adrenocorticosteroids Flashcards
describe the hormonal steroids..
- glucocorticoids - effects on intermediary metabolism and immune function
- mineralocorticoids - principally salt-retaining activity
- steroids c androgenic and estrogenic activity
describe the layers of adrenal glands..
capsule
adrenal cortex
zona glomerulosa - mineralocorticoids, mainly aldosterone
zona fasciculata - glucocoricoids, mainly cortisol
zona reticularis - androgens
adrenal medulla - chromaffin cells secrete Epi and NE
glucocorticoid agonists?
prednisone hydrocortisone dexamethasone beclomethasone triamcinolone methylprednisolone
minderalocorticoid agonists?
aldosterone
fludrocortisone
glucocorticoid antagonists?
mifepristone
mineralocorticoid antagonists?
spironolactone
drugs that cause hormonal synthesis inhibition?
ketoconazole
aminoglutethimide
metyrapone
describe cortisol (hydrocortisone)
circadian rhythm and stress stimulate hypothalamus to release CRH -> act on the anterior pituitary to release ACTH -> act on the adrenal cortex -> release cortisol -> tissue responses (physiological/metabolic effects)
cortisol has negative feedback to the hypothalamus and anterior pituitary.
secretion and synthesis tightly regulated by CNS
Cortisol (hydrocortisone)
MOA?
- effects mediated by widely distributed glucocorticoid receptors.
- steroid-receptor complex enters the nucleus and interacts c promoters of (and regulates the transcription of) target genes
- produce tissue-specific responses
Cortisol (hydrocortisone)
Metabolic effects?
- stimulates and is required for gluconeogenesis & glycogen synthesis (which maintains hepatic glycogen avail) in fasting state
- -> increase serum glucose levels (thus leading to stimulation of insulin release) & inhibiting uptake by muscle cells.
- stimulates lipolysis (leading to fat deposition and redistribution & increased release of fatty acids & glycerol)
- stimulates protein catabolism & release of amino acids
NET result: maintenance of an adequate glucose supply to brain (most apparent in fasting state)
Cortisol (hydrocortisone)
Catabolic effects?
- in addition to protein catabolism, cortisol also has effects in lymphoid and connective tissue, muscle, peripheral fat and skin (wasting occurs at high conc).
- catabolic effects on bone = osteoporosis
- in children = growth retardation
Both are major limitations in long term tx c glucocorticoids.
Cortisol (hydrocortisone)
Immunosuppressive effects?
effects on leukocytes:
- increased neutrophils (increased influx into blood & decreased migration from blood vessels)
- decreased lymphocytes (T and B cells), monocytes, eosinophils and basophils (movement from vascular bed to lymphoid tissue)
vasoconstriction due possibly to suppression of mast cell degranulation
- decreased histamine release and capillary permeability
Cortisol (hydrocortisone)
Anti-inflammatory effects?
- inhibit PLA2 (through induction & activation of annexin I) which blocks arachidonic acid release (major precursor for PG)
- cyclooxygenase-2 synthesis is reduced (through inhibition of NF-kappB)
- induction of MAPK phophatase I (inhibits MAPK activated proinflammatory signaling pathways).
Cortisol (hydrocortisone)
other effects?
CNS: behavioral changes (insomnia, euphoria -> depression)
Increased ICP: large doses
Suppression of release of ACTH, GH, TSH, LH: chronic use
Peptic ulcers: stimulation of gastric acid. Suppression of immune response to H. pylori?
increase platelets & RBCs
Renal function: impaired c cortisol deficiency
Devel of fetal lungs.
Cortisol (hydrocortisone)
Pharmacokinetics?
short duration of action
diffuses poorly across skin (unless inflamed)
diffuses well across mucous membranes
some salt-retaining effects
prednisone, methylprednisolone, dexamethasone, beclometahsone, triamcinolone
PK?
prednisone = prodrug (rapidly converted to active prednisolone)
Beclomethasone = short t1/2, penetrates airway mucosa (low systemic toxicity)
prednisone, methylprednisolone, dexamethasone, beclometahsone, triamcinolone
Routes of Administration?
orall = all
IM = triamcinolone
IV,IM = dexamethasone, hydrocortisone, methylprednisolone, prednisolone
Aerosol = beclomethasone, triamcinolone
Topical = beclomethasone, dexamethasone, hydrocortisone, triamcinolone
Mineralocorticoids
MOA?
- bind to mineralocorticoid receptor
- drug-receptor complex acts in similar fashion to glucorticoid drug-receptor complex
- major effect of activation of aldosterone receptor:
- — increased expression of Na/K ATPase
- — increased expression of ENaC
Mineralocorticoids
Major effects?
natural mineralocorticoid = aldosterone
salt-retaining hormones.
Under control and regulated of CRH, ACTH, and renin-angiotensin system.
Help to control body’s water vol & electrolyte concntrations (Na & K)
- promote Na reabsorption from renal tubule
- promote K and H excretion.
tx for Addison’s disease?
Addison’s disease
- characterized by weakness, fatigue, weight loss, hypotension, hyperpigmentation, inability to maintain blood glucose levels fasting.
- tx: daily hydrocortisone (increase dose during stress) + fludrocortisone.
