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Glucocorticoids Flashcards

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1
Q

LO
- what are GCs
- regulation of GC release
- GC synthesis, secretion, metabolism

A
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2
Q

Where are glucocorticoids synthesised?

A

adrenal cortex of the adrenal gland

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3
Q

many actions of GC are ‘permissive’
eg effects of catecholamines on vascular tone.
what does this mean?

A

dont directly initiate but allow to occur in presence of other factors

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4
Q

what system are GCs important in?

A

homeostasis
eg conditioning bodys response to stress

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5
Q

In simple terms, what are glucocorticoids? + role

A

Steroid hormones/ chemical messengers secreted into blood that travel around body to mediate essential metabolic function in target tissues
eg cortisol

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6
Q

why are GCs termed the nemesis of insulin?

A

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

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7
Q

What are some functions of glucocorticoids?

A
  • 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
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8
Q

What 2 areas of the brain control cortisol production?

A

Hypothalamus and the pituitary gland

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9
Q

During stress, how is glucose mobilisation increased?

A

gluconeogenesis is increased

amino acid generation

lipolysis is increased

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10
Q

During stress, what is the effect of glucocorticoids on circulation?

A

Increases blood flow and vascular tone (more blood flow)

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11
Q

what are the 3 main functions of GCs? and how does this occur?

A
  1. increase glucose mobilisation
    - augment gluconeogenesis
    - amino acid generation
    - increased lipolysis
  2. maintenance of circulation
    - vascular tone
    - salt and water balance
  3. immunomodulation
    - dampens/suppresses the immune system
    DURING STRESS
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12
Q

upon what stimuli/ condition does body release GCs to inc BP, suppress inflammation etc

A

stress.

similar to fight/flight

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13
Q

What was discovered about glucocorticoids at higher doses?

A

They are potently anti-inflammatory but this may not mean it is therapeutically very applicable

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14
Q

What are potential SEs of excess glucocorticoids

bones
vascular
general
skin
liver
muscle

A

bones
- osteoporosis
- increase fracture risk

vascular
- increase BP

general
- weight gain
- gluc intolerance

skin
- skin thinning
-striae

liver
- hepatic steatosis

muscle
- wasting and weakness

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15
Q

why do GCs have so many SEs?

A

because there are GC receptors on almost all tissues in the body so they have a wide range of effects

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16
Q

GCs used therpeutically to treat what type of diseases?

A

chronic inflammatory

… but long term use: SEs :(

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17
Q

What are steroid hormones?

A

Members of a family of hormones deriving from organic mol cholesterol

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18
Q

steroid hormones 6 examples?

A
  • glucocorticoids
  • mineralocorticoids
  • vitamin D
  • androgens
  • progesterone
  • oestrogen
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19
Q

why do GCs share some same properties to cholesterol?

A

they are derived form circ cholesterol. and similar struc

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20
Q

is cortisol lipo or hydrophilic?

A

lipophilic so it can cross the phospholipid membrane

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21
Q

what does cortisol bind to and to produce what effect?

A

bind distinct cytosolic receptors -> alters gene transcription to mediate effects

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22
Q

where is cortisol released from and how does it travel?

A

form adrenal gland,
in bloodstream

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23
Q

what is cortisol also known as ?

A

hydrocortisone

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24
Q

what 3 classifications of steroids?

A

1, corticoids
2. androgens
3. oestrogens

small structural modification can substantially alter specificity for steroid receptors

