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BIOM 4090 > Adrenocorticosteroids and Adrenocortical Antagonists > Flashcards

Adrenocorticosteroids and Adrenocortical Antagonists Flashcards

1
Q

What are the three andrenocorticosteroids?

A
  • Mineralocorticoids
  • Glucocorticoids
  • Androgens
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2
Q

With regards to the morphology of the adrenal gland what are the parts and what are they responsible for?

A
  • Z.glomerulosa is controlled by angiotensin II and K+ to produce aldosterone
  • Z.fasciculata is responsible for production of cortisol
  • Z.reticularis is responsible for production of DHEA and estrogen
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3
Q

Discuss the Hypothalamus Pituitary Adrenal Axes with respect to cortisol (hydrocortisone) regulation and aldosterone regulation

A
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4
Q

Mineralocorticoids: Aldosterone - what is it? what regulates its synthesis? What are the effects of this?

A

Mineralocorticoids: Aldosterone
- Aldosterone = steroid hormone from cholesterol
Three systems regulate aldosterone synthesis:
- The renin-angiotensin system (main one)
- Blood potassium levels
- ACTH
- The renin-angiotensin system regulates extracellular fluid (ECF) volume
- ↓ ECF volume = ↓ perfusion pressure at the afferent arteriole of the renal glomerulus (baroreceptor)
- This stimulates the juxtaglomerular cells to secrete renin, a protease that cleaves angiotensinogen → angiotensin I → angiotensin II
- Angiotensin II has direct arteriolar pressure effects, and it stimulates aldosterone synthesis by binding to a G protein-coupled receptor in the zona glomerulusa

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5
Q

Mineralocorticoids and the renin angiotensin system - role of angiotensin I/II, aldosterone and its effect on renal sodium and blood volume (flow chart style)

A
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6
Q

What are the parts of the renal juxtaglomerular apparatus?

A
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7
Q

How is cholesterol converted to Pregnenolone (P5)?

A
  • Cholesterol is the precursor of cortisol and aldosterone and converts to P5 via cytochrome P450 which is found in the liver and is the dependent enzyme
  • Biotransformation of P5 to glucocorticoids:
    - P5 → deoxycortisol → cortisol
  • Biotransformation of P5 to androgens
    - P5 → DHEA → androstenedione
  • Biotransformation of P5 to aldosterone
    - P5 → DOC → aldosterone
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8
Q

Describe Adrenocorticosteroid Transport

A

Cortisol
- 5% free
- 75% transcortin (CBG)
- 20% albumin
Aldosterone
- Almost no binding

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9
Q

Describe the steroid hormone action of cortisol (hydrocortisone)?

A
  • Numerous effects; direct and permissive
  • CHO, protein and lipid metabolism
    - Increase blood-glucose overall; protects heart/brain
    - Liver – gluconeogenesis, glycogen storage
    - Periphery-decrease glucose use, increase protein and lipid breakdown
  • Anti-inflammatory and immunomodulatory effects
    - Inhibit production of proinflammatory mediators
  • Stress coping support
  • CNS; sense of well-being, mood and behaviour
  • Cardiovascular integrity
  • Stimulation for development of fetal lung-surfactant
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10
Q

Describe the steroid hormone action of aldosterone

A
  • Fluid and electrolyte balance; Na+ and K+ homeostasis
    - Rapid activation of Na+ channels in the apical membrane of principal cells (Distal Collecting Tubes + Collecting ducts)
    - Promotes Na+ reabsorption, H+/K+ excretion
    - Cardiovascular support; blood pressure
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11
Q

Modification of Glomerular Filtrate with reabsorption of sodium in the distal tubule and collecting duct

A

Distal tubule
* Reabsorption of 7% of Na+
* Impermeable to water → further decreases in concentration to a value lower than plasma
Collecting duct
* Reabsorption of 2-3% of Na+; permeability to water and of concentrated vs. dilute urine dependent on presence of vasopressin (ADH)

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12
Q

The steroid hormone preparations for the short-medium acting (<24hr) agents and its activity (potency)

A
  • Cortisol - use as standard → 1 is “base” value
  • Prednisolone and methylprednisolone are better anti-inflammatory vs. salt retaining
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13
Q

The steroid hormone preparations for the intermediate acting (24-48hr) agents and its activity (potency)

A
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14
Q

The steroid hormone preparations for the long acting (>48hr) agents and its activity (potency)

A
  • Long-acting is 30x greater than cortisol
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15
Q

The steroid hormone preparations for the mineralocorticoid agents and its activity (potency)

A

Fludrocortisone and desoxycorticosterone acetate are better as salt retaining drugs than anti-inflammatory

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16
Q

What is the Special Case with steroid hormone preparations?

A
  • Special case: topically active glucocorticoid – good anti-inflammatory
    - Fluticasone Propionate (flonase)
    - Very good option instead of antibiotics → avoid problem of antibiotic resistance
    - Used for sinus infection, asthma, allergies
  • Glucocorticoid and progesterone antagonist:
    -Mifepristone (treats “Cushing’s syndrome”)
17
Q

Clinical applications - Hyperadrencorticism (Cushing’s syndrome) what is it? Its causes? its diagnosis?

