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Foundations of Disease > Exam 2: Adrenal Steroids > Flashcards

Exam 2: Adrenal Steroids Flashcards

1
Q

Adrenal Medulla

A
  • Secretes cathecholamines as part of SNS
  • Also produces a small amount of Norepi and dopamine
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2
Q

Adrenal Cortex

A

Secretes several steroid hormones ⇒ adrenocortical hormones

  • Mineralocorticoids ⇒ salt balance
  • Glucocorticoids ⇒ intermediary metabolism and immune function
  • Androgens
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3
Q

Corticosteroid Synthesis

A
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4
Q

Zona glomerulosa

A

Makes mostly mineralocorticoid aldosterone.

  • Does not express 17α-hydroxylase (CYP17)
    • Required for cortisone and androgens
    • Not needed for aldosterone
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5
Q

Zona fasciculata

A

Makes mostly glucocorticoid cortisol (aka hydrocortisone)

  • Expresses 11β-hydroxylase (CYP11B1)
    • Required for cortisol
  • Does not express enzymes unique to androgen or aldosterone synthesis
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6
Q

Zona reticularis

A

Makes mostly adrogens

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7
Q

HPA Axis

A

Controls release of cortisol from zona fasciculata.

  • Hypothalamus
    • Corticotropin-releasing hormone (CRH)
      • ∆ by circadian rhythms and stress
      • ⊕ pro-opiomelanocortin (POMC) by ant. pituitary
        • Precursor to sevaral peptide hormones
  • Anterior pituitary
    • Adrenocorticotropic hormone (ACTH)
    • 𝛾-melanocyte-stimulating hormone (MSH)
    • β-endorphin
  • Adrenal cortex
    • ACTH → melanocortin-2-receptor (MC2R)
      • On membrane of all 3 types of steroid-secreting cells
      • ⊕ Cholesterol ⇒ pregnenolone
        • ⇒⇒ cortisol
          • Freely diffuses out of cell
          • ⊖ feedback on CRH and ACTH
      • Trophic effects on zona fasciculata and zona reticularis
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8
Q

Zona glomerulosa receives trophic effects from ACTH but also…

A

angiotensin II and high serum K+

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9
Q

Cortisol Transport

A

90% bound to plasma proteins

  • Transcortin
    • High affinity
    • Low total binding capacity
  • Albumin
    • Low affinity
    • Higher binding capacity
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10
Q

Cortisol

Mechanism

A
  • Diffuses across plasma membrane
  • Binds cytoplasmic glucocorticoid receptor (GR)
    • “Type II glucocorticoid receptor”
    • GR bound to HSP90 in the absence of cortisol
  • Cortisol-GR complex ⇒ nucleus ⇒ binds glucocorticoid response elements (GREs)
  • ∆ gene transcription
    • ~10% of all genes contain GREs
  • Profound influence on cell and organ physiology
    • Metabolic effects
    • Anti-inflammatory effects
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11
Q

Cortisol

Metabolic Effects

A
  • Liver
    • ↑ gluconeogenesis
    • ↑ glycogenolysis
    • ↑ AA metabolism
  • Muscle
    • ↑ AA breakdown and release
  • Adipose
    • ⊕ hormone sensitive lipase (HSL)
    • ↑ fat metabolism & FA release
    • Some fat deposited in face and trunk
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12
Q

Cortisol

Anti-inflammatory Effects

A
  • ⊕ Annexin I
    • ⊖ phospholipase A2
      • PL-A2 makes arachidonic acids
        • ⇒ leukotrienes & prostaglandins
  • ⊕ MAPK phosphatase I
    • ⊖ c-Jun regulated genes
      • ∆ cytokine production
  • ⊗ Activation of NF-𝜅B
    • Normally ⊕ gene transcription
      • Cytokines, chemokines, cell-adhesion molecules, complement, receptors
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13
Q

Addison’s Disease

A
  • Primary adrenal insufficiency
  • Caused by destruction of the adrenal cortex
    • Autoimmune, infection, cancer, hemorrhage
  • ↓ synthesis of all adrenocorticosteroids
    • ↓ aldosterone ⇒ hyperkalemia
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14
Q

Secondary Adrenal Insufficiency

A
  • Causes:
    • Hypothalamic or pituitary disorders
    • Prolonged glucocorticoid therapy
  • ↓ ACTH ⇒ ↓ cortisol and androgens
    • Aldosterone not affected
  • Sx:
    • Fatigue
    • Loss of appetite
    • Weight loss
    • Dizziness on standing
    • Nausea
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15
Q

Cushing’s Syndrome

A
  • Group of diseases causing ↑ cortisol
    • Cushing’s disease
    • Ectopic secretion of ACTH or CRH
    • Cortisol secreting adrenal cortex tumors
    • Iatrogenic
      • Caused by pharmacologic treatment with exogenous glucocorticoids
      • Most common cause
  • Sx:
    • Adipose redistribution
    • HTN
    • Osteoporosis
    • Immunosuppression
    • DM
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16
Q

Cushing’s Disease

A

Cushing’s syndrome specifically caused by a ACTH-secreting pituitary adenoma

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17
Q

Glucocorticoid Agonist

Modifications

A

All clinical glucocorticoids based on structure of cortisol.

