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MD4001 Week 11 > 1. Actions of adrenal steroids and treatment of adrenal disorders > Flashcards

1. Actions of adrenal steroids and treatment of adrenal disorders Flashcards

1
Q

Origins and secretions of the adrenal medulla?

A

Adrenal medulla
• Neural crest origin
• Secretes catecholamines

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2
Q

Origin and secretions of the adrenal cortex?

A 
Adrenal cortex
• Mesodermal origin
• Zona glomerulosa
– Produces mineralocorticoids
(Aldosterone)
• Zona fasciculata
– Produces mainly glucocorticoids
(Cortisol and Corticosterone)
• Zona reticularis
– Produces mainly androgens (DHEA and Testosterone precursors)
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3
Q

Role of mineralocorticoids?

A
  • Mineralocorticoids regulate salt/electrolyte and water balance - important for Na+ retention in the kidney to maintain blood pressure.
  • The main mineralocorticoid is aldosterone.
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4
Q

Role of glucocorticoids?

A
  • The glucocorticoids have widespread actions affecting carbohydrate and protein metabolism but also have potent effects on host defence mechanisms – largely immunosuppressive and anti-inflammatory.
  • The main glucocorticoid in humans is hydrocortisone (also called cortisol)
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5
Q

How does hydrocortisone have a mineralocorticoid effect?

A

Hydrocortisone actions are not completely separate from mineralocorticoid actions because it has equal potency for the GR and MR, so can have substantial effects on water and electrolyte balance.

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6
Q

What are the indications for glucocorticoid use?

A

With the exception of replacement therapy, glucocorticoids are used most commonly for their anti-inflammatory and immunosuppressive properties.

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7
Q

Other name for ADH?

A

AVP

Vasopressin

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8
Q

What makes up the HPA axis?

A

• Adrenals are part of the (H-P-A) axis.
• CRF and ADH (vasopressin) act on corticotrophs
in anterior pituitary inducing ACTH release.
• ACTH stimulates the synthesis and secretion of both glucocorticoids and mineralocorticoids from the adrenal cortex.

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9
Q

Effect of RAAS on HPA axis?

A

Renin-Angiotensin system aids ACTH to promote mineralocorticoid secretion.

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10
Q

Recombinant ACTH is seldom used, instead a synthetic analogue is used - ___________.

A

Recombinant ACTH is seldom used, instead a synthetic analogue is used - Tetracosactide.

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11
Q

To mimic mineralocorticoid effect ___________ is principally used.

A

To mimic mineralocorticoid effect Fludrocortisone is principally used.

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12
Q

To mimic glucocorticoids effect ________ is principally used.

A

To mimic glucocorticoids effect Prednisolone is principally used.

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13
Q

Role of ACTH in pregnenolone synthesis?

A

Controls the rate limiting step of cholesterol from pregnenolone. This then goes onto break down to form all the mineralocorticoids, glucocorticoids and sex hormones

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14
Q

What drug inhibits the RLS in mineralocorticoids, glucocorticoids and sex hormones biosyntheis?

A

• Aminoglutethimide

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15
Q

Action of trilostane? Use?

A

Trilostane blocks 3 β-dehyd - used in treating Cushing’s and primary hyperaldosteronism.

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16
Q

Action of metapyrone?

A

Metapyrone prevents the β- hydroxylation of C11

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17
Q

Action of carbenoxolone?

A

Carbenoxolone inhibits the conversion of hydrocortisone to cortisone in the kidney.

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18
Q

Drugs that prevents biosynthesis of corticosteroids, mineralocorticoids and sex hormones

A

Aminoglutethimide inhibits RLS
• Trilostane blocks 3 β-dehyd - used in treating Cushing’s and primary hyperaldosteronism.
• Metapyrone prevents the β- hydroxylation of C11
• Carbenoxolone inhibits the conversion of hydrocortisone to cortisone in the kidney.
RLS
Precursor

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19
Q

MoA of glucocorticoids?

A
  1. Genomic
    Bind intracellular receptors
    Migrate to the nucleus where they dimerize and regulate gene transcription
  2. Non-genomic
    Rapid effects mediated through signalling systems in the cytosol
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20
Q

Common analogue GC drugs used?

A

Hydrocortisone, Prednisolone and Dexamethasone

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21
Q

Mediation of metabolic effects of glucocorticoids?

A

Metabolic effects of glucocorticoids are mediated by enzymes such as cAMP-dependent protein kinase (PKA) but not all the target genes are known - varies between tissues.

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22
Q

Regulatory actions of GCs?

