Glucocorticoids Flashcards
LO
- what are GCs
- regulation of GC release
- GC synthesis, secretion, metabolism
Where are glucocorticoids synthesised?
adrenal cortex of the adrenal gland
many actions of GC are ‘permissive’
eg effects of catecholamines on vascular tone.
what does this mean?
dont directly initiate but allow to occur in presence of other factors
what system are GCs important in?
homeostasis
eg conditioning bodys response to stress
In simple terms, what are glucocorticoids? + role
Steroid hormones/ chemical messengers secreted into blood that travel around body to mediate essential metabolic function in target tissues
eg cortisol
why are GCs termed the nemesis of insulin?
glucose/energy mobilising
FED: produce insulin, gluc taken up by muscle -> causes glyconeogenesis in liver to lower gluc.
GC do opposite
inc and inc serum gluc when fasted and hungry
What are some functions of glucocorticoids?
- can raise or lower mood
- stimulates gluconeogenesis in the llver
- slows digestion
- raises blood sugar
- raises BP
- reduces allergic reactions
- anti-inflammatory
- dampens pain sensation
What 2 areas of the brain control cortisol production?
Hypothalamus and the pituitary gland
During stress, how is glucose mobilisation increased?
gluconeogenesis is increased
amino acid generation
lipolysis is increased
During stress, what is the effect of glucocorticoids on circulation?
Increases blood flow and vascular tone (more blood flow)
what are the 3 main functions of GCs? and how does this occur?
- increase glucose mobilisation
- augment gluconeogenesis
- amino acid generation
- increased lipolysis - maintenance of circulation
- vascular tone
- salt and water balance - immunomodulation
- dampens/suppresses the immune system
DURING STRESS
upon what stimuli/ condition does body release GCs to inc BP, suppress inflammation etc
stress.
similar to fight/flight
What was discovered about glucocorticoids at higher doses?
They are potently anti-inflammatory but this may not mean it is therapeutically very applicable
What are potential SEs of excess glucocorticoids
bones
vascular
general
skin
liver
muscle
bones
- osteoporosis
- increase fracture risk
vascular
- increase BP
general
- weight gain
- gluc intolerance
skin
- skin thinning
-striae
liver
- hepatic steatosis
muscle
- wasting and weakness
why do GCs have so many SEs?
because there are GC receptors on almost all tissues in the body so they have a wide range of effects
GCs used therpeutically to treat what type of diseases?
chronic inflammatory
… but long term use: SEs :(
What are steroid hormones?
Members of a family of hormones deriving from organic mol cholesterol
steroid hormones 6 examples?
- glucocorticoids
- mineralocorticoids
- vitamin D
- androgens
- progesterone
- oestrogen
why do GCs share some same properties to cholesterol?
they are derived form circ cholesterol. and similar struc
is cortisol lipo or hydrophilic?
lipophilic so it can cross the phospholipid membrane
what does cortisol bind to and to produce what effect?
bind distinct cytosolic receptors -> alters gene transcription to mediate effects
where is cortisol released from and how does it travel?
form adrenal gland,
in bloodstream
what is cortisol also known as ?
hydrocortisone
what 3 classifications of steroids?
1, corticoids
2. androgens
3. oestrogens
small structural modification can substantially alter specificity for steroid receptors
what 2 determines GC synthesis and secretion?
1 diurnal rhythm (highest serum cortisol levels in the morning)
2. hypothalamus regulation
Under normal conditions, what do serum cortisol levels display?
Diurnal rhythm
(of the day/ occurring during daylight hrs)
- demonstrating a clear pattern of regulation and control over its release
why are worst complications of disease seen in morning?
GCs observe diurnal rhythm.
need high gluc when wake up.
worst comps in morning before GC kick in. then slowly increase and suppress inflammation
master regulator of GC release?
hypothalamus
hypothalamus = collection of brian ‘nuclei’ / cnetres which have important control functions. what does it control?
endocrine function via pit gland through secreted factors/ through direct neuronal projection
communicates w pit gland
what 3 things may -> ACTH release?
diurnal rhythm (visual clues like daylight)
stress (physical trauma, emotional)
inflammation (pro-inflamm cytokines)
How does stress cause the release of ACTH?
p453
Stress -> release of corticotropin-releasing hormone (CRH) from hypothalamus -> blood stream via arterial blood and reaches venous blood …… acth?
hypothalamus detects the stress/stimuli
then alerts pituitary gland
pituitary gland releases hormones to endocrine glands
what hormone is released by the pituitary gland?
adrenocorticotropic hormone (ACTH)
role of adrenocorticotropic hormone (ACTH)
regulate GC synthesis
How does ACTH regulate glucocorticoid synthesis?
