Konorev - Corticosteroids

Question 1

Adrenal CS act where?

Answer 1

they are ligands at nuclear receptors, translocate from cytoplasm to nucleus.

Question 2

MC target cells where?

Answer 2

• Kidney: cells in principal cells of DcT and CD.

- Heart and vasculature: non-epithelial tissue

Question 3

Action of MC in kidney.

Answer 3

Increase Na reabsorption/water retention.

Question 4

Excess aldosterone (MC) adverse effects on heart and effects on vasculature.

Answer 4

• Cardiac fibrosis and hypertrophy

- Vascular remodeling and inflammation

Question 5

Decreased activity (inactivating mutations) of what enzyme will cause excessive activation of MR mediated by cortisol to cause HTN and edema?

Answer 5

11beta-hyroxysteroid dehydrogenase, type 2

Question 6

Two steroids that bind to MC-receptors with similar affinity?

Answer 6

aldosterone and cortisol

Question 7

What converts cortisol into inactive cortisone?

Answer 7

11beta-hyroxysteroid dehydrogenase, type 2

Question 8

Excessive activation of MR by cortisol causes what adverse effects?

Answer 8

HTN and edema

Question 9

Three metabolic effects of excess GC

Answer 9

1. Carbohydrate metabolism decrease - development of hyperglycemia
2. Lipid metabolism increase - development of change in fat distribution (thinning of arms/legs; accumulation in upper body)
3. Protein metabolism increase - myopathy and muscle wasting

Question 10

GC interact with insulin in what way?

Answer 10

ANTI-INSULIN ACTIONS. Change gene expression in favor of lipolysis and protein breakdown = increased substrates for gluconeogenesis and HYPERGLYCEMIA.

Question 11

effect GC has inflammation

Answer 11

decrease inflammation

Question 12

effect GC has on immune system

Answer 12

immune suppression and decreased allergic hypersensitivity reactions.

Question 13

A person has Addison’s Disease and needs replacement therapy - what combination of corticosteroids should be administered?

Answer 13

GC (hydrocortisone) + MC (fludrocortisone)

Question 14

What three broad categories are clinical indications for CS administration?

Answer 14

1. Replacement therapy
2. Immunosuppression (transplant or immune disease)
3. Inflammatory/allergic conditions (asthma, RA, IBD, etc)

Question 15

AE of MCs (Fludrocortisone)

Answer 15

(AE of aldosterone)

• Na/H2O retention = edema, HTN
• Increased preload and hypertrophy of heart = CHF
• K+ loss and alkalosis

Question 16

AE of GCs

Answer 16

hyperglycemia, suppressed ability to fight infections, muscle wasting and myopathy, development of striae, easy bruising, hypertension, osteoporosis, peptic ulcers, increased appetite and weight gain, retarded growth in children, glaucoma, psychiatric symptoms (euphoria, mania, anxiety)

Question 17

Goals for CS dosing/admin.

Answer 17

• Shortest, fastest, smallest distribution and duration.

- TAPER

Question 18

Do not give GC in pts with:

Answer 18

• Diabetes (hyperglycemia)
• Immunocompromised or with infections (suppressed ability to fight infections)
• Children (retarded growth)
• Psych conditions (euphoria, mania, anxiety)
• Cardiovascular conditions (HTN, CHF, Angina)
• Osteoperosis (post-menopausal)
• Peptic ulcers

Question 19

Aminoglutethimide - Drug class, MOA

Answer 19

• Drug class: Steroid synthesis inhibitor

- MOA: blocks conversion of cholesterol to pregnenolone»_space; reduces production of all steroid hormones

Question 20

Aminoglutethimide - Clinical indications, AE

Answer 20

• Clinical indications: breast cancer tx (historical), adrenocortical cancer
• AE: GI upset, drowsiness

Question 21

Ketoconazole - Drug class, MOA

Answer 21

• Drug class: steroid synthesis inhibitor

- MOA: inhibits CYP450s; reduces synthesis of adrenal and sex hormones

Question 22

Ketoconazole - Clinical indications, AE

Answer 22

• Clinical indications: antifungal; Cushing’s syndrome; suppression of androgenic hair loss; prostate cancer
• AE: hepatotoxicity, gynecomastia

