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14 Cards in this Set
- Front
- Back
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What are glucocorticoids used for?
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Glucocorticoids are used systemically, as well as locally (for example in opthalmic, ear or skin preparations, topically, or as intra-articular or intralesional injection)
-they are used for adrenal disorders → in treatment of Addison's disease (deficiency of glucocorticoids (cortisol) and mineralcorticoids (aldosterone)), and for non-adrenal disorders → inflammatory, allergic, autoimmune |
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How is the synthesis of glucocorticoids and mineralcorticoids controlled?
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-synthesized by the adrenal cortex
-control of glucocorticoid release depends on the hypothalamic-pituitary axis (HPAA): ❤Adrenocorticotrophic hormone (ACTH) stimulates synthesis and release of glucocorticoids from the adrenal cortex ❤Corticotrophin releasing factor (CRF) from the hypothalamus regulates ACTH release, and is in turn regulated by neural factors and negative feedback effects of plasma glucocorticoids ❤long feedback loop: CRF release is suppressed by high levels of glucocorticoids ❤short feedback loop: CRF release is suppressed to a lesser extent by blood ACTH ❤psychological factors, excessive heat or cold, injury, pain, or infection increases the release of CRF from the hypothalamus ❤ACTH has only minimal effect on mineralocorticoid production. Mineralocorticoid production is stimulated by the renin-angiotensin system and by plasma electrolyte concentrations |
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What is the molecular mechanims of action of glucocorticoids?
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-glucocorticoids enter and bind to cytoplasmic receptors
-after binding with the steroid, the receptor becomes "activated" exposing a DNA binding domain -steroid-receptor complexes form pairs, then move to the nucleus and bind to steroid response elements in the DNA -the effect is either to repress (prevent transcription of ) or induce (initiate transcription of) particular genes |
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What does repression of genes do? What does induction of genes do?
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Repression involves inhibition of transcription factors that normally switch on genes for COX-2, various cytokines, and the inducible form of nitric oxide synthase
-induction involves formation of specific messenger RNA's which direct the synthesis of specific proteins - e.g. enzymes involved in metabolic processes, lipocortin that inhibits phospholipase A in the inflammatory response -most nuclear mediated actions have an onset of pharmaological effects that requires several hours |
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What are the actions of cortisol?
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❤Promotes energy mobilization via gluconeogenesis: cortisol effectively increases blood glucose concentration. Cortisol reduces the uptake of glucose into cells, while simultaneously increasing the amount of substrate (gluconeogenic amino acids from muscle & glucerol) for glucose conversion in the liver. Cortisol does so by stimulating lipolysis and protein catabolism, leading to mobilization of fatty acids and amino acids, respectively
-chronic glucocorticoid excess therefore produces redistribution of fat -also can lead to reduced anabolism leading to muscle wasting and weakness with chronic exogenous glucocorticoid use ❤Anti-inflammatory effects: cortisol both prevents inflammation and reduces existing inflammatory conditions -by stabilizing lysosomal membranes, it reduces the risk of lysosomal membrane rupture and minimizes the amount of proteolytic enzymes acting within the inflammatory milieu -it promotes synthesis of lipocortin, an inhibitor of phosphilipase A2. Phospholipase A2 normally supplies arachidonic acid for the synthesis of prostaglandins and leukotrienes. Lack of these inflammatory mediators decreases capillary permeability and the recruitment of leuocytes to the inflamed tissue -it also decreases expression of COX-2 -cortisol decreases production of inflammatory cytokines (e.g. TNF-α) leading to a reduction in macrophage activation -cortisol also boosts the function of the adaptive immune system by inhibiting the production of interleukin-2 (IL-2), a cytokine involved in promoting T-cell proliferation. Other cytokines are also disrupted in this process -lastly, cortisol blocks the release of histamine from mast cells and serotonin from platelets, thereby inhibiting allergic reactions ❤Adrenergic receptor upregulation: Cortisol helps smooth muscle maintain responsiveness to the vasoconstrictive effects of norepinephrine by upregulating α1-adrenergic receptors on vascular smooth muscle cells. Cortisol also contributes to vascular tone through inhibition of nitric oxide synthase, decreasing the production of the vasodilator nitric oxide. ❤Vascular events: reduces vasodilation, decreased fluid exudation as a result of decreased production of prostanoids via inhibition of COX-2 & phospholipase A2 |
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What controls the mineralcorticoid aldosterone's secretion? What are it's actions?
