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27 - Adrenocorticosterioids Flashcards

1
Q

Adrenocoricosteroids (or glucocorticoids) are widely used for ________ and ________

A

Adrenocoricosteroids (or glucocorticoids) are widely used for inflammation and immunosuppression

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2
Q

The adrenal medulla secretes which two hormones?

A
  1. Adrenaline
  2. Catecholamine / amino acid hormone
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3
Q

What are the three regions of the adrenal cortex?

A
  1. Zona glomerulosa
    • produces mineralocorticoids
  2. Zona fasciculata
    • produces Glucocorticoids
  3. Zona reticularis
    • produces androgens
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4
Q

What hormones are produced by the Zona Glomerulosa (outermost region) of the adrenal cortex?

A

Mineralocorticoids

  • eg Aldosterone
    • Salt balance
    • part of RAAS system
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5
Q

What hormones are produced by the Zona Fasciculata (middle region) of the adrenal cortex?

A

Glucocorticoids

  • eg cortisol
    • Metabolic and immune effects
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6
Q

What hormones are produced by the Zona Reticularis (innermost region) of the adrenal cortex?

A
  • Androgens
    • eg DHEA
      • Precursors for strong androgens (testosterone) and estrogens
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7
Q

_________ is the common precursor for all adrenal steroid hormones?

A

Cholesterol is the common precursor for all adrenal steroid hormones?

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8
Q

What system controls cortisol release from the zona fasciculata?

A

HPA Axis

  • Hypothalamus
  • Pituitary (anterior)
  • Adrenal cortex
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9
Q

What hormone stimulates cortisol production?

A

The anterior pituitary releases ACTH (Adrenocorticotropic hormone aka Corticotropin) which acts on the adrenal cortex to stimulate steroid (cortisol) production

  • after meals
  • linked to circadian rhythm (high just before waking)
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10
Q

What controls ACTH release from the anterior pituitary?

A

Adrenocorticotropic hormone is controlled by CRH (corticotropin-releasing hormone) from the hypothalamus

  • CRH is also called CRF (corticotropin-releasing factor)
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11
Q

Where are steroid hormones stored?

A

Unlike Peptides, Steroid Hormones CANNOT be stored.

ACTH stimulates cortisol synthesis

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12
Q

Steroid hormones are not controlled at the point of release because they are __________, and instead they are controlled at the level of _______

A

Steroid hormones are not controlled at the point of release because they are membrane-permeable, and instead they are controlled at the level of synthesis

  • ie steroid hormones are not stored but are synthesized when needed
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13
Q

Cortisol exerts negative feedback on: (2)

A
  • CRH (hypothalamus)
    • stops release of corticotropin releasing hormone
  • ACTH (Anterior pituitary)
    • Stops release of corticotropin
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14
Q

Cortisol suppresses stress signals like _______ (“other regulatory signals”)

A

Cortisol suppresses stress signals like inflammatory cytokines which are involved in the stress response (“other regulatory signals”)

  • ie cortisol exerts powerful immunosuppressant effects that shuts down the synthesis of the cytokines and other aspects of the stress response
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15
Q

Cortisol acts on _________ target tissues.

A

Cortisol acts on glucocorticoid target tissues

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16
Q

What is the response of cortisol acting on glucocorticoid target tissues?

A
  • Glucocorticoid response
    • Stress response
    • Catabolism
    • Immunosuppression
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17
Q

What does RAAS stand for?

A

Renin - Angiotensin- Aldosterone - System

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18
Q

Renin is released by the ____________ in the _______ and generates _____ from __________

A

Renin is released by the Juxtaglomerular apparatus in the kidney and generates AT1 from angiotensinogen

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19
Q

What is ACE and what role does it play in RAAS?

A

ACE = Angiotensin converting enzyme

Converts AT1 to AT2

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20
Q

What triggers aldosterone release?

A

AT2 (angiotensin 2) triggers aldosterone release from adrenal cortex

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21
Q

The primary target of aldosterone is the ______ where it causes:

A

The primary target of aldosterone is the kidneys where it causes:

  • increased Na+/water reabsorption
  • increased K+ secretion
  • Mineralocorticoid response
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22
Q

What is the primary role of RAAS?

A

To control blood pressure and blood volume

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23
Q

Why do corticosteroids generate different responses (eg Glucocorticoid response or Mineralocorticoid response)?

A

The response depends on the type of receptor

We have

  • Glucocorticoid receptors = stimulate GC response
  • Mineralocorticoid receptors = stimulate MC response
24
Q

What is interesting about cortisol affinity for Glucocorticoid receptors vs Mineralocorticoid receptors?

