Steroids

Question 1

Cortisol

Answer 1

Class: Glucocorticoid
Mech: Binds GR, which regulates expression of genes with many effects on carbohydrate metabolism and immune function
Important SE’s: Cushing’s; glucocorticoid-induced osteoporosis; iatrogenic adrenal insufficiency
Misc: RelAnti-Inflam: 1; RelMin: 1; DoA: 8-12 hours

Question 2

Cortisone acetate (Cortone): difference with cortisol:

Answer 2

Misc: RelAnti-Inflam: 0.8; RelMin: 0.8; DoA: 8-12 hours

Question 3

Hydrocortisone: difference with cortisol:

Answer 3

Thera: Chronic primary adrenal insufficiency (maintenance); CAH
Misc: RelAnti-Inflam: 1; RelMin: 1; DoA: 8-12 hours

Question 4

Prednisone (Deltasone): difference with cortisol:

Answer 4

Thera: CAH
Misc: RelAnti-Inflam: 4; RelMin: 0.8; DoA: 12-36 hours; 1/4 dose of cortisol

Question 5

Prednisolone (Orapred): difference with cortisol:

Answer 5

Misc: RelAnti-Inflam: 4; RelMin: 0.8; DoA: 12-36 hours; 1/4 dose of cortisol

Question 6

Methylprednisolone (Medrol): difference with cortisol:

Answer 6

Misc: RelAnti-Inflam: 5; RelMin: 0.5; DoA: 12-36 hours; 1/5 dose of cortisol

Question 7

Triamcinolone: difference with cortisol:

Answer 7

Misc: RelAnti-Inflam: 5; RelMin: 0; DoA: 12-36 hours; 1/5 dose of cortisol

Question 8

Dexamethasone (Decadron): difference with cortisol:

Answer 8

Thera: Emergency treatment (severe adrenal crisis, PAI); suppression test (Cushing’s); CAH
Misc: RelAnti-Inflam: 30; RelMin: 0; DoA: 8-12 hours; <1/20 dose of cortisol

Question 9

Fludrocortisone

Answer 9

Class: Mineralocorticoid
Mech: Binds aldosterone receptor (AR) which increases Na+K+ATPase expression and increase epithelial sodium channel experession
Thera: Chronic primary adrenal insufficiency (maintenance); CAH
Important SE’s: Primary aldosteronism
Misc: RelAnti-Inflam: 10; RelMin: 125; DoA: 12-36 hours; very small dose

Question 10

Aminoglutethide (Cytadren)

Answer 10

Mech: Blocks conversion of cholesterol to pregnenolone
Thera: Cushing’s Syndrome

Question 11

Ketoconazole (Nizoral)

Answer 11

Class: Anti-fungal imidazole derivitive
Mech: Potent, nonselective inhibitor of adrenal and gonadal steroid synthesis
Thera: Cushing’s Syndrome

Question 12

Mitotane (Lysodren)

Answer 12

Class: DDT insecticide relative
Mech: Nonselective cytotoxic action on adrenal cortex
Thera: Cushing’s Syndrome
Important SE’s: Bad side effect profile

Question 13

Metyrapone (Metopirone)

Answer 13

Mech: Relatively selective inhibitor of 11-hydroxylation (interferes with cortisol and corticosterone synthesis)
Thera: Cushing’s syndrome; can use diagnostically to test anterior pituitary;
Misc: ACTH levels should rise in compensatory response to decreased cortisol and corticosterone, with precursor 11-deoxycortisol increasing also during metyrapone test

Question 14

Mifepristone (RU-486)

Answer 14

Mech: Progesterone receptor antagonist; GR antagonist at high concentrations
Thera: Cushing’s syndrome (controls hyperglycemia secondary to hypercortisolism in those with endogenous Cushing’s syndrome who had issues with surgery); cortisol-induced psychosis
Important SE’s: Fatigue, nausea, headache, hypokalemia (moderate to severe since now crtisole can overwhelm the mineralocorticoid system), arthralgias
Other SE’s: edema and endometrial thickening in women;
Adrenal insufficiency that needs to be treated with withdrawal of mifepristone and then high-dose dexamethasone

Question 15

Pasireotide

Answer 15

Class: somatostatin analog
Mech: Binds to somatostatin receptorand blocks release of ACTH from corticotropes
Thera: Cushing’s disease (pituitary)
Important SE’s: Hyperglycemia, GI problems