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ACTH promotes aldosterone secretion but it has little effect on it's rate of secretion. The most important determinants of aldosterone secretion are:
-high serum potassium increases secretion -the RAS increases secretion -high serum sodium decreases secretion (minimally) EFFECTS: ❤increased sodium reabsorption: Aldosterone stimulates the synthesis of new sodium channels in the principle cells of the collecting tubules. These additional sodium channels promote sodium reabsorption and reduce sodium excretion in the urine ❤Increased arterial pressure: Increases total sodium reabsorption, but does not significantly alter serum sodium concentration. This is because water is not reabsorbed by the collecting tubules. The net effect is an increase in extracellular volume, which over time, can cause arterial pressure to rise ❤Increased potassium secretion: Aldosterone induces the opening of large numbers of sodium and postassium channels in the principal cells of the collecting ducts. Enhanced sodium reabsorption is accompanied by increased potassium secretion into the tubule lumen. |
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What can long term administration of glucocorticoids due to the adrenal cortex?
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-can cause atrophy of the adrenal cortes, taking many months to return to normal
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What have synthetic glucocorticoids been manufactured to do? Are more potent glucocorticoids better?
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They have been manufactured to increase their anti-inflammatory protency and reduce their mineralocorticoid (sodium & water retention) effects
-the more potent the glucocorticoid, the greater the potential for adverse effects |
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What affects duration of action?
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-synthetic glucocorticoids bind less avidly to plasma proteins, have a LONGER DURATION OF ACTION because of increased glucocorticoid receptor affinity, and are more resistant to hepatic degradation
-the rate of absorption is slowed and the duration prolonged if the corticosteroid is bound to a poorly soluble ester e.g. acetate, acetonide, for intramuscular injection -prolongation of effect also means prolongation of suppression of H-P-A-Axis -the duration of adrenal suppression is greater than the duration of anti-inflammatory treatment with depot administration |
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Describe the pharmacokinetics of glucocorticoids
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-for physiological cortisol, only 4% is free in plasma, the rest is bound with high affinity to CBG (corticosteroid binding globulin)
-synthetic glucocorticoids have a lower affinity for CBG -free corticosteroid enters cells by diffusion across the cell membrane -CBG-bound glucocorticoid is not metabolized so CBG may serve to form a reservoir for glucocorticoid -glucocortcoids are metabolised in the liver |
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What are the most important toxic effects of glucocorticoids?
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❤suppression of response to infection, leading to increased susceptibility to infection
❤suppression of endogenous glucocorticoid synthesis leading to secondary adrenocortical insufficiency ❤metabolic actions ❤iatrogenic Cushings syndrome |
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What are the most important side effects of glucocorticoids?
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❤polyuria & polydipsia:
- consistent and early effect - glucocorticoids inhibit release and action of anti-diuretic hormone (ADH), as well as altering the animal's psyche, both of which lead to increased water intake ❤metabolic effects and polyphagia: -glucocortioids stimulate appetite (mechanism unknown - psychogenic) and so cause lipogenesis and weight gain -concurrent lipolysis (glucocorticoid enhanced) leads to fat redistribution int he body, hepatomegaly and increased abdominal fat -increased protein catabolism leads to muscle wasting and weakness -glucocorticoid promotion of hyperglycemia predisposes the animal to diabetes mellitus ❤skin & connective tissue: -glucocorticoids reduce collagen synthesis, leading to thinning of skin, increased bruising due to increased capillary fragility, bilateral symmetrical alopecia "Cushingoid" appearance, and reduced rate of wound healing -occasionally glucocorticoid administration leads to calcium deposition in dystrophic skin "calcinosis cutis" -glucocorticoid suppresses growth of articular cartilage leading to development of "steroid arthropathy" ❤gastrointestinal -liver changes as previously describe, leading to micronodular cirrhosis and hepatomegaly -also reduced activity of cytoprotective prostaglandins leading to gastric ulceration or more commonly colonic problems and potential perforation ❤immunologic effects as above ❤reproductive system: -high doses of glucocorticoids induce parturition during the latter part of pregnancy in horses and ruminants -glucocorticoids have teratogenic effects in early pregnancy |
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What are the contraindications/precaustions of glucocorticoid use?
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-contraindicated in immature animals, in patients with bone healing occuring, or post surgery, patients with diabetes mellitus, protein-losing diseases (e.g. nephropathy), liver disease or during pregnancy
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What are the principles of glucocorticoid therapy?
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-in order to minimize the risk of serious adverse effects they should be administered at the lowest dose and for the shortest duration required for the effect required
-often this can be achieved with alternate day therapy, thereby reducing the inhibition of the HPA Axis -abrupt cessation of therapy should be avoided, to reduce risk of iatrogenic hypoadrenocorticism (Addisonian crisis) as a result of failure of normal endogenous cortisol production secondary to ACTH suppression by administered glucocoritcoids |
