Thyroid and Antithyroid Drugs

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Chapter 42 Thyroid and Antithyroid Drugs

Abbreviations
cAMP Cyclic adenosine monophosphate
D1 Iodothyronine deiodinase type 1
D2 Iodothyronine deiodinase type 2
D3 Iodothyronine deiodinase type 3
DIT Diiodotyrosine
MIT Monoiodotyrosine
NADPH Reduced nicotinamide adenine dinucleotide phosphate
PTU Propylthiouracil
rT3 Reverse T3
T3 L isomer of triiodothyronine
T4 L isomer of thyroxine, tetraiodothyronine
TBPA Transthyretin, thyroxine-binding prealbumin
TBG Thyroxine-binding globulin
Tg Thyroglobulin
TR Thyroid hormone receptor
TRH Thyrotropin-releasing hormone
TSH Thyroid-stimulating hormone, thyrotropin

Therapeutic Overview

Thyroid gland hormones, L-tetraiodothyronine (T4, also known as thyroxine) or L-triiodothyronine (T3), are potent effectors of energy metabolism. Specifically a direct correlation exists between the levels of these hormones and whole body O2 consumption, heart rate and force of contraction, glucose and fatty acid use by muscle, lipolysis by adipose tissue, hepatic glycogenolysis, and gluconeogenesis. Further, these hormones are essential for neonatal growth and development. Levels of thyroid hormones are tightly regulated to properly maintain function. When circulating levels are excessive, hyperthyroidism ensues, and when levels are deficient, hypothyroidism is manifest.

Acquired hypothyroidism is commonly associated with loss of thyroid, usually involving advanced-stage thyroiditis, in which autoantibodies destroy the thyroid gland. Childhood hypothyroidism usually has a genetic origin and is complicated by its effects on growth and maturation, particularly in the brain. Other causes of hypothyroidism include familial goiter and surgical removal of the thyroid. Irrespective of the cause, hypothyroidism is treated by thyroid hormone replacement with either T4 or T3.

The most common causes of hyperthyroidism are Graves’ disease (a thyroid autoimmune disease) and toxic nodular goiter. In Graves’ disease, autoantibodies directed at thyroid-stimulating hormone (TSH) receptors in the thyroid membrane stimulate the unregulated overproduction of thyroid hormone. Although not presently possible, optimal therapy would be to specifically block the formation or effects of these antibodies. Current treatment strategies are directed at interfering with the effects of excess thyroid hormone levels through the use of β adrenergic receptor antagonists or cortisol, inhibiting the synthesis of thyroid hormones with antithyroid drugs, or ablation therapy through the use of radioactive iodine or surgery. Treatments for hypothyroidism and hyperthyroidism are summarized in the Therapeutic Overview Box.

Therapeutic Overview
Hypothyroidism
Replacement therapy with synthetic thyroxine (T4)
Hyperthyroidism
Thioureylene drugs
β Adrenergic receptor antagonists
Glucocorticoids
Radioactive iodine
Surgery

Mechanisms of Action

Thyroid Hormones

Thyroid Hormone Biosynthesis

The iodinated compounds in thyroid follicular cells (thyrocytes) are derived by enzymatic condensation of the iodinated tyrosyl residues in thyroglobulin (Fig. 42-1). Among these are the two major thyroid hormones, L-isomers of T4 and T3. All of the T4 that is made is derived from the thyroid. In contrast, only a small fraction of the most biologically active form, T3, is produced and released from the thyroid. Most T3 is produced by peripheral tissues by removing an iodide from the outer ring of T4 through the action of 5’-deiodinase.

