Corticosteroids Flashcards
Zona glomerulosa secretes:
Aldosterone.
Zona fasiculata secretes:
Cortisol (glucocorticoid).
Zona reticularis secretes:
DHEA and androstenedione.
Corticosteroid MOA:
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).
Mineralocorticoid effects:
Water and ion balance:
- Increased Na/K ATpase expression on distal tubules and collecting duct to enhance Na+ and water reabsorption and K+ secretion.
Pseudo Cushing’s:
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:
- Euphoria.
- Psychosis.
- Depression.
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):
- Block and replace.
- Patients with erratic cortisol secretion. - Normalization.
- Patients with invariant hypercortisolism.
Ketoconazole:
- Antifungal
- 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.
Metyrapone:
- 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.
Mitotane:
- 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.
Mifepristone (RU-486):
- 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.
