2/28/17 Overview of Topics • Thyroid Disorders • Hypothyroidism • Myxedema Coma/Stupor • Hyperthyroidism Adrenal & Thyroid • Thyroid Storm • Euthyroid Sick Syndrome Pharmacotherapy • Adrenocor/cal Insufficiency Sarah A. Myers, PharmD Candidate • ACute & ChroniC management January 18, 2017 • Glucocorcoids Objectives • Understand the physiology of the thyroid gland, hypothalamiC-pituitary-adrenal axis, and hormones • IdenIfy the signs and symptoms of various thyroid disorders Thyroid Disorders & • DisCuss appropriate uses of mediCaons in the treatment of various thyroid disorders and adrenal insuffiCienCy Pharmacotherapy The Thyroid Thyroid Hormones • BuQerfly-shaped organ responsible for synthesizing and Thyroid folliCular Cells produCe two primary hormones: releasing thyroid hormones • Tetraiodothyronine (thyroxin, T4) • Minimal hormonal acIvity (prohormone) • Serves as a reservoir for Conversion to T3 • Thyroid hormones have an effeCt on virtually every organ system in the body • Triiodothyronine (T3) • Most potent in binding nuClear reCeptors • Children: CriICal for groWth and development • Less than 20% of T3 is produCed in the thyroid gland • Adults: metaboliC stability • Primarily formed by breakdoWn of T4 in the peripheral Issues InacIve produCt of T4 deiodinaon: • Thyroid folliCles: struCtural & funCIonal units • Reverse Triiodothyronine (rT3) • No metaboliC/physiologiC funCIon • Only organ Capable of absorbing iodine • Thyroid hormones Composed of: Iodine and tyrosine Pappa, 2011; Umpierrez, 2002 1 2/28/17 Thyroid Hormones Hormone Synthesis Thyroid peroxidase Dipiro, 2010 Häggström, 2014 Thyroid Hormone Regulation Peripheral Thyroid Function Nega/ve FeedBack InhiBi/on TRH: Thyrotropin- • T4 and T3 are 99% protein bound releasing hormone • T3 is the reCeptor-acIve thyroid hormone • T4 ! T3 in peripheral Issues by iodothyronine deiodinase • Pharmacologic target in hyperthyroidism TSH: Thyroid- sImulang hormone • T3 binds to two speCifiC nuClear reCeptors • Thyroid hormone reCeptor alpha and beta • Regulates expression of many genes involved in numerous physiologic funcons • InCreases Issue thermogenesis and basal metaboliC rate emediCine.medsCape.Com/arICle/122393-overvieW Drug-Induced Thyroid Hormone Changes Effect on thyroid hormone Select medicaons Decreased TSH Dopamine agonists, gluCoCorICoids Increased TSH MetoClopramide, domperidone Decreased T3/T4 secreon Lithium, Iodide, amiodarone Increased T3/T4 secre/on Iodide, amiodarone Increased TBG binding Estrogens (pregnanCy), tamoxifen, methadone/ heroin/methadone, fluouracil, mitotane Decreased TBG binding Androgens/anaboliC steroids, gluCoCorICoids, heparin, saliCylates, furosemide (high-doses) Increased Thyroid Phenobarbital, phenytoin, rifampin, MetaBolism Carbamazepine Decreased T4 ! T3 PTU, B-blockers, amiodarone, glucocorcoids conversion HYPOTHYROIDISM Garber J, Cobin R, Woeber K, et al 2 2/28/17 Hypothyroidism Hypothyroidism Hypothyroidism Hyperthyroidism • Primary Hypothyroidism—insuffiCient funCIon of the thyroid Symptoms Weight gain Weight loss (inCreased appeIte) • Elevated TSH and loW free T4 ConsIpaon Nervousness • Overt Weakness Anxiety • Elevated TSH and normal free T4 Lethargy