THYROID DISORDERS & PARATHYROID DISORDERS PHARMACOTHERAPY 2 ONANONG WALEEKHACHONLOET THANANAN RATTANACHOTPHANIT

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1 THYROID DISORDERS & PARATHYROID DISORDERS PHARMACOTHERAPY 2 ONANONG WALEEKHACHONLOET THANANAN RATTANACHOTPHANIT

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3 ตำแหน ง Thyroid gland & Parathyroid glands Larynx Trachea Superior parathyroid gland Inferior parathyroid gland

4 Thyroid hormone function Thyroid hormones are critical determinants of brain and somatic development in infants and of metabolic activity in adults. Thyroid hormones also affect the function of virtually every organ system. Major targets of thyroid hormone: skeleton, heart, and metabolic regulation Thyroid hormones must be constantly available to perform these functions, there are large stores of thyroid hormone in the thyroid gland to maintain their availability.

5 Thyroid disorder I. ควำมผ ดปกต ของกำรทำงำนของต อม thyroid - Thyrotoxicosis / Hyperthyroidism - Hypothyroidism II. ต อมธ ยรอยด thyroid ทำงำนปกต แต ม ขนำดโตข น - Diffuse euthyroid goiter - Solitary thyroid nodule - Multinodular goiter III. ควำมผ ดปกต ของ thyroid function test โดยท ต อม thyroid ทำงำนปกต - Euthyroid hyperthyroxinemia - Euthyroid sick syndrome - Euthyroid hypothyroxinemia IV. ควำมผ ดปกต ของต อมธ ยรอยด แบบ subclinical - Subclinical hypothyroidism - Subclinical hyperthyroidism

6 Thyroid gland Biggest endocrine gland ส งเคราะห Thyroid hormone - Triiodothyronine (T3) - Tetraiodothyronine (Thyroxine) (T4) ส งเคราะห Calcitonin Synthesis and Release is achieved by an intricate negative feedback mechanism involving gland and hypothalamic-pituitary axis Autoregulation depend on iodine: Wolff-Chaioff effect Wolff-Chaioff effect: A reduction in thyroid hormone levels/production caused by ingestion of a large amount of iodine กลไกการปร บต วของต อมไธรอยด ขณะท ร างกายม ระด บ iodine ในเล อดส งโดยเก ดการ ย บย งการสร าง thyroid hormone ช วคราว

7 Iodine & Thyroid hormones synthesis iodine ในอาหารถ กเปล ยนเป น inorganic iodide และถ กด ดซ มใน ล าไสเล ก เพ อน าไปใช ในการสร าง thyroid hormone ผ ำน 3 ข นตอนใหญ ๆ ค อ 1. Iodide transport 2. Oxidation ของ iodine และ organic iodination 3. การสร าง iodothyronine TG= thyroglobulin, a large glycoprotein synthesized in the thyroid cell

8 Thyroxine (T4) and triiodothyronine (T3) are formed within thyroglobulin The unique tertiary structure of this glycoprotein (iodinated tyrosine residues present in TG) are able to bind together to form active thyroid hormones

9 Thyroid hormones synthesis ค ณสมบ ต Thyroid hormones: "double" tyrosine with the critical incorporation of 3 or 4 iodine atoms lipid soluble

10 T4 and T3 are transported in the bloodstream primarily by three proteins : thyroxine-binding globulin (TBG), transthyretin (TTR), and albumin (มากกว าร อยละ 99 จ บก บโปรต น) Circulating T3 : 80 % is derived from extrathyroidal conversion of T4 to T3, 20% from direct thyroidal secretion Only the free thyroid hormone is able to diffuse into the cell and some tissues, such as the brain, by active transport.

11 การควบค มการสร าง thyroid hormone Pathway I: ควบค มโดย TSH ซ งหล ง จำก anterior pituitary gland The secretion of TSH is itself under negative feedback control by the circulating level of free thyroid hormone and positive influence of hypothalamic thyrotropin-releasing hormone (TRH). Pathway II: Extrathyroidal deiodination of T4 to T3 is regulated by a variety of factors including nutrition, nonthyroidal hormones, ambient temperatures, drugs, and illness. TRH= thyrotropin releasing hormone TSH= thyroid stimulating hormone

12 Hypothalamus & Pituitary Negative feedback ถ าร างกายม ระด บธ ยรอยด ฮอร โมนในกระแสเล อดส งจะกด การสร างและหล ง TSH ท าให ระด บ TSH ในกระแสเล อดต าลง ตรงก นข าม ถ าร างกายม ระด บธ ยรอยด ฮอร โมนในกระแสเล อดลดลงจะ กระต นการสร างและหล ง TSH ให ม ระด บส งข น Thyroid hormone biosynthesis and secretion are maintained within narrow limits by a regulatory mechanism that is very sensitive to small changes in circulating hormone concentrations. TRH= thyrotropin releasing hormone TSH= thyroid stimulating hormone

13 THYROID FUNCTION TEST: Normal value Current units SI units Total T G/dl nmol/l Free T ng/dl pmol/l Free T ng/dl pmol/l Total T ng/dl nmol/l T4 index TSH U/ml mu/l

14 Metabolism of thyroid hormones Primary metabolism of thyroxine is deiodination. Deiodination of T4 may occur by monodeiodination of outer ring producing 3,5,3 - triiodothyronine - T3 by 5 -monodeiodinase. (T3 is 4 times more potent than T4) Deiodination of inner ring produce 3,3,5 reverse triiodothyronine rt3 (inactive) by 5-monodeiodinase. In extrathyroidal tissue: T4 change to T3 by using 5-deiodinases in liver.

15 Metabolism of thyroid hormones Beta blockers High dose propylthiouracil Steroid Outer ring 5 -monodeiodinase. Inner ring 5-monodeiodinase. low T3 & high of rt3

16 การสร าง Thyroid Hormone Thiocyanate Hypochlorite T4 (prohormone) T3 (active hormone)

17 Thyroid Hormone Synthesis and Secretion Inhibitors Blocks iodide transport into the thyroid : Bromine, Fluorine, Lithium Impairs organification and coupling of thyroid hormones: Thionamides, Sulfonylureas, Sulfonamide (?), Salicylamide (?), Antipyrine (?) Inhibits thyroid hormone secretion: Iodide (large doses), Lithium 17

18 MEDICATION &THYROID FUNCTION Drugs affecting the secretion of TSH Dopamine: 1 microgram/kg/min Glucocorticoids: dexamethasone at least 0.5 mg/day hydrocortione at least 100 mg/day Octreotide: 100 microgram/day Drugs affecting the secretion of thyroid hormone Lithium: interfere synthesis and decrease secretion (occur in long term treatment ~ 50%) Iodine containing medications: iodide, amiodarone, aminoglutethimide Drugs affecting T4 absorption Colestipol, Cholestyramine, Aluminium hydroxide, Ferrous sulfate, Sucralfate

