Thyroid Hormones

BASIC PHARMACOLOGY OF THYROID & ANTITHYROID DRUGS

THYROID HORMONES

Chemistry

The structural formulas of thyroxine and triiodothyronine as well as reverse triiodothyronine (rT₃) are shown in Figure 38–2. All of these naturally occurring molecules are levo (L) isomers. The synthetic dextro (D) isomer of thyroxine, dextrothyroxine, has approximately 4% of the biologic activity of the L-isomer as evidenced by its lesser ability to suppress TSH secretion and correct hypothyroidism.

Pharmacokinetics

Thyroxine is absorbed best in the duodenum and ileum; absorp-tion is modified by intraluminal factors such as food, drugs, gas-tric acidity, and intestinal flora. Oral bioavailability of current preparations of L-thyroxine averages 80% (Table 38–1). In con-trast, T₃ is almost completely absorbed (95%). T₄ and T₃ absorp-tion appears not to be affected by mild hypothyroidism but may be impaired in severe myxedema with ileus. These factors are important in switching from oral to parenteral therapy. For paren-teral use, the intravenous route is preferred for both hormones.

In patients with hyperthyroidism, the metabolic clearances of T₄ and T₃ are increased and the half-lives decreased; the opposite is true in patients with hypothyroidism. Drugs that induce hepatic microsomal enzymes (eg, rifampin, phenobarbital, carbamazepine, phenytoin, tyrosine kinase inhibitors, HIV protease inhibitors) increase the metabolism of both T₄ and T₃ (Table 38–3). Despite this change in clearance, the normal hormone concentration is maintained in the majority of euthyroid patients as a result of compensatory hyperfunction of the thyroid. However, patients dependent on T₄ replacement medication may require increased dosages to maintain clinical effectiveness. A similar compensation occurs if binding sites are altered. If TBG sites are increased by pregnancy, estrogens, or oral contraceptives, there is an initial shift of hormone from the free to the bound state and a decrease in its rate of elimination until the normal free hormone concentration is restored. Thus, the concentration of total and bound hormone will increase, but the concentration of free hormone and the steady-state elimination will remain normal. The reverse occurs when thyroid binding sites are decreased.

Mechanism of Action

A model of thyroid hormone action is depicted in Figure 38–4, which shows the free forms of thyroid hormones, T₄ and T₃, dissociated from thyroid-binding proteins, entering the cell by active transport. 

Within the cell, T₄ is converted to T₃ by 5’-deiodinase, and the T₃ enters the nucleus, where T₃ binds to a specific T₃ receptor protein, a member of the c-erb oncogene family. (This family also includes the steroid hormone receptors and receptors for vitamins A and D.) The T₃ receptor exists in two forms, α and β. Differing concentrations of receptor forms in different tissues may account for variations in T₃ effect on different tissues.

Most of the effects of thyroid on metabolic processes appear to be mediated by activation of nuclear receptors that lead to increased formation of RNA and subsequent protein synthesis, eg, increased formation of Na⁺/K⁺-ATPase. This is consistent with the observation that the action of thyroid is manifested in vivo with a time lag of hours or days after its administration.

Large numbers of thyroid hormone receptors are found in the most hormone-responsive tissues (pituitary, liver, kidney, heart, skeletal muscle, lung, and intestine), while few receptor sites occur in hormone-unresponsive tissues (spleen, testes). The brain, which lacks an anabolic response to T₃, contains an intermediate number of receptors. In congruence with their biologic potencies, the affinity of the receptor site for T₄ is about ten times lower than that for T₃. Under some conditions, the number of nuclear recep-tors may be altered to preserve body homeostasis. For example, starvation lowers both circulating T₃ hormone and cellular T₃ receptors.

Effects of Thyroid Hormones

The thyroid hormones are responsible for optimal growth, devel-opment, function, and maintenance of all body tissues. Excess or inadequate amounts result in the signs and symptoms of hyper-thyroidism or hypothyroidism, respectively (Table 38–4). Since T₃ and T₄ are qualitatively similar, they may be considered as one hormone in the discussion that follows.

Thyroid hormone is critical for the development and function-ing of nervous, skeletal, and reproductive tissues.Its effects depend on protein synthesis as well as potentiation of the secretion and action of growth hormone. Thyroid deprivation in early life results in irreversