Lect. 3 of 6_Thyroid Disorders and Anti-thyroid Drugs

Photo: Colorized transmission electron micrograph of an endocrine cell from the anterior pituitary gland. The secretory vesicles (brown) contain hormones.

From: Seeley’s Anatomy & Physiology 10th ed New York, NY: McGraw-Hill 2010.

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Learning Objectives 2. Thyroid and Anti-thyroid Drugs 1. The concept that thyroid hormone plays a major role in regulating development as well as metabolism and calorigenesis.

2. The steps in synthesis of tetraiodothyronine (T4) and triiodothyronine (T3) 3. The endocrine regulation of T3 and T4 production and feed-back loops 4. The physiological roles of T3 and T4 and, therefore, the changes associated with hypothyroidism and hyperthyroidism.

5. The mechanism of action, adverse effects and contraindications of drugs used to treat hyperthyroidism.

Marc Imhotep Cray, MD

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Thyroid Disorders

Marc Imhotep Cray, MD

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Thyroid Disorders

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Baron SJ and Lee CI. Lange Pathology Flash Cards. New York: McGraw-Hill, 2009

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Case 42 Thyroid Hormones A 44-year-old woman presents to the office because of fatigue. She has felt sluggish for months and thinks she may be anemic. She has started taking iron pills but isn’t feeling any better. She has been sleeping well and doesn’t feel depressed.

She has noticed some thinning of her hair and feels as if her skin is dry. She takes a multivitamin and iron supplement, otherwise no medications. She has smoked a pack of cigarettes a day for approximately 20 years, occasionally drinks alcohol, and doesn’t exercise.

Her mother takes some kind of thyroid pill and has diabetes.

On examination, her blood pressure and pulse are normal. Her hair is thinned but there are no focal patches of alopecia or scarring of the scalp. Her skin is diffusely dry. Her thyroid gland feels diffusely enlarged, is nontender, and has no nodules. The remainder of her examination is unremarkable. Lab tests show a normal complete blood count (CBC), glucose, and electrolytes. Her thyroid-stimulating hormone (TSH) level is elevated, and T 4 level is reduced. You diagnose her with hypothyroidism and start her on oral levothyroxine sodium. _ What is levothyroxine sodium? _ How is triiodothyronine (T 3) produced in the body? _ What is the mechanism of action of thyroid hormones?

Marc Imhotep Cray, MD

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Thyroid Hormones Thyroid gland is responsible for regulating normal growth and development by maintaining a level of metabolism in body tissues that is optimal for normal function Thyroid synthesizes, stores, and releases 2 major, metabolically active hormones: triiodothyronine (T3) and thyroxine (T4)  T3, the active form of thyroid hormone, is 4 times more potent than T4, but its serum concentration is lower

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Thyroid Hormones (2) Approximately 80% of gland’s total daily production of T3 results from conversion of T4 to T3 through deiodination of T4  T3 and T4 exist in either free (active) or protein-bound (inactive) forms  More than 99% of circulating T4 is bound to plasma proteins, so only a small fraction exists in free form o As a result, T4 is metabolized very slowly and has a long half-life (7 days) o T3 is less bound to plasma proteins and thus undergoes faster metabolism and has a shorter half-life (1.5 days)

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Thyroid Hormones (3)  Both T4 and T3 are absorbed after oral administration  Food, calcium preparations, and aluminum-containing antacids can decrease absorption of T4 but not of T3  T4 is converted to T3 by one of two distinct deiodinases, depending on the tissue

 Hormones are metabolized through microsomal P450 system  Drugs that induce P450 enzymes, such as phenytoin, rifampin, and phenobarbital, accelerate metabolism of thyroid hormones o enzyme induction can increase metabolism of thyroid hormones, making levels subtherapeutic while treating hypothyroidism Marc Imhotep Cray, MD

