Corticosteroids: Steroidal anti-inflammatory agents week 5

Question 1

What are the 2 main classes of steroids the adrenal cortex synthesizes? How many carbons do they have?

Answer 1

• Adrenal cortex synthesizes two main classes of Steroids
• Corticosteroids (C21)
• Glucocorticoids (Cortisol)
• Mineralocorticoids (aldosterone)

•Androgens (C19)

Question 2

What is the rate limiting step in cholesterol synthesis? What enzyme catalyzes this rxn?

What stimulates this rxn? What inhibits it?

Answer 2

Rate limiting step is conversion of cholesterol to pregnenolone. Catalyzed by cholesterol desmolase, CYP11A1

ACTH activates enzyme to cleave cholesterol’s side chain. Aminoglutethimide and Ketoconazole (see FA) inhibit this rxn.

Question 3

Explain the neurohormonal loop and the points of feedback inhibition in cortisol release.

Answer 3

Question 4

What are the effect of glucocorticoids on the processes of inflammation? What stages of inflammation can they have an effect on?

Where are cortisol (glucocorticoid) receptors located within cells? What keeps them in the inactive conformation? Explain what occurs when cortisol binds to its receptor.

Answer 4

Glucocorticoids and inflammation:

Palliative:

– Does not address underlying cause

• Decrease heat, redness and swelling

– Can act at early stage

• Edema, capillary dilation, leukocyte migration

– Can act at late stage

• Capillary proliferation, deposition of collagen, scar formation

Steroid receptors (R) are inactive and found in the cytoplasm. Inactivity is maintained due to complex with heat shock protein 90 (Hsp90). Glucocorticoids (S) diffuses across the membrane and binds to the receptor. The receptor undergoes a conformational change, disassociates from HSP 90. Receptor dimers form and translocate to nucleus, binding to GRE response elements that induce, inhibit or regulate gene expression.

Question 5

State the specific effects cortisol has in reducing the inflammatory response. (think of the cells of the immune reponse and their functions)

Answer 5

Anti inflammatory effects

• Increase apoptosis in activated lymphocytes

– Limit activation of NF-kB

• Inhibit cytokine production:

– IL-1, IL-2, IL-6, TNF-a, IL-8 via NF-kB

• Inhibit activation of neutrophils & Leukocytes

– decrease ICAM, selectins, integrins

• Stabilize leukocyte lysosomal membranes
• Reduction in capillary permeability and edema
• Antagonism to histamine activity and edema

Also inhibit prostaglandin & leukotriene synthesis

• Stimulate synthesis of lipocortin

– Lipocortin inhibits Phospholipase A2

• Reduces Arachidonic Acid production: Starting point for prostaglandin, leukotriene synthesis

Question 6

State the relative anti-inflammatory and mineralocorticoid potentcies of the following steroids:

hydrocortisone (cortisol)

cortisone

dexamethosone

CH3- prednisolone

triamcinolone

prednisolone and prednisone

betamethasone

fludrocortisone

Answer 6

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(increase in glucocorticoid potentcy)

Cortisone, Prednisone, Methylprednisone, Triamcinolone (same as methylprednisone but has no mineralocorticoid activity), Betamethasone, Dexamethasone

Question 7

Glucocorticoids

drugs in this class

mechanims

clinical use

toxicitites

What occurs when glucocorticoid medications are stopped abruptly after chronic use?

Answer 7

Beclomethasone, dexamethasone, fludrocortisone (mineralocorticoid and glucocorticoid activity), hydrocortisone, methylprednisolone, prednisone, triamcinolone:

MOA: metabolic, catabolic, anti-inflammatory, and immunosuppressive effects mediated by interactions with glucorticoid response elements, inhibition of phospholipase A2, and inhibition of transcription factors such as NF-kB.

clinical use: Addison disease, inflammation, immunosuppression, asthma

Toxicities: Iatrogenic Cushing syndrome (hypertension, weight gain, moon facies, trunchal obesity, buffalo hump, thinning of skin, striae, osteoporosis, hyperglycemia, amenorrhea, immunosupression), adrenocortical atrophy, peptic ulcers, steroid diabetes, steroid psychosis. Adrenal insufficency when drug stopped abruptly after chronic use.

Question 8

Chronic administration of glucocorticoids results in a suppression of the release of what hormones?

Answer 8

ACTH, GH, TSH, LH

All stimulate processes that require a lot of energy.

Question 9

State the MOA and clinical use of aminoglutethimide.

What drug is coadministered with this drug and why?

Answer 9

Aminoglutethimide

Blocks the conversion of cholesterol to pregnenolone.

– Given with Hydrocortisone (replacement dose)

• Prevents over-ride of block by ACTH

– Results in the reduction of all hormonally active steroids

• Eliminating the influence of hormones in hormone dependent cancers

Hydrocortisone is also given to:

• Replace cortisol
• Replace mineralocorticoid activity (remeber hydrocortisone has some of this activity)
• Keep ACTH levels low. If only gave aminoglutethimide, ACTH levels would rise and override effect of drug.

Question 10

State the MOA and clinical use of metyrapone.

State the MOA and clinical use of trilostane.

Answer 10

Metyrapone

– Inhibits 11B-hydroxylation

– Interferes with cortisol and corticosterone synthesis

– Treatment of Cushings

Testing the integrity of the feedback loop

• Trilostane

– Inhibits 3B dehydrogenase.

Treatment of Cushings