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Pharmacology Ch 27 480-488 Thyroid Gland Follicular thyroid cells – constitute majority of thyroid tissue and secrete thyroxine (T4) and triiodothyronine (T3), and reverse triiodothyronine (rT3) -regulate growth, metabolism, and energy expenditures in body Parafollicular C cells of thyroid gland secrete calcitonin a regulator of bone mineral homeostasis Synthesis and Secretion of Thyroid Hormones – thyroid hormones are built on a backbone of two tyrosine molecules: Thyroxine has 4 iodines and is the major form of thyroid hormone secreted. Triiodothyronine has 3 iodines on tyrosine backbone, and is a converted to T4 in the periphery after secretion -Reverse Triiodothyronine (rT3) – biologically inactive form of T3 because single iodine is on opposite tyrosine in backbone relative to T3 -Body secretes 90% T4, 9% T3, and 1% rT3, most of proteins bound to albumin 1. Thyroid follicular cells concentrate iodiode via a Na/I symporter on basolateral membrane, an active transport mechanism that concentrates iodide up to 500x plasma 2. Once inside follicular cells, iodide is transported to apical membrane of cell and oxidized by thyroid peroxidase to an intermediate that couples it to tyrosine residues on thyroglobulin -thyroglobulin is a protein on thyroid follicular cells secreted at apical surface into colloid space -Thyroid peroxidase is also at apical surface, and generation of oxidized iodide allows for reaction with newly synthesized thyroglobulin -process of thyroglobulin iodination is known as organification, resulting in thyroglobulin molecules monoiodotyrosine (MIT) and diiodotyrosine (DIT) -once generated, MITs and DITs are coupled by thyroid peroxidase; MIT + DIT T3, and DIT + DIT T4 and stored on thyroglobulin in the colloid -majority of plasma T3 is produced by metabolism of T4 in plasma 3. TSH stimulates follicular cells to endocytose colloid; ingested thyroglobulin enters lysosomes where proteases digest thyroglobulin to release free T3, T4, MIT, and DIT -T3/4 transported across basolateral membrane into blood while MIT and DIT are deiodinated and iodide recycled for new thyroid hormone -thyroid gland is unusual in that it stores large quantities of thyroid hormone in the form of thyroglobulin Metabolism of Thyroid Hormones – thyroid hormone circulates mostly bound to thyroid binding globulin (TBG) and transthyretin -T4 is predominant thyroid hormone; T3 has 4x the physiologic effect compared to T4 -Most T4 is deiodinated to more active T3 in several location in body, catalyzed by iodothyronine 5’-deiodinase -there are 4 different subtypes of deiodinase: 1. Type I deiodinase – expressed in liver and kidneys; converts majority of serum T4T3 2. Type II deiodinase – pituitary gland, brain, and brown fat and converts T4T3 locally 3. Type III deiodinase – converts T4rT3 (biologically inactive T3) -presence of T4 in blood provides a buffer/reservoir for thyroid hormone effects. Most T4T3 happens in the liver, and so pharm agents that increase hepatic cytochrome P450 increase T4T3 conversion -T4 has longer plasma half-life than T3, and so changes in thyroid function not seen for weeks Effects of Thyroid Hormones on Target Tissues – every cell of the body is affected; majority of effects are on gene transcription, but some act at plasma membrane mediated by thyroid hormone receptors (TRs) -free hormone enters cell by both passive diffusion and active transport -TRs are proteins containing thyroid hormone-binding, DNA-binding, and dimerization domains -Two classes of thyroid hormone receptor: -TRα and TRβ – can interact as subunits for various isoforms; can dimerize to form homodimers or interact with another transcription factor retinoid X receptor (RXR) to form heterodimers -in absence of thyroid hormone, inhibitors of TRa and B or RXR heterodimers exist, which the hormones knock out -Thyroid hormone is able to down-regulate TSH gene expression causing negative feedback of thyroid hormone on hypothalamic-pituitary-thyroid axis -Thyroid hormone is important in infancy for growth and development of nervous system, and congenital deficiency leads to cretinism (form of mental retardation) -in adult, thyroid hormone regulates body metabolism and energy expenditure, such as regulating Na/K ATPase activity and many enzymes in metabolism, can increase body temperature -many effects resemble sympathetic neural stimulation, such as increased cardiac contractility, heart rate, excitability, nervousness, and diaphoresis -low levels of thyroid hormone result in myxedema – hypometabolic state characterized by lethargy, dry skin, coarse voice, and cold intolerance Hypothalamic-Pituitary-Thyroid Axis – thyroid hormone secretion follows negative regulatory feedback scheme -thyrotropin releasing hormone (TRH) released by hypothalamus travels to anterior pituitary gland and binds to G-protein coupled receptor located on plasma membrane of thyrotropes (TSH-producing cells) to stimulate synthesis and release of TSH, the most important regulator of thyroid gland function (stimulates every aspect of thyroid hormone production) -TSH promotes vascularization and growth of thyroid gland -Thyroid hormone enters thyrotropes, binds to nuclear receptor to negatively inhibit TSH gene transcription Pathophysiology – most thyroid conditions best categorized as hyperthyroid (increased