Corticosteroids Flashcards
Describe how mineralocorticoid synthesis is regulated.
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.
Glucocorticoids upregulate the gluconeogenic enzyme ________ and the anti-inflammatory enzyme __________.
PEP carboxykinase, lipocortin 1
Name a mechanism other than eicosanoid synthesis suppression by which glucocorticoids suppress inflammation.
binding to and preventing NFkB from binding to DNA
Outline the RAS system, including significant hormones, enzymes, and organs.
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.
Describe the physiologic effects of glucocorticoids on the liver.
(1) increased gluconeogenesis
(2) increased glycogen synthesis
What are the effects of glucocorticoids on muscle tissue?
(1) decreased sensitivity to insulin
(2) decreased protein synthesis
(3) promoting of protein degradation
What are the effects of glucocorticoids on adipose tissue?
(1) breakdown of fatty acids
(2) decreased sensitivity to insulin
How is the immune system affected by glucocorticoids?
(1) inflammation suppression via blocking of eicosanoid synthesis
(2) immunosuppression by cytokine synthesis suppression
What is Addison’s disease?
hypoadrenalism; by some mechanism the body’s ability to synthesize or release glucocorticoids has been compromised. The body cannot handle stress.
Addison’s disease symptoms
extreme weakness, mental depression, N/V/anorexia, anemia, hyperpigmentation of skin, hypotension
Which symptoms of Addison’s disease are unique to primary Addison’s?
hyperpigmentation of the skin and hypotension
How are (1) CRH (2) ACTH (3) cortisol and (4) aldosterone levels affected by (a) primary (b) secondary and (c) tertiary Addison’s disease?
1a&b: elevated 1c: decreased 2a: elevated 2b: decreased 2c: decreased 3a,b,&c: decreased 4a: decreased 4b&c: unaffected
What is Cushing’s disease?
hyperadrenalism
What are the potential causes of Cushing’s disease?
(1) excess exogenous glucocorticoids (drugs)
(2) adrenal carcinoma
(3) ectopic production of ACTH via some bodily tumor
(4) pituitary tumor
symptoms of Cushing’s disease
(1) increased protein synthesis
(2) increased BG
(3) osteoporosis
(4) opportunistic infections form immunosuppression
How are (1) CRH (2) ACTH and (3) cortisol levels affected in (a) adrenal (b) pituitary and (c) ectopic Cushing’s disease?
1a,b,&c: decreased
2a: decreased
2b&c: elevated
3a,b,&c: elevated
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.
Conn’s, sex organs, cortisol
What symptoms would suggest Conn’s syndrome to a practitioner?
(1) hypernatremia
(2) alkalosis
(3) polyuria (increased salt in blood causes increased thirst)
(4) hypertension
The ideal glucocorticoid will maximize _________ activity while minimizing _________ activity.
anti-inflammatory, mineralocorticoid
What structural elements are required for glucocorticoid activity?
(1) 4,5-double bond
(2) 3 ketone
(3) 11-beta hydroxyl
(4) 17-alpha hydroxyl
What structural elements are required for mineralocorticoid activity?
(1) 4,5-double bond
(2) 3 ketone
hydroxyls not required/less important
Explain why topical cortisone is not effective, but systemic cortisone is.
Cortisone is inactive and requires activation in the liver by 11-beta hydroxysteroid dehydrogenase. If applied topically, this activation will never take place.
Name some commonly used glucocorticoids in each class (short, intermediate, and long acting)
short: hydrocortisone, cortisone
intermediate: prednisone, prednisolone, methylprednisolone, triamcinolone
long: beta/dexa
Which glucocorticoid has a greatly enhanced mineralocorticoid activity and is used in mineralocorticoid replacement therapy? What structural element is responsible for this?
the 9-alpha fluoro group of fludrocortisone adds some GC activity, but even more MC activity
What structural modification has been made to prednisone and prednisolone that increase their GC activity? By how much does it do this?
An extra double bond between C1&2, GC activity enhance about 4 times and MC reduced to 0.25
Methylprednisolone has an extra methyl group at carbon __. What effect does this have on GC an MC activity?
6, GC increased to 5x, MC almost 0
The methyl group at carbon __ in dexa/betamethasone increases GC activity to ___ times that of hydrocortisone.
16, 25
Modification of the hydroxyl group at carbon ___ to a(n) ______ allows for control of the absorption/length of action of glucocorticoids.
21, ester
Describe the effect of conjugating the hydroxyl with an acetate/butyrate, succinate, and phosphate group at carbon 21.
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
What structural modifications are most common to topical GCs? Why is this?
halogenation, addition of acetonide ring or esterification at C17
increases lipophilicity to aid in absorption
Substitution with what halogen at what carbon is commonly employed to increase topical anti-inflammatory activity?
chlorine at C21
Give examples of some 21-chlorocorticoids.
clobetasol, halobetasol, halcinonide
Give two examples of medium potency topical steroids.
fluticasone propionate, mometasone furoate
Inhaled corticosteroids must have high lipophilicity, but solubility is not as important because _________?
poorly soluble inhaled glucocorticoids are acceptable because the microcrystals that form can sit in the airways and slowly be absorbed into the airways.
What are some adverse effects associated with glucocorticoid therapy?
(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)