The synthesis and release of T3 and T4 are shown in Figure 42-2. Thyrocytes concentrate iodide from the circulation via a symporter present on their basolateral surface that admits Na+ down its electrochemical gradient. This sodium/iodide symporter, which is also present in salivary glands, breast, and stomach, can transport other anions, such as pertechnetate and perchlorate, which can competitively inhibit iodide transport. Once iodide enters the thyrocyte, it is transported to the follicular lumen by an anion transporter in the apical membrane termed pendrin. As iodide reaches the follicular lumen, it is oxidized by a mechanism involving thyroperoxidase, H2O2, and two reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidases. Activated iodide forms covalent links with specific tyrosyl residues on thyroglobulin (Tg), which is present in the follicular lumen, producing the thyroid hormone precursors monoiodotyrosine (MIT) and diiodotyrosine (DIT). This process is referred to as organification of iodide. MIT or DIT can donate their iodinated phenolic rings to acceptor iodotyrosyl residues on DIT in the Tg backbone and form an ether linkage with the acceptor phenolic ring to form T4 and T3 covalently bound to Tg. This process is called coupling. Iodinated Tg is transported to and stored associated with the apical membrane. When thyroid hormone is required, iodinated Tg is transported into follicular cells by endocytosis, where it undergoes proteolysis, releasing T4 and T3 into the circulation. MIT and DIT are deiodinated and reused.

If the circulating level of iodide is elevated persistently, it may cause the thyroid to overproduce thyroid hormone. Thyrocytes use several mechanisms to maintain iodide homeostasis to prevent hormone overproduction from occurring. Initially, high levels of iodide cause thyrocytes to shut down organification and coupling, an inhibitory response referred to as the Wolff-Chaikoff effect. With continued iodide elevations, this inhibitory effect diminishes. However, the activity of the sodium/iodide symporter decreases in response to elevated iodide levels, preventing overproduction of thyroid hormone. In some patients with thyroiditis or in the fetus, the thyroid does not escape from the Wolff-Chaikoff effect, and persistently high iodine levels can cause hypothyroidism, leading to goiter formation.

Hormone synthesis in thyrocytes is regulated by TSH released from the pituitary. If the circulating level of thyroid hormone is abnormally elevated, pituitary sensitivity to thyrotropin-releasing hormone (TRH) is reduced, causing decreased production of TSH. Pituitary portal blood also carries counter-regulatory compounds that inhibit TSH release (i.e., dopamine and somatostatin) (see Chapter 38).

If levels of circulating thyroid hormone are abnormally decreased, pituitary sensitivity to TRH is increased, which stimulates TSH secretion and ultimately increases the release thyroid hormone.

Thyroid Hormone Receptors

Thyroid hormones exert their major effects by binding to thyroid hormone receptors (TRs), members of the nuclear receptor superfamily (see Chapter 1). Two genes encode TRs, and each can be transcribed into alternatively spliced products. The relative proportions of each isoform expressed are developmentally dependent and tissue specific. TRs can homodimerize but are generally present as heterodimers, most commonly with the receptor for 9-cis-retinoic acid but also with other nuclear hormone receptors. TRs associate with DNA as part of a complex of transcription factors, even in the absence of thyroid hormone. When T3 binds to its receptor, the interactions of the receptor with transcription corepressors and coactivators change, and local chromatin structure is modified by changes in histone acetylation. Binding of T3 increases transcription of some genes and decreases the transcription of others. Thyroid hormones also regulate the processing of ribonucleic acid transcripts and the stability of specific messenger ribonucleic acids, and have other non-nuclear actions. Another potential regulatory process is the expression of the TR splice variant (TRα2), which interacts with thyroid hormone response elements but is not activated by T3. Consequently, expression of TRα2 can reduce sensitivity to thyroid hormone.

Antihyperthyroid Drugs

As shown in Table 42-1, antithyroid drugs can inhibit the synthesis, release, and metabolism of thyroid hormone and alter its peripheral effects.

TABLE 42–1 Antithyroid Drugs

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Compound Mechanism of Action
Perchlorate Inhibition of iodide transport
Thioureylenes Inhibition of organification and coupling
Iodide, lithium Inhibition of deiodination of T4 to T3
  Inhibition of hormone release
β Adrenergic receptor blockers