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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
What are the regulatory actions of glucocorticoids?
- 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
What are the metabolic actions of glucocorticoids?
- 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
What are the anti-inflammatory and immunosuppressive effects of glucocorticoids?
- 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
What kind of diseases are anti-inflammatory/immunosuppressive therapies given?
- 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
What is the steriod of choice for systemic ant-inflammatoy and immunosuppressive effects?
Prednisolone (more potency for anti-inflammatory processes vs Na+ retaining processes)
30
What is the steriod of choice for anti-inflammatory and immunosuppressive effects where water retention is undesirable? (e.g cerebral oedema)
Dexamethasone (minimal effect on Na+ retention) - Drug of choice for suppression of ACTH production - Also Betamethasone, triamcinolone (toxic), methylprednisolone
31
What is the drug of choice when wanting to produce specific mineralcorticoid effects?
Fludrocortisone
32
What are the the adverse or unwanted effects of corticosteroids? (uncommon in replacement therapy but more in prolonged systemic use)
- 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
How may Cushing's syndrome affect fertility?
Women - amenorrhea | Men - Infertility and low libido
34
What is the treatment of iatrogenic Cushing's syndrome?
- Decrease or withdraw use of corticosteroids | - Must be done gradually to avoid any unpleasant side effects
35
What is a major risk of Cushing's syndrome?
- Hypertension | - Increases risk of heart attack and stroke
36
What is the main endogenous mineralocorticoid?
Aldosterone
37
What drug inhibits Aldosterone?
Spironalactone
38
Describe the mechansim of action of Aldosterone?
- 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
What is the drug of choice to treat Addison's disease?
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
Why is synthetic aldosterone not used to treat addison's disease?
75% of it is broken down to inactive form in liver in first pass metabolism
41
What is spironalactone?
Competitive antagonsit of aldosterone | - K+-sparing diuretic
42
What diseases can spironalactone be used to treat?
- Hypoeraldosteronism (e.g Conn's) - Resistant hypertension - Heart Failure - Oedema
43
What percentage of hyperaldosteronism is caused by adrenal adenomas (Conn's syndrome)?
80%
44
What is Addison's disease?
A condition where the adrenal glands are dysfunctional
45
What percentage of Addison's disease cases are due to an autoimmune disease?
7 in 10
46
What are other causes of Addison's disease other than autoimmune?
- TB which has spread to adrenals - Metastatic cancers - Atrophy due to prolonged steroid therapy - Haemochromatosis - Amyloidosis
47
How many people suffer from Addison's disease UK?
8,000 (usually between ages of 30 - 50)
48
What are the symptoms of Addison's disease?
- Anorexia - Vomitting Nausea - Weakness - Hypotension - Skin pigmentation (due to ACTH) - Low Na+, High K+ - Chronic dehydration - Sexual dysfunction
49
What does Addison's disease treatment look like?
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
How are side effects reduced when prescribing corticosteroids?
By slowly increasig dose
51
How is Conn's syndrome treated / primary hyperaldosteronism?
- Spironalactone (4 weeks prior to surgery) | - Surgical treatment involving surgical adrenalectomy, laproscopic surgery is preferred to open
52
What complication of Conn's syndrome may persist even after removal of adenoma?
Hypertension (due to effects of the previous hypertension on vasculature)
53
What are other cause of primary hyperaldosteronism? (other than Conn's)
- Bilateral adrenal hyperplasia (BAH) (adrenal cells become hyperplastic) - 15% - Unilateral adrenal hyperplasia (rare) (adrenalectomy) - Adrenal carcinoma (rare)
54
When is an adrenal carcinoma usually diagnosed?
Once an adrenal adenoma has been removed and examined histologically
55
What enzyme is missing in Congenital Adrenal Hyperplasia?
C-21 hydroxylase enzyme is missing. | - Non hydoxylated versions of cortisol, corticosterone and aldosterone are made
56
How do non hydroxylated cortisol, corticosterone and aldosterone act?
- 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
How is Congenital Adrenal Hyperplasia treated?
- Cortisol to replace the missing cortisol and cause negative feedback on HPA - Replace mineralocorticoids with fludrocortisone

MD4001 Pharmacology (8 decks)

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