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Endo/Eye/Derm - Women/Men > EXAM 3 Adrenocorticosteroids and Adrenocortical antagonists Dr. Pond > Flashcards

EXAM 3 Adrenocorticosteroids and Adrenocortical antagonists Dr. Pond Flashcards

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1
Q

What is a Corticosteroid?

A

-A steroid that is released by the adrenal cortex or a steroid that is related to steroids synthesized by adrenal cortex

Cortico - adrenal cortex
steroid - steroid based molecule derived from cholesterol

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2
Q

Which molecules are produced by the cortex (outer part of the adrenal gland)?

A

produces steroid-based hormones

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3
Q

Which part of the adrenal gland produces NE and epinephrine?

A

the adrenal medulla (inner part)
-synthesis and secretion of NE and epinephrine in response to sympathetic signals

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4
Q

What are the 3 classes of steroid-based hormones?

A

-Glucocorticoids
-Mineralcorticoids
-Gonadocorticoids

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5
Q

Which class of molecules do Glucocorticoids refer to?

A

Cortisol
-> affecting glucose metabolism
(GLUCOse + CORTex + sterOID)

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6
Q

Which class of molecules do Mineralcorticoids refer to?

A

Aldosterone

-> affect salt and water balance (MINERAL + CORTex +
sterOID)

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7
Q

Which class of molecules do Gonadocorticoids refer to?

A

Steroid hormones

-> produced by the adrenal cortex that affects sexual function -> similar to those of the gonads

(GONAD + CORTex + sterOID)

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8
Q

What are the 3 layers of the adrenal cortex (outer part) and what do they secrete?

A

-Zona glomerulosa -> mineralcorticoids
-Zona fasciculata -> glucocorticoids
-Zona reticularis -> sex steroids (gonadocorticoids)

Go find Rex - make good sex

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9
Q

Hypothalamus-anterior pituitary-adrenal cortex Axis

A
  1. Hypothalamus -> CRH (corticotrophin-releasing hormone)
  2. CRH on anterior pituitary -> ACTH (adrenocorticotropic hormone)
  3. ACTH on adrenal cortex -> Cortisol
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10
Q

What are the main steroids produced by the adrenal cortex?

A

-Glucocorticoid: Cortisol
-mineralcorticoid: Aldesterone
-Gonadocorticoid: Dehydroepiadrosterone (DHEA), a weak androgen -> can be converted to testosterone or estradiol (stronger sex hormones)

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11
Q

Which hormone is primarily secreted by the adrenal gland?

A

Cortisol

-aldosterone (mineralocorticoid) is more regulated by the RAAS system, as well as sodium and potassium level

-the amount of sex hormones released from adrenal gland is minor (more from the gonads)
FYI: post-menopausal women mainly produce their sex hormones form the adrenal gland

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12
Q

What triggers CRH release from the Hypothalamus?

A

-Circadian rhytm
-Stress

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13
Q

Negative feedback in the HPA axis

A

-high cortisol -> negatively back to the anterior pituitary and hypothalamus

-high ACTH -> back to the hypothalamus

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14
Q

Where does Cortisol bind to in the plasma?

A

90% bound to corticosteroid-binding globulin (CBG)

-the remainder is free or closely bound to albumin

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15
Q

When do we see an increased level of free Cortisol and the plasma?

A

when plasma levels exceed 20-30 μg/dL
-> CBG is saturated

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16
Q

What may cause high levels of Cortisol in the plasma?

A

-severe stress
-Cushings disease

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17
Q

Where is cortisol metabolized?

A

-mostly in the liver -> activated from cortisone to cortisol

Kidney (also placenta)
-20% converted to cortisone - inactive
(by 11-hydroxysteroid DH 2)

-1% excreted unchanged

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18
Q

Which enzyme in the kidney converts Cortisol to Cortisone?

A

11-hydroxysteroid DH 2

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19
Q

Which receptor solely binds to Cortisol?

A

Glucocorticoid receptor (GR)

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20
Q

Which receptor does Cortisol and aldosterone bind to?

