Corticosteroids

Question 1

Describe how mineralocorticoid synthesis is regulated.

Answer 1

Aldosterone synthesis is not regulated by the HPA axis, unlike cortisol. Aldosterone synthesis is regulated by the renin-angiotensin-aldosterone system, one of the end results of which is aldosterone production.

Question 2

Glucocorticoids upregulate the gluconeogenic enzyme ________ and the anti-inflammatory enzyme __________.

Answer 2

PEP carboxykinase, lipocortin 1

Question 3

Name a mechanism other than eicosanoid synthesis suppression by which glucocorticoids suppress inflammation.

Answer 3

binding to and preventing NFkB from binding to DNA

Question 4

Outline the RAS system, including significant hormones, enzymes, and organs.

Answer 4

It begins with the liver, which releases angiotensinogen. This is converted by renin (released by the kidneys) to angiotensin I. ACE in the lungs converts angiotensin I to angiotensin II. Angiotensin II has several effects, one of which is on the adrenal glands, where it stimulates aldosterone release.

Question 5

Describe the physiologic effects of glucocorticoids on the liver.

Answer 5

(1) increased gluconeogenesis

(2) increased glycogen synthesis

Question 6

What are the effects of glucocorticoids on muscle tissue?

Answer 6

(1) decreased sensitivity to insulin
(2) decreased protein synthesis
(3) promoting of protein degradation

Question 7

What are the effects of glucocorticoids on adipose tissue?

Answer 7

(1) breakdown of fatty acids

(2) decreased sensitivity to insulin

Question 8

How is the immune system affected by glucocorticoids?

Answer 8

(1) inflammation suppression via blocking of eicosanoid synthesis
(2) immunosuppression by cytokine synthesis suppression

Question 9

What is Addison’s disease?

Answer 9

hypoadrenalism; by some mechanism the body’s ability to synthesize or release glucocorticoids has been compromised. The body cannot handle stress.

Question 10

Addison’s disease symptoms

Answer 10

extreme weakness, mental depression, N/V/anorexia, anemia, hyperpigmentation of skin, hypotension

Question 11

Which symptoms of Addison’s disease are unique to primary Addison’s?

Answer 11

hyperpigmentation of the skin and hypotension

Question 12

How are (1) CRH (2) ACTH (3) cortisol and (4) aldosterone levels affected by (a) primary (b) secondary and (c) tertiary Addison’s disease?

Answer 12

1a&b: elevated
1c: decreased
2a: elevated
2b: decreased
2c: decreased
3a,b,&c: decreased
4a: decreased
4b&c: unaffected

Question 13

What is Cushing’s disease?

Answer 13

hyperadrenalism

Question 14

What are the potential causes of Cushing’s disease?

Answer 14

(1) excess exogenous glucocorticoids (drugs)
(2) adrenal carcinoma
(3) ectopic production of ACTH via some bodily tumor
(4) pituitary tumor

Question 15

symptoms of Cushing’s disease

Answer 15

(1) increased protein synthesis
(2) increased BG
(3) osteoporosis
(4) opportunistic infections form immunosuppression

Question 16

How are (1) CRH (2) ACTH and (3) cortisol levels affected in (a) adrenal (b) pituitary and (c) ectopic Cushing’s disease?

Answer 16

1a,b,&c: decreased
2a: decreased
2b&c: elevated
3a,b,&c: elevated

Question 17

A lack of 17-alpha hydroxylation strictly in the adrenal cortex results in _____ disease. Because it is only in the adrenal cortex, __________ will develop normally, but levels of ______ will still be low.

Answer 17

Conn’s, sex organs, cortisol

Question 18

What symptoms would suggest Conn’s syndrome to a practitioner?

Answer 18

(1) hypernatremia
(2) alkalosis
(3) polyuria (increased salt in blood causes increased thirst)
(4) hypertension

Question 19

The ideal glucocorticoid will maximize _________ activity while minimizing _________ activity.

Answer 19

anti-inflammatory, mineralocorticoid

Question 20

What structural elements are required for glucocorticoid activity?

Answer 20

(1) 4,5-double bond
(2) 3 ketone
(3) 11-beta hydroxyl
(4) 17-alpha hydroxyl

Question 21

What structural elements are required for mineralocorticoid activity?

Answer 21

(1) 4,5-double bond
(2) 3 ketone
hydroxyls not required/less important

Question 22

Explain why topical cortisone is not effective, but systemic cortisone is.

Answer 22

Cortisone is inactive and requires activation in the liver by 11-beta hydroxysteroid dehydrogenase. If applied topically, this activation will never take place.

Question 23

Name some commonly used glucocorticoids in each class (short, intermediate, and long acting)

Answer 23

short: hydrocortisone, cortisone
intermediate: prednisone, prednisolone, methylprednisolone, triamcinolone
long: beta/dexa

Question 24

Which glucocorticoid has a greatly enhanced mineralocorticoid activity and is used in mineralocorticoid replacement therapy? What structural element is responsible for this?

Answer 24

the 9-alpha fluoro group of fludrocortisone adds some GC activity, but even more MC activity

Question 25

What structural modification has been made to prednisone and prednisolone that increase their GC activity? By how much does it do this?

Answer 25

An extra double bond between C1&2, GC activity enhance about 4 times and MC reduced to 0.25

Question 26

Methylprednisolone has an extra methyl group at carbon __. What effect does this have on GC an MC activity?

Answer 26

6, GC increased to 5x, MC almost 0

Question 27

The methyl group at carbon __ in dexa/betamethasone increases GC activity to ___ times that of hydrocortisone.

Answer 27

16, 25

Question 28

Modification of the hydroxyl group at carbon ___ to a(n) ______ allows for control of the absorption/length of action of glucocorticoids.

Answer 28

21, ester

Question 29

Describe the effect of conjugating the hydroxyl with an acetate/butyrate, succinate, and phosphate group at carbon 21.

Answer 29

acetate/butyrate: increases lipophilicity and prolongs duration of action succinate: slows hydrolysis phosphate: increases solubility to enhance drug delivery, suitable for IM or IV injection in emergency situations

Question 30

What structural modifications are most common to topical GCs? Why is this?

Answer 30

halogenation, addition of acetonide ring or esterification at C17 increases lipophilicity to aid in absorption

Question 31

Substitution with what halogen at what carbon is commonly employed to increase topical anti-inflammatory activity?

Answer 31

chlorine at C21

Question 32

Give examples of some 21-chlorocorticoids.

Answer 32

clobetasol, halobetasol, halcinonide

Question 33

Give two examples of medium potency topical steroids.

Answer 33

fluticasone propionate, mometasone furoate

Question 34

Inhaled corticosteroids must have high lipophilicity, but solubility is not as important because _________?

Answer 34

poorly soluble inhaled glucocorticoids are acceptable because the microcrystals that form can sit in the airways and slowly be absorbed into the airways.

Question 35

What are some adverse effects associated with glucocorticoid therapy?

Answer 35

(1) crossover mineralocorticoid activity-increased BP and edema (2) steroid myopathy (3) osteoporosis (4) increased BG (5) fat redistribution (6) reduced long bone growth in children (7) adrenal insufficiency upon withdrawal (Addisonian crisis)