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
2
Q
Adrenal Cortex
A
Secretes several steroid hormones ⇒ adrenocortical hormones
- Mineralocorticoids ⇒ salt balance
- Glucocorticoids ⇒ intermediary metabolism and immune function
- Androgens
3
Q
Corticosteroid Synthesis
A
4
Q
Zona glomerulosa
A
Makes mostly mineralocorticoid aldosterone.
- Does not express 17α-hydroxylase (CYP17)
- Required for cortisone and androgens
- Not needed for aldosterone
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
6
Q
Zona reticularis
A
Makes mostly adrogens
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
-
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)
8
Q
Zona glomerulosa receives trophic effects from ACTH but also…
A
angiotensin II and high serum K+
9
Q
Cortisol Transport
A
90% bound to plasma proteins
-
Transcortin
- High affinity
- Low total binding capacity
-
Albumin
- Low affinity
- Higher binding capacity
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
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
12
Q
Cortisol
Anti-inflammatory Effects
A
-
⊕ 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
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
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
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
16
Q
Cushing’s Disease
A
Cushing’s syndrome specifically caused by a ACTH-secreting pituitary adenoma
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
Glucocorticoid Therapy
Indications
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
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
27
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
28
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
29
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**
30
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**
31
Depot Corticosteroids
* **Depot prep of methylprednisolone suspended in polyethylene glycol**
* **Used for intra-articular admin**
* RA or gout
32
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
33
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
34
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
35
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
36
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**
37
Aldosterone
Regulation
_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
Aldosterone Hypofunction
* **Primary hypofunction**
* Addison's disease
* **Secondary hypofunction**
* ↓ renin production
* Diabetic renal insufficiency
* _Net result:_
* **Salt wasting**
* **Volume depletion**
* **Hyperkalemia**
* **Acidosis**
39
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**
40
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
41
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
* **Can cause severe hyperkalemia**