A

Mineralocorticoid receptor (MR)

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21
Q

How does the body steer Cortisol to bind to Glucocorticoid receptors (GR) rather than mineralcorticoid receptors (MR)?

A

with the enzyme 11-hydroxysteroid DH 2

by converting Cortisol into Cortisone in the kidney
-> Cortisone is inactive and won’t bind to GR or MR

anything that does bind to GR will be converted to cortisone, to prevent effects that come from MR???

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22
Q

What is the MOA cortisol?

A

-regulates gene transcription in the nucleus

-first bound to CBG in the plasma -> crosses the membrane and binds to Glucocorticoid receptors -> enters the nucleus and activates transcription in the GRE glucocorticoid response element (promotor region)

-long process -> so onset is delayed: 8-12hr

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23
Q

Other MOA

A

cortisol binds to GR and forms a complex with other transcription factors and regulates non-GRE-containing promotors

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24
Q

What is the effect of glucocorticoids in the plasma?

A

CATABOLIC EFFECTS

increase glucose in the plasma at the expense of proteins

-protein catabolism in bone, lymph, muscle, and elsewhere -> to make GLUCOSE

-more liver uptake of AS to make GLUCOSE (gluconeogenesis)

-it tries to keep blood glucose levels high -> so it breaks down things to keep it high (maintenance)

-triglycerides catabolism in adipose tissue -> release of glycerol and fatty acids into the blood - this effect is different in different body parts -> Cushings disease

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25
Q

Why do we see fat storage in Cushings disease?

A

release of Insuilin promotes fat storage in the stomach region

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26
Q

What are the consequences of the catabolic activity of Glucocorticoids?

A

-osteoporosis in the bone (collagen = protein used for glucogeonesis)

-glucocorticoids inhibit the vitamin D effect -> block the absorption of calcium and phosphate from the gut -> less mineralization of the bone

-reduce growth in children

-decreases what is considered unnecessary in a stress situation: things like growth and fertility

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27
Q

Anti-inflammatory and immunosuppressive effects of glucocorticoids

A

-decreases of function of peripheral leukocytes
-Inhibition of prostaglandin and leukotriene synthesis and cytokines

-inhibits macrophages and other antigen-presenting cells (activating the induced immune responses)

-decreases capillary permeability by reducing
histamine release via basophils and mast cells
-> so leukocytes cant move to the site of infection readily

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28
Q

What is one of the important anti-inflammatory proteins that is stimulated by glucocorticoids?

A

Annexin A1

-inhibits prostaglandin synthesis
-decreaseing function of neutrophils
-> anti-inflammatory, anti-immune effect

29
Q

Other effects of Corticosteroids

A

CNS:
increased mood first, later depression
also can contribute to psychosis at high doses

GI:
immune-repressive -> so increases peptic ulcers (H. pylori)
inhibits Vitamin D and Ca2+ absorption from the gut -> decreased bone mass
increase in appetite and weight gain

Blood:
increase in RBC, decrease in WBC

Endocrine:
chronically used: suppresses CRH, ACTH, GH, TSH, LH

Lungs:
increases development of fetal lungs by increasing absorption of surfactants

30
Q

What are the major effects of Aldosterone?

A

Na+ and water retention at expense of potassium (excreted)
-> increases extracellular fluid (ECF) and blood volume -> increase in BP

31
Q

Factors that regulate Aldosterone release

A

-RAS system
-directly via Na+/K+
-ANF (atrial natriuretic factor)
-ACTH

32
Q

RAAS system

A

Renin converts Angiotensionogen to Angiotensin I
Angiotensin I to Angiotensin II by ACE
Angiotensin II ->
increases aldosterone release -> inc BP
acts as a vasoconstrictor -> inc BP

33
Q

How do Na+ and K+ levels affect Aldosterone synthesis?

A

stimulated by
low Na+
high K+

since Aldosterone cause Na+ retention and K+ loss

34
Q

How does ANF affect Aldosterone synthesis?

A

stretch of the atria -> caused by high blood volume
-> release of ANF -> decreases aldosterone since blood volume and BP is already high

35
Q

What is Addison’s disease?

