Pharm adrenal steroids Flashcards
what are the layers of the adrenal gland
zona glomerulosa, zona fasciculata, zona reticularis
what does zona glomerulosa make
aldosterone
what does zona fasciculata make
glucocorticoids (cortisol)
what does zona reticularis make
cortisol and androgens
Common enzyme for androgens and cortisol
17-alpha hydroxylase
common enzyme for aldosterone and cortisol
21-beta hydroxylase
mineralcorticoids
aldosterone and deoxycorticosterone (DOC)
cortisol has weak mineralcorticoid activity
glucocorticoids
cortisol
cortisol mechanism of action
works within nucleus (diffuses through membrane)
what controls the release of cortisol from the adrenal gland?
ACTH from anterior pituitary
what controls the release of ACTH from the anterior pituitary?
CRH from hypothalamus
glucocorticoid effects
stress hormone
carbohydrate metabolism
immune function
glucocorticoid metabolic effects
- increase gluconeogenesis,
- release amino acids through muscle catabolism,
- inhibit peripheral glucose uptake,
- simulate lipolysis,
- maintain adequate glucose for brain!
- increase blood pressure
- decrease bone formation
how does glucocorticoid increase blood pressure?
upregulates alpha 1 receptors on arterioles and leads to increased sensitivity to norepi and epi
glucocorticoid anti-inflammatory effects
upregulation of anti-inflammatory proteins, down regulation or pro-inflammatory, decreased leukocyte presence and function at site of inflammation
mineralcorticoid effects
-active in distal convoluted and collecting tubules maintaining electrolyte balance and intravascular volume
what are the most significant regulators of aldosterone secretion?
increased potassium, angiotensin II
ACTH, sodium deficiency
mineralcorticoid specificity with aldosterone receptors
cortisol binding AR is prevented by 11 beta-hydroxysteroid dehydrogenase type 2
(cortisol –> cortisone)
pharmacologic uses of corticosteroids
- adrenal insufficiency
- establish diagnosis and cause of cushing’s syndrom
- treat inflammatory, allergic, immunological disorders
what is the synthetic mineralcorticoid? difference from cortisol?
fludrocortisone
-very high mineralcorticoid effect with a longer duration of action
what are the disorders of adrenal function?
adrenocortical insufficiency
congenital adrenal hyperplasia
cushing’s syndrome
aldosteronism
primary vs secondary adrenocortical insufficiency
primary: anatomic destruction of adrenal gland (autoimmune)
secondary: decreased pituitary production of ACTH
causes for secondary adrenal insufficiency
ACTH deficiency due to iatrogenic and hypopituitarism
primary adrenal insufficiency symptoms/signs
weakness, fatigue, nausea, vomiting, diarrhea, salt craving, postural dizziness, anorexia, weight loss, skin pigmentation
primary adrenal insufficiency labs
hyponatremia, hyperkalemia, anemia, eosinophilia, azotemia
secondary adrenal insufficiency symptoms/signs
same as primary except NO hyperpigmentation (ACTH is low not elevated) and near-normal aldosterone levels
how to diagnose adrenal insufficiency
measure plasma cortisol level at baseline and 30-60 min after cosyntropin (synthetic ACTH)
if cortisol is greater than 18 = normal
if cortisol is less than 18 = abnormal
diagnosis adrenal insufficiency: primary vs secondary
primary = low cortisol and high ACTH secondary = low cortisol and low ACTH
causes for acute adrenal insufficiency “adrenal crisis”
rapid withdrawal of steroids from someone how has been on them for a long time
signs/symptoms of adrenal crisis
volume depletion and hypotension, lassitude, nausea, vomiting, hyperkalemia, hyponatremia (mineralcorticoid deficiency, increased ADH)
treatment of adrenal crisis
- support with large amounts of IV fluids
- high-dose IV glucocorticoid (dexamethasone if no previous dx of adrenal insufficiency, or hydrocortisone)
treatment of chronic adrenal insufficiency
- maintenance therapy: glucocorticoid replacement (hydrocortisone 2x per day) and mineralocorticoid replacement (fludrocortison, liberal salt intake)
- stress dosing
congenital adrenal hyperplasia
inherited AR disorders caused by deficient adrenal corticosteroid synthesis d/t mutations of genes involved with adrenal steroidogenesis
-enzyme deficiency
what is the MCC of congenital adrenal hyperplasia? what does it cause?