thyroid hormone secretion) or hypothyroid (decreased thyroid hormone secretion) -two common thyroid diseases are Graves’ disease and Hashimoto’s thyroiditis, each believed to be autoimmune, but graves is hyperthyroid and hashimoto’s is hypothyroid -Graves Disease – IgG autoantibody specific for TSH receptor, known as thyroid-stimulating immunoglobulin is produced to act as an agonist and activate TSH receptor to stimulate follicular cells to synthesize TSH, however TsIg is NOT SUBJECT TO NEGATIVE FEEDBACK, it continues to stimulate thyroid even when plasma thyroid levels rise to pathologic range Hashimoto’s thyroiditis – selective destruction of thyroid gland through antibodies specific for many thyroid gland proteins including thyroglobulin, resulting in hypothyroidism Treatment of Hypothyroidism – thyroid hormone is a well-established therapy for long-term treatment of hypothyroidism, and exogenous hormone is identical to T4 produced chemically -Levothyroxine, the L-isomer of T4, is treatment choice for hypothyroidism, and efficacy is monitored by plasma TSH and thyroid hormone levels -resins such as sodium polystyrene sulfonate and cholestyramine may decrease absorption of T4 -drugs that increase activity of hepatic P450, including rifampin and phenytoin increase hepatic excretion of T4 Treatment of Hyperthyroidism – Inhibitors of Iodide Uptake – iodide is brought into follicular cell via Na/I symporter. Perchlorate, thiocyanate, and pertechnetate compete for iodide uptake into thyroid gland follicular cell, resulting in decreased amount of iodide available for thyroid hormone synthesis -use is uncommon because of potential causing for aplastic anemia Inhibitors of Organification and Hormone Release 1. Iodides – two distinct iodides are used in practice, the first: 131I-, is a radioactive iodide isotope that emits B-particles toxic to cells, and since the Na/I symporter cannot distinguish between the two iodides, the radioactive form goes into cell to destroy thyroid gland locally and treat hyperthyroidism a. Goal is to administer enough to result in euthyroid state without causing too much damage and causing hypothyroidism 2. Inorganic Iodide – high levels of iodide inhibit thyroid hormone synthesis and release, a phenomenon known as Wolff-Chaikoff effect, likely mediated by down-regulation of the Na/I symporter in thyroid gland (negative feedback event) Thioamines – the thioamines propylthiouracil and methimazole important and useful inhibitors of thyroid hormone production by competing with thyroglobulin for oxidized iodide in a process catalyzed by enzyme thyroid peroxidase -by competing for oxidized iodide, thioamine treatment causes selective decrease in organification and coupling of thyroid hormone precursors, and thereby inhibits thyroid hormone production -thioamine treatment often results in goiter formation, the drugs that cause this are called goitrogens -inhibition of thyroid hormone production by thioamines causes upregulation of TSH release by anterior pituitary, causing hypertrophy of thyroid gland and formation of goiter -Propylthiouracil inhibits thyroid peroxidase as well as peripheral T4T3 conversion, whereas methimazole only inhibits thyroid peroxidase Inhibitors of Peripheral Thyroid Hormone Metabolism – although majority of thyroid hormone synthesized in thyroid gland as T4, thyroid hormone principally acts peripherally as T3, which is dependent on peripheral 5’-deiodinase, and inhibitors of this enzyme are effective adjuncts in treating symptoms of hyperthyroidism B-adrenergic Blockers – B-blockers are useful therapies for symptoms of hyperthyroidism because many effects of high plasma thyroid hormone levels resemble nonspecific B-adrenergic stimulation. B-blockers can reduce peripheral conversion of T4T3 -Esmolol is preferred B-adrenergic antagonist for treatment of thyroid storm Ipodate – radiocontrast agent formerly used for visualization of biliary ducts, but it also inhibits peripheral T4T3 conversion by inhibiting 5’-deiodinase Other Drugs affecting thyroid hormone homeostasis Lithium – lithium can cause hypothyroidism and is actively concentrated in the thyroid gland; it can inhibit thyroid hormone release from thyroid follicular cells Amiodarone – antiarrhythmic drug that has both positive and negative effects on thyroid hormone function -structure resembles thyroid hormone and contains a large amount of iodine -metabolism of amiodarone releases iodine as iodide, increasing plasma concentration of iodide, which is concentrated in thyroid gland and cause hypothyroidism due to Wolff-Chaikoff effect -amiodarone can ALSO CAUSE HYPERTHYROIDISM by two mechanisms: 1. in TYPE 1 THYROTOXICOSIS – excess iodide leads to increased thyroid hormone synthesis and release 2. in TYPE 2 THYROTOXICOSIS – autoimmune thyroiditis is induced that leads to release of excess thyroid hormone from colloid -amiodarone also competitively inhibits type I 5’deiodinase to reduce peripheral T4T3 conversion Corticosteroids – cortisol and glucocorticoid analogues inhibit 5’deiodinase enzyme that converts T4T3 -because T4 is less active than T3, corticosteroids reduce net thyroid hormone activity -decreased T3 results in increased TSH release which stimulates greater T4 synthesis until T4 produced generates a sufficient level of T3 to inhibit hypothalamus and pituitary gland to reach new steady state