 4

Effects of adrenocortical steroids

Answer 4

• regulate carbs, protein, and lipid metabolism (cortisol)
• maintain fluid and electrolyte balance (aldosterone)
• capacity to resist stress

** some effects of corticosteroids have permissive effects!

Question 5

MOA of corticosteroids

Answer 5

• bind nuclear receptors and increase or decrease DNA transcription leading to changes in concentrations of specific proteins –> delayed effects (several hours)
• immediate corticosteroid effect are mediated by membrane receptors

Question 6

How does glucocorticoid therapy create major problems for diabetics?

Answer 6

• glucocorticoids (Cortisol) increase gluconeogenesis and glycogenolysis in the liver.
• in peripheral tissues, they decrease glucose utilization, increase proteolysis, and activate lipolysis –> oppose insulin

**glucocorticoids/cortisol protect brain tho during starvation/overnight fast by keeping blood glucose elevated

Question 7

Effects of glucocorticoids on lipid metabolism?

Answer 7

• redistribution of body fat (cushing’s and long term glucocorticoid therapy)
• you see slim arms and legs d/t decreased muscle mass but increased fat at back of neck and face

Question 8

How does aldosterone regulate electrolyte and water balance?

Answer 8

• act on distal tubules and collecting ducts of kidney to increase Na reabsorption and increased excretion of K and H
• similar actions on colon, salivary glands, and sweat glands
• loss of aldosterone leads to Na loss, **decreased EFV, hyponatremia, hyperkalemia, and acidosis. **

Question 9

Side effects of mineralocorticoid agonists?

Answer 9

• increase Na retention –> hypertension

**- **CHF, cerebral hemorrhage, stroke, hypertensive cardiomyopathy

Question 10

How do excess glucocorticoids and mineralocorticoids impair muscle function?

Answer 10

• aldosterone cause muscle weakness via hypokalemia
• glucocorticoids cause muscle weakenss d/t muscle wasting/steroid myopathy (increased proteolysis)

Question 11

Effects of corticosteroids on CNS?

Answer 11

• glucocorticoid tx result in euphoria, feeling of well being, high motor activity, insomnia and restlessness
• addison’s dz (insufficient adrenocortical function) cause apathy, depresison, and irritability
• cushing’s (too much ACTH)- high incidence of neuroses and psychoses

Question 12

How are glucocorticoids antiinflammatory/immunosuppresive?

Answer 12

• inhibit release of arachidonic acid from PL
• decrease synthesis of prostaglandins and leukotrienes through decreased expression of phospholipase-A2
• inhibit production and release of cytokines (IL-1, IL-6, and TNF-alpha)
• inhibit histamine release

Question 13

What is the half life of the different corticosteroids?

Answer 13

Question 14

Side effects of glucocorticoid therapy

Answer 14

• suppression of ACTH and TSH production from pituitary. Recovery from suppression is dependent on dose and time of therapy (can take weeks-months) so don’t stop abruptly!!
• induce osteoporosis esp in postmenopausal women and children
• induce diabetes in pre-diabetic populations
• increase incidence of peptic ulcers
• CNS side effects of arousal and euphoria followed by depression and sleep disturbances
• In Men: suppress gonadotrophin secretion –> hypogonadism d/t decreased testosterone production
• In women: stop ovulation or cause dysmenorrhea or dysfunctional uterine bleeding
• In children: impair linear growth rate d/t decreased GH and inhibition of IGF-1 effects

Question 15

General principles for corticosteroid therapy:

Answer 15

• long term therapy impose increasing risk
• cessation after long term therapy has serios consequences, possibly fatal
• must use smallest dose that achieves desired effect
• minimize steroid adverse effect via local application, alternate day therapy to reduce pituitary suppression, and tapered dose soon after achieving therapeutic response.

Question 16

What are the most used systemic steroids in practice and their duration of action?

Answer 16

Hydrocortisone- short

methylprednisolone- intermediate

dexamethasone- long

**Can give all of these drugs by PO, IV, IM excep methylprednisolone which is only IV and IM

Question 17

Tx for acute adrenal insufficiency- disorders of adrenal gland or abrupt withdrawal of glucocorticoids?

Answer 17

• IV isotonic NaCl + 5% glucose + corticosteroids
• start dexamethasone, test for ACTH secretion, then hydrocortisone

Question 18

Tx for chronic adrenal insufficiency- less severe symptoms

Answer 18

• daily hydrocortisone or cortison acetate (divied dose 2/3 morn- 1/3 evening)
• or dexamethasone or prednisone
• most require mineralocorticoid like fludrocortisone acetate

Question 19

What is congenital adrenal hyperplasia? and what is tx for it?

