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Endocrine 2 > Adrenal Corticosteroids (Konorev) > Flashcards

Adrenal Corticosteroids (Konorev) Flashcards

1
Q

What are the 2 broad categories of adrenal corticosteroid drugs

A
  • Mineralocorticoids

- Glucocorticoids

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2
Q

What is the one mineralocorticoid

A

Fludrocortisone

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3
Q

What are the short to medium acting <12 hours glucocorticoids

A
  • Hydrocortisone
  • Cortisone
  • Prednisone
  • Prednisoone
  • Methyprednisolone
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4
Q

What is the intermediate acting 12-36 hours glucocorticoid

A

Triamcinolone

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5
Q

What are the Long acting >35 hour glucocorticoids

A
  • Betametasone

- Dexametasone

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6
Q

What are the 3 categories of inhibitors of adrenal corticosteroid action?

A
  • Steroid synthesis inhibitors
  • Glucocorticoid antagonists
  • Aldosterone antagonists
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7
Q

What are the steroid synthesis inhibitors

A
  • Aminoglutethimide
  • Ketoconazole
  • Metyrapone
  • Mitotane
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8
Q

What is the glucocorticoid antagonist

A

Mifepristone

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9
Q

What are the aldosterone antagonists?

A
  • Spironolactone

- Eplerenone

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10
Q

What are mineralocorticoids induced by

A

-Ang II and K+

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11
Q

What do mineralocorticoids do

A

-regulate electrolytes and H2O balance and blood pressure

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12
Q

What are glucocorticoids induced by

A

ACTH

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13
Q

What do glucocorticoids do

A

regulate metabolism and immunity

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14
Q

What is the high affinity protein that binds cortisol and aldosterone

A

-Transcortin, or Corticosteroid Binding Globulin

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15
Q

What condition is Transcortin levels high?

Low?

A
  • pregnancy, with estrogen administration and in hyperthyroidism
  • Liver disease (cirrhosis)
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16
Q

What protein binds corticosteroids loosely which makes them basically free even when bound

A

albumin

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17
Q

When plasma cortisol exceeds _________, the binding capacity of transcortin is saturated, and concentration of free cortisol rises rapidly

A

20-30 ug/dL

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18
Q

Describe the role of the liver in pharmacokinetics of cortisol

A
  • liver produces transcortin
  • about 80% of cortisol is metabolized by the liver
  • The half live of cortisol is normally about 60-90 min and is often increased in pts with liver diseases
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19
Q

Describe why cortisol does not have a big effect on mineralocorticoid receptor even though it is in higher concentration in blood and has same affinity for it as aldosterone?

A

-it is converted to cortisone by 11 B-HSD2 in renal tubular epithelium, salivary glands, sweat glands, and colon which is inactive

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20
Q

What happens when 11B-HSD2 is inhibited

A

excessive activation of MR by cortisol . . . leads to hypertension

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21
Q

What are the 2 things in the powerpoint that inhibit 11B-HSD2

A
  • Glycyrrhizin (licorice root extract)

- Carbenoxolone (approved in UK to treat esophageal ulcers)

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22
Q

Describe what AME (apparent mineralocorticoid excess) is

A
  • inactivating mutations in 11B-HSD2
  • presents as a form of severe juvenile hypertension
  • autosomal recessive
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23
Q

What cells do mineralocorticoids target

A

-Principal cells of collecting tubule and collecting duct

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24
Q

What is the effect of mineralocorticoids on gene expression in principal cells

A
  • increase epithelial sodium channels on apical membrane (ENaC)
  • increase Na/K pump (basolateral membrane)
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25
Q

What are the electrolyte consequences of mineralocorticoids

A
  • Na and water retention

- K loss

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26
Q

What non epithelial cells do mineralocorticoids target

A
  • Heart

- vasculature

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27
Q

What are the effects of gene expression on mineralocorticoids on non epithelial cell types

A
  • NADPH reductase: oxidative stress
  • Collagen, TGF-B: fibrosis, cell senescence
  • IL-6, cell adhesion molecules: inflammation
  • PAI-1: inhibition of fibrinolysis, blood clotting
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28
Q

Aldosterone excess (directly) causes what?