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Thyroid Hormones: Synthesis, Release, and Regulation  Thyroid hormones are synthesized and stored as amino acid residues of thyroglobulin  Major steps in synthesis and release of T3/T4 include: thyroid uptake of iodide oxidation of iodide and iodination of tyrosyl groups of thyroglobulin coupling iodotyrosine residues to produce iodothyronines proteolysis of thyroglobulin release of T4 and T3 into blood conversion of T4 to T3 in peripheral tissues and thyroid

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Thyroid Hormones: Synthesis, Release, and Regulation (2) Hormone synthesis and release are controlled by a negative feedback mechanism (thyroid; hypothalamic-pituitary axis; autoregulation of iodide uptake)  Low circulating hormone levels trigger hypothalamic release of thyrotropin-releasing factor (TRF) which induces pituitary secretion of thyrotropin (thyroid-stimulating hormone, TSH)  Increasing TSH levels stimulate thyroid iodide uptake and hormone synthesis  Circulating hormones halt TRF and TSH secretion  Thyroid also regulates its own iodine uptake to protect against excess hormone production if extra iodide is ingested Marc Imhotep Cray, MD

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Marc Imhotep Cray, MD

Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edn, 2014

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Marc Imhotep Cray, MD

Page et al. Integrated Pharmacology 3rd Ed. Elsevier, 2006

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The hypothalamic-pituitary-thyroid axis a. Thyroid hormone regulation illustrates major features of endocrine systems regulated by hypothalamus and pituitary ď ą Hypothalamic thyrotropin-releasing hormone (TRH), released into portal circulation, stimulates pituitary thyroidstimulating hormone (TSH) release ď ą Circulating TSH stimulates thyroid to release thyroxine (tetraiodothyronine or T4) and triiodothyronine (T3) from stores in thyroid follicles Marc Imhotep Cray, MD

Page et al. Integrated Pharmacology 3rd Ed. Elsevier, 2006

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The hypothalamic-pituitary-thyroid axis cont.  Ligand-bound thyroid receptor may dimerize with itself or with retinoic acid receptor (RxR) before translocation to nucleus  Bound thyroid hormone receptors (TR) interact with specific thyroid response elements (TREs) of thyroid hormoneresponsive genes

 Hypothalamus and pituitary also contain thyroid hormone receptors, which mediate feedback inhibition by circulating thyroid hormone Page et al. Integrated Pharmacology 3rd Ed. Elsevier, 2006 Marc Imhotep Cray, MD

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Thyroid regulation, physiology, and pathophysiology

Brown TA. Rapid Review Physiology 2nd Ed. Philadelphia: Mosby, 2012

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Mechanism of action of thyroid hormones ď ą Bind with receptors in nuclei of target cells and alter synthesis rates of specific messenger ribonucleoprotein acids (mRNAs), increasing production of certain proteins including Na + , K+ ATPase

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Myxedema  Can be described as hypothyroidism of adult  Causes  Hashimoto thyroiditis  Idiopathic causes  Iodine deficiency o A problem in geographic areas with poor nutrition o Deficiency in pregnant women can lead to cretinism in the child

 Paradoxically, high doses of iodine lead to a decrease in thyroid hormone Production  Overirradiation of thyroid using iodine-131 for treatment of hyperthyroidism

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Goitrous Hypothyroidism Epidemiology (Endemic goiter)  Worldwide, goiter is most common endocrine disorder with rates of 4% to 15% in areas of adequate iodine intake and more than 90% where there is iodine deficiency  Endemic goiter is defined as goiter that affects more than 5% of population  Most goiters are not associated with thyroid dysfunction  Prevalence of goitrous hypothyroidism varies from 0.7% to 4% of population Subclinical hypothyroidism is present in 3% to 10% of population groups and in 10% to 18% of elderly persons  Female-to-male ratio of goiter is 3:1, and 6:1 for goitrous hypothyroidism  Annual incidence of autoimmune hypothyroidism is 4 in 1000 women and 1 in 1000 men, with a mean age at diagnosis of 60 years From: Usatine RP etal. (Eds.) The Color Atlas of Family Medicine. McGraw-Hill, 2013 Marc Imhotep Cray, MD

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Massive goiter in an Ethiopian woman who lives in an endemic area for goiters. Many adults have large goiters in Ethiopia where there is little iodine in their diets.

