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PMCOL 200 > 27 - Adrenocorticosterioids > Flashcards

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
Q

Using the image, describe the generalized mechanism for steroid hormone action

A
  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
Q

What are two key targets of Glucocorticoid receptor binding?

A

Lipocortin

COX-2

27
Q

Many tissues that are glucocorticoid target tissues, have the hormone ___________ which activates cortisol (from cortisone)

A

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
Q

Corticosteroid specificity arises from ______

A

Corticosteroid specificity arises from affinity of the compound/receptor AND metabolism in target tissues

  • Because target tissues have the enzyme which activates cortisol
29
Q

Which topical would have a higher topical effect, prednisone or prednisolone?

A

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
Q

Why is prednisone ineffective as a topical treatment, but effective when taken orally?

A

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
Q

Cortisol activates the GR and MR but has weak mineralocorticoid effects in vivo. Why?

A

Kidney cells (mineralocorticoid targets) express an enzyme (11Beta Hydroxysteroid Dehydrogenase Type 2 (HSD-2)) that renders cortisol inactive

32
Q

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?

A

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
Q

What is Pseudohyperaldosteronism and what are two causes?

A
  • 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
Q

What are the metabolic effects of glucocorticoids?

A
  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
Q

What is the main pharmacological use of glucocorticoids?

A

For anti-inflammatory effects

36
Q

What are the two key Glucocorticoid-mediated mechanisms in inflammation?

A
  1. Inhibit AA (arachidonic acid) generation by phospholipase A2
  2. Inhibit prostanoid synthesis

These two effects have widespread downstream effects on inflammatory reactions

37
Q

What action does glucocorticoid have on cyclooxygenase-2 (COX-2)?

How does it exert this effect?

A
  • 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
Q

What are Lipocortins/Annexins?

A

Large family of proteins characterized by “Annexin repeats”

  • anti-inflammatory role
39
Q

What two ways does Annexin A-1 play an important anti-inflammatory role?

When in the inflammatory response does Annexin act?

A
  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
Q

What effect do Glucocorticoids have on Lipocortins/Annexins?

A

Lipocortin/Annexin Induction

41
Q

Lipocortin is a ______ - expression is induced by ________

A

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
Q

What is Addison’s disease?

How is it typically treated?

A
  • 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
Q

What is Cushing’s syndrome?

A
  • 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
Q

What are four ways Cushing’s syndrome might be caused?

A
  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
Q

Why is cushing’s syndrome helpful in Pharmacology?

A

Understanding the features of Cushing’s syndrome is helpful to understand the side effects of GC treatment

46
Q

GC (glucocorticoids) are most widely used for:

A
  • 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
Q

What might happen if Glucocorticoids are abruptly stopped?

A
  • 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
Q

What is addisonian crisis?

A
  • Hypoglycemia (low blood sugar/glucose)
  • Hyponatremia (low blood Na+)
  • Hyperkalemia (high K+)
  • Low blood pressure
49
Q

What are metabolic side effects of glucocorticoid treatment?

A
  • Hyperglycemia
    • Care must be taken with diabetic patients
50
Q

What are immunosuppressive side effects of glucocorticoid treatment?

A
  1. Latent infections can emerge (TB)
  2. Opportunistic infections can emerge

Use caution with patients carrying infections

51
Q

What are catabolic side effects of glucocorticoid treatment?

A

Osteoporosis, muscle wasting

52
Q

What are anti-inflammatory side effects of glucocorticoid treatment?

A

Slow wound healing, ulcerations

53
Q

What are two “other” side effects of glucocorticoid treatment?

A
  1. Hypertension considerations (non-specific MR effects of some GCs)
  2. Psychosis (elderly patients especially)
54
Q

What is Cushingoid Appearance?

A

Fat deposition in the trunk but wasting away in the limbs

55
Q

What effect would Dexamethasone have?

A

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
Q

What effect would Prednisone have?

A

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
Q

What effect would Fludrocortisone have?

A

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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