A

Cortisol has a fairly equal affinity for both receptors (1:1)

ie it’s activity is fairly equal for both receptors

25
Using the image, describe the generalized mechanism for steroid hormone action
1. Cytoplasmic unliganded receptor is in a complex with chaperones (Hsp90 in this case) 2. Binding of hormone (S) causes dissociation from chaperones and the ligand-receptor complex (activated steroid-receptor dimer) is transported into the nucleus 3. Dimerized receptors interact with DNA and influence transcription of target genes 4. **Glucocorticoid receptor/response element** (**GRE**)
26
What are two key targets of Glucocorticoid receptor binding?
Lipocortin COX-2
27
Many tissues that are glucocorticoid target tissues, have the hormone ___________ which activates cortisol (from cortisone)
Many tissues that are glucocorticoid target tissues, have the enzyme _11 Beta hydroxysteroid dehydrogenase, TYPE 1_ which activates cortisol (from cortisone) * Ketone in cortisone is replaced with an * Alcohol in cortisol
28
Corticosteroid specificity arises from \_\_\_\_\_\_
Corticosteroid specificity arises from _affinity of the compound/receptor AND metabolism in target tissues_ * Because target tissues have the enzyme which activates cortisol
29
Which topical would have a higher topical effect, prednisone or prednisolone?
We know that the inactive form of corticosteroids has a ketone whereas the active form has an alcohol therefore prednisolone would be the active form of prednisone and, as such, would have a stronger topical effect. * Prednisone would be used via oral intake or injection
30
Why is prednisone ineffective as a topical treatment, but effective when taken orally?
Orally administered prednisone is significantly metabolized to prednisolone in the liver (*first-pass metabolism*) and in important GC target tissues (by HSD-1 enzyme) GC= Glucocorticoid HSD-1 = 11Beta Hydroxysteroid dehydrogenase type 1
31
Cortisol activates the GR and MR but has weak mineralocorticoid effects *in vivo.* Why?
Kidney cells (mineralocorticoid targets) express an enzyme (11Beta Hydroxysteroid Dehydrogenase Type 2 (HSD-2)) that renders cortisol inactive
32
If the HSD-2 enzyme were deficient or inhibited, what consequences would you expect? How would this affect the tissues targeted by glucocorticoids, and the spectrum of glucocorticoid effects?
HSD-2 (11 Beta - hydroxysteroid dehydrogenase type 2) is an enzyme in kidney cells that inactivates cortisol. * Pseudohyperaldosteronism * increase cortisol activation = inappropriate effect in aldosterone target tissues (like the kidney) * Can cause high BP because of aldosterone-like effects (Na+ and H2O reabsorption)
33
What is **Pseudohyperaldosteronism** and what are two causes?
* Pseudohyperaldosteronism * deficiency or inhibition of HSD-2 enzyme * increase cortisol activation in aldosterone target tissues = inappropriate effect in aldosterone target tissues (like the kidney) * Can cause high BP because of aldosterone-like effects (Na+ and H2O reabsorption) * Causes: 1. Licorice overdose * licorice has an inhibitor of 11beta hydroxysteroid dehydrogenase 2 2. Apparent Mineralocorticoid Excess * Genetic disease arising from mutations in HSD-2 gene
34
What are the metabolic effects of **glucocorticoids**?
1. Carbohydrate metabolism: * Increases circulating blood glucose 2. Fat/Lipid balance: * promotes fat deposition in the trunk but fat breakdown in the limbs 3. Overall * **Catabolic** (breakdown) effects, loss of muscle and bone mass in the limbs * Increase fat in viscera and trunk * Skinny fat
35
What is the main pharmacological use of glucocorticoids?
For anti-inflammatory effects
36
What are the two key Glucocorticoid-mediated mechanisms in inflammation?
1. Inhibit AA (arachidonic acid) generation by phospholipase A2 2. Inhibit prostanoid synthesis These two effects have widespread downstream effects on inflammatory reactions
37
What action does glucocorticoid have on cyclooxygenase-2 (COX-2)? How does it exert this effect?
* Suppresses Cox-2 * Glucocorticoid regulation of COX-3 does NOT involve direct receptor antagonism * Glucocorticoids suppress transcription of the COX-2 gene, leading to a long-term suppression of COX-2 expression (protein levels) * they do not directly inhibit COX activity * Cox-2 * Important inflammatory mediator (early in the process of inflammation) * Plays an early step in metabolism of arachidonic acid to prostanoids
38
What are Lipocortins/Annexins?
Large family of proteins characterized by "Annexin repeats" * anti-inflammatory role
39
What two ways does Annexin A-1 play an important anti-inflammatory role? When in the inflammatory response does Annexin act?
