Download Pharm 27 Introduction Follicular thyroid cells constitute majority of

Pharm 27
Introduction
 Follicular thyroid cells constitute majority of thyroid tissue; produce and secrete classical thyroid hormones (T4,
T3, and rT3)
o Thyroid hormones regulate growth, metabolism, and energy expenditure, from oxygen consumption to
cardiac contractility
 Parafollicular C cells secrete calcitonin (regulator of bone mineral homeostasis)
 Replacement of deficient thyroid hormone is effective and established therapy for hypothyroidism
 Treatment of hyperthyroidism is more complex, with options including antithyroid drugs, radioactive iodide, and
surgical excision of abnormal tissue
Thyroid Gland Physiology
 Main function of thyroid gland is to produce T3 and T4
 Structurally, thyroid hormones are built on backbone of 2 tyrosine molecules that are iodinated and connected
by ether linkage; important structural feature of thyroid hormone is placement of iodines on backbone
o Position and relative orientation of iodines attached to tyrosine residues determine specific form of
thyroid hormone
 3,5,3’,5’-Tetraiodothyronine (thyroxine, T4) has 4 iodines attached to tyrosine backbones and is
major form of thyroid hormone secreted by thyroid gland
 3,5,3’-triiodothyronine (T3) has 3 iodines; most is produced by peripheral 5’ deiodination of T4
 3,3’,5’-triiodothyronine (reverse triiodothyronine) is biologically inactive form; single iodine is on
opposite tyrosine in backbone relative to T3
o In normal individual, circulating thyroid hormone consists of 90% T4, 9% T3, and 1% rT3; most of
hormone bound to plasma proteins
 Thyroid follicular cells selectively concentrate I- via Na+/I- symporters located on basolateral membrane of cell
o Active transport mechanism has ability to concentrate I- to intracellular concentrations 500x plasma
o Most individuals 30x plasma concentration I- in their thyroid glands
o Once inside follicular cells, I- transported across apical membrane of cell and concurrently oxidized by
thyroid peroxidase; oxidation reaction creates reactive iodide intermediate that couples to specific
tyrosine residues on thyroglobulin (protein synthesized by follicular cells and secreted at apical surface
into colloid space)
o Thyroid peroxidase also concentrated at apical surface; generation of oxidized iodide at surface allows
iodide to react with tyrosine residues in newly secreted thyroglobulin molecules
 Organification – process of thyroglobulin iodination; results in thyroglobulin molecules containing
monoiodotyrosine (MIT) and diiodotyrosine (DIT) residues
o After MITs and DITs generated within thyroglobulin, thyroid peroxidase catalyzes coupling between
residues (MIT + DIT = T3; DIT + DIT = T4); majority of T3 produced by metabolism of T4 in circulation
o Thyroglobulin molecules with hormones inside stored in lumen of follicle (colloid)
 When TSH stimulates thyroid gland to secrete thyroid hormone, follicular cells endocytose colloid
o Ingested thyroglobulin enters lysosomes, where proteases digest thyroglobulin
o Proteolytic digestion releases free T3, T4, MIT, and DIT
o T3 and T4 transported across follicular cell basolateral membrane into blood
o Free MIT and DIT rapidly deiodinated within cell, allowing I- to be recycled for new thyroid hormone
synthesis
 Most endocrine organs concurrently synthesize and release new hormone when activated, rather than storing
large quantities of precursor hormone; thyroid unusual in that it stores large quantities of thyroid prohormone
in form of thyroglobulin
o Makes it possible to maintain plasma thyroid hormone at constant level despite fluctuations in
availability of dietary I Thyroid hormone circulates mostly bound to plasma proteins (notably thyroid binding globulin (TBG) and
transthyretin); although T4 is predominant thyroid hormone found in blood, T3 has 4x physiologic activity of T4
on target tissues
o Some serum T4 inactivated by deamination, decarboxylation, or conjugation and excretion by liver
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Most T4 deiodinated to more active T3 form in several locations in body; catalyzed by iodothyronine 5’deiodinase
 Type I 5’-deiodinase expressed in liver and kidneys; important for converting T4 to majority of
serum T3
