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MD4001 Pharmacology > Actions of Adrenal Steroids and Treatment of Adrenal Disorders > Flashcards

Actions of Adrenal Steroids and Treatment of Adrenal Disorders Flashcards

1
Q

What does the zona reticularis produce?

A

Mainly androgens (DHEA and Testosterone precursors)

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2
Q

What glucocorticoids are produced by the zona fasciculata?

A

Cortisol / Hydrocortisoneand corticosterone

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3
Q

What are glucocorticoids most commonly used for?

A
  • Anti-inflammatory and immunosuppressive properties

- Exception is replacement therapy

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4
Q

What glucocorticoid can be used for the treatment of rheumatoid arthritis?

A

Dexamethasone

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5
Q

What does the hypothalamus release to stimulate ACTH release from anterior pituitary in the HPA axis?

A

CRF (corticotropin releasing factor)

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6
Q

What hormones stimulate the anterior pituitary to produce ACTH?

A
  • CRF

- ADH

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7
Q

What cells produce ACTH?

A

Corticotrophs

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8
Q

What does ACTH stimulate the synthesis and secretion of?

A
  • Glucocorticoids (Cortisol)

- Mineralcorticoids (Aldosterone)

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9
Q

What hormone from the adrenal cortex is secreted in response to stimulation by the RAAS system ?

A

Aldosterone (mineralocorticoid)

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10
Q

What is the synthetic analogue of ACTH used to treat those with low ACTH?

A

Tetracosactide (contains first 24 amino acids of ACTH) - stimulates release of cortisol (glucocorticoid)

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11
Q

What medication mimics the action of a mineralocorticoid (aldosterone)?

A

Fludrocortisone

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12
Q

What medication mimics the action of a glucocorticoid (cortisol)?

A

Prednisolone

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13
Q

What hormone is used to treat secondary adrenal insufficiency?

A

Tetracosactide (ACTH analogue)

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14
Q

What is a significant side-effect of long term prednisolone?

A

Adrenal atrophy

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15
Q

What is the precursor protein for mineralocorticoids, glucocorticoids and sex hormones?

A

Cholesterol

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16
Q

What is the rate limiting step in the synthesis of cholesterol to eventually mineralo/glucocorticoids / sex homrones?

A

Conversion of cholesterol to pregnenolone

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17
Q

What are the rate limiting step (cholesterol to pregnenolone) regulators?

A
  • ACTH (+)
  • Angiotensin II (+)
  • Amino-glutethimide (drug) (-)
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18
Q

What drug inhibits the Rate-limiting step (cholesterol to pregnenolone)?

A

Aminoglutethimide

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19
Q

What does Trilostane block?

A

3 Beta-dehydrogenase (Pregnenolone tp progesterone) blocks synthesis of all adrenal hormones

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20
Q

What diseases can trilostane be used to treat?

A
  • Cushing’s

- Hyperaldosteronism (Conn’s)

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21
Q

What does Metapyrone blocK?

A

11-Beta-OH (Beta hydroxylation of carbon 11)

- Blocks formation of hydrocortisone and corticosterone

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22
Q

Where does angiotensin II act in the steroid pathway?

A
  • Formation of aldosterone

- Formation of pregnenolone (from cholesterol)

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23
Q

Describe the mechanism of action of glucocorticoids?

A
  • Pass through cell membrane
  • Bind to intracellular receptor
  • Migrate to nucleus
  • In nucleus ligand bound receptor will dimerise and bind DNA and promotor of a target gene
  • Reguate the trascript of multiple genes (activate or inhibit)
  • Metabolic effects are mediated by enzymes such as cAMP-dependant protein kinase (PKA) but not all the target genes are known -vaaries between tissues
24
Q

What are the common glucocorticoid drugs used systematically?

A
  • Hydrocortisone
  • Prednisolone
  • Dexamethasone
25
Q

What are the regulatory actions of glucocorticoids?