19 MEDICATION AND THYROID FUNCTION Drugs affecting transportation Increased TBG concentration: estrogen, tamoxifen, heroin, methadone, mitotane, fluorouracil Decreased TBG concentration: androgen, anabolic steroids, slow release nicotinic acid, glucocorticoids Displacement from protein-binding site: furosemide, fenclofenac, mefenamic acid, salicylates Drugs that alter T4 and T3 metabolism Increased hepatic metabolism: phenobarbital, rifampin, phenytoin, carbamazepine Decreased 5-deiodinase activity: PTU, amiodarone, beta antagonist, glucocorticoids Cytokines: interferon alfa, interleukin-2

20 Hyperthyroidism & Hypothyroidism

21 Thyroid evaluation Symptoms of thyroid excess or deficiency History of familial thyroid abnormality Examination of thyroid for enlargement, consistency, nodularity Medication history Thyroid function test (TSH, T3, T4) ผ ป วยส วนใหญ ม กจะมาด วยภาวะ abnormal thyroid hormone levels diffuse or nodular thyroid enlargement MNG=Multinodular goiter

22 Physical examination Weight Blood pressure Pulse rate & cardiac rhythm Thyroid palpation & auscultation Neuromuscular examination Eye examination Dermatologic examination Cardiovascular examination Lymphatic examination (nodes and spleen)

23 Hypothyroidism Hyperthyroidism 23

24 Physiological system Skin -- appendages Eyes, face Cardiovascular Hyperthyroidism (thyrotoxicosis) warm, moist skin; sweating; fine, thin hair; Plumber's nails; pretibial dermopathy (Graves' disease) Upper lid retraction (wide stare); periorbital edema; exophthalmos, diplopia (Graves' disease) decreased peripheral resistance, increased cardiac output, stroke volume, heart rate, pulse pressure; congestive heart failure (high-output); increased contractility,. arrhythmogenic; angina Hypothyroidism pale, cool, puffy skin; brittle hair and nails Eyelid drooping; periorbital edema; puffy, nonpitting facies; large tongue increased peripheral resistance, decreased cardiac output, stroke volume, heart rate, pulse pressure; congestive heart failure (low output); bradycardia (low voltage ECG with prolonged PR interval, flat T wave); pericardial effusion

25 Physiological system Hyperthyroidism (thyrotoxicosis) Hypothyroidism Respiratory dyspnea; reduced vital capacity hypoventilation (CO 2 retention) pleural effusions Gastrointestinal increased appetite; increased bowel movement frequency; hypoproteinemia decreased appetite, decreased bowel movement frequency; ascites CNS Nervousness, hyperkinesia, variable emotional states lethargy, neuropathy Musculoskeletal Weakness; fatigue; hypercalcemia, osteoporosis, increased deep tendon reflex muscle fatigue, reduced deep tendon reflex, increased alkaline phosphatase, LDH, AST

26 Physiological system Renal Hematopoietic Reproductive Hyperthyroidism (thyrotoxicosis) Increased renal blood flow; increased GFR; mild polyuria anemia (increased RBC turnover); increased erythropoiesis decreased fertility; menstrual irregularity; enhanced gonadal steroid metabolism Hypothyroidism Decreased renal blood flow; decreased GFR; reduced water excretion anemia (decrease production rate, decreased iron absorption, decreased folate acid absorption, autoimmune pernicious anemia),decreased erythropoiesis infertility;hypermenorrhea, decreased libido; impotence, decreased gonadal steroid metabolism

27 Physiological system Metabolic Hyperthyroidism (thyrotoxicosis) increased basal rate; negative nitrogen balance, hyperglycemia; increased free fatty acids, decreased cholesterol and triglycerides; increased hormone degradation; increased requirement for fat-and watersoluble vitamins; enhanced drug detoxification Hypothyroidism decreased basal rate; delayed insulin degradation, with increased sensitivity; enhanced cholesterol and triglyceride levels; decreased hormone degradation; decreased requirements for fat-and water-soluble vitamins; decreased drug detoxification.

28 Thyroid function test The most common Lab used: TSH, total T4 free T4 total T3 free T3 TSH: the most cost effective screening test but it is not reliable in secondary hypothyroidism FT4: patients recently treated for thyroid disorder Nonspecific indice: cholesterol and other lipid profile, SGOT, SGPT, CPK, Cr *** Drug or disease state can alter laboratory value

29 THYROID FUNCTION TEST: Normal value Current units SI units Total T G/dl nmol/l Free T ng/dl pmol/l Free T ng/dl pmol/l Total T ng/dl nmol/l T4 index TSH U/ml mu/l

30 CASE 1: 55 yrs Thai female, TSH = 52 U/ml, Free T3 = 0.01 ng/dl CASE 2: 36 yrs Thai female, TSH = 0.20 U/ml, Free T3 = 0.3 ng/dl

31 Thyroid binding globulin (TBG) level & Thyroid hormone level ความผ ดปกต ของระด บ TBG ในเล อด หร อม ป จจ ยรบกวนการจ บก นของธ ย รอยด ฮอร โมนก บโปรต น จะส งผลให การว ดระด บธ ยรอยด ฮอร โมนรวม (total T3, total T4) ผ ดปกต ได โดยท ระด บ free T3, Free T4 ไม เปล ยนแปลงตาม ร างกายม ระด บ IBPs ในเล อดส งข น จะท าให total T3 และ total T4 ส ง กว าปกต แต free T3, T4 ปกต เร ยกว า Euthyroid hyperthyroxinemia ร างกายม ระด บ IBPs ในเล อดต ำลง จะท าให total T3, total T4 ต ากว า ปกต แต free T3, T4) ปกต เร ยกว า Euthyroid hypothyroxinemia ม ความจ าเป นท ต องทราบและประเม นร วมด วยว าผ ป วยม ภาวะใดหร อไม ท จะท า ให ม ความผ ดปกต ของโปรต นท จ บอย ก บธ ยรอยด ฮอร โมน IBP= iodothyronine binding proteins

32 ภำวะท ทำให ระด บซ ร ม TBG ผ ดปกต TBG เพ มข น TBG ลดลง ต งครรภ ม การเจ บป วย (major systemic illness) ทารกหล งคลอด กล มอาการเนโฟรต ค ม ภาวะเอ สโตรเจนมากเก น ภาวะท พโภชนาการ ได ร บเอ สโตรเจน active acromegaly ได ร บยาค มก าเน ด ได ร บฮอร โมนเพศชาย ได ร บเฮโรอ นได ร บยา tamoxifen ได ร บยากล โคคอร ต คอยด ในขนาดส ง ได ร บยา perphenazine ได ร บยา L-asparaginase ต ดเช อโรคเอดส พ นธ กรรม Chronic active hepatitis Biliary cirrhosis Acute intermittent porphyria พ นธ กรรม TBG= thyroid binding globulin