A

Chronic adrenocortical insufficiency
-too little glucocorticoids
-too little mineralcorticoids

(gonadocorticoids is also low, but there is not much production from the adrenal glands anyway)

36
Q

How does Aldosterone cause Na+ retention/K+ excretion?

A

-synthesis of Na+/K+ transporter on the interstitial site and Na+ transporter on the lumen side of kidneys (reasborption)

-aldosterone binds to mineralocorticoid receptors (MR) reguate genes that encode for these transporter proteins

-Cortisol also binds to MR but we want to limit it -> conversion to inactive Cortisone via 11ßHSD2

37
Q

Effects of Addison’s disease

A

low plasma sodium, high potassium
low blood pressure

-> since Aldosterone is low (low in Na+/K+ transporter)

-muscle weakness, fatigue
-vomitig, loss of appetite, dehydration (weight loss)

-hyperpigmentation in some patients
-blood glucose cannot be maintained during fasting - due to low levels of glucocorticoid

38
Q

How is hyperpigmentation in Addison’s disease explained?

A

low levels of Cortisol we lose negative feedback to ACTH (anterior pituitary) and CRH (hypothalamus), also low level increases ACTH and CRH???
->high levels of ACTH

-the proprotein pro-opiomelanocortin of ACTH also contains MSH (melanocyte-stimulatiing hormone)
-> high melanin production

39
Q

What is Cushing’s disease?

A

Excessive glucocorticoids

-might be due to an adrenal tumor (zona fasciculata)
-pituitary tumor - too much ACTH -> too much cortisol
-or ectopic (somewhere else) ACTH-producing tumor

40
Q

Presentation

A

-upper body obesity (thin arms and legs)
-fat deposits between the shoulder blades (buffalo hump)
-moon face

41
Q

Symptoms Cushings disease

A

-Euphoria (initially)
-HTN (sometimes with high cortisol due to binding to MR and causing Na+ retention)
-redistribution of fat
-infections

42
Q

Protein wasting symptoms in Cushing’s disease

A

-muscle wasting
-thin skin with strae (failure of collagen production in the skin)
-bruising
.poor wound healing
-fragile bones/osteoporosis

43
Q

Which of the steroid receptors have anti-inflammatory and which one has salt retention activity?

A

-glucocorticoid receptor (GR): anti-inflammatory

-mineralocorticoid receptor (MR): salt retention

44
Q

Which steroid drug is short-acting with anti-inflammatory activity?

A

-Prednisone (prodrug) 4:0.3
-Prednisolone 5:0.3
-Methylprednisolone 5:0.25

Cortisone is inactive 0.8:0.8
Hydrocortison (cortisol) binds to both receptors 1:1

45
Q

Which steroid drug is long-acting with anti-inflammatory activity?

A

Dexamethasone 30:0

Bethametasone 25-40:0

46
Q

Which steroid drug is long-acting with salt-retaining activity?

A

Fludrocortisone 10:250

so 10x than cortisol (which has 1)
but very potent for MR so we use a small dose (2mg) to minimize anti-inflammatory activity from GR

47
Q

Treatment approach Addison’s Disease

A

since too little cortisol and aldosterone

-> treat with glucocorticoids and Fludrocortisone (MR activity)

48
Q

Drug targets in Cushing’s disease

A

too much glucocorticoids

Pituitary gland:
-Cabergoline
-Pasereotide

Glucocorticoid receptor antagonist:
-Mifepristone

Adrenal gland:
-Ketoconazole
-Metyrapone
-Mitotane

-Surgery: remove the tumor that is causing the overproduction

49
Q

MOA of Ketocanozole

A

in Cushing’s disease

inhibits the production of corticosteroids (adrenal steroidogenesis), inhibits multiple enzymes involved in the synthesis -> decrease in cortisol

-since cortisol will be decreased we expect ACTH and CRH to go up (loss of negative feedback)
-but we don’t see an increase in ACTH - not understood, it somehow also blocks ACTH

50
Q

ADE of Ketocanole

A

-potential impact on gonads (especially testes)
-> Hypogonadism
-> Gynecomastia

51
Q

What is the BBW for Ketocanozole?