Question 23

Metyrapone - Drug class, MOA

Answer 23

• Drug class: steroid synthesis inhibitor

- MOA: inhibits 11-hydroxylation of steroids, selectively suppresses cortisol and cortisone production

Question 24

Metyrapone - Clinical indications, AE

Answer 24

• Clinical indications: Cushing’s Syndrome (esp PREGNANT women)
• AE: Na/H2O retention and hirsutism in women (due to accumulation of 11-deoxycortisol); GI upset, dizziness

Question 25

Mitotane - Drug class, MOA

Answer 25

- Drug class: steroid synthesis inhibitor - MOA: blocks Na and Ca channels; inhibits protein kinase C and adenylyl cyclase > nonselective cytotoxic action on adrenal cortex

Question 26

Mitotane - Clinical Indications and AE

Answer 26

- Clinical Indications: adrenal carcinoma | - AE: depression, somnolence; GU upset (N/V/D); rash

Question 27

Mifepristone - Drug class and MOA

Answer 27

- Drug Class: GC antagonist - MOA: stabilizes chaperone proteins (hsp90) on glucocorticoid receptor complex in the cytosol and prevents translocation to the nucleus; antagonist at progesterone receptors

Question 28

Mifepristone - Clinical Indications and AE

Answer 28

- Clinical Indications: hypercortisolism in adults with Cushing's syndrome; ABORTIONS - AE: dizziness, GI upset (nausea/anorexia/vomiting), fatigue

Question 29

Spironolactone - Drug class and MOA

Answer 29

- Drug class: aldosterone antagonist | - MOA: Aldosterone receptor antagonist; also some antagonism of androgen receptors

Question 30

Spironolactone - Clinical Indications and AE

Answer 30

- Clinical Indications: primary hyperaldosteronism, hirsutism in women, K-sparing diuretic (HF and HTN) - AE: hyperkalemia; gynecomastia and impotence in men; menstrual abnormalities in women

Question 31

Eplerenone - Drug class and MOA

Answer 31

- Drug class: aldosterone (MC) antagonist - MOA: antagonist of aldosterone at the mineralocorticoid receptor; some androgen receptor antagonism, but less than spironolactone

Question 32

Eplerenone - Clinical Indications and AE

Answer 32

- Clinical Indications: HTN, HF | - AE: hyperkalemia

Question 33

CS binding to TRANSCORTIN/CBG (corticosteroid binding globulin) has a high affinity in what two states. Low affinity in what state? (free:protein bound drug)

Answer 33

Low affinity during LIVER DISEASE (increased free-protein-bound drug) High affinity during PREGNANCY or HYPERTHYROIDISM (decreased free-protein-bound drug)

Question 34

When is transcortin saturated?

Answer 34

When plasma cortisol exceeds 20-30micrograms/dL.

Question 35

1/2 life of cortisol is increased in what two cases?

Answer 35

liver diseases and hypothyroid. Why? Because cortisol is metabolized by the liver. Transcortin is produced in the liver.

Question 36

11beta-hyroxysteroid dehydrogenase, type 2 converst CORTISOL into inactive MR cortisone in kidney, salivary glands, sweat glands, colon epithelium, resulting in what?

Answer 36

Making them MC responsive.

Question 37

What could result in inhibition of 11beta-hyroxysteroid dehydrogenase, type 2?

Answer 37

- Apparent MC Excess Syndrome (AME) | - glycyrrhizin (active ingredient in licorice root) --> HTN

Question 38

cortisol/cortisone ratio is ____ in urine in AME. | This syndrome results in what?

Answer 38

- increased | - excessive activation of MR mediated cortisol (bc cannot be inactivated to cortisone)

Question 39

Drugs with both MC and GC actions.

Answer 39

hydrocortisone, cortisone, prednisone, methylprednisolone, fludrocortisone