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Home , Euthyroid sick syndrome, Liotrix, Reverse triiodothyronine, Thyroid storm

2/28/17

Overview of Topics

• Disorders • • Coma/Stupor • Adrenal & Thyroid • • Pharmacotherapy • Adrenocorcal 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 • Idenfy the of various thyroid disorders Thyroid Disorders & • Discuss appropriate uses of medicaons in the treatment of various thyroid disorders and adrenal insufficiency Pharmacotherapy

The Thyroid

• Buerfly-shaped organ responsible for synthesizing and Thyroid follicular cells produce two primary hormones: releasing thyroid hormones • Tetraiodothyronine (thyroxin, T4) • Minimal hormonal acvity (prohormone) • Serves as a reservoir for conversion to T3 • Thyroid hormones have an effect on virtually every organ system in the body • (T3) • Most potent in binding nuclear receptors • Children: crical 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 ssues

Inacve product of T4 deiodinaon: • Thyroid follicles: structural & funconal units • (rT3) • No metabolic/physiologic funcon • Only organ capable of absorbing • Thyroid hormones composed of: Iodine and

Pappa, 2011; Umpierrez, 2002

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Thyroid Hormones Hormone Synthesis

Thyroid peroxidase

Dipiro, 2010 Häggström, 2014

Thyroid Hormone Regulation Peripheral Thyroid Function Negave Feedback Inhibion TRH: Thyrotropin- • T4 and T3 are 99% protein bound releasing hormone • T3 is the receptor-acve thyroid hormone • T4 ! T3 in peripheral ssues by iodothyronine • Pharmacologic target in hyperthyroidism TSH: Thyroid- smulang hormone • T3 binds to two specific nuclear receptors • alpha and beta • Regulates expression of many genes involved in numerous physiologic funcons • Increases ssue thermogenesis and basal metabolic rate

emedicine.medscape.com/arcle/122393-overview

Drug-Induced Thyroid Hormone Changes Effect on thyroid hormone Select medicaons Decreased TSH agonists, glucocorcoids Increased TSH Metoclopramide, domperidone Decreased T3/T4 secreon , Iodide, Increased T3/T4 secreon Iodide, amiodarone Increased TBG binding (), tamoxifen, methadone/ heroin/methadone, fluouracil, mitotane Decreased TBG binding Androgens/anabolic steroids, glucocorcoids, , salicylates, furosemide (high-doses) Increased Thyroid , , rifampin, Metabolism Decreased T4 ! T3 PTU, B-blockers, amiodarone, glucocorcoids conversion HYPOTHYROIDISM

Garber J, Cobin R, Woeber K, et al

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Hypothyroidism Hypothyroidism

Hypothyroidism Hyperthyroidism • Primary Hypothyroidism—insufficient funcon of the thyroid Symptoms Weight gain Weight loss (increased appete) • Elevated TSH and low free T4 Conspaon Nervousness • Overt Weakness Anxiety • Elevated TSH and normal free T4 Lethargy Palpitaons Depression Emoonal lability • Subclinical Dry skin Menstrual disturbances Muscle cramps, myalgia Heat intolerance • Secondary Hypothyroidism—insufficient smulaon 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 Prebial myxedema (Grave’s) Coarse hair/skin Fine hair Cold dry skin Periorbital puffiness Fine tremor Bradycardia Hyperacve 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 Medicaons causing Hypothyroidism • most common cause worldwide Inhibion of thyroid hormone synthesis/ Lithium release Aminoglutethimide Iodine-containing drugs • Chronic autoimmune thyroidis (Hashimoto’s thyroidis) (Amiodarone, guaifenesin) • Most common cause in areas of iodine sufficiency (U.S.) TSH suppression Dopamine • Autoimmune 5-10 mes more common in Destrucve thyroidis Suninib females Increased type-3 deiodinaon Sorafenib Increased T4 clearance and suppression of Bexarotene • Thyroid carcinoma TSH • Radioacve 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 • (T4) • American Academy of Family Physicians • • Paents 60 years of age and older (no frequency) (T3) • Levothyroxine/liothyronine (T3/T4) • Desiccated thyroid (T3/T4)

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Levothyroxine, T4 Levothyroxine Dosing

