Adrenocorticosteroids and Adrenocortical Antagonists Flashcards
Half life of glucocorticoids
t ½ ~ 60–90 minutes
t ½ increases when hydrocortisone (pharmaceutical prep) is administered in large amounts, or stress, hypothyroidism, or liver disease is present
How do glucocorticoids travel in circulation
After absorption, >90% of cortisol in plasma is reversibly bound to protein
Only a fraction of the unbound is active and can enter cells
2 plasma binding proteins:
corticosteroid-binding globulin (CBG, transcortin) – high affinity, low capacity
albumin – low affinity, high capacity
Where and how are glucocorticoids usually metabolized
~ 1% of cortisol is excreted unchanged in the urine as free cortisol;
~ 20% of cortisol is converted to cortisone (inactive) by 11b-hydroxysteroid dehydrogenase in the kidney and tissues with mineralocorticoid receptors.
Most cortisol is metabolized in the liver.
Glucocorticoids pharmodynamics
Travel bound to proteins and enter cell to bind to nuclear receptor superfamily. Response require protein synthesis so can be slower
Metabolic effects of glucocorticoids
Stimulates hepatic gluconeogenesis
Inc. blood sugar
muscle protein is catabolized (generating amino acids)
Lipolysis (and lipogenesis) is stimulated
Inc insulin secretion
Increases the storage of glucose as glycogen
What do glucocorticoids act on to reduce inflammation
Reduce expression cyclo-oxygenase II in inflammatory cells.
Inhibitor of PLA2 – Key component in synthesis of prostaglandins and eicosanoids
Reduce prostaglandin, leukotriene, and platelet-activating factor synthesis
Where are glucocorticoid receptors found
Throughout the body
Mineralcorticoids half life and how they travel through plasma
t ½ = 15-20 min
Minimal binding to plasma proteins
Mineralcorticoid pharmacodynamics. How does it relate to cortisol?
Similar to glucocorticoids with binding to nuclear receptors.
Cortisol can also bind to mineralcorticoid receptors at a higher affinity. 11B-HSD2 converts it to cortisone, which has a lower affinity and allows for the mineralcorticoids to bind
Effects of mineralcorticoids
Act on renal distal tubules and collecting ducts
Increase Na+ reuptake (increase K+ and H+ excretion)
positive Na+ balance
increase extracellular fluid volume
High levels of MCC
Increased blood pressure
Hypokalemia, hypernatremia, and alkalosis
Low levels of MCC
Decreased blood pressure
Hyperkalemia, hyponatremia, and acidosis
What are the short acting synthetic adrenocorticoids
Intermediate acting synthetic adrenocorticoids
Long acting adrenocorticoids
What disease uses glucocorticoids for treatment
Addison’s disease - adrenocortical insufficiency
What is used to stimulate lung maturation in the fetus
Glucocorticoids
Treatment of the mother with large doses of glucocorticoid reduces the incidence of respiratory distress syndrome in infants delivered prematurely. When delivery is anticipated before 34 weeks of gestation, intramuscular betamethasone
Toxicity of glucocorticoids
Peptic ulcers/increased infections - due to suppression of immune system.
CNS effects: drugs may produce a euphoria or even psychosis, insomnia.
Steroid diabetes – pre-diabetic may exhibit signs of clinical diabetes
Nausea, dizziness, weight loss (treated with changing drug or dose, inc. K+ and protein
Skeletal effects – osteoporosis, inc. bone resorption and dec. bone formation
Delayed wound healing - in Cushing’s disease adrenolytic drugs are used prior to surgery
Acute pancreatitis is a rare but serious acute adverse effect of high-dose glucocorticoids.
Corneal wounds are a contraindication!
What can happen to adrenal glands if systemic administration of glucocorticoids
Adrenal atrophy
Use alternate day dosing, use targeted dosing of diseased organ/tissue
Examples of Inhibitors of Adrenocorticoid Synthesis
Aminoglutethimide
Metyrapone
Etomidate
Mitotane
What is the treatment for Cushing’s Syndrome without surgery
Ketoconazole
Antifungal imidazole derivative.
Potent and rather nonselective inhibitor of adrenal and gonadal steroid synthesis. Inhibits the cholesterol side-chain cleavage, P450c17, C17,20-lyase, 3β-hydroxysteroid dehydrogenase, and P450c11 enzymes required for steroid hormone synthesis.
Inhibitory effects on steroid biosynthesis only at high doses.
What are the targets of Ketoconazole
17,20 lyase and 3B HSD
Drug that is used for ectopic ACTH secretion or those who failed with other therapies
Mifepristone (RU 486), has strong anti-progestin activity and blocks GC receptor
Treatment for primary aldosteronism, excessive aldosterone secretion, used as a diuretic, and for hursutism in women
Spironolactone (7a-acetylthiospironolactone), MC receptor blocker
