Adrenocortical Steroids and Antagonists PDF

Adrenocortical steroids and antagonists Glucocorticoids Cortisol Metabolism, especially glucose regulation Immune function Mineralocorticoids Primary mineralocorticoid is aldosterone Salt and water retention Weak androgens and estrogen DHEA, androstenedione, an...

Adrenocortical steroids and antagonists Glucocorticoids Cortisol Metabolism, especially glucose regulation Immune function Mineralocorticoids Primary mineralocorticoid is aldosterone Salt and water retention Weak androgens and estrogen DHEA, androstenedione, and androstenediol (potent estrogen) Androstenedione can be converted to testosterone and then estradiol in tissues Major source of estrogen in post-menopausal females  Cortisol (hydrocortisone) Metabolic effects Growth, cardiovascular function, immunity Regulation : axis very sensitive to negative feedback by cortisol levels ( also synthetic glucocorticoids) Secretion follows a circadian pattern ACTH rises in early morning and following meals Sensitivity also varies diurnally Lower in am, higher at night Bound in plasma to Corticosteroid binding globulin (CBG) CBG increases in pregnancy, estrogen administration and hyperthyroidism  Mechanism Mediated by glucocorticoid receptors Nuclear receptors Intracellular GR are predominantly cytoplasmic Dimerize upon ligand binding and enter nucleus Ligand activated transcription factors Also bind mineralocorticoid receptors and exert effects Metabolic effects CHO protein and fat metabolism Stress hormone Produced in fasting state To provide glucose for brain and heart Gluconeogenesis, glycogen synthesis Release of amino acids (muscle breakdown) to provide for gluconeogennesis Stimulate lipolysis Catabolic action in lymphoid and connective tissue, muscle, fat , and skin High doses result in muscle loss and weakness Elevate blood glucose Inhibit glucose uptake by muscle However Stimulate insulin release Muscle glucose uptake disallowed But… insulin Stimulates lipogenesis and inhibits lipolysis to a degree Net effect on adipose tissue Increase in fat deposition with increased free fatty acids in blood  Important in stress responses Elevate blood glucose to maintain adequate supply to brain and heart Maintains energy levels Vasoconstriction Also important for surfactant production in near term babies  Immune system Powerful anti-inflammatory effects Due primarily to reduction in levels and function of leukocytes Greatly reduced macrophage function and cell mediated immunity Reduce prostaglandin and leukotriene production due to reduction of arachidonic acid synthesis by inhibition of phospholipase A2 Reduce cyclooxygenase 2 expression Reduced thromboxane, and prostaglandins Antihistamine effects Inhibits histamine release from basophils and decreases capillary permeability Very useful therapeutically but also responsible for side effects Nervous system Insomnia, euphoria, depression Chronic administration Suppresses ACTH, GH, TSH and LH High doses PUD ? Due to reduction in H. Pylori suppression Abnormal fat distribution Antagonize Vitamin D mediated calcium absorption Increase platelets and RBCs  Natural glucocorticoid Cortisol/hydrocortisone (Cortef, A-hydrocort) Highly bound to plasma proteins 75-90% to CBG (corticosteroid-binding globulin) 5% to albumin , 5-20% free Pharmacokinetics Good oral bioavailability Topically absorbed Metabolized by the liver, eliminated by the kidneys Half-life of 60-90 min Exhibits mineralocorticoid activity Synthetic Corticosteroids Medium to short acting Hydrocortisone(Cortef), Cortisone(Cortone) are not synthetic, Prednisone(Deltasone), Prednisolone(Delta-Cortef), Methylprednisone(Medrol) Have mineralocorticoid activity Intermediate acting Triamcinolone(Aristocort, Nasacort, Kenalog) Topically active, great lipid penetration Excellent anti-inflammatory properties Mineralocorticoid activity absent Fludricortisone (Florinef) mineralocorticoid  Long acting Betamethasone (Diprosone), Dexamethasone(Maxidex) ( long- acting forms) Most Potent systemic agents No mineralocorticoid activity Topical forms have increased activity and duration over triamcinolone Locally acting agents Beclomethasone (Qvar, Beconase AQ, Qnasl) Budesonide (Pulmicort) Ciclesonide (Alvesco, Omnaris, Zetonna) Flunisolide (Aerospan, Aerobid) Fluticasone (Flovent HFA, Flovent Diskus, Arnuity, Ellipta, Flonase, Veramyst) Mometasone (Asmanex, Nasonex) Nasal or inhalation Used for allergies and asthma maintenance primarily ( inhaled corticosteroids first line) Rapidly metabolized Systemic side effects greatly reduced  Uses and Indications of adrenocortical agents Diagnosis and treatment of disturbed adrenal function Chronic addisons disease Weakness, fatigue, weight loss, hypotension, skin darkening, inability to maintain fasting blood glucose levels