2/13 Adrenal Pharm - Pilch Flashcards
HPA axis
hypothal: CRH → ant pituitary: ACTH → adrenal cortex: aldosterone, cortisol/hydrocortisone, androgenic precursors
pharma of adrenal steroids
glucocorticoids target glucocorticoid receptors
mineralocorticoids target mineralocorticoid receptors
steroid-bound receptors dimerize → dimers target GREs (glucocorticoid receptor elements) → activate gene transcription
- see pleiotropic effects stemming from impact on array of genes’ expression
comparison of natural/synthetic adrenal steroids
all orally bioavailable
most have some GC and some MC effects (see chart)
glucocorticoids
- short acting
- cortisol/hydrocortisone, cortisone
- intermed acting
- prednisone
- prednisolone
- long acting
- dexamethasone (completely GC selective)
mineralocorticoids
- intermed acting
- fludrocortisone (synth aldosterone)
glucocorticoids
indications
disorders with infl or immune response as part of major manifestation
- allergic rxn
- asthma
- IBD (ulcertaive colitis, Crohn’s Disease)
- lupus erythematosus
- temporal arteritis
- arthritis
- bursitis
- cerebral edema
- dermatitis
- sarcoidosis
glucocorticoid toxicity
3x impact on intermed metabolism aka “Cushingoid effects”
others
usually after 2+ weeks of tx
- glucose metabolism : hyperglycemia → incr need for insulin, onset of diabetes
- fat metabolism : central obesity, fat redistribution to selected anatomical sites (face, trunk w sparing of limbs)
- protein metabolism : catabolic effects → muscle wasting, osteoporosis, thinning and purple striation of skin (bruising), poor wound healing, reduced linear growth in kids
other complications:
- androgenic effects: hirsutism, sweating, acne
- CNS effects: depression, anxiety, hypomania
- ocular effects: incr intraocular pressure, glaucoma, cataracts
- GI effects: peptic ulcers and consequences
- immunosuppressive effects: opportunistic bacterial and fungal inf
- sleep effects: insomnia
- hypertensive effects (GC with some degree of MC activity, ex. cortisol)
primary adrenocortical insufficiency
aka
sx
tx
Addison’s Disease
- weakness, fatigue, weight loss
- hypotension
- inability to maintain blood glucose level (fasting), hyperpig
tx: REPLACEMENT
- hydrocortisone (daily oral doses, incr amt during stress periods)
- supplelented with mineralocorticoid
acute adrenal insufficiency
what is it?
tx
potentially life-threatening, requires immediate tx
- large dose parenteral hydrocortisone
- correction of fluid electrolytes
- tx of underlying cont (ex. inf, trauma, hemorrhage)
congenital adrenal hyperplasia
characterized by specific defects in cortisol biosynthesis
- impaired cortisol prod → incr ACTH release (due to lack of neg feedback inhibition)
- adrenal gland becomes hyperplastic → other hormonally active steroids proximal to the enzyme block are produced in excess
- sx will vary dependingon which enzymes is deficient
90% result from mutations in 21beta-hydroxylase (CYP21)
- results in production of lots of precursor which is shunted toward the androgen pathway → virilization, other androgenic effects
CAH tx
if not treated in utero with glucocorticoids…
- female infants born with virilized ext genitalia
- males are normal at birth, but can devp chars of precocious puberty
tx:
- if preg has high risk of CAH? protect fetus via dexamethasone to MOM
-
pt with classical CAH? replacement tx w hydrocortisone or sub
- adjust dosage to allow nl growth/bone maturation
- alt-day tx w prednisone → ACTH suppression without growth inhibition
- fludrocortisone w salt to maintain nl bp, pl renin activity, eletrolytes
Cushing’s Syndrome
(hypercortisolism)
signs/sx
causes
signs/sx:
- moon facies, central obesity
- osteoporosis, muscle wasting/thinning, poor wound healing
- DM, HTN (bc cortisol has some MC activity!)
- violaceous striae, easy bruising
- mental disorders
causes
- most common cause is IATROGENIC from chronic use of exogenous corticosteroids
- also caused by endog overproduction by adrenal glands
- usually pituitary adenoma secreting ACTH (Cushing’s Disease) → bilat adrenal hyperplasia
- also adrenal gland tumor secreting cortisol or ectopic production of ACTH by other tumors
tx of exogenous Cushing’s Syndrome
what is “exogenous” CS
tx
exogenous CS = NOT due to cancer
need to reduce corticosteroid dosage gradually → avoid acute withdrawal sx
- 2-12mo for HPA axis to fx normally, addtl 6-9mo for cortisol level to normalize
- withdrawal sx? anorexia/wt loss, n/v, lethargy, headache, fever, jt/muscle pain, postural hypotension
tx of endogenous CS/disease
- first line:* surgical removal of tumor making ACTH or cortisol
- inoperable/recurrent/persistent disease?* radiotx, bilateral adrenalectomy, pharm
-
adrenal blockers
- adrenal steroid biosynth inhibitors
- KETOCONAZOLE
- METYRAPONE
- glucocorticoid receptor antagonist
- MIFEPRISTONE
- adrenal steroid biosynth inhibitors
-
ACTH antagonists
- DA receptor agonist
- CABERGOLINE
- SST receptor agonist
- PASIREOTIDE
- DA receptor agonist
goal: normalize cortisol production; might require combo of both groups of drugs
aldosteronism
causes
sx
tx
- Conn’s Syndrome: adrenal adenoma → excessive production of aldosterone (2/3 cases)
- other: abnl secretion by hyperplastic adrenal gland or malignant tumor
signs/sx
- HTN, weakness, tetany, hypoK, alkalosis
tx: unilat adrenalectomy, pharma
-
mineralocorticoid receptor antagonists → normalize bp, K levels
- SPIRONOLACTONE
- can also antagonize androgen and progesterone receptors
- side effects: gynecomastia, decr libido, impotence, menstrual irreg
- EPLERENONE
- specific for MC receptors → no sex hormone side effects!
- SPIRONOLACTONE
pheochromocytoma
causes
sx
tx
neuroendocrine tumor of adrenal medulla derived from chromaffin cells → excess secretion of catecholamines (esp NE, E)
- adrenal in nature BUT DOESNT INVOLVE STEROIDS
- HTN, tachycardia, palpitations (&diaphoresis, headache, paroxysmal pattern)
tx: SURGICAL RESECTION, but requires prep tx with drugs to stabilize bp/pulse bc physical stim can lead to release of stored catecholamines
-
alpha-adrenoreceptor antagonists (alpha blockers) for pre-op mgmt
- PHENOXYBENZAMINE
- PRAZOSIN
- TERAZOSIN
- DOXAZOSIN
-
beta-adrenoreceptor antagonists (beta blockers) for pre-op mgmt AFTER ALPHA-BLOCKERS INITIATED
- ATENOLOL
- METORPOLOL
- PROPRANOLOL
-
catecholamine biosynth inhibitor (Tyr hydroxylase)
- METYROSINE (mgmt of pheo HTN)
