glucocorticoids Flashcards
corticotrophins make
ACTH
lactotrophs make
prolactin PRL
somatotropin make
GH
tyrotrophs make
TSH
gonadotrophhs make
FSH/LH
HPA axis
regulates synthesis and secretion of adrenal corticosteroids
hypothalamus releases CRF in a pulsatile manner
CRF acts on corticotrophins in the anterior lobe pituitary making it release ACTH
ACTH
- acts on adrenal glands to stimulate glucocorticoids
- has a trophic effects on the adrenal cortex (atrophy of the adrenal cortex without sufficient ACTH)
- negative feedback effect on the hypothalamus
glucocorticoids have a negative feedback loop to the HT and downstream effects on the body
3 effects of ACTH
- acts on adrenal glands to stimulate glucocorticoids
- has a trophic effects on the adrenal cortex (atrophy of the adrenal cortex without sufficient ACTH)
- negative feedback effect on the hypothalamus
THE HPA axis is responsible for
regulating synthesis and secretion og adrenal corticosteroids
what does the hypothalamus do in the HPA axis
releases CRF in a pulsatile manner
CRF stimulated anterior lobe pituitary to produce ACTH
3 zones adrenal cortex
- zona glomerulosa
- zona fasciculata
- zona reticularis
zona glomerulosa makes
mineralocorticoids
zona fascicula makes
glucocorticoids
zona reticularis makes
sex hormones
glucocorticoids
cortisol/hydrocortisone - main ones
corticosterone
secreted in a circadian/diural rhythm - peak at 9am and troph at midnight
mineralocorticoids
aldosterone
adrenal steroidogenesis
synthesised from cholesterol
side chain cleavage (this is the rate limiting step)
AACTH (GC) and angiotensin 2 (MC) positively regulate conversion of cholesterol to pregnenolone
cortex zone - expression of spefici steroidogenic enzymes, required for synthesis of aldosterone of GCs or sex hormones
adrenal steroidogenesis
synthesised from cholesterol
side chain cleavage (this is the rate limiting step)
AACTH (GC) and angiotensin 2 (MC) positively regulate conversion of cholesterol to pregnenolone
cortex zone - expression of spefici steroidogenic enzymes, required for synthesis of aldosterone of GCs or sex hormones
cortex zone -
cortex zone - expression of spefici steroidogenic enzymes, required for synthesis of aldosterone of GCs or sex hormones
ACTH and angiotensin 2
increase conversion of cholesterol to pregnenolone
increases side chain cleavage
aminoglutethimide
reduced side chain cleavage
stops production of steroids
aaldosterone synthesis is increased by
angiotensin 2
metabolic effects of glucocorticoids
- CHO metabolism
- protein catabolism
- adipose tissue distribution
antiinflammatory/immunosuppressive effects endogenously
resistance to stress
metabolic effects of mineralocorticoids
water and electrolyte homeostasis
- Na retention
- H2O retention
- K excretion
- H excretion
all in order to maintain blood pressure
glucocorticoids are bound to
cortisol binding globulins CBG
when they reach the plasma membrane they can cross without needing a receptor
glucocorticoid receptor is in the cytoplasm (not the plasma membrane) (GR) binds hydrocortisone and dimerises and translocates to the nucleus
binds GREs (glucocorticoid response elements) to alter transcription of target genes
glucocorticoid receptor
ligand activated transcription factor
ligand is hydrocortisol
glucocorticoid receptor
ligand activated transcription factor
ligand is hydrocortisone
when glucocorticoid receptor Is bound
it dimerises and binds glucocorticoid response elements which alter transcription of target genes
glucocorticoids receptor is located in
the cytoplasm, not plasma membrane
transcriptional activation by glucocorticoid receptor
most glucocorticoid metabolic effects
represses pro inflammatory genes
transcriptional tethering - tether partner transcription factors to alter gene transcription
GR and MR
highly homologous receptors
aldosterone is specific for MR does not activate GR)
cortisol binds both, binds MR with equal affinity as aldosterone
cortisol circulates at much higher levels than aldosterone
why do MR expressing tissues response to aldosterone and not cortisol
because they express
11beta hydroxysteroid dehydrogenase
converts cortisol to cortisone
cortisone is inactive and doesn’t activate MR
why do MR expressing tissues response to aldosterone and not cortisol
because they express
11beta hydroxysteroid dehydrogenase
converts cortisol to cortisone
cortisone is inactive and doesn’t activate MR
Addison’s disease
primary adrenal insufficiency
usually autoimmune in origin in western societies causing bilateral destruction of the adrenal cortex
in third world countries it is more likely to be infection (mostly TB)
diagnosis effects mineralocorticoid producing, glucocorticoids producing and sex hormone producing layers (all three layers)
clinical presentation of Addisons disease
- fatigue and weakness
nausea and vomiting, diarrhoea, salt craving
hypoglycaemia and low blood pressure
hyperpigmentation due to increase ACTH - GC deficiency affects CHO metabolism causing decrease in glucose (hypoglycaemia)
- MC deficiency affects blood pressure, low blood pressure, hyponatraemic, hyperkalaemic
- impaired stress tolerance (addisonian/adrenal crisis)
secondary deficiency of corticosteroids causes
- usually exogenous steroid use - HPA axis suppression due to low ACTH
- hypopituitarism
- postpartum pituitary necrosis - Sheehan’s syndrome
