Pharmacology: Thyroid Drugs

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Thyroid Hormone Preparations

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•Levothyroxine (Levoxyl, Synthroid)
•Liothyronine (Cytomel)

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Antithyroid Agents

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Thioamide Drugs
β-Adrenoceptor Antagonists
Other Antithyroid Agents

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Thioamide Drugs

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•Methimazole (Tapazole)
•Propylthiouracil (PTU)

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β-Adrenoceptor Antagonists

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•Propranolol (Inderal)

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Other Antithyroid Agents

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•Potassium iodide solution
•Sodium iodide I-131 (131I)

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The thyroid gland synthesizes and secretes

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triiodothyronine (T3) and tetraiodothyronine (T4, thyroxine).

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Thyroid hormones are necessary for

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normal growth and development and timely sexual maturation

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Thyroid hormones have a crucial role in

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metabolic processes, including those involved in the synthesis and degradation of essentially all other hormones.

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Thyroid hormones also augment

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sympathetic nervous system function, primarily by increasing the number of adrenoceptors in target tissues.

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secretion of thyroid hormones is initiated by a hypothalamic hormone called

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thyrotropin-releasing hormone (TRH)

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thyrotropin-releasing hormone (TRH) increases secretion of an anterior pituitary hormone called

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thyroid-stimulating hormone (TSH, or thyrotropin)

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TSH is the prime regulator of

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iodide uptake and thyroid hormone formation by the thyroid gland. It fulfills this role by inducing the expression of three genes involved in iodide uptake and hormone production: (1) the sodium/iodide symporter that transports iodide into the thyroid gland, (2) thyroglobulin, and (3) thyroperoxidase.

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thyrotropin-releasing hormone (TRH) increases secretion of an anterior pituitary hormone called

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thyroid-stimulating hormone (TSH, or thyrotropin)

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Thyroid hormones are synthesized in a process that involves

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the uptake and organification of iodide and the subsequent coupling of iodotyrosine residues of thyroglobulin.

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TSH is the prime regulator of

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iodide uptake and thyroid hormone formation by the thyroid gland. It fulfills this role by inducing the expression of three genes involved in iodide uptake and hormone production: (1) the sodium/iodide symporter that transports iodide into the thyroid gland, (2) thyroglobulin, and (3) thyroperoxidase.

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After iodide is actively transported into thyroid follicle cells, it diffuses across the cells to the

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apical membrane, where it is oxidized and attached to tyrosine residues of thyroglobulin. This process is called iodide organification

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Thyroid hormones are synthesized in a process that involves

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the uptake and organification of iodide and the subsequent coupling of iodotyrosine residues of thyroglobulin.

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The iodinated tyrosine residues, monoiodotyrosine and diiodotyrosine are then coupled to form

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T3 and T4

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After iodide is actively transported into thyroid follicle cells, it diffuses across the cells to the

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apical membrane, where it is oxidized and attached to tyrosine residues of thyroglobulin. This process is called iodide organification

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Iodide organification and the coupling reactions are catalyzed by

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thyroperoxidase.

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The iodinated tyrosine residues, monoiodotyrosine and diiodotyrosine are then coupled to form

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T3 and T4

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Thyroglobulin is stored as colloid in the

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follicular lumen.

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Iodide organification and the coupling reactions are catalyzed by

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thyroperoxidase.

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During the release of thyroid hormones, thyroglobulin reenters the

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follicular cell by endocytosis and undergoes proteolysis

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Thyroglobulin is stored as colloid in the

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follicular lumen.

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The release of T4 and T3 is stimulated by TSH via the formation of

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cyclic adenosine monophosphate in thyroid follicular cells.

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During the release of thyroid hormones, thyroglobulin reenters the

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follicular cell by endocytosis and undergoes proteolysis

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T4 and T3 are transported to target organs by

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thyroid-binding globulin, thyroid-binding prealbumin, and albumin

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The release of T4 and T3 is stimulated by TSH via the formation of

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cyclic adenosine monophosphate in thyroid follicular cells.

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T4 and T3 are transported to target organs by

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thyroid-binding globulin, thyroid-binding prealbumin, and albumin

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The rate of conversion of T4 to T3 is also affected by a variety of

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hormones, nutrients, and disease states

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T3 and rT3 are eventually metabolized by

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deiodinase and sulfotransferase reactions to diiodothyronine sulfate.

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Normal thyroid function, or euthyroidism, is maintained via feedback inhibition of

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TSH secretion so as to keep the plasma concentration of free (circulating or unbound) T4 within a narrow range.

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Abnormally low or high T4 and T3 levels result in clinical manifestations of

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hypothyroidism or hyperthyroidism, respectively

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Hypothyroidism is characterized by

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low T4 levels, and leads to impaired growth and development and decreased metabolic activity.

