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Health 31 > Glucocorticoids > Flashcards

Glucocorticoids Flashcards

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
Q

what 2 determines GC synthesis and secretion?

A

1 diurnal rhythm (highest serum cortisol levels in the morning)
2. hypothalamus regulation

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26
Q

Under normal conditions, what do serum cortisol levels display?

A

Diurnal rhythm
(of the day/ occurring during daylight hrs)

  • demonstrating a clear pattern of regulation and control over its release
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27
Q

why are worst complications of disease seen in morning?

A

GCs observe diurnal rhythm.
need high gluc when wake up.
worst comps in morning before GC kick in. then slowly increase and suppress inflammation

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28
Q

master regulator of GC release?

A

hypothalamus

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29
Q

hypothalamus = collection of brian ‘nuclei’ / cnetres which have important control functions. what does it control?

A

endocrine function via pit gland through secreted factors/ through direct neuronal projection

communicates w pit gland

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30
Q

what 3 things may -> ACTH release?

A

diurnal rhythm (visual clues like daylight)
stress (physical trauma, emotional)
inflammation (pro-inflamm cytokines)

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31
Q

How does stress cause the release of ACTH?
p453

A

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

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32
Q

what hormone is released by the pituitary gland?

A

adrenocorticotropic hormone (ACTH)

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33
Q

role of adrenocorticotropic hormone (ACTH)

A

regulate GC synthesis

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34
Q

How does ACTH regulate glucocorticoid synthesis?

A

Acutely stimulates cortisol release
Stimulates corticosteroid synthesis (and capacity)
CRH stimulates ACTH release
Negative feedback of cortisol on CRH and ACTH
production

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35
Q

ACTH: potent driver of adrenal output.
where does it produce corticosteroids, and catecholamine?

A

produces corticosteroids in the adrenal cortex

and catecholamines in the adrenal medulla

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36
Q

What is the negative feedback loop for corticosteroids in stress?

(p455!!!)

A
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37
Q

the 2 functions of GCs eg cortisol released form adrenal cortex as repsonse to release of CRH and ACTH form stress?

A

metabolism and immune function. suppress

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38
Q

problem with continued stress on HPA axis?

A

-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

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39
Q

what is pulsatile release of GCs?

A

ACTH inc and so do cortisol levels at lunch, dinner, morning and breakfast

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40
Q

what do you get as reuslt of ACTH deficiency?

A

atrophy of adrenal gland. (shrink)

41
Q

what do you get as reuslt of ACTH excess eg from pit tumour?

A

hypertrophy of adrenal gland (fat and bigger)

42
Q

adrenal gland is very sensitive and repsonsive to what?

A

ACTH

43
Q

what are the three layers of the adrenal gland cortex?
for corticosteroid synthesis

A

zona glomerulosa
zona fasciculata
zona reticularis

44
Q

zona glomerulosa is the outermost layer of renal cortex. what does it produce?

A

mineralocorticoids
(permissive BP steroids - regulate salt + water retention)

45
Q

zona fasciculata: middle layer of renal cortex. what is produced?

A

GCs

46
Q

where are GCs produced specifically?

A

zona fasciculata

47
Q

zona reticularis: innermost part of the cortex. what produced?

A

sex steroids: androgens

48
Q

MOA p 462

A
49
Q

synthesis p 463

A
50
Q

in circulation, are GCs mainly free/ bound to proteins?
give %

A

heavily bound to proteins

90% bound to corticosteroid-binding globulins

5% are bound to albumin

5% are free

51
Q

what type of GCs (free/ bound) are bioavailable?

A

only free. tehrefore used

52
Q

How are cortisol levels measured in clinical practice?

A

“total” is measured rather than “free”

53
Q

how is CBG bound GCs made free and thus bioavailable, in bloodstream?

A

currently, bound and inert state. but… CBG levels dec with inflammation thus % free cortisol inc.
= inc GC signalling by inc bioavailable component

54
Q

why is the cortisol bound to CBG (image p465) essentially meaningless?

A

cant act on receptor as cant passively diffuse across membs

55
Q

How are cortisone and cortisol different?

A

Cortisone is inactive

Cortisol is active

56
Q

How are cortisone and cortisol interconverted?

A

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
Q

what enz converts inert steroids (cortisone) -> active (cortisol)?
liver adipose tissue lung macrophage vascular tissue CNS

A

11b-HSD1

58
Q

what enz converts active steroids (cortisol) -> inert (cortisone)?
kidney colon slaivary gland placenta mid-gestation fetus

A

11b-HSD2

59
Q

GCs from adrenal gland undergo ___ ___ to form inactive form cortisone

A

renal inactivation
(5a reductase)

60
Q

GCs ___ ___ to form active form cortisol

A

hepatic reactivation
(5a and 5b reductase)

61
Q

11b-HSD type 1 amplifies GCs at what sites?

A

sites of inflammation
== like body signposting where needs the GCs to act + that works well for many therap formulations

62
Q

how is GC release regulated? via…

A

HPA axis

63
Q

Pt2
- therapeutic GCs
- trans repression hypothesis revisited
- future approaches

A
64
Q

key action of GC function (repsonse to stress)?

