SM_253a: Pharmacology: Glucocorticoids Flashcards
Inflammation involves ___, ___, ___, and ___
Inflammation involves vasodilation, increased vascular permeability, extravasation of plasma proteins, and migration of leukocytes into affected tissue
(hypothalamic-pituitary-adrenal axis and glucocorticoids are essential in limiting and resolving the inflammatory process, can lead to tissue destruction and disease if persistent)
Describe the hypothalamic-pituitary-adrenal axis
Hypothalamic-pituitary-adrenal axis: regulates signaling by the glucocorticoid receptor
- Multiple signals coverge at the hypothalamus to control secretion of corticotropin-releasing hormone (CRH)
- CRH stimulates release of corticotropin from the pituitary
- Corticotropin induces synthesis and secretion of cortisol by adrenal cortex (free cortisol is biologically active)
Cortisol acts via ____ and ____ pathways
Cortisol acts via genomic and nongenomic pathways
____ is quicker than ____ pathways for glucocorticoid action
Nongenomic activation is quicker than genomic pathways for glucocorticoid action
Nongenomic action of cortisol involves ____
Nongenomic action of cortisol involves activation of anti-inflammatory proteins that inhibit inflammation over seconds to minutes
Describe genomic pathways of cortisol action
Genomic pathways of cortisol action
- Cortisol-glucocorticoid receptor complex moves to nucleus
- Occurs over hours to days
- First pathway: initiates transcription of RNA polymerase II -> induces anti-inflammatory pathways -> inhibit inflammatory proteins
- Second pathway: blocks other pro-inflammatory transcription factors (i.e. NF-kappaB) -> decreased production of inflammatory proteins
Describe the arachidonic acid cascade
Arachidonic acid cascade
- Cytosolic phospholipase A2alpha catalyzes production of arachidonic acid from triglyceride
- Arachidonic acid -> COX-2 and peroxidase -> feedback for synthesis of prostacyclin, prostaglandins, thromboxanes
- Arachidonic acid -> 5-lipooxygenase -> leukotrienes
Describe nongenomic action of cortisol-glucocorticoid receptor complex in the cell
Nongenomic action of cortisol-glucocorticoid receptor complex in the cell
- Cytosolic steroid receptor coactivation c-Src is accessory protein
- Induces phosphorylation of annexin 1
- Inhibits cPLA2alpha
- Reduces production of arachidonic acid
Describe genomic action of cortisol-glucocorticoid receptor complex in the cell
Genomic action of cortisol-glucocorticoid receptor complex in the cell
- Decreases expression of activator protein (AP1) and NF-kappaB: AP1 is inflmamatory transcription factor composed of two polypeptides
- Increases expression of annexin 1
- Glucocorticoids induces lymphocyte apoptosis in part through modulation of microRNA expression and processing
Hyperactivity of hypothalamic-pituitary-adrenal axis causes ____, while hypoactivity of hypothalamic-pituitary-adrenal axis causes ____
Hyperactivity of hypothalamic-pituitary-adrenal axis causes Cushing’s syndrome, while hypoactivity of hypothalamic-pituitary-adrenal axis causes adrenal insufficiency (Addison’s disease)
___ is most likely to be treated with oral glucorticoids as the sole primary treatment
Polymyalgia rheumatica is most likely to be treated with oral glucorticoids as the sole primary treatment
Glucocorticoids are used in treatment of ____, ____, ____, ____, and ____
Glucocorticoids are used in treatment of rheumatoid arthritis, polymyalgia rheumatica, lumbosacral radiculopathy, knee osteoarthritis, and tendinopathy
Rheumatoid arthritis is treated with ____ and ____ to ____
Rheumatoid arthritis is treated with methotrexate and oral glucocorticoids (prednisone) to reduce inflammation
(low doses of glucocorticoids confer additional structural protection compared to methotrexate alone)
Polymyalgia rheumatica is treated with ____
Polymyalgia rheumatica is treated with prednisone (oral glucocorticoid) with tapering down to lower dose over 4-8 weeks
Lumbosacral radiculopathy is treated with ____
Lumbosacral radiculopathy is treated with epidural injection of glucocorticoid (usually dexamethasone)
Knee osteoarthritis is treated with ____ for ____
Knee osteoarthritis is treated with triamcinolone for acutely inflammed joints
Oral glucocorticoids are associated with presence of ____ and injected glucocorticoids may weaken the ____, but ____ are sometimes used to treat ____
Oral glucocorticoids are associated with presence of tendinopathy and injected glucocorticoids may weaken the tendon, but injected glucocorticoids (triamcinolone) are sometimes used to treat tendinopathy
Adverse effects of exogenous glucocorticoids include ____, ____, ____, ____, and ____
Adverse effects of exogenous glucocorticoids include osteoporosis, elevated blood surgars, hypertension, effect of injections on cortisol stimulation test, and acquired glucocorticoid resistance
Cortisol ____ after single injection for _____
Cortisol decreases after single injection for 7-14 days
(higher dose suppress for longer, may affect body’s ability to deal with acute stress or infection)
Glucocorticoids can cause ____ due to ____ and increase the number of bone-resorbing ____
Glucocorticoids can cause vertebral fractures due to osteoporosis and increase the number of bone-resorbing osteoclasts
Glucocorticoids may lead to ____ blood sugars after single injection
Glucocorticoids may lead to elevated blood sugars after single injection
Glucocorticoids may lead to ____ blood pressure after long-term use due to ____ and ____
Glucocorticoids may lead to increased blood pressure after long-term use due to increased blood volume from renal sodium retention and potentiation of vasopressor responses to angiotensin II and catecholamines
Glucocorticoids can cause glucocorticoid ____ due to ____, ____, and ____
Glucocorticoids can cause glucocorticoid resistance due to decreased expression of glucocorticoid receptor alpha, increased expression of glucocorticoid receptor beta, or activation MAPK
(MAPK phosphorylates glucocorticoid receptor -> inhibits glucocorticoid signaling)
Glucocorticoids can cause ____, which is the breakdown of bone faster than it can be created
Glucocorticoids can cause osteonecrosis, which is the breakdown of bone faster than it can be created
