Glucocorticoids Flashcards
What are the two types of corticosteroids?
- Glucocorticoids (eg. cortisol)
- Mineralocorticoids (eg. aldosterone)
Both synthesised and released from adrenal cortex
In regards to the corticosteroids, what is meant by the ‘salt and sugar’ hormones?
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Glucocorticoids:
- ‘sugar’ hormone, for carbohydrate + protein metabolism
- potent anti-inflammatory / immunosuppressant
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Mineralocorticoids:
- ‘salt’ hormone, controls electrolyte + H2O in kidney
How is cortisol released?
- Stimulus = stress (eg extreme exercise)
- Hypothalamus stimulated -> CRH release (from PVN)
- CRH acts on anterior pituitary
- ACTH secreted from anterior pituitary
- Acts on adrenal gland to secrete cortisol
What are the physiological actions of cortisol?
- Regulates glucose (blood sugar) levels
- Increases fat in the body
- Helps to defend body against infection
- Helps body respond to stress
What stimulates/controls release of aldosterone?
Decreased sodium or inc potassium in blood / decreased blood volume/BP -> stimulation of kidneys -> renin -> RAAS cascade -> ang II formed -> vasoconstriction -> bring up BP
Ang II also stimulates production of aldosterone from adrenal cortex + that will regulate how much water is retained. Sodium and water reabsorption increases, so increases blood volume.
Which hormone has an inhibitory effect on the adrenal cortex, therefore inhibiting release of aldosterone?
- Atrial natirueretic peptide (ANP)
- Inhibits zona glomerulosa of adrenal cortex
- This is in response to increased BP/BV so aim is to decrease BP by decreasing aldosterone secretion
Can cortisol bind to the same receptor that aldosterone binds to? What can this lead to?
Yes, cortisol + aldosterone have equal affinity for the mineralocortiocid (AT1) receptor. So high levels of cortisol -> BP will go up, by mimicking aldosterone action.
What are the metabolic actions/effects of glucocorticoids?
- Breakdown of protein + fats (muscle wasting, etc)
- Decreased glucose usage + increased gluconeogenesis
- Tendency to hyperglycaemia and increased glycogen storage
What effect do glucocorticoids have on the cardiovascular system?
Decrease in both microvascular permeability and vasodilatation
What changes occur in the CNS as a result of glucocorticoids?
Mood changes, linked with changes in memory/stress
What effect do glucocorticoids have on the hypothalamic-pituitary-adrenal axis?
Negative feedback on anterior pituitary and hypothalamus
Why go glucocorticoids decrease microvascular fluid exudation?
As they reduce influx of cells to areas of inflammation
Which enzyme expression do glucocorticoids decrease in order to bring about anti-inflammatory effects?
- COX-2
- Reduced levels of eicosanoids
- Decreased levels of cytokines + complement levels
What are the decreased functions of inflammatory effector cells brought about by glucocorticoids?
- Inhibition of cell migration + mediator release
- Reduced clonal expansion of T + B cells
- Reduced in chronic inflammatory events
- NB healing + repair inhibited
What are the cellular effects of inhaled corticosteroids?
Also reduce movement and activity of chemotactic cells
Where is the glucocorticoid receptor?
Found intracellularly in almost all tissues
How do glucocorticoids bind to their receptor and what happens after this? (just talk about cellular mechanisms, not the biological effects)
- Glucocorticoids enter cells through passive diffusion
- Form complex with GCR (receptor protein) in cytoplasm
- GCR dissociates HSP (heat shock protein)
- Glucocorticoid-GCR complex translocated to nucleus
- Can bind to specific regulatory components in nucleus
- Expression of genes can be both increased or decreased
- ~1% of genome is steroid-sensitive
What are the biological effects induced by glucocorticoids binding to its receptor?
- increased hepatic gluconeogenesis
- increased lipolysis
- muscle catabolism
- inhibition of peripheral glucose uptake in muscle + adipose
How does NF-kB play a key role in the activation of inflammatory response genes?
- Resting cells - NF-kB in cytoplasm associated with inhibitory protein IkB
- Inflammatory cytokines -> activate IKK
- IKK phosphorylates IkB
- IkB then ubiquinated + degraded by proteasome
- Freeing NF-kB to migrate into nucleus + activate gene expression
Glucocorticoids induce inhibition of NF-kB (IkB-a), what does this lead to?
Increased expression of anti-inflammatory proteins:
- Inc B2 adrenergic receptors; inc lipocortin which decreases AAs/eicosanoids
- Levels of some anti-inf cytokines go up: IL-10, IL-12
Decreased expression of pro-inflammatory cytokines:
- Decrease cytokine production (eg TNF-a, IL-1b); endothelin-1
What actions will dexamethasone have?
- Glucocorticoid agonist
- Anti-inflammatory actions
- Inhibition of leukocyte infiltration at site of inflammation
- Interference in function of mediators of inflammatory repsonse
- Suppression of humoral immune responses
- Reduction in oedeoma + scar tissue
All thought to be done by Phospholipase A2 inhibitory proteins, lipocortins, which control biosynthesis of potent mediators of inflammation such as prostaglandins + leukotrienes.
What are therapeutic uses of glucocorticoids?
- Adrenal insufficiency or failure (Addison’s Disease) - congenital or drug-induced, treatment requires combined GC + MC
- Treatment of inflammation - asthma, rhinitis, skin disorders, sports injuries, reduction of cerebral oedema in patients w brain tumors
- Immunosuppression - inhibit graft v host reaction in tissue transplantation
Give examples of glucocorticoids/drugs
- Hydrocrotisone
- Prednisolone
- Dexamethasone
- Betamethasone
- Beclomethasone
What are the comparative effects of NSAIDs and glucocorticoids on Eicosanoid biosynthesis?
- Glucocorticoids inhibit formation of arachidonic acid (by decreased PLA2)
- Glucocorticoids also decrease expression of COX-2
- NSAIDs decrease activity of COX-2 - thus only inhibiting the prostaglandin/thromboxane formation pathway, whereas glucocorticoids will inhibit all eicosanoids forming
Name an endogenous mineralocorticoid
- Aldosterone
- Secretion controlled by renin-angiotensin system + ACTH
Where are mineralocorticoid receptors found?
- Only in few places
- Kidney, colon, bladder
What does aldosterone do?
Increases Na+ retention in distal tubules of kidney
- stimulates Na+/H+ exchanger via aldosterone receptors
- enters cells + up-regulates Na+-permeable epithelial Na channels in cell membrane
- enters cells + stimulates up-reg of basolateral Na+/K+ ATPase pump
- also causes H2O retention, loss of K+ and H+
Low Na+ plasma levels increase aldosterone by directly activating adrenal gland + stimulating RAAS to produce Ang II
What are therapeutic uses of mineralocorticoids?
- Adrenal insufficiency (eg Addison’s)
- Electrolyte disorders (cerebral salt wasting)
- Orthostatic/postural hypotension (failure of baroreceptor reflex)
Name an example of a mineralocorticoid drug
Fludrocortisone
What are side effects of corticosteroids?
Cushing’s-like syndrome
- Euphoria
- Buffalo hump
- Round face with red cheeks
- Thinning skin
- Thin arms + legs, muscle wasting
- Increased abdominal fat
- Poor wound healing
Others: opportunistic infection, osteoporosis, gastric ulcers, growth suppression, behavioural/repro problems
