Antithyroid agent

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An antithyroid agent is a hormone inhibitor acting upon thyroid hormones.

Contents

The main antithyroid drugs are carbimazole (in the UK), methimazole (in the US), and propylthiouracil (PTU). A less common antithyroid agent is potassium perchlorate.

Classification based on mechanisms of action

The mechanisms of action of antithyroid drugs are not completely understood. Based on their mechanisms of action, the drugs are classified into following six classes.

Thyroid hormone synthesis inhbitors

These drugs probably inhibit the enzyme thyroid peroxidase (a.k.a. thyroperoxidase), decreasing iodide oxidation, iodination of tyrosyl residues in thyroglobulin, and coupling of iodotyrosyl and iodothyronyl residues. [1] It is thought that they inhibit the thyroperoxidase-catalyzed oxidation reactions by acting as substrates for the postulated peroxidase-iodine complex, thus competitively inhibiting the interaction with the amino acid tyrosine. The most common drugs in this class are thioamides, which include propylthiouracil, methimazole and its prodrug carbimazole.

Additionally, propylthiouracil may reduce the de-iodination of thyroxine (tetraiodothyronine; T4) into triiodothyronine (T3) in peripheral tissues. [2]

Lugol's iodine is used to temporarily block thyroid hormone synthesis before surgeries. [3] It is also used to treat patients with thyroid storm or, more commonly, to reduce thyroid vascularity before thyroidectomy (surgical removal of the thyroid gland). [4]

Iodide uptake inhibitors

They decrease uptake of iodide ions (I−) into follicular cells of the thyroid gland. Since their molecules have structural similarities with the iodide ion, they compete with iodide for being transported by the sodium/iodide symporter, which is a transporter protein that co-transports Na+ and I− ions. Iodide transport is a key step in the biosynthesis of the thyroid hormones T4 and T3. [5] [6] For example, potassium perchlorate competitively inhibits the active iodide transport mechanism in the thyroid gland, which has the capacity to selectively concentrate iodide against a large concentration gradient. [5] [6]

Besides perchlorates, other examples of iodide uptake inhibitors include pertechnetates, thiocyanates, nitrates. [7]

These drugs are no longer used due to high toxicity and adverse effects. [8] [9]

Thyroid hormone release inhibitors

They inhibit release (secretion) of thyroid hormones by the thyroid gland. The most studied drug in this class is lithium, which inhibits thyroid hormone secretion by inhibiting iodotyrosine coupling, thyroidal iodide uptake, and alteration in structure of thyroglobulin, [10] a protein which acts as a substrate for the synthesis of thyroid hormones and storage of inactive forms of T3, T4 and iodine within the lumen of thyroid follicular cells. [11] Since lithium is neither metabolized nor protein-bound, its bioavailability usually is close to 100%. [12] Hence, there are risks of serious side effects such as lithium toxicity, hypothyroidism, and diabetes insipidus. [13]

Excess iodine

Excessive iodine intake can temporarily inhibit production of thyroid hormones. This occurs because of the Wolff-Chaikoff effect, which is a phenomenon of rejection of large quantities of iodine by the thyroid gland, therefore preventing it from synthesizing large quantities of thyroid hormones. [14]

Iodine radiopharmaceuticals

They are radioisotopes of iodine. In small doses, when they are taken up by overactive thyroid follicular cells, they emit small amounts of beta radiation that destroys not all, but many thyroid follicular cells, thereby reducing thyroid hormone production. [15] This is a form of targeted therapy for hyperthyroidism. Since even low levels of ionizing radiation are highly mutagenic and can cause cancer, [16] less toxic iodine isotopes such as iodine-123 [17] are more commonly used in nuclear imaging, while iodine-131 is used for its cytolytic (cell-destroying) effects in hyperthyroidism and thyroid tumors. [15]

Thyroid hormone receptor antagonists

Also called TR antagonists, they inhibit action of thyroid hormones by blocking TR receptors (thyroid hormone receptors). Antagonist 1-850 and its derivatives have been found to be coactivator interaction inhibitors, which interfere with the interaction between TR receptors and coactivator proteins such as nuclear hormone receptor coregulator (NRC). As a result, the receptors are unable to recruit coactivators, causing stoppage of transcription of target genes, thereby preventing activation of TR receptors, ultimately leading to inhibition of effects of thyroid hormones because they can bind to only inactive TR receptors, and these receptors can't be activated in presence of TR antagonists. [18] Antagonist 1-850 has also been found to inhibit binding of [125I]T3 [lower-alpha 1] to TRs in intact GH4 cells. [18]

