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Endocrine II midterm > Konorev: Adrenal Corticosteroids > Flashcards

Konorev: Adrenal Corticosteroids Flashcards

1
Q

Mineralocorticoids

A
  • induced by Ang II and K+
  • regulate electrolyte, water balance and BP
  • apprently come from aldosterone… (from CYP11B2)
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2
Q

Glucocorticoids

A
  • induced by ACTH
  • regulate metabolism and immunity
  • come from cortisol (CYP11B1 and 17)
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3
Q

Weak androgens

A
  • converted into potent adrogens in males
  • converted into estrogens in females
  • come from DHEA (CYP17)
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4
Q

What is the protein carrier for the steroid hormones?

A
  • Transcortin… or corticosteroid binding globulin (CBG)
  • high during preggo, with Est administration, and in hyperthyroidism
  • low in liver disease (cirrhosis)
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5
Q

After 90% of steroids are bound to transcortin, what is the rest bound to?

A

-albumin (low affinity, high capacity

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6
Q

What is the main carrier for synthetic corticosteroid (CS) drugs?

A

albumin

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7
Q

When is transcortin capacity saturated?

A

when plasma cortisol exceeds 20-30 ug/dL

-concentration of free cortisol rises rapidly

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8
Q

What is the role of liver in pharmacokinetics of cortisol?

A
  • produces transcortin
  • 80% of cortisol is metabolized by liver
  • 1/2 life of cortisol is normally about 60-90 min and is often increased in patients with liver diseases
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9
Q

In general, what does the steroid hormone do to the nuclear receptor?

A

-makes hsp90 go away so it can bind to and activate DNA

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10
Q

What 2 things bind an MR with equal affinity?

A

-aldosterone and cortisol

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11
Q

how much cortisol and aldosterone is made each day?

A
  • cortisol= 10 mg/day

- aldosterone= 0.125 mg/day

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12
Q

What enzyme changes Cortisol to cortisone?

A

11 B-HDS2 11B-dehydrogenase

  • changes an HO to just O (ketone… “one”
  • cortisone is inactive
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13
Q

What enzyme changes cortisone to cortisol?

A

11 B-HSD1 11-ketoreductase

-turns the ketone back into an alcohol (“ol”)

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14
Q

What happens at the MR (mineralocorticoid receptor) with cortisol

A
  • 11B-HSD 2 converts it into cortisone
  • cortisone can’t bind the MR
  • so, now it renders that tissue responsive to mineralocorticoids (aldosterone!)
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15
Q

What tissues does that thing with cortisole happen at?

A
  • renal tubular epithelium
  • salivary glands
  • sweat glands
  • colon eptithelium
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16
Q

So, what will inhibition of 11B-HSD type 2 result in?

A
  • excessive activation of the MR mediated by cortisol

- increased activation of MR by cortisol to cause hypertension

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17
Q

What two things will inhibit 11B-HSD 2?

A
  • Glycyrrhizin (licorice root)

- Carbenoxolone (approved in UK to treat esophageal ulcers)

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18
Q

What is it called when there are inactivating mutations in 11B-HSD2?

A
  • AME
  • apparent mineralocorticoid excess
  • presents as a form of severe juvenile htn that is usually transmitted as an auto recessive trait
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19
Q

What is the mineralocorticoid we have to know?

A

Fludrocortisone

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20
Q

What are the short to medium-acting glucocorticoids?

A
  • hydrocortisone (cortisol)
  • cortisone
  • prednisone
  • prednisolone
  • methprednisolone
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21
Q

Intermediate -acting glucocorticoid

A

-triamcinolone

22
Q

Long acting glucocorticoid

A
  • betametasone

- dexametasone

23
Q

What is released from the kidney in response to decreased blood volume?

A

-renin

24
Q

What does renin do?

A

-turns angiotensinogen into Ang I

25
Q

Where does Ang I go?

A

to the lungs

-ACE turns it into Ang II

26
Q

What are the effects of Ang II?

A
  • vasoconstriction of arterioles

- adrenal cortex

27
Q

What does the adrenal cortex secrete then?

A

aldosterone

28
Q

What does aldosterone do?

A

-in kidneys, increases Na+ and water reabsorption and increased secretion of K+ and H+ into urine

29
Q

What specific cells are targeted by aldosterone?

A

-principal cells of collecting tubule and collecting duct

30
Q

aldosterone’s effect on gene expression in principal cells?

A
  • high epithelial sodium channel (apical membrane)- ENaC

- high Na+/K+ pump (basolateral membrane)

31
Q

What are the overall consequences of aldosteron then?

A
  • Na+ retention
  • Water retention
  • K+ loss
32
Q

What non-epithelial tissues do mineralocorticoids target?

A
  • heart

- vasculature

33
Q

What are aldosterone’s effects on gene expression in non-epithelial tissues?