A
  • cardiac fibrosis and hypertrophy
  • Vascular remodeling and inflammation

-why we used aldosterone antagonists in hypertension and heart failure

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29
Q

Transactivation mechanism of Glucocorticoids

A
  • GR-ligand complex bind to GRE in gene promoters to activate gene expression
  • effects on carbohydrate, lipid, protein metabolism
30
Q

Transexpression of Glucocorticoids

A
  • GR-ligand complex binds to other transcription factor complexes to suppress their activation of gene transcription
  • NF-kappaB, AP-1 transcription factors
  • Antiinflammatory, immunosuppressive, anti growth effects
31
Q

What is the prototypical (fully functional) isoform of glucocorticoid receptors?
Which one lack 35 aa at the C terminal and does not bind ligands and is inactive?

A
  • alpha

- bets

32
Q

What GR isoform is induced by TNF-alpha and may be responsible for glucocorticoid resistance?

A

beta

33
Q

Describe the carbohydrate metabolism of glucocorticoids

A
  • increase phosphoenolpyruvate carboxykinase —-> increased gluconeogenesis
  • Increased G6P –> increased glucose output into circulation
  • increase glycogen synthase so more glycogen synthesis
  • decrease GLUT4 –> decreased glucose uptake by muscle and adipose tissues
  • Hyperglycemia
34
Q

Describe the lipid metabolism of glucocorticoids

A
  • stimulation of hormone sensitive lipase in adipose tissue –>increase lypolysis
  • increase mobilization of free fatty acid and glycerol into the gluconeogenic pathway
  • increase insulin secretion: increasd lipogenesis
  • Net increase in fat deposition
  • change in fat distrubution
35
Q

Describe the change in fat distribution caused by glucocorticoids

A
  • Adipocyte sensitivity to insulin vs. glucocorticoids varies in differetn areas of the body
  • Increased fat accumulation in upper body (shoulders, neck area, rounded face)
  • thinning arms and legs
36
Q

Describe the Protein metabolism of glucocorticoids

A
  • Decreased amino acid uptake into cells
  • Decreased protein synthesis, negative nitrogen balance
  • mobilization of amino acids into the gluconeogenic pathway
  • Skeletal muscle: suppressed protein synthesis will lead to the development of myopathy and muscle wasting
37
Q

What are the effects of glucocorticoids on intermediary metabolism antagonize actions of insulin

A
  • Changes in gene expression that favor lipid and protein breakdown to supply substrates for gluconeogenesis
  • Direct interference with the insulin receptor signal transduction
38
Q

What are the immune and inflammatory effects of glucocorticoids due to transrepression of NF-kappaB and AP-1

A
  • decreased in phospholipase A2 and COX2 –> decreased prostaglandins and leukotrienes
  • decrease production and increased apoptosis of immune cells
  • decreased cytokines (TNF-alpha, IL-1, IFNgamma,
  • decreased cell adhesion molecules
  • decrease transmigration of neurtrophils and macrophages from blood into tissues
39
Q

What are the consequences of the effects that glucocorticoids have on immune system

A
  • decreased inflammation and its manifestations
  • immune suppression
  • decreased allergic/hypersensitivity reactions
40
Q

What endocrine conditions can you use corticosteroids for replacement therapy?

A
  • Acute and chronic adrenal insufficiency (e.g. Addison Disease): a combo of a glucocorticoid (hydrocortisone) and a mineralocorticoid (fludrocortisone)
  • congenial adrenal hyperplasia (21a-hydroxylase deficiency)
41
Q

What are the clinical applications of corticosteroid use for immunosuppression?

A
  • following organ or hematopoietic stem cell transplantation
  • Autoimmune disease (MS)
  • Hematological cancers (leukemia)
42
Q

use corticosteroids for what inflammatory and allergic conditions

A
  • RA
  • IBD
  • Asthma and COPD
  • Allergic rhinitis
  • Skin diseases: inflammatory dermatoses (psoriasis)
  • hypersensitivity reactions
43
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 (muscle spasms and tetany)
44
Q

Adverse effects of Glucocorticoids

A
  • Suppressed ability to fight infections, development of opportunistic infections
  • Hyperglycemia
  • Striae and easy bruising
  • muscle wasting, steroid myopathy
  • HTN
  • steroid induced glaucoma
  • cataracts
  • peptic ulcers
  • psychiatric disorders: euphoria, mania, anxiety
  • increased appetite and weight gain
  • Osteoporosis
  • retarded growth in children
45
Q

Describe the dosing of coricosteroids

A
  • use lowest dose for shortest duration possible: use intermediate or short acting vs. long acting
  • Reduce distribution of drugs into systemic circulation: use topical, inhalation routes, etc
  • Give single daily dose in morning
  • Alternate day, short course, pulse therapy administration
  • Dose tapering (to allow recovery of hypothalamic-pituitary-adrenal system)
46
Q

What is a prodrug activated by esterases present in bronchial epithelial cells; systemically absorbed active drug is tightly bound to serum proteins

A

-Ciclesonide (Alvesco)

47
Q

What are the patient populations in which systemic glucocorticoid administration is problematic?