Usatine RP etal. (Eds.) The Color Atlas of Family Medicine. McGraw-Hill, 2013 Marc Imhotep Cray, MD

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Hypothyroidism Hypothyroidism, a syndrome that results from a deficiency of thyroid hormones caused by either primary (thyroid gland) or secondary (hypothalamic pituitary) dysfunction Most common cause of primary hypothyroidism is Hashimoto thyroiditis  an autoimmune disorder in which unsuppressed T lymphocytes produce excessive amounts of antibodies that destroy thyroid cells

Certain drugs, such as lithium, nitroprusside, iodides, and sulfonylureas, can also induce hypothyroidism Hypothyroidism is more prevalent in females and persons older than 60 years Marc Imhotep Cray, MD

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Hypothyroidism (2)  Typically presents with symptoms of “slowing down” including:  weight gain  fatigue  sluggishness  cold intolerance  constipation  muscle aches  Goiter may be present  Patients with end-stage hypothyroidism or myxedema coma may experience hypothermia, confusion, stupor or coma, carbon dioxide retention, hyponatremia, and ileus  Laboratory findings include increased TSH and low free T4 levels Marc Imhotep Cray, MD

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Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edn, 2014

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Hypothyroidism: Treatment of Choice Principal treatment goal for hypothyroidism is to achieve a euthyroid state with thyroid replacement therapy Preparation of choice is levothyroxine, a synthetic T4 formulation with advantages including:  stability  uniform potency  relatively low cost  once-daily dosing and  lack of foreign proteins

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Hypothyroidism: Treatment of Choice cont.  Levothyroxine may have innate metabolic activity, but most of its activity is due to its conversion to T3  Patients should notice improvement in typical symptoms of hypothyroidism after 3 to 4 weeks of treatment  Toxicity is directly related to T4 levels and manifests as nervousness, tachycardia, heat intolerance, and weight loss

 Levothyroxine is available in various brands and generics, which may not be bioequivalent, so only 1 product should be used throughout treatment Marc Imhotep Cray, MD

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Liothyronine and T3/T4 Combination  Liothyronine is a pure T3 preparation that is not recommended for routine thyroid replacement  After oral ingestion, T3 is absorbed more rapidly than T4, which may produce supraphysiologic plasma T3 levels can lead to thyrotoxicosis  Also, free T4 levels remain low during T3 administration and, if misinterpreted, could lead to incorrect use of more hormone T3 levels must be monitored  Other disadvantages are need for multiple doses, higher expense, and greater potential for cardiotoxicity  T3 is therefore not better than T4, which is converted to T3 anyway o However, T3 is recommended for acute severe myxedema Marc Imhotep Cray, MD

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Liothyronine and T3/T4 Combination (2)  Liotrix (a stable synthetic) and desiccated thyroid contain T4

plus T3  Liotrix uses a physiologic ratio of 4 : 1 but has same problems as T3 and is more expensive 

Desiccated thyroid, derived mostly from pork, is not recommended product potency and composition vary and can result in toxic effects, including allergic reactions to animal protein

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Hyperthyroidism Hyperthyroidism, or thyrotoxicosis, is due to excessive thyroid hormone production and is characterized by increased metabolism in all body tissues Most common cause of hyperthyroidism is Graves disease an autoimmune disorder in which an abnormal thyroid immunoglobulin binds to TSH receptor and causes uncontrolled thyroid hormone production Drugs such as amiodarone, iodides, and lithium can also cause hyperthyroidism  Like hypothyroidism, hyperthyroidism more often in FM than in M Marc Imhotep Cray, MD

