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PT4023 CA1 > L4 Mineralocorticoids > Flashcards

L4 Mineralocorticoids Flashcards

1
Q

What is the main endogenous mineralocorticoid in the body?

A

Aldosterone

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2
Q

Where is aldosterone produced?

A

in the zona glomerulosa of the adrenal cortex

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3
Q

Effect of aldosterone

A

Aldosterone acts on mineralocorticoid receptors in kidneys to increase both sodium reabsorption and potassium excretion - helps to regulate plasma electrolyte composition and BP

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4
Q

How does aldosterone regulate extracellular volume and potassium homeostasis?

A

by binding to the renal cortical collecting duct principle epithelial cell mineralocorticoid receptor

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5
Q

What happens when the activated MR translocates to the nucleus?

A

it binds to the glucocorticoid response element and functions as a transcription factor

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6
Q

Aldosterone increases the expression of which gene? What is the effect of this?

A

Serum- and glucocorticoid-inducible kinase (Sgk1) - leads to phosphorylation & inactivation of neural-precursor-cell-expressed developmentally downregulated gene (Nedd) 4-2, a ubiquitin ligase which is responsible for degrading the ENaC. Therefore, aldosterone stimulates ENaC to increase Na+ reabsorption, as well as K+ secretion.

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7
Q

What drives the uptake of potassium and export of sodium?

A

Na+/K+-ATPase activation at the basolateral membrane

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8
Q

GC & MC bind equally to the MR but specificity of action is due to what?

A

the glucocorticoid-degrading enzyme, 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which prevents glucocorticoids from interacting with the receptor

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9
Q

Example of a synthetic mineralocorticoid that acts as a diuretic and is also often prescribed for PCOS?

A

Spironolactone

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10
Q

Example of an aldosterone antagonist and potassium-sparing diuretic?

A

Eplerenone

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11
Q

What is the most common synthetic mineralocorticoid and what is it used for?

A

Fludrocortisone: used to replace endogenous aldosterone in adrenocortical insufficiency and salt-losing adrenogenital syndrome

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12
Q

Fludrocortisone may mask signs of __.

A

infection (by depressing the normal immune response)

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13
Q

How does fludrocortisone work?

A
  • binds MR, alters translation of proteins, increases density of Na+ channels & Na+/K+-ATPase
  • this increases plasma Na+ conc, increasing BP & decreasing plasma K+ conc
  • also acts on GC receptors, but with a much lower affinity
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14
Q

What is thought to be one of the reasons behind fludrocortisone’s profound mineralocorticoid pathway?

A

the reduction in 11β-oxidation

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15
Q

Fludrocortisone is not recommended to be given with what drugs?

A

strong inhibitors/inducers of CYP3A

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16
Q

Examples of conditions with low renin and high aldosterone

A

primary aldosteronism e.g. aldosterone-producing adenoma, bilateral idiopathic hyperplasia, unilateral adrenal hyperplasia, familial hyperaldosteronism

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17
Q

What condition has both low renin and aldosterone?

A

Hyperdeoxycorticosteronism e.g. congenital adrenal hyperplasia, deoxycorticosterone-producing tumour, primary cortisol resistance

18
Q

What is the most common cause of Cushing Syndrome?

A

exogenous glucocorticoid administration

19
Q

Management of Addison’s disease

A

hydrocortisone, fludrocortisone acetate

20
Q

What causes congenital adrenal hyperplasia?

A

enzymatic defects in adrenal steroidogenesis that result in deficient secretion of cortisol

21
Q

What does the lack of inhibitory feedback by cortisol on the hypothalamus and pituitary produce?

A

an ACTH-driven build-up of cortisol precursors proximal to the enzymatic deficiency

22
Q

What causes the hypertension and hypokalaemia in CAH?

A

hypersecretion of the mineralocorticoid DOC (11-deoxycorticosterone)

23
Q

2 types of CAH

A
  1. 11β-hydroxylase (CYP11B) deficiency
  2. 17α-hydroxylase (CYP17) deficiency
24
Q

The mineralocorticoid effect of increased circulating levels of DOC decreases…

A

PRA and aldosterone secretion

25
Q

CAH is autosomal __.

A

recessive

26
Q

Markedly increased levels of what confirm the diagnosis of 11β-hydroxylase deficiency?

A

high levels of DOC, 11-deoxycortisol and adrenal androgens (due to the impaired conversion of DOC to corticosterone)

27
Q

How does 11β-hydroxylase deficiency presentation differ between males and females?

A
  • Males present with pseudoprecocious puberty
  • Females present in childhood with hypertension, hypokalaemia, acne, hirsutism and virilisation
28
Q

What normalises the steroid abnormalities and hypertension in CAH?

A

glucocorticoid and mineralocorticoid replacement

29
Q

What does 17α-hydroxylase deficiency cause?

A

decreased production of cortisol and gonadal (sex) hormones

30
Q

How does 17α-hydroxylase deficiency presentation differ between males and females?

A
  • XY males present with either pseudohermaphroditism or as phenotypic females
  • XX females present with primary amenorrhea
31
Q

Biochemical findings of 17α-hydroxylase deficiency?

A
  • low concentrations of plasma adrenal androgens, plasma 17α-hydroxyprogesterone and cortisol
  • aldosterone and PRA are suppressed
32
Q

Deoxycorticosterone-producing tumours are usually __ and __.

A

large and malignant

33
Q

Some DOC-producing tumours secrete __ and __ in addition to DOC. What is the effect of this?

A

androgens and oestrogens
(this may cause virilisation in women and feminisation in men)

34
Q

What confirms the diagnosis of DOC-producing tumours?

A

a high level of plasma DOC or urinary tetrahydrodeoxycorticosterone and a large adrenal tumour seen on CT

35
Q

Optimal treatment for DOC-producing tumours?

A

Complete surgical resection

36
Q

What is found in patients with primary cortisol resistance?

A

increased cortisol secretion and plasma cortisol concentrations without evidence of Cushing Syndrome

37
Q

What does cortisol resistance lead to?

A

increased ACTH secretion, and subsequent increased steroid production

38
Q

What is primary cortisol resistance characterised by?

A

hypokalaemic alkalosis, hypertension, increased plasma concentrations of DOC & cortisol, and increased adrenal androgen secretion

39
Q

High rates of cortisol production overwhelm __.

A

11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) activity

40
Q

Treatment for mineralocorticoid-dependent hypertension

A

blockade of the MR with a mineralocorticoid receptor antagonist or suppression of ACTH secretion with dexamethasone

41
Q

What can impair renin release?

A

NSAIDs, beta blockers, diabetes, elderly, cyclosporine, tacrolimus

42
Q

What can impair aldosterone metabolism?

A

Adrenal disease, heparin, ketoconazole (anti-fungal)

PT4023 CA1 (8 decks)

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