33 Hyperthyroidism & Thyrotoxicosis Hyperthyroidism (ภาวะฮ ยเปอร ธ ยรอยด สซ ม): ภาวะท ต อมธ ย รอยด ท างานมากผ ดปกต เป นผลให ม การสร างและหล งธ ยรอยด ฮอร โมน มากกว าปกต ระด บธ ยรอยด ฮอร โมนในกระแสเล อดท ส งข นจะเก ดจากความผ ดปกต จาก ต อมธ ยรอยด เอง Thyrotoxicosis (ภาวะธ ยรอยด ฮอร โมนเป นพ ษ): ภาวะท ร างกายม อาการและอาการแสดงเน องจากเมตะบอล สมของร างกายท ส งข น อ น เป นผลมาจากการท ระด บธ ยรอยด ฮอร โมนในกระแสเล อดส งกว าปกต ระด บธ ยรอยด ฮอร โมนท ส งข นเก ดได จากหลายสาเหต โดยระด บฮอร โมน ท ส งอาจม การสร างจากอว ยวะอ นๆ เช น เน องอกของร งไข, ได ร บยาธ ยรอยด ฮอร โมนขนาดมากเก นไป หร อ ภาวะธ ยรอด อ กเสบ (Thyroiditis ) ซ งม การปล อยธ ย รอยด ฮอร โมนมากผ ดปกต Tissues are exposed to excessive levels of T4, T3, or both.

34 Thyorotoxicosis ท ม Hyperthyroidism Graves' disease Toxic multinodular goiter Toxic adenoma Hashimoto s thyroiditis (Hashitoxicosis ) Jod-Basedow (Iodine induced) TSH- producing pituitary tumor Hydratidiform mole Thyorotoxicosis ท ไม ม Hyperthyroidism Subacute thyroiditis Transient painless thyroiditis (Postpartum thyroiditis ) Lymphocyte (silent) thyroiditis Thyrotoxic factitia Ectopic thyroid: Struma ovarii Metastatic follicular carcinoma Drug associated thyroiditis (amiodarone, lithium ) Cytokine associated thyroiditis (Interferon, Interleukin-2 )

35 HYPERTHYROIDISM Epidemiology Women > Men (2% : 0.2%) (~ 10 times) Peak incidence in children: year old Most common causes: Graves disease: an autoimmune disorder in which thyrotropin receptor antibodies (TRAbs) stimulate the TSH receptor, increasing thyroid hormone production. (60-90%) Toxic multinodular goiters (TMNG, 10-20%) Toxic adenoma: autonomous hormone production can be caused by somatic activating mutations of genes regulating thyroid hormone synthesis (5-10%)

36 CASE FINDING FOR THYROID DYSFUNCTION Previous thyroid dysfunction Goiter Surgery or radiotherapy affecting the thyroid gland DM Vitiligo (depigmentation of parts of the skin) Pernicious anemia Premature gray hair Medications: lithium, amiodarone, radiocontrast, potassium iodide Goiter: a swelling of the neck or larynx resulting from enlargement of the thyroid gland (thyromegaly), associated with a thyroid gland that is not functioning properly.

37 Signs & Symptoms of Hyperthyroidism ผ ป วยบางรายอาจไม ม อาการหร อ อาการแสดงท เป นล กษณะจ าเพาะ ของภาวะธ ยรอยด ฮอร โมนเป นพ ษ โดยเฉพาะในผ ป วยส งอาย บางรายอาจม อาการและอาการแสดง ทางระบบใดระบบหน ง บางรายม อาการตรงก นข ามก บอาการ และอาการแสดงท ควรจะเป น COMPLICATIONS Atrial fibrillation CHF Osteoporosis

38 Hormone: Laboratory test: Hyperthyroidism Low TSH, Elevated free and total T3 and T4 serum concentrations, particularly in more severe disease. 90%: T4 และ T3 ส งข น 5-30%: T3 ส ง แต T4 ปกต (T3 toxicosis) พบน อยมาก: T4 ส ง แต T3 ปกต (T4 toxicosis)

39 Laboratory test: Hyperthyroidism Radioactive iodine uptake (RAIU): การตรวจความสามารถใน กระบวนการจ บสารไอโอด นของต อมธ ยรอยด บ งช สภำวะกำรทำงำนของ ต อมธ ยรอยด Normal 24-hour RAIU ranges from 10% to 30% Elevated RAIU by the thyroid gland when hormone is being overproduced; Suppressed RAIU in thyrotoxicosis due to thyroid inflammation (thyroiditis) ว ธ ทดสอบ: ให ผ ป วยก น Radioactive iodine (ขนาดโดยท วไปประมาณ 5-20 uci) แล วว ดปร มาณ Radioactivity ท ต อมธ ยรอยด ตามเวลาท กาหนดไว หล งก น Radioactive iodine และค านวณเป นค าร อยละของ จ านวน Radioactivity ท ได ร บ ไม แนะน า ให ท าการตรวจ RAIU ในผ ป วยท ม อาการช ดเจนท กราย ข อห ามสาหร บการตรวจ RAIU ได แก ภาวะต งครรภ, ขณะให นมบ ตร, และผ ท แพ สารไอโอด น 131-ไอโอด น (I 131 ) half-life 8 days, 123-ไอโอด น I 123 half- life 13 hours 39

40 Differential diagnosis of thyrotoxicosis hcg= human chorionic gonadotropin; RAIU = radioactive iodine uptake; TSAb = thyroid-stimulating antibody; TSH = thyroid-stimulating hormone. a = The RAIU may be decreased if the patient has been recently exposed to excess iodine.

41 Laboratory test: Hyperthyroidism Other tests: Thyroid-stimulating antibodies (TSAbs) Thyroglobulin (TG) Thyrotropin receptor antibodies 41

42 HYPERTHYROIDISM (THYROTOXICOSIS) Treatment goals : Reverse sign & symptoms of hyperthyroidism, reduce goiter size, Normalize thyroid hormone levels, Prevent thyroid storm, Improve cardiac function and prevent systemic embolism Preserve bone density and prevent osteoporosis Improve overall functional capacity and quality of life

43 Graves disease Autoimmune disease: สามารถตรวจ Autoantibody ต อ Ag หลายชน ดท Thyroid cells ได แก TSH receptor (TSHR), thyroid peroxidase (TPO), thyroglobulin (TG) และ thyroidal iodide transporter % ของผ ป วย ม Ab ชน ด IgG ต อ TSHR (TSHRAb) TSHRAb ชน ดท พบบ อยและม ปร มาณมากท ส ด ได แก Thyroid Stimulating Immunoglobulin (TSI) หร อ Thyroid Stimualting Antibody (TSAb) พบได บ อยในช วงอาย ป ล กษณะทางคล น ก: hyperthyrodism, diffuse goiter, ophthalmopathy, dermopathy localized myxedema