A

immunomodulation
- dampen immune reponse

65
Q

GCs may be used in what studied disease?

A

RA

66
Q

what do GCs allow immune cells to do under inflamm. stimuli?

A

invade into tissues

67
Q

What is the effect of GCs on membrane permeability?

A

reduce permeability of membranes which reduces recruitment of leukocytes into tissues therefore reducing inflammation in tissues

(also reduce endothelial dysfunction)

68
Q

GC action in anti-inflamm effect + immunosuppression

A

decrease:
pain
swelling
stiffness
physical disability

69
Q

GCs dec pain and inflamm but even ibuprofen does that. why are these more useful?

A

also modify how the disease progresses = improved outcome

70
Q

What are some pro-inflammatory molecules that GCs suppress?/ turn off

A
  • cytokines - IL6, TNF alpha
  • chemokines - IL8
  • adhesion molecules - E selectin
  • proteases - MMP1
  • signalling enzymes - COX2 that produce PGs
71
Q

GCs suppress pro-inflamm pathways but what else?

A

TFs including AP1, NFkB, p38 MAPK

72
Q

GCs suppress/ prevent cytokines that…

A

drive inflammation

73
Q

GCs suppress/ prevent chemokines that…

A

recruit leukocytes

74
Q

What are a range of inflammatory diseases that GCs are useful for?

A

RA

Ankylosing Spondylitis

Crohn’s disease

Asthma

IBD

Eczema

Dermatitis

75
Q

GCs immunosuppressives (transplantation) and are effective in what

A

some haematological malignancies causing leukocyte apoptosis

76
Q

for what reason are GCs used in RA?

A

as bridging therapy, for control of inflammatory flares
in many cases for long term maintenance therapy

77
Q

What immune cells do GCs act on?
… do slide 478 and 479

A

They suppress almost all major immune cells

  • B cells - preventing immune cell production
  • Dendritic cells - less antigen presentation
78
Q

20mg cortisol equates to (Modifications):
- 5mg prednisolone
- 4mg methylprednisolone
- 0.75mg dexamethasone
why is this beneficial?

A
  • More resistant to metabolism
  • greater affinity for receptor = more potent GCs that don’t require high dose to be effective
79
Q

main/most severe SE from GC excess?

A

cushings syndrome
-> pit tumours that overproduced GCs

80
Q

What are symptoms of cushing’s syndrome caused by excess GCs?

A
  • facial fullness
  • central obesity
  • muscle wasting!
  • osteoporosis !
  • skin thinning
  • bruising
  • immune suppression
  • inc CVD RISK FACTORS
81
Q

GCs lots of SEs and very limited as a therapeutic. how must drug course be stopped?

A

px tapered off as rapidly as possible

82
Q

SE of GCs (not done) p 483

A
83
Q

GC SEs still poorly understood, unpredictable, and many clearly related to the normal physiological functions of GCs.
what is the risk proportional to?

A

cumulative dose of GC

84
Q

GCs bind to what?

A

GC receptor (NR3C1)
GRA = classical GC receptor

85
Q

the 3 domains on a GC receptor?

A

N-terminal transactivation domain (N-TD)

DNA binding domain (DBD)

Ligand binding domain (LBD)

86
Q

N-terminal transactivation domain (N-TD) of GC receptor contains transcriptional activation function 1 (AF1) + interacts with ____ and ___ ____

A

coregulators and transcription machinery
(to help facilitate receptor action)

87
Q

DNA binding domain (DBD) of GC receptor contains 2 Zn fingers to mediate dimerisation + target DNA sequences called…

A

GC responsive elements (GREs)

88
Q

Ligand binding domain (LBD) of GC receptor contains transcriptional activation function 2 (AF2) + interacts with ____ and ___ ____

A

coregulatory factorsfor transactivation

89
Q

when cortisol enters through memb, it acts on GR and causes…

A

dissociation of various things like heat shock proteins HSPs (steering wheel lock that prevents receptor form doing anything)
these fall off
conformational change

90
Q

what happens once HSPs removed from the GR?

A

monomer able to travel

binds to GRE (GC response element)

.. and get recruitment of those Coactivators –> gene transcription

(form homodimer. classic transactivation)

91
Q

GR variants differ in their ability to..

A

reuglate gene expression

92
Q

list some further post translational modifications (protein modulations)

A

phosphorylation
acetylation
sumolytation
ubiquitylation

93
Q

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

A

blocks GRa.
heterodimer
more of an inhibiting one.

dominant blockade

94
Q

What is transactivation?

A

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
Q

What is transpression?
what does it prevent?

A

Monomeric! GC receptors hold ‘tether’ TFs

-> prevents DNA binding + downstream gene signalling
(-ve actions of GCs)

96
Q

What is the transrepression hypothesis and what is incorrect about this?

A

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
Q

What is a SEGRAM?

A

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
Q

do last couple slides

A

Health 31 (16 decks)

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