Corticosteroids

Pharmacology of corticosteroids

1. CORTICOSTEROIDS Dr Mrunal Dhole

2. LAYOUT History Synthesis and Release Structure-Activity Relationship Available agents Mechanism of Action Effects Therapeutic Uses Corticosteroid Inhibitors

3. History

4. Thomas Addison 1855; On The Constitutional And Local Effects Of Disease Of The Supra-Renal Capsules Destruction of adrenal glands → Death Charles- Eduoard Brown- Séquard 1856 Bilateral adrenalectomy in lab animals → Death Adrenal cortex is essential for survival T. Reichstein & E. C. Kendall 1930s Isolated & identified CORTISONE ; Affects carbohydrate metabolism Tait & colleagues Isolated & identified ALDOSTERONE ; Affects fluid and electrolyte balance P. S. Hench 1949 Improvement in Rheumatoid arthritis with cortisone Reichstein, Kendall and Hench were jointly awarded the Nobel Prize for Physiology or Medicine in 1950

5. Synthesis and Release

6. Ach , 5-HT, NE, GABA Corticotropin-releasing hormone (CRH) Arginine Vasopressin (AVP); potentiates the effect of CRH CNS Hypothalamus (Parvocellular neurons of paraventricular nucleus) Anterior Pituitary (Corticotropes) Synthesis and release of Adreno- cortico tropic hormone (ACTH) Adrenal Cortex Steroids Hypothalamus-Pituitary-Adrenal (HPA) axis

7. (19 carbon atoms) (21 carbon atoms)

8. ACTH binds to MC2R present on cells of adrenal cortex Translocation of cholesterol to inner mitochondrial matrix

9. Cholesterol Pregnenolone Progesterone 17 α - Hydroxypregnenolone DHEA 17α-Hydroxyprogesterone 11-Deoxycortisol Cortisol Deoxycorticosterone Corticosterone 18-Hydroxycorticosterone Aldosterone CYP11A1 3 β-HSD CYP21 CYP11B2 CYP11B2 CYP11B2 CYP17 CYP11B1 3 β-HSD CYP21 Zona glomerulosa, predominantly regulated by Ang-II & K + Zona fasciculata, predominantly regulated by ACTH; zona reticularis Rate-limiting step CYP17 CYP11B1 - Steroid 11 β -hydroxylase; CYP11B2 - Aldosterone synthase; CYP17 – Steroid 17 α -hydroxylase; CYP21 – Steroid 21 α -hydroxylase

10. Endogenous corticosteroids CORTISOL ALDOSTERONE Type Glucocorticoid Mineralocorticoid Potency Effect on glucose metabolism Anti-inflammatory effects Na + retention Rate of secretion under optimal conditions 10 mg/day 0.125 mg/day Concentration in peripheral plasma 8 A.M. 16 µg/100 ml 0.01 µg/100 ml 4 P.M. 4 µg/100 ml 0.01 µg/100 ml DIURNAL RHYTHM OF BASAL STEROIDOGENESIS Glucocorticoid production is at peak in the morning

11. Negative Feedback Regulation Stress As a response to stress, cortisol production is markedly increased overriding the diurnal variations in ACTH secretion as well as negative feedback regulation Important homeostatic mechanism to meet the increased demands of the body 1. 2.

12. Structure-activity relationship

13. A C D B Steroid nucleus Ring Glucocorticoid activity Mineralocorticoid activity A 4,5 double bond, 3-keto group Required Required C 11 β -hydroxyl group Required No D Hydroxyl group on C21 No Required

14. A C D B Steroid nucleus Ring Glucocorticoid activity Mineralocortocoid activity D 17 α -hydroxyl group ↑↑ A 1,2 double bond ↑↑ (Prednisone) ↑ G/M potency B Fluorination at 9 α Comparatively low ↑↑ (Fludrocortisone) D Substitutions at C16 ↑↑↑ (Beclomethasone) Virtually non-existent

15. Glucocorticoid Forms available Hydrocortisone Oral Injectable Topical Cortisone (Prodrug) Oral - - Prednisone (Prodrug) Oral - - Prednisolone Oral Injectible Methylprednisolone Oral Injectible - Triamcinolone Oral Injectable Topical Betamethasone Oral Injectable Topical Dexamethasone Oral Injectable Topical Mineralocorticoid Fludrocortisone Oral - - Water-soluble esters – IM/IV Water-insoluble esters - IM

