Glucocorticoids and Mineralocorticoids Donald P Mc Donnell Ph

Glucocorticoids and Mineralocorticoids Donald P. Mc. Donnell, Ph. D.

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.

Classification of Steroids Corticosteroids Sex Hormones Progestins Androgens Estrogens Glucocorticoids Testosterone Estradiol Cortisol (hydrocortisone) Mineralocorticoids Aldosterone

Nuclear Receptor Gene Family DBD N LBD C Genome Size (Mb) No. of NR Genes C. elegans 80 228 D. melanogaster 137 20 H. sapiens 3300 48 AR COUPa COUPg DAX ERa ER ERRa ERRg FXR GCNF 1 GR HNF 4 a HNF 4 g LRH LXRa LXR MR NGFI-Ba NGFI-Bg PNR PPARa PPARg PPARd PR PXR RARa RARg reverba reverb RORa RORg RXRa RXRg SF 1 SHP Tlx TRa TR TR 2 a TR 2 VDR

Amino Acid Similarities Among Steroid Receptor Superfamily h. GR 777 100 h. MR 984 94 57 h. PR-B 934 90 55 h. AR 918 78 46 h. ER 595 52 30 h. TRβ 456 47 17 h. RARβ 448 45 <15 h. VDR 427 42 <15

Mechanisms of Glucocorticoid Receptor Signaling

An Updated Model of GR Pharmacology Co. R Antagonist GR GRE SGRMs GRE Agonist Co. A GRE X

Adrenocortical Steroids Broad Definitions Glucocorticoids: Regulation of carbohydrate metabolism Mineralocorticoids: Regulation of electrolyte balance

Regulation of Cortisol Production Higher centers Hypothalamus CRH Pituitary Cortisol ACTH Adrenal

Corticosteroid Biosynthesis in the Adrenal Cholesterol ACTH Mineralocorticoid excess (hypokalemia, hypertension, fluid overload) Pregnenolone Progesterone Corticosterone Aldosterone 17 OHPregnenolone 17 OHProgesterone 11 -Deoxycortisol Cortisol Glucocorticoid loss DHEA Androstenedione Testosterone DHT Androgen depletion

Receptor-independent Mechanism for Conferring Specificity of Glucocorticoid Action 11β-HSD 2* Cortisone 11β-HSD 1 Cortisol Aldosterone X Mineralocorticoid Receptor X Does not bind Transcriptional Activation *Hydroxysteroid dehydrogenase

Integrated Actions of Glucocorticoids in Man

Glucocorticoid Effects on Metabolism £ protein degradation �protein synthesis �glucose utilization �insulin sensitivity �amino acids muscle liver glucose £ glycogen storage £ gluconeogenesis �glucose utilization �insulin sensitivity £ lipolysis �glycerol fat

Regulation of Aldosterone Production (-) Plasma Na+ in Filtrate stim. Plasma Na+ Macula Densa JG cells Na+ Reabsorption Angiotensinogen Renin Adrenal Cortex (-) Distal Tubule Angiotensin I c. e. Aldosterone Angiotensin II

Mineralocorticoids Exert Biological Activity in the Late Distal Tubule and Collecting Ducts

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 p 21 hydroxylase

Diagnosis of Adrenocortical Diseases –Hypocortisolism • ACTH stimulation test • CRH stimulation test

Diagnoses of Adrenocortical Diseases –Hypercortisolism • Midnight plasma cortisol measurement • 24 -hour urinary free cortisol • Low dose Dexamethasone suppression test • Combination Dex suppression / CRH test

Serum Cortisol Levels During Circadian Studies and High and Low Dexamethasone Suppression Tests dexamethasone suppression test circadian studies serum cortisol (nmol/l) 800 600 400 200 oral dexamethasone (mg/six hours) 2 1 0 <50 0900 1800 2400 time (hours) serum cortisol (nmol/l) Day 1 Day 2 Day 3 Day 4 800 600 400 200 <50 normal range normal pituitary-dependent disease ectopic ACTH syndrome 0900 0900 time (hours)

Pharmacologic Inhibition of Glucocorticoid Function (A) Inhibition of cortisol biosynthesis Direct - ketoconazole: 11β hydroxylase inhibitor - metapyrone: 11β hydroxylase inhibitor - aminoglutethimide: side chain cleavage enzyme Indirect - mitotane: ACAT 1 inhibitors - pasireotide: Somatostatin 5 agonist (B) Inhibition of glucocorticoid receptor action Mifepristone

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

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

Clinically Important Corticosteroids Hormone Action Use Duration Route Cortisol Cortisone Prednisone Triamcinolone Betamethasone Dexamethasone GC, MC GC GC Replace, Anti-inf Anti-inf Short Medium Long IM, IV, Oral, Topical Oral IM, IV Oral, Topical Beclomethasone Fluticasone Fludrocortisone GC GC MC Anti-inf Replace Long Inhalation Oral

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

Glucocorticoid-induced Osteoporosis Physiologic Replacement Dose Pharmacologic Doses Increasing Risk of GIOP 2. 5 mg 7. 5 mg Low Dose 10 mg 15 mg 20 mg Moderate Dose Physiologic Cutoff 25 mg >1 High Dose “Pulse” g

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

Spironolactone and Eplerenone are Mineralocorticoid Antagonists Spironolactone o CH 3 o H H H S o CH 3 o Eplerenone