A

-Hepatoxicity
-DDIs: dysrhytmia risk

52
Q

MOA of Metyrapone

A

inhibits the final step in the corticoid synthesis pathway
by blocking the enzyme 11ß-hydroxylase

ADE: adrenal insufficiency

53
Q

MOA of Mitotane

A

Adrenolytic: destroys adrenal cells by disruption of mitochondrial cristae -> mitochondrial swelling -> lysis

Adrenostatic: inhibtis multiple enzymes involved in the production of cortisol

54
Q

What is the BBW for Mitotane

A

Adrenal insufficiency
bc it literally destroys cells of the adrenal gland

ADE: Neurotoxicity -> ataxia, somnolence, anorexia, vertigo, parashetsia, dizziness, parkinsonian syndrome

55
Q

MOA of Mifepristone

A

Glucocorticoid receptor antagonist
(also prgesterone receptor antagonist RU-486 for pregnancy termination)

ADE: HTN, periperhal edema, fatigue, hyperkalemia, reduced appetite, N/V, dizziness, headache, hypertrophy of endometrium (progesterone receptor-related)

56
Q

Where is 11ßHSD2 expressed during pregnancy affecting and affecting fetal lung development?

A

in the placenta
->in the late phase of pregnancy the maternal corticosol goes up, so that enough crosses the placenta to overcome 11ßHSD2 and increases fetal lung development

57
Q

Which drug may be used at the late stage of pregnancy for fetal development in case of early delivery?

A

Betamethasone or Dexamethasone
->they have high potency of glucocorticoid receptors and they are not affected by 11ßHSD2 metabolism

-given to the mother if there is risk for early delivery

58
Q

ADE with long-term ADE of corticosteroids

A

Cushings-like symptoms
-redristribution of fats
-poor wound healing
-breakdown of skin and other places to build glucose
-growth suppression in kids

-short-term (<2 weeks):
-insomnia
-psychosis (with large doses)
-acute peptic ulces (H. pylori, or due to increased gastric secretion)

59
Q

What are the effects of binding to mineralocorticoid receptors?

A

-Na+ and flutid retention
-hypokalemia

60
Q

What are signs of corticoid withdrawal?

A

-fewer
-headache, fatigue
-joint pain, muscle plain
-low BP
-N/V

-> must taper therapy to restore HPA axis function,
patients would have adrenal insufficiency

61
Q

How is water solubility achieved in corticosteroid formulation?

A

as esters or salts (only salts are soluble enough for injections

-topical (creams)
-inhaled for asthma
-nasal sprays for allergic
-rhinitis, IM, IV, oral

62
Q

Which drugs bind to Mineralocorticoid receptors?

A

-Spironolactone
-Eplerenone
-Drospirenone

63
Q

Which of the Mineralocorticoid antagonists also bind to androgen receptors (AR)?

A

Spironolactone

64
Q

Indication of Spironolactone

A

-treatment of aldosteronism
->the adrenal glands produce too much aldosterone

-diuretic: heart failure, HTN

65
Q

Patient presentation in aldosteronism

A

-hypertension
-muscle weakness
-tetany
-hypokalemia

66
Q

Adverse effects of Spironolactone

A

-hyperkalemia (blocking Na+/K+ transporter synthesis), cardiac arrhythmias!!!
-sedation
-headache
-GI disturbances
-rash

androgen receptor-specific ADEs
-menstrual abnormalities (in women)
-gynecomastia (in men)

67
Q

Indication of Drospirenone

A

progestin in oral contraceptives
-> also has diuretic effects due to binding to MR

ADE: hyperkalemia

68
Q

Indication for Finerenone

A

used for chronic kidney disease in patients with T2DM
-High potency and selectivity for the MR

ADE:
(blocking Na+/K+ transporter synthesis)
-hyponatremia
-hyperkalemia
-hypotension

Endo/Eye/Derm - Women/Men (30 decks)

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