21-hydroxylase deficiency
cuases inability to make aldosterone and cortisol which causes increased androgens
what is measured for diagnosis of 21-hydroxylase deficiency?
17-OH-progesterone (if it is raised means there is 21-hydroxylase deficiency)
21-hydroxylase deficiency treatment
steroids (dexmethasone, prednisone, hydrocortisone)
if salt-wasting, also add fludrocortisone
glucocorticoid excess
Cushing’s syndrome
caused by 1. ACTH dependent (pituitary adenoma or ectopic ACTH production)
2. ACTH independent (adrenal adenoma and adrenal carcinoma)
3. iatrogenic
signs and symptoms of Cushing’s syndrome
weight gain (truncal), moon face, HTN, bruising, thin skin, striae, ankle edema, proximal myopathy, hirsutism, psychiatric dysfxn, backache, muscle weakness, loss of scalp hair, fractures
cushing disease
pituitary ademona causing the glucocorticoid excess
diagnosis of cushing’s syndrome
-ACTH (high = dependent, low = independent)
-24-hr urine free cortisol excretion
-low-dose overnight dexamethasone suppression test (less than 1.8 is normal)
-midnight salivary cortisol level
need at least TWO of these tests positive
medical treatment of cushing’s syndrome
aminoglutethimide ketoconazole mitotane metyrapone mifepristone
aminoglutethimide mechanism and use
blocks conversion of cholesterol to pregnenolone (treats cushing’s)
ketoconazole mechanism and use
antifungal imidazole derivative. potent, nonselective inhibitor of adrenal and gonadal steroid synthesis (treats cushing’s)
mitotane mechanism and use
related to DDT insecticides. nonselective cytotoxic action on adrenal cortex - bad SE (treats cushing’s)
metyrapone mechanism and use
relatively selective inhibitor of 11-hydroxylation. interferes with cortisol and corticosterone synthesis
-can be used diagnostically to test anterior pituitary (ACTH levels should rise in compensatory response to decreased cortisol and corticosterone as should precursor 11-deoxycortisol)
(treats cushing’s)
mifepristone mechanism
initally developed as progesterone receptor antagnoist
-has glucocorticoid receptor antagonist activity at higher concentrations (only binds glucocorticoid receptor)
mifepristone use
cushing’s syndrome - controls hyperglycemia secondary to hypercortisolism in adults with endogenous cushing’s syndrome who have failed or are not candidates for surgery
-also used for rapid treatment of cortisol-induced psychosis
mifepristone side effects
fatigue, nausea, headache, hypokalemia, arthralgias, edema and endometrial thickening
also: adrenal insufficiency
pasireotide mechanism and uses
somatostatin analog binds to somatostatin receptors and blocks release of ACTH from the corticotropes via high affinity for somatostatin receptor subtype 5
use: cushing’s disease pituitary
pasireotide side effects
hyperglycemia and gastrointestinal symptoms
aldosteronism
increased aldosterone, decreased renin d/t HTN and hypokalemia
when to screen for primary aldosteronism
- HTN with hypokalemia
- resistant HTN
- adrenal incidentaloma
- HTN early onselt
- severe HTN
treatment for priamry aldosteronism
surgery for unilateral adenoma and medical for bilateral adrenal hyperplasia (spironolactone and eplerenone - aldosterone receptor blocking agents)
difference between spironolactone and eplerenone
eplerenone is newer with less antiandrogen effects
nonendocrinologic use of corticosteroids
for suppressing inflammatory and immune response
acute side effects of corticosteroids
insomnia, behaviour changes (hypomania, acute psychosis), acute peptic ulcers, acute pancreatitis (rare)
withdrawal from steroid therapy
- adrenal suppression can occur after 2 weeks
- withdrawal syndrome of anorexia, nausea, vomiting, weight loss, lethargy, headache, fever, joint or muscle pain, postural hypotension d/t dependence
- need to taper off steroid therapy (2-12 months)
