Editing File Mnemonic File Endocrine Block Pharmacology team 438 Pharmacology of Corticosteroids Objectives: By the end of the lecture , you should know: ● Revise the synthesis of steroids ● Mechanism of action ● Pharmacokinetics of cortisol, pharmacodynamic actions and ● therapeutic uses ● Adverse reaction ● Steroids agonists and antagonists and their therapeutic applications. Color index: Black : Main content Purple: Females’ slides only Red : Important Grey: Extra info or explanation Blue: Males’ slides only Green : Dr. notes Biosynthesis of Adrenal Hormone1 Corticosteroid is present in Mineralocorticoids Glucocorticoids Sex hormones the blood bound to the 1 corticosteroid binding The intracellular receptor is bound globulin (CBG) and enters the Cholesterol to the stabilizing proteins, cell as the free molecule. including heat shock protein 90 ACTH (Hsp90) and several others (X). 2 When the complex binds a 11αOH 11-OH 17,20 lyase Dehydroepiandro Pregnenolone molecule of steroid, the Hsp90 and pregnenolone sterone (DHEA) associated molecules are released. The Steroid – receptor complex enters the nucleus as a dimer, 11αOH 11-OH 17,20 lyase Progesterone Androstenodione binds to the glucocorticoid progesterone response element (GRE) on the 3 11-Deoxy gene, and regulates gene transcription by RNA corticosterone 11-Deoxy cortisol Testosterone The resulting mRNA is edited polymerase2 and associated and exported to the transcription factors. Corticosterone cytoplasm for the production 4 of protein that brings about AT II the final hormone response. - Dihydrotestosterone Aldosterone Cortisol - Estradiol Corticosteroid is present in the blood bound to the corticosteroid binding globulin (CBG) and enters Corticosteroids The intracellular receptor is bound to the the cell as the free molecule. stabilizing proteins, including heat shock Corticosteroids are steroid hormones produced by the adrenal cortex. They consist of two groups: protein 90 (Hsp90) and several others (X). When the complex binds a molecule of They have important The Steroid – receptor complex enters the They have steroid, the Hsp90 and associated molecules effects on nucleus as a dimer, binds to the 3 Glucocorticoids: salt-retaining activity are released. intermediary 2 glucocorticoid response element (GRE) on Cortisol (Hydrocortisone ) which regulate Na & K metabolism, the gene, and regulates gene transcription reabsorption in the catabolism, immune Mineralocorticoids: by RNA polymerase2 and associated collecting tubules of The resulting mRNA is edited and responses, growth & Aldosterone transcription factors. inflammation. the kidney exported to the cytoplasm for the production of protein that brings about the final hormone response. Mechanism of action: Corticosteroid is present in the blood bound to the corticosteroid binding globulin (CBG) 1 and enters the cell as the free molecule. 2 The intracellular receptor is bound to the stabilizing proteins, including heat shock protein 2 90 (Hsp90) and several others (X). When the complex binds a molecule of steroid, the Hsp90 and associated molecules are released. 3 1 The Steroid – receptor complex enters the nucleus as a dimer, binds to the glucocorticoid response 3 element (GRE) on the gene, and regulates gene transcription by RNA polymerase 2 and associated 4 transcription factors. The resulting mRNA is edited and exported to the cytoplasm for the production of protein 4 that brings about the final hormone response. 1: all are derivatives of cholesterol 2: synthetic/pharmaceutical form of cortisol. 3: Are all reactions related to generation and storage of metabolic energy Effects of Glucocorticoids: ● Glucocorticoid stimulate gluconeogenesis, as a result: ○ Blood glucose rises ○ Insulin secretion is stimulated→Lipolysis and lipogenesis are stimulated. With a net increase of Metabolic effects fat deposition in certain areas [e.g. the face (moon facies), shoulder and back (buffalo hump)] ★ These effects occur when the patient is treated with 100 mg (high dose) of hydrocortisone or > for longer than 2 weeks. ● Glucocorticoids cause muscle protein catabolism(↓muscle mass/muscle wasting). ● Lymphoid and connective tissue fat and skin undergo Catabolic effects wasting . ● Catabolic effects on bone lead to osteoporosis ★ In children growth is inhibited1. ● Glucocorticoids inhibit cell mediated immunologic functions, especially dependent on lymphocytes & Immunosuppressive decrease interleukins secretion. effects2 ★ Glucocorticoids do not interfere with the development of normal acquired3 immunity but delay rejection reactions in patients with organ transplants. ● Glucocorticoids have important inhibitory effects on the distribution, function and migration of leukocytes. Anti inflammatory ● Suppressive effect on the inflammatory cytokines & effect2 chemokines. ● These drugs increase neutrophils and decrease lymphocytes, eosinophils, basophils and monocytes. ★ Inhibit phospholipase A24 & Prostaglandins synthesis. ● Renal: Glucocorticoids such as cortisol are required for normal renal excretion of water loads. ● CNS: When given in large doses these drugs may cause Other effects profound behavioral changes (first insomnia & euphoria then depression). ● GIT: Large doses also stimulate gastric acid secretion and decrease resistance5 to ulcer formation. 