Anti-Inflammatory Corticosteroids

Question 1

Effects of Glucocorticoids on Carbohydrate Metabolism

Answer 1

Gluconeogenesis, increase in blood glucose leading to insulin release, and glycogen synthesis with deposition in the liver

Question 2

Effect of excess glucocorticoids on carbohydrate metabolism

Answer 2

Diabetes-like state

Question 3

Effect of Glucocorticoids on Protein Metabolism

Answer 3

Increased aminoacid uptake from liver and kidney, decreased protein synthesis (except in liver), result is a net transfer of AAs from muscle/bone to liver

Question 4

Effect of excess glucocorticoids on protein metabolism

Answer 4

Muscle wasting, catabolism of skin and connective tissue

Question 5

Effect of Glucocorticoids on Lipid Metabolism

Answer 5

Net effect is lipogenesis due to increased insulin release. There is a greater lipogenic effect in the central tissues.

Question 6

Effect of excess glucocorticoids on lipid metabolism

Answer 6

Centripetal obesity, buffalo hump and increased abdominal fat.

Question 7

What is the physiologic mechanism of action of mineralcorticoids?

Answer 7

Aldosterone binds cytosolic receptor, migrates to nucleus where it increased translation of specific proteins: Na-K-ATPase, sodium channels, and potassium channels.

Question 8

Physiologic effect of mineralcorticoid

Answer 8

Increased reabsorption of sodium from renal distal tubules, and increased secretion of protons and potassium.

Question 9

What are therapeutic doses of corticosteroids generally used for?

Answer 9

Suppress inflammatory and immune responses. Most useful if the host response is the cause of deleterious effects of the disease.

Question 10

Anti-Inflammatory effects of glucocorticoids

Answer 10

Decreased production and action of cytokines, reduced generation of leukotrienes and prostaglandins via decreased expression of COX-2 and inhibition of Phospholipase-A2.

Question 11

Immunosuppressive effects of glucocorticoids

Answer 11

Reduction in chronic inflammation and autoimmune reactions BUT decreased healing and protective aspects of the immune system

Question 12

How do glucocorticoids enact their immunosuppressive effects?

Answer 12

Suppress T-cell activation, suppress cytokine production, prevent mast cells and eosinophils from releasing chemical mediators

Question 13

Effects of glucocorticoids on vascular events

Answer 13

Decreased vasodilation, decreased fluid exudation

Question 14

Effects of glucocorticoids on cellular events

Answer 14

Overall decrease in accumulation and activation of cells

Question 15

Mineralocorticoid activity refers to…

Answer 15

The salt (Na+)-retaining actions at the kidney.

Question 16

Glucocorticoid activity refers to…

Answer 16

The metabolic effects: hyperglycemia, protein wasting, and lipid redistribution.

Question 17

Compare the anti-inflammatory potency to the salt-retaining potency of cortisol (aka hydrocortisone)

Answer 17

1 : 1. i.e. Cortisol defines the potency. Just know Cortisol does both and we compare everything else to it.

Question 18

Compare the anti-inflammatory potency to the salt-retaining potency of aldosterone. (relative to cortisol)

Answer 18

0.3 : 3000 i.e. Aldosterone’s effect is essentially only salt-retaining.

Question 19

Compare the anti-inflammatory potency to the salt-retaining potency of Prednisone, Triamcinolone, and Dexamethasone. (relative to cortisol)

Answer 19

4-30 : 0-0.3 i.e. a lot of anti-inflammatory effect with little to no salt-retaining effect. Good choice to suppress immune system without mineralcorticoid activity.

Question 20

Compare the anti-inflammatory potency to the salt-retaining potency of Fludrocortisone. (relative to cortisol)

Answer 20

10 : 125-250 i.e. a lot of salt-retaining effect with little immunosuppression.

Question 21

Where is 11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1) expressed? And what reactions does it catalyze?

Answer 21

Liver. Converts cortisone to the active cortisol or prednisone to the active prednisolone. i.e. activating step.

Question 22

Where is 11ß-hydroxysteroid dehydrogenase 2 (11ß-HSD2) expressed? And what reactions does it catalyze?

Answer 22

Kidney. Converts cortisol to cortisone or prednisolone to prednisone i.e. inactivating step.

Question 23

Can you treat a pregnant woman with glucocorticoids without effect on the fetus?