Adverse effects

The most dangerous side effect is agranulocytosis (1/250, more in PTU); this is an idiosyncratic reaction which generally resolves on cessation of drug. It occurs in about 0.2 to 0.3% of cases treated with antithyroid drugs. [19] Other side effects include granulocytopenia (dose dependent, which improves on cessation of the drug) and aplastic anemia, and in case of propylthiouracil, severe, fulminant liver failure. [20] Patients on these medications should see a doctor if they develop sore throat or fever.

The most common side effects are rash and peripheral neuritis. [21] These drugs also cross the placenta and are secreted in breast milk. [22]

Graves' disease

In Graves' disease, treatment with antithyroid medications must be given for six months to two years, in order to be effective. Even then, upon cessation of the drugs, the hyperthyroid state may recur. Side effects of the antithyroid medications include a potentially fatal reduction in the level of white blood cells.

A randomized control trial testing single dose treatment for Graves' found methimazole achieved euthyroidism (normal thyroid function that occurs within normal serum levels of TSH and T4 [23] ) more effectively after 12 weeks than did propylthiouracil (77.1% on methimazole 15 mg vs 19.4% in the propylthiouracil 150 mg groups). [24] But generally both drugs are considered equivalent.

A study has shown no difference in outcome for adding thyroxine to antithyroid medication and continuing thyroxine versus placebo after antithyroid medication withdrawal. However, two markers were found that can help predict the risk of recurrence. These two markers are an elevated level of thyroid stimulating hormone receptor antibodies (TSHR-Ab) and smoking. A positive TSHR-Ab at the end of antithyroid drug treatment increases the risk of recurrence to 90% (sensitivity 39%, specificity 98%), a negative TSHR-Ab at the end of antithyroid drug treatment is associated with a 78% chance of remaining in remission. Smoking was shown to have an impact independent to a positive TSHR-Ab. [25]

Competitive antagonists of thyroid stimulating hormone receptors are currently being investigated as a possible treatment for Grave's disease.

See also

Notes

  1. ↑ [125I]T3 is a radiopharmaceutical formulation of triiodothyronine having iodine-125 atoms instead of iodine.

Related Research Articles

<span class="mw-page-title-main">Hyperthyroidism</span> Thyroid gland disease that involves an overproduction of thyroid hormone

Hyperthyroidism is the condition that occurs due to excessive production of thyroid hormones by the thyroid gland. Thyrotoxicosis is the condition that occurs due to excessive thyroid hormone of any cause and therefore includes hyperthyroidism. Some, however, use the terms interchangeably. Signs and symptoms vary between people and may include irritability, muscle weakness, sleeping problems, a fast heartbeat, heat intolerance, diarrhea, enlargement of the thyroid, hand tremor, and weight loss. Symptoms are typically less severe in the elderly and during pregnancy. An uncommon but life-threatening complication is thyroid storm in which an event such as an infection results in worsening symptoms such as confusion and a high temperature; this often results in death. The opposite is hypothyroidism, when the thyroid gland does not make enough thyroid hormone.

<span class="mw-page-title-main">Thyroid</span> Endocrine gland in the neck; secretes hormones that influence metabolism

The thyroid, or thyroid gland, is an endocrine gland in vertebrates. In humans, it is in the neck and consists of two connected lobes. The lower two thirds of the lobes are connected by a thin band of tissue called the isthmus (pl.: isthmi). The thyroid gland is a butterfly-shaped gland located in the neck below the Adam's apple. Microscopically, the functional unit of the thyroid gland is the spherical thyroid follicle, lined with follicular cells (thyrocytes), and occasional parafollicular cells that surround a lumen containing colloid. The thyroid gland secretes three hormones: the two thyroid hormones – triiodothyronine (T3) and thyroxine (T4) – and a peptide hormone, calcitonin. The thyroid hormones influence the metabolic rate and protein synthesis and growth and development in children. Calcitonin plays a role in calcium homeostasis. Secretion of the two thyroid hormones is regulated by thyroid-stimulating hormone (TSH), which is secreted from the anterior pituitary gland. TSH is regulated by thyrotropin-releasing hormone (TRH), which is produced by the hypothalamus.