 Type II 5’-deiodinase expressed primarily in pituitary gland, brain, and brown fat; located
intracellularly and converts T4 to T3 locally
 Type III 5-deiodinase responsible largely for conversion of T4 to rT3
Presence of T4 in blood provides buffer (reservoir) for thyroid hormone effects
o Most T4 to T3 conversion occurs in liver, and many pharmacologic agents that increase hepatic
cytochrome P450 enzyme activity also increase T4 to T3 conversion
o T4 has half-life in plasma of about 6 days, whereas plasma T3 has half-life of 1 day
o Because T4 has long plasma half-life, changes in thyroid hormone-regulated functions caused by
pharmacologic intervention generally not observed for period of 1-2 weeks
Thyroid hormones have effects on virtually every cell of body; while majority of effects occur at level of gene
transcription, they also act at PM
o Both modes of action mediated by hormone binding to thyroid hormone receptors (TRs)
o Free hormone enters cell by both passive diffusion and active transport; active transport mediated by
hormone-specific and nonspecific carriers such as organic anion and monocarboxylate transporters
o TRs – proteins containing thyroid hormone-binding, DNA-binding, and dimerization domains
 2 classes of TR: TRα and TRβ; both can be expressed as multiple isoforms
 TR monomers can interact with dimerization reaction to form homodimers, or with another
transcription factor (retinoid X receptor (RXR)) to form heterodimers
 TR dimers bind to gene promoter regions and are activated by binding of thyroid hormones
 Multiple different combinations of TRs and variability in their tissue distributions create tissue
specificity for thyroid hormone effects
In absence of hormone, TR dimers associate with co-repressor molecules and constitutively bind to (and thereby
inactivate) thyroid hormone-stimulated genes
o Binding of thyroid hormone to TR:RXR or TR:TR dimers promotes dissociation of co-repressors and
recruitment of co-activators to DNA; thus, thyroid hormone binding to TR dimers serves as molecular
switch from inhibition to activation of gene transcription
o Thyroid hormone also acts to downregulate gene expression by TR-dependent mechanism
 For example, thyroid hormone able to downregulate TSH gene expression, causing negative
feedback of thyroid hormone on hypothalamic-pituitary-thyroid axis
o Thyroid hormone also has non-genomic effects on mitochondrial metabolism and interacts with PM
receptors to stimulate intracellular signal transduction
Thyroid hormone important in infancy for growth and development of nervous system
o Cretinism – congenital deficiency of thyroid hormone; severe but preventable form of mental
retardation
o In adult, thyroid hormone regulates general body metabolism and energy expenditure
 Enzymes regulated by thyroid hormone include Na+/K+-ATPase and many enzymes of
intermediary metabolism, both anabolic and catabolic
 At high levels of thyroid hormone, effect can result in futile cycling and consequent increase in
body temperature
o Many effects of thyroid hormone resemble effects of SNS stimulation, including increased cardiac
contractility and heart rate, excitability, nervousness, and diaphoresis (sweating)
o Low levels of thyroid hormone result in myxedema; hypometabolic state characterized by lethargy, dry
skin, coarse voice, and cold intolerance
Thyroid hormone secretion follows negative regulatory feedback scheme similar to that of other hypothalamicpituitary-target organ axes
o Thyrotropin-releasing hormone (TRH) secreted by hypothalamus that travels via hypothalamic-pituitary
portal circulation to anterior pituitary gland
 TRH binds to G protein-coupled receptor located on PM of anterior pituitary gland thyrotropes
(TSH-producing cells)
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TRH binding stimulates signal transduction cascade (ultimately promotes synthesis and release of TSH)
TSH is most important distance regulator of thyroid gland function; stimulates every known aspect of
thyroid hormone production: I- uptake, organification, coupling, thyroglobulin internalization, and
secretion of thyroid hormone
 TSH promotes increased vascularization and growth of thyroid gland
 In pathologic conditions where TSH or TSH mimic secreted at high levels, thyroid gland can