Answer 19

• genetic disorder lacking enzymes to produce cortisol or aldosterone or both –> increased ACTH secretion for lack of feedback
• hydrocortison with or without fludrocortison acetate

Question 20

MOA spironolactone and side effects

Answer 20

• aldosterone antagonist
• anti-androgen effects like gynecomastia and can cause decreased spermatogenesis

Question 21

MOA of eplerenone and side effects

Answer 21

• similar to spironolactone in that it is a mineroalocorticoid repceotr antagonist but it is more selective for mineralocorticoid receptor and has little to no anti-androgen effect)

-

Question 22

Side effects of aldosterone therapy?

Answer 22

• salt and water rentention
• increased blood volume
• CHF

Question 23

MOA of ketoconazole

Answer 23

• blocks fungal and mammallian CYP450 enzymes so it causes hepatic dysfunction and many drug-drug CYP450 interactions
• used to block cortisol production in cushing’s but it blocks all steroid hormone synthesis
• useful in adrenal carcinoma, breast and prostate ca, and hirsuitism

** MAY CAUSE SEVERE HEPATOTOXICITY OR PRODUCE ADRENAL INSUFFICIENCY

Question 24

MOA of aminoglutethimide

Answer 24

• inhibit cyp450scc in syntehtic pathway
• inhibit overproduction of cortisol in cushin’s syndrome but also inhibits all steroid production jsut like ketoconazole. Both drugs block cholesterol conversion to pregnenolone

Question 25

What are the aldosterone antagosnists and the glucocorticoig antagnosits?

Answer 25

- aldosterone antagonist: spironolactone and epleronone - glucorocoticoid antagonist- mifepristone, RU-486

Question 26

Does this person have corticosteroid therapy suppression that you need to worry about correcting via peri-operative steroid therapy?

Answer 26

- no, have patient maintain normal dialy dose of glucocorticoids in the perioperative period? - monitor for hemodynamic instability peri-operatively

Question 27

Does this person have corticosteroid therapy suppression that you need to worry about correcting via peri-operative steroid therapy?

Answer 27

SO this is long term corticosteroid use and with any other patient with cushing's syndrom physical appearance, you should assume they have suppressed HPA axis and should give peri-operative corticosteroid therapy -for example you can give 50mg IV before surger of hydrocortisone then 25mg q8h x 3 or 100mg IV before sugery then 50mg q8h x 3 then taper to usual dose \*\*basically you want to give supraphysiologic dose right before surgery for these patients that have HPA suppression

Question 28

Why and when do you taper off doses?

Answer 28

- taper to avoid acute adrenal insufficiency - short term (up to 3 weeks) tx will be unlikely to produce hPA suppresion so you dont need to worry abou taper for short term use. -

Question 29

how do you evaluate HPA axis suppression?

Answer 29

you stop GC for 24hrs and measure cortisol levels. - if morning serum cortisol is \<5 ten you have impaired HPA axis but if \>10 you do NOT have impaired HPA AXIS. - You can give ACTH stimulation tests where you measure serum cortisol 30 mins after 250mcg ACTH stimulation and if \>18mcg/dL then it predicts adequae adrenal reserve during surgery with no need for perioperative tx. - for cushing's give dexamethasone and not hydrocortisone because you are measuring cortisol levels. Low dose test show that dexa inhibits pituitary ACTH secretion but no direct effect on adrenals. - With high dose test, acth suppresion in most pts with cushings. non-pituitary malignant tumors producing ectopic ACTH are NOT responsive to glucocorticoid negative feedback

Question 30

how do you treat addison's disease?

Answer 30

- it's life threatening so treat as emergency without waiting for tests!! - in acute crisis give dexamethasone IV q12h - in subacute give ACTH stimulation test and taper GC dose and begin fludrocortison tx - in chronic addison's give lowest dose of hydrocortisone to relieve symptoms

Question 31

what sort of side effects can you see with long term fludrocortisone use?

Answer 31

- glucocorticoid effects may appear with long-term treatment even though it is a mineralocorticoid receptor agonist.

Question 32

MOA of mifepristone RU486 and what is it used for in the treatment of?

Answer 32

- binds with high affinity to GC receptor making functionally inactive GC-R complex in the nucleus. - high doses to treat cushing's - for inoperable patients with ectopic ACTH secretion or adrenal carcinoma who have failed to respond to other tx \*\*ru486 means it is used to terminate pregnancies (progesterone antagonist---for GU module)