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Chapter: Basic & Clinical Pharmacology : Thyroid &Antithyroid Drugs

Thyroid Physiology

The normal thyroid gland secretes sufficient amounts of the thyroid hormones—triiodothyronine (T3) and tetraiodothyronine(T4, thyroxine)—to normalize growth and development, bodytemperature, and energy levels.


The normal thyroid gland secretes sufficient amounts of the thyroid hormones—triiodothyronine (T3) and tetraiodothyronine(T4, thyroxine)—to normalize growth and development, bodytemperature, and energy levels. These hormones contain 59% and 65% (respectively) of iodine as an essential part of the molecule. Calcitonin, the second type of thyroid hormone, is important in the regulation of calcium metabolism.

Iodide Metabolism

The recommended daily adult iodide (I) intake is 150 mcg (200 mcg during pregnancy).Iodide, ingested from food, water, or medication, is rapidly absorbed and enters an extracellular fluid pool. The thyroid gland removes about 75 mcg a day from this pool for hormone synthesis, and the balance is excreted in the urine. If iodide intake is increased, the fractional iodine uptake by the thyroid is diminished.

Biosynthesis of Thyroid Hormones

Once taken up by the thyroid gland, iodide undergoes a series of enzymatic reactions that incorporate it into active thyroid hormone (Figure 38–1). The first step is the transport of iodide into the thy-roid gland by an intrinsic follicle cell basement membrane protein called the sodium/iodide symporter (NIS). This can be inhibited by such anions as thiocyanate (SCN), pertechnetate (TcO4), and perchlorate (ClO4). At the apical cell membrane a second I trans-port enzyme called pendrin controls the flow of iodide across the membrane. Pendrin is also found in the cochlea of the inner ear. If pendrin is deficient or absent, a hereditary syndrome of goiter and deafness, called Pendred’s syndrome, ensues.

 At the apical cell mem-brane, iodide is oxidized by thyroidal peroxidase to iodine, in which form it rapidly iodinates tyrosine residues within the thyroglobulin molecule to form monoiodotyrosine (MIT) and diiodotyrosine(DIT). This process is called iodide organification. Thyroidal per-oxidase is transiently blocked by high levels of intrathyroidal iodide and blocked more persistently by thioamide drugs.

Two molecules of DIT combine within the thyroglobulin mol-ecule to form L-thyroxine (T4). One molecule of MIT and one molecule of DIT combine to form T3. In addition to thyroglobulin,other proteins within the gland may be iodinated, but these iodo-proteins do not have hormonal activity. Thyroxine, T3, MIT, and DIT are released from thyroglobulin by exocytosis and proteolysis of thyroglobulin at the apical colloid border. The MIT and DIT are then deiodinated within the gland, and the iodine is reutilized. This process of proteolysis is also blocked by high levels of intrathyroidal iodide. The ratio of T4 to T3 within thyroglobulin is approximately 5:1, so that most of the hormone released is thy-roxine. Most of the T3 circulating in the blood is derived from peripheral metabolism of thyroxine (, Figure 38–2).

Transport of Thyroid Hormones

T4 and T3 in plasma are reversibly bound to protein, primarily thyroxine-binding globulin (TBG). Only about 0.04% of total T4 and 0.4% of T3 exist in the free form. Many physiologic and pathologic states and drugs affect T4, T3, and thyroid transport. However, the actual levels of free hormone generally remain nor-mal, reflecting feedback control.

Peripheral Metabolism of Thyroid Hormones

The primary pathway for the peripheral metabolism of thyroxine is deiodination. Deiodination of T4 may occur by monodeiodina-tion of the outer ring, producing 3,5,3’-triiodothyronine (T3), which is three to four times more potent than T4. Alternatively, deiodina-tion may occur in the inner ring, producing 3,3’,5’-triiodothyronine (reverse T3, or rT3), which is metabolically inactive (Figure 38–2). Drugs such as amiodarone, iodinated contrast media, β blockers, and corticosteroids, and severe illness or starvation inhibit the 5’-deiodinase necessary for the conversion of T4 to T3, resulting in low T3 and high rT3 levels in the serum. The pharmacokinetics of thyroid hormones are listed in Table 38–1. The low serum levels of T3 and rT3 in normal individuals are due to the high metabolic clearances of these two compounds.

Evaluation of Thyroid Function

The tests used to evaluate thyroid function are listed in Table 38–2.

A. Thyroid-Pituitary Relationships

Briefly, hypothalamic cells secrete thyrotropin-releasing hormone (TRH) (Figure 38–3). TRH is secreted into capillaries of the pituitary portal venous system, and in the pituitary gland, TRH stimulates the synthesis and release of thyrotropin (thyroid-stimulating hormone, TSH). TSH in turn stimulates an adenylyl cyclase–mediated mechanism in the thyroid cell to increase the synthesis and release of T4 and T3. These thyroid hormones act in a negative feedback fashion in the pituitary to block the action of TRH and in the hypothalamus to inhibit the synthesis and secretion of TRH. Other hormones or drugs may also affect the release of TRH or TSH.

B. Autoregulation of the Thyroid Gland

The thyroid gland also regulates its uptake of iodide and thyroid hormone synthesis by intrathyroidal mechanisms that are inde-pendent of TSH. These mechanisms are primarily related to the level of iodine in the blood. Large doses of iodine inhibit iodide organification (Wolff-Chaikoff block, see Figure 38–1). In certain disease states (eg, Hashimoto’s thyroiditis), this can inhibit thyroid hormone synthesis and result in hypothyroidism. Hyperthyroidism can result from the loss of the Wolff-Chaikoff block in susceptible individuals (eg, multinodular goiter).

C. Abnormal Thyroid Stimulators

In Graves’ disease , lymphocytes secrete a TSH recep-tor-stimulating antibody (TSH-R Ab [stim]), also known asthyroid-stimulating immunoglobulin (TSI). This immunoglobulin binds to the TSH receptor and stimulates the gland in the same fashion as TSH itself. The duration of its effect, however, is much longer than that of TSH. TSH receptors are also found in orbital fibrocytes, which may be stimulated by high levels of TSH-R Ab [stim] and can cause ophthalmopathy.

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