Glucocorticoids Flashcards
what are GCs?
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
where are GCs made?
secreted by the adrenal gland
what do GCs do?
mediate essential metabolic functions in target tissues
what is the effect of GCs?
- raise/lower mood state
- stimulate gluconeogenesis
- digestion is slowed
- permanently increased dosage = increase Osteoporosis and muscle weakness
- production of cortisol via the hypothalamus and the pituitary gland
- increase blood sugar levels
- reduces allergic reactions/anti-inflammatorys
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
what is cortisol also known as ?
hydrocortisone
what family are GCs apart of?
cholesterol family
what else are within the cholesterol family?
steroid hormones
- GCs
- mineralocorticoids
- vitamin D
- androgens (sex hormone)
- oestrogens
- progesterone
what structural properties are within GCs?
lipophilic = cross membranes
bind to cytosolic receptors
how do GCs mediate their effects
alter gene transcription
GC bind to GC receptors that act as TF that determine gene expression applying its effects to distant tissues
what the classifications of steroids?
- corticoids
- androgens
- oestrogens
what determines GC synthesis and secretion?
- diurnal rhythm (highest serum cortisol levels in the morning)
- hypothalamus regulation
how can GC cause morning sickness?
high conc of GC’s in the morning = inducing sickness
how does the hypothalamus control GC synthesis?
hypothalamus detects the stress/stimuli
then alerts pituitary gland
pituitary gland releases hormones to endocrine glands
what stimuli is detected by the hypothalamus?
- diurnal rhythm (e.g. daylight)
- stress (physical trauma/emotional)
- inflammation (pro-inflammatory cytokines)
what hormone is released by the pituitary gland?
adrenocorticotropic hormone (ACTH)
anterior
what does ACTH do?
regulate GC synthesis
GC synthesis pathway
Hypothalamus detects signal
CRH released and detected by anterior pituitary
releasing ACTH
ACTH regulated GC synthesis
GC negative response on CRH and ACTH production
what are the three layers of the adrenal gland?
zona glomeruloas
zona fasciculata
zona reticularis
what do the different layers in the adrenal gland produce due to ACTH stimulus?
zona glomeruloas - mineralocorticoids
zona fasciculata - GCs
zona reticularis - androgens
what do mineralocorticoids do?
permissive blood pressure steroid that regulate salt and water retention therefore control volemia
how do GCs transport around the body?
highly protein bound (to CBG 90% and albumin 5%) and
5% free GCs - bioavailable - inducing effect
how does inflammation affect GC transportation?
inflammation = decrease CBG levels = decrease bound CBG and GCs = increase free GCs= increase GC signalling
CBG (Corticosteroid-Binding Globulin)
how is cortisol activated and deactivated?
how is inactivated and activated cortisol cleared?
through the urine
how do GCs treat chronic inflammatory diseases?
decrease endothelial dysfunction
= decrease endothelial permeability
= decrease leukocyte recruitment
what symptoms do GCs treat?
decrease pain
decrease swelling
decrease stiffness
decrease physical disability
what do GCs suppress?
decrease cytokines - IL1B IL6 TNFa
decrease chemokines - IL8
decrease adhesion molecules - ICAM
decrease proteases - MMP1
decrease signalling enzymes -COX2
what are GCs effective for?
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.
what drugs are contra-indicated w GCs?
NSAIDs
TNFa inhibitors e.g. influximab
where do GCs exert effects to the immune systems?
anti-inflammatory action on neutrophils
prevent osteoblasts (bone formation)
therefore preventing osteoclasts (bone resorption)
what is 20mg of hydrocortisone (cortisol) equal to?
5mg prednisolone, 4mg methylprednisolone, 0.75mg dexamethasone, 0.75mg betamethasone
what was the main issue highlighted with GCs?
Cushings syndrome
what are the symptoms of Cushings syndrome?
Facial fullness
Central obesity
Buffalo hump
Muscle wasting
Osteoporosis
Skin thinning
Bruising
Immune suppression
how can GC regulate transcription?
+ transactivation
- transrepression
what is transactivation?
MONOMERIC
Direct binding of glucocorticoid receptor to specific DNA sequences, termed glucocorticoid response elements (GREs) to increase gene transcription
what is transrepression?
Monomeric glucocorticoid receptors ‘tether’ transcription factors
Preventing their DNA binding and downstream gene signalling
what is transrepression hypothesis?
explain what dexamethasone and chaperone proteins do?
toggle between both transrepression (anti-inflammatory effects) and transactivation (side effects)
what are some examples of chaperone proteins?
heat shock proteins
immunophilins
what do SEGRAMs and dexamesome do?
toggle between both transrepression (anti-inflammatory effects) and transactivation (side effects)
what are SEGRAMs?
Selective GC receptor agonists (SEGRA) and Selective GC receptor modulators (SGRM)
what are the problems with transrepression hypothesis?
The transrepression hypothesis does not fully explain the broad spectrum of GC actions, particularly their effects on gene expression.
The transrepression hypothesis primarily focuses on the downregulation of pro-inflammatory genes, but GCs also upregulate anti-inflammatory genes through the activation of glucocorticoid response elements (GREs).
