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HDT 3.1 > Glucocorticoids > Flashcards

Glucocorticoids Flashcards

1
Q

what are GCs?

A

Synthesised in the adrenal gland
steroid hormone- chemical messengers secreted into the blood
e.g. the effects of catecholamines on vascular tone
* Important in homeostasis e.g. conditioning the body’s
response to stress

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2
Q

where are GCs made?

A

secreted by the adrenal gland

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3
Q

what do GCs do?

A

mediate essential metabolic functions in target tissues

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4
Q

what is the effect of GCs?

A
  1. raise/lower mood state
  2. stimulate gluconeogenesis
  3. digestion is slowed
  4. permanently increased dosage = increase Osteoporosis and muscle weakness
  5. production of cortisol via the hypothalamus and the pituitary gland
  6. increase blood sugar levels
  7. reduces allergic reactions/anti-inflammatorys
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5
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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6
Q

what is cortisol also known as ?

A

hydrocortisone

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7
Q

what family are GCs apart of?

A

cholesterol family

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8
Q

what else are within the cholesterol family?

A

steroid hormones
- GCs
- mineralocorticoids
- vitamin D
- androgens (sex hormone)
- oestrogens
- progesterone

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9
Q

what structural properties are within GCs?

A

lipophilic = cross membranes
bind to cytosolic receptors

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10
Q

how do GCs mediate their effects

A

alter gene transcription

GC bind to GC receptors that act as TF that determine gene expression applying its effects to distant tissues

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11
Q

what the classifications of steroids?

A
  1. corticoids
  2. androgens
  3. oestrogens
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12
Q

what determines GC synthesis and secretion?

A
  1. diurnal rhythm (highest serum cortisol levels in the morning)
  2. hypothalamus regulation
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13
Q

how can GC cause morning sickness?

A

high conc of GC’s in the morning = inducing sickness

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14
Q

how does the hypothalamus control GC synthesis?

A

hypothalamus detects the stress/stimuli
then alerts pituitary gland
pituitary gland releases hormones to endocrine glands

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15
Q

what stimuli is detected by the hypothalamus?

A
  1. diurnal rhythm (e.g. daylight)
  2. stress (physical trauma/emotional)
  3. inflammation (pro-inflammatory cytokines)
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16
Q

what hormone is released by the pituitary gland?

A

adrenocorticotropic hormone (ACTH)
anterior

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17
Q

what does ACTH do?

A

regulate GC synthesis

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18
Q

GC synthesis pathway

A

Hypothalamus detects signal
CRH released and detected by anterior pituitary
releasing ACTH
ACTH regulated GC synthesis

GC negative response on CRH and ACTH production

19
Q

what are the three layers of the adrenal gland?

A

zona glomeruloas
zona fasciculata
zona reticularis

20
Q

what do the different layers in the adrenal gland produce due to ACTH stimulus?

A

zona glomeruloas - mineralocorticoids
zona fasciculata - GCs
zona reticularis - androgens

21
Q

what do mineralocorticoids do?

A

permissive blood pressure steroid that regulate salt and water retention therefore control volemia

22
Q

how do GCs transport around the body?

A

highly protein bound (to CBG 90% and albumin 5%) and
5% free GCs - bioavailable - inducing effect

23
Q

how does inflammation affect GC transportation?

A

inflammation = decrease CBG levels = decrease bound CBG and GCs = increase free GCs= increase GC signalling

24
Q

how is cortisol activated and deactivated?

A
25
Q

how is inactivated and activated cortisol cleared?

A

through the urine

26
Q

how do GCs treat chronic inflammatory diseases?

A

decrease endothelial dysfunction
= decrease endothelial permeability
= decrease leukocyte recruitment

27
Q

what symptoms do GCs treat?

A

decrease pain
decrease swelling
decrease stiffness
decrease physical disability

28
Q

what do GCs suppress?

A

decrease cytokines - IL1B IL6 TNFa
decrease chemokines - IL8
decrease adhesion molecules - ICAM
decrease proteases - MMP1
decrease signalling enzymes -COX2

29
Q

what are GCs effective for?

A

Rheumatoid Arthritis, Giant Cell Arthritis, SLE, Ankylosing Spondylitis, Asthma, Crohn’s Disease, IBD, Eczema, Dermatitits

Immunosuppressives: (transplantation), and are effective in some haematological malignancies causing leukocyte apoptosis

In RA GCs are used as bridging therapy, for control of inflammatory flares, and in many cases for long term maintenance therapy.

30
Q

what drugs are contra-indicated w GCs?

A

NSAIDs
TNFa inhibitors e.g. influximab

31
Q

where do GCs exert effects to the immune systems?

A

anti-inflammatory action on neutrophils
prevent osteoblasts (bone formation)
therefore preventing osteoclasts (bone resorption)

32
Q

what is 20mg of hydrocortisone (cortisol) equal to?

A

5mg prednisolone, 4mg methylprednisolone, 0.75mg dexamethasone, 0.75mg betamethasone

33
Q

what was the main issue highlighted with GCs?

A

Cushings syndrome

34
Q

what are the symptoms of Cushings syndrome?

A

Facial fullness
Central obesity
Buffalo hump
Muscle wasting
Osteoporosis
Skin thinning
Bruising
Immune suppression

35
Q

how can GC regulate transcription?

A

+ transactivation
- transrepression

36
Q

what is transactivation?

A

MONOMERIC
Direct binding of glucocorticoid receptor to specific DNA sequences, termed glucocorticoid response elements (GREs) to increase gene transcription

37
Q

what is transrepression?

A

Monomeric glucocorticoid receptors ‘tether’ transcription factors
Preventing their DNA binding and downstream gene signalling

38
Q

what is transrepression hypothesis?

A
This hypothesis proposes that glucocorticoids exert their anti-inflammatory effects by inhibiting the activity of pro-inflammatory transcription factors, particularly nuclear factor-kappa B (NF-κB), rather than solely by activating glucocorticoid receptor-mediated gene transcription (transactivation).
39
Q

explain what dexamethasone and chaperone proteins do?

A

toggle between both transrepression (anti-inflammatory effects) and transactivation (side effects)

40
Q

what are some examples of chaperone proteins?

A

heat shock proteins
immunophilins

41
Q

what do SEGRAMs and dexamesome do?

A

toggle between both transrepression (anti-inflammatory effects) and transactivation (side effects)

42
Q

what are SEGRAMs?

A

Selective GC receptor agonists (SEGRA) and Selective GC receptor modulators (SGRM)

43
Q

what are the problems with transrepression hypothesis?

A

Requires the GC receptor to display convenient mechanistic separation of +ve and -ve actions

Ignored alternative more complex mechanisms of GC signalling and is frequently at odds with ongoing experimental observation

No SEGRAM has progressed past phase II clinical trial (Equivalent efficacy to classical GCs, but improved safety profile)

HDT 3.1 (13 decks)

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