44 การร กษา Hyperthyroid ท เก ดจากโรค Graves' disease ม 3 ว ธ 1. การร กษาด วยสารร งส (Radioactive iodine: I 131 ) 2. Subtotal thyroidectomy 3. Medical treatment Factors need to be considered Cause of hyperthyroidism Severity Patient s age Size of goiter Other complications Social and economic issues The American Association of Clinical Endocrinologists Guideline (AACE)

45 Method Cost Efficacy Failure Adverse events Surgery 5, % 20-30% Hypothyroid 20-30% Thyroidectomy 20,000 Graves disease vocal abnormal 1:500 total or near Toxic adenoma Hypoparathyroid total Toxic multinodular 1:500 goiter RAI 1,800-3, % Graves disease Toxic multinodular goiter Toxic adenoma no data Hypothyroid 3-6% Teratogenicity Medications?? 30-40% Graves disease 60% 5-10% Hypothyroid S/E, hypersensitivity

46 Contraindications of each treatment Surgery 131 I Antithyroid drugs Substantial comorbidity - Cardiopulmonary diseases - End stage cancer Pregnancy (trimester 1 and 3) Pregnancy Lactation Thyroid cancer Unable to comply with guideline Females planing a pregnancy with in 4-6 mon Major adverse reactions

47 : update May 24, 2011

48 การร กษา Hyperthyroid ท เก ดจากโรค Graves' disease Surgery Advantages Disadvantages Comment Rapid, effective treatment, especially in patients with large goiters Most invasive Least costly in long term after qualityof-life adjustment Permanent hypothyroidism Pain, scar Potential choice in pregnancy if major side effect from antithyroid drugs Potential complications (recurrent laryngeal nerve damage, hypoparathyroidism) Useful when coexisting suspicious nodule present Option for patients who refuse radioiodine

49 SURGERY Treatment of choice for extremely large nodule (>80g), severe ophthalmopathy, not response to antithyroid medications Complication: rate < 4 % - Recurrent hyperthyroidism - Hypothyroidism - Hypoparathyroidism - Vocal cord abnormalities

50 SURGERY Prepartion of surgery: - PTU or MMI for 6-8 weeks until euthyroid (having normal thyroid gland function) - Iodide 500 mg/day for days - Propranolol for days Relapse of hyperthyroidism occurs in at least 10% Permanent hypothyroidism occurs in 5% of patients within the first year, and thereafter in one or two patients per year.

51 การร กษา Hyperthyroid ท เก ดจากโรค Graves' disease Radioactive iodine ( 131 I) Advantages Disadvantages Comment Cure of hyperthyroidism Lowest cost, before adjustment for quality of life Permanent hypothyroidism almost inevitable Might worsen ophthalmopathy Pregnancy must be deferred for 6 12 months; no breastfeeding Small potential risk of exacerbation of hyperthyroidism Best treatment for toxic nodules and toxic multinodular goiter

52 RADIOACTIVE IODINE (RAI) 131 I colorless and tasteless liquid that is well absorbed and concentrates in the thyroid Mechanism: 131 I disrupt hormone synthesis Benefit for debilitated, cardiac, elderly, drug failure or toxic, relapse after surgery Β-blockers are adjunct therapy prior to RAI. 1/+00 If MMI is given, discontinue MMI 3-5 days before RAI, restart 3-7 days later and taper over 4-6 weeks. If hyperthyroidism persists after 6 month of RAIs, retreatment with RAI is suggested. 2/+00

53 FACTS ABOUT RADIOACTIVE IODINE Pregnancy is an absolute contraindication After receiving RAI for 4-6 months, patient should avoid pregnant. It needs 3-4 months in men to allow for turnover of sperm production. Radiation thyroiditis can occur within the first two weeks after RAI Hypothyroidism commonly occur following RAI Hypothyroidism after RAI for 6 months may be transient or permanent RAI worsening ophthalmopathy Theoretical risk of genetic abnormality: 0.005%

54 Instructions for patients after RAI Do not share food or eating utensil for 5 days Avoid close contact with infants, young children (under 8 years), pregnant women for 5 days No breast feeding is allowed for lactation: at least 6 weeks Flush the toilet twice after urinating and wash hand throughly If note increased nervousness, tremulousness, or palpitations, call a physician

55 การร กษา Hyperthyroid ท เก ดจากโรค Graves' disease Methimazole (PTU only second-line therapy) Advantages Disadvantages Comment Noninvasive Low initial cost Low risk of permanent hypothyroidism Possible remissions due to immune effects Low cure rate (30 80%; average 40 50%) Adverse drug reactions Drug compliance บ ญช ยาหล กแห งชาต First-line treatment in children, adolescents, and pregnancy Initial treatment in severe cases or preoperative preparation

56 carbimazole, a precursor of MMI, 10 mg of carbimazole is metabolized to approximately 6 mg of MMI THIOUREA DRUGS (Thioamides)

57 Mechanism : Methimazole (MMI), Propylthiouracil (PTU) inhibit the peroxidase enzyme system (peroxidation) and coupling process PTU can also inhibit peripheral conversion from T4 to T3 Patient characteristics for good outcome : small goiter (<50g), short duration of disease (< 6 month), no previous history of relapse with antithyroid drugs

58 Pharmacology Thiourea drugs (Thioamides) PTU tab 50 mg MMI tab 5, 10, 20 mg Serum protein binding ~75% none Serum half-life 75 นาท ~4-6 ช วโมง Volume of distribution ~20 ล ตร ~40 ล ตร Metabolism of drug illness Severe liver disease ปกต ลดลง Severe kidney disease ปกต ปกต Transplacental passage น อย มากกว า Levels in breast milk น อย มากกว า Potency 1 10 Inhibition of peripheral ม ไม ม conversion of T 4 to T 3

59 PTU MMI All adverse reactions 7.1% 3.3% Major adverse reactions Agranulocytosis 0.4% (idiosyncrasy) 0.1%(dose related) Hepatotoxicity hepatocellular damage cholestasis Vasculitis พบบ อยกว า พบน อยกว า

60 Adverse effect Cross sensitivity: 50% Most common Rash Itching Hives (urticaria) Abnormal hair loss Skin Pigmentation Transient leukopenia (WBC < 4000/mm 3) Less common Swelling Nausea Vomiting Heartburn Loss of taste Joint or muscle aches Numbness and headache

61 Adverse effect Rare case but severe (first 2 month of therapy) Agranulocytosis: PTU> MMI Aplastic anemia Lupus-like syndrome: occur after 6 months Polymyositis Hepatotoxic: occur within the first 3 months Hypoprothrombinemia Vasculitis ** If these complications occur, antithyroid drugs should be discontinued (absolute contraindication)

62 Agranulocytosis: Thiourea drugs One of serious adverse effects of thiourea drug therapy An idiosyncratic reaction: mostly occur in the first 3 month Common among patients over 40 year old Rare among patients receiving < 30 mg of MMI/day Symptoms: fever, rash, jaundice, arthralgia, oropharyngitis Granulocyte count <250 per cubic millimeter Patients can recover within 2-3 wks after the drug is stopped. Warning: Agranulocytosis is an absolute contraindication of antithyroid drug therapy.

