Pharm - Steroids Flashcards
3 Zona of Adrenal Cortex from Outside In:
Glomerulosa — Fasciculata — Reticularis
15% — 75% — 10%
Main hormone(s) of each adrenal cortex
Glomerulosa = aldosterone (mineralcorticoid) Fasciculata = cortisol (glucocorticoid) Reticularis = cortisol and Androgens
remember: salty dinner, sweet desert, sex
Where and on what hormones does cortisol have negative feedback effects?
Hypothalamus – CRH (corticotropin releasing hormone)
Anterior Pituitary – ACTH
How and through what receptor do glucocorticoids affect BP?
Increases BP – a1 adrenergic receptors on arterioles –> increased sensitivity to NE and Epi
Glucocorticoids (increase/decrease) gluconeogenesis
Increase gluconeogensis – MORE GLUCOSE FOR BRAIN
Glucocorticoids (increase/decrease) amino acid release through muscle catabolism
Increase
Glucocorticoids (increase/decrease) peripheral glucose uptake
Decrease – MORE FOR BRAIN
Glucocorticoids (increase/decrease) lipolysis
Increase – less fat, more SUGAR for brain
Glucocorticoids (increase/decrease) bone Formation
Decrease
Glucocorticoids (increase/decrease) anti-inflammatory proteins
Increase – up-regulation
Glucocorticoids (increase/decrease) pro-inflammatory proteins
Decrease – downregulation
2 Naturally occurring mineralcorticoids:
- -Aldosterone
- -Deoxycorticosterone
(High/Low) potassium upregulates aldosterone
High
Blood concentration of [cortisol/aldosterone] is higher
Cortisol – 2000fold higher than Aldosterone
What prevents cortisol from binding to aldosterone receptors?
11B-hydroxysteroid dehydrogenase TYPE 2 – converts intracellular cortisol to cortisone
–Type 1 reverses
What commonly used corticosteroid has 0 mineralcorticoid activity (relative to cortisol)?
Dexamethasone – 30 anti-inflammatory, 0 mineralcorticoid, 36-72hr
What commonly used corticosteroid has the highest mineralcorticoid activity (relative to cortisol)
Fludrocortisone – 10 anti-inflammatory, 125 mineralcorticoid
Cause of primary vs. secondary adrenocortical insufficiency:
Primary – anatomic destruction of adrenal gland
Secondary – decreased pituitary production of ACTH
[Primary/Secondary] Adrenal insufficiency causes hyperpigmentation
Primary – hyperpigmented skin, hand creases, and nails
Cortisol and ACTH levels in Primary adrenal insufficiency
- -Low cortisol – can’t make
- -High ACTH – can’t use
Cortisol and ACTH levels in Secondary adrenal insufficiency
- -Low cortisol – doesn’t make
- -low ACTH – doesn’t make
What is Cosyntrpin test and how does it work?
ACTH stimulation test to determine primary vs 2ndary adrenal insufficiency
- -Primary = No increase in Cortisol
- -2ndary = Increase in Cortisol
Na and K changes in acute Adrenal Insufficiency “Adrenal Crisis”
- -Hyperkalemia
- -Hyponatremia – b/c high ADH from cortisol deficiency, low mineralcorticoid
CAH inheritence is [autosomal/x-linked] [dominant/recessive]
Autosomal recessive
Most common form of CAH involves what enzyme?
21-hydroxylase deficiency
What is increased in most common form of CAH?
17-hydroxy-progesterone and androgens (DHEA, androstenedione, testosterone, estradiol)
In Cushing’s Syndrome, glucocorticoids are [increased/decreased]
Increased – too much adrenal cortex activity
ACTH dependent Cushing’s Syndrome causes:
- -Pituitary adenoma (Cushing’s Disease)
- -Ectopic ACTH production (small cell lung Cx, bronchial carcinoid)
ACTH independeing Chushing’s Syndrome causes:
- -Adrenal adenoma
- -Adrenal carcinoma
Characteristics of abdominal striae in Cushing’s Syndrome
- -Greater than 1cm in width
- -Violaceous color
4 Diagnostic tests for Cushing’s Syndrome
1–ACTH
2–24hr urine free cortisol excretion
3–Low dose overnight dexamethasone suppression test
4–Midnight salivary cortisol level test
**Need 2+ tests for diagnosis
ACTH dependent Cushing’s Syndrome has what ACTH and Cortisol levels?
- -High ACTH
- -High Cortisol
ACTH independent Cushing’s Syndrome has what ACTH and Cortisol levels?
- -Low ACTH
- -High Cortisol
What is the mechanism of Metyrapone?
- -Selective inhibitor of 11-hydroxylase
- -Results in increased 11-deoxycortisol
- -Increased ACTH due to lower feedback inhibition
This drug for Cushing’s Syndrome was developed as a progesterone receptor antagonist, but has glucocorticoid receptor antagonist activity at higher concentrations
Mifepristone (RU-486)
This drug for Cushing’s Syndrome blocks conversion of cholesterol to pregnenolone
Aminoglutethimide
This drug for Cushing’s Syndrome is a potent, nonselective inhibitor of adrenal and gonadal steroid synthesis; imidazole derivative
Ketoconazole – antifungal
This drug for Cushing’s Syndrome is a DDT insecticide relative w/ bad side effect profile
Mitotane – nonselective cytotoxic action on adrenal cortex
This drug for Cushing’s Syndrome binds to somatostatin receptors to block release of ACTH
Pasireotide – high affinity for somatostatin receptor subtype 5
Classic presentation of Primary aldosteronism:
Hypertension w/ hypokalemia
2 Drugs used for medical management of Primary Aldosteronism:
- -Spirinolactone – aldosterone receptor blocker
- -Eplerenone – less anti-androgen effect
What Cushing Syndrome cause leads to bilateral adrenal atrophy?
Exogenous corticosteroids ( low ACTH)
No atrophy causes:
- -Primary adrenal adenoma/hyperplasia/carcinoma
- -Cushing Disease (ACTH secreting pituitary adenoma)
- -Paraneoplastic ACTH secretion
[FA]
Cortisol mnemnoic: BIG FIB
Blood pressure = increased
Insulin resistance
Gluconeogenesis + lipolysis, proteolysis –> hyperglycemia
Fibroblast activity –> striae
Inflammatory and Immune =
—inhibit leukotriene, prostaglandin synthesis
—inhibit WBC adhesion –> neutrophilia
—block histamine release from mast cells
—reduce eosinophils
—block IL-2 producction
Bone formation = decreased ( low osteoblast activity)
Scenario: Already know high 24hr urine cortisol, high midnight salivary cortisol and no suppression w/ overnight low-dose dexamethasone test.
- -What if ACTH is low?
- -What if ACTH is high?
Low ACTH = think adrenal tumor or exogenous glucoccorticoid cause
High ACTH = high dose dexamethasone suppression to differentiate Cushing disease (suppressed) vs. ectopic secretion (no suppression)
How is metyrapone stimulation test used?
Metyrapone given to block 11-hydroxylase (11-deoxycortisol–>cortisol)
Normal: low cortisol, compensatory high ACTH, 11-deoxycortisol
Primary adrenal insufficiency: high ACTH, low 11-deoxycortisol
2ndary adrenal insufficiency: low ACTH, low 11-deoxycortisol
