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Glucocorticoids and Mineralocorticoids Donald P. McDonnell, Ph.D.
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Glucocorticoids and Mineralocorticoids
Learning Objectives By the conclusion of this lecture, students should be able to: Describe the role of the hypothalamus, pituitary and adrenal in the regulated synthesis of glucocorticoids. List both the major medical uses and the potential side effects of glucocorticoid administration. Describe the importance of 11-hydroxysteroid dehydrogenase in glucocorticoid pharmacology. List the medical uses of mineralcorticoid agonists and antagonists.
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Classification of Steroids
Sex Hormones Corticosteroids Progestins Androgens Estrogens Glucocorticoids Mineralocorticoids Testosterone Estradiol Cortisol (hydrocortisone) Aldosterone
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Nuclear Receptor Gene Family
DBD LBD C Genome C. elegans D. melanogaster H. sapiens Size (Mb) 80 137 3300 No. of NR Genes 228 20 48 AR CAR COUPa COUPb COUPg DAX ERa ERb ERRb ERRg FXR GCNF1 GR HNF4a HNF4g ERRa LXRb MR NGFI-Ba NGFI-Bb NGFI-Bg PNR LRH LXRa PXR RARa RARb RARg PPARa PPARg PPARd PR RXRb RXRg reverba reverbb RORa RORb RORg RXRa SF1 SHP Tlx TRa TRb TR2a TR2b VDR
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Amino Acid Similarities Among Steroid Receptor Superfamily
hGR 777 100 100 hMR 984 94 57 hPR-B 934 90 55 hAR 918 78 46 hER 595 52 30 hTRβ 456 47 17 hRARβ 448 45 <15 hVDR 427 42 <15
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Mechanisms of Glucocorticoid Receptor Signaling
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An Updated Model of GR Pharmacology
X CoR CoR Antagonist GRE GR SGRMs GRE Agonist CoA CoA GRE
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Adrenocortical Steroids -
Broad Definitions Glucocorticoids: Regulation of carbohydrate metabolism Mineralocorticoids: Regulation of electrolyte balance
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Regulation of Cortisol Production
Higher centers Hypothalamus CRH Pituitary Cortisol ACTH Adrenal
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Corticosteroid Biosynthesis in the Adrenal
Cholesterol ACTH Mineralocorticoid excess (hypokalemia, hypertension, fluid overload) Pregnenolone Progesterone Corticosterone Aldosterone 17 OH- Pregnenolone 17 OH- Progesterone 11-Deoxycortisol Cortisol Glucocorticoid loss DHEA Androstenedione Testosterone DHT Androgen depletion
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X X Receptor-independent Mechanism for
Conferring Specificity of Glucocorticoid Action 11β-HSD2* Cortisone Cortisol Aldosterone 11β-HSD1 X Mineralocorticoid Receptor Mineralocorticoid Receptor X Does not bind Transcriptional Activation *Hydroxysteroid dehydrogenase
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Integrated Actions of Glucocorticoids in Man
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Glucocorticoid Effects on Metabolism
protein degradation protein synthesis glucose utilization insulin sensitivity amino acids muscle liver glucose glucose utilization insulin sensitivity lipolysis glycogen storage gluconeogenesis glycerol fat
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Regulation of Aldosterone Production
( - ) Plasma Na+ Plasma Na+ Na+ in Filtrate stim. Macula Densa Na+ Reabsorption Angiotensinogen JG cells Renin Adrenal Cortex Distal Tubule ( - ) Angiotensin I c.e. Aldosterone Angiotensin II
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Mineralocorticoids Exert Biological Activity in
the Late Distal Tubule and Collecting Ducts
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Defects in the HPA/Glucocorticoid Axis
Primary Adrenal Insufficiency (Addison’s Disease) - Autoimmune - Tuberculosis - Breast cancer metastasis - Fungal CMV infection Secondary Adrenal Insufficiency - Following exogenous glucocorticoid treatment - Hypothalamic and pituitary lesions Congenital Adrenal Hyperplasia - Mutation in the p21 hydroxylase
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Diagnosis of Adrenocortical Diseases
–Hypocortisolism ACTH stimulation test CRH stimulation test
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Diagnoses of Adrenocortical Diseases
–Hypercortisolism Midnight plasma cortisol measurement 24-hour urinary free cortisol Low dose Dexamethasone suppression test Combination Dex suppression / CRH test
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Serum Cortisol Levels During Circadian Studies
and High and Low Dexamethasone Suppression Tests circadian studies dexamethasone suppression test serum cortisol (nmol/l) 800 600 oral dexamethasone (mg/six hours) 2 400 1 200 <50 Day 1 Day 2 Day 3 Day 4 0900 1800 2400 time (hours) serum cortisol (nmol/l) 800 600 400 200 <50 normal range 0900 0900 0900 0900 0900 time (hours) normal pituitary-dependent disease ectopic ACTH syndrome
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Pharmacologic Inhibition of Glucocorticoid Function
Inhibition of cortisol biosynthesis Direct ketoconazole: 11β hydroxylase inhibitor - metapyrone: 11β hydroxylase inhibitor - aminoglutethimide: side chain cleavage enzyme Indirect - mitotane: ACAT1 inhibitors - pasireotide: Somatostatin 5 agonist (B) Inhibition of glucocorticoid receptor action Mifepristone
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Typical Uses of Glucocorticoids
Allergic diseases: asthma, atopic dermatitis, anaphylactic shock Autoimmune diseases: Lupus, rheumatoid arthritis, myasthenia gravis Inflammatory disorders: Crohn’s disease Graft rejection
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Principles of Glucocorticoid Therapy
Deliver locally if possible Deliver for as brief a time as possible Taper therapy to permit resumption of normal adrenal function Give alternate day therapy if possible
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Clinically Important Corticosteroids
Hormone Cortisol Cortisone Prednisone Triamcinolone Betamethasone Dexamethasone Beclomethasone Fluticasone Fludrocortisone Action GC, MC GC MC Use Replace, Anti-inf Anti-inf Replace Duration Short Medium Long Route IM, IV, Oral, Topical Topical Oral IM, IV Oral, Topical Inhalation
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Adrenal Steroid Toxicities Glucocorticoid Actions
Hyperglycemia Negative nitrogen balance Growth failure Osteoporosis Cataract formation Impaired wound healing Truncal obesity Psychosis Prolonged suppression of HPA axis
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Glucocorticoid-induced Osteoporosis
Physiologic Replacement Dose Pharmacologic Doses Increasing Risk of GIOP 2.5 mg 5 mg 7.5 mg 10 mg 15 mg 20 mg 25 mg >1 g Low Dose Moderate Dose High Dose “Pulse” Physiologic Cutoff
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Indications for Mineralocorticoid Antagonists
Primary hyperaldosteronisms Adrenal hyperplasia / adenomas Edematous conditions Congestive heart failure Edema due to cirrhosis of the liver Nephrotic syndrome Essential hypertension Hypokalemia
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Spironolactone and Eplerenone are Mineralocorticoid Antagonists
CH3 CH3 H H H o S o CH3
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