enlarge to several times its normal size, resulting in characteristic diffusely hypertrophied
thyroid gland (goiter)
o Negative feedback of hypothalamic-pituitary-thyroid axis occurs through regulator actions of thyroid
hormone on both hypothalamus and pituitary gland
 Secreted thyroid hormone diffuses into thyrotropes of anterior pituitary gland, where it binds
and activates nuclear thyroid hormone receptors
 Bound receptors inhibit TSH gene transcription, and hence, TSH synthesis
o Thyroid hormone has important regulatory effects on hypothalamus; thyroid hormone binding to
receptors in hypothalamic cells inhibits transcription of gene that codes for TRH precursor protein
Pathophysiology
 Pathophysiology of thyroid diseases are disturbance of physiologic hypothalamic-pituitary-thyroid axis
 Physiologic decrease in thyroid hormones normally activates TSH synthesis and release, which leads to increased
release of thyroid hormones by thyroid gland and restoration of normal thyroid hormone levels
o Thyroid gland pathology can cause thyroid hormone insufficiency, which reduces negative feedback of
thyroid hormone on TSH release; although TSH levels elevated, there is no increase in thyroid hormone
release because thyroid gland can’t respond
 Graves’ disease – IgG autoantibody specific for TSH receptor (thyroid-stimulating immunoglobulin or TsIg)
produced and acts as agonist, activating TSH receptor and thereby stimulating thyroid follicular cells to
synthesize and release thyroid hormone
o TsIg not subject to negative feedback control, so there is high thyroid hormones and low TSH
 Hashimoto’s thyroiditis – selective destruction of thyroid gland; antibodies specific for many thyroid gland
proteins, including thyrogloblulin and thyroid peroxidase, found in plasma
o Clinical course involves gradual inflammatory destruction of thyroid gland with resultant hypothyroidism
o Early in course of disease, destruction of thyroid follicular cells can release excessive quantities of stored
colloid, resulting in transiently increased levels of thyroid hormone
o Eventually gland almost completely destroyed and clinical symptoms of hypothyroidism develop
(lethargy and decreased metabolic rate)
o Therapy involves pharmacologic replacement with oral synthetic thyroid hormone
 Other causes of hypothyroidism and hyperthyroidism include developmental anomalies, subacute (de
Quervain’s) thyroiditis, and thyroid adenomas and carcinomas
Treatment of Hypothyroidism
 Therapy aims to replace missing endogenous thyroid hormone with regularly administered exogenous thyroid
hormone; exogenous thyroid hormone structurally identical to endogenous thyroid hormone (generally T4) and
is produced by chemical synthesis
o T3 is metabolically more active form, but most thyroid hormone in blood is T4, though T4 has lower
activity than T3 and is eventually metabolized to T3
o Having large reservoir of thyroid “prodrug” (T4) in plasma important as effective buffer to normalize
metabolic rates over wide range of conditions
o Half-life of T4 is 6 days compared to 1-day half-life of T3; extended half-life of T4 allows patient to take
one pill per day
 Levothyroxine (L-isomer of T4) is treatment of choice for hypothyroidism
o One exception is myxedema coma, where faster onset of T3 may provide enhanced recovery from lifethreatening hypothyroidism
o Efficacy monitored by assays of plasma TSH and thyroid hormone levels
o TSH is accurate marker of thyroid hormone activity because anterior pituitary gland release of TSH
exquisitely sensitive to feedback control by thyroid hormone in blood
o Once patient taking stable dose of levothyroxine, monitoring TSH levels performed every 6-12 months
o
Sudden alterations in TSH levels despite constant dosing of levothyroxine may be due to drug-drug
interactions affecting absorption and metabolism
 Resins such as sodium polystyrene sulfonate (Kayexalate) and cholestyramine may decrease
absorption of T4
 Adequate gastric acidity required for absorption of exogenous levothyroxine, so dose may need
to be increased in patients with H. pylori infection or who start taking proton pump inhibitor
 Drugs that increase activity of certain hepatic P450 enzymes (rifampin and phenytoin) increase hepatic excretion
of T4, so dose of levothyroxine may need to be increased
