Transcript Introduction to Endocrine 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
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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)
Adrenal Gland
Adrenocorticosteroids
Glucocorticoids
Transport of Cortisol
• 95% bound to corticosteroid binding globulin (CBG)
• 5% free, bioactive
• cortisol half-life (90-110 min)
Metabolism of Cortisol
Hypothalamic-Pituitary-Adrenal (HPA) Axis
Circadian Rhythm of Cortisol Secretion
Mechanism of Glucocorticoid Action
Physiological Actions of Glucocorticoids
• Metabolic
Glucose Availability for the Brain
• Anti-inflammatory
• Immunosuppression
Metabolic Actions of Cortisol
Anti-inflammatory Actions of Cortisol
• phagocytic cell function
pyrogens,elastase,collagenase
• reduces edema
capillary permeability
arteriole vasoconstriction
• blocks basophil histamine
Immunosuppressive Actions of Cortisol
Mineralocorticoids
Transport and Metabolism of Aldosterone
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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
Control of Aldosterone Secretion
Mechanisms of Aldosterone Action
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
Side Effects of Glucocorticoid Therapy
Synthetic Mineralocorticoids
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
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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)