A
  • NADPH reductase…. oxidative stress
  • Collagen, TGF B…. fibrosis, cell senescence
  • IL-6, cell adhesion molecules…. inflammation
  • PAI-1…. inhibition of fibrinolysis, blood clotting
34
Q

What does aldosterone excess directly cause?

A
  • cardiac fibrosis and hypertophy

- vascular remodeling and inflammation

35
Q

When should we use aldosterone antagonists?

A

in hypertension and heart failure

36
Q

In the cell, what is the end result of glucocorticoids?

A

receptor dimer bound to a promoter region of one of the responsive Genes
-remember that it dimerizes before entering the nucleus

37
Q

What is the transactivation mechanism?

A
  • GR-ligand complex binds to GRE in gene promoters to activate gene expression
  • effects on carb, lipid, and ptn metabolism
38
Q

What is transrepression?

A
  • GR-ligand complex binds to other transcription factor complexes to suppress their activation of gene transcription
  • NFKB, AP-1 tf’s
  • antiinflammatory, immunosuppressive, anti-growth effects
39
Q

What % of genes in a human genome are regulated by glucocorticoids?

A

10-20%

40
Q

What are glucocorticoid receptor isoforms?

A
  • encoded by same gene
  • products of alt splicing
  • GRa is prototypical (functional) isoform
  • GRb lacks 35 aa at C-terminal… does not bind ligands and is inactive
41
Q

Glucocorticoids effects on carbohydrate metabolism

A
  • increased PEP carboxykinase… increased gluconeogenesis
  • increased G6Pase…increased glc output into circulation
  • increased glycogen synthase… incrased glycogen synthesis
  • decreased expression of GLUT4… decrased glc uptake by muscle and adipose tissues
  • development of hyperglycemia
42
Q

Glucocorticoids effects on lipid metabolism

A
  • promote stimulation of HSL in adipose tissue… increased lipolysis
  • increase mobilization of FFA and glycerol into gluconeogenic pathway
  • increase insulin secretion… increased lipogenesis
  • Net incrase in fat deposition
  • change in fat distribution (shoulders, neck, rounded face): bc that’s where the adipocyte sensitivity to glucocorticoids is the greatest
43
Q

Glucocorticoids effect on protein metabolism

A
  • decreased aa uptake into cells
  • decreased ptn synthesis, negative nitrogen balance
  • mobilization of aa’s into the gluconeogenic pathway
  • suppressed ptn synth will lead to development of myopathy and muscle wasting
44
Q

What does the effect of glucocorticoids on intermediary metabolism do to the actions of insulin?

A

antagonizes them

  • changes in gene expression that favor lipid and ptn breakdown to supply substrates for gluconeogensis
  • direct interference with the insulin receptor signal transduction
45
Q

Effects of glucocorticoids on immune system and inflammation.

A

suppresses everything

46
Q

Common clinical applications of adrenal corticosteroids

A
  • Endocrine conditions: replacement therapy
  • acute and chronic adrenal insufficiency: a combo of glucocorticoid and mineralocorticoid is used
  • congenital adrenal hyperplasia
  • Non-endocrine conditions:
  • immunosuppression
  • inflammatory and allergic conditions
47
Q

adverse effects of mineralocorticoids

A
  • retention of sodium and water, edema
  • htn
  • increased preload and cardiac enlargement… development of congestive heart failure
  • K+ loss and alkalosis (muscular spasms and tetany)
  • wherever Na+ goes, K+ will usually go the opposite
48
Q

adverse effects of Glucocorticoids

A
  • suppressed ability to fight infections, development of opportunistic infections
  • hyperglycemia
  • skin: striae, easy bruising
  • muscle wasting, steroid myopathy
  • Hypertension
  • steroid-induced glaucoma
  • Cataracts
  • peptic ulcers
  • psych disorders
  • osteoporosis
  • retarded growth in children
49
Q

Dosing of corticosteroids

A
  • use lowest dose for the shortest duration possible depending on the condition
  • use intermediate or short-acting vs. long-acting drugs
  • reduce distribution of drugs into systemic circulation
50
Q

How would we go about reducing distribution of drugs into systemic circulation?

A
  • use topical, inhalational routes, etc…
  • Ciclesonide, a prodrug activated by esterases present in bronchial epithelial cells; systemically absorbed active drug tightly bound to serum proteins
51
Q

How else should we dose Corticosteroids?

A
  • give single daily doses in the morning
  • alternate day, short-course, pulse therapy administration
  • dose tapering (to allow the recovery of hypothalamic-pituitary-adrenal system
  • rate of taper depends on severity of illness, duration of steroid therapy and maintenance dosage
52
Q

Which patient populations have problems with glucocorticoids?

A
  • IC patients
  • diabetics
  • infections
  • peptic ulcer
  • CV conditions
  • psych conditions
  • osteoporosis
  • children

Endocrine II midterm (13 decks)

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