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43 Cards in this Set
- Front
- Back
Hypothalamic-Pituitary-Adrenal Axis: Hypothalamus releases ______ to the Anterior pituitary Anterior Pituitary release ______ to the Adrenal cortex Adrenal cortex release _______ into circulation |
Hypothalamus releases CRH (corticotropin-releasing hormone)
Anterior Pituitary release ACTH (adrenocorticotropic hormone)
Adrenal Cortex releases Cortisol |
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________ has negative feedback effect on BOTH ACTH & CRH release
What may override this negative feedback? |
Cortisol
stress (hypoglycemia, trauma, cold, etc) |
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Cortisol release follows what? |
circadian rhythm
*peaks early morning & after meals
(2/3 dose in morning, 1/3 later in day to follow natural cycle) |
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___________ is synthesized & released from the zona fasciulata of the adrenal cortex, in response to the HPA axis.
What does this hormone do? |
glucocorticoids - CORTISOL |
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________ is synthesized & released from the zona glomerulosa of the adrenal cortex, in response to the renin-angiotensin system (angiotensin II receptors).
What does this hormone do? |
Mineralocorticoids - ALDOSTERONE |
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Most of circulating cortisol is (active/inactive)
Why? |
Inactive
Most circulating cortisol is bound to corticosteroid-binding globulin (CBG), making it inactive (cortisol is hydrophobic, thus must be bound)
(synthetics such as dexamethesone mostly bound to albumin) |
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11-keto formulation (Hydroxyl at carbon 11 converted to ketone) confers a ____________ state on glucocorticoids
What enzyme converts the ketone back to a hydroxyl? |
less active state
11-beta-hydroxysteroid dehydrogenase (converts prodrug prednisone--> active prednisolone) |
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3-keto formulation (carbon 3 ketone) & 4, 5 double bonds (carbons 4 & 5) are required for __________ |
glucocorticoid, mineralcorticoid, & androgen activity |
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Where is cortisol metabolized?
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LIVER, via - reduction of double bonds between C4,5 - conversion of ketone at C3 to a hydroxyl - conjugation with sulfate glucuronate,
*excretion by kidneys. |
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T/F Cortisone & Prednisone are used topically |
FALSE
these require activation via 11-beta-hydroxysteroid dehydrogenase, which is in the liver |
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What determines the potency of topical GCs? |
1. intrinsic activity 2. concentration 3. vehicle |
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Physiological Effects of Corticosteroids: Metabolism |
(sometimes referred to as the anti-insulin) = Redistribution of body fat (extremities/lateral--> central/medial region) |
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Physiological Effects of Corticosteroids: Electrolyte and water balance |
- distal tubules and collecting ducts of kidney to enhance reabsorption of Na+ |
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Physiological Effects
of Corticosteroids: Cardiovascular
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(effects are secondary to MC changes in renal Na+ excretion) |
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Physiological Effects of Corticosteroids: CNS |
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Physiological Effects of Corticosteroids: Bone
What should you give along side chronic corticosteroids to prevent neg. bone effects? |
- Decr. osteoblast bone formation
= Osteoporosis
* give bisphosphonates (prevent bone loss) |
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Physiological Effects of Corticosteroids: Immune System
*primary therapeutic effects* |
Anti-inflammatory & immunosuppressive effects (primarily GC, not MC) = impair proliferation, activation, & chemotaxis of leukocytes |
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where are GC receptors (GCR) & MC receptors (MCR) located? |
GCR: Widely distributed throughout the body
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Direct, Type I MOA: GC |
- GC enters cellular membrane via passive diffusion (d/t lipophilic cholesterol-like backbone) |
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Indirect, Type II MOA: GC |
-GC/Receptor complex binds to HAT (histone acetyl transferase) -Complex recruits HDAC2 (histone deacetylase 2) --> causes gene supression of pro-inflammatory genes |
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GCs cause (decrease/increase) in NF-kB
what does this lead to? |
Decrease NF-κB = -> Decr COX-2 --> *Decr PGs -> Decr NOS -> Decr IL-5 -> Decr eosinophil -> Dec GM-CSF* -> Dec leukocytes -> TNFalpha activity* |
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GCs decrease signal transduction of TNFalpha via impaired NF-kB. What does this lead to?
