SM 243: Glucocorticoids Flashcards
What is the classic cause of Inflammation?
A response to infection
What is the classic response to inflammation?
Vasodilation, increased vascular permeability, PMN transmigration into affected tissue
What are the signs of inflammation?
Increased warmth, pain, redness, and swelling that lead to disturbance of function
What hormonal axis and what class of hormones are essential in resolving the inflammatory porcess?
Hypothalmic-pituitary-adrenal axis + glucorcorticoids are needed to resolve the inflammatory process
What can excessive inflammation lead to?
Tissue destruction and disease
What can drive excessive inflammation?
Allergies, Asthma, Autoimmune disease, Sepsis
What receptor does the HPA axis use to control inflammation?
The Glucocorticoid receptor
Describe the signaling pathway along the HPA?
Multiple signals cause the Hypothalamus to secrete CRH
CRH stimulates the release of Corticotropin from the Pituitary
Corticotropin induces the synthesis and secretion of Cortisol by the Adrenal Cortex into the bloodstream
Does Cortisol exert genomic or nongenomic effects on target cells?
Both - nongenomic is faster
What nongenomic effects does Cortisol have on target cells?
Cortisol can activate anti-inflammatory proteins that inhibit inflammatory proteins over seconds to minutes
What genomic effects does Cortisol have on target cells?
After Cortisol binds to the Glucocorticoid Receptor, the two form a complex that translocates to the nucleus and initiates transcription of RNA Poly II while repressing activity of NFkB
What effect does Cortisol have on RNA Poly II and to what end result?
Cortisol + Glucocorticoid Receptor = Complex that translocates to Nucleus; Increased transcription of RNA Poly II produces antiinflammatory proteins
What effect does Cortisol have on NFkB and to what end result?
Cortisol + Glucocorticoid Receptor = Complex that translocates to Nucleus; Blocks NFkB to decrease production of inflammatory proteins
Is RNA Poly II pro or anti inflammatory?
Anti-inflammatory, hence the Coritsol + Glucocorticoid Receptor complex increases transcription
Is NFkB pro or anti inflammatory?
Pro-inflammatory, hence the Cortisol + Glucocorticoid Receptor complex blocks transcriptional activity
Describe the Arachidonic Acid cascade and it’s relationship to inflammation?
Cytosolic Phosphoplipase A2 (PLA2) converts Triglycerides into Arachidonic Acid
COX converts Arachidonic Acid into Prostaglandin percursors
5-Lipooxygenase (LOX) converts these Prostaglandin precursors into Leukotrienes = pro-inflammatory
How does Cortisol repress Leukotriene-mediated inflammation at a protein level?
The Glucocorticoid Receptor-Cortisol comples uses a cofactor, c-Src
c-Src phosphorylates Annexin 1 to inhibit PLA2 and reduce production of Arachidonic acid, a precursor for Leukotrienes
How does the Cortisol-Glucorcorticoid Receptor complex reduce inflammation at a genomic level?
The Cortisol-Glucocorticoid Receptor complex decreases expression of AP1 and NFkB, both of which are inflammatory transcription factors
What disorders result from hyperactivity of the HPA axis?
Cushing’s Syndrome, Pain, Caloric Restriction, Immunosuppression
What disorders result from hypoactivity of the HPA axis?
Adrenal insufficiency aka Addison’s Disease
What is the strongest Corticosteroid?
Betamethasone and Dexamethasone
What does the joint swelling in RA reflect and why do we use medication?
Swelling in RA reflects synovial membrane inflammation and the goal of using medications is to reduce inflammation
What medications can be used as a first line for RA?
Methotrexate + Glucocorticoid
How are Glucocorticoids used to treat RA?
Used in low doses wit Methotrexate to achieve Low Disease Activity, and then tapered off
Also can be injected in local areas for acute inflammation
How does Polymyalgia Rheumatica present?
Shoulder +/- hip stiffness and pain with elevated ESR
How should Polymyalgia Rheumatica be managed?
Predinose daily, tapering every 4 weeks until discontinuation
What is Lumbosacral Radiculatopathy?
Radiating pain originated from a compressed or inflamed nerve root
How can Lumboscaral Radiculopathy be treated?
Imaging-guided epidural injections of Glucocorticoids like Dexamethasone
Can a Glucocorticoid steroid injection be done repeatedly?
Yes, up to 4 times a year, but consider risks as well
Do glucocorticosteroids benefit Knee OA?
May be helpful for a few weeks, but not useful for signs of active inflammation
Can glucocorticosteroids be used to treat Tendinopathy?
No, because tendon’s don’t show signs of inflammation
What are tissue-specific side effects of high dose corticosteroids?
Adrenal atrophy, hypertension, dyslipedemia, immunosuppression, cataracts, and a lot of others
How long does a single Corticosteroid dose suppress native Cortisol levels?
7 - 14 days after a single injection, and higher doses suppress longer
How do Corticosteroids cause Osteoperosis?
Corticosteroids increase the number of bone-resorbinb osteoclasts, increasing the risk of Vertebral fractures within 3months after initiation
What type of bone injury is common in people who take Corticosteroids?
Osteoperosis-mediated vertebral fractures
How do Corticosteroids alter blood sugar levels?
Glucosteroids cause elevated blood sugars for up to 10 days
How do Coricosteroids alter blood pressure?
Elevated blood pressure can occur from long term use of Corticosteroids due to renal sodium retention and potentiation of the Vasopressor responses to AngII and Catecholamines
What 2 mechanisms do Corticosteroids use to raise blood pressure?
Increased Renal Sodium retention = increase blood volume
Potentiation of vasopressor responses to AngII and Catecholamines
What patients tend to develop Glucocorticoid resistance?
Those with severe RA
What mediates Gluoccorticoid Resistance?
Decreased expression of Glucocorticoid receptor alpha, increased expression of Glucocorticoid receptor beta, or phosphorylation of the glucocorticoid receptor to inhibit signaling
What is Osteonecrosis and how does it relate to Glucocorticoids?
Necrosis of the bone, associated with daily Glucocorticoid use
How are Glucocorticosteroids administered?
Orally, IV, and IM or directly into joints/soft tissue
What is Osteonecrosis and how does it relate to Glucocorticoids?
Necrosis of the bone, associated with daily Glucocorticoid use
How are Glucocorticosteroids administered?
Orally, IV, and IM or directly into joints/soft tissue