Acutely stimulates cortisol release
Stimulates corticosteroid synthesis (and capacity)
CRH stimulates ACTH release
Negative feedback of cortisol on CRH and ACTH
production
ACTH: potent driver of adrenal output.
where does it produce corticosteroids, and catecholamine?
produces corticosteroids in the adrenal cortex
and catecholamines in the adrenal medulla
What is the negative feedback loop for corticosteroids in stress?
(p455!!!)
the 2 functions of GCs eg cortisol released form adrenal cortex as repsonse to release of CRH and ACTH form stress?
metabolism and immune function. suppress
problem with continued stress on HPA axis?
-ve feedback
GCs act on tissues that regulate their release so directly on anterior pit + hypothalamus to suppress CRH + ACTH release –> pulsatile release of GCs
what is pulsatile release of GCs?
ACTH inc and so do cortisol levels at lunch, dinner, morning and breakfast
what do you get as reuslt of ACTH deficiency?
atrophy of adrenal gland. (shrink)
what do you get as reuslt of ACTH excess eg from pit tumour?
hypertrophy of adrenal gland (fat and bigger)
adrenal gland is very sensitive and repsonsive to what?
ACTH
what are the three layers of the adrenal gland cortex?
for corticosteroid synthesis
zona glomerulosa
zona fasciculata
zona reticularis
zona glomerulosa is the outermost layer of renal cortex. what does it produce?
mineralocorticoids
(permissive BP steroids - regulate salt + water retention)
zona fasciculata: middle layer of renal cortex. what is produced?
GCs
where are GCs produced specifically?
zona fasciculata
zona reticularis: innermost part of the cortex. what produced?
sex steroids: androgens
MOA p 462
synthesis p 463
in circulation, are GCs mainly free/ bound to proteins?
give %
heavily bound to proteins
90% bound to corticosteroid-binding globulins
5% are bound to albumin
5% are free
what type of GCs (free/ bound) are bioavailable?
only free. tehrefore used
How are cortisol levels measured in clinical practice?
“total” is measured rather than “free”
how is CBG bound GCs made free and thus bioavailable, in bloodstream?
currently, bound and inert state. but… CBG levels dec with inflammation thus % free cortisol inc.
= inc GC signalling by inc bioavailable component
why is the cortisol bound to CBG (image p465) essentially meaningless?
cant act on receptor as cant passively diffuse across membs
How are cortisone and cortisol different?
Cortisone is inactive
Cortisol is active
How are cortisone and cortisol interconverted?
via enzymes 11b-HSD(1+2) where it is the active cortisol formed in the liver and the inactive cortisone formed in the kidneys
what enz converts inert steroids (cortisone) -> active (cortisol)?
liver adipose tissue lung macrophage vascular tissue CNS
11b-HSD1
what enz converts active steroids (cortisol) -> inert (cortisone)?
kidney colon slaivary gland placenta mid-gestation fetus
11b-HSD2
GCs from adrenal gland undergo ___ ___ to form inactive form cortisone
renal inactivation
(5a reductase)
GCs ___ ___ to form active form cortisol
hepatic reactivation
(5a and 5b reductase)
11b-HSD type 1 amplifies GCs at what sites?
sites of inflammation
== like body signposting where needs the GCs to act + that works well for many therap formulations
how is GC release regulated? via…
HPA axis
Pt2
- therapeutic GCs
- trans repression hypothesis revisited
- future approaches
key action of GC function (repsonse to stress)?
immunomodulation
- dampen immune reponse
GCs may be used in what studied disease?
RA
what do GCs allow immune cells to do under inflamm. stimuli?
invade into tissues
What is the effect of GCs on membrane permeability?
reduce permeability of membranes which reduces recruitment of leukocytes into tissues therefore reducing inflammation in tissues
(also reduce endothelial dysfunction)
GC action in anti-inflamm effect + immunosuppression
decrease:
pain
swelling
stiffness
physical disability
GCs dec pain and inflamm but even ibuprofen does that. why are these more useful?
also modify how the disease progresses = improved outcome
What are some pro-inflammatory molecules that GCs suppress?/ turn off
- cytokines - IL6, TNF alpha
- chemokines - IL8
- adhesion molecules - E selectin
- proteases - MMP1
- signalling enzymes - COX2 that produce PGs
GCs suppress pro-inflamm pathways but what else?
