Flashcards in Corticosteroids Deck (37):
Zona glomerulosa secretes:
Zona fasiculata secretes:
Zona reticularis secretes:
DHEA and androstenedione.
Bind to cytoplasmic receptor, which is a ligand activated transcription factor.
- Takes time, not a rescue drug.
Glucocorticoid effects on metabolism:
Glucose regulation, induce hyperglycemia:
- Liver increases glucose synthesis and glycogen storage.
- Peripheral tissues: protein breakdown, decreased utilization of glucose, lipolysis, decreased uptake of glucose.
Fats, redistribution of body fats:
- Round face and back fat.
- Marked central obesity, reduced peripheral fats.
Glucocorticoid effects on calcium balance:
Induces a negative calcium balance, decreases calcium uptake in the gut, increase calcium secretion by the kidney.
Glucocorticoid effects on cardiovascular and blood:
Most glucocorticoids have some mineralocorticoid activity, sodium excretion can promote HTN.
Glucocorticoid effects on inflammation:
Reduces NF-kappa-B levels - inhibits:
- Proteolytic enzymes, vasoactive and chemoatractant factors.
- Pro-inflammatory enzymes such as COX-2 and NOS.
Stimulates the synthesis of lipocortin, inhibits phospholipase A2 activity, decreases arachidonic acid release and subsequent production of ecosanoids.
(Main non-endocrine use.)
Glucocorticoid effects on endocrine:
- Inhibits TSH release, can lead to misinterpretation of TSH assays for hyperthyroidism.
- Decrease serum levels of TBG.
- Decreased T3 levels.
- Inhibit growth via inhibition of IGF-1
- Prolonged --> inhibits FSH and LH surges
Glucocorticoid effects on bone/connective tissue/skin:
- Inhibits osteoblast function.
- Decreases collagen and osteocalin synthesis.
- Increased bone reabsorption (promotes osteoporosis).
- Inhibits fibroblast function.
- Decreased synthesis of collagen, fibronectin etc. (promotes stria and bruising).
Water and ion balance:
- Increased Na/K ATpase expression on distal tubules and collecting duct to enhance Na+ and water reabsorption and K+ secretion.
Physiological hypercortisolism associated with disorders other than Cushing's syndrome:
- Significant physical inflammatory stress.
- Severe obesity.
- Malnutrition, anorexia nervosa, intense chronic exercise.
- Psychological stress, severe MDD
- Chronic alcoholism.
Cushing syndrome - ACTH dependent:
Associated with excessive ACTH secretion leading to adrenocortical hyperplasia:
- Cushing's disease (pituitary hypersecretion of ACTH).
- Ectopic secretion of ACTH by nonpituitary tumors.
- Ectopic secretion of CRH by nonhypothalamic tumors.
- Iatrogenic or factitious Cushing's syndrome due to administration of exogenous ACTH.
Cushing syndrome - ACTH independent:
Iatrogenic or factitious Cushing's syndrome.
- Most commonly due to long term glucocorticoid use.
- Adrenocortical adenomas and carcinomas.
- Primary pigmented nodular adrenocortical disease (PPNAD).
- Bilateral macronodular adrenal hyperplasia (BMAH).
Cushing's syndrome - symptoms:
- Central obesity, round "moon face", "buffalo hump".
- Excessive sweating.
- Muscle wastage.
- Skin striae
- Neurological complaints:
Cushing's syndrome - diagnosis:
- Rule out exogenous glucocorticoids/pharmacological reasons.
- 24 hour urine cortisol.
- Late night salivary cortisol.
- Dexamethasone test.
- Metyrapone test.
Dexamethasone test - low dose:
Differentiates if Cushing's or not:
- If Cushing's no suppression of cortisol.
Dexamethasone test - high dose:
Differentiates type of Cushing's:
- ACTH undetectable but no suppression of cortisol: adrenal tumor.
- ACTH elevated and no suppression of cortisol: ectopic ACTH syndrome.
- ACTH normal to elevated and suppression of cortisol: Cushing's disease.
Cushing's syndrome - pharmacological approach (2):
1. Block and replace.
- Patients with erratic cortisol secretion.
