Anti-Inflammatory Corticosteroids Flashcards
Which class of corticosteroids has anti-inflammatory activity?
glucocorticoids
What do glucocorticoids regulate?
protein and carbohydrate metabolism, anti-inflammation, immunosuppression
What do mineralocorticoids regulate?
Sodium and water retention (acts on kidneys)
What is the main endogenous mineralocorticoid?
aldosterone
What is the main endogenous glucocorticoid?
cortisol (cortisol also possesses equal mineralocorticoid activity)
Which corticosteroid triggers the release of androgens from the adrenal gland?
Cortisol (adrenal androgens; dihydroandrostenedione and androstenedione)
How is corticosteroid production stimulated (HPA axis)?
CRF from hypothalamus triggers the release of ACTH from anterior pituitary, which stimulates production of corticosteroids from the adrenal gland
How is the HPA axis regulated (3 modes)?
- Circadian (diurnal) rhythm of CRF synthesis, regulated by higher brain areas. (CRF production levels naturally change during the day; peak in AM and after meals)
- Negative feedback of circulating glucocorticoids stops production of both CRF (at the level of the hypothalamus) and ACTH (at the level of the AP)
- Stress overrides negative feedback. (= increased steroidogenesis)
What is the exact mechanism of ACTH for steroidogenesis of glucocorticoid?
ACTH catalyzes the rate-limiting conversion of cholesterol to pregnenolone
What directly stimulates steroidogenesis of mineralocorticoids?
Renin-angiotensin system. Angiotensin II stimulates conversion of cholesterol to pregnenolone and conversion of corticosterone to aldosterone
What are the two general mechanisms of glucocorticoid action?
- Interaction with membrane receptors (fast)
2. Gene transcription, protein synthesis (slow)
What is the half-life of cortisol?
60-90 minutes; can be increased by stress, hypothyroidism, or liver disease (metabolised in liver)
How do glucocorticoids affect carbohydrate metabolism?
stimulates gluconeogenesis and glycogen synthesis –> increased blood glucose, increased glycogen deposition
Note: increased blood glucose also leads to increased blood insulin
CHRONIC: Diabetes-like state
How do glucocorticoids affect protein metabolism?
Increase uptake of AA into liver and kidney for conversion into glucose –> decreased protein synthesis (net movement of protein from muscle –> liver)
CHRONIC: Muscle wasting
How do glucocorticoids affect lipid metabolism?
Decrease glucose uptake by fat cells –> lipolysis
Increased blood insulin –> lipogenesis
In central tissues, lipogenesis > lipolysis
CHRONIC: Centripetal obesity (buffalo hump, abdominal fat)
What is the ultimate physiological goal of glucocorticoids?
To maintain glucose supply to the brain
What is a permissive effect, and what are examples?
A permissive effect is an effect that is observed in the presence of glucocorticoids but not increased by increased glucocorticoids.
Ex) Vasoconstriction and bronchodilation, lipolysis, cardiac output
What is the mechanism of mineralocorticoid action?
Transcription and synthesis of proteins (channels) that increase reabsorption of Na from renal distal tubules.
This reabsorption is loosely coupled to increased H and K excretion.
What is the pharmacological use of glucocorticoids?
Suppressing inflammatory and immune responses
What are the mechanisms for the anti-inflammatory effects of glucocorticoids?
- Decreased production and action of cytokines
- Inhibition of inducible COX-2 and phospholipase A2 (via annexins), which results in decreased production of prostaglandins and leukotrienes
What are the mechanisms for the immunosuppressive effects of glucocorticoids?
- Decreased T cell activation
- Decreased cytokine production (also anti-inflammatory)
- Prevention of mast cells and eosinophils from releasing chemical mediators of inflammation (histamine, leukotrienes, prostaglandins)
Ultimately: less vasodilation (and less fluid exudate) and less accumulation/activation of cells
Side effects: slower healing, less protection
Drugs that are either glucocorticoid or mineralocorticoid with little/no overlap are ideal. What else would be ideal, but isn’t possible?
An anti-inflammatory steroid with no glucocorticoid activity.
Since its not, glucocorticoid side effects must always be monitored in PTs:
blood glucose
muscle wasting
obesity
What makes glucocorticoids physiologically active?
A hydroxyl group on the 11th carbon (11-hydroxy)
What activates glucocorticoids that do not have an 11-hydroxy group (11 keto glucocorticoids)?
11beta hydroxysteroid dehydrogenase I (11beta HSDI); in liver
cortisone –> cortisol/hydrocortisone