Synthroid, Tirosint, Tirosint-Sol, Levoxyl, Unithroid Narrow therapeuc range: careful dose traon 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 iniated on full replacement MOA: T4 converted to acve metabolite T3, which binds to dose thyroid receptor proteins in the nucleus to exert metabolic • Adults <50 years with cardiac disease: iniate at 25-50 mcg/day, effects through control of DNA transcripon and protein trate by 12.5 to 25 mcg every 6 to 8 weeks synthesis • Adults >50 years without cardiac disease: iniate at 25-50 mcg/day, trate by 12.5 to 25 mcg every 6 to 8 weeks

• Adults >50 years with cardiac disease: iniate 12.5-25 mcg/day, Indicaons: Hypothyroidism, pituitary TSH suppression, trate 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 soluon, oral soluon*

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/iniaon unl euthyroid • TSH 6 months aer euthyroid on stable dose • TSH every 12 months thereaer

Contraindicaons: • Acute MI, uncorrected adrenal insufficiency, thyrotoxicosis • Adrenal insufficiency: glucocorcoid 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), 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, , • 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.

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Myxedema Coma Myxedema Coma

Extreme manifestaon of hypothyroidism with mulple organ abnormalies and mental deterioraon • Occurs when compensatory responses are overwhelmed by a precipitang factor (infecon, trauma)

Presentaon: • Decreased mental status • (<35.5 C) • Hypotension • Hypovenlaon

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 and electrolytes • Treatment of precipitang factors • steroids • Hydrocorsone 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 producon and secreon of thyroid Disease hormone • Autoimmune disorder in which thyrotropin receptor anbodies (TRAb) smulate TSH receptor, increasing thyroid hormone producon 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, Burch H, Walter M, et al. , 2016 Ross D, Burch H, Walter M, et al. , 2016

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Consequences of Treatment: Hyperthyroidism thyrotoxicosis • Three common treatment modalies: • Weight loss • —thyroidectomy • Exopthalmos • Radioacve Iodine (RAI) • Osteoporosis • Anthyroid medicaons • Atrial fibrillaon • Tachycardia • Treatment of hyperthyroidism depends on cause and severity of disease • Embolic events • Muscle weakness • Goals of therapy: • Tremor • Correct hypermetabolic state • Neuropsych manifestaons • Establish euthyroid • Rare CV collapse and death • Minimize symptoms and consequences of hyperthyroidism

Ross D, Burch H, Walter M, et al. , 2016

Hyperthyroidism Treatment Treatment: Hyperthyroidism

Medicaon Class MOA Medicaons Beta-blockers Beta-blockers Inhibit adrenergic • Appropriate for symptomac control in hyperthyroidism effects (palpitaons, tremors, tachycardia, heat intolerance) Iodides Block conversion & Iodine soluon of T4 ! T3 (Lugol’s soluon) • First-line therapy before other agents Inhibit hormone • Propranolol is the drug of choice release Saturated soluon of potassium iodide (SSKI, ThyroShield) Radioacve Destroys thyroid 131-I Iodine ssue Thionamides Interferes with (PTU) organificaon of iodine (synthesis) Methimazole (Tapazole)

Ross D, Burch H, Walter M, et al. , 2016

Treatment: Hyperthyroidism Thionamides

Thionamides—inhibit synthesis of thyroid hormones (T3 and T4) Propylthiouracil (PTU) Methimazole by prevenng oxidaon of iodine within the thyroid (inhibit Preferred in thyroid crisis/ thyroid storm Associated with rare congenital fetal peroxidase-catalyzing reacons) BBW: Severe liver / acute liver abnormalies failure Oral Oral, rectal* • Methimazole (Tapazole) AEs: Hepas, agranulocytosis (rare); GI upset, drug-induced lupus • 0.4 mg/kg/day (three divided doses) inial erythematous, exfoliave dermas, pruris, taste-perversion

• 0.2 mg/kg/day (three divided doses) maintenance 1-3 months before euthyroid state restored

• Propylthiouracil (PTU) Long-term use can lead to thyroid hyperplasia

• PTU also inhibits conversion of T4 ! T3 in the periphery Pregnancy: • 300 mg/day (three divided doses) inial* • Hyperthyroidism diagnosed during 1st trimester: begin PTU st • 100-150 mg/day (three divided doses) maintenance • Hyperthyroidism diagnosed aer 1 trimester: begin Methimazole • Taking Methimazole prior to pregnancy—switch to PTU or withdraw Methimazole Nabil N, Miner D, Amatruda J, 1982; Ross D, Burch H, Walter M, et al. , 2016