A

@ Hypothalamus and pituitary – negative feedback on CRF and ACTH leading to reduced release of endogenous glucocorticoids
@ Cardiovascular – reduced vasodilation and fluid exudation.
@ Musculoskeletal – decreasing osteoblast and increasing osteoclast
activity to give a tendency for osteoporosis.

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23
Q

Metabolic actions of GCs?

A

Carbohydrates (build up and storage)

  • Decreased uptake and utilization of glucose
  • Increased gluconeogenesis to cause hyperglycaemia.
  • Increased glycogen storage (may be the result of increased insulin secretion due to hyperglycemia).

• Proteins (breakdown)

  • increased catabolism
  • reduced anabolism particularly in muscle. Can lead to muscle wasting.

• Lipids

  • permissive effect on lipolytic hormones
  • redistribution of fat as observed in Cushing’s Syndrome.
24
Q

anti-inflammatory and immunosuppressive effects of GC?

A

• Acute inflammation- decreased influx and activity of leukocytes.

• Chronic inflammation- decreased activity of mononuclear cells,
decreased angiogenesis and fibrosis.

• Lymphoid tissue- decreased clonal expansion of T and B cells and decreased activation of cytokine-secreting T cells. Switch from Th-1 to Th- 2 responses.

25
Q

GC actions of mediators of inflammatory and immune responses?

A
  • Decreased production and action of cytokines including interleukins, TNF-α, cell adhesion factors and induced nitric oxide.
  • Reduced generation of eicosanoids due to decreased COX-2 expression
  • Reduced generation of IgG and complement components in the blood.
  • Increased release of anti-inflammatory factors (IL-10 and Annexin-1).
  • Overall reduction in activity of the innate and acquired immune systems.
26
Q

What are the clinical uses for glucocorticoids?

A
  1. Replacement therapy: for patients with adrenal failure (Addison’s disease).
  2. Anti-inflammatory/ immunosuppressive therapy:
  3. Cancer - In combination with cytotoxic drugs in the treatment of Hodgkin’s disease and acute lymphocytic leukaemia. Reduce oedema in tumours (Dexamethasone).
27
Q

What are the anti-inflammatory/immunosuppressive therapeutic uses of glucocorticoids?

A
  • Hypersensitivity states and asthma
  • Topical use to skin, ear, ear, throat e.g. eczema, allergic conjunctivitis, rhinitis)
  • Diseases with inflammatory and immune components e.g. rheumatoid arthritis , IBD, anaemias)
  • Graft rejections
28
Q

What is the drug of choice for corticosteriod replacement therapy?

A

Hydrocortisone

Short duration of action

29
Q

Name 11 corticosteroid agents used?

A 
Hydrocortisone (standard)
Cortisone
Deflazacort
Prednisolone
Prednisone
Methylprednisolone
Triamcinolone
Dexamethasone
Betamethasone
Fludrocortisone
Aldosterone
30
Q

What is the drug of choice for systemic anti-inflammatory and immunosuppressive effects/

A

Prednisolone

31
Q

Name the drug:
Anti-inflammatory and immunosuppressive
Used when water/Na retention is undesirable e.g. cerebral oedema
Drug of choice for suppression of ACTH production

A

Dexamethasone

32
Q

Which corticosteroid is used for mineralocorticoid effects?

A

Fludrocortisone

33
Q

What are the adverse effects of corticosteriod use?

A

Mainly seen after prolonged system use NOT following replacement therapy

Injury and infection response is suppressed leading to:

  • Opportunistic infections
  • Oral fungal infections
  • Wound healing is poor

Osteoporosis

Hyperglycaemia + muscle weakness/wasting

Inhibition of growth in children

CNS: Depression, euphoria, psychosis

Glaucoma

34
Q

Symptoms of cushing’s?

A 
Euphoria
Buffalo bump
Thinning skin
Muscle wasting
Poor wound healing
Easy bruising
Increased abdominal fat
Moon face with red cheeks
35
Q

Cause of cushing’s syndrome?

A

Exogenous:
Prolonged administration of glucocorticoid drugs

Endogenous: Overproduction of cortisol due to disease (e.g. tumour) e.g.

  • Pituitary tumour (cushing’s disease) 70% of cases
  • Adrenal tumour 15% of cases
  • Other
36
Q

Treatment for iatrogenic Cushing’s?

A

The main treatment for iatrogenic Cushing’s syndrome is to decrease or withdraw the use of corticosteroids. However, this must be done gradually to avoid any unpleasant side effects.