16. PHARMACOKINETICS Absorption Distribution 90% bound to CBG ( transcortin ) and albumin at normal concentrations Metabolism Metabolized to tetrahydrocortisone in liver and conjugated Excretion Mainly in urine

17. Mechanism of Action

18. GR + Transcription factors (AP-1 & NF- ĸB ) Gene transcription and protein synthesis takes time Effects apparent after several hours

19. MINERALOCORTICOIDS: Effects Deoxycorticosterone Aldosterone Fludrocortisone Mineralocorticoid deficiency Hyponatremia, Hyperkalemia, acidosis, volume depletion → CV collapse Mineralocorticoid excess ↑ Na + conc., hypokalemia, alkalosis, fluid retention → Hypertension Excess aldosterone contributes to progression of CHF Increase reabsorption of Na + from tubular fluid and urinary K + / H + excretion Maintain fluid and electrolyte balance Action on distal tubules and collecting ducts of kidney

20. MINERALOCORTICOIDS: Mechanism of Action MR is expressed in epithelial tissues involved in electrolyte transport Aldosterone binds to MR m-RNA transcription in renal tubular cells Synthesis of Na + K + ATPase of basolateral membrane Synthesis and activation of β -subunit of Na + sensitive amiloride channel Na + resorption; K + , H + excretion

21. Both aldosterone and cortisol bind the MR with equal affinity Cortisol Cortisone (Active) (Inactive) Prevents binding of cortisol to MR & GR Receptor-Independent Mechanism for Corticosteroid Specificity Present in kidney, colon & salivary glands Aldosterone ( Hemiacetyl derivative) is resistant to 11 βHSD2 action Not inactivated; binds to MR 11 β -hydroxysteroid dehydrogenase (11 β HSD2)

22. Upregulation of adrenergic receptors → C onstriction of vascular and bronchial smooth muscles in response to adrenaline Lipolysis due to adrenaline and growth hormone → Increased fatty acids in circulation

23. Direct Effects

24. CARBOHYDRATE AND PROTEIN METABOLISM Maintenance of adequate glucose supply to the brain in the fasting state LIPID METABOLISM ↑ Serum glucose levels Stimulate insulin release → Lipogenesis & fat deposition in truncal adipocytes Lipolysis in peripheral adipocytes due to increased expression of 11 β HSD1 Hyperglycemia with glycosuria; can precipitate diabetes Managed with diet or insulin Dramatic redistribution of body fat Increased fat in the back of the neck (buffalo hump) and face (moon facies) Loss of fat in the extremities

25. SKELETAL MUSCLES Disorder Cause of weakness & fatigue Adrenal insufficiency Hypodynamic circulation Excess mineralocorticoids Hypokalemia Excess glucocorticoids Muscle wasting of proximal limbs CNS Adrenal insufficiency → Apathy, depression, irritability WATER EXCRETION Maintenance of normal g.f.r . Glucocorticoid deficiency → ↑ AVP secretion → Inability to excrete water Behavioural changes such as mild euphoria, nervousness, insomnia, overt psychosis

26. CALCIUM METABOLISM ↓ Ca 2+ uptake from the gut ;↑ Ca 2+ excretion from the kidney Chronic glucocorticoid therapy will ultimately lead to osteoporosis Fractures of ribs and vertebrae GI TRACT Increase in both basal and nocturnal gastric acid secretion Peptic ulcers with insidious onset of hemorrhage and perforation EYE Topical glucocorticoid therapy increases intraocular pressure in eyes Glaucoma; children at risk of developing cataracts FORMED ELEMENTS OF BLOOD Increase in circulating RBCs, platelets and neutrophils Decrease in lymphocytes, monocytes, eosinophils and basophils

27. Iatrogenic Cushing’s Syndrome Red cheeks Fat pads Buffalo Hump Thin skin Thin arms, Thin Legs Moon Face Bruising Ecchymosis Red striation Pendulous abdomen Poor wound healing Acne hirsutism Amenorrhea in females Erectile dysfunction in males

28. Anti-inflammatory actions Mechanism Action Inhibition of phospholipase-A 2 ↓ production of arachidonic acid → ↓ PGs, LTs and PAF Block production and release of cytokines ↓ tissue damage ↓ activation of T lymphocytes & suppression of fibroblast proliferation ↓ chemotaxis Inhibit ELAM-1 and ILAM-1 Inhibition of leucocyte migration to the site of inflammation ↓ IgE -dependent release of histamine and LTC-4 from basophils ↓ capillary permeability ↓ collagenase and stromelysin production Prevent collagen degradation