A
  • Immunocompromised
  • Diabetics
  • infections
  • peptic ulcers
  • Cardiovascular conditions: HTN, congestive heart failure, angina
  • psychiatric conditions
  • osteoporosis (post menopausal women)
  • children
48
Q

MOA of Aminoglutethimide

A
  • Blocks conversion of cholesterol to pregnenolone

- reduces production of all steroid hormones

49
Q

Indications for Aminoglutethimide

A
  • Was used for breast cancer treatment

- ADRENOCORTICAL cancer

50
Q

Side effects of Aminoglutethimide

A
  • Drowsiness

- GI upset

51
Q

MOA of Ketoconazole

A
  • P450 inhibition

- Reduces synthesis of adrenal sex hormones

52
Q

Indications for Ketoconazole

A
  • Antifungal druge
  • Cushing’s syndrome
  • Suppresses androgenic hair loss
  • Prostate cancer
53
Q

Side effects of Ketoconazole

A
  • Hepatotoxicity

- Gynecomastia in males

54
Q

MOA of Metyrapone

A
  • Inhibition of steroid 11-Hyroxylation

- Relatively selectively suppresses formation of cortisol and corticosterone

55
Q

Indications for Metyrapone

A

-Cushing’s syndrome (only drug for this indiciation used in PREGNANCY)

56
Q

Side effects of Metyraone

A
  • Accumulationg of 11-Deoxycortisol
  • increased aldosterone–> Na and water retention
  • increased androgen -> hirsutism in women
  • GI upset
  • Dizziness
57
Q

MOA of Mitotane

A
  • Na and Ca ionofore
  • protein kinase C and adenylyl cyclase inhibitor
  • non selective cytotoxic action on adrenal cortex
58
Q

indications for Mitotane

A

Adrenal Carcinoma

59
Q

Side effects of Mitotane

A
  • Depression, somnolence
  • GI upset
  • Rashes
60
Q

MOA of mifepristone

A
  • Glucocorticoid receptor antagonist
  • Stabilizes hsp90-GR complex in cytosol so prevents nuclear translocation of GR
  • Progesterone receptor antagonist
61
Q

inidications for Mifepristone

A
  • hypercortisolism in adult patients with endogenous Cushing’s syndrome
  • Anti-progesterone action: used for medical termination of intrauterine pregnancy
62
Q

Side effects of mifepristone

A
  • Dizziness
  • GI upset
  • Fatigue
63
Q

MOA of Spironolactone

A
  • Aldosterone receptor antagonist

- Also an antagonist of androgen receptors

64
Q

indications of Spironolactone

A
  • Primary Hyperaldosteronism
  • Hirsutism in women
  • Diuretic - used in treatment of HF and HTN
65
Q

Side effects of Spironolactone

A
  • Hyperkalemia
  • Gynecomastia and impotence in men
  • menstrual abnormalities in women
66
Q

MOA of Eplerenone

A
  • A competitive antagonist of aldosterone at mineralocorticoid receptors
  • Lower affinity for androgen receptors vs. Spironolactone
67
Q

indications for Eplerenone

A
  • HTN

- HF (reduces cardiac remodeling and increases survival in HF patients in recent clinical trials

68
Q

side effects of Eplerenone

A

-hyperkalemia

69
Q

What 3 glucocorticoids do not have any mineralcorticoid receptor action so could be used to treat apparent juvenile hypertension because they will negatively feedback to hypothalamus and ultimately decrease production of cortisol?

A
  • Triamcinolone
  • Dexamethosone
  • Betamethosone
70
Q

Describe the relationship b/t ketoconazole and Atorvastatin?

A
  • ketoconazole inhibits CYP 34A which metabolizes Atorvastatin
  • so half life is increased and you get liver damage and skeletal muscle damage . .Rhabdo and acute renal failure

Endocrine 2 (10 decks)

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