37
Q

Treatment for endogenous Cushings?

A

For endogenous Cushing’s syndrome, surgery to remove the tumour is usually recommended. If surgery is unsuccessful, or it is not possible to remove the tumour safely, medication can be used to counter the effects of the high cortisol levels.

38
Q

Risk of not treating Cushing’s?

A

Left untreated, Cushing’s syndrome can cause high blood pressure which increases the risk of heart attack and stroke.

39
Q

Main endogenous mineralocorticoid?

A

aldosterone

40
Q

Main clinical use of mineralocorticoids?

A

Replacement therapy in Addison’s disease due to decreased aldosterone secretion

41
Q

Most common mineralocorticoid replacement drug?

A

Fludrocortisone taken orally

42
Q

Actionof fludrocortisone?

A

It increases Na+ reabsorption in distal tubules and increases K+ and H+
efflux
• Acts on intracellular receptors that modulate DNA transcription.

43
Q

___________ is a competitive antagonist and is a potassium-sparing diuretic.
• Used also to treat hyperaldosteronism, resistant hypertension, heart failure and oedema.

A
  • Spironolactone is a competitive antagonist and is a potassium-sparing diuretic.
  • Used also to treat hyperaldosteronism, resistant hypertension, heart failure and oedema.
44
Q

Addison’s disease is _______. Just over 8,000 people in the UK have Addison’s disease at any one time. Most cases first develop in people aged between ______ and 50, but can occur at______

A

Addison’s disease is rare. Just over 8,000 people in the UK have Addison’s disease at any one time. Most cases first develop in people aged between 30 and 50, but can occur at any age.

45
Q

Causes of addison’s?

A
  1. Autoimmune in 70% e.g. autoimmune adrenalitis. Antibodies destroy adrenal cortex cells that makes cortisol and aldosterone
  2. TB spread from the lungs to destroy adrenals
  3. Mets
  4. Atrophy due to steroid prolonged use
  5. Hemochromatosis
  6. Amyloidosis
46
Q

Addison’s symptoms?

A

Anorexia, nausea, vomiting, weakness, hypotension, skin pigmentation (due to ACTH), low sodium/high potassium, Chronic dehydration and sexual dysfunction.

47
Q

Addison’s disease treatment

A
  • Treatment will usually involve corticosteroid (steroid) replacement therapy for life.
  • Corticosteroid mediation is used to replace endogenous cortisol and aldosterone that are no longer produced.

E.g. hydrocortisone tablets 2/3 times a day. 25mg in morning and 12.5mg in afternoon.
Fludrocortison is used if greater mineralocorticoid effect is desired

48
Q

Adrenal adenoma presents as…

A

Conn’s syndrome

49
Q

Main primary hyperaldosteronism?

A

Adrenal adenoma

50
Q

Treatment of primary hyperaldocteronism?

A

Medical management is used in the period prior to surgery - involves the use of aldosterone antagonists, e.g. Spironolactone usually for 4 weeks.
• Surgical treatment involves surgical adrenalectomy, laparoscopic surgery is preferred over open surgery.

  • Hypertension may persist after removal of the adenoma, due to effects of the previous hypertension on vasculature *
51
Q

Causes for primary hyperaldosteronism?

A

Adrenal adenoma

Adrenal hyperplasia

Adrenal carcinoma

52
Q

Adrenal hyperplasia and a cause for primary hyperaldosteronism?

A

In bilateral adrenal hyperplasia (BAH) the adrenal cells become hyperplastic, resulting in excessive secretion of aldosterone. This accounts for 15% of all cases of hyperaldosteronism.

53
Q

Adrenal carcinoma as a cause for primary hyperaldosteronism?

A

This is a rare cause of primary hyperaldosteronism but one that should not be missed. It is usually only diagnosed once an adrenal adenoma has been removed and examined histologically

54
Q

Cause for congenital adrenal hyperplasia?

A

Genetic disorder where the C-21 hydroxylase enzyme is missing.
Non-hydroxylated versions of cortisol, corticosterone and aldosterone are made.

55
Q

Congenital adrenal hyperplasia?

Treatment

A

Genetic disorder where the C-21 hydroxylase enzyme is missing.
Non-hydroxylated versions of cortisol, corticosterone and aldosterone are made.
• These lack normal activity and do not negatively feedback on the HPA axis.
• High levels of ACTH cause constant stimulation of production of C-19 androgens.
• Treat with cortisol to replace the missing cortisol and cause negative feedback on HPA.
• Replace the mineralocorticoid.

MD4001 Week 11 (7 decks)

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