Term
| How are corticosteriods produced? |
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Definition
| The hypothalamus is stimulated by some stressor (pain, cold, emotions etc.) and releases CRF. CRF then binds to a receptor on the pitutary gland, which stimulates the release of ACTH. ACTH then binds to the adrenal cortex, which then secretes different corticosteriods. |
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Term
| What are the major effects and the minor effects of stimulation of the adrenal cortex? |
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Definition
MAJOR: the release of cortisol
MINOR: the release of aldosterone (aldosterone is mostly produced from angiotension II. A little bit of testosterone is produced as well |
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Term
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Definition
| The body secretes the corticosteriods at specific times throughout the day. Around 5 am is the peak of ACTH and around 8am is the peak of cortisol. The lowest of cortisol would be around midnight |
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Term
| how is hormone production regulated? |
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Definition
| Hormone production is regulated by negative feedback. When there is an increase in cortisol, for example, it can bind to receptors on the hypothalamus and/or the pituitary gland, which would then cause the inhibition release of ACTH or CRF |
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Term
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Definition
| Glucocorticoid receptor is a nuclear hormone receptor, which resides in the cytosol. Within in the cytosol, it is complexed with proteins I and HSP. When glucocorticoid comes, the molecule penetrates the cell membrane. Once glucocorticoid binds, it changes the conformation of the complex, and I and HSP come off. Then a dimerazation occurs between the two ligand bound receptors and is able to go into the nucleus and act like a transcription factor, where is binds to the GRE on the promotor |
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Term
| Glucocorticoid response element |
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Definition
| GRE is on the promoter site where the transcription factor binds to. This can cause an increase (or decrease) in gene expression. (changes the assembly of chromatin. Now it is easier for the RNA polymerase to increase transcription of the gene |
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Term
| Mineralocorticoid receptor (MR) |
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Definition
MR is analogous to GR, but the difference is MR is expressed in the kindeys at the distal tubule and the collecting duct.
Example: Aldosterone binds to MR in the cytosol, which then goes into the nucleus to bind to MRE on the promoter sight, which increases the expression of Na channels, which causes sodium retention and water reabsorption. This can also lead to hypokalemia |
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Term
| Besides aldosterone, cortisol has high affinity to the MR, but it doesn't respond well. Why is this? |
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Definition
| There is an enzyme called 11 beta HSD which converts cortisol to cortisone. This does not have high affinity so cannot cause stimulation. Therefore, MR responds only to aldosterone. |
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Term
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Definition
| Liquorish can actually induce HTN because it blocks the 11 beta-HSD by glyzeryladehyde. This can then allow cortisol to bind to the MR receptor, which causes Na retention, and water reabsorption. |
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Term
| Corticosteriods as replacement therapy |
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Definition
-GR and MR can be used for either replacement therapy or therapeutic uses.
-It can be used for primary or secondary adrenal insuffciency |
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Term
| Primary adrenal insufficiency |
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Definition
-This is when the adrenal cortex is the problem itself (damage, missing enzymes)
- this includes addisons disease, which is an autoimmune disease that attacks/damages the adrenal cortex, so the patient cant make cortisol or aldosterone.
Also it includes cogenital adrenal hyperplasia: enzymes that produce cortisol is mutated and becomes larger
-Fludrocortisone and cortisol are BOTH used for primary adrenal insufficiency |
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Term
| Secondary adrenal insufficiency |
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Definition
- structural or functional lesions of pitutary gland or hypothalamus
-treat with cortisol only because since there is nothing wrong with the adrenal cortex, it is able to produce enough Aldosterone, since we also have Ang II producing Aldosterone as well |
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Term
| Therapeutic uses of glucocorticoids |
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Definition
-acute or chronic inflammation and immunosuppression (organ transpant rejection, reduce lymphocyte activity in acute lymphocytic leukemia and lymphomas)
-replacement therapy with mineralocorticoids |
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Term
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Definition
Inside a WBC we have a transcription factor called NFKB. In the cytosol, NFKB is normally inactivated by IKB. When a viral/bacteria protein stimulates an inflammatory response, the IKB is degraded and we have free NFKB. This translocates in the nucleus where is acts as a transcription factor, to increase cytokines, adhesion molecules, and COX-2
-Cytokines: fight pathogens but can also cause tissue damage
-Adhesion molecules: ICAM/VCAM: binds to the endothelial cells, which can then go into the tissue and fight the pathogen
-COX-2: AA is the subtrate for COX-2, which produces PGE. This causes dilation of the vessels, warmth, tenderness |
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Term
| Anti-inflammatory effect of glucocorticoids |
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Definition
| The NFKB is inhibited by the ligand bound glucocorticoid receptor. In addition, the dimerazation acts like a transcripton factor and upregulates the expression of annexia and IKB. Annexia can inhibit PLA2, which cleaves of AA from the cell membrane, so there is no longer a substrate for COX-2. In addition, we have no up regulation of COX-2, cytokines, or adhesion molecules |
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Term
| How come NSAIDS dont do the same as corticosteroids? |
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Definition
| NSAIDS only work on the prostaglandin |
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Term
| Adverse effects of glucocorticoids |
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Definition
acute: hyperglycemia
Long term: thinning of the skin, loss in muscle mass, increased lipolysis, increased intraocular pressure (leading to glaucoma), cataracts (esp. in children), osteoporosis, growth retardation in children, increased suspectibility to infection, poor wound healing, insomnia, reduced memory, psychoses, hypertention, increase acid in the stomach |
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Term
| How should we distribute glucocorticoids to reduce adverse effects? |
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Definition
-dose and duration dependant
- use smallest effective dose
-local administration if possible
-chronic is benefits > risk |
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Term
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Definition
When a patient is taking glucocorticoids exogenously, the patient will end up turning off their H-P-A axis in about one week to inhibit the production of endogenous substances. It can turn back on in 2-3 days becuase the enzymes have to be upregulated
-we should taper down the dose inorder for the H-P-A axis to turn back on to avoid adrenal insufficiency (this can be fatal) |
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Term
| When should cortisol be administered? |
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Definition
2/3 of the dose should be in the morning (around 8am) and the 1/3 of the dose should be given around 3 pm. This is divided like this so it can mimic the diurnal rhythm
-this does not apply to fludrocorticoids |
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Term
| Diagnose for Adrenal insufficiency |
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Definition
-CRF or ACTH
-if a patient has a normal adrenal cortex, when the patient recieves CRF or ACTH, we should find in the blood cortisol |
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