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Treatment: Hyperthyroidism Thyroid Storm

Iodides—temporarily inhibit thyroid hormone release and block • Life-threatening medical emergency 2/2 decompensated peripheral conversion of T4 ! T3 hyperthyroidism • Can be precipitated by infecon, surgery, trauma, radio-acve Potassium Iodide and Iodine soluon (Lugol’s soluon) iodine treatment Saturated soluon of potassium iodide (SSKI, ThyroShield) • Treatment: • An-thyroid (PTU is preferred treatment in Thyroid Storm) • • Reduce gland vascularity before surgery for Graves, adjuncve Plus before emergency • Inorganic iodide therapy (SSKI or Lugol’s) • : Propranolol • Steroid: Hydrocorsone or • Administraon of iodine should be delayed for at least one • Aggressive cooling and other supporve treatment hour aer thionamide administraon Significant interacons: warfarin

Thyroid Storm: Dosing

EUTHYROID SICK SYNDROME

Euthyroid Sick Syndrome (ESS) Euthyroid Sick Syndrome (ESS)

Abnormalies in thyroid hormone observed during severe systemic Roune thyroid funcon tests? illnesses • Many crically-ill paents with non-thyroid illnesses exhibit: • Not recommended for crically ill paents unless primary • Low T3 state concern involves thyroid dysfuncon • Low T4 state • Increased reverse T3 (rT3) • TSH not generally elevated Thyroid replacement? • Clinically euthyroid • Thyroid replacement for paents presenng with euthyroid sick syndrome is not recommended Proposed mechanisms: • • Increased turnover of T4 and T3 No benefit demonstrated • Decreased T4 ! T3 conversion • Decreased rT3 clearance Treat the underlying disorder—results of thyroid funcon tests will • Decreased TBG binding normalize aer resoluon of underlying illness • Decreased TSH secreon • Pro-inflammatory (TNF, IL-1) likely involved

Pappa T, Vagenakis A, Alevizaki M, 2011; Umpierrez G, 2002 Pappa T, Vagenakis A, Alevizaki M, 2011; Umpierrez G, 2002

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Hypothalamic-Pituitary- Adrenal (HPA) Hormones • Adrenocortical • Corcotropin releasing hormone (CRH) • Vasopressin (AVP) • Pituitary Suppression & • Adrenococotropic hormone (ACTH) • Adrenal gland Pharmacotherapy • Adrenal medulla: • Epinephrine & Norepinephrine Sarah A. Myers, PharmD Candidate • Adrenal cortex • Zona glomerulosa: mineralocorcoid (Aldosterone) • Zona fasciculata: glucocorcoids (Corsol) • Zona recularis: androgens (Testosterone)

Hypothalamic-Pituitary-Adrenal (HPA) - Axis Adrenal Hormone Synthesis

Regulation of Hormone Secretion • Glucocorcoid secreon regulated by the anterior pituitary • Adrenocorcotropic hormone (ACTH) or Corcotropin

• ACTH is released in response to corcotropin-releasing hormone (CRH), which is secreted by hypothalamus

• CRH plays a pivotal role in the HPA-axis response to stress • -mediated inflammatory/immune response • Catecholamines

• Prolonged adrenal smulaon ! down-regulaon and desensizaon of pituitary to CRH • Reduced ACTH and corsol response to stressor ADRENAL INSUFFICIENCY

Silverman M, Pearce B, Biron C, et. al. 2005

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Adrenal Insuficiency Adrenal Insuficiency

• Results from insufficient producon of glucocorcoids and mineralocorcoids by the adrenal gland Adrenal Insufficiency

Weakness Hyperpigmentaon • Primary Adrenal Insufficiency (Addison’s Disease) Fague Hypotension • Deficiency of Aldosterone, corsol, DHEA Orthostasis Orthostac changes Weight loss • Requires replacement of endogenous steroids Poor appete Weak pulse • Can precipitate acute adrenal insufficiency (Adrenal crisis) Salt craving • Acute volume depleon and shock Adrenal crisis Severe weakness Hypotension • Secondary and terary adrenal insufficiency Peripheral vascular collapse Abdominal tenderness Severe pain (abdomen, back, legs) Reduced consciousness • Disorders of pituitary or hypothalamus Confusion Delirium • Severe illness ()