- Patients with invariant hypercortisolism.
- At higher doses than antifungal therapy: inhibits CYP17.
- Inhibits glucocorticoid and androgen synthesis.
- Even higher doses: inhibits CYP11A1.
- Inhibits corticotroph adenylate cyclase activation.
- Reduces ACTH secretion at therapeutic doses.
- Drug interactions: inhibits CYP1A2, CYP2C9, CYP3A4.
- Co-administration with ergot derivatives, cisapride or triazolam is contraindicated --> fatal cardiac arrhythmias.
- MOA: selective inhibitor of CYP11B1 reducing the biosynthesis of cortisol.
- Use: hypercorticism resulting from adrenal neoplasms or tumors producing ACTH; diagnostic test for Cushing's syndrome.
- Side effects: Hirsutism, nausea, headache, sedation and rash.
- Hirsutism due to increased synthesis of adrenal androgens upstream from the enzymatic block.
- Acts on CYP11B1 and CYLP11A1 enzymes.
- Causes mitochondrial destruction and necrosis of adrenocortical cells.
- Has long term effect.
- Not used in pregnancy.
- Need to supplement with exogenous glucocorticoids.
- MOA: inhibits the release of the glucocorticoid receptor from the HSP chaperone proteins.
- Reduces transcriptional effects of glucocorticoids.
- Progesterone antagonist (abortion pill).
- Use: controlling hypercortisolism in patients with Cushing's syndrome caused by inoperable ACTH tumors, adrenal carcinomas unresponsive to other therapies.
- Side effects: vaginal bleeding, headache, dizziness, abdominal pain, nausea, vomiting, diarrhea and abdominal cramps.
- Drug interactions: increased metabolism of some drugs.
Adrenal insufficiency - Primary:
- Structural or functional deficiency of the adrenal cortex (Addison's disease). High ACTH levels and low glucocorticoids and mineralocorticoids.
Primary adrenal insufficiency treatment:
Combination of glucocorticoids and mineralocorticoids required.
- Hydrocortisone or cortisone preferred.
- Supplementation with fludrocortisone for mineralocorticoid effect.
Used to determine between primary and secondary adrenal insufficiency.
- Primary = ACTH levels high but low cortisol levels.
- Symptoms: weakness, wt loss, anorexia, HTN, *dark skin pigmentation*, hyponatremia.
- Secondary = baseline ACTH low and cortisol levels low
- Symptoms: malaise, anorexia, *no hyperpigmentation*.
Secondary adrenal insufficiency:
Pituitary or hypothalamic deficiency.
- Low ACTH and low-normal glucocorticoids/androgens, normal mineralocorticoids.
Secondary adrenal insufficiency treatment:
Hydrocortisone, cortisone or prednisone.
- Mineralocorticoid not needed.
Acute adrenal insufficiency:
Life threatening, should also consider isotonic NaCl and glucose therapy in conjunction with steroids.
Congenital adrenal hyperplasia (CAH):
- Deficiency in CYP21 most common.
- Reduced levels of corticosteroids.
- Increased 17-hydroxyprogesterone (clinical test), DHEA and androgens due to lack of feedback inhibition and excess ACTH.
- Classic-severe deficit:
- Females - pseudohermaphroditism.
- Males - normal at birth, precocious puberty.
- Non-classic: post puberty presentation.
- Treat with corticosteroids, females with classic can be treated in utero.
Excessive production of aldosterone leading to HTN and hypokalemia.
- Most common: aldosterone producing adenomas and bilateral idiopathic hyperaldosteronism.
- Less common: Unilateral hyperplasia, adrenal hyperplasia, familial or pure aldosterone producing carcinomas and tumors.
- Tx: Surgery, aldosterone antagonist.
Spironolactone (aldactone) side effects:
- Breast tenderness and menstrual irregularities in women.
- Impotence, decreased libido and gynecomastia in men.
Most anti-inflammatory potent glucocorticoids (2):
Glucocorticoid with the highest relative mineralocorticoid potency:
Longest lasting (half-life) glucocorticoid:
- HSD1 activates (cortisone --> cortisol).
- HSD2 deactivates (cortisol --> cortisone).