Palpitaons Depression EmoIonal lability • SubCliniCal Dry skin Menstrual disturbanCes MusCle Cramps, myalgia Heat intoleranCe • Secondary Hypothyroidism—insuffiCient sImulaon of the Menorrhagia thyroid Cold intoleranCe • Central hypothyroidism—HypothalamiC or pituitary Signs Weakness (proximal Warm, moist skin muscles) Exophthalmos (Grave’s) • LoW free T4 Without elevated TSH SloW DRTs PreIbial myxedema (Grave’s) Coarse hair/skin Fine hair Cold dry skin TachyCardia Periorbital puffiness Fine tremor BradyCardia HyperacIve DTRs SloW, hoarse speeCh Thyromegaly Garber J, Cobin R, Woeber K, et al , 2012. Medication-Induced Hypothyroidism Hypothyroidism • Common eologies of Primary Hypothyroidism • Iodine defiCienCy Medica/ons causing Hypothyroidism • most Common Cause worldwide InhibiIon of thyroid hormone synthesis/ Lithium release Aminoglutethimide Iodine-Containing drugs • ChroniC autoimmune thyroidiIs (Hashimoto’s thyroidiIs) (Amiodarone, guaifenesin) • Most Common Cause in areas of iodine suffiCienCy (U.S.) TSH suppression Dopamine • Autoimmune thyroid disease 5-10 Imes more Common in DestruCIve thyroidiIs Suninib females InCreased type-3 deiodinaon Sorafenib InCreased T4 ClearanCe and suppression of Bexarotene • Thyroid CarCinoma TSH • RadioacIve iodine or surgiCal treatment for hyperthyroid • MediCaon-induCed Garber J, Cobin R, Woeber K, et al , 2012. Garber J, Cobin R, Woeber K, et al , 2012. Hypothyroidism: Screening Treatment: Hypothyroidism • AmeriCan Thyroid AssoCiaon: Goals of Treatment: • Women and men >35 years of age—sCreen every 5 years • Restore euthyroid state • Resolve signs/symptoms of hypothyroidism • AmeriCan AssoCiaon of CliniCal EndoCrinologists • Avoid thyrotoxiCosis • Older paents (espeCially Women), no speCifiC age reCommendaon Thyroid Replacement Products • Levothyroxine (T4) • AmeriCan ACademy of Family PhysiCians • • Paents 60 years of age and older (no frequenCy) Liothyronine (T3) • Levothyroxine/liothyronine (T3/T4) • DesiCCated thyroid (T3/T4) 3 2/28/17 Levothyroxine, T4 Levothyroxine Dosing Synthroid, Tirosint, Tirosint-Sol, Levoxyl, Unithroid Narrow therapeuc range: Careful dose Itraon to avoid under- or over- treatment • Dosing based on age, Weight, CardiovasCular status Treatment of choice for hypothyroidism (ATA/AACE) • Thyroid replacement dose (overt): 1.6 mcg/kg/day • Healthy adults age <50 years can be iniBated on full replacement MOA: T4 Converted to acIve metabolite T3, WhiCh binds to dose thyroid reCeptor proteins in the nuCleus to exert metaboliC • Adults <50 years With Cardiac disease: iniIate at 25-50 mCg/day, effeCts through Control of DNA transCripIon and protein Itrate by 12.5 to 25 mCg every 6 to 8 Weeks synthesis • Adults >50 years Without Cardiac disease: iniIate at 25-50 mCg/day, Itrate by 12.5 to 25 mCg every 6 to 8 Weeks • Adults >50 years With Cardiac disease: iniIate 12.5-25 mCg/day, IndiCaons: Hypothyroidism, pituitary TSH suppression, Myxedema Coma Itrate by 12.5 to 25 mCg every 6 to 8 Weeks • Thyroid replacement (suBclinical, if treated): 1 mcg/kg/day Available dosage forms: tablets, Capsules, IV soluIon, oral soluIon* Garber J, Cobin R, Woeber K, et al , 2012.; AbbVie, 2010. Garber J, Cobin