OST 529 Systems Biology: Endocrinology Keith Lookingland Associate Professor Dept. Pharmacology &...
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Transcript of OST 529 Systems Biology: Endocrinology Keith Lookingland Associate Professor Dept. Pharmacology &...
OST 529 Systems Biology: Endocrinology
Keith Lookingland
Associate Professor
Dept. Pharmacology & Toxicology
Adrenocorticosteroids
Goodman & Gilman’s
“The Pharmacological Basis of Therapeutics” 10th Edition
Chapter 60: 1649-1677
Hormone Negative Feedback Hypothalamic-Pituitary Systems
• Thyroid Axis (Thyroid Hormones)
• Adrenocortical Axis (Glucocorticoids)
• Ovarian Axis (Estrogen/Progesterone)
• Testicular Axis (Testosterone)
Peripheral Substrate Systems
• Glucose - Insulin/Glucagon
• Sodium/Potassium - Aldosterone
• Calcium - PTH/Calcitonin/Vitamin D
Adrenocorticosteroids
• Glucocorticoids + Mineralocorticoids– Synthesis and metabolism– Secretion– Actions
• Adrenocortical Insufficiency– Addison’s disease (primary & secondary)
• Adrenocortical Hyperactivity– Congenital adrenal hyperplasia– Cushing’s disease– Conn’s syndrome (primary aldosteronism)
Transport of Cortisol
• 95% bound to corticosteroid binding globulin (CBG)• 5% free, bioactive• cortisol half-life (90-110 min)
Physiological Actions of Glucocorticoids
• Metabolic
Glucose Availability for the Brain
• Anti-inflammatory
• Immunosuppression
Anti-inflammatory Actions of Cortisol
• phagocytic cell function
pyrogens,elastase,collagenase• reduces edema
capillary permeability
arteriole vasoconstriction• blocks basophil histamine
Transport and Metabolism of Aldosterone
• weakly bound to plasma proteins • 95% free, bioactive• aldosterone half-life (20-30 min) • degraded in liver, secreted in urine as a water
soluble conjugate
Adrenocortical Insufficiency
• Primary (Addison’s Disease)– hyposecretion of both cortisol & aldosterone– hypersecretion of ACTH (loss of negative feedback)– glucocorticoid insufficiency
• weakness, fatigue • inability to maintain fasting plasma glucose
– mineralocorticoid insufficiency• sodium loss, potassium retention • dehydration
• Secondary – defect in hypothalamic-pituitary axis – hyposecretion of ACTH and cortisol
Synthetic Glucocorticoids • Cortisol
– short-acting– orally active– glucocorticoid replacement adrenal insufficiency
• Triamcinolone– intermediate-acting– topical– localized allergic and arthritic disorders
• Dexamethasone– long-acting– diagnostic
• Dexamethasone Suppression Test
Synthetic Mineralocorticoids
Fludrocortisone– oral, injectable, topical compilations – mimics aldosterone action
• sodium retention• potassium excretion
– mineralocorticoid replacement adrenal insufficiency
Adrenocortical Hyperactivity
• Congenital Adrenal Hyperplasia– primary defect in cortisol biosynthetic enzymes
• 21-B hydroxylase
• shunts precursors into androgen pathway
– compensatory increase in ACTH (loss of negative feedback)– adrenal hypertrophy– virilization of physical features– im cortisone/dexamethasome to
suppress ACTH– oral cortisol
Adrenocortical Hyperactivity
• Cushing’s Syndrome– adrenal hyperplasia
– secondary to ACTH-secreting pituitary or ectopic tumor
– loss of negative feedback
unresponsive to low dose dexamethasone
Adrenocortical Hyperactivity
• Cushing’s Syndrome
– excessive glucocorticoid activity• muscle atrophy, thinning of skin (protein catabolism)• facial & truncal obesity (lipid deposition insulin-dependent
adipocytes)• poor wound healing (immunosuppression)
– surgical removal of tumor (oral cortisol)– adrenalectomy (oral cortisol & fludrocortisone)
Adrenocortical Hyperactivity
• Primary Aldosteronism (Conn’s Syndrome)– aldosterone-secreting adrenal adenoma – excessive mineralocorticoid activity (electrolyte imbalance)
• hypertension (sodium retention)
• muscle weakness, tetany (potassium excretion)
– adrenalectomy (oral cortisol & fludrocortisone)– spironolactone
• aldosterone receptor antagonist
• genomic actions (slow onset of action)