63 THIOUREA DRUGS MMI should be used in virtually every patient who chooses antithyroid drug therapy for Grave disease, except during the first trimester of pregnancy when PTU is preferred, in the treatment of thyroid storm.1/++0 Medication should be continued for approximately months, then tapered or discontinued if the TSH is normal at that time. 1/+++ Patient should be alerted to stop the medications (PTU and MMI) immediately and call their physician when there are symptoms suggestive of agranulocytosis or hepatic injury. 1/+00

64 THIOUREA DRUGS When MMI is discontinued, thyroid function testing should continue to be monitored at 1 3-month intervals for 6 12 months to diagnose relapse early. If a patient with Grave s disease becomes hyperthyroid after completing a course of MMI, consideration should be given to treatment with RAI or thyroidectomy. Low-dose MMI treatment for longer than months may be considered in patients not in remission who prefer this approach. 2/+00

65 Thiourea drugs Usual initial dose MMI mg OD (single dose), Max dose 120 mg/day PTU 100 mg TID ( mg/day), Max dose 1200 mg/day Improvement in symptom & lab test should be ensured within 4-8 wks Monthly dose titrations as needed (based on symptoms and free T4 concentrations); TSH may remain low months after starting therapy Maintenance dose for month MMI : once euthyroid, may reduce to 5 10 mg/day PTU: once euthyroid, may reduce to 50 mg 2-3 times daily Monitoring: baseline, 2 month, 6 month, course of therapy After remission: monitoring every 6-12 month

66 THIOUREA DRUGS IN PREGNANCY PTU should be used when antithyroid drug therapy is started during the first trimester. MMI should be used when antithyroid drug therapy is started after the first trimester. 1/+00 Patients taking MMI who decide to become pregnant should be switched to PTU as soon as possible in the first trimester and changed back to MMI at the beginning of the second trimester. 2/+00 GD during pregnancy should be treated with the lowest possible dose of antithyroid drugs.1/+00

67 BETA BLOCKER used as adjunctive therapy with antithyroid drugs, RAI, or iodides when treating Graves disease or toxic nodules; in preparation for surgery; or in thyroid storm. used to ameliorate thyrotoxic symptoms such as palpitations, anxiety, tremor, and heat intolerance, Beta-adrenergic blockade should be given to elderly patients with symptomatic thyrotoxicosis and to other thyrotoxic patients with resting heart rates in excess of 90 bpm or coexistent cardiovascular disease. 1/++0 Beta-adrenergic blockade should be considered in all patients with symptomatic thyrotoxicosis. 1/+00 Contraindications of beta-adrenergic blockade: severe asthma, CHF, cardiomyopathy CCBs: verapamil and diltizem oral can be used in patients with contraindications with beta-adrenergic blockade

68 BETA BLOCKER From AACE guideline 2011

69 IODIDES Short term therapy before surgical, after radiotherapy, acutely thyroid storm Often used as adjunctive therapy to surgery patient to shrink the size of the gland. Do not use in the days before ablative surgery because it may reduce uptake of radioactive iodine Mechanism: block releasing and inhibit synthesis of thyroid hormone. Limited efficacy after 7 14 days of therapy because thyroid hormone release will resume. Symptom improvement occur 2-7 day after treated. ADR : Hypersensitivity (rash, fever, rhinitis,cough) Salivary gland swelling Iodism (Metalic taste, burning mouth, stomach upset) Gynecomastia

70 IDODIDES Lugol solution: ml three time daily (5% iodine +10% potassium iodide) (6.3 8 mg of iodide per drop) 20 drop = 1 ml, 1 drop =0.05 ml Saturated solution of potassium iodide, SSKI (38 50 mg of iodide per drop) typical starting dose of SSKI is 3 to 10 drops daily (120 to 400 mg) in water or juice. Potassium iodide: 60 mg three time daily 130-mg tablets contain 100 mg of iodide

71 SUBCLINICAL HYPERTHYROIDISM Serum TSH below the lower limit of the reference range combined with free T4 and T3 concentrations that are normal Potentially increase risk to develop cardiac and bone density abnormality Few data are available to guide clinical decision regarding the treatment of subclinical hyperthyroidism These patients could be treated with antithyroid agents, surgery, radioactive iodine.

72 SUBCLINICAL HYPERTHYROIDISM Most practitioners agree that treatment of older patients (> 65 yrs) with TSH values below 0.1 milli international unit/l is reasonable. From AACE guideline 2011

73 THYROID STORM A life-threatening medical emergency Signs and symptoms - High Fever - Tachycardia - Agitation - Weakness - Dehydration - Delirium - Coma - Nausea/vomiting - Diarrhea Precipitating factor - Surgical procedures - RAI treatment - Infection - Noncompliance of thioamides - Illness - Accident - Excessive iodine - Excessive thyroid hormone

74 Diagnosis of thyroid storm From AACE guideline 2011

75 Thyroid storm : Treatment 1. Correction for hyperthyroidism: suppression of thyroid hormone, formation and secretion - Antithyroid drugs: PTU high dose ( mg divide to 4-6 times/day) - Lugol s solution - Dexamethasone (inhibit conversion T4 to T3) - Antiadrenergic therapy - Other methods: plasmapheresis to remove excess hormone (and to remove thyroid-stimulating immunoglobulins in Graves disease) when the patient has not responded to more conservative measures, although these measures do not always work Inhibition of thyroid hormone biosynthesis: Inhibition release of thyroid hormone from the thyroid gland: Decreasing of the peripheral effects of thyroid hormone: PTU, MMI potassium iodide, lithium, ipodate PTU, corticosteroids, ipodate, iopanic acid

76 Drug Drugs used in thyroid storm Regimen Propylthiouracil Methimazole Sodium iodide Lugol s solution Saturated solution of potassium iodide Propranolol Dexamethasone Prednisone Methylprednisolone Hydrocortisone 900 1,200 mg/day orally in four or six divided doses mg/day orally in four or six divided doses Up to 2 g/day IV in single or divided doses 5 10 drops three times a day in water or juice 1 2 drops three times a day in water or juice mg every 6 hours 5 20 mg/day orally or IV in divided doses mg/day orally in divided doses mg/day IV in divided doses mg/day IV in divided doses

