Glucocorticoids Flashcards
What are the two different types of corticosteroids?
Glucocorticoids
Mineralocorticoids
How do is cortisol release controlled?
- Stress and extreme exercise can cause the release of CRH by the PVN
- Acts on anterior pituitary, causing release of ACTH
- ACTH acts on adrenal cortex to release cortisol
What are cortisol’s effects?
- Promotes normal metabolism
- inhibits insulin product/ controls blood sugar levels
- Controls BP
- Acts as an anti-inflammatory agent
- Mobilises fatty acids from fat cells
- Increases gluconeogenesis
- Helps body respond to stress
How is aldosterone release controlled?
- Renin release causes cleavage of angiotensinogen to angI.
- ACE in the lungs causes AngI to be converted to AngII
- AngII acts on zona glomerulosa of adrenal cortex and causes the release of Aldosterone
What can happen if you have too much cortisol?
- Overwhelm the enzyme involved in cortisol metabolism (11b-steroid dehydrogenase)
- Cortisol then binds to the aldosterone receptor, stimulating its effects -> increasing blood volume -> increased BP
What are the metabolic actions of glucocorticoids?
- Breakdown of protein and fats (muscle wasting etc) - gives disproportionate distribution (buffalo hump, moon face, distended belly)
- Decreased glucose usage and increased gluconeogenesis
- Tendency to hyperglycaemia and increased glycogen storage - can lead to diabetes
What are the cardiovascular effects of glucocorticoids?
Decrease in both microvascular permeability and vasodilation
What are the CNS effects of glucocorticoids?
Mood changes, linked with changes in memory/stress
What are effects do glucocorticoids have on the immune system?
Decrease the amount of immune ells such as neutrophils, lymphocytes etc
What are the anti-inflammatory effects of glucocorticoids?
- Decreased microvascular fluid exudation (reduces immune cell chemotaxis)
- decreased inflammatory mediators and cytokines (less IL-1b and TNFa so less AA, also reduces COX-2, so less eicosanoids, less complement)
- Decreased function of inflammatory effector cells
What are the cellular effects of inhaled corticosteroids?
- Decreased numbers of eosinophils, t-cell cytokines and mast cells reduces the numbers of harmful mediators they produce
- less dendritic cells to present antigens
- less mucus secretion and endothelial cell leakage
- less cytokines and mediators from epithelial cells
- Less cytokines from airway smooth muscle, but increased B2 recptors -> relaxation with salbutamol
What is the cellular mechanism of action for glucocorticoids?
- Binds to its receptor in the cytoplasm
- dissociates HSP
- Glucocorticoid-receptor complex enters nucleus and binds to regulatory elements in DNA promoters - alters gene expression
- Coactivators carry out histone acetylation, opening up the chromatin strture, allowing transcription
- Deacetylation stops the production of mediators
What does NF-kB do?
- Activation of inflammatory response genes
- In resting cells, NF-kB is inhibited by association with IkB
- Inflammatory cytokines activate IkB kinase (IKK), phosphorylating IkB on two serine residues
- IkB is then ubiquitinated and degraded by the proteasome - allowing NF-kB to go to the nucleus and activate gene expression
- NF-kB has signals telling it where to go to get to the nucleus
- IkB-alpha proteins can mask these signals, keeping the NF-kB sequestered in the cytoplasm
- If it cannot go to the nucleus, then DNA transcription wont happen, and so COX-2 and cytokines wont be synthesised
How do glucocorticoids switch gene expression on and off?
- interaction of steroid/receptor with promoter regions - these gene promoters have glucocorticoid response elements (GREs); activation of these turns on/off certain genes (off = damage and inflammation, on = resolution)
- Steroid receptor complexes can prevent gene activation by other transcription factors - e.g. phosphorylation of IkB -> NFkB activation
What are the therapeutic uses of glucocorticoids?
- Adrenal insuffiiency or failure (Addisons) - congenital or drug-induced; treatment requires combined GC and MC
- Treatment of inflammation - asthma, rhinits etc
- Immunosupression - inhibit graft vs host reaction in tissue transplants
Give 5 examples of glucocorticoids
- hydrocortisone
- prednisolone
- dexamethasone
- betamethasone
- beclomethasone
Glucocorticoids vs NSAIDS in eicosanodi biosynthesis
- Glucocorticoids decrease levels of Phospholipase A2 -> decreased AA
- AA can be metabolised into PGs and TXs or LTs and other lipoxygenase products such as lipoxins
- Glucocorticoids also decrease expression of COX-2
- NSAIDs just decrease activity of COX-2
Give an example of an endogenous mienralocorticod
Aldosterone
What does aldosterone do?
- Its secretion is controlled by RAAS and ACTH
- Increases Na retention in DCT of kidneys
- Simulates Na/H exchanger via aldosterone receptors
- Enters cells and upregulates ENaC channels in membrane
- Enters cells and stimualtes upregulation of basolateral Na/K ATPase
- Also causes water retention so loss of K and H
What are the therapeutic uses of mineralocorticoids?
- Adrenal insufficiency - Addisons
- Electrolyte disorders - cerebral salt wasting (EC volume depletion due to a renal sodium transport abnormality)
- Orthostatic (postural) hypotension - failure of baroreceptor reflex
Give an example of a therapeutic MC?
Fludrocortisone
What is the mechanism of cerebral/renal salt wasting?
Brain injury leads to increased adrenergic activity, and increased production of natriuretic peptides
- Causes natriuresis in the kidney
- Increased adrenergic activity causes increased perfusion pressure and dopamine levels, which also acts on the kidney and causes natriuresis
What are the side effects of corticosteroids?
- Cushings
- Opportunistic infection
- Osteoporosis
- Gastric ulceration (inhibits PGE2 synthesis so less mucus and bicarbonate secretion)
- Growth suppression
- Behavioural or reproductive problems
What is cushings syndrome?
- Abnormally high levels of cortisol
- Reasons for high cortisol = overuse of corticosteroids/adenoma
- Symptoms = moon face, upper body weight gain, easily bruised skin
What is negative nitrogen balance?
- Associated with burns, serious tissue injuries, fevers, hyperT, wasting diseases and during fasting periods
- The amount of nitrogen excreted is greater than the amount of nitrogen ingested