A
  • Hypothalamus and pituitary - negative feedback on CRF and ACTH leading to reduced release of endogenous glucocorticoids
  • Cardiovascular - reduced vasodilation and fluid extraction
  • Musculoskeletal - decreasing osteoblast and increasing osteoclast activity to give a tendency for osteoperosis
26
Q

What are the metabolic actions of glucocorticoids?

A
  • Carbohydrates - decreased uptake and utilization of glucose accompanied by increased gluconeogenesis to cause hyperglycaemia. Also increased glycogen storage (may be the result of increased insulin secretion due to hyperglycemia)
  • Proteins - increased catabolism and reduced anabolism particularly muscle - can lead to wasting
  • Lipids - permissive effect on lipolytic hormones and a redistribution of fat as observed in Cushing’s syndrome
27
Q

What are the anti-inflammatory and immunosuppressive effects of glucocorticoids?

A
  • Decrease influx and activity of leukocytes (acute inflammation)
  • Decrease activity of mononuclear cells, angiogenesis and fibrosis (chronic inflammation)
  • Lymphoid tissue - decrease clonal expansion of T and B cells and decreased activation of cytokine-secreting T cells. Switch from Th-1 to Th-2 responses
  • Decreased production and action of cytokines including interleukins, TNF-alpha, cell adhesion and induced Nitric oxide
  • Reduced generation of eicosanoids due to decreased COX-2 expression
  • Reduced generation of IgG and complement components in blood
  • Increasded release of anti-inflammatory factors (IL-10 and Annexin-1)
  • Overall reduction in activity of the innate and acquired immune systems
28
Q

What kind of diseases are anti-inflammatory/immunosuppressive therapies given?

A
  • Hypersensitivity
  • Topically in inflammatory conditions of skin, eye, ear, throat (e.g eczema)
  • IBDs, RA, haemolytic anaemias, idiopathic thrombocytopaenia
  • Prevention of graft-versus host disease (rejection) following organ or bon emarrow transplantation
  • Cancer - in comboniation with cytotoxic drugs in treatment of Hodgkin’s disease and acute lymphocytic leukaemia. Reduce oedema in tumours (dexamethasone)
29
Q

What is the steriod of choice for systemic ant-inflammatoy and immunosuppressive effects?

A

Prednisolone (more potency for anti-inflammatory processes vs Na+ retaining processes)

30
Q

What is the steriod of choice for anti-inflammatory and immunosuppressive effects where water retention is undesirable? (e.g cerebral oedema)

A

Dexamethasone (minimal effect on Na+ retention)

  • Drug of choice for suppression of ACTH production
  • Also Betamethasone, triamcinolone (toxic), methylprednisolone
31
Q

What is the drug of choice when wanting to produce specific mineralcorticoid effects?

A

Fludrocortisone

32
Q

What are the the adverse or unwanted effects of corticosteroids? (uncommon in replacement therapy but more in prolonged systemic use)

A
  • Suppression of response to infection and injury
  • Opportunistic infections can be problematic
  • Oral fungal or yeast infections can occur
  • Wound healing is impaired
  • Osteoperosis
  • Hazard or fractures
  • Hyperglycemia
  • Muscle wasting and weakness
  • Inhibtion of growth in children
  • CNS effects - euphoria, depression, psychosis
  • Glaucoma
33
Q

How may Cushing’s syndrome affect fertility?

A

Women - amenorrhea

Men - Infertility and low libido

34
Q

What is the treatment of iatrogenic Cushing’s syndrome?

A
  • Decrease or withdraw use of corticosteroids

- Must be done gradually to avoid any unpleasant side effects

35
Q

What is a major risk of Cushing’s syndrome?

A
  • Hypertension

- Increases risk of heart attack and stroke

36
Q

What is the main endogenous mineralocorticoid?

A

Aldosterone

37
Q

What drug inhibits Aldosterone?

A

Spironalactone

38
Q

Describe the mechansim of action of Aldosterone?