<span class="mw-page-title-main">Graves' disease</span> Autoimmune endocrine disease

Graves' disease, also known as toxic diffuse goiter, is an autoimmune disease that affects the thyroid. It frequently results in and is the most common cause of hyperthyroidism. It also often results in an enlarged thyroid. Signs and symptoms of hyperthyroidism may include irritability, muscle weakness, sleeping problems, a fast heartbeat, poor tolerance of heat, diarrhea and unintentional weight loss. Other symptoms may include thickening of the skin on the shins, known as pretibial myxedema, and eye bulging, a condition caused by Graves' ophthalmopathy. About 25 to 30% of people with the condition develop eye problems.

Thyroid-stimulating hormone (also known as thyrotropin, thyrotropic hormone, or abbreviated TSH) is a pituitary hormone that stimulates the thyroid gland to produce thyroxine (T4), and then triiodothyronine (T3) which stimulates the metabolism of almost every tissue in the body. It is a glycoprotein hormone produced by thyrotrope cells in the anterior pituitary gland, which regulates the endocrine function of the thyroid.

<span class="mw-page-title-main">Triiodothyronine</span> Chemical compound

Triiodothyronine, also known as T3, is a thyroid hormone. It affects almost every physiological process in the body, including growth and development, metabolism, body temperature, and heart rate.

<span class="mw-page-title-main">Thyroid follicular cell</span>

Thyroid follicular cells (also called thyroid epithelial cells or thyrocytes) are the major cell type in the thyroid gland, and are responsible for the production and secretion of the thyroid hormones thyroxine (T4) and triiodothyronine (T3). They form the single layer of cuboidal epithelium that makes up the outer structure of the almost spherical thyroid follicle.

<span class="mw-page-title-main">Potassium perchlorate</span> Chemical compound

Potassium perchlorate is the inorganic salt with the chemical formula KClO4. Like other perchlorates, this salt is a strong oxidizer although it usually reacts very slowly with organic substances. This, usually obtained as a colorless, crystalline solid, is a common oxidizer used in fireworks, ammunition percussion caps, explosive primers, and is used variously in propellants, flash compositions, stars, and sparklers. It has been used as a solid rocket propellant, although in that application it has mostly been replaced by the higher performance ammonium perchlorate.

<span class="mw-page-title-main">Propylthiouracil</span> Medication used to treat hyperthyroidism

Propylthiouracil (PTU) is a medication used to treat hyperthyroidism. This includes hyperthyroidism due to Graves' disease and toxic multinodular goiter. In a thyrotoxic crisis it is generally more effective than methimazole. Otherwise it is typically only used when methimazole, surgery, and radioactive iodine is not possible. It is taken by mouth.

<span class="mw-page-title-main">Wolff–Chaikoff effect</span> Effect of iodine on the thyroid

The Wolff–Chaikoff effect is a presumed reduction in thyroid hormone levels caused by ingestion of a large amount of iodine.

<span class="mw-page-title-main">Thiamazole</span> Chemical compound

Thiamazole, also known as methimazole, is a medication used to treat hyperthyroidism. This includes Graves disease, toxic multinodular goiter, and thyrotoxic crisis. It is taken by mouth. Full effects may take a few weeks to occur.

<span class="mw-page-title-main">Thyroid peroxidase</span> Enzyme expressed mainly in the thyroid gland

Thyroid peroxidase, also called thyroperoxidase (TPO), thyroid specific peroxidase or iodide peroxidase, is an enzyme expressed mainly in the thyroid where it is secreted into colloid. Thyroid peroxidase oxidizes iodide ions to form iodine atoms for addition onto tyrosine residues on thyroglobulin for the production of thyroxine (T4) or triiodothyronine (T3), the thyroid hormones. In humans, thyroperoxidase is encoded by the TPO gene.

<span class="mw-page-title-main">Thyroid disease</span> Medical condition

Thyroid disease is a medical condition that affects the function of the thyroid gland. The thyroid gland is located at the front of the neck and produces thyroid hormones that travel through the blood to help regulate many other organs, meaning that it is an endocrine organ. These hormones normally act in the body to regulate energy use, infant development, and childhood development.