Adrenal Insuficiency Chronic Adrenal Insuficiency

• Mineralocorcoid deficiency: • Chronic Treatment • Hyponatremia • Glucocorcoid replacement • Mineralocorcoid deficiency • Hydrocorsone 15-25 mg (two to three divided doses) • Inappropriate secreon of andiurec hormone (vasopressin) from • Corsone acetate 20-35 mg (two to three divided doses) corsol deficiency • Largest dose in the AM, 2nd dose 2 hours aer lunch, 3rd dose 4-6 hours • Hyperkalemia before bedme

• Mineralocorcoid deficiency • Mineralocorcoid replacement • Fludrocorsone (Florinef) • Glucocorcoid deficiency: • 0.5 to 1 mg daily • Hypotension • Dose adjustments required to manage fluid balance and blood pressure • Heightened sensivity • (DHEA) replacement • Trial of DHEA appropriate in symptomac paents

Critical Illness-related Acute Adrenal Insuficiency Corticosteroid Insuficiency (CIRCI) When severe adrenal insufficiency or adrenal crisis is suspected: Acute adrenal insufficiency in the presence of precipitang illness • Corsol producon is oen insufficient to meet demand during acute, severe illnesses (sepsis) • Diagnosc tesng to exclude/confirm diagnosis • Funconal adrenal insufficiency • Corcotropin-smulaon test • Relave adrenal insufficiency • Not feasible? Corsol & ACTH

Difficult diagnosis in crically ill paents • Immediate stress dose IV hydrocorsone • Plasma corsol concentraon and response to ACTH are oen • 100mg IV hydrocorsone IVP, then 50 mg every 6 hours unreliable measures in crical illness

• Fluid resuscitaon Hydrocorsone 200-300 mg/day • Decrease duraon of vasopressor-dependency • Reverse (dextrose) • 28-day mortality • Taper when vasopressor withdrawn

Asare K, 2007

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Glucocorticoid comparison

All steroids are not created equal / MINERALOCORTICOIDS

References

Pappa T, Vagenakis A, Alevizaki M. The nonthyroidal illness syndrome in the non-crically ill paent. European Journal Of Clinical Invesgaon. 2011;41(2):212-220.

Umpierrez G. Euthyroid sick syndrome. Southern Medical Journal. 2002;95(5):506-513.

DiPiro J, Talbert G, Matzke B, et al. Pharmacotherapy: A Pathophysiologic Approach.

Garber J, Cobin R, Woeber K, et al. CLINICAL PRACTICE GUIDELINES FOR HYPOTHYROIDISM IN ADULTS: COSPONSORED BY THE AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND THE AMERICAN THYROID ASSOCIATION. Endocrine Pracce. 2012;18(6):989-1028

Ross D, Burch H, Walter M, et al. 2016 American Thyroid Associaon Guidelines for Diagnosis and Management of Hyperthyroidism and other causes of Thyrotoxicosis. Thyroid: Official Journal Of The American Thyroid Associaon. August 12, 2016 Adrenal & Thyroid

SYNTHROID (levothyroxine sodium) [package insert]. Chicago, IL: AbbVie Inc.; 2010.

Mathew V, AhmadMisgar R, Chowdhury S, et al. Myxedema Coma: A New Look into an Old Crisis. Journal Of Thyroid Research. January 2011:1-7.

Ross, D. Myxedema coma. In: UpToDate, Cooper D (Ed), UpToDate, Waltham, MA. 2015. Pharmacotherapy

MacKerrow SD, Osborn LA, Levy H, et al. Myxedema-associated treated with intravenous triiodothyronine. Ann Intern Med 1992; 117:1014. Sarah A. Myers, PharmD Candidate Nabil N, Miner DJ, and Amatruda JM, "Methimazole: An Alternave Route of Administraon," J Clin Endo Metab, 1982, 54(1):180-1. January 18, 2017 SILVERMAN MN, PEARCE BD, BIRON CA, MILLER AH. Immune Modulaon of the Hypothalamic-Pituitary-Adrenal (HPA) Axis during Viral Infecon. Viral immunology. 2005;18(1):41-78. doi:10.1089/vim.2005.18.41.

Bornstein S, Allolio B, Arlt W, et al. Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Pracce Guideline. J Clin Endocrinol Metab. 2016 Feb;101(2):364-89.

Asare K. Diagnosis and treatment of adrenal insufficiency in the crically ill paent. Pharmacotherapy. 2007 Nov;27(11):1512-28.

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