Hydrocortisone Doses increased during stress ( trauma , infection, etc) Mineralocorticoid may also be added Minor trauma or infection may produce acute adrenal insufficiency which can be fatal Due to circulatory shock Requires immediate treatment High hydrocortisone doses and fluid and electrolyte correction Congenital adrenal hyperplasia Associated with defects in cortisol and aldosterone synthesis Cushings syndrome Usually adrenal hyperplasia secondary to ACTH secreting tumor Excessive glucocorticoid levels Surgical removal of tumor Treatment required after surgery large doses of cortisol during and after surgery, then tapered to maintenance doses  Glucocorticoid resistance GR mutation Lung maturation in fetus Premature delivery if anticipated Corticosteroids to mom will stimulate fetal surfactant production Bone and joint inflammatory conditions Bursitis, tendonitis, arthritis GI IBS, Crohns disease, ulcerative colitis Eye Optic Neuritis, Uveitis, conjunctivitis Leukemias and lymphomas MS Many other conditions Asthma, transplants, autoimmune disorders ( RA, lupus) , dermatitis, allergic reactions including bee stings, hives, and as adjunctive therapy in anaphylaxis  Dosage forms Oral, topical ( ointments, inhalation, nasal sprays) i.v., i.m. Well distributed and absorbed Highly bound to CBGs Metabolized in liver Glucuronidated Excreted by kidneys into urine  Drugs used in asthma Beclomethasone Budesonide (Pulmicort) Budesonide/Formoterol (Symbicort) Combination steroid and LABA Ciclesonide (Alvesco) Flunisolide (Aerospan) Fluticasone (Flovent HFA, Flovent Diskus) Fluticasone/Salmeterol (Advair Diskus, Advair HFA) Combination steroid and LABA Mometasone (Asmanex) Mometasone/Formoterol (Dulera) Combination steroid and LABA  Allergies Beclomethasone (Beconase AQ, Qnasl) Budesonide (Rhinocort Aqua) Ciclesonide (Omnaris, Zetonna) Flunisolide Fluticasone (Flonase) Mometasone (Nasonex) Triamcinolone (Nasacort)  Adverse effects Numerous Increase with long-term use Cushing like syndrome Elevated blood glucose, blood pressure, muscle wasting, weakness, abnormal fat distribution, bruising, striae due to skin thinning, puffiness in face, insomnia, psychosis, osteoporosis, impaired wound healing, infection susceptibility, ulcers, sodium and fluid retention , potassium loss due to aldosterone like effects Adrenal suppression if given > 2 weeks Increased doses during stress Doses MUST be tapered slowly Even when switching from oral to inhaled form Topical administration reduces adverse effects q.o.d. dosing can be tried Shortest possible course  Contraindications PUD, HTN , heart failure , infections, psychosis, diabetes , osteoporosis, or glaucoma Mineralocorticoids Aldosterone, Deoxycorticosterone, Fludricortisone Promote absorption of sodium and water from the distal nephron Promote potassium/H+ excretion Act via mineralocorticoid receptors Receptor mechanism similar to glucocorticoid receptors Fludricortisone (Florinef) Most widely used Has both glucocorticoid and mineralocorticoid activity  Fludricortisone Exhibits mineralocorticoid and glucocorticoid activity Mineralocorticoid activity greater Salt and water retention at doses that do not shown glucocorticoid effects Uses Corticosteroid replacement when mineralocorticoid replacement required Addisons disease Congenital adrenal hyperplasia Adrenalectomy Adverse effects Salt and water retention Hypokalemia/alkalosis Edema and HTN Corticosteroid receptor Antagonists Spironolactone(Aldactone) and Eplerenone(Inspra) Antagonizes the aldosterone receptor Cause sodium and water excretion Potassium retention Diuresis (potassium sparing) Uses Primary aldosteronism (Conns disease) Hypokalemia Commonly employed with loop and thiazides to offset potassium losses HTN, edema Heart failure in conjunction with other agents Spironolactone has benefits above diuretic effects Reduction in cardiac remodeling Adverse effects Hyperkalemia Cardiac rhythm disturbances Gynecomastia and menstrual irregularities in women  Mifeprestone (Korlym, RU-486) GR antagonist Has partial agonist action at GR and Progesterone receptor Binds weakly, drug receptor complex dissociates too quickly to allow efficient nuclear translocation Uses Hyperglycemia reduction in Cushings syndrome ABSOLUTELY contraindicated in pregnancy Progesterone blockade will terminate pregnancy Also teratogenic Adrenocortical synthesis inhibitors Aminoglutethimide (Cytadren) Blocks conversion of cholesterol to pregnenolone Reduces synthesis of all adrenocortical steroids Ketoconazole Antifungal agent Inhibits adrenal steroid synthesis Used in cushings syndrome Abiraterone (Zytiga) Steroid synthesis inhibitor (17 alpha hydroxylase inhibitor) Reduces cortisol synthesis and adrenal and gonadal steroid Targets adrenal androgens Approved for hormone refractory prostate cancer