1: Steroids are contraindicated in children 2: most common therapeutic uses of steroids.. 3: = Adaptive. 4: enzyme responsible for liberation of arachidonic acid (first step in the arachidonic acid pathway) which inhibit the production of all prostanoids and leukotrienes. 5: decrease prostaglandins Natural Overview Cortisol ( hydrocortisone) Glucocorticoids Synthetic E.g Prednisone \ Dexamethasone1 Agonist Antagonist Budesonide \ Beclomethasone Agonist Spironolactone Natural Aldosterone Glucocorticoids Mineralocorticoids Mineralocorticoids Aldosterone Mifepristone Synthetic Flucocortisone (Fludrocortisone) Natural synthetic Glucocorticoids Glucocorticoids Ketoconazole Glucocorticoids Cortisol receptors Prednisone (hydrocortisone) E.g Mifepristone Aminogluthemide Receptor antagonist Prednisolone Mineralocorticoids receptors Metrapone E.g Spironolactone Dexamethasone Antagonist Classification of Corticosteroids Triamcinolone Synthetic E.g Ketoconazole inhibitors Beclomethasone Glucocorticoids Some commonly used naturalBudesonide and synthetic corticosteroids for general use Natural cortisol (hydrocortisone) Synthetic Glucocorticoids ● Cortisol is the major natural glucocorticoid. Activity Activity ● AgentsThe physiologic secretion of cortisol is regulated by adrenocorticotropic (ACTH) & secretion rate ● is the major natural glucocorticoid. Agent varies during the dayAnti-inflammatory (Circadian rhythm). Peaks in the Topical morning and trough (declines)Salt-retaining in midnight. ● The physiologic secretion of cortisol is ● Prednisone and its active Anti-inflammatory Topical Salt-retaining Drugs regulated by adrenocorticotropic metabolite prednisolone Short to medium acting glucocorticoids (ACTH) & secretion rate varies during ● Dexamethasone Short to medium acting glucocorticoids the day (Circadian rhythm). Peaks in ● Budesonide Hydrocortisone the morning and trough (declines) in ● Beclomethasone Hydrocortisone 1 1 1 1 1 1 (cortisol) midnight. (cortisol) Cortisone 0.8 0 0.8 ● Given orally, cortisol is well absorbed Cortisone 0.8 0 0.8 from GIT Prednisone 4 0 0.3 ● Cortisol in the plasma is 95% bound Prednisone 4 0 0.3 to CBG Prednisolone 5 4 0.3 ● It is metabolized by the liver & has ★ Their properties in compared to Prednisolone 5 4 0.3 short duration of action compared cortisol include: Methyl- with the synthetic congeners ○ longer half life Long acting glucocorticoids prednisolone ● It diffuses poorly across normal skin ○ longer duration of action P.K & mucous membranes ○ reduce salt retaining effect Betamethasone 25-40 10 0 Meprednisone ● The cortisol molecule also has a small ○ better penetration of lipid but significant mineralocorticoid barriers for topical activity. Dexamethasone 30 10 0 Long acting glucocorticoids effect. This is an important cause of hypertension in patients with cortisol Mineralocorticoids Betamethasone 25-40 10 0 secreting adrenal tumor or a pituitary ACTH secreting tumor (Cushing’s Fludrocotisone 10 0 250 Dexamethasone 30 10 0 syndrome) Mineralocorticoids 1: long acting. Fludrocortisone 10 0 250 Glucocorticoids Cont... Drugs Natural cortisol (hydrocortisone) Synthetic Glucocorticoids ● Adrenal Disorder: 1. Addison’s disease (chronic adrenocortical insufficiency) 2. Acute adrenal insufficiency associated with life threatening shock, infections or trauma 3. Congenital adrenal hyperplasia (in which synthesis of abnormal forms of corticosteroids are stimulated by ACTH). ● Non- adrenal Disorder: 1. Allergic reactions1 (e.g. bronchial asthma, angioneurotic edema,drug reactions, urticaria, allergic rhinitis) a. Beclomethasone & budesonide have been developed for use in asthma and other condition in which good surface activity on mucous membrane or skin is needed and systemic effects are to be avoided. b. Rapidly penetrate the airway mucosa but have very short half lives after they enter the blood, so that systemic effects and toxicity are greatly reduced. (advantage) Uses 2. Collagen vascular disorder2 (e.g rheumatoid arthritis, systemic lupus erythematosus, giant cell arteritis, polymyositis, mixed connective tissue syndrome) 3. Organ transplants (prevention & treatment of rejection – immunosuppression) 4. GI disorders (e.g inflammatory bowel disease)