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25
what 2 determines GC synthesis and secretion?
1 diurnal rhythm (highest serum cortisol levels in the morning) 2. hypothalamus regulation
26
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
27
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
28
master regulator of GC release?
hypothalamus
29
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
30
what 3 things may -> ACTH release?
diurnal rhythm (visual clues like daylight) stress (physical trauma, emotional) inflammation (pro-inflamm cytokines)
31
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
32
what hormone is released by the pituitary gland?
adrenocorticotropic hormone (ACTH)
33
role of adrenocorticotropic hormone (ACTH)
regulate GC synthesis
34
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
35
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
36
What is the negative feedback loop for corticosteroids in stress? (p455!!!)
37
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
38
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
39
what is pulsatile release of GCs?
ACTH inc and so do cortisol levels at lunch, dinner, morning and breakfast
40
what do you get as reuslt of ACTH deficiency?
atrophy of adrenal gland. (shrink)
41
what do you get as reuslt of ACTH excess eg from pit tumour?
hypertrophy of adrenal gland (fat and bigger)
42
adrenal gland is very sensitive and repsonsive to what?
ACTH
43
what are the three layers of the adrenal gland cortex? for corticosteroid synthesis
zona glomerulosa zona fasciculata zona reticularis
44
zona glomerulosa is the outermost layer of renal cortex. what does it produce?
mineralocorticoids (permissive BP steroids - regulate salt + water retention)
45
zona fasciculata: middle layer of renal cortex. what is produced?
GCs
46
where are GCs produced specifically?
zona fasciculata
47
zona reticularis: innermost part of the cortex. what produced?
sex steroids: androgens
48
MOA p 462
49
synthesis p 463
50
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
51
what type of GCs (free/ bound) are bioavailable?
only free. tehrefore used
52
How are cortisol levels measured in clinical practice?
"total" is measured rather than "free"
53
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
54
why is the cortisol bound to CBG (image p465) essentially meaningless?
cant act on receptor as cant passively diffuse across membs
55
How are cortisone and cortisol different?
Cortisone is inactive Cortisol is active
56
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
57
what enz converts inert steroids (cortisone) -> active (cortisol)? liver adipose tissue lung macrophage vascular tissue CNS
11b-HSD1
58
what enz converts active steroids (cortisol) -> inert (cortisone)? kidney colon slaivary gland placenta mid-gestation fetus
11b-HSD2
59
GCs from adrenal gland undergo ___ ___ to form inactive form cortisone
renal inactivation (5a reductase)
60
GCs ___ ___ to form active form cortisol
hepatic reactivation (5a and 5b reductase)
61
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
62
how is GC release regulated? via...
HPA axis
63
Pt2 - therapeutic GCs - trans repression hypothesis revisited - future approaches
64
key action of GC function (repsonse to stress)?
immunomodulation - dampen immune reponse
65
GCs may be used in what studied disease?
RA
66
what do GCs allow immune cells to do under inflamm. stimuli?
invade into tissues
67
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)
68
GC action in anti-inflamm effect + immunosuppression
decrease: pain swelling stiffness physical disability
69
GCs dec pain and inflamm but even ibuprofen does that. why are these more useful?
also modify how the disease progresses = improved outcome
70
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
71
GCs suppress pro-inflamm pathways but what else?
TFs including AP1, NFkB, p38 MAPK
72
GCs suppress/ prevent cytokines that...
drive inflammation
73
GCs suppress/ prevent chemokines that...
recruit leukocytes
74
What are a range of inflammatory diseases that GCs are useful for?
RA Ankylosing Spondylitis Crohn's disease Asthma IBD Eczema Dermatitis
75
GCs immunosuppressives (transplantation) and are effective in what
some haematological malignancies causing leukocyte apoptosis
76
for what reason are GCs used in RA?
as bridging therapy, for control of inflammatory flares in many cases for long term maintenance therapy
77
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
78
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
79
main/most severe SE from GC excess?
cushings syndrome -> pit tumours that overproduced GCs
80
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
81
GCs lots of SEs and very limited as a therapeutic. how must drug course be stopped?
px tapered off as rapidly as possible
82
SE of GCs (not done) p 483
83
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
84
GCs bind to what?
GC receptor (NR3C1) GRA = classical GC receptor
85
the 3 domains on a GC receptor?
N-terminal transactivation domain (N-TD) DNA binding domain (DBD) Ligand binding domain (LBD)
86
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)
87
DNA binding domain (DBD) of GC receptor contains 2 Zn fingers to mediate dimerisation + target DNA sequences called...
GC responsive elements (GREs)
88
Ligand binding domain (LBD) of GC receptor contains transcriptional activation function 2 (AF2) + interacts with ____ and ___ ____
coregulatory factorsfor transactivation
89
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
90
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)
91
GR variants differ in their ability to..
reuglate gene expression
92
list some further post translational modifications (protein modulations)
phosphorylation acetylation sumolytation ubiquitylation
93
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
94
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
95
What is transpression? what does it prevent?
Monomeric! GC receptors hold 'tether' TFs -> prevents DNA binding + downstream gene signalling (-ve actions of GCs)
96
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)
97
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
98
do last couple slides

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