∆ various parts of the molecule alters selectivity of the drug for glucocorticoid vs mineralocorticoid activity.

  • ↑ glucocorticoid activity
    • Double bond between C-1 & C-2
    • Methyl group @ C-6
    • Methyl group @ C-16
  • ↑ glucocorticoid & ↑↑↑ mineralocorticoid activity
    • Fluorine @ C-9
  • ↑ glucocorticoid but ↔︎ mineralocorticoid
    • Fluorine @ C-9 + Methyl @ C-16
  • ⊗ glucocorticoid activity
    • Replace OH @ C-11 with carbonyl
18
Q

Prodrugs

A

Cortisone and prednisone are prodrugs:

Converted to active -OH containing form by 11-β-hydroxysteroid dehydrogenase 1 (11-β-HSD1) in the liver

11-β-HSD2 found mostly in the kidney catalyzes reverse rxn from cortisol ⇒ cortisone

19
Q

Cortisol vs Cortisone

A
  • Equally active PO
  • Cortisone may be absorbed beteer
  • Cortisone + other carbonyl-containing prodrugs inactive topically
  • Prodrugs may show reduced efficacy in patients with impaired liver function
20
Q

Common Clinical Glucocorticoids

A
21
Q

Glucocorticoids

Short - Medium Acting

A

Hydrated Cows Pretend People Make Milk

22
Q

Glucocorticoids

Intermediate Acting

A

Try Parasailing Floozies

23
Q

Glucocorticoids

Long Acting

A

If you wanna last… Bet Dexter

24
Q

Mineralocorticoids

A

Flat Discs

25
Q

Glucocorticoid Therapy

Indications

A

Two main indications:

  1. Replacement therapy ⇒ for adrenal insufficiency
    • Physiological doses ⇒ small
      • To ameliorate effects of insufficiency
  2. Anti-inflammatory therapy ⇒ to suppress inflammation
    • Pharmacological doses ⇒ high
      • To achieve suppression
26
Q

Replacement Therapy

A
  • Provide exogenous agents to replace “missing” cortisol
  • Use smallest effective dose ⇒ avoid adverse effects of chronic glucocorticoid excess
  • For primary adrenal insufficiency ⇒ glucocorticoid + mineralocorticoid
    • Use oral cortisol
  • For secondary adrenal insufficiency ⇒ only glucocorticoid
    • Again use oral cortisol
27
Q

Anti-Inflammatory Therapy

A
  • High levels of glucocorticoids ⇒ suppression of immune & inflammatory responses
    • ⊗ cytokine release
    • ⊗ synthesis of arachidonic acid metabolites
  • Widespread use including asthma, SLE, RA, Crohn’s, temporal arteritis, anti-rejection
  • Do not correct the underlying defect
  • Only limits the effects of inflammation
  • Discontinuation of treatment often results in resumption of sx
28
Q

Glucocorticoids

Administration Routes

A
  • Pharmacologic doses ⇒ adverse effects
    • Esp. when given systemically
  • Use targeted delivery methods whenver possible
    • High doses locally
    • Provide desired clinical effect
    • Minimalize systemic adverse effects
29
Q

Inhaled Corticosteroids

A

* Used for asthma and COPD ⇒ reduce airway inflammation

  • Some does enter systemic circulation
    • Choose glucocorticoid that undergoes extensive first-pass metabolism
    • Actual amount entering systemic circulation negligible
  • Glucocorticoids delivered via inhaer includes:
    Fat friends try better
    • Fluticasone
    • Flunisolide
    • Triamcinolone
    • Beclometasone
30
Q

Topical Corticosteroids

A
  • Used for dermatologic disorders
    • Ex. psoriasis and atopic dermatitis
  • Very little gets into systemic circulation
  • Skin has little 11-β-HSD1
    • Cannot use prodrugs
  • Topical corticosteroids includes:
    • Hydrocortisone (cortisol)
    • Methylprednisolone
    • Dexamethasone
31
Q

Depot Corticosteroids

A
  • Depot prep of methylprednisolone suspended in polyethylene glycol
  • Used for intra-articular admin
    • RA or gout
32
Q

Glucocorticoid

Side Effects

A

High pharmacological doses for anti-inflammatory therapy ⇒ adverse effects with chronic use.

