Glucocortocoids Flashcards
Describe the regulation of glucocorticoid secretion by the hypothalamic-pituitary-adrenal gland axis.
- Diurnal rhythm of basal steroidogenesis, entrained by higher neuronal centers that release CRH from hypothalamus in response to sleep-wake cycles → pituitary releases ACTH → adrenals release cortisol
- Negative feedback regulation by circulating corticosteroids (endogenous AND exogenous) at the hypothalamus and pituitary decreases ACTH release and steroidogenesis. NOTE: Chronic use of glucocorticoids can suppress the HPA axis and result in adrenal atrophy and insufficient adrenal response to environmental stressors (known as an adrenal crisis).
- Stress (injury, hemorrhage, severe infection, surgery, hypoglycemia, cold, pain, fear) can override negative feedback and produce marked increases in steroidogenesis.
Describe the metabolic effects of glucocorticoids and explain how these effects can result in serious adverse conditions.
Metabolic Effects: Normal physiologic effects that are the basis for some of the serious adverse effects that occur when high (pharmacologic) doses of glucocorticoids are used for extended periods.
Effects of physiologic levels of glucocorticoids: Maintenance of glucose supply to brain.
• Carbohydrate: Stimulate gluconeogenesis (in fasting state) → increased blood glucose (leading to ↑ insulin release). Stimulates gluconeogenesis and glycogen synthase activity → increased liver glycogen deposition.
[Excessive use in therapy can lead to diabetes-like state]
• Protein: Increase amino acid uptake into liver and kidney, decreased protein synthesis → net transfer of amino acid from muscle / bone to liver (into glucose)
[Excessive use in therapy can lead to catabolic (tissue breakdown) effects resulting in muscle wasting (systemic use) and atrophy of skin and connective tissue (topical use)]
• Lipid: Inhibit uptake of glucose by fat cells → stimulate lipolysis (but net effect is lipogenesis due to increased insulin release). Greater lipogenic effect in central tissues vs peripheral sites
[Excessive use in therapy can lead to centripetal obesity (buffalo hump, increased abdominal fat)]
Differences among the various GCs?
- Cortisol (aka Hydrocortisone): Common use in physiologic doses for replacement therapy and emergencies; glucocorticoid and mineralocorticoid actions [1:1]; administered orally and parenterally
- Prednisone: Most commonly used oral agent when steroid burst therapy desired; glucocorticoid and mineralocorticoid actions [13:1]; activated to prednisolone in liver. NO topical activity, activated by first pass hepatic metabolism.
- Methylprednisolone: Used if parenteral administration desired for steroid burst (no better than oral prednisone in acute exacerbations of asthma); minimal mineralocorticoid action. Oral (Medrol®) and parenteral (Solu-Medrol®)
- Dexamethasone (Decadron®): Most potent anti-inflammatory agent, used in cerebral edema, chemotherapy-induced vomiting; no mineralocorticoid action, greatest suppression of ACTH secretion at pituitary.
- Triamcinolone (Kenalog®): Potent systemic agent- excellent topical activity; no mineralocorticoid action
Compare and contrast their relative salt-retaining vs anti-inflammatory activities vs ACTH suppression and their routes of administration.
see table
Explain the rationale for alternate day therapy and the necessity for tapered withdrawal following chronic therapy with glucocorticoids.
Chronic use of glucocorticoids can suppress the HPA axis and result in adrenal atrophy and insufficient adrenal response to environmental stressors (known as an adrenal crisis).
• Alternate day schedule can minimize adverse effects (lessens growth-suppressive effects because anti-inflammatory actions apparently outlast suppressive effect on HPA axis); make gradual transition to alternate day schedule after control of disease achieved.
• Terminate administration gradually if taken longer than 7-10 to 28 days, otherwise may cause severe rebound of disease or symptoms of adrenal insufficiency (adrenal crisis).
