Pharm Ch 39- Corticosteroids And Antagonists

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corticosteroids are produced where

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adrenal cortex

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two major physiologic and pharmacologic groups of corticosteroids

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glucocorticoids- effects on intermediary metabolism, immune responses, inflammation
mineralocorticoids- regulate sodium and potassium reabsorption in collecting tubules of the kidney

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MOA of glucocorticoids

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enter cell, bind to cytosolic receptors that transport the steroid into the nucleus
-steroid-receptor complex alters gene expression by binding to glucocorticoid response elements (GREs)
-tissue specific responses to steroids due to presence in each tissue of different protein regulators that control interaction between hormone-receptor complex and particular response elements

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metabolic effects of glucocorticoids

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-stimulate gluconeogenesis
- blood glucose rises
- muscle protein is catabolized
- insulin secretion is stimulated
- lipolysis and lipogenesis are stimulated- net increase of fat deposition in certain areas (face, shoulders, back)

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catabolic effects of glucocorticoids

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- muscle protein catabolism
- lymphoid and connective tissue, fat, skin undergo wasting under influence of high concentration of steroids
- catabolic effects on bone= osteoporosis
- growth inhibition in children

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immunosuppressive effects of glucocorticoids

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-inhibit cell mediated immunologic functions-esp those dependent on lymphocytes
- actively lymphotoxic and are important in treatment of hematologic cancers
-do not interfere with development of normal acquired immunity
- delay rejection reactions in pt with organ transplants

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anti-inflammatory effects of glucocorticoids

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- dramatic effect on distribution and function of leukocytes
- increase neutrophils and decrease lymphocytes, eosinophils, basophils, and monocytes
- migration of leukocytes inhibited

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biomechanical explanation of anti-inflammatory effects of glucocorticoids

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-induced synthesis of an inhibitor of phospholipase A2, decreased mRNA for cyclooxygenase-2 (COX-2), decreases in IL-2 and IL-3, decreases in platelet activating factor (PAF)

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Other effects of glucocorticoids

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-required for normal renal excretion of water
- effects on CNS-behavioral changes
- large doses stimulate gastric acid secretion and decrease resistance to ulcer formation

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major natural glucocorticoid and its regulation

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cortisol
- regulated by ACTH and varies during the day

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circadian rhythm of cortisol

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peak levels in the morning and trough occurs around midnight

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form of cortisol in plasma

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95% bound to corticosteroid-binding globulin

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route of cortisol absorption/excretion

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given orally, absorbed well from the GI tract
- cleared by the liver
-short duration of action
-diffuses poorly across normal skin but is readily absorbed across inflamed skin/mucous membranes

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secondary effect of cortisol

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small salt-retaining mineralocorticoid effect
- important cause of HTN in patients with a cortisol-secreting adrenal tumor or a pituitary ACTH-secreting tumor (Cushings)

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synthetic glucocorticoids

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prednisone and active metabolite (prednisolone), dexamethasone, triamcinolone

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properties of synthetic vs, cortisol

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longer half-life and duration of action, reduced salt-retaining effect, better penetration of lipid barriers for topical activity

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glucocorticoids that penetrate the airway mucosa but have very short half-lives after they enter, reducing systemic effects and toxicity

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beclomethasone and budesonide

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Clinical Uses of glucocorticoids

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adrenal disorders- preserve life in patients with chronic adrenal cortical insufficiency (Addison's disease)
- necessary in acute adrenal insufficiency associated with life-threatening shock, infection, trauma
- used in CAH, where synthesis of abnormal forms of corticosteroids are stimulated by ACTH
- giving potent synthetic suppresses ACTH secretion enough to reduce synthesis of abnormal

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Clinical use of nonadrenal disorders

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inflammatory or immunological (asthma, organ transplant rejection, collagen diseases, rheumatic disorders)
- treatment of hematopoietic cancers, neuro disorders, chemo-induced vomiting, hypercalcemia, mountain sickness

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blucocorticoid with low degree of protein binding

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pregnant women in premature labor to hasten maturation of fetal lungs

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toxicity of glucocorticoids

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-some life threatening- growth inhibition, diabetes, muscle wasting, osteoporosis, salt retention, psychosis
- minimize these by alternate-day therapy
- doses need to be tapered over several months to allow recovery of normal adrenal function

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Major mineralocorticoid

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-aldosterone--> regulates blood pressure and blood volume

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secretion of aldosterone regulated by

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ACTH and renin-angiotensin system

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other mineralocorticoids

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deoxycorticosterone, naturally occurring precursor of aldosterone
- fludrocortisone- glucocorticoid activity- long duration of action so favored for replacement therapy after adrenalectomy

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Receptor Antagonists of corticosteroids

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spironolactone and eplerenone- antagonists of aldosterone at its receptor- diuretics

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Mifepristone (RU-486)

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competitive inhibitor of glucocorticoid receptors as well as progesterone receptors and used in Cushing's

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synthesis inhibitors

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-ketoconazole- antifungal that inhibits the cytochrome P450 enzymes needed for synthesis of all steroids- used when steroids are bad- adrenal carcinoma, hirsutism, breast and prostate cancer)
-aminoglutethimide- blocks conersion of cholesterol to pregnenolone- inhibits synthesis of all hormonally active steroids- in conjunction w/ other drugs for treatment of steroid-producing adrenocortical cancer
- metyrapone- inhibits normal synthesis of cortisol but not precursors- diagnostic tests of adrenal function