TFs including AP1, NFkB, p38 MAPK
GCs suppress/ prevent cytokines that…
drive inflammation
GCs suppress/ prevent chemokines that…
recruit leukocytes
What are a range of inflammatory diseases that GCs are useful for?
RA
Ankylosing Spondylitis
Crohn’s disease
Asthma
IBD
Eczema
Dermatitis
GCs immunosuppressives (transplantation) and are effective in what
some haematological malignancies causing leukocyte apoptosis
for what reason are GCs used in RA?
as bridging therapy, for control of inflammatory flares
in many cases for long term maintenance therapy
What immune cells do GCs act on?
… do slide 478 and 479
They suppress almost all major immune cells
- B cells - preventing immune cell production
- Dendritic cells - less antigen presentation
20mg cortisol equates to (Modifications):
- 5mg prednisolone
- 4mg methylprednisolone
- 0.75mg dexamethasone
why is this beneficial?
- More resistant to metabolism
- greater affinity for receptor = more potent GCs that don’t require high dose to be effective
main/most severe SE from GC excess?
cushings syndrome
-> pit tumours that overproduced GCs
What are symptoms of cushing’s syndrome caused by excess GCs?
- facial fullness
- central obesity
- muscle wasting!
- osteoporosis !
- skin thinning
- bruising
- immune suppression
- inc CVD RISK FACTORS
GCs lots of SEs and very limited as a therapeutic. how must drug course be stopped?
px tapered off as rapidly as possible
SE of GCs (not done) p 483
GC SEs still poorly understood, unpredictable, and many clearly related to the normal physiological functions of GCs.
what is the risk proportional to?
cumulative dose of GC
GCs bind to what?
GC receptor (NR3C1)
GRA = classical GC receptor
the 3 domains on a GC receptor?
N-terminal transactivation domain (N-TD)
DNA binding domain (DBD)
Ligand binding domain (LBD)
N-terminal transactivation domain (N-TD) of GC receptor contains transcriptional activation function 1 (AF1) + interacts with ____ and ___ ____
coregulators and transcription machinery
(to help facilitate receptor action)
DNA binding domain (DBD) of GC receptor contains 2 Zn fingers to mediate dimerisation + target DNA sequences called…
GC responsive elements (GREs)
Ligand binding domain (LBD) of GC receptor contains transcriptional activation function 2 (AF2) + interacts with ____ and ___ ____
coregulatory factorsfor transactivation
when cortisol enters through memb, it acts on GR and causes…
dissociation of various things like heat shock proteins HSPs (steering wheel lock that prevents receptor form doing anything)
these fall off
conformational change
what happens once HSPs removed from the GR?
monomer able to travel
binds to GRE (GC response element)
.. and get recruitment of those Coactivators –> gene transcription
(form homodimer. classic transactivation)
GR variants differ in their ability to..
reuglate gene expression
list some further post translational modifications (protein modulations)
phosphorylation
acetylation
sumolytation
ubiquitylation
homodimer mechanism. got GRa and GRb.
if 2x GRa bind to GRE (+GC to them) -> transactivation.
but what happens when GRb binds to GRE, next to GRa?
p489
blocks GRa.
heterodimer
more of an inhibiting one.
dominant blockade
What is transactivation?
Direct binding of GC receptor to specific DNA sequences aka GC response elements (GREs) to increase gene transcription
- this is when the GC receptor is a dimer
What is transpression?
what does it prevent?
Monomeric! GC receptors hold ‘tether’ TFs
-> prevents DNA binding + downstream gene signalling
(-ve actions of GCs)
What is the transrepression hypothesis and what is incorrect about this?
It was believed that transsrepression caused the anti-inflammatory effects and transactivation caused the side effects (in reality it is more complicated than this and they do overlap - dimer and monomer can both transrepression and transactivation)
What is a SEGRAM?
Selective glucocorticoid receptor agonist and modulator, a drug class that selectively activates GR to encourage transrepression to enable more anti-inflammatory effects and away from transactivation to reduce side effects
- this assumes the simplistic model of transrepression hypothesis which is not considered accurate
do last couple slides