77 Drugs used in thyroid storm PTU in large doses may be the preferred thionamide because, in addition to interfering with the production of thyroid hormones, it also blocks the peripheral conversion of T4 to T3. However, β-blockers and corticosteroids will serve the same purpose. Iodides, which rapidly block the release of preformed thyroid hormone, should be administered after thionamide is initiated to inhibit iodide utilization by the overactive gland. If iodide is administered first, it could theoretically provide substrate to produce even higher levels of thyroid hormone. Corticosteroids are generally recommended, although there is no convincing evidence of adrenocortical insufficiency in thyroid storm, and the benefits derived from steroids may be caused by their antipyretic action and their effect of stabilizing blood pressure. 77

78 Thyroid storm : Treatment 2. Prevention and correction for complications - Water and electrolyte imbalance: D5W - Fever : paracetamol (do not use aspirin or other nonsteroidal antiinflammatory agents because they may displace bound thyroid hormone) - CHF, arrhythmia 3. Correction for precipitating factors

79 Thyroiditis (Inflammatory Thyroid Disease) Thyroiditis: hyperthyroidism results from unregulated, inflammationinduced release of stored thyroxine and triiodothyronine. It should be suspected if patient have pain and tenderness in the thyroid region Hyperthyroidism from thyroiditis usually is mild and lasted only a few weeks Treatment with antithyroid or RAI is not work. Short term salicylate or glucocorticoid may be needed to relieve thyroid pain and tenderness

80 Treatment consideration for specific population Pregnancy: use PTU low dose ( 300 mg or less and tapered to 50 to 150 mg daily after 4 to 6 weeks) Neonatal and pediatric: PTU 5-10 mg/kg/day or MMI mg/kg/day for 8-12 weeks, Iodides for few days

81 HYPOTHYROIDISM (ภาวะพร องธ ยรอยด ฮอร โมน) Women > men (1.4% : 0.1%) Majority of patients have primary hypothyroidism due to thyroid gland failure due to chronic autoimmune thyroiditis. Cretinism (Child) Myxedema (Adult) Hashimoto s thyroiditis Special populations with higher risk: Postpartum women, FH of autoimmune thyroid disorders, Patients with previous head and neck or thyroid irradiation or surgery, Other autoimmune endocrine conditions (e.g., Type 1 DM, adrenal insufficiency, and ovarian failure), Some other non-endocrine autoimmune disorders (e.g., Celiac disease, vitiligo, pernicious anemia, sjögren s syndrome, and multiple sclerosis), Primary pulmonary hypertension, Down s and turner s syndrome

82 Causes of Hypothyroidism Primary hypothyroidism Secondary hypothyroidism Hashimoto s disease Pituitary disease Iatrogenic hypothyroidism Hypothalamic disease Iodine deficiency Enzyme defects Caused by drug induce: amiodarone, Thyroid hypoplasia povidone iodine, iodinate contrast Goitrogens media, lithium, nitroprusside Goitrogens = substances that suppress the function of the thyroid gland by interfering with iodine uptake, which can, as a result, cause an enlargement of the thyroid 82

83 Causes of Hypothyroidism 1. Primary (Thyroidal hypothyroidism) 1.1) Loss of functional thyroid tissue Postoperative and postradiation (I131 or external irradiation) Chronic autoimmune thyroiditis (Hashimoto s thyroiditis) Reversible autoimmune hypothyroidism (Silent and postpartum thyroiditis, cytokine thyroiditis) Idiopathic myxedema 1.2) Functional defects in thyroid hormone biosynthesis and releases Congenital defects in thyroid hormone biosynthesis Iodine deficiency Iodine induced hypothyroidism Drug : antithyroid agents, lithium, natural and synthetic goitrogenic chemicals

84 2. Central (hypothalamic/pituitary) hypothyroidism 2.1) Loss of functional tissue Tumors ( pituitary adenoma, craniopharyngioma, meningioma, dysgerminoma, glioma, metastasis ) Trauma ( Surgery, irradiation, head injury ) Vascular ( ischemic necrosis, hemorrhage, stalk interruption, aneurysm of internal carotid a. ) Infections ( abscess; tuberculosis, syphilis, toxoplasmosis ) Infiltrative ( sarcoidosis, histiocytosis, hemochromocy tosis ) Chronic lymphocytic hypophysitis Congenital ( pituitary hypoplasia, septo-optic dysplasia, basal encephalocele ) 2.2) Functional defects in TSH biosynthesis and release Isolate TSH deficiency, TSH synthesis defect, defect in TSH receptor Mutation in genes encoding for TRH receptor, TSH- or Pit-1 Drugs : dopamine, glucocorticoids, L-thyroxine withdrawal 3. Peripheral (extrathyroid) hypo thyroidism Thyroid hormone resistance

85 General: Cold intolerance, weight gain, decrease appetite and sweating,easily fatigue Head: Dry, brittle, sparse hair Face: puffy face, large tongue Neck: goiter in primary hypothyroidism Cardiac: Cardiac enlargement, poor heart sounds, dypsnea, low output failure GI: Constipation Genitourinary: Amenorrhea Extremities: Broad hand and feet, cold and dry skin, brittle nail, yellowish skin Neuromuscular: Muscle pain and weakness, paresthesia, delay deep tendon reflexes Emotional: Emotional instability, depression, lethargy, decrease energy, increase sleep requirement Sign & Symptom

86 Thyroid Function Test In 1 ๐ hypothyroidism, TSH level should be elevated. In 2 ๐ hypothyroidism, TSH levels may be within or below the reference range; when TSH bioactivity is altered, the levels reported by immunoassay may even be elevated. Free and/or total T4 and T3 serum concentrations should be low. 86

87 TREATMENT: HYPOTHYROIDISM There is general agreement that patients with primary hypothyroidism with TSH levels above 10 miu/l should be treated, which patients with TSH levels of miu/l will benefit is less certain. TREATMENT GOALS : Reverse physical finding, and normalize thyroid hormone level Reduce goiter size Reduce serum cholesterol level Improve quality of life In neonate and children : maintain normal growth, physical and mental development

88 Complications: CNS: depression, dementia, psychosis, convulsion Neuromuscular: Malaise, increasing of creatine phosphokinase (CPK) CVS: increasing risk of coronary heart disease

89 TREATMENT Drug of Choice : Sodium levothyroxine (L-thyroxine) Daily dosage of L-thyroxine is dependent on age, sex, body size (need Ideal body weight for daily requirement) Initial dose: Existing cardiovascular disease microgram/day Adult: microgram/day or 1.7 microgram/kg/day Children: 4 microgram/kg/day Elderly: < 1microgram/kg/day Dose titration based on response (control of symptoms, normalization of TSH and free T4), Can increase or decrease in to 25-mcg/day increments Adverse effect: hyperthyroidism, osteoporosis, drug allergy, adrenal crisis.