Question 16

Spironolactone (Aldactone)

Answer 16

Mech: Aldosterone receptor antagonist
Thera: Primary aldosteronism
Important SE’s; Anti-androgenic

Question 17

Eplerenone (Inspra)

Answer 17

Mech: Aldosterone receptor antagonist
Thera: Primary aldosteronism
Misc: More specific; less anti-androgenic effect than spironolactone

Question 18

Glucocorticoids bind to _____, which proceeds to _____ and head into the ____ to activate _____

Answer 18

glucocorticoid receptor; dimerize; nucleus; GRE (glucocorticoid response element)

Question 19

Glucocorticoid effects:

Answer 19

1. Carb metabolism: increase gluconeogenesis, release aa’s through muscle catabolism, inhibits peripheral glucose uptake, stimulate lipolysis (FOR THE BRAIN)
2. Immune function
3. Anti-inflamm effects (upreg anti-inflamm proteins, downreg pro-inflamm proteins, decrease leukocyte presence and function at inflamm sites)
4. Fetal development (LUNGS especially)
5. Cognitive function/CNS effects

Question 20

Mineralocorticoids:

Answer 20

Aldo and deoxycorticosterone (DOC) naturally occur; cortisol has WEAK mineralocorticoid activity

Question 21

Mineralocoid mech of action and effects:

Answer 21

1. Binds to AR particularly in principle cells of distal convoluted and collecting tubules in the kidney
2. AR activated means more Na/K ATPase expression and more epi Na channel expression;
   You maintain electrolytes and intravascular volume (increased Na resorption, with water following to increase ECV and increase renal excretion of K)

Question 22

Although cortisol at higher levels than aldo, what allows for aldosterone to bind to AR knowing they have similar affinities for the receptor?

Answer 22

Use 11beta-hydroxysteroid DH type 2 to convert cortisol to cortisone

Question 23

Most significant regulators of aldosterone secretion:

Answer 23

1. Concentration of K ions in EC fluid (small increase leads to aldo secretion strongly stimulated
2. AII;
   other factors are ACTH and Na deficiency

Question 24

In general, what do glucocorticoids do?

Answer 24

1. Establish diagnosis and cause of Cushing’s
2. Treat adrenal insufficiency and CAH;
3. in general, can treat inflamm, allergic, immunological disorders at supraphysiologic doses

Question 25

Disorders of adrenal function often

Answer 25

treated and/or diagnosed using corticosteroids

Question 26

ACTH dependent vs. ACTH independent causes of Cushing's syndrome; what are the ACTH and cortisol levels in either:

Answer 26

1. Pituitary adenoma (Cushing's DISEASE) 2. Ectopic ACTH production; 1. adrenal adenoma 2. adrenal carcinoma; IATROGENIC Cushing's syndrome; high ACTH and cortisol in dependent; low ACTH and high cortisol in independent

Question 27

Diagnosis of Cushing's syndrome:

Answer 27

1. 24-hr urine free cortisol excretion 2. low-dose overnight dexamethasone suppression teset 3. midnight salivary cortisol level; diagnosis requires AT LEAST TWO positive tests

Question 28

Difference b/w primary and secondary adrenocortical insufficiency causes; consequence of either:

Answer 28

1. Primary will have decreased cortisol and aldo production with HIGH ACTH levels 2. Secondary with decreased pituitary production of ACTH and decreased production primarily of cortisol (not as much aldo); can't handle physiologic stress like trauma or infection, and leads to life-threatening shock

Question 29

Causes of secondary adrenal insufficiency:

Answer 29

1. suppression from exogenous glucocorticoid therapy 2. Hypopituitarism: removal of pituitary adenoma, pituitary tumors or surgery (craniopharyngiomas), pituitary apoplexy among others

Question 30

Difference in symptoms with secondary adrenal and primary adrenal insufficiency:

Answer 30

1. No hyperpigmentation (ACTH not elevated) | 2. Near-normal aldo levels

Question 31

Adrenal crisis and the signs/symptoms:

Answer 31

1. Lack of cortisol: most common if primary adrenal insufficiency; 2. LIFE-THREATENING emergency, and needs immediate treatment; volume depletion and hypotension, N/V, hyperkalemia, hyponatremia (mineralocorticoid deficiency and increased ADH b/c of cortisol deficiency)