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hyperthyroidism is due to

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high T4 levels, leading to hyperactivity of organ systems (particularly the nervous and cardiovascular systems) and an increased metabolic rate

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Thyroid disorders are diagnosed primarily on the basis of their

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clinical manifestations and plasma T4 and TSH levels

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TSH levels are abnormally high in persons with

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hypothyroidism

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TSH levels are abnormally low in persons with

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hyperthyroidism

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In infants and children, hypothyroidism causes irreversible

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mental retardation and impairs growth and development

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In adults, hypothyroidism is associated with

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impairment of physical and mental activity and with slowing of cardiovascular, gastrointestinal, and neuromuscular functions

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Hypothyroid patients may complain of

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lethargy, cold intolerance, weight gain, and constipation. The skin may become coarse, dry, and cold.

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Eventually, hypothyroidism causes myxedema, which is

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a dry, waxy swelling of the skin with nonpitting edema. Myxedema coma is characterized by hypothermia, hypoglycemia, weakness, stupor, and shock and is the end stage of long-standing, untreated hypothyroidism.

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Many patients with mild hypothyroidism have a T4 level within

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the normal range. As the disease progresses, however, the T4 level usually falls below normal.

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The most common cause of hypothyroidism in adults is

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autoimmune thyroiditis (Hashimoto's disease)

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causes of hypothyroidism include

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thyroid surgery or radioactive iodine (RAI) treatment for hyperthyroidism; dietary iodine deficiency; and thyroid hypoplasia or enzymatic defects. Pituitary or hypothalamic dysfunction can cause secondary hypothyroidism.

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drugs that can induce thyroid disorders are

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Lithium inhibits the release of thyroid hormones by the thyroid gland and can cause hypothyroidism by this mechanism. Amiodarone is an iodine-containing antiarrhythmic drug that can cause either hypothyroidism or hyperthyroidism through a variety of mechanisms that alter multiple thyroid functions.

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The treatment for all forms of hypothyroidism is

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replacement therapy with a thyroid hormone preparation.

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Manifestations of hyperthyroidism, or thyrotoxicosis, can include

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nervousness, emotional lability, weight loss despite an increased appetite, heat intolerance, palpitations, proximal muscle weakness, increased frequency of bowel movements, and irregular menses.

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Most cases of hyperthyroidism are associated with

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overproduction of thyroid hormones by the thyroid gland, as indicated by the finding of increased RAI uptake.

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in patients with TSH-secreting pituitary adenomas excessive thyroid hormone production can result from

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excessive TSH

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Excessive thyroid hormone production can result from gland stimulation by thyroid antibodies, as occurs in patients with

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Graves' disease.

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Graves' disease results from the formation of antibodies directed against

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the TSH receptor on the surface of thyroid cells. These antibodies stimulate the receptor in the same manner as TSH, resulting in overproduction of thyroid hormones. Graves' disease is characterized by hyperthyroidism, thyroid enlargement, and exophthalmus (abnormal protrusion of the eyeball). Exophthalmus results from stimulation of orbital muscles by thyroid antibodies.

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Inflammatory thyroid disease (subacute thyroiditis) can cause a transient form of hyperthyroidism that is caused by

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the release of preformed thyroid hormone from thyroid follicles.

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Three treatment modalities are used in hyperthyroidism:

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antithyroid agents, surgery, and RAI treatment.

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Synthetic levothyroxine is widely considered the drug of choice for thyroid hormone replacement in persons with

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hypothyroidism

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animal thyroid preparations are no longer recommended by endocrinologists because of

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variable composition and stability, and their potential to cause allergic reactions to animal proteins contained in these preparations.

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synthetic thyroid hormone preparations include

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levothyroxine (T4), liothyronine (T3), and liotrix (a mixture containing T4 and T3 in a ratio of 4:1).

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A twofold change in the free T4 level can cause a

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100-fold change in the TSH level.

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The oral bioavailability of levothyroxine is about

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80%

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Food also affects the bioavailability of levothyroxine, and it is now recommended that levothyroxine be taken

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at the same mealtime each day in order to obtain consistent blood levels

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Levothyroxine is the drug of choice for thyroid hormone replacement in patients with hypothyroidism, because it is

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chemically stable, nonallergenic, and can be given orally once a day. Levothyroxine administration produces a stable pool of T4 that is converted to T3 at a steady and consistent rate.

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A gradual increase in the dose prevents

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excessive stress on the cardiovascular and other organ systems and thereby causes fewer adverse reactions.

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The steady-state maintenance dose of levothyroxine is determined on the basis of

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the patient's clinical response, TSH levels, and T4 levels.

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An elevated TSH level indicates that the levothyroxine dose is

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not sufficient

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Levothyroxine is also the drug of choice for suppressive therapy in patients with

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thyroid nodules, diffuse goiters, or thyroid cancer. In these conditions, levothyroxine acts to suppress TSH production and reduce stimulation of abnormal thyroid tissue. Suppressive therapy thereby reduces goiter size and thyroid gland volume.

