Corticosteroids DSA Flashcards
aldosterone
mineralocorticoid
cortisol
glucocorticoid
CRH
corticotropin releasing hormone
ACTH
adrenicorticotropic hormone
dexamethasone
semisynthetic glucocorticoid
aka decadron
hydrocortisone
semisynthetic glucocorticoid
methylprednisolone
semisynthetic glucocorticoid
aka medrol
prednisolone
semisynthetic glucocorticoid
prednisone
semisynthetic glucocorticoid
fludrocortisone
mineralocorticoid
zona glomerulosa
ANG II receptor
synthesis of aldosterone
zona fasciculata and reticularis
17 alpha hydroxylase and 11-beta hydroxylase
regulated by ACTH
POMC
precursor protein
forms MSH, ACTH, LPH, and beta endorphin
ACTH MOA
GPCR activity
activates synthesis of corticosteroids
mobilization of cholesterol
also - trophic (growth) effect on adrenal cortical cells
diurnal ACTH
peak ACTH early in the morning
cortisol negative feedback
inhibit release of CRH from hypothalamus
inhibit release of ACTH from pituitary
therapeutic glucocorticoids
high doses for long time
-supress HPA axis
stress stimuli
injury, hemorrhage, infection, surgery, cold, pain, fear, etc.
can override normal negative feedback
-leading to elevated levels of adrenocortical steroids
cushings syndrome
hypercortisol
addisons disease
primary adrenocortical insufficiency
T cell mediated autoimmune destruction, infection, infiltration, cancer, b/l TB of adrenals, hemorrhage
-in adrenal cortex
decreased
secondary adrenocortical insufficiency
decreased circulating ACTH levels
adrenal atrophy and low levels of glucocorticoids
may be due to prolonged glucocorticoid tx**
ACTH plasma concentration measure
immunoradiometric assay
adrenal cortex steroids
corticosteroids - gluco and mineralo - 21 carbons
androgens - 19 carbons
type I GR
glucocorticoid receptor - GR
type II GR
mineralocorticoid receptor - MR
steroid hormone receptor mechanisms
in cytoplasm of cells
complexed with heat shock proteins
-dissociate when bind steroid
activated receptor - to nucleus and bind GREs**
GRE site binding - either activates or inhibits transcription of specific genes
cortisol and aldosterone
both bind MR with equal affinity
mineralocorticoid specificity
tissue specific localization of receptor
enzymatic protection against glucocorticoid excess
-11-beta hydroxysteroid DH inactivates cortisol to cortisone
differential binding of GR and MR to nuclear transcription factors
11-beta hydroxysteroid DH
inactivates cortisol to cortisone
effect of corticosteroids
decrease peripheral glucose uptake (anti-insulin)
stimulate protein breakdown and lipolysis
stimulate gluconeogenesis in liver
net effect - elevated blood glucose**
also - redistribution of body fat - moon facies and buffalo hump
aldosterone effect
enhance reabsorption of Na in kidney distal tubules and collecting ducts
increased K and H secretion in urine
excess aldosterone
elevated Na expansion of ECF volume, hyponatremia, hyperkalemia, acidosis
glucocorticoids and immunosuppression
can prevent or suppress inflammation
inhibit production and release of cytokines that normally stimulate proliferation and function of B and T cells
glucocorticoids - suppress IFN, GM-CSF, ILs, TNF, prostaglandins, and leukotrienes
IL-1
inflammatory cytokine
- stimulate release of CRH and ACTH
- increase glucocorticoids
- which in response inhibit immune/inflammatory response further
steroid absorption
lipophilic
diffuse across cell membranes
wide volume of distribution
steroid transport
90% cortisol bound to protein
albumin and corticosteroid binding globulin (CBG
transcortin
CBG
-corticosteroid binding globulin
higher steroid levels
binding capacity of CBG and albumin is overwhelmed - much more free state and is more active
biological half life
used for steroid
because plasma drug concentration does not correlate with time course of bio effects
anti-inflammatory effects
mediated by same receptor as metabolic effects
-none of glucocorticoid derivatives have selective anti-inflammatory activity without also affecting carb, protein, fat metabolism
compounds that are classified as glucocorticoids
also have modest but significant mineralocorticoid activity
long acting glucocorticoids
betamethasone
dexamethasone
short acting glucocorticoids
cortisol and cortisone
intermediate acting glucocorticoids
prednisone
prednisolone
methylprednisolone
triamcinolone
mineralocortoids
corticosterone
fludrocortisone
beclomethasone dipropionate
inhalation for asthma or COPD
toxicity of adrenocortical steroids
1 - withdrawal effects
2- continued use of high dose
withdrawal of adrenocorticosteroids
flare up of underlying disease
acute adrenal insufficiency**
consider this in any patient with high dose over 2 weeks
continued use of high dose corticosteroids
suppression of HPA axis HTN and hypoerglycemia increased infections peptic ulcers myopathy behavioral changes cataracts osteoporosis osteonecrosis growth retardation
unharmful steroid therapy
single dose or short course (1 week)
steroid therapy for life-threatening disease
initial dose should be large - aimed at achieving rapid control of crisis
no benefit observed - dose doubled or tripled
steroid therapy regimens
alternate day - to diminish HPA suppression
pulse therapy - for high dose glucocorticoids
glucocorticoid therapy
palliative
because underlying cause of disease remains
glucocorticoids inhibit
both early inflammatory processes and later manifestations
lipocortins
induced by glucocorticoids
-inhibit phospholipase A2 activity and suppress release of lipid mediators from cells
rheumatoid arthritis
main cytokine - TNF-alpha
tx - glucocorticoids
osteoarthritis tx
intraarticular joint injections
ICS therapy
inhaled corticosteroids
-for tx of bronchial asthma
for prophylaxis
severe asthma attack tx
aggressive treatment with parenteral glucocorticoids
IV methylprednisolone
-followed by oral prednisone
dose tapered gradually
tx allergic disease
immediate epinephrine tx
glucocorticoids to suppress delayed inflammation
tx of ocular diseases
topical glucorticoids
may exacerbate glaucoma - increased intraocular eye pressure
may also mask ocular infection - CI in herpes simplex infections
CI for glucocorticoids in eye disease
herpes simplex infection
mechanical laceration/abrasion - impaired wound healing
skin disease tx
topical glucocorticoids
-hydrocortisone 1%
tx of ulcerative colitis and crohns
oral prednisone and enteric coated budesonide
cerebral edema tx
corticoisteroids useful with parasites and neoplasms
mitotane
o,p - DDD
-similar to insecticides
selective toxicity for adrenal cortex
used only to treat inoperable adrenal tumors
RU-486
progesterone receptor antagonist
aka mifepristone
use to terminate early pregnancy
inoperable patients with ectopic ACTH secretion or adrenal cracinoma failed to respond to other tx options
spironolactone
K-sparing diuretic
-competes for mineraolcorticoid receptor
aldosterone antagonist
effective tx for hyperaldosteronism