Question 32

Causes of adrenal crisis (acute adrenal insufficiency) and how can we diagnose it:

Answer 32

1. Think sepsis, surgical stress, trauma 2. hemorrhagic destructino of gland like WF syndrome or anticoag therapy or caog disorder 3. Rapid withdrawal of steroids; give synthetic ACTH to see if cortisol levels get spiked (normal) or not

Question 33

Adrenal insufficiency differences in primary and secondary:

Answer 33

1. Primary with decreased cortisol, HIGH ACTH | 2. secondary with decreased cortisol, ACTH

Question 34

Treatment of chronic primary adrenal insufficiency:

Answer 34

1. Glucocorticoid replacement (physiologic); monitor clinical symptoms and morning ACTH 2. Mineralocorticoid replacement: liberal salt intake; fludrocortisone; keep an eye on supine/standing BP and serum K and plasma renin; if a minor febrile illness, increase glucocorticoid dose for the few days of illness, but NOT mineralocorticoid; educate pt about the disease and also use medical alert bracelet/necklace

Question 35

Adrenal crisis treatment:

Answer 35

DO NOT DELAY treatment while waiting for definitive proof of diagnosis; Need support with large amounts of IV fluids, and hypotonic saline will worsen hyponatremia; also need high-dose IV glucocorticoid and gradual tapering to maintenance dose

Question 36

When to screen for primary aldosteronism:

Answer 36

1. HTN with hypokalemia 2. Treatment with resistant HTN 3. Adrenal incidentaloma 4. HTN of early onset (160 systolic, >100 diastolic) 6. Also considering secondary HTN

Question 37

Screening tests for primary aldosteronism:

Answer 37

1. Plasma aldo concentration 2. Plasma renin activity 3. 24-hr urine collection for aldo and Na

Question 38

Treatment of primary aldo:

Answer 38

1. Surgery (unilateral adenoma) | 2. Med (bilateral adrenal hyperplasia): spironolactone and eplerenone (latter less antiandrogenic)

Question 39

21-hydroxylase deficiency: mech and symptoms:

Answer 39

1. defective conversion of 17-hydroxyprogesterone to 11-deoxycortisol (and progesterone to DOC) 2. Increased adrenal androgens produce hirsutism and/or other forms of virilization

Question 40

CAH with 21-hydroxylase deficiency early and late onset, and diagnosis:

Answer 40

Early: virilizing with clitoral enlargement, labial fusion, urogenital sinus, sexual ambiguity; salt wasting crisis and hypotension Late: think high DHEAS, androstenedione leading to sexual precocity or hirsutism or irregular menstruation; hyponatremia, hyperkalemia, increased renin in salt wasters; Diag: increased response of plasma 17-hydroxyprogesterone to ACTH (cosyntropin stimulation test)

Question 41

Treat 21-hydroxylase deficiency:

Answer 41

1. Steroids (dexamethasone, prednisone, hydrocortisone) 2. In salt-wasting, need fludrocortisone 3. Treat gluco and mineralo deficiency if there 4. Give steroids to suppress ACTH production and reduce androgen overproduction

Question 42

Toxicity of corticosteroids; acute SE's:

Answer 42

1. Can get iatrogenic Cushing's syndrome (osteoporosis, diabetes, infections) with supraphysiological steroid doses 2. Withdrawal of steroid therapy resulting in adrenal insufficiency; insomnia, behavior changes (hypomania, acute psychosis), acute peptic ulcers, acute pancreatitis (rare at high dose)

Question 43

Prolonged CS use complications:

Answer 43

1. peptic ulcer 2. masking symptoms of infection 3. severe myopathy 4. nausea 5. depression

Question 44

Alternate day therapy indicated for

Answer 44

minimizing SE's of HPA suppression and iatrogenic Cushings syndrome, NOT for adrenal insufficiency; we use prednisone, prednisolone, methylprednisolone We need a Head Coach, not an Assistant

Question 45

Withdrawal from steroid therapy; how to avoid:

Answer 45

Anorexia, NV, weight loss, lethargy, headache, fever, joint or muscle pain, postural hypotension; suggests glucocorticoid dependence even with normal or high plasma cortisol levels; could be during withdrawal or treatment of Cushing's syndrome; TAPER THERAPY very slowly, and during recovery you'll have hypothalamic pituitary function coming back before adrenocortical function, and pts at risk of ADRENAL crisis