Glucocorticoids Flashcards
What is the structural difference between Cortisol and aldosterone?
Cortisol has a 17-para-OH group
Where are corticoids released from?
Adrenal Cortex
What is the hypothalamic-pituitary-adrenal axis?
Stress signals release of CRH from hypothalamus, which signals release of ACTH from adrenal gland, which signals release of Cortisol from the adrenal gland
Cortisol is in a negative feedback loop on ACTH and CRH
What are the major functions of mineralocorticoids?
Regulate Na/K levels and blood pressure
What are the major functions of glucocorticoids?
Release stress homes, increase glucose concentration, anti-inflammator
What type of receptor is glucocorticoid receptor?
Nuclear–leads to gene activation
What effects does glucocorticoid have in the liver?
Gluconeogenesis and glycogen storage
What effects does glucocorticoid have in the muscle?
Protein degradation, decreased protein synthsis, decreases insulin sensitivity
What effects does glucocorticoid have on adipose tissue?
Lipolysis, decreased sensitivity to insulin
What effects does glucocorticoid have on the immune system?
Anti-inflammation (blocks eicosonaid synthesis)
Immunosuppression (blocks cytokine synthesis)
Why are glucocorticoids therapeutically useful?
For their anti-inflammatory action
What is a hormone response element (HRE)
The exact DNA sequence upstream of genes to be regulated by a nuclear receptor dimer
What are the two ways that glucocorticoids stop inflammation?
Up-regulate anti-inflammatory proteins like lipocortin
Down-regulate inflammatory proteins like cytokines
What does lipocortin I do?
Suppresses the production of phospholipase A2, which is used in eicosonoid production
How do glucocorticoids effect cytokine synthesis?
Activated glucocorticoid receptors bind to NFKB, so that it cannot bind to an HRE and cause cytokine production
What does NFKB do?
It acts as a transcription factor for cytokine synthesis
What normally inhibits NFKB?
IKB
What is Addisonian?
Too little glucocorticoid–causes severe weakness and can be fatal
What can cause Addisonian crisis?
Suddenly stopping glucocorticoids because of the negative feedback loop
What is Cushing’s syndrome?
Too much glucocorticoid–causes hyperglycemia, hypocalcemia, redistribution of fat, CNS effects)
What structural features are necessary for glucocorticoid and mineralocorticoid function?
C3 ketone
C3-4 double bond
What structure features are necessary only for glucocorticoid function?
17-alhpa-hydroxyl
11-para-hydroxyl
What is fludrocortisone?
A potent mineralocorticoid activator with a 9-alpha-F
What is the structural difference between prednisolone and cortisol?
C1-2 double bond
What is the structural difference between prednisone and prednisolone?
Prednisone has a ketone on 11-C that needs to be hydrolyzed before active (prodrug)
What is the structural difference between methylprednisolone and prednisolone?
Methylprednisolone has a 6-alpha-methyl group
What is the functional difference between methylprednisolone and prednisolone?
Methylprednisolone has a similar glucocorticoid potency with reduced mineralocorticoid activity
What is the structural difference between triamcinolone and prednisolone?/
9-alpha F
16-alpha-OH
What is the functional difference between triamcinolone and prednisolone?
Same glucocorticoid activity
Increased solubility, so poor absoroption/bioavailability
What is the structural difference between dexamethasone and prednisolone?
9-alpha-F
16-alpha-methasone
How does dexamethasone compare to prednisolone?
Stronger glucocorticoid activity with reduced mineralocorticoid
Better bioavailability than triamcinolone
How does betamethasone compare to prednisolone structurally?
9-alpha-F
16-para-methasone
(like dexamethasone but with an opposite methyl group)
What drug is betamethasone comparable to functionally?
Dexamethasone
What is the benefit of a 21-ester?
They are activated by hydrolysis so you can control their delivery
Which type of ester has the fastest hydrolysis?
Phosphate
Which type of ester has the slowest hydrolysis?
Succinate
When is phosphate ester used?
In emergency settings
What does adding a 1,2 double bond do to drug activity?
Increase GR/MR
What does adding a 6-alpha-CH3 or F do to activity?
Increase GR/MR
What does adding a 9-alpha or Cl do to activity?
Increase GR and MR potency
What does adding a 11-Beta-OH do?
Required for any activity
What does adding a 16 alpha or Beta-CH3 or O do?
Decrease MR activity
What does adding a 17-alpha-O do?
Required for GR activity
What does adding a 21-OH or F or Cl do?
Required for Gr/MR activity
What are the adverse effects of glucocorticoids?
Mineralocorticoid activity, metabolic effects, Cushing’s, impaired glucose tolerance, suppression of immune system, gastrointestinal, CNS, or cataracts, or Addisonian crisis
What are the metabolic effects of glucocorticoids?
Steroid myopathy (muscle wasting), reduced lung bone growth in children, osteoporosis
How can osteoporosis be prevented?
Bisphosphonate
What Gastrointestinal problems can glucocorticoids cause?
Peptic ulcer
What are effects can glucocorticoids have on the CNS?
Euphoria, depression
What properties are desired for inhaled glucocorticoids?
High lipophilicty, low oral bioavailability, rapid clearance from body
