Exam 2: Adrenal Steroids Flashcards
Adrenal Medulla
- Secretes cathecholamines as part of SNS
- Also produces a small amount of Norepi and dopamine
Adrenal Cortex
Secretes several steroid hormones ⇒ adrenocortical hormones
- Mineralocorticoids ⇒ salt balance
- Glucocorticoids ⇒ intermediary metabolism and immune function
- Androgens
Corticosteroid Synthesis
Zona glomerulosa
Makes mostly mineralocorticoid aldosterone.
- Does not express 17α-hydroxylase (CYP17)
- Required for cortisone and androgens
- Not needed for aldosterone
Zona fasciculata
Makes mostly glucocorticoid cortisol (aka hydrocortisone)
- Expresses 11β-hydroxylase (CYP11B1)
- Required for cortisol
- Does not express enzymes unique to androgen or aldosterone synthesis
Zona reticularis
Makes mostly adrogens
HPA Axis
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
-
Corticotropin-releasing hormone (CRH)
-
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
- ⇒⇒ cortisol
- Trophic effects on zona fasciculata and zona reticularis
-
ACTH → melanocortin-2-receptor (MC2R)
Zona glomerulosa receives trophic effects from ACTH but also…
angiotensin II and high serum K+
Cortisol Transport
90% bound to plasma proteins
-
Transcortin
- High affinity
- Low total binding capacity
-
Albumin
- Low affinity
- Higher binding capacity
Cortisol
Mechanism
- 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
Cortisol
Metabolic Effects
-
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
Cortisol
Anti-inflammatory Effects
-
⊕ Annexin I
-
⊖ phospholipase A2
- PL-A2 makes arachidonic acids
- ⇒ leukotrienes & prostaglandins
- PL-A2 makes arachidonic acids
-
⊖ phospholipase A2
-
⊕ MAPK phosphatase I
-
⊖ c-Jun regulated genes
- ∆ cytokine production
-
⊖ c-Jun regulated genes
-
⊗ Activation of NF-𝜅B
-
Normally ⊕ gene transcription
- Cytokines, chemokines, cell-adhesion molecules, complement, receptors
-
Normally ⊕ gene transcription
Addison’s Disease
- Primary adrenal insufficiency
- Caused by destruction of the adrenal cortex
- Autoimmune, infection, cancer, hemorrhage
- ↓ synthesis of all adrenocorticosteroids
- ↓ aldosterone ⇒ hyperkalemia
Secondary Adrenal Insufficiency
- 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
Cushing’s Syndrome
- 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
Cushing’s Disease
Cushing’s syndrome specifically caused by a ACTH-secreting pituitary adenoma
Glucocorticoid Agonist
Modifications
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
Prodrugs
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
Cortisol vs Cortisone
- 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
Common Clinical Glucocorticoids
Glucocorticoids
Short - Medium Acting
Hydrated Cows Pretend People Make Milk
Glucocorticoids
Intermediate Acting
Try Parasailing Floozies
Glucocorticoids
Long Acting
If you wanna last… Bet Dexter
Mineralocorticoids
Flat Discs
Glucocorticoid Therapy
Indications
Two main indications:
-
Replacement therapy ⇒ for adrenal insufficiency
-
Physiological doses ⇒ small
- To ameliorate effects of insufficiency
-
Physiological doses ⇒ small
-
Anti-inflammatory therapy ⇒ to suppress inflammation
-
Pharmacological doses ⇒ high
- To achieve suppression
-
Pharmacological doses ⇒ high
Replacement Therapy
- 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
Anti-Inflammatory Therapy
-
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
Glucocorticoids
Administration Routes
-
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
Inhaled Corticosteroids
* 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
Topical Corticosteroids
-
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
Depot Corticosteroids
- Depot prep of methylprednisolone suspended in polyethylene glycol
-
Used for intra-articular admin
- RA or gout
Glucocorticoid
Side Effects
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
Glucocorticoid
Treatment Withdrawal
-
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
Mifepristone (RU-486)
-
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
- Treat life-threatening elevated glucocorticoid levels
Glucocorticoid
Synthesis Inhibitors
Not specific enough to block synthesis of a particular compound.
-
Aminoglutethimide
- ⊗ side chain cleave enzyme
- ⊗ all corticosteroids
-
Metyrapone
- ⊗ 11-β-hydroxylase
- ⊗ cortisol and aldosterone
Mineralocorticoid
Overview
- 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
Aldosterone
Regulation
3 factors regulate Aldosterone synthesis:
-
Renin-angiotensin system
- ↓ BP ⇒ ↑ renin by juxtaglomerular apparatus
- ↑ Ang II
- Acts at angiotensin AT1 receptors
- ↑ [Ca2+]
- ↑ activity of sidechain cleavage enzyme
-
↑ extracellular [K+]
- Depolarization of glomerulosa cells
- ↑ [Ca2+]
-
ACTH
- Acts via melanocortin-2 receptor (MC2R)
Aldosterone Hypofunction
-
Primary hypofunction
- Addison’s disease
-
Secondary hypofunction
- ↓ renin production
- Diabetic renal insufficiency
- ↓ renin production
-
Net result:
- Salt wasting
- Volume depletion
- Hyperkalemia
- Acidosis
Aldosterone Hyperfunction
-
Most common causes:
- Bilateral zona glomerulosa adrenal hyperplasia
- Aldosterone-producing adenomas
-
Net effect:
- Extracellular volume expansion
- ⊗ renin release
- Potassium wasting and hypokalemia
- HTN
Mineralocorticoid
Agonists
-
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
Mineralocorticoid
Antagonists
- 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
-
Spironolactone
- Can cause severe hyperkalemia