R, Woeber K, et al , 2012.; AbbVie, 2010. Levothyroxine Dosing Levothyroxine, T4 Monitoring (TSH and free T4) • TSH every 4-8 weeks aer dose Changes/iniIaon unIl euthyroid • TSH 6 months aer euthyroid on stable dose • TSH every 12 months thereaer Contraindicaons: • ACute MI, unCorreCted adrenal insuffiCienCy, thyrotoxiCosis • Adrenal insuffiCienCy: glucocorBcoid treatment should precede levothyroxine Garber J, Cobin R, Woeber K, et al , 2012.; AbbVie, 2010. Garber J, Cobin R, Woeber K, et al , 2012.; AbbVie, 2010. Levothyroxine: Interactions Treatment: Hypothyroidism Drugs decreasing aBsorpon of levothyroxine: Not recommended by AACE for replacement therapy • Antacids (aluminum, magnesium), Bile acid sequestrants • Desiccated thyroid (Armour Thyroid) (Cholestyramine, colespol), CalCium Carbonate, Caon • Natural, porCine-derived thyroid (T3-T4 Combinaon, 1:4 rao) exChange resins (Kayexalate), ferrous sulfate, Orlistat, • Dosed in grains simethiCone, suCralfate • Preparaons may Contain less prediCtable potenCy • Liothyronine, T3 (Cytomel, Triostat IV) Drugs increasing metaBolism: • Liothyronine- levothyroxine, T3/T4 (Thyrolar) • Rifampin, Carbamazepine, phenobarbital, phenytoin Thyroid replacement produCt Conversions: Drugs reducing protein binding of levothyroxine: 100 mcg levothyroxine = 60-65 mg (1 grain) desiccated thyroid • Heparin, SaliCylates (>2 g/day), phenytoin, mefenamiC acid, = 25 mcg liothyronine (T3) = 12.5 mcg T3/ 50 mcg T4 (Liotrix) furosemide (>80mg IV) Garber J, Cobin R, Woeber K, et al , 2012. Garber J, Cobin R, Woeber K, et al , 2012. 4 2/28/17 Myxedema Coma Myxedema Coma Extreme manifestaon of hypothyroidism With mulIple organ abnormaliIes and mental deterioraon • OCCurs When Compensatory responses are overWhelmed by a preCipitang factor (infeCIon, trauma) Presentaon: • DeCreased mental status • Hypothermia (<35.5 C) • Hypotension • HypovenIlaon MatheW V, Ahmadmisgar R, Chowdhury S, et al., 2011 Myxedema Coma Prompt treatment should inClude: • Thyroid hormone replacement Monotherapy dose Combinaon therapy dose levothyroxine 300-500 mCg IVP, then 200-400 mCg IVP, then 50-100 mCg 50-100 mCg daily daily triiodothyronine 25-50 mCg IVP, then 5-20 mCg IVP, then 2.5-10 mCg Q8H Q4-12H • ICU treatment • Intubaon • CorreCt hypotension and eleCtrolytes • Treatment of preCipitang factors • Stress steroids • HydroCorIsone 50-100mg IV Q6H HYPERTHYROIDISM MacKerroW S, Osborn L, Levy H et al., 2009; MatheW V, Ahmadmisgar R, Chowdhury S, et al., 2011; Ross D, 2015. Hyperthyroidism Hyperthyroidism Overacve thyroid or thyrotoxicosis • Endogenous hyperthyroidism most Commonly due to Graves • Inappropriately high produCIon and seCreIon of thyroid Disease hormone • Autoimmune disorder in WhiCh thyrotropin reCeptor anIbodies (TRAb) sImulate TSH reCeptor, inCreasing thyroid hormone produCIon and release Overt hyperthyroidism • LoW/undeteCtable serum TSH With elevated free T4 or T3 • Thyroid CarCinoma, ovarian tumors, pituitary tumors Subclinical hyperthyroidism • MediCaon-induCed hyperthyroidism • LoW/undeteCtable serum TSH With relavely normal serum T4 and T3 • Iodine • Amiodarone (up to 12% treated pts, Contains up to 37% iodine) • Levothyroxine Ross D,