Steroids Flashcards
Cortisol
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
Cortisone acetate (Cortone): difference with cortisol:
Misc: RelAnti-Inflam: 0.8; RelMin: 0.8; DoA: 8-12 hours
Hydrocortisone: difference with cortisol:
Thera: Chronic primary adrenal insufficiency (maintenance); CAH
Misc: RelAnti-Inflam: 1; RelMin: 1; DoA: 8-12 hours
Prednisone (Deltasone): difference with cortisol:
Thera: CAH
Misc: RelAnti-Inflam: 4; RelMin: 0.8; DoA: 12-36 hours; 1/4 dose of cortisol
Prednisolone (Orapred): difference with cortisol:
Misc: RelAnti-Inflam: 4; RelMin: 0.8; DoA: 12-36 hours; 1/4 dose of cortisol
Methylprednisolone (Medrol): difference with cortisol:
Misc: RelAnti-Inflam: 5; RelMin: 0.5; DoA: 12-36 hours; 1/5 dose of cortisol
Triamcinolone: difference with cortisol:
Misc: RelAnti-Inflam: 5; RelMin: 0; DoA: 12-36 hours; 1/5 dose of cortisol
Dexamethasone (Decadron): difference with cortisol:
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
Fludrocortisone
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
Aminoglutethide (Cytadren)
Mech: Blocks conversion of cholesterol to pregnenolone
Thera: Cushing’s Syndrome
Ketoconazole (Nizoral)
Class: Anti-fungal imidazole derivitive
Mech: Potent, nonselective inhibitor of adrenal and gonadal steroid synthesis
Thera: Cushing’s Syndrome
Mitotane (Lysodren)
Class: DDT insecticide relative
Mech: Nonselective cytotoxic action on adrenal cortex
Thera: Cushing’s Syndrome
Important SE’s: Bad side effect profile
Metyrapone (Metopirone)
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
Mifepristone (RU-486)
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
Pasireotide
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
Spironolactone (Aldactone)
Mech: Aldosterone receptor antagonist
Thera: Primary aldosteronism
Important SE’s; Anti-androgenic
Eplerenone (Inspra)
Mech: Aldosterone receptor antagonist
Thera: Primary aldosteronism
Misc: More specific; less anti-androgenic effect than spironolactone
Glucocorticoids bind to _____, which proceeds to _____ and head into the ____ to activate _____
glucocorticoid receptor; dimerize; nucleus; GRE (glucocorticoid response element)
Glucocorticoid effects:
- Carb metabolism: increase gluconeogenesis, release aa’s through muscle catabolism, inhibits peripheral glucose uptake, stimulate lipolysis (FOR THE BRAIN)
- Immune function
- Anti-inflamm effects (upreg anti-inflamm proteins, downreg pro-inflamm proteins, decrease leukocyte presence and function at inflamm sites)
- Fetal development (LUNGS especially)
- Cognitive function/CNS effects
Mineralocorticoids:
Aldo and deoxycorticosterone (DOC) naturally occur; cortisol has WEAK mineralocorticoid activity
Mineralocoid mech of action and effects:
- Binds to AR particularly in principle cells of distal convoluted and collecting tubules in the kidney
- 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)
Although cortisol at higher levels than aldo, what allows for aldosterone to bind to AR knowing they have similar affinities for the receptor?
Use 11beta-hydroxysteroid DH type 2 to convert cortisol to cortisone
Most significant regulators of aldosterone secretion:
- Concentration of K ions in EC fluid (small increase leads to aldo secretion strongly stimulated
- AII;
other factors are ACTH and Na deficiency
In general, what do glucocorticoids do?
- Establish diagnosis and cause of Cushing’s
- Treat adrenal insufficiency and CAH;
- in general, can treat inflamm, allergic, immunological disorders at supraphysiologic doses
Disorders of adrenal function often
treated and/or diagnosed using corticosteroids
ACTH dependent vs. ACTH independent causes of Cushing’s syndrome; what are the ACTH and cortisol levels in either:
- Pituitary adenoma (Cushing’s DISEASE)
- Ectopic ACTH production;
- adrenal adenoma
- adrenal carcinoma;
IATROGENIC Cushing’s syndrome;
high ACTH and cortisol in dependent; low ACTH and high cortisol in independent
Diagnosis of Cushing’s syndrome:
- 24-hr urine free cortisol excretion
- low-dose overnight dexamethasone suppression teset
- midnight salivary cortisol level;
diagnosis requires AT LEAST TWO positive tests
Difference b/w primary and secondary adrenocortical insufficiency causes; consequence of either:
- Primary will have decreased cortisol and aldo production with HIGH ACTH levels
- 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
Causes of secondary adrenal insufficiency:
- suppression from exogenous glucocorticoid therapy
- Hypopituitarism: removal of pituitary adenoma, pituitary tumors or surgery (craniopharyngiomas), pituitary apoplexy among others
Difference in symptoms with secondary adrenal and primary adrenal insufficiency:
- No hyperpigmentation (ACTH not elevated)
2. Near-normal aldo levels
Adrenal crisis and the signs/symptoms:
- Lack of cortisol: most common if primary adrenal insufficiency;
- 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)
Causes of adrenal crisis (acute adrenal insufficiency) and how can we diagnose it:
- Think sepsis, surgical stress, trauma
- hemorrhagic destructino of gland like WF syndrome or anticoag therapy or caog disorder
- Rapid withdrawal of steroids;
give synthetic ACTH to see if cortisol levels get spiked (normal) or not
Adrenal insufficiency differences in primary and secondary:
- Primary with decreased cortisol, HIGH ACTH
2. secondary with decreased cortisol, ACTH
Treatment of chronic primary adrenal insufficiency:
- Glucocorticoid replacement (physiologic); monitor clinical symptoms and morning ACTH
- 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
Adrenal crisis treatment:
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
When to screen for primary aldosteronism:
- HTN with hypokalemia
- Treatment with resistant HTN
- Adrenal incidentaloma
- HTN of early onset (160 systolic, >100 diastolic)
- Also considering secondary HTN
Screening tests for primary aldosteronism:
- Plasma aldo concentration
- Plasma renin activity
- 24-hr urine collection for aldo and Na
Treatment of primary aldo:
- Surgery (unilateral adenoma)
2. Med (bilateral adrenal hyperplasia): spironolactone and eplerenone (latter less antiandrogenic)
21-hydroxylase deficiency: mech and symptoms:
- defective conversion of 17-hydroxyprogesterone to 11-deoxycortisol (and progesterone to DOC)
- Increased adrenal androgens produce hirsutism and/or other forms of virilization
CAH with 21-hydroxylase deficiency early and late onset, and diagnosis:
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)
Treat 21-hydroxylase deficiency:
- Steroids (dexamethasone, prednisone, hydrocortisone)
- In salt-wasting, need fludrocortisone
- Treat gluco and mineralo deficiency if there
- Give steroids to suppress ACTH production and reduce androgen overproduction
Toxicity of corticosteroids; acute SE’s:
- Can get iatrogenic Cushing’s syndrome (osteoporosis, diabetes, infections) with supraphysiological steroid doses
- Withdrawal of steroid therapy resulting in adrenal insufficiency;
insomnia, behavior changes (hypomania, acute psychosis), acute peptic ulcers, acute pancreatitis (rare at high dose)
Prolonged CS use complications:
- peptic ulcer
- masking symptoms of infection
- severe myopathy
- nausea
- depression
Alternate day therapy indicated for
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
Withdrawal from steroid therapy; how to avoid:
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