1. Direct effects on leukocytes inhibits their tissue infiltration 2. Suppression of Phospholipase A2 activity * prevents AA (arachidonic acid) generation and thereby suppresses downstream generation of prostanoids * These effects are very early in the inflammatory response, so they have broad powerful anti-inflammatory effects
40
What effect do Glucocorticoids have on Lipocortins/Annexins?
Lipocortin/Annexin Induction
41
Lipocortin is a ______ - expression is induced by \_\_\_\_\_\_\_\_
Lipocortin is a _protein_ - expression is induced by _GC receptor activation_ * Mechanism of inhibition of PLA2 is debated, could be by sequestering lipid substrates or direct inhibition of PLA2
42
What is Addison's disease? How is it typically treated?
* Chronic adrenocortical insufficiency * fatigue, salt balance, sugar balance problems, skin discoloration * Low production of glucocorticoids and often mineralocorticoids * Typically treated with GC/MC supplementation (Hydrocortisone)
43
What is Cushing's syndrome?
* Adrenal **overactivity** leading to excessive cortisol * adrenal tumor (cortisol producing) * Pituitary tumor (ACTH production, stimulation of Adrenal cortex) * Drug-induced (long course of GC treatment) * Ectopic tumor (ACTH producing) * Round face, fat deposition in trunk * Muscle loss, osteoporosis - protein and bone catabolism * Resection of adrenals or pituitary tumor followed by gradual adjustment towards a maintenance dose of cortisol *
44
What are four ways Cushing's syndrome might be caused?
1. adrenal tumor (cortisol producing) 2. Pituitary tumor (ACTH production, stimulation of Adrenal cortex) 3. Drug-induced (long course of GC treatment) 4. Ectopic tumor (ACTH producing)
45
Why is cushing's syndrome helpful in Pharmacology?
Understanding the features of Cushing's syndrome is helpful to understand the side effects of GC treatment
46
GC (glucocorticoids) are most widely used for:
* Powerful anti-inflammatory, immunosuppressive actions of cortisol and analogs * Allergic rxn * Eye inflammation * reduction of pain by reducing inflammation * Gastrointestinal diseases * Hematologic disorders (leukemia, myeloma) * Asthma * Organ transplants (immunosuppression to avoid rejection)
47
What might happen if Glucocorticoids are abruptly stopped?
* Addison-like symptoms * fatigue, salt balance, sugar balance, skin discoloration * Because Negative feedback from glucocorticoid administration will suppress CRH and ACTH production (ie body is not making its own) * Tapering is needed
48
What is addisonian crisis?
* Hypoglycemia (low blood sugar/glucose) * Hyponatremia (low blood Na+) * Hyperkalemia (high K+) * Low blood pressure
49
What are metabolic side effects of glucocorticoid treatment?
* Hyperglycemia * Care must be taken with diabetic patients
50
What are immunosuppressive side effects of glucocorticoid treatment?
1. Latent infections can emerge (TB) 2. Opportunistic infections can emerge Use caution with patients carrying infections
51
What are catabolic side effects of glucocorticoid treatment?
Osteoporosis, muscle wasting
52
What are anti-inflammatory side effects of glucocorticoid treatment?
Slow wound healing, ulcerations
53
What are two "other" side effects of glucocorticoid treatment?
1. Hypertension considerations (non-specific MR effects of some GCs) 2. Psychosis (elderly patients especially)
54
What is Cushingoid Appearance?
Fat deposition in the trunk but wasting away in the limbs
55
What effect would Dexamethasone have?
Dexamethasone has a higher affinity for Glucocorticoid receptor (30:0) over Mineralocorticoid receptor and would therefore stimulate GC response * potent inhibitors of inflammatory processes * Induce lipocortin/annexin - leukocytes can't infiltrate tissues * inhibits phospholipase A2 * stops generation of Arachidonic acid * Inhibit induction of COX-2 (suppress transcription of COX-2) * inhibit prostanoid synthesis
56
What effect would Prednisone have?
Prednisone has a higher affinity for Glucocorticoid receptor over Mineralocorticoid receptor (4: 0.3) and would therefore stimulate GC response * potent inhibitors of inflammatory processes - * Induce lipocortin/annexin - leukocytes can't infiltrate tissues * inhibits phospholipase A2 * stops the generation of Arachidonic acid * Inhibit induction of COX-2 (suppress transcription of COX-2) * inhibit prostanoid synthesis
57
What effect would Fludrocortisone have?
Fludrocortisone has a higher affinity for Mineralocorticoid receptors over Glucocorticoid receptor (0:250) and would therefore stimulate MC response * ​Promotes Na+/Water Reabsorption * Promote K+ excretion * increased Blood Pressure

PMCOL 200 (30 decks)

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