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Glucocorticoids
Glucocorticoids
Category/Class
Short-acting
Glucocorticoids
Prototype
Cortisol (hydrocortisone)
Mechanism of Action
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Table 2 – pg 10
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11 keto group converted to
11B-hydroxyl in liver
(rapid) to become
biologically active cortisol
Repress cytokine
transcription via interact
with negative GFE’s.
Inhibit transcription of
cytokine receptors and
cytokine induced TF’s
(like AP1 and NF-kB)
Stimulate synthesis of
lipocortin 1 to inhibit
PLA2 to inhibit LTRs,
PGs and PAF.
Inhibit cytokine induced
COX2 and NO synthase
(inducible genes)
Regulate expession of
CAMS on endothelium
and alter vascular
permeability to decrease
migration of inflammatory
cells to sites of injury.
Toxicities/Side Effects
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Intermediate-acting
Glucocorticoids
Long-acting
Glucocorticoids
Prednisone
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Dexamethasone
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11 keto group converted to
11B-hydroxyl in liver
(rapid) to become
biologically active
prednisolone.
As above
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inhibit fibroblasts -> thin
skin & stria, poor wound
healing
decrease bone cell
proliferation, RNA,
protein, collagen, and
hylauronate synthesis,
and stimulate bone
resorbing cells 
osteolysis
Reduce Ca absorption &
increase
excretionstimulate
PTHbone resorption
Decrease growth due to
above and lower GH
Increase FFA & TGs,
mobilize fat stores,
hypergycemia,
hyperlipidemia
Renal – increase
COincrease
GFRincrease Na and
water excretion
GI – gastritic & ulcers
due to low PGs
CNS – euphoria,
irritability, depression,
memory and conc
impariment
Supress HPA axis – if
over 10 days = bad.
Drugs or disease that
affect liver function
(liver disease,
hyper/hypo thryroid)
increase toxicity.
Treatment
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Other / Pharmacodynamics/kinetics
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plamsa ½ life 60-90
min. Biological ½ life
8-12 hrs. (biological
longer since they go
into cells and activate
transcription)
Minimize toxicities by
giving dose 6-9 am
when body does so to
decrease ACTH no
more than the body
would anyway – also
give every other day.
(NOT in the case of
acute asthma though)
Minimize toxicities by
giving only at site not
systemic (inhaled for
asthma, local for
topical skin probs),
weigh risks.
Metabolism by liver
reductio to 17
hydroxyconticosteriod, so
less than 1% unchanged in
urine (can measure
17Hcortisol to find body
levels of cortisol)
Glucocorticoids
2
Glucocorticoids: used in rheumatoid arthritis, severe allegic reaction bronchial asthma, dermatoses, suppression of graft rejection, leukemia.
Receptors in virtually all tissues. Only relieve symptoms and do not affect the underlying disease. CRHACTH  stimulates cAMP formation
steroidogenesis from cholesterolPregnenoloneprogesteroneblahblahblahCortisol. ACTH adrenal gland Glomerulose (aldosterone)
Fasiculata (glucocorticoids) Reticularis (glucocorticoids and androgens) Medulla (epinephrine). Circadian ACTH (lowest in evening and peak 6
am). ACTH responds to stress (parturition, cold, exercise, starvation, surgery, illness). Cortisol does feedback inhibition to H-P-A axis (so down
regulated if on above drugs). Aldosterone can bind cortisol receptors and visa versa but aldosterone is in way lots lower conc so not big effects and it
also has an enzyme to inactive cortisol around the kidney to maintain aldosterones power! In above drugs more selective for cortisol receptor so
greater anti-inflamatory activity, pituitary suppression, and duration of action, with less Na retention.
Cortisol binds CBG called transcortin to transport it in blood, less than 4% of cortisol is free and thus biologically active. But tissues take up free
new CBG releases some cortisoladrenal makes more…(sythtetics bind CBG less so more taken up) Glucocorticoid receptors are found in the
cytoplasm bound to heat shock protiens (that take care of them, get them where they need to be, and don’t let them bind any DNA). When Cortisol
comes into the cell it binds the receptors so the heat shock protein falls off, then the cortisol and its receptor dimerize with a buddy in the same
situiation. Next the dimer (so 2 receptors with cortisol bound) go into the nucleus and bind DNA glucocorticoid response elements (GRE) to: 1)
sterically hinder TF binding 2)sequester TF’s like AP-1 (jun and fos TF’s) so they can’t do their job 3) stimulate proteins like IKB that will inhibit TF
activation like NF-KB. (NF-KB is stimulated by cytokines to cause lots of inflamation – so find a selective inhibitor and you will be rich (antiinflamatory with no cortisol side effects!)
WHAT THEY DO (overall conserve glucose): 1)increase hepatic gluconeogenesis (stimulate enzymes) 2) Increase hepatic responsiveness to the
glucogenic hormones glucagon and catecholamines 3) Enhance hepatic glycogen storage by stimulating hepatic glycogen synthetase (insulin
dependant) 4)Stimulate breakdown of protein and FA 5)Decrease glucose uptake 6) Increase Lipocortin to shut down PGA2 for LTR & PG synthesis