Pharmacology of glucocorticoids

Question 1

What does corticotropin do?

Answer 1

It induces synthesis and secretion of cortisol by the adrenal cortex

Question 2

What stimulates the release of corticotropin?

Answer 2

Corticotropin-releasing hormone

Question 3

Where is corticotropin released from?

Answer 3

Anterior pituitary

Question 4

What form does most secreted cortisol take?

Answer 4

90% of it is bound to corticosteroid-binding globulins in the blood

Question 5

What enzyme converts cortisol to cortisone?

Answer 5

Type 2 11beta-hydroxysteroid dehydrogenase

Question 6

What enzyme converts cortisone to cortisol?

Answer 6

Type 1 11beta-hydroxysteroid dehydrogenase

Question 7

What is the active form of the product of corticotropin?

Answer 7

Cortisol

Question 8

What are the three main functions of cortisol?

Answer 8

1) The cortisol-glucocorticoid receptor complex moves to the nucleus as a homodimer to act as a coactivator or corepressor for transcription
2) The receptor complex interacts with other transcription factors (e.g. nuclear factor kbeta) that affects transcription at lower cortisol levels than the direct action
3) Glucocorticoid signaling through membrane-associated receptors and second messengers

Question 9

What is the general effect of glucocorticoid receptor signaling?

Answer 9

It inhibits inflammation through all signaling/transcription regulating mechanisms (direct and indirect genomic effects and nongenomic mechanisms)

Question 10

What is the pathway of cytokine signaling leading to pain perception?

Answer 10

Cytokines/inflammatory mediators activate peripheral pain receptors that project to the dorsal horn and synapse with the lemniscal tract, which carries pain signals to the thalamus and somatosensory cortex

Question 11

What is the negative feedback loop of glucocorticoids?

Answer 11

Cytokines activate pain receptors, leading to activation of the hypothalamic-pituitary-adrenal axis which in turn produces glucocorticoids that downregulate inflammatory mediators and cytokines

Question 12

What is the time scale of effects of glucocorticoids?

Answer 12

Genomic effects = hours to days

Nongenomic effects = seconds to minutes

Question 13

What is the effect of binding of glucocorticoids on eicosanoid-mediated inflammation?

Answer 13

It leads to release of cytosolic steroid receptor , which induces phosphorylation of annexin 1, inhibiting cytosolic phospholipase A2alpha acitivity, reducing production of arachidonic acid (thus inhibiting eicosanoid synthesis)

Question 14

What does annexin 1 do?

Answer 14

When active/phosphorylated, it normally inhibits cytosolic phospholipase A2alpha activity, which decreases to production of arachidonic acid

Question 15

What are the rapid effects of glucocorticoids?

Answer 15

The eicosanoid pathway via c-Src and annexin1 phosphorylation

Question 16

What are the specific slow genomic effects of glucocorticoids?

Answer 16

Ligand-bound glucocorticoid receptor in the nucleus represses expression of AP1 and NFkB (immune stimulators) and activates expression of annexin 1 (inhibitor of inflammation and immune modulator)

Question 17

What are the end products of the arachidonic acid pathway?

Answer 17

Prostacyclin, prostaglandins, thromboxanes, leukotrienes

Question 18

What is the use of steroids in rheumatoid arthritis?

Answer 18

Oral or injected glucocorticoids that can help achieve low disease activity

Question 19

What is the use of steroids in polymyalgia rheumatica treatment?

Answer 19

Prednisone is used for the first 4-8 weeks, restart if symptoms recur

Question 20

What is the use of steroids for lumbosacral radiculopathies?

Answer 20

They can be helpful for a limited number of times per year, but excess injection can decrease bone density

Question 21

What is the most common adverse event associated with glucocorticoids?

Answer 21

Bone fracture (especially vertebral fractures and hip fractures)

Question 22

How do glucocorticoids lead to osteoporosis?

Answer 22

They increase the number of bone resorbing osteoclasts, which leads to increased risk of fracture

Question 23

What is the effect of glucocorticoids on blood sugars?

Answer 23

They can lead to 2 to 3 weeks of persistent elevated blood sugar

Question 24

What are the mechanisms of glucocorticoid induced hypertension?

Answer 24

Renal sodium retention, vasopressor potentiation to angiotensin II and catecholamines

Question 25

What is the effect of glucocorticoid injection on cortisol levels?

Answer 25

It causes transient decreases in cortisol levels

Question 26

For which of the following diagnoses are oral glucocorticoids the first-line therapy?

a) knee osteoarthritis
b) lumbosacral radiculitis
c) polymyalgia rheumatica
d) rotator cuff tendinopathy

Answer 26

c) polymyalgia rheumatica

Question 27

Which of the following effects can be long-lasting if induced by administration of glucocorticoids?

a) hypertension
b) elevated blood glucose level
c) osteoporosis
d) decreased blood cortisol levels

Answer 27

c) osteoporosis

Question 28

What are the effects of hyperactive hypothalamic-pituitary-adrenal axis?

Answer 28

Cushing’s syndrome, physical pain, emotional trauma, immunosuppression