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Hyperthyroidism cont.  Symptoms of hyperthyroidism include goiter, exophthalmos, nervousness, heat intolerance, palpitations, weight loss, insomnia, and new or worsening cardiac findings (atrial fibrillation, angina) Untreated hyperthyroidism can progress to thyroid storm, a possibly fatal state with acute onset of high fever, exaggerated thyrotoxicosis symptoms, cardiovascular collapse, and shock  Laboratory findings include high serum levels of free T4, undetectable TSH levels, or both Marc Imhotep Cray, MD

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Hyperthyroidism cont.  Of the pharmacologic options, Thionamides [propylthiouracil (PTU) and methimazole] are preferred agents for children, pregnant women, and young adults with uncomplicated Graves disease  These agents can be used as long-term therapy or as short-term therapy to reduce thyroid hormone levels before RAI or surgery  

Treatment of choice is radioactive iodine Surgery (subtotal or total thyroidectomy) is considered treatment of choice in cases of suspected malignancy, esophageal obstruction, respiratory difficulties, presence of large goiter

Marc Imhotep Cray, MD

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Graves disease Exophthalmos

Inc. osmotic muscle swelling, muscle inflammation, and adipocyte countďƒ exophthalmos Le T and Bhushan V. First Aid for the USMLE Step 1 2015 (McGraw-Hill 2015) Marc Imhotep Cray, MD

Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edn, 2014

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Question A 42-year-old woman with a history of pernicious anemia comes to the physician complaining of increased anxiety, heart palpitations, heat intolerance, unexplained weight loss, and multiple daily bowel movements. She has not had a period in 4 months. On physical examination, the patient is found to have a goiter, a thyroid bruit, and mild exophthalmos. Laboratory studies show elevated triiodothyronine and free thyroxine levels, and an undetectable thyroid-stimulating hormone.

Which of the following is the most likely etiology of this patient’s disease?

(A) Autoimmune stimulation of thyroid-stimulating hormone receptors (B) Idiopathic replacement of thyroid tissue with fibrous tissue (C) Thyroid adenoma (D) Thyroid hormone-producing ovarian teratoma (E) Viral infection leading to destruction of thyroid tissue Marc Imhotep Cray, MD

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The correct answer is A This patient presents as a classic case of Graves’ disease.

In Graves’ disease, thyroid-stimulating IgG antibodies bind to TSH receptors and lead to thyroid hormone production. This causes glandular hyperplasia and enlargement characteristic of the goiter associated with Graves’ disease.

Graves’ disease is the most common cause of thyrotoxicosis.

Patients with this condition may have other autoimmune diseases, such as pernicious anemia or type 1 diabetes mellitus Symptom, they frequently present with anxiety, irritability, tremor, heat intolerance with sweaty skin, tachycardia and cardiac palpitations, weight loss, increased appetite, fine hair, diarrhea, and amenorrhea or oligomenorrhea.

Signs include diffuse goiter, proptosis, periorbital edema, and thickened skin on the lower extremities. Laboratory values reveal increased thyroid hormone levels and decreased TSH levels.

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Hyperthyroidism: Treatment  Primary treatment options for patients with hyperthyroidism include Thionamides (propylthiouracil and methimazole), radioactive iodine (RAI), and surgery  Adjuncts to primary therapies include adrenergic antagonists and iodides  Surgery (subtotal or total thyroidectomy) is considered treatment of choice in cases of suspected malignancy, esophageal obstruction, respiratory difficulties, presence of large goiter, or contraindications to other treatments Marc Imhotep Cray, MD

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Thioamides (Thionamides) MOA thioamides inhibit formation of thyroid hormones by  

interfering with incorporation of iodine into tyrosyl residues of thyroglobulin and inhibiting coupling of iodotyrosyl residues to form iodothyronines

 Thioamides also block oxidative binding of iodide because they are iodinated and degraded within the thyroid gland which diverts oxidized iodide away from thyroglobulin  PTU, but not methimazole, inhibits peripheral deiodination of T4 to T3, which causes a more rapid decline in T3 levels in patients with thyroid storm Marc Imhotep Cray, MD

