Pharmacology: Test 3: Adrenal Steroids Lec 59

Front 1

activating receptor for steroids is called?

Back 1

GRalpha

Front 2

Inhibitory receptor for steroids is called?

Back 2

GRbeta (made from the same GR transcript but alternatively spliced).

Increase in GRbeta/GRalpha may be responsible for steroid-resistant asthma.

Front 3

At physiological conc., what keeps the mineralocorticoid activity of glucocorticoids minimum/low in mineralocorticoid target tissue?

Back 3

Done by 11beta-hydroxysteroid dehydrogenase (HSD11B2), which inactivates cortisol in those tissues, because cortisol has a 1:1 GC and MC activity otherwise.

At pharmacologic conc., this enzyme is insufficient to inactivate all MC activity of cortisol, and unwanted side effects result.

Front 4

List drugs with more GC activity than MC activity?

Back 4

Prednisone (not active until metabolized), Prednisolone, Dexamethasone, Betamethasone.

Last 2 has zero MC acitivty

Front 5

List drugs with more MC acitivity than GC activity?

Back 5

Aldosterone, corticosterone, Fludrocortisone

Front 6

Availability and Metabolism of steroids?

Back 6

unlike the natural occuring cortisol, synthetic analogues do not bind CBG in plasma so more are availabe. Also, most synthetic i.e. dexamethasone are excluded from CNS by mdr1a p glycoprotein.

Metabolic modifications can lead to increase or decreased acitivty. Fluticasone and budesonide are extensive metabolized during first pass hepatic metabolism.

Front 7

Some disorders?

Back 7

Addison's Dz: Adrenal insufficiency

Apparent MC excess: mutation in HSD11B2 in kidney resulting in decreased conversion of cortisol to cortisone

CAH: enzyme defect causing low cortisol and aldosterone and increased androgens (21-hydroxylase)

Conn's: hyeraldosteronism

Cushing's: hypercortisolism

Front 8

Dosing regiment: Some different stratergies?

Back 8

Replacement such as in addison's: give a 5mg prednisone in the morning.

Divided dose in AM and PM given to keep ACTH low and repress Adrenal function and reduce adrenal androgens such as in CAH.

Daily dose given to supress inflammatory disorders.

Alternate Day therapy: given to pts in remission to avoid/minimize immunosupressive side effects while maintaining inflammation supression.

Front 9

Adr Steroid Antagonists: mifepristone

Back 9

aka RU 486, Antiprogestin (induction of early term abortion) and anti-glucocorticoid (in Cushing's).

Front 10

Adr Steroid Antagonists: Spironolactone

Back 10

Competitive Inhibitor of Aldosterone binding to MC receptors. Used in HTN, effective in severe CHF.

side effects: hyperkalemia, gynecomastia and impostence

Front 11

Adre Steroid Antagonists: Eplerenone

Back 11

selective MC receptor antagonist (fewer side effects), for HTN, CHF

Front 12

Adr Steroid Biosynthesis Inhibitors: Dexamethasone

Back 12

This and other glucocorticoids feedback inhibit ACTH andhence endogenous corticosteroid production

Front 13

Adr Steroid Biosynthesis Inhibitors: metyrapone

Back 13

inhibits 11beta-hydroxylation, so no corticosterone and hence aldosterone

and Cortisol can be synthesized

Front 14

Adr Steroid Biosynthesis Inhibitors: aminoglutethimide

Back 14

Inhibits first comitted step from Cholesterol to Pregnenolone;

ALSO inhibits aromatase

Front 15

Adr Steroid Biosynthesis Inhibitors: ketoconazole

Back 15

an antifungal, inhibits side chain cleavage, and 11beta-hydroxylase (just like metyrapone).