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Myxedema coma is

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a medical emergency that requires intravenous administration of a loading dose of levothyroxine or liothyronine followed by smaller maintenance doses.

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ADVERSE EFFECTS

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Thyroid hormone preparations rarely cause adverse reactions if dosing is appropriate and is carefully monitored during the initial treatment of hypothyroidism and periodically thereafter. Excessive doses produce symptoms of hyperthyroidism.

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INTERACTIONS

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Aluminum hydroxide, cholestyramine, ferrous sulfate, and sucralfate are among the drugs that interfere with the absorption of levothyroxine. These drugs should be administered 2 hours before or after levothyroxine is administered. Estrogens, androgens, and glucocorticoids can alter thyroid-binding globulin and total T4 and T3 levels, but free T4 and TSH levels usually remain normal in patients taking these steroid hormones. For this reason, the dosage of levothyroxine usually does not need to be adjusted in persons who are taking steroid hormones.

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liothyronine (T3) is more potent than levothyroxine (T4) and has a higher oral bioavailability. It is seldom used in the treatment of hypothyroidism, however, because

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it has several disadvantages. Liothyronine has a much shorter half-life than levothyroxine, and multiple daily doses may be needed to obtain a smooth response during hormone replacement therapy. Liothyronine does not increase plasma T4 levels, so it is difficult to monitor the response to treatment. Liothyronine also causes more adverse cardiac effects and is more expensive than levothyroxine.

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Antithyroid agents used in the treatment of hyperthyroidism include

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thioamide drugs, β-adrenoceptor antagonists, iodide salts, and radioactive iodine.

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thioamide drugs inhibit the

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synthesis of thyroid hormones

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sufficient doses of iodide salts inhibit the

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release of these hormones.

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β-blockers are used to control the cardiovascular symptoms of hyperthyroidism until

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definitive treatment becomes effective

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β-blockers, the corticosteroids, some thioamide derivatives (see below), and some iodinated contrast agents (e.g., ipodate) also inhibit the

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peripheral conversion of T4 to T3. Because of this action, ipodate is being investigated for the treatment of acute thyrotoxicosis.

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The thioamide drugs include

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methimazole and propylthiouracil (PTU).

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the synthesis of thyroid hormones requires

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oxidation of trapped iodide, formation of iodotyrosines, and the coupling of iodotyrosines to form T3 and T4.

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Methimazole and PTU inhibit

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thyroperoxidase

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PTU (but not methimazole) inhibits the conversion of

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T4 to T3 in peripheral tissues

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thioamide drugs are

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well absorbed from the gut following oral administration

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ADVERSE EFFECTS

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Pruritic maculopapular rash, arthralgia, and fever occur in up to 5% of persons treated with a thioamide drug. Less frequently, a lupus erythematosus-like syndrome, hepatitis, or gastrointestinal distress is reported.

Many patients experience benign and transient leukopenia, with a white blood cell count of less than 4000/μL. This condition does not appear to be associated with the more severe agranulocytosis that sometimes occurs and is characterized by a granulocyte count of less than 250/μL. Severe agranulocytosis usually develops during the first 3 months of therapy and can be prevented by advising patients to stop treatment and immediately contact their physician if they experience fever, malaise, sore throat, or other flu-like symptoms.









Methimazole and PTU exhibit cross-sensitivity in about 50% of patients. For this reason, patients who have experienced a major adverse reaction should not be switched to the other drug.

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The plasma half-lives of methimazole and PTU are about

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7 and 2 hours, respectively

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Thyroid hormones and the sympathetic nervous system act synergistically on

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cardiovascular function

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increased levels of thyroid hormones cause

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tachycardia, palpitations, and arrhythmias

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β-Adrenoceptor antagonists (e.g., propranolol) are used to

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reduce cardiovascular stimulation associated with hyperthyroidism

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Iodide salts are contained in potassium iodide solutions, such as saturated solution of potassium iodide and Lugol's solution. They are used on a short-term basis to

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treat patients with acute thyrotoxicosis, to prepare patients for thyroid surgery, and to inhibit the release of thyroid hormones following RAI treatment. Iodide salts can also be used to competitively block RAI uptake by the thyroid gland in the event of a nuclear reactor accident or other accidental exposure to toxic levels of RAI.

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In patients scheduled for thyroid surgery, a potassium iodide solution is usually administered preoperatively for

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7 to 14 days to reduce the size and vascularity of the thyroid gland.

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adverse effects of iodide salts are usually mild and can include

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skin rashes and other hypersensitivity reactions, salivary gland swelling, metallic taste, sore gums, and gastrointestinal discomfort.

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Radioactive iodine is usually administered as a colorless and tasteless solution of

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sodium iodide I 131 (131I)

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Treatment with RAI is absolutely contraindicated in pregnant women, because

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it destroys fetal thyroid tissue