Lecture 3: Steroids

Question 1

Describe the mechanism of action of glucocorticoids.

Answer 1

Should know this by now. Remember for immunosuppression, IkappaBetaalpha is produced by glucocorticoid action, inhibiting NF-kappab and resulting immuno response.

For mineralcorticoid action, know that Aldosterone causes Sgk1 production, going on to make ENaC Na+ channels (b/w lumen and cell) and Na/K ATPase channels (b/w interstitum and cell).
*Cortisol has the same mineracorticoid activity, however it is DEACTIVATED FOR MINERALCORTICOID ACTIVITY BY 11BETA-HYDROXYSTEROID DEHYDROGENASE2 ENZYME INTO CORTISONE WITH NO MINERALCORTICOID ACTIVITY

Question 2

Understand the physiological effects of the glucocorticoids on metabolism.

Answer 2

1. Carbohydrate and protein:
2. Lipid metabolism
3. Mineral and electrolyte metabolism
4. CNS: Sleepiness, lability of mood
5. Immune system:
6. Anti-inflammatory activity

Question 3

Effects of glucocorticoids on carbohydrate and protein metabolism

Answer 3

a. Mediated by glucocorticoid receptor.
b. Enhances liver gluconeogenesis from protein.
c. Stimulates AA mobilization.
d. Increases plasma glucose.
e. Increases liver glycogen
f. Increases urinary nitrogen excretion
g. Reduces peripheral glucose utilization

Question 4

Effects of glucocorticoids on lipid metabolism

Answer 4

Redistribution of body fat (moon face, buffalo hump). Stimulates release of fatty acids from adipose tissue

Question 5

Effects of glucocorticoids on Mineral and electrolyte metabolism

Answer 5

a. Increases sodium reabsorption. b. Increases potassium and hydrogen ion excretion. c. Responsible for cardiovascular effects-hypertension

Question 6

Effects of glucocorticoids on CNS

Answer 6

Sleepiness, lability of mood

Question 7

Effects of glucocorticoids on immune system

Answer 7

Lymphocytopenia and monocytopenia (redistribution of cells out of vascular space… to spleen, lymph nodes, thoracic duct, bone marrow, other sites)

Prevent neutrophil adherence to endothelium

Inhibit action of chemotactic factors

Macrophage: Inhibits antigen processing, inhibits binding to Fc receptors, inhibits synthesis and release of IL-1

B-lymphocytes

T-lymphocytes: Interfere with macrophage antigen processing, Absence of IL-1 prevents activation, Reduces IL-2 synthesis, messes with actions of lymphokines

Question 8

Know the effects of the glucocorticoids on the immune system that contribute to their anti-inflammatory/immunosuppressive effects.

Answer 8

a. Inhibits immune system
b. Inhibits arachidonic acid release (decrease synth of prostaglandins and leukotrienes)
c. Inhibits induction of COX-2
d. Decrease capillary permeability

Question 9

Know the major therapeutic uses for glucocorticoids.

Answer 9

1. Adrenal insufficiency
2. Rheumatoid arthritis (use only in progressive disease in combination with salicylates, gold salts, and physical therapy
3. Osteoarthritis- given into joint for acute inflammation
4. Allergic diseases
5. Inflammatory diseases of eye, ear, skin, etc
6. Cerebral edema
7. Shock (questionable value)
8. Miscellaneous-organ transplantation, thrombocytopenia, liver diseases, collagen diseases, renal diseaes, etc.

Question 10

Know the relative glucocorticoid properties and mineralocorticoid properties of the major therapeutically useful natural and synthetic steroids.

Answer 10

Aldosterone        .2 to 250
Cortisol        1 to 1
Dexamethasone        20 to 0
Prednisolone        3 to 0.8
Fludrocortisone        12 to 100

Question 11

Describe the major toxicities of adrenal steroids.

Answer 11

Rapid withdrawal (Acute adrenal insufficiency occurs. Salt wasting and cardiovascular collapse).

Large doses for periods longer than 2 weeks, then you must be careful

May last for periods longer than 12 months.

Reduce dosage slowly

Question 12

Cushings syndrome symptoms

Answer 12

1. Moon face and buffalo hump
2. Poor wound healing
3. Thin skin
4. Hypertension
5. Thin extremities
6. Striae

Question 13

List the major contraindication of glucocorticoids.

Answer 13

Existing infection, particularly tuberculosis

Question 14

Relative anti-inflammatory potency to relative mineralocorticoid potency: Aldosterone

Answer 14

.2 to 250

Question 15

Relative anti-inflammatory potency to relative mineralocorticoid potency: Cortisol

Answer 15

1 to 1

Question 16

Relative anti-inflammatory potency to relative mineralocorticoid potency: Dexamethasone

Answer 16

20 to 0

Question 17

Relative anti-inflammatory potency to relative mineralocorticoid potency: Prednisolone

Answer 17

3 to 0.8

Question 18

Relative anti-inflammatory potency to relative mineralocorticoid potency: Fludrocortisone

Answer 18

12 to 100

Question 19

Metyrapone

Answer 19

Mechanism: Blocks 11 beta hydroxylation so synthesis is stopped at 11-desoxycortisol. Does not inhibit ACTH release, so plasma ACTH increases stimulating synthesis and excretion of 17-hydroxycorticoids as 11-desoxycortisol.

Used as a diagnostic test

Question 20

Mifepristone

Answer 20

Competitive antagonist at progesterone and glucocorticoid receptors

Progesterone antagonist- Termination of pregnancy
Glucocorticoid antagonist- Treat cushing syndrome etc.

Question 21

Spironolactone

Answer 21

Competitive antagonists at mineralcorticoid receptor

Uses: diuretics, cardiac fibrosis/hypertrophy, HTN

Question 22

Eplerenone

Answer 22

Competitive antagonists at mineralcorticoid receptor

Uses: diuretics, cardiac fibrosis/hypertrophy, HTN

Question 23

Drospirenone

Answer 23

Progesterone agonist
Mineralocorticoid antagonist
Androgen receptor antagonist

Progesterone Agonist- Used with estrogen to suppress ovulation and as hormone replacement therapy in post menopausal women
Mineralcorticoid antagonist-diuretic, antagonizes the salt retaining effects of estrogen
Androgen receptor antagonist