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(TNFα signaling impaired since NF-κB is an intracellular 2nd messenger for TNF)
-- dec macrophage activation, acute phase protein release, Selectin & CAM expression, CCL3 & CXCL8-IL8 expression, & dec integrins |
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GC also cause a decrease in transcription of.... |
*IL-1 (--> dec macrophage, CAM, CCL3, CXCL8-IL8, integrin, & chemotaxis*) *IL-6 (--> dec acute phase proteins, B cell & neutrophil) *GM-CSF (--> dec leukocytes) *AP-1
(also IL-3 & IFNgamma dec) |
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GC decrease in AP-1 activity leads to? |
Decrease AP-1 transcription of Collagenase & IL-2 genes
(AP-1 = c-Jun + c-Fos--> binds to RNA polymerase II to cause gene transcription) |
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GCs increase the transcription of what? |
*IL-10--> suppresses helper T cells
*IkBalpha--> inhibits NF-kB |
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Glucocorticoids: Adverse Effects of Cushing Syndrome/Hypercortisolism |
|
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Hypocortisolism is due to? |
-primary adrenal insufficiency/Addisons = no cortisol production
-secondary adrenal insufficiency (defective HPA axis or ant pit.)= not enough cortisol
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Glucocorticoids: Adverse Effects of Addison's / Hypocortisolism (adrenal insufficiency) |
*life-threatening (if acute adrenal insufficiency) -GI symptoms (nausea/vommiting) -dehydration -hyponatriemia -hyperkalemia -weakness -hypotension |
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Why should you NEVER withdraw corticoisteroids abruptly after prolonged therapy? |
*may result in acute adrenal insufficiency (LIFE-THREATENING, d/t offset HPA axis)
- Recovery of full adrenal function may take 2-18 months |
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T/F you should always use the lowest dose, the shortest time, & as local of administration possible when using corticosteroids |
TRUE!
limits neg side effects |
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What GC is used for the diagnosis of Cushing Syndrome? |
Dexamethasone administered at night- -if hypercortisol due to over production of hypothalamic or pituitary hormone the cortisol levels are decrease in morning (=HPA response) |
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GC Therapeutic Uses: |
*Primary Addisons, secondary or tertiary adrenocortical insufficiency *Inflammatory bowel disease (IBD) *Asthma *Eczema *Psoriasis *Inflammation *Immunosuppresion *Allergies *Stimulation of Lung maturation in fetus |
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Primary (Addisons), Secondary, Tertiary adrenocortical insufficiency: DOC |
hydrocortisone
*2/3 dose in morning, 1/3 dose later in day |
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Addison's disease tx may also requires |
Fludrocortisone (a mineralcorticoid)
(ONLY in Addisons) |
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IBD, severe asthma (systemic/oral tx of inflammation): DOC |
Prednisolone |
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Asthma (inhalation therapy): DOCs |
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Allergic rhinitis: DOC |
Fluticason |
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Immunosuppression (graft vs. host): DOC |
methylprednisone or dexamethasone |
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Severe psoriasis: DOC |
Triamcinolone acetonide |
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Topical therapy (Eczema, distal UC, Crohn/s): DOC |
hydrocortisone |
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Lung maturation in developing Fetus: |
Beclomethasone
|
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Which GC drugs have poor bioavailability & are rapidly metabolized?
What are they used for? |
Beclomethasone dipropionate Budesonide Flutocasone
anti-inflammation (allergy, asthma), either inhaled or topical |
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What are the oral glucocorticoids?
Which one's have the greatest systemic effects? |
short-acting (8-12 hrs): hydrocortisone (cortisol)
intermediate-acting (18-36): triamcinolone, beclomethasone, prednisolone, methylprednisone
long-acting (36-54): dexamethasone *greatest systemic (HPA) effects (longer they last) (also have less salt-retaining effects) |