DO NOT adminster long-acting glucocorticopids or ones lacking salt-retaining effects.
tx that is associated c life-threatening shock, infxn, trauma?
tx: start immediately
Large amounts of parenteral hydrocortisone + correction of fluid & electrolyte abnlities.
Can adminster salt-retaining hormone once hydrocortisone levels are reduced (~5days)
describe Congenital Adrenal Hyperplasia…
defect in cortisol synthesis: CRH production by hypothalamus or corticotropin production by pituitary -> decreased steroid levels -> increase ACTH and hyperplasia in adrenal gland -> increased amounts of cortisol precursors that are diverted to the androgen pathway.
MOST common defect in adrenal hyperplasia = 21-hydroxylase activity
TX for Congenital Adrenal Hyperplasia?
glucocorticoid admin. leads to suppression of ACTH.
tx initially as an acute adrenal crisis
once stabilized: oral hydrocortisone or prednisone + fludrocortisone
Fetus can be protected in high-risk pregnancies by dexamethasone admin. to mother.
Tx for Cushing syndrome?
usually result of B/L adrenal hyperplasia secondary to ACTH-secreting pituitary adenoma.
Manifestations associated c chronic presence of excessive glucocorticoids
TX: surgical removal of tumor, irradiation of pituitary tumor, or resection of one of both adrenals.
pts must receive high doses of cortisol before and after surgery (dose has to be slowly decreased to prevent withdrawal)
TX for Aldosteronism?
primary aldosteronism usually results from excessive production by adrenal adenoma (can be from malignant tumor)
sx: result from renal loss of K (hypokalemia, alkalosis, & elevation of serum Na)
DX and TX:
spironolactone
describe using dexamethasone suppression test…
Cushing’s syndrome: dexamethasone suppresses cortisol release in individuals c pituitary-dependent Cushing’s syndrome (not released from adrenal tumors)
Depressive psychiatric states.
TX in Lung maturation in fetus?
IM dexamethasone.
fetal lung maturation is regulated by cortisol secretion. If premature delivery is expected, tx of the mother c large doses of glucocorticoids reduces incidence of respiratory distress syndrome.
Tx of non-adrenal disorders with synthetic corticosteroids?
- numerous immunological inflammatory conditions: asthma, collagen vascular disorders (RA), ocular diseases (uveitis, optic neuritis, exopthalmos)
- allergic rxns (contact dermatitis, urticaria)
- Hodgkin’s lymphoma (prednisone)
- cerebral edema (dexamethasone)
- chemotherapy-induced vomiting
- hematologic disorders (anemia, leukemia)
- organ transplants (prev of rejection)
- renal disorders (nephrotic syndrome)
- hypercalcemia
- mountain sickness
- inflammatory bowel disease
- idiopathic orthostatic hypotension (fludrocortisone)
what to consider when tx c corticosteroid?
- balance benefits c adverse effects.
- short-term use = few serious a.e
- try to tx c short-intermediate acting steroids as much as possible
- long-term used produces predictable toxicity based on their physiological effects.
corticosteroids a.e’s?
- metabolic effects (cushing’s syndrome manifestations)
- peptic ulcers
- clinical findings of certain disorders (particularly bacterial/mycotic infxns) may be masked by steroid use
- myopathy (part. c long-acting steroids)
- nausea, dizziness, weight loss
- CNS (euphoria, psychosis, depression)
- increased intraocular pressure (glaucoma)
- posterior subcapsular cataracts
- Na & fluid retention, loss of K
- Growth retardation (children)
- adrenal suppression
how to minimize toxicities in corticosteroid uses?
- local application
- use as low a dose as possible
- taper dose soon after achieving tx goal
- alternate-day therapy
- adm. pts c adrenal insufficiency ‘stress dose’ during serious illness or prior surgery
- prevent K loss c supplementation
- prev effects on bone by Ca and vitD supplements
corticosteroid contraindications?
- peptic ulcers
- heart disease or HTN c heart failure
- TB, VZV infxn
- psychoses
- diabetes
- osteoporosis
- glaucoma
corticosteroid withdrawal complications?
- abrupt c/drawal can be a serious problem (acute adrenal insufficiency syndrome can result)
- dose must be tapered according to individual
- monitor closely
Spironolactone
clinical applications?
- aldosteronism (dx and tx)
- hirsutism in women (acts as androgen antagonist)
- diuretic
spironolactone
Adverse effects?
- hyperkalemia
- cardiac arrythmia
- menstrual abnormalities
- gynecomastia
- sedation
- HA
- GI disturbances
- Skin rashes
aminoglutethimide
MOA?
blocks conversion of cholesterol to prenenolone -> reduces synthesis of all hormonally active steroids
aminoglutethimide
Clinical application?
adrenal cancer (+hydrocortisone or dexamethasone)
Ketoconazole
MOA?
potent & non-selective inhibitor or adrenal & gonadal steroid synthesis
ketoconazole
CLinical applications?
Cushing’s syndrome
Prostate cancer
Metyrapone
MOA?
Relatively selective inhibitor of steroid 11-hydroxylation (interferes c cortisol & corticosterone synthesis)
metyrapone
Clinical applications?
tests of adrenal function
tx of pregnant women c cushing’s
metyrapone
Adverse Effects?
salt & water retention
Hirsutism
transient dizziness
GI disturbances
