Endocrine Pharmacology: Adrenocorticoids PDF

ENDOCRINE PHARMACOLOGY: ADRENOCORTICOIDS Chapter 37: Basic & Clinical Pharmacology, Katzung, 15th ed. (pgs. 691-710) Chapter 42: Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 13th ed. Chapter 34: Principles of Medicinal Chemistry, Foye, 8th ed. (pgs. 1446-54)  HYPOTHALAMUS- PI...

ENDOCRINE PHARMACOLOGY: ADRENOCORTICOIDS Chapter 37: Basic & Clinical Pharmacology, Katzung, 15th ed. (pgs. 691-710) Chapter 42: Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 13th ed. Chapter 34: Principles of Medicinal Chemistry, Foye, 8th ed. (pgs. 1446-54)  HYPOTHALAMUS- PITUITARY - ENDOCRINE AXES 1. Hypothalamus produces (releasing) hormones / biomolecules to stimulate (+) or inhibits (-) the pituitary 2. Pituitary responds  synthesizes and releases specific hormones that enter the circulation 3. Circulating hormones act on specific endocrine glands/ tissues that respond by producing a biological effect HPT: hypothalamus – pituitary – thyroid Harrison’s Principles of Internal Medicine, 18 th ed.  Normal Anatomy The adrenal glands are two small, yellowish bodies located in the perirenal space, immediately anterosuperior to the upper pole of the kidneys.  Adrenal Glands An adrenal gland is found on top of each kidney. Each adrenal gland has two regions that carry out separate functions! The adrenal medulla The adrenal cortex  The Adrenal Cortex Acts like a regular endocrine organ Secretes many hormones, but most importantly secretes the following steroids: – aldosterone – cortisol – sex hormones Synthesis of Adrenocortical hormones Drugs covered in this section  Glucocorticoids( agonists)  A. Natural  Mineralocorticoids  1. Hydrocortisone  1. Aldosterone  B. Synthetic   2. Deoxycorticosterone 1. Prednisone (s. acting)  2. Prednisolone (s. acting)  3. Fludrocortisone  3. Triamcinolone (I. Acting)  4. Betamethasone (L. acting)  Antagonist  5. Dexamethasone (L. acting)  1. Spironolactone  Antagonists(Synthesis Inhibitors)  2. Eplerenone  1. metyrapone  3. Drospirenone  2. ketoconazole  4. Finerenone  3. Mifepristone (Receptor blocker)   CELLULAR RESPONSE OF STEROID SS SIGNALING Transcription H2 N regulating DNA binding domain Ligand binding COOH domain Type I nuclear receptors domain 13th ed Fig. 46-5: Goodman-Gilman;  Inactive form bound to repressor (HSP70 / HSP90)  Ligand binds and induces conformational change  Dimerization and translocation  nucleus  Binds glucocorticoid response elements (GRE) & TFs  Regulates transcription of target 14th ed Fig. 39-4: Katzung; genes S Glucocorticoids (cortisol)  Activates genes  regulate glucose metabolism  DRUG INTERACTIONS WITH GLUCOCORTICOIDS All GCs are substrates for CYP3A4 (some can induce CYP3A4)  CYP3A4 inducer  phenytoin, phenobarbital, rifampin ( GC dose)  CYP3A4 inhibitors  ritonavir, darunavir ( GC dose)  GCs may increase NSAID – related GI adverse effects - why???  Glucocorticoids increase renal clearance of salicylates (aspirin)  GC can reduce effects of hypoglycemic agents  Fluoroquinolones (e.g., levofloxacin),  risk tendon rupture  Hormonal contraceptives (norethindrone)   GC metabolism  GLUCOCORTICOID STRUCTURE AND ACTIVITY Necessary for GR activity  11b-OH  Unsaturated (D4) and C3 ketone (planar) Increases GR activity  Ring A double bond (D1)  17a and C21-OH  9a-F and 6a-F; CH3 at 16a/b Fig. 28: Foye’s; Increases stability (prevents metabolism)8th ed  Ring A double bond (D1) (reduces [H] of 3-ketone)  17a and 21 esters (C17 [O] requires free OHs at C17a and 21)  9a-F (reduces oxidation at C11)  GLUCOCORTICOSTEROIDS: STRUCTURES Hydrocortisone Cortisone Betamethasone (cortisol) Prednisone Prednisolone Methylprednisolone R=H Or some type of ester Triamcinolone acetonide Triamcinolone (free) formulation Prednisone MOA: mimics the effects of indigenous Glucocorticoid agonists Absorption: 50% to 90% (altered in hepatic failure, chronic renal failure, inflammatory bowel disease, hyperthyroidism, and in the elderly) Protein binding :