Answer 23

Yes, because fetus expresses the inactivating enzyme (11(beta)-HSD2) in the kidney but does not express the activating enzyme (11(beta)-HSD1) in the liver i.e. it can convert the drug back to the prodrug. (assumption is you don’t saturate the inactivating enzyme)

Question 24

Clinical considerations for use of Cortisol (aka Hydrocortisone)

Answer 24

Common use in physiologic doses for replacement therapy and emergencies; glucocorticoid and mineralocorticoid actions [1:1]; administered orally and parenterally

Question 25

Clinical considerations for use of Prednisone

Answer 25

Most commonly used oral agent when steroid burst therapy desired; glucocorticoid and mineralocorticoid actions [13:1]; activated to prednisolone in liver. NO topical activity, not activated until first pass hepatic metabolism

Question 26

Clinical considerations for use of Methylprednisolone

Answer 26

Used if parenteral administration desired for steroid burst (no better than oral prednisone in acute exacerbations of asthma); minimal mineralocorticoid action. Oral (Medrol) and parenteral (Solu-Medrol

Question 27

Clinical considerations for use of Dexamethasone (Decadron)

Answer 27

Most potent anti-inflammatory agent, used in cerebral edema, chemotherapy-induced vomiting; no mineralocorticoid action, greatest suppression of ACTH secretion at pituitary

Question 28

Clinical considerations for use of Triamcinolone (Kenalog)

Answer 28

Potent systemic agent - excellent topical activity; no mineralocorticoid action

Question 29

What Inflammatory-type disorders are glucocorticoids used for?

Answer 29

Allergic reactions, collagen-vascular, GI disease, eye diseases, hematologic disorders, neurologic disorders, pulmonary disease, skin disorders, hypercalcemia and mountain sickness.

Question 30

What 3 categories of drugs is Rheumatoid Arthritis managed with?

Answer 30

Nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, and disease modifying antirheumatic drugs (DMARDs).

Question 31

How can we minimize adverse effects of glucocorticoid therapy?

Answer 31

Alternate day schedule. Lessens growth-suppressive effects because anti-inflammatory actions outlast suppressive effect on HPA axis.

Question 32

Why is it important to terminate administration of glucocorticoids gradually?

Answer 32

If taken longer than 7-10 to 28 days, otherwise may cause severe rebound of disease or symptoms of adrenal insufficiency (adrenal crisis).

Question 33

Dosage forms of glucocorticoids

Answer 33

Oral. Most common route when systemic actions desired (also intravenous / intramuscular) Topical (skin disease). Relatively insoluble steroids, but can see systemic effects if potent steroids are applied for long periods, under occlusive dressings, or over large areas. Inhalants (asthma). Metabolized in lungs before absorption, thus decreased systemic effects. Ophthalmic (eye disease). Intra-articular (into joint for rheumatoid arthritis). Enemas (ulcerative colitis). Nasal sprays (allergic rhinitis).

Question 34

Adverse Mineralocorticoid effects of acute, short course, high dose steroids

Answer 34

Na+ and H2O retention, edema, increased BP, hypokalemia

Question 35

Adverse Glucocorticoid effects of acute, short course, high dose steroids

Answer 35

Glucose intolerance, mood changes (up or down), insomnia, GI upset

Question 36

Adverse Glucocorticoid effects expected with high dose sustained therapy (> 2 weeks) (+ short-term effects)

Answer 36

Iatrogenic Cushing’s syndrome [hyperglycemia, protein wasting (muscle), lipid deposition (weight gain) leading to diabetes-like state] Hypothalamic-pituitary-adrenal axis suppression results in insufficient response to stress; more suppression with dexamethasone and betamethasone. Also in ACTH, GH, TSH, LH, sex steroids. Mood disturbance [initial euphoria, then psychic letdown or psychosis (rarely) when dose reduced; high concentration of glucocorticoid receptors in hippocampus] Impaired wound healing, increased protein catabolism via effects on collagen and fibroblasts Increased susceptibility to infection (bacterial, viral, fungal) + short-term effects too.

Question 37

Possible Adverse effects with large cumulative doses

Answer 37

Osteoporosis via direct effect (decrease in osteoblasts, block of vitamin D3 induced osteocalcin gene) and indirect effect (decreased Ca absorption and increase in PTH release). Risk and rate of osteoporosis decreased by use of bisphosphonates (e.g., alendronate). Posterior capsular cataracts, esp. in children receiving prolonged treatment for asthma. Skin atrophy, loss of collagen support. Catabolic effects on skin and connective tissue. Growth retardation in children. Decreased growth hormone secretion and impaired action of somatomedins. Growth resumes upon discontinuation of glucocorticoids and expected height is often obtained. Peptic ulceration with higher doses via decrease in protective mucopolysaccharides, increase in histamine-induced H+ secretion, decreased immune response to H. pylori; reduce risk with antacids. Occasionally seen - avascular necrosis, myopathy, fatty liver, hirsutism

Question 38

Effects of prolonged glucocorticoid excess

Answer 38

Iatrogenic Cushing’s syndrome. Italicized effects are particularly common. Less frequent effects, related to dose and duration of therapy, are shown in parentheses.

Question 39

Functional Relationships in the HPA Axis (and select drugs)

Answer 39