A
  • Affects principle cell in Collecting Tubule
  • Region usually impermeable to water and salts
  • Binds to Na+ H+ exchanger to promote Na+ reabsorption back into blood
  • Also activates gene transcription of Na+/K+ antiporter on apical membrane
39
Q

What is the drug of choice to treat Addison’s disease?

A

Oral Fludrocortisone (synthetic mineralocorticoid)

  • Increases Na+ reabsorption in distal tubule and increases K+ and H+ efflux
  • Acts on intracellular receptors that modulate DNA transcription
40
Q

Why is synthetic aldosterone not used to treat addison’s disease?

A

75% of it is broken down to inactive form in liver in first pass metabolism

41
Q

What is spironalactone?

A

Competitive antagonsit of aldosterone

- K+-sparing diuretic

42
Q

What diseases can spironalactone be used to treat?

A
  • Hypoeraldosteronism (e.g Conn’s)
  • Resistant hypertension
  • Heart Failure
  • Oedema
43
Q

What percentage of hyperaldosteronism is caused by adrenal adenomas (Conn’s syndrome)?

A

80%

44
Q

What is Addison’s disease?

A

A condition where the adrenal glands are dysfunctional

45
Q

What percentage of Addison’s disease cases are due to an autoimmune disease?

A

7 in 10

46
Q

What are other causes of Addison’s disease other than autoimmune?

A
  • TB which has spread to adrenals
  • Metastatic cancers
  • Atrophy due to prolonged steroid therapy
  • Haemochromatosis
  • Amyloidosis
47
Q

How many people suffer from Addison’s disease UK?

A

8,000 (usually between ages of 30 - 50)

48
Q

What are the symptoms of Addison’s disease?

A
  • Anorexia
  • Vomitting Nausea
  • Weakness
  • Hypotension
  • Skin pigmentation (due to ACTH)
  • Low Na+, High K+
  • Chronic dehydration
  • Sexual dysfunction
49
Q

What does Addison’s disease treatment look like?

A

Corticosteroid therapy for life

  • Hydrocortisone (2-3 times a day, 25 mg in morning, 12.5 mg in afternoon)
  • Prednisolone and Dexamethasone less common
  • If greater mineralocorticoid effects needed aldosterone replaced with fludrocortisone (more selective)
50
Q

How are side effects reduced when prescribing corticosteroids?

A

By slowly increasig dose

51
Q

How is Conn’s syndrome treated / primary hyperaldosteronism?

A
  • Spironalactone (4 weeks prior to surgery)

- Surgical treatment involving surgical adrenalectomy, laproscopic surgery is preferred to open

52
Q

What complication of Conn’s syndrome may persist even after removal of adenoma?

A

Hypertension (due to effects of the previous hypertension on vasculature)

53
Q

What are other cause of primary hyperaldosteronism? (other than Conn’s)

A
  • Bilateral adrenal hyperplasia (BAH) (adrenal cells become hyperplastic) - 15%
  • Unilateral adrenal hyperplasia (rare) (adrenalectomy)
  • Adrenal carcinoma (rare)
54
Q

When is an adrenal carcinoma usually diagnosed?

A

Once an adrenal adenoma has been removed and examined histologically

55
Q

What enzyme is missing in Congenital Adrenal Hyperplasia?

A

C-21 hydroxylase enzyme is missing.

- Non hydoxylated versions of cortisol, corticosterone and aldosterone are made

56
Q

How do non hydroxylated cortisol, corticosterone and aldosterone act?

A
  • Do not negatively feed back on HPA axis

- High levels of ACTH cause constant stimulation of production of C-19 androgens (causes precocious puberty)

57
Q

How is Congenital Adrenal Hyperplasia treated?

A
  • Cortisol to replace the missing cortisol and cause negative feedback on HPA
  • Replace mineralocorticoids with fludrocortisone

MD4001 Pharmacology (8 decks)

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