Week 4 - Adrenal Flashcards
What is the action of Amiloride?
Blocks ENaC channels –> K+ sparing diuretic
What is the action of Spironolactone?
Antagonist of mineralocorticoid (aldosterone) and androgen receptors –> K+ sparing diuretic
What is the screening test for Cushing’s Syndrome?
- ACTH level
- Overnight dexamethasone suppression test
What is the test for differentiating Cushing’s Disease from other causes of Cushing’s syndrome?
Petrosal sinus sampling
What lab tests are required to rule out Pheochromocytoma?
Urine catecholamines and catecholamine metabolites (ex. metanephrine)
What is Conn’s syndrome?
Primary hyperaldosteronism due to aldosterone-secreting adenoma
What test is useful to rule out Conn’s syndrome?
Aldosterone:renin ratio
What is the first investigation for adrenal insufficiency?
Rapid ACTH stimulation test (with baseline ACTH and cortisol measurements)
For ACTH stimulation test, what does it mean if there is blunted cortisol response with high ACTH?
- with low ACTH?
- what about normal ACTH and normal cortisol response?
High ACTH, Low cortisol response ==> Primary Adrenal Insufficiency (Addison’s disease)
Low ACTH, Low cortisol response ==> Secondary Adrenal Insufficiency or Chronic Steroid Use
Normal ACTH, Normal cortisol response ==> Not Addison’’s
What are the cells in the adrenal medulla called?
- what do they secrete?
Chromaffin cells
- secrete catecholamines
What does MEN stand for?
Multiple Endocrine Neoplasia
What are the types and subtypes of MEN?
MEN-1
MEN-2: subclassified to
- MEN-2a
- MEN-2b
- MCT (Medullary carcinoma of the thyroid)
What are the main symptoms associated with MEN-2?
- Medullary carcinoma of the thyroid (>95%)
2. Pheochromocytoma (50%)
What are the main symptoms associated with MEN-1?
“P-P-P triad”
- Parathyroid
- Pancreatic Islet cell (usually insulin or gastrin secreting)
- Pituitary (anterior)
What’s the difference in clinical presentation between MEN-2a & MEN-2b?
MEN-2a has hyperparathyroidism.
MEN-2a is more common than 2b.
How is the presentation of medullary carcinoma of the thyroid different than other MEN-2 presentations?
MCT is not a/w pheos.
MCT and MEN-2b do not have hyperPTH, but Men-2a does.
ie. the only symptom a/w MCT is MCT.
How is dx of MEN-2 confirmed?
- Bx of mass in neck (most important early finding).
- Measure for elevated calcitonin
What is a marker for MCT?
elevated calcitonin
What is the rate of secretion of cortisol under physiological conditions?
10mg/day
What is the normal range for K+ in the blood?
3.5-5mmol/L
List the types of corticosteroids and state their main function.
Glucocorticoids - regulate carbohydrate metabolism (& anti-inflammatory)
Mineralocorticoids - regulate electrolyte balance (mainly Na+ retention)
What is the transport protein for cortisol in the blood?
CBG (Corticosteroid binding globulin)
Name a short-acting glucocorticoid.
- what is the approximate half life of this?
Hydrocortisone (cortisol) or cortisone
- t(1/2) = 8-12 hrs
Name a intermediate-acting glucocorticoid.
- what is the approximate half life of this?
Prednisone
- t(1/2) = 12-36 hrs
Name a long-acting glucocorticoid.
- what is the approximate half life of this?
Dexamethasone
- t(1/2) = 36-72 hrs
What synthetic corticosteroid has much more potent mineralocorticoid action (as opposed to glucocorticoid action)
Fludrocortisone
What is the benefit of taking steroids in the inhaled form?
Prevents systemic effects of the drug
What are the pharmacokinetics of ingested cortisol (ADME)?
A: well absorbed via GI
D: binds to CBG or albumin in blood
M: hepatic metabolism
E: excreted by kidneys
Of the alpha and beta type catecholamine receptors, which one has a much higher affinity for Epi over NE?
beta-2 receptors
How does cortisol act in catecholamine production?
Induces PNMT (enzyme that converts NE –> Epi
What is the rate-limiting step in catecholamine synthesis?
Tyrosine –> DOPA
enzyme = Tyrosine hydroxylase
What is the enzyme that catalyzes the rate-limiting step in cholesterol synthesis?
HMG-CoA reductase
Why does the adrenal medulla get stained dark brown?
Due to conversion of catechols to melanin (occurs in granules)
Is the adrenal medulla necessary for life?
no.
What are the pathways for the metabolism of Epi & NE?
(include enzymes)
Epi –(COMT)–> metanephrine –(MAO)–> VMT
NE –(COMT)–> normetanephrine –(MAO)–> VMT
Why is dexamethasone given after surgery?
To prevent nausea/vomiting
What are some of the main complications of long-term glucocorticoid tx?
Adrenal atrophy –> iatrogenic Cushing’s (due to too much synthetic glucocorticoid action)
Glucocorticoid withdrawal –> acute adrenal insufficiency
What is the similarity between the following drugs?
- Aminoglutethimide
- Metyrapone
- Ketoconazole
- Etomidate
CYP 450 inhibitors
- affect the production of corticosteroids and androgens
What is the molecular action of finasteride?
- 5-alpha-reductase inhibitor
- prevents conversion of T –> DHT
What is the action of Mifepristone?
Progesterone receptor blocker
What cells are in the adrenal medulla to support the spindle cells?
Sustentacular cells
Where are the spindle cells?
At periphery of the nests of chromaffin cells.
What is the most common adrenal mass in children?
Neuroblastoma
What is the DDx for bilateral adrenal masses?
- pheo
- cushing’s disease (excess ACTH stimulation)
- ectopic ACTH/CRH production
- mets
- hemorrhage
- adrenal nodular hyperplasia
- lymphoma
In Addison’s disease, what percent of the adrenal cortex has to be destroyed before symptoms present?
90% compromised
What are some causes of Addison’s disease?
- autoimmune
- infections (TB, histoplasmosis, coccidiodes)
- mets/lymphomas
- hemorrhage
- HH (hemochromatosis)
What virus is common in adrenal glands of AIDS patients?
CMV
Where are steroid receptors when not activated?
In cytoplasm, bound to HSD (heat shock protein)
What are fibrates used to treat?
- what receptor do they bind to?
Treat dyslipidemia
- bind PPAR-alpha receptor
What is Vit D used to prevent?
- which receptor does it bind?
Prevents rickets & ostemalacia, diabetes, CA
- binds VDR (Vit D receptor)
What are thiazolidinediones used to treat?
- what receptor does it bind?
Diabetes
- binds PPAR-gamma receptor
How are blood glucose levels related to serum K+?
Hypokalemia causes inhibition of insulin secretion, thus leading to hyperglycemia
How does cortisol affect GFR?
Cortisol increases GFR –> increases free water clearance
What’s associated with mutations in the RET proto oncogene?
MEN-2a
MEN-2b
MCT
Hirschprung’s syndrome
What happens in Addisonian Crisis?
hypotension, hyperkalemia, hyponatremia
