The Court of Sone Henge Glucocorticoids

3.4 – “The C Court ourt of Sone He Henge”: nge”: Gluc Glucocorticoids ocorticoids • Cortisol (endogenous glucocorticoid), aldosterone (mineralocorticoid), & DHEA (androgen) all released from adrenal (head druid wearing adrenal cap). Here we focus on effects of glucocorticoids, either endogenous or exogenous (moon face). Exogenous formulations include dexamethasone, fludrocortisone, prednisone, budesonide (-sone suffix, hence sone henge) • Effects are mediated by widely distributed cytosolic glucocorticoid receptor (receptor scepter in outer scepter); enters the nucleus & acts as transcription factor at glucocorticoid receptor elements (GREs) (activated scepter in the inner circle, representing the nucleus; has many effects, pictured as blue squiggles). Effects include: o Upregulate inhibitor of PLA2 (inhibited A-frame catapult A2). ▪ PLA2 releases arachidonic from cell membranes → metabolism to several inflammatory compounds. By inhibiting this, GCs block COX (prostaglandin synthesis) (bat) & LOX (leukotriene synthesis) (lacrosse stick) o Inhibits NFκB (nuclear factor kappa-Β), inhibiting activation of lymphocytes by inhibiting proinflammatory cytokines (inhibited N-Flame Krossbow). ▪ End effect: ↓recruitment & activation of T & B cells (blocked T-cell knight and antibody archer). ▪ Decreased neutrophil recruitment by causing demargination & ↓synthesis adhesion molecules. Results in circulating neutrophilia (i.e. an acute rise in WBC count) (congregation of neutrophilic first responders). This will present as apparent elevation of white counts, but will increase risk of infection. o Rapidly reduce peripheral lymphocytes by ↓Ig synthesis, stimulation of apoptosis, & redistribution into spleen, lymph nodes, & bone marrow (T-cell knit, helper T-cell squire, & antibody archer, eosinophil slingshot dropping into chasm). ▪ Hence utility as immunosuppression (transplant rejection prevention, autoimmune disorders) (eclipsed inflammatory sun), ▪ inflammatory conditions (gout, RA, asthma, IBD) (cracked antibodies on standing stone). ▪ Eosinophil decrease; useful in atopic conditions (eosinophil slingshot dropping into chasm) o Metabolic effects ▪ Recall that glucocorticoids are essentially the body’s stress hormones. As such, will upregulate the systems needed to maintain metabolic & circulatory function in times of stress. ▪ Can cause hyperglycemia (elevated candy jar held by statue) • Peripheral antagonism of insulin, i.e. insulin resistance (locked welcome mat). • Stimulate gluconeogenesis via production of gluconeogenesis enzymes (liver shaped bag producing candy). • Increase glycogen synthesis → increased glycogen storage (candy filled liver-shaped candy jar) ▪ Will not see these homeostatic effects in adrenal insufficiency (fainted druid with cracked moon face on ground). Can see collapse of circulatory function, leading to shock and even death, with even minor noxious stimuli. • Exogenous glucocorticoids must be given to treat acute adrenal insufficiency (extra moon face being extended). May also prevent in cases of primary adrenal insufficiency (e.g. Addison’s disease). • Chronic exogenous glucocorticoid use causes adrenal cortical atrophy d/t negative feedback on the pituitary →↓ACTH production (secondary adrenal insufficiency) (shriveled adrenal hat on fallen man) o Note: oral budesonide often given in a delayed release preparation targeting the ilium; especially useful in Chron’s because it has high topical potency & fewer systemic adverse effects than other glucocorticoids d/t high first pass metabolism. o Adverse effects (altar and moon statue) ▪ ↓overall white counts → immunosuppression; ↑risk of infection • Reactivation of latent infections ▪ Promote peripheral catabolism, proteolysis in skeletal muscle, lipolysis. (falling ham & donuts). ▪ Cushing’s syndrome can occur with chronic glucocorticoid use (cushion; demonstrated in moon statue) • Results in adipose redistribution with central adiposis (fat stomach) • Myopathy, muscle wasting, proximal weakness (scrawny arms) • Inhibit fibroblast proliferation → weakened skin, capillary damage (fine cloth with purple striae) • Direct inhibition of osteoblasts → osteoporosis & fractures (osteoporotic altar). Chronic, can cause osteonecrosis, classically aseptic necrosis of the hip. o Chronic users should take supplementary calcium & vitamin D • Psychosis: hypomania, confusion, hallucinations (cracked and cross-eyed moon head) • immunosuppression (cane). o May reactivate latent infections, e.g. TB (TB cacti with reactivation in upper lobes) • Hypokalemia d/t mineralocorticoid cross reactivity (banana peel)