Pharmacology of glucocorticoids Flashcards
What does corticotropin do?
It induces synthesis and secretion of cortisol by the adrenal cortex
What stimulates the release of corticotropin?
Corticotropin-releasing hormone
Where is corticotropin released from?
Anterior pituitary
What form does most secreted cortisol take?
90% of it is bound to corticosteroid-binding globulins in the blood
What enzyme converts cortisol to cortisone?
Type 2 11beta-hydroxysteroid dehydrogenase
What enzyme converts cortisone to cortisol?
Type 1 11beta-hydroxysteroid dehydrogenase
What is the active form of the product of corticotropin?
Cortisol
What are the three main functions of cortisol?
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
What is the general effect of glucocorticoid receptor signaling?
It inhibits inflammation through all signaling/transcription regulating mechanisms (direct and indirect genomic effects and nongenomic mechanisms)
What is the pathway of cytokine signaling leading to pain perception?
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
What is the negative feedback loop of glucocorticoids?
Cytokines activate pain receptors, leading to activation of the hypothalamic-pituitary-adrenal axis which in turn produces glucocorticoids that downregulate inflammatory mediators and cytokines
What is the time scale of effects of glucocorticoids?
Genomic effects = hours to days
Nongenomic effects = seconds to minutes
What is the effect of binding of glucocorticoids on eicosanoid-mediated inflammation?
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)
What does annexin 1 do?
When active/phosphorylated, it normally inhibits cytosolic phospholipase A2alpha activity, which decreases to production of arachidonic acid
What are the rapid effects of glucocorticoids?
The eicosanoid pathway via c-Src and annexin1 phosphorylation
What are the specific slow genomic effects of glucocorticoids?
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)
What are the end products of the arachidonic acid pathway?
Prostacyclin, prostaglandins, thromboxanes, leukotrienes
What is the use of steroids in rheumatoid arthritis?
Oral or injected glucocorticoids that can help achieve low disease activity
What is the use of steroids in polymyalgia rheumatica treatment?
Prednisone is used for the first 4-8 weeks, restart if symptoms recur
What is the use of steroids for lumbosacral radiculopathies?
They can be helpful for a limited number of times per year, but excess injection can decrease bone density
What is the most common adverse event associated with glucocorticoids?
Bone fracture (especially vertebral fractures and hip fractures)
How do glucocorticoids lead to osteoporosis?
They increase the number of bone resorbing osteoclasts, which leads to increased risk of fracture
What is the effect of glucocorticoids on blood sugars?
They can lead to 2 to 3 weeks of persistent elevated blood sugar
What are the mechanisms of glucocorticoid induced hypertension?
Renal sodium retention, vasopressor potentiation to angiotensin II and catecholamines
What is the effect of glucocorticoid injection on cortisol levels?
It causes transient decreases in cortisol levels
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
c) polymyalgia rheumatica
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
c) osteoporosis
What are the effects of hyperactive hypothalamic-pituitary-adrenal axis?
Cushing’s syndrome, physical pain, emotional trauma, immunosuppression