Treatment of Hyperthyroidism
 Inhibitors of iodide uptake – I- brought into thyroid follicular cell via Na+/I- symporters; certain anions with
approximate atomic radius of I- (perchlorate, thiocyanate, and pertechnetate) compete with I- for uptake into
thyroid gland follicular cell
o Results in decreased amount of I- available for thyroid hormone synthesis
o Effects of anion uptake inhibitors usually not immediately apparent because of large store of preformed
thyroid hormone in colloid
o Use uncommon because of potential for causing aplastic anemia and thioamines generally more
effective
o Many uptake inhibitors also used as radiopaque contract materials, so important to keep physiologic
antagonism in mind whenever patient has symptoms of hypothyroidism after extensive radiographic
studies employing contrast material
 Inhibitors of organification and hormone release
o Iodides – take advantage of thyroid gland’s selective uptake and concentration if I- to levels much higher
than that in blood
 131I- is radioactive I- isotope that strongly emits β-particles toxic to cells; Na+/I- symporters can’t
distinguish between 131I- and normal stable 127I-, so 131I- becomes sequestered within thyroid
gland; makes radioactive iodide specific and effective therapy for hyperthyroidism
 Concentrated intracellular radioactive iodide continues to emit β-particles, resulting in
selective local destruction of thyroid gland
 Radioactive iodide used to treat thyrotoxicosis and serves as alternative to surgery in
treatment of hyperthyroidism
 Patients may eventually develop hypothyroidism after treatment because it’s difficult to
ascertain for given patient extent to which 131I- will kill all or most of follicular cells
 Development of hypothyroidism easier to manage clinically than hyperthyroidism
 Unlikely that therapeutic doses of 131I- have any effect on incidence of thyroid cancer
 High levels of normal 127I- inhibit thyroid hormone synthesis and release (Wolff-Chaikoff effect)
 Mediated by downregulation of Na+/I- symporters in thyroid gland
 Negative feedback effect of high intrathyroidal I- concentrations is reversible and
transient; thyroid hormone synthesis and release returns to normal few days later
 Not useful long-term therapy
 Reduces size and vascularity of thyroid gland, so often administered before thyroid
gland surgery, resulting in easier excision
 Large doses of 127I- can prevent uptake of environmental radioactive Io Thioamines – compete with thyroglobulin for oxidized iodide in process catalyzed by thyroid peroxidase;
causes selective decrease in organification and coupling of thyroid hormone precursors, and thereby
inhibits thyroid hormone production
 Iodinated thioamines capable of binding to thyroglobulin, further antagonizing any coupling
 Colloid can provide sufficient amount of thyroid hormone for more than a week in absence of
any new synthesis
 Because thioamines affect synthesis but not secretion of thyroid hormone, effects not
manifested until several weeks after initiation of treatment
 Thioamine treatment often results in goiter formation, so drugs also called goitrogens
 Inhibition of thyroid hormone production results in upregulation of TSH release by
anterior pituitary gland in attempt to reestablish homeostasis
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Increased plasma TSH can’t raise thyroid hormone levels because of actin of thioamine
In response to TSH, thyroid gland hypertrophies in attempt to increase thyroid hormone
synthesis, resulting in goiter
 Propylthiouracil – inhibits thyroid peroxidase as well as peripheral T4 to T3 conversion; short
half-life that necessitates dosing 3x daily
 Methimazole – inhibits thyroid peroxidase; administered once daily
 Both propylthiouracil and methimazole generally well tolerated; most frequent adverse effect is
pruritic rash early in course of treatment, which may remit spontaneously
 Arthralgia common reason for stopping agents
 Can interfere with vitamin K-dependent synthesis of prothrombin, leading to
hypoprothrombinemia and increased bleeding tendency
 Agranulocytosis occurs in <0.1% of cases, usually within first 90 days of treatment;
because of risk, patients should have baseline measurement of WBCs and should be
