37. Steroids Flashcards
What are corticosteroids generally used to treat?
Why does synthetic prednisone work (treat) better than natural cortisol?
How does cortisol change with circadian rhythm?
What is Hans Selye’s General Adaptation Syndrome?
Inflammatory and autoimmune diseases
It has lots of activity for corticosteroid path (nat. cortisol works on this path and mineralcorticoid path)
Highest on waking (due to potential foreign material), lowest before bed.
3 stages of stress response (irrespective of source): alarm (acute stress), resistance (chronic stress), exhaustion (death)
What was found as cortisol was given in vitro (in terms of mediators and receptors)?
Describe the action of the stress-induced cortisol on the graph below.
List some things which might cause this increase of stress-induced glucocorticoid hormone.
Fall in conc of inflammatory/immune mediators but increase in receptors for the mediators.
In range of stress induced: body creates more cortisol to decrease potential activity = endogenous glucocorticoid hormones prevent overzealous rebound responses to stress
Metabolic disturbance (e.g. BG), neural disturbance, infection (immune reaction), tissue damage (inflammation), fluid loss (ADH etc.)
List some SE of systemic corticosteroids.
What is Cushing’s Syndrome? What is the cause?
Odema, glaucoma, weight gain, glycosuria, hypertension, osteoporosis, juvenille growth retardation, GI bleeding, thrombosis, depression
Collection of signs and symptoms due to prolonged cortisol exposure e.g. hypertension, abdo obesity, “buffalo hump”., round red face, stretch marks, stomach ulcers, weak muscles and bones. Cause: excessive medication (prednisone e.g.) or tumour producing/releasing excessive cortisol by adrenal glands
How do steroids affect bone?
Explain how corticosteroids work.
What are the 2 types of glucorticoid receptor?
Suppress osteoclasts and osteoblasts in high doses but supress osteoclast less, so net effect = breakdown of bone matrix (increased resporption) -> fracture easily. Causes avascular necrosis.
Glucocorticoid receptor found in cytoplasm and nucleus of most body cells (hence the wide range of effects). Receptor associates with large number of other proteins in cyt/nuc or causes transcription of genes
1) alpha (binds steroid)
2) beta (doesn’t bind steroid - instead can bind DNA without need for steroid -> stops active stroid changing things in nucleus = regulatory!)
Explain the 2 glucocorticoid receptor activites upon binding of the glucocorticoid.
Describe the transactivation mechanism of glucocorticoid action.
1) Genomic (slow): 6-12hr, transactivation of transcription by direct inteaction with DNA (can work -vely to prod SEs), AND transrepression via interaction with other cyt/nuc proteins (can work +vely - good effects)
2) Non-genomic (rapid): interaction of GC with cytoplasmic CR/plasma membrane GR/ membrane
GC + transporter (e.g. albumin) -> free glucocorticoid -> lipophilic so passes through bilayer -> binds to GR + chaperone protein -> chaperone released and receptor dimerises -> goes to nucleus to up/down regulate gene expression and transcription. Can also get post-transcriptional procesing.
Describe the transrepressive action of a glucocorticoid receptor.
TNF-alpha (e.g.) binds to receptor on cell surface -> transcription factor activation e.g. CREB, STAT, AP1 -> migrate to nucleus and promote transcirption of pro-inflammatory genes. Corticosteroid binds to receptor for e.g. TNF-alpha and prevents it binding to DNA and activating the pro-inflamm genes.
Describe the 3 possible non-genomic mechanisms of glucocorticoid action.
What 3 important areas of GC future are being researched?
1) Membrane GR: First warning of what’s happening outside -> rapid response -> signal to inside cell.
2) Cytosolic GR signalling: first few molecules can trigger signalling cascases
3) Intercollation in membranes: if high steroid doses, can intercalate GR in membranes - stabilises cell.
1) Better 2nd gen ‘dissociated steroids’ (i.e. work via transrepressive path than transactivation = decrease SEs)
2) Novel biomarkers of steroid sensitivity for pts taking long-term corticosteroids (to give the right dose)(CD163 found)
3) 3rd gen steroids which target specific paths in steroid receptosome (all proteins interacting with glucocorticoid receptor - changes response)