29. Immunosuppressive actions 1. 2. 3. 4. Prolonged therapy Masking of symptoms of a serious illness Increased susceptibility to infection Opportunistic infections with low grade pathogens (Candidiasis) Risk for reactivation of latent tuberculosis

30. Replacement Therapy Adrenal Insufficiency Acute IV bolus of hydrocortisone 100 mg followed by continuous infusion every 8 hours till the patient is stable followed by a maintenance dose Chronic Daily treatment with hydrocortisone + fludrocortisone orally Congenital Adrenal Hyperplasia Daily treatment with hydrocortisone + fludrocortisone orally

31. Anti-inflammatory therapy Immunosuppresive therapy

32. CEREBRAL OEDEMA due to neoplasms ACUTE LYMPHOCYTIC LEUKEMIA Lympholytic action attributed to activation of programmed cell death ALLERGIC REACTIONS Serum sickness Urticaria Angioneurotic edema BRONCHIAL ASTHMA Inhaled glucocorticoids: Beclomethasone, budesonide, fluticasone In combination with a long acting β 2 agonist daily Systemic: Hydrocortisone IV in status asthmaticus

33. AIDS Pneumonia due to Pneumocystis carinii with moderate to severe hypoxia Glucocorticoids + Antibiotics SEPTIC SHOCK associated with Gr- ve bacteremia Hydrocortisone used in patients whose blood pressure fails to respond adequately to fluids and vasopressors MENINGITIS due to Haemophilus influenzae Type B Decreased incidence of associated long-term neurological impairment in infants 2 months  

34. BETAMETHASONE is administered to pregnant women for lung maturation and surfactant production in the foetus in the dose of 12 mg i.m ., to be repeated after 24 hours to prevent neonatal respiratory distress syndrome when delivery is anticipated before the 34 th week of gestation Diagnostic applications of DEXAMETHASONE To find biochemical evidence of increased cortisol levels in Cushing’s syndrome Differential diagnosis of biochemically documented Cushing’s syndrome (Cushing’s disease or Adrenocortical tumours )

35. CONTRAINDICATIONS Absolute Herpes Simplex keratitis Relative

36. Glucocorticoid therapy longer than two weeks → HPA suppression Cortical atrophy; no increase in endogenous cortisol levels during stress if therapy is continued for months Measures to minimize HPA suppression

37. Corticosteroids Inhibitors Agent Mechanism Use Ketoconazole (anti-fungal agent) Inhibits steroidogenic enzymes in higher doses Treat Cushing’s disease when surgery is not an option Mifepristone ( antiprogestin ) Competitive antagonist for GR Inoperable cases of adrenal carcinoma & ectopic ACTH production Metyrapone Inhibits 11-β hydroxylase preventing synthesis of hydrocortisone ↑ ACTH → ↑ 11-deoxycortisol in urine Test ACTH producing capacity of pituitary Spironolactone Blocks MR Treatment of primary aldosteronism

38. References Schimmer BP, Funder JW. ACTH, Adrenal Steroids and Pharmacology of the Adrenal Cortex. In: Brunton LL, Chabner BA, Knollmann BC, editors. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 12 th ed. New York. The McGraw-Hill Companies, Inc.; 2011. Chrousos GP. Adrenocorticosteroids & Adrenocortical Antagonists. In: Katzung BG, Trevor AJ, editors. Basic & Clinical Pharmacology. 13 th ed. New Delhi. McGraw Hill Education (India) Private Limited; 2015. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang and Dale’s Pharmacology. 8 th Ed. Spain: Elsevier Ltd; 2016. Chapter 33, The pituitary and the adrenal cortex; p.402-17. Satoskar RS, Rege NN, Tripathi RK, Bhandarkar SD. Pharmacology and Pharmacotherapeutics. 25 th ed. Mumbai: Popular Prakashan Private Limited; 2017. Chapter 66, Adrenal Cortical Steroids; p.917-33. Tripathi KD. Essentials of Medical Pharmacology. 7 th Ed. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd; 2013. Chapter 20, Corticosteroids; p.282-95. Sharma HL, Sharma KK. Sharma’s & Sharma’s Principles of Pharmacology. 3 rd Ed. New Delhi: Paras Medical Publisher; 2017. Chapter 42, Adrenocortical Steroids & their Analogues; p.568-83.

39. Thank you