11 - Glucocorticoids Flashcards
Are adrenocorticoids the same as androgens?
NO
What causes the body to induce production of adrenocorticoids?
- Stress
- Stress causes release of corticotropin releasing hormone (CRH) from hypothalamus, stimulating release of adrenocorticotropic hormone (ACTH) from pituitary gland, which stimulates uptake of LDL into adrenal cortical cells to produce adrenocorticoids
What are the most important adrenocorticoids?
Cortisol (hydrocortisone) and aldosterone
What are the functions of glucocorticoids?
- Stimulate gluconeogenesis (liver)
- Stimulate bone loss
- Suppress production of inflammatory mediators, “turning down” immune activity
What is the main mechanism of action for anti-inflammatory effects of glucocorticoids?
- GCs stimulate production of lipocortin (cytosolic protein) that is believed to bind to membrane phospholipids, preventing phospholipase A2 (PLA2) from hydrolyzing ester linkage btwn phospholipid and arachidonic
- Arachidonic acid can’t be released => less production of prostaglandins, leukotrienes, and platelet activating factor inflammatory mediators
What is the outcome of glucocorticoids anti-inflammatory effects?
Inhibition of macrophages in tissues, neutrophils in or near blood, and eosinophils in bronchi
___ is responsible for the majority of glucocorticoid effects
Hydrocortisone
What is the difference btwn hydrocortisone and cortisone? How are they interconverted?
- Hydrocortisone has OH at C-11; cortisone has =O
- Dehydrogenase converts hydrocortisone to cortisone; reductase converts cortisone to hydrocortisone
Why is hydrocortisone not stored in LDL and HDL particles?
B/c it is a stress hormone, so we only want it around when it is immediately needed
What are some adverse effects of glucocorticoids?
- Infections
- Osteoporosis
- Increased CV risk
- Myopathy
- Weight gain/obesity
- Gastric ulcer
- Skin thinning
- Glaucoma, cataract
What is the primary use of glucocorticoids as drugs?
Suppression of inflammation
What are the routes of administration for glucocorticoids as drugs? What is most common?
Oral, IV, IM, inhaled, and topical (most common is topical)
What preparations is hydrocortisone used in?
Ointments and creams (but not o/w lotions) to enhance dermal uptake
Are synthetic glucocorticoids more or less potent than natural glucocorticoids?
More potent
Does hydrocortisone produce any active metabolites?
No
Does prednisolone produce any active metabolites?
Yes
What is the difference btwn prednisone and prednisolone?
Prednisone is the prodrug form of prednisolone
When is prednisolone used instead of prednisone?
In px w/ hepatic failure, b/c they won’t be able to convert the prodrug to the active form
Is hydrocortisone more active than betamethasone?
No, betamethasone is 30X more active
Rank from most active to least active – hydrocortisone, betamethasone, dexamethasone
Betamethasone > dexamethasone > hydrocortisone
How are glucocorticoids metabolized?
- Reduction of double bond at C-4 and C-5
- Reduction of ketone in C-3 to hydroxyl group
What happens to the inactive metabolites of glucocorticoids?
Enzymatically coupled through C-3 hydroxyl w/ sulfate or glucuronic acid to yield more water soluble compounds, which are excreted via kidneys
What does the presence of a double bond at C1 and C2 and a fluorine at C6 or C9 of a glucocorticoid cause?
- Increased resistance to degradation
- Reduced clearance
- Prolonged effects
What is involved in the secondary deactivation pathway for glucocorticoids?
Oxidation at positions C-21 and C-6
What effect does fluorination at C-6 or C-9 have on hydroxylation?
Slows hydroxylation at C-6
Do glucocorticoids have high or low plasma protein binding?
Very high, over 90%
What can long-term administration of glucocorticoids cause?
- Adrenal suppression
- High BP
- Hyperglycemia
- Glaucoma
- Osteoporosis
- Reduced immune system function
What can abruptly ceasing glucocorticoid use cause?
Hypocortisolism; hyperpigmentation of skin
What is done to synthetic glucocorticoids to prevent systemic uptake from lungs or GI tract?
Designed to be highly lipophilic
What is the effect of steroid hormones on salt and water balance?
- Increase production of Na+/K+ transporter protein
- Increase production of Na+/H2O reabsorption
- Increase K+ excretion
How are the effects of mineralocorticoid mediated?
- Slow genomic mechanisms through nuclear receptors
- Fast non-genomic mechanisms through membrane-associated receptors or signalling cascades
What are some characteristics of aldosterone?
- Agonist
- Highly potent
- Never used as a drug b/c too potent, so would cause too many SE
What is used for aldosterone replacement therapy for aldosterone insufficiency?
Fludrocortisone
What are some characteristics of spironolactone?
- Antagonist of aldosterone receptors
- Orally bioavailable
- Major metabolite is very active
- K-sparing diuretic
Glucocorticoids w/ a ___ are generally used for injectables
Salt
What is the difference between dexamethasone, betamethasone, and paramethasone?
- Dexamethasone has fluorine at C-9 and conformation at C-16 is alpha
- Betamethasone has fluorine at C-9 and conformation at C-16 is beta
- Paramethasone has fluorine at C-6 and conformation at C-16 is alpha