90 Monitoring Therapeutic Monitoring Patients should be evaluated q 6-8 weeks initially. TSH and T4 concentration should be checked monthly until euthyroid state is achieved. Once TSH is normal: visit q 6-12 months is sufficient, TSH should be measured at least annually. Plasma TSH concentrations begin to fall within hours and are usually normalized within 2 weeks, but they may take up to 6 weeks for some patients, depending on the baseline value. TSH concentration is the most sensitive and specific monitoring parameter for adjustment of L-thyroxine dose. 90

91 Drug/Dosage Form Content Relative Dose Comments/Equivalency Synthetic T4 Levothyroxine Synthroid, Levothroid, Levoxyl, Thyro-Tabs, Unithroid, and other generics 25, 50, 75, 88, 100, 112, 125, 137, 150, 175, 200, 300 mcg tablets; 200 and 500 mcg per vial injection Thyroid USP Armour Thyroid, Nature-Throid, and Westhroid (T4:T3 ratio approximately 4.2:1); Armour, one grain = 60 mg; Nature- Throid and Westhroid, one grain = 65 mg. Doses include 1/4, 1/2, 1, 2, 3, 4, and 5 grain tablets Liothyronine Cytomel 5, 25, and 50 mcg tablets Liotrix Thyrolar 1/4-, 1/2-, 1-, 2-, and 3- strength tablets Desiccate d pork thyroid gland Synthetic T3 Synthetic T4:T3 in 4:1 ratio 100 mcg Stable; predictable potency; generics may be bioequivalent; when switching from natural thyroid to L-thyroxine, lower dose by one half grain; variable absorption between products; half-life = 7 days, so daily dosing; considered to be drug of choice 1 grain (equivalent to 74 mcg [ ] mcg of T4) 33 mcg ( equivalent to 100 mcg T4) Thyrolar 1 = 50 mcg T4 and 12.5 mcg T3 High T3:T4 ratio; inexpensive Uniform absorption, rapid onset; halflife = 1.5 days, rapid peak and troughs Stable; predictable; expensive; lacks therapeutic rationale because T4 is converted to T3 peripherally. 91

92 Dosage adjustments: L-thyroxine Sodium levothyroxine has narrow therapeutic range Excessive dose of thyroid hormone may lead to CHF, angina pectoris and MI Bioequivalent If dosage, type, or brand of thyroid preparation changed, TSH concentration should be measured after 8-12 weeks. Decreases in L-thyroxine requirements occur as patients age and following significant weight loss. Patients older than years, without evidence of coronary heart disease (CHD) may be started on doses of 50 μg daily. with known CHD, usual starting dose is reduced to μg/day. In pregnancy thyroid hormone requirements are increased, then revert back to baseline after delivery 92

93 ข อม ลยา L-thyroxine L-thyroxine is better absorbed before a meal, instructing patients to consistently take it with water between 30 and 60 minutes prior to eating breakfast or at bedtime 4 hours after last meal; L-thyroxine should be protected from light and moisture. Drug interactions: - Decrease absorption: cholestyramine, ferrous sulfate, calcium, antacid, sucralfate, lovastatin - Protein binding: anticonvulsants - Increase metabolism: rifampin, phenytoin, carbamazepine, phenobarbital

94 Effects of hypothyroidism on some drugs Metabolism of drugs can be altered for patients with hypothyroidism. Digitalis (increased sensitivity to the digitalis effect) Insulin (Insulin degradation may be delayed) Warfarin (delays the catabolism of clotting factors) Barbiturate, Phenothiazines, Opioid analgesics (increased sensitivity may increase carbon dioxide retention and precipitate myxedema coma)

95 Drug induced thyroid disorders Drug Mechanism Results Nitroprusside inhibit hormone effect hypothyroidism Lithium inhibit hormone release hypothyroidism Iodides Wolff-Chaikoff effect hypothyroidism or or iodine-containg hyperthyroidism Sertraline increase T4 elimination hypothyroidism Sulfonylureas, inhibit organic bindiing hypothyroidism sulfonamides Immunotherapy Autoimmune process hypothyroidism or hyperthyroidism

96 Effect of Thyroid Status on Drug Action Drug Hyperthyroidism Hypothyroidism Sympathomimetics increase response Blunted response Digoxin increase Vd, clearance increase sensitivity Insulin increase metabolism, Prolong effect increase clearance Coumadin decrease need of drugs increase need of drugs Beta-blocker increase clearance not significant Theophylline not significant decrease clearance Cortisol decrease half life increase half life

97 SUBCLINICAL HYPOTHYROIDISM Normal free T4 but elevated TSH Therapy is recommended if thyroid autoantibodies are positive: levothyroxine If not treated, the patient should be evaluated at yearly intervals

98 MYXEDEMA COMA An uncommon but life-threatening form of untreated hypothyroidism with physiological decompensation. S&S: hypothermia, advanced stages of hypothyroid symptoms, and altered sensorium (delirium to coma) Precipitating factors: Infections Transquilizer, nacrotic analgesic Some medications: amiodarone, lithium carbonates, sedatives, narcotics, anesthesia Cold weather Other conditions eg. Paralysis, CHF

99 Treatment IV thyroid hormone replacement T4: 100- to 500-mcg loading dose, followed by mcg/day, until patient can tolerate oral therapy. Lower the initial dose in frailer patients or in patients with established cardiovascular disease. Some advocate the use of T3 over T4, given that T3 is more biologically active and that T4/T3 conversion may be suppressed in myxedema coma. Cost and availability limit intravenous T3 use. Antibiotic therapy: Given common infectious causes, some advocate empiric therapy with broad-spectrum antibiotics. Corticosteroid therapy Hydrocortisone 100 mg q 8 hours (or equivalent steroid) Can be discontinued if random cortisol concentration not depressed 99

100 Euthyroid goiter Goiter without other symptoms and having normal laboratory value of thyroid hormone, TSH Causes: - Starvation: iodine - Goitrogenic food, drugs - Congenital abnormality of thyroid gland Treatment: Iodine supplement, thyroid hormone Goitrogen" is a term used to describe any substance that can cause enlargement of the thyroid gland

101

102 Parathyroid Disorders Role of parathyroid glands: control calcium within the blood Four parathyroid glands make more or less parathyroid hormone (PTH) in response to the level of calcium in the blood. Increased PTH causes body to put more calcium into the blood causes the bones to release their calcium into the blood.