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Thioamides cont.  Methimazole is 10 times more potent than PTU, but both drugs are equally effective if given in equipotent dosages  Methimazole can be given once daily, whereas PTU must be given every 6 to 8 hours  PTU is preferred for pregnant women  A clinical response is usually seen after 6 to 8 weeks of therapy with thioamides  The duration of therapy is usually 12 to 18 months Marc Imhotep Cray, MD

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Thionamides MOA

Marc Imhotep Cray, MD

Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edn, 2014

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Thioamides: Adverse Effects  A pruritic maculopapular rash, without other systemic symptoms, is most common adverse effect of thioamides  In mild cases, rash resolves despite therapy, or another thioamide can be used (minimal cross-sensitivity exists)  If systemic symptoms (eg, fever, arthralgias) occur, thioamide therapy should be stopped  Hepatotoxicity involves hepatocellular damage (with PTU) and obstructive jaundice (with methimazole)  Liver function test (LFT) results should be watched if a history of liver disease or risk for hepatitis exists.

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Thioamides: Adverse Effects cont.  Agranulocytosis (leukopenia with much lower polymorphonuclear leukocyte numbers) is most serious adverse effect  Onset of symptoms (fever, malaise, sore throat) is quite sudden high methimazole doses may lead to greater risk o If this disorder is diagnosed, thioamide administration should be stopped, and patient should be monitored for infection

 Other serious effects include:  peripheral neuritis  neuropathy  taste disorders  nephrotoxicity  myopathy  arthritis  SLE

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N.B. Drugs that induce cytochrome P450 enzymes, such as phenytoin, rifampin, and phenobarbital, accelerate metabolism of thyroid hormone and may decrease effectiveness

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Radioactive lodine Radioactive iodine is used for postadolescent patients, patients with Graves ophthalmopathy or history of thyroid surgery, poor surgical candidates, and those who do not respond to thioamides  It is the treatment of choice in older patients with heart disease and those with toxic multinodular goiter. The maximal effects of RAI do not occur for 3 to 4 months  131I, used most often, is rapidly trapped by thyroid β particles act mostly on parenchymal thyroid cells, with minimal damage to adjacent tissues Effects of radiation depend on dosage, with larger doses causing cytotoxicity.

Proper RAI doses can destroy the gland without injuring nearby tissues Marc Imhotep Cray, MD

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Radioactive lodine: Adverse Effects  Major adverse effect of RAI is hypothyroidism  Post-RAI hyperthyroidism caused by hormones leaking from damaged thyroid--can occur but is minimized by use of thioamides or β blockers before RAI (depletes gland of hormones)  Immediate adverse effects include mild thyroid pain and hair thinning  Long-term effects include carcinogenesis and genetic damage

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Iodide  Iodide (ie, Lugol solution: 5% iodine and 10% potassium iodide) is oldest known remedy for symptomatic relief of hyperthyroidism, and, before advent of pharmacologic therapy, it was the sole treatment available  Today, iodide therapy has been mostly replaced by thioamides and β blockers  Iodides act by  blocking organification of iodine  inhibiting release of thyroid hormones, and  decreasing gland size and vascularity  Iodides act rapidly and produce symptomatic relief after 2 to 7 days  They are thus useful in patients with thyroid storm and  those awaiting relief from thioamide therapy (6 to 8 weeks) Marc Imhotep Cray, MD

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Iodide cont. Iodides are also routinely given, preferably with thioamides, 10 to 14 days before surgery to facilitate removal of the gland by reducing its size and vascularity  Iodide cannot be given before RAI because it can block retention of RAI by the gland Major adverse effects of iodide include  hypersensitivity reactions and  risk of hypothyroidism or worsening of hyperthyroidism

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Adrenergic Antagonists  Many signs and symptoms of hyperthyroidism are mediated through sympathetic nervous system logical to use adrenergic antagonists for symptomatic relief because these agents block effects of thyroid hormones on catecholamines  Adrenergic antagonists do not affect underlying disease process, so they are not used as primary therapy  but they are quite useful in providing rapid symptomatic relief before thioamides, RAI, or surgery can take effect  They can also be used as adjuncts to thioamides and RAI for  neonatal thyrotoxicosis  thyrotoxicosis in pregnancy, and  thyroid storm Marc Imhotep Cray, MD