deficiencies in Addison’s disease
GC deficiency affects CHO metabolism causing decrease in glucose (hypoglycaemia)
- MC deficiency affects blood pressure, low blood pressure, hyponatraemic, hyperkalaemic
- addisonian/adrenal crisis (impaired stress tolerance)
secondary deficiency of corticosteroids
MC secretion is preserved
Na/K balance is normal
ACTH levels are low/normal - no hyperpigmentation
rapid ACTH test will differentiate from primary disease
adrenal crisis in 1st and 2nd degree
endocrine emergency
precipitated by any stress that increases adrenal demands
treated with IV/IM hydrocortisone/cortisol
glucocorticoid excess causes
Cushing’s syndrome, which can be caused by
- cuchings disease increase in ACTH produced by a corticotrophin adenoma in the pituitary
- increase in ACTH from ectopic source
- increase in GCs from adrenal adenoma/carcinoma
- increase in GCs from prescribed GCs = iatrogenic
effects of glucocorticoids
CHO metabolism - hyperglycaemia, T2DM
protein - catabolism, protein breakdown, thin skin, purple stretch marks, fragile blood vessels causing bruising, fractures from osteoporosis,
fat - redistribution, face, back and abdomen
anti inflammatory/immunosuppression - infections
CNS - mood changes, cognitive impairment, psychosis
common signs of sucking’s syndrome
catabolic - thin skin and striae, bruising, muscle wasting (thin arms and legs)
fat redistribution - moon faces, buffalo hump, abdomen
clinical uses of GCs and MCs as replacement therapies
physiological doses - replacement therapy
adrenocortical insufficiency - IV replacement in ED
once stabilised, replaced with physiological levels
hydrocortisone to replicate diurnal rhythm (double dose in the morning)
fludrocortisone once daily (synthetic MC)
in cases of stress - surgery, infection, major trauma - double hydrocortisone dose
clinical uses of GC as anti-inflammatory
supra physiological doses - GCs only
anti inflammatory action of GC
inhibit inflammation
- early during - heat, pain and swelling
- late - during wound healing and repair
target all types of inflammation
- infections, chemical stimuli, physical stimuli
- inappropriate immune responses - hypersensitivity and autoimmune disease
prophylactically used to prevent allograft rejection
neoplasia - combination chemotherapy and cerebral oedema
effects of GCs
- anti inflammatory/immunosupressive
- metabolic effects - CHO metabolism, protein catabolism, adipose tissue distribution
to isolate anti inflammatory effects of GCs
keep anti inflammatory effects but avoid metabolic effects
some synthetic corticosteroids have increased effect on GR and reduced effect on MR
some last longer
bioavailability altered to they can be topically administered
cannot completely seperate anti inflammatory from metabolic effects
hydrocortisone
equally effective on GC
more effective on MC but inactivated
short half life, short duration of action
prednisolone
oral glucocorticoid in wide use clinically
4x more potent than hydrocortisone
lower affinity for MC
intermediate half life
triamcinolone
topical
relative GC receptor potency 5x as potent
doesn’t activate MC receptor
intermediate half life
dexamethosone
far more potent on GC receptor
doesn’t activate MC
long half life
fludrocortisone
most potent on MC
intermediate half life
pharmacokinetics of GC
oral, IM, IV, inhaled, topical, intra-articular, rectal
where possible use locally due to side effects
good oral availability
GC injectables
succinate/PO4 esters rapidly absorbed Solu-medrone
validate/acetate esters slowly absorbed Depo-medrone
topical/local - huge variety but all have systemic effects
distribution, metabolism and excretion of GCs
lipid soluble - need to be carried by a carrier protein (some albumin)
rapidly distributed to cells through blood stream
plasma half life is short, biological half is long
sulphated and glucuronated in the liver and excreted into the bile and urine
iatrogenic Cushing’s syndrome
common side effect of systemic GCs
universal with high dose, long term GC use
patients looks cushingoid
if children are given GC
growth suppression if >6 months
suppression of HPA axis in GC use
adrenal atrophy may occur
abrupt withdrawal causes addisionian crisis
must slowly withdraw high dose steroids
minimising risk of GC use
- use GC sparing agents
- Lowest effectje dose for the shortest time
time dose effectively - give in the morning
- alternative days with double dose
steroid card/bracelet
all patients on steroids should be wearing a bracelet carrying steroid card
topical GC
vast range available
applicable for psoriasis, excess, dermatitis, allergic conjunctivitis
inhaled GC
used for asthma and allergic rhinitis
metered dose inhalers e.g. fluticasone
intra-lesional GC
long acting depot injection
intra/peri articular in RA for bursitis, tenditis etc
rectal GC
hydrocortisone ointment/suppositories, prednisolone enema/suppositories
inflammatory bowel disease (UC, chrons)
GC with vaccines and attenuated live virus immunisation interaction
failure to develop immunity
systemic infection for live virus vaccines
insulin and oral hypoglycaemia agents with GC interaction
hyperglycaemia
antacids and GC interaction
Impaired GC absorption
carbamazepine, phenytoin, barbiturates with GC interaction
GC metabolism induction may occur
dose may need to be increased
digoxin and GC interaction
can cause arrhythmias if there is hypokalaemia
