Download Pharmacology Ch 27 480-488 Thyroid Gland Follicular thyroid cells

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 T4T3
2. Type II deiodinase – pituitary gland, brain, and brown fat and converts T4T3 locally
3. Type III deiodinase – converts T4rT3 (biologically inactive T3)
-presence of T4 in blood provides a buffer/reservoir for thyroid hormone effects. Most T4T3
happens in the liver, and so pharm agents that increase hepatic cytochrome P450 increase
T4T3 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 T4T3 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 T4T3
-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 T4T3 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 T4T3
conversion
Corticosteroids – cortisol and glucocorticoid analogues inhibit 5’deiodinase enzyme that
converts T4T3
-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