<span class="mw-page-title-main">Carbimazole</span> Medication used for hyperthyroidism

Carbimazole (brand names Neo-Mercazole, Anti-Thyrox, etc.) is used to treat hyperthyroidism. Carbimazole is a pro-drug as after absorption it is converted to the active form, methimazole. Methimazole prevents thyroid peroxidase enzyme from iodinating and coupling the tyrosine residues on thyroglobulin, hence reducing the production of the thyroid hormones T3 and T4 (thyroxine).

<span class="mw-page-title-main">Toxic multinodular goitre</span> Medical condition

Toxic multinodular goiter (TMNG), also known as multinodular toxic goiter (MNTG), is an active multinodular goiter associated with hyperthyroidism.

Thyroid storm is a rare but severe and life-threatening complication of hyperthyroidism. It occurs when overactive thyroid activity leads to hypermetabolism, the end result being death from cardiac arrest or multiple organ failure.

<span class="mw-page-title-main">Liothyronine</span> Chemical compound

Liothyronine is a manufactured form of the thyroid hormone triiodothyronine (T3). It is most commonly used to treat hypothyroidism and myxedema coma. It can be taken by mouth or by injection into a vein.

Goitrogens are substances that disrupt the production of thyroid hormones. This triggers the pituitary to release thyroid-stimulating hormone (TSH), which then promotes the growth of thyroid tissue, eventually leading to goiter.

<span class="mw-page-title-main">Thyroid hormones</span> Hormones produced by the thyroid gland

Thyroid hormones are any hormones produced and released by the thyroid gland, namely triiodothyronine (T3) and thyroxine (T4). They are tyrosine-based hormones that are primarily responsible for regulation of metabolism. T3 and T4 are partially composed of iodine, derived from food. A deficiency of iodine leads to decreased production of T3 and T4, enlarges the thyroid tissue and will cause the disease known as simple goitre.

<span class="mw-page-title-main">Iopanoic acid</span> Chemical compound

Iopanoic acid is an iodine-containing radiocontrast medium used in cholecystography. Both iopanoic acid and ipodate sodium are potent inhibitors of thyroid hormone release from thyroid gland, as well as of peripheral conversion of thyroxine (T4) to triiodothyronine (T3). These compounds inhibit 5'deiodinase (5'DID-1 and 5'DID-2) enzymes, which catalyse T4-T3 conversion in the thyroid cell, liver, kidney, skeletal muscle, heart, brain, pituitary. This accounts for the dramatic improvement in both subjective and objective symptoms of hyperthyroidism, particularly when they are used as an adjunctive therapy with thioamides (propylthiouracil, carbimazole). They can be used in the treatment of patients with severe thyrotoxicosis (thyroid storm) and significant morbidity (e.g., myocardial infarction, or stroke) for rapid control of elevated plasma triiodothyronine concentrations. The use of iopanoic acid for treatment of thyrotoxicosis has been discontinued in the United States.

Thyroid disease in pregnancy can affect the health of the mother as well as the child before and after delivery. Thyroid disorders are prevalent in women of child-bearing age and for this reason commonly present as a pre-existing disease in pregnancy, or after childbirth. Uncorrected thyroid dysfunction in pregnancy has adverse effects on fetal and maternal well-being. The deleterious effects of thyroid dysfunction can also extend beyond pregnancy and delivery to affect neurointellectual development in the early life of the child. Due to an increase in thyroxine binding globulin, an increase in placental type 3 deioidinase and the placental transfer of maternal thyroxine to the fetus, the demand for thyroid hormones is increased during pregnancy. The necessary increase in thyroid hormone production is facilitated by high human chorionic gonadotropin (hCG) concentrations, which bind the TSH receptor and stimulate the maternal thyroid to increase maternal thyroid hormone concentrations by roughly 50%. If the necessary increase in thyroid function cannot be met, this may cause a previously unnoticed (mild) thyroid disorder to worsen and become evident as gestational thyroid disease. Currently, there is not enough evidence to suggest that screening for thyroid dysfunction is beneficial, especially since treatment thyroid hormone supplementation may come with a risk of overtreatment. After women give birth, about 5% develop postpartum thyroiditis which can occur up to nine months afterwards. This is characterized by a short period of hyperthyroidism followed by a period of hypothyroidism; 20–40% remain permanently hypothyroid.

References

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