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Adrenergic Antagonists cont.  The β blocker propranolol, which reduces conversion of T4 to T3, is most widely used adrenergic antagonist  it relieves o Palpitations o tachycardia o anxiety o sweating o tremor o neuromuscular manifestations of hyperthyroidism  The calcium channel blocker diltiazem may be useful when propranolol should be avoided (eg, patients with asthma, CHF, diabetes) Marc Imhotep Cray, MD

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Case 42 Answers Thyroid Hormones Summary: A 44-year-old woman is diagnosed with hypothyroidism and prescribed levothyroxine.

• Levothyroxine sodium: Synthetic sodium salt of thyroxine (T4).

• Derivation of T3 in the body: Approximately 75 percent from the deiodination of T4; also produced by the coupling of monoiodotyrosine (MIT) and diiodotyrosine (DIT).

• Mechanism of action of thyroid hormones: Bind with receptors in nuclei of target cells and alter synthesis rates of specific messenger ribonucleoprotein acids (mRNAs), increasing production of certain proteins including Na + , K+ -ATPase.

Marc Imhotep Cray, MD

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Case 42 Answers ,Thyroid Hormones cont.

CLINICAL CORRELATION

Thyroid hormones have wide-ranging effects of tissues throughout the body.

They are involved primarily in the regulation of metabolism. The hypothalamicpituitary-thyroid axis regulates release of active hormone from the thyroid via a feedback loop. Thyrotropin-releasing hormone (TRH) is produced in the hypothalamus and stimulates the release of TSH from the anterior pituitary. TSH binds to membrane receptors in the thyroid and stimulates the production and release of T 4 and T 3 via a cyclic adenosine monophosphate (cAMP)-mediated system. Synthesis of T 4 exceeds T3 by approximately fourfold; most circulating T 3 comes from peripheral deiodination of T 4. T 4 and T 3 are almost entirely protein bound, mostly to thyroxine binding globulin (TBG) and albumin. Unbound thyroid hormone binds to receptors located in the nuclei of target cells. This alters transcription of specific mRNAs, which lead to the increased production of proteins, including Na +, K + -ATPase. This results in a net increase in ATP and Marc Imhotep Cray, MD oxygen consumption, raising the metabolic rate.

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Case 42 Answers Thyroid Hormones cont.

Hypothyroidism occurs when there is inadequate thyroid hormone production and release to meet the body’s metabolic demands. In primary hypothyroidism the thyroid gland is unable to synthesize adequate amounts of thyroid hormone. The pituitary releases increasing amounts of TSH to try to stimulate production, leading to the characteristic laboratory findings of low circulating levels of thyroid hormones with an elevated TSH. Conversely, primary hyperthyroidism is diagnosed by the presence of elevated thyroid hormone levels and a suppressed level of TSH. Hypothyroidism is most often treated by the oral administration of synthetic T 4 in the form of levothyroxine sodium. This replaces both T 4 and, by deiodination, T 3.

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THE END

See next slide for further study.

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Sources and further study: eLearning Endocrine cloud folder tools and resources MedPharm Guidebook: Unit 5 Drugs Used In Disorders of Endocrine System Endocrine and Reproductive System Pharmacology eNotes Clinical Pharmacology Cases 39 to 44 (Learning Triggers) Textbooks Brunton LL, Chabner BA , Knollmann BC (Eds.). Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 12th ed. New York: McGraw-Hill, 2011 Katzung, Masters, Trevor. Basic and Clinical Pharmacology, 12th ed. New York: McGraw-Hill, 2012 Mulroney SE. and Myers AK. Netter's Essential Physiology. Philadelphia: Saunders, 2009 Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition.

Philadelphia: Sanders, 2014 Toy E C. et.al. Case Files-Pharmacology Lange 3rd ed. New York: McGraw-Hill 2014.

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