  • Hyerglycemia and insulin resistance
    • Pancreatic β-cells ↑ insulin production to ↓ BGL
    • Can result in DM
      • Especially in patients with decreased β-cells cell reserves
  • Atrophy of fast-twitch muscle fibers
  • Redistribution of fat
    • Peripheral wasting
    • Central obesity
    • Excessive fat deposition
      • Back ⇒ buffalo hump
      • Face ⇒ moon facies
  • ⊗ Vit D mediated Ca2+ absorption
    • Secondary hyperparathyroidism
  • ⊗ osteoblast function
    • Osteoporosis
    • Slow linear bone growth in children
    • Short stature if taken throughout adolescence
33
Q

Glucocorticoid

Treatment Withdrawal

A
  • High [glucocorticoids]plasma ⇒ CRH and ACTH suppresion
    • Via negative feedback
  • ACTH trophic factor ⇒ cortical atrophy possible
  • Abrupt withdrawal of corticosteroids ⇒ acute adrenal insufficiency
    • Can take several months to reactivate HPA axis & restore cortical function
  • Gradual withdrawal ⇒ allows axis to recover slowly
    • < 2 week treatment ⇒ usually no tapering needed
    • 2-4 weeks ⇒ taper over 1-2 weeks
    • > 4 weeks ⇒ taper 1-2 months
34
Q

Mifepristone (RU-486)

A
  • At low levels ⇒ progesterone receptor antagonist
    • Used to induce abortion early in pregnancy
  • At high levels ⇒ glucocorticoid receptor antagonist
    • Treat life-threatening elevated glucocorticoid levels
      • Ex. ectopic ACTH syndrome
35
Q

Glucocorticoid

Synthesis Inhibitors

A

Not specific enough to block synthesis of a particular compound.

  • Aminoglutethimide
    • ⊗ side chain cleave enzyme
    • ⊗ all corticosteroids
  • Metyrapone
    • ⊗ 11-β-hydroxylase
    • ⊗ cortisol and aldosterone
36
Q

Mineralocorticoid

Overview

A
  • Aldosterone made in zona glomerulosa only
  • Acts via mineralocorticoid receptor (MR)
    • “Type I glucocorticoid receptor”
  • Renal tubule
    • ↑ Na/K ATPase expression
    • ↑ apical ENaC Na+ channel expression
    • ↑ Na/K/Cl cotransporter expression
  • Net effect: ↑ Na+ reabsorption & ↑ K+ secretion
    • ↑ extracellular volume expansion
  • Also ∆ salt and water transport in the colon, salivary glands, and sweat glands
37
Q

Aldosterone

Regulation

A

3 factors regulate Aldosterone synthesis:

  • Renin-angiotensin system
    1. ↓ BP ⇒ ↑ renin by juxtaglomerular apparatus
    2. ↑ Ang II
    3. Acts at angiotensin AT1 receptors
    4. ↑ [Ca2+]
    5. ↑ activity of sidechain cleavage enzyme
  • ↑ extracellular [K+]
    • Depolarization of glomerulosa cells
    • ↑ [Ca2+]
  • ACTH
    • Acts via melanocortin-2 receptor (MC2R)
38
Q

Aldosterone Hypofunction

A
  • Primary hypofunction
    • Addison’s disease
  • Secondary hypofunction
    • ↓ renin production
      • Diabetic renal insufficiency
  • Net result:
    • Salt wasting
    • Volume depletion
    • Hyperkalemia
    • Acidosis
39
Q

Aldosterone Hyperfunction

A
  • Most common causes:
    • Bilateral zona glomerulosa adrenal hyperplasia
    • Aldosterone-producing adenomas
  • Net effect:
    • Extracellular volume expansion
    • ⊗ renin release
    • Potassium wasting and hypokalemia
    • HTN
40
Q

Mineralocorticoid

Agonists

A
  • Not possible to use aldosterone as replacement agent
    • Extensive first-pass metabolism
  • Fludrocortisone used ⇒ cortisol analog
    • Minimal first-pass metabolism
    • High mineralocorticoid/glucocorticoid activity ratio
    • Adverse effects same as excessive aldosterone production
41
Q

Mineralocorticoid

Antagonists

A
  • Used in treatment of HTN and CHF
  • K+-sparing diuretics
    • Spironolactone
      • Also an androgen and progesterone receptor angtagonist
      • Can cause gynecomastic in males
      • Limited usefulness in some
    • Eplerenone
      • Pure MR antagonist
  • Can cause severe hyperkalemia

Foundations of Disease (46 decks)

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