advised to discontinue drug immediately if they develop fever and sore throat
 Hepatotoxicity – rare adverse effect; hepatitis typically cholestatic in pattern and may
represent allergic reaction to drugs
o Severe hepatitis leading to liver failure and death associated with
propylthiouracil treatment
 Vasculitis from agents can manifest as drug-induced lupus or anti-neutrophil
cytoplasmic antibody (ANCA)-associated vasculitis
 Because incidence of serious adverse effects less frequent with methimazole than with
propylthiouracil, methimazole generally preferred in clinical practice; exceptions are thyroid
storm and pregnancy
 In acute management of severe hyperthyroidism (thyroid storm), additional ability of
propylthiouracil to block peripheral conversion of T4 to T3 makes it more useful
 In pregnancy, propylthiouracil is preferred because it has more extensive safety record
and because methimazole use during pregnancy associated with development of aplasia
cutis (congenital absence of epidermis with or without other skin layers)
 Large percentage of patients taking these go into remission over course of 6-23 months and may
be able to maintain euthyroid state after discontinuation of medications
 Some patients develop persistent hyperthyroidism despite treatment; require more
definitive treatment of hyperthyroidism by either radioactive iodide therapy or surgical
removal of thyroid gland
 Inhibitors of peripheral thyroid hormone metabolism – conversion of T4 to T3 dependent on peripheral 5’deiodinase, and inhibitors of this enzyme are effective adjuncts in treating symptoms of hyperthyroidism
o Propylthiouracil – inhibits both organification in thyroid gland and peripheral conversion of T4 to T3
o β-adrenergic antagonists useful for symptoms of hyperthyroidism because many effects of high plasma
thyroid hormone resemble nonspecific β-adrenergic stimulation (sweating, tremor, tachycardia)
 β-blockers can reduce peripheral conversion of T4 to T3, but this effect not clinically relevant
 Because of rapid onset of action and short elimination half-life (9 minutes), esmolol is preferred
β-adrenergic antagonist for treatment of thyroid storm
o Ipodate – radiocontrast agent formerly used for visualization of biliary ducts in endoscopic retrograde
cholangiopancreatography (ERCP) procedures
 Significantly inhibits conversion of T4 to T3 by inhibiting 5’-deiodinase
 No longer commercially available for hyperthyroidism treatment
Other Drugs Affecting Thyroid Hormone Homeostasis
 Lithium – used in treatment of bipolar affective disorder; can cause hypothyroidism
o Actively concentrated in thyroid gland, and high levels inhibit thyroid hormone release from follicular
cells; some evidence that lithium may inhibit thyroid hormone synthesis as well
 Amiodarone – antiarrhythmic drug that has both positive and negative effects on thyroid hormone function
o Structurally resembles thyroid hormone and, as result, contains large concentration of iodine
o Metabolism of amiodarone releases iodine as I-; increased plasma I- concentrated in thyroid gland and
can result in hypothyroidism by Wolff-Chaikoff effect
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Can cause hyperthyroidism by 2 mechanisms
 Type I thyrotoxicosis – excess iodide load provided by amiodarone leads to increased thyroid
hormone synthesis and release
 Type II thyroiditis – autoimmune thyroiditis induced that leads to release of excess thyroid
hormone from colloid
o Because of close structural similarity to thyroid hormone, amiodarone may act as homologue of thyroid
hormone at receptor
o Amiodarone competitively inhibits type I 5’-deiodinase, resulting in decreased peripheral conversion of
T4 to T3 and increased plasma concentrations of rT3
Corticosteroids – cortisol and glucocorticoid analogues; inhibit 5’-deiodinase enzyme that converts T4 to
metabolically more active T3
o Treatment with corticosteroids reduces net thyroid hormone activity
o Decreased serum T3 results in increased release of TSH; increased TSH stimulates greater T4 synthesis
until amount of T4 produced generates sufficient level of T3 to inhibit hypothalamus and pituitary
 When faced with decreased peripheral conversion of T4 to T3, thyroid gland releases T4 at
higher rate, and serum T4 and T3 levels reach new steady state