A
  • Marked by presence of elevated cortisol levels in the body – clinical signs of hypercortisolism
    - Upper body obesity “moon face”, “buffalo hump”
    - Thinning of skin; easily bruised
    - Muscle wasting (thinning) of arms and legs (↓ muscle mass)
    - Weakening of bones; osteopenia
    - Elevated liver enzymes
  • Causes:
    - Pituitary adenoma; women > men by 5X
    - Iatrogenic; long term steroid treatment for another problem
    - Ectopic ACTH syndrome
    - Adrenal gland tumors
  • Diagnosis: clinical signs, blood tests, imaging
    - 24-hour urine collection; elevated cortisol
    - Provocative tests to rule out adrenal vs pituitary vs ectopic
18
Q

What are the therapy options for Cushing’s?

A
  • Surgery – Resectable tumors; pituitary, adrenal, ectopic
  • Radiation – Alone or follow-up surgery of tumor
  • Adrenocorticosteroid Inhibitors – Mitotane
    - Adrenolytic; specific for adrenals
  • Hormone Synthesis Inhibitors
    - Ketoconazole; most effective inhibitor; liver damage
    - Aminoglutethimide; inhibits conversion of cholesterol to pregnenolone; adrenal tumors
    - Trilostane; inhibits conversion of pregnenolone to progesterone (next step in synthesis) – available in the UK
  • Glucocorticoid receptor antagonists
    - Mifepristone: at higher doses may be effective
    - Used on inoperable patients (no other therapeutic option available) with ectopic or adrenal tumors not responding to other therapy
19
Q

Clinical Applications - Hypoadrenocorticism (Addison’s disease) what is it? its causes? and discuss its acute vs chronic effects

A

Adrenal Insufficiency “Addison’s disease”
- Not enough production of cortisol (opposite of Cushing’s syndrome)
- Most commonly primary adrenal insufficiency from autoimmune disease and adrenal destruction (used to be common in cases of tuberculosis)
- Other common cause is abrupt steroid withdrawal
- Possible following surgery (no longer have stimulus to produce cortisol) for adrenal tumors or pituitary tumors
- Acute vs Chronic adrenal insufficiency
- Acute adrenal crisis is often due to abrupt withdrawal of long-standing glucocorticoid therapy, but can also precipitate from exacerbation of chronic adrenal insufficiency
- Acute emergency often; IV fluid support (isotonic NaCl) and IV corticosteroids (hydrocortisone), other supportive care as needed e.g. antibiotics (for possible bacterial infection)
- Chronic-similar signs to acute but less severe (not as intense but long term)
- Long-term glucocorticoid (hydrocortisone or prednisone) replacement therapy
- Fludrocortisone (mineralocorticoid) if primary Addison’s disease present

20
Q

Clinical Applications – Non endocrine diseases

A

Non-endocrine Use of Glucocorticoids
- Anti-inflammatory and anti-allergy therapy
- Mainstay of glucocorticoid use/misuse in medicine
- Plethora of allergic conditions; most organ systems
- Reduce proinflammatory mediators by multiple mechanisms
- Intensive short-term or emergency therapy
- Anaphylaxis, shock, heat stroke
- Rapidly acting IV preparations of glucocorticoids
- Usually given in high doses for pronounced effects
- Immunosuppressive therapy
- Used to quiet an overzealous immune system that is detrimental – organ transplants (help body not reject new organ), autoimmune ds
- Neoplasia
- Glucocorticoids have antilymphoproliferative effects
- Useful for certain hematologic malignancies such as lymphoma, certain leukemias
- Adjunct therapy for inflammation following radiation and with mast cell tumors

21
Q

Clinical Applications - Appropriate Glucocorticoid Therapy

A
  • Glucocorticoids use in non-endocrine disease merely mask symptoms of condition being treated; need to correct underlying problem
  • Adverse effects of steroid therapy can be minimized
    - Lowest dose possible
    - Low potency steroids; prednisone
    - Alternate day therapy; give HPA a day off
    - Tapered reduction of steroid therapy to allow HPA axis time to recover following treatment
22
Q

Clinical Applications - Mineralocorticoid Antagonists

A
  • Primary aldosteronism (want to ↓ levels of aldosterone); adrenal adenoma is usual cause
    - Signs of hypertension and hypokalemia
    - Treatment is usually surgical; can be curative
    - Blockade of aldosterone can be accomplished also with drugs
    -Spironolactone, Eplerenone
  • Hypertension and heart failure; increased aldosterone contributes to adverse effects
    - Eplerenone
23
Q

Adrenal: Take Home Messages

A
  • Adrenal steroids are very powerful, affecting the entire body
    - Aldosterone (Z. Glomerulosa)
    - Cortisol and androgens (Z fasciculata and Z reticularis)
  • Aldosterone (mineralocorticoid) controlled by kidney renin-angiotensin system
  • Cortisol (Glucocorticoid) by hypothalamic-pituitary ACTH
  • Aldosterone controls kidney sodium and water retention
  • Cortisol controls metabolism, promoting glucose regeneration and entry to the blood
  • Cortisol, but not aldosterone, largely carried bound to proteins in the blood
  • Pharmacological targets: enzymes involved in steroid synthesis, as well as steroid receptors
  • Mineralocorticoid (MR) and glucocorticoid (GR) receptors are very similar, so high cortisol increases sodium retention
  • Different synthetic corticosteroids available – MR as well as GR specific, differing in duration of action, some only surface active, as well as some antagonists (mifepristone, GR antagonist; spironolactone, MR antagonist)
  • Widely used as anti-inflammatories, immune suppressants treatment of glucocorticoid insufficiency, treatment of women in premature labor
  • Very powerful drugs, so long term glucocorticoids suppress ACTH, and must be tapered off slowly – or the patient may suffer an Addisonian crisis when the glucocorticoid is stopped
24
Q
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BIOM 4090 (25 decks)

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