103 Calcium is the most important element for the nervous system, muscular system, and skeletal system.

104 Parathyroid When the calcium in our blood goes too low, the parathyroid glands make more PTH.

105 Homeostatic mechanisms to maintain serum calcium concentrations.

106 Pathology: parathyroid gland Hypoparathyroidism Pseudohypoparathyroidism 1 o hyperparathyroidism 2 o hyperparathyroidism 3 o hyperparathyroidism

107 Hypoparathyroidism Rare disease Most common cause is thyroid gland surgical complication other causes are RAI, idiopathic Signs and Symptoms: Hypocalcemia - Seizures - Mental changes: emotional instability - Parkinson-like movement disorder - Cardiac conduction abnormalities - Neuromuscular irritability - Dry hair, brittle nails, dry & scaly skin - Calcification: cataract

108 Diagnosis: Hypoparathyroidism: Hypocalcemia Hyperphosphatemia Chronic tetany Normal alkaline phosphatase No CKD, diarrhea Increase phosphorous in urine after PTH is given Pseudohypoparathyroidism: Hypocalcemia Hyperphosphatemia High level of serum PTH Hypoparathyroidism which is not response to exogenous PTH

109 Hypocalcemia

110 Treatment Calcium and vitamin D supplement Type calcium (mg) Amount (mg) Elemental Calcium lactate Calcium gluconate Calcium carbonate Initial therapy 1 to 3 g/day of elemental calcium. Average maintenance doses range from 2 to 8 g of elemental calcium per day in divided doses. Asymptomatic and chronic hypocalcemia associated with hypoparathyroidism and vitamin D deficient states can be managed by oral calcium and vitamin D supplementation

111 Hyperparathyroidism Incidence: In US 100,000 person/year Female: male =2:1 Most common age group: yrs The most common cause is the development of a benign tumor (Familia endocrine neoplasia type I) 95% of patients have one enlarged, overactive gland (single adenoma) 1 o hyperparathyroidism adenoma, hyperplasia, carcinoma high serum calcium 2 o hyperparathyroidism high PTH from negative feedback mech. in CKD 3 o hyperparathyroidism autonomous parathyroid hyperfunction in secondary hyperparathyroidism

112 Sign & Symptoms MOANS, GROANS, STONES, AND BONES "Psychiatric moans : effects on CNS including lethargy, fatigue, depression, memory loss, psychosis, ataxia, delirium, and coma. "Abdominal groans : constipation, indigestion, nausea and vomiting, GERD (high calcium increase acid production), Pancreatitis "Stones" : kidney stones, hypercalciuria, nephrocalcinosis, diabetes insipidus (polyuria and polydipsia). These can ultimately lead to renal failure Kidney stone, kidney failure "Bones : Osteoporosis High BP (75% of patients) Cardiac symptoms: palpitation, arrhythmia, heart value problem Headache: recurrent headache Stroke

113 Laboratory tests Hypercalcemia (>10.5 mg/d) Hypophosphatemia Hyperchloremia (>102 meq/l) High level of parathyroid hormone Low level of bicarbonate High level of cyclic AMP in urine X-ray, ultrasound, CT scan Treatment: Parathyroidectomy: symptomatic 1 ๐ hyperparathyroidism Volume expansion Furosemide Pamidronate Ibandronate Zoledronate Calcitonin Glucocorticoids Dialysis

114 Hypercalcemic crisis & acute symptomatic severe hypercalcemia should be considered medical emergencies and treated immediately

115 Hypercalcemia: Emergency case Hydration: NSS 3-4 L Increase excretion: Furosemide IV Decrease bone resorption: osteoclast inhibitor: - Calcitonin 4-8 unit/kg SC q 6-12 hr - Etidronate 7.5 mg/kg IV - Plicamycin (cause: cancer): mg/kg Hydrocortisone mg/day Dialysis

116 Drug interactions PTU - warfarin, digoxin, theophylline MMI - warfarin, digoxin, theophylline Levothyroxine Warfarin, Digoxin PTU Warfarin (Moderate): may increase the hypoprothrombinemic response to oral anticoagulants PTU- Digoxin (Moderate): clearance of digitalis glycosides may be reduced when a euthyroid state is achieved after the addition of antithyroid agents. PTU- Theophylline (Moderate): Clearance of theophylline and related agents depends upon thyroid function. In the hyperthyroid state, clearance may be enhanced. In the hypothyroid state, clearance may be reduced. Levothyroxine Warfarin (Moderate): Since thyroid hormones may increase the catabolism of vitamin K-dependent clotting factors, the hypoprothrombinemic response to oral anticoagulants may be enhanced during the initiation of thyroid hormone therapy. Levothyroxine- Digoxin (Moderate): clearance of or sensitivity to digitalis glycosides may be increased in previously hypothyroid patients when a euthyroid state is achieved after the addition of thyroid hormones.

117 Amiodarone and thyroid dysfunction Both hypo- and hyperthyroidism are complications of amiodarone therapy Meta-analysis of 4 RCTs (n=1465 euthyroid patients): prevalence of clinical thyroid disease was higher in patients receiving amiodarone therapy (150 to 330mg/day for a minimum of one year) when compared with placebo (3.7% VS 0.4%, respectively). In other reviews and reports, Risk of amiodarone-induced thyroid dysfunction ranges from 2 to 30% depending upon an individual's underlying thyroid status, dietary iodine intake, and whether cases of subclinical thyroid disorders (eg, slight rise in thyroid-stimulating hormone [TSH] without symptoms) are included.

118 Amiodarone and thyroid dysfunction Amiodarone contains two iodine atoms. Amiodarone metabolism in the liver releases ~ 3 mg of inorganic iodine into the systemic circulation per 100 mg of amiodarone ingested. Average iodine content in a typical American diet is about 0.3 mg/day. Thus, 6 mg of iodine associated with a 200 mg dose of amiodarone markedly increases the daily iodine load. Effects of amiodarone on thyroid function can be divided into Effects that are intrinsic properties of the drug Effects that are due to iodine

119 Effects that are intrinsic properties of the drug Amiodarone inhibits outer ring 5'-monodeiodination of thyroxine (T4), thus decreasing triiodothyronine (T3) production; reverse T3 accumulates since it is not metabolized to T2. Amiodarone, and particularly the metabolite desethylamiodarone, blocks T3-receptor binding to nuclear receptors and decreases expression of some thyroid hormone-related genes. Amiodarone may have a direct toxic effect on thyroid follicular cells, which results in a destructive thyroiditis Effects due to iodine Iodine is a substrate for thyroid hormone synthesis. Iodine is actively transported into thyroid follicular cells and organified onto tyrosyl residues in thyroglobulin.

120 Management Amiodarone-induced hypothyroidism: is essentially the same as for any patient with hypothyroidism, although higher doses of thyroxine may be required to normalize the serum TSH level. Amiodarone-induced hyperthyroidism (AIT): Type I AIT : hyperthyroidism with increased synthesis of thyroid hormone induced by amiodarone Thionamides Type II AIT: destructive thyroiditis with loss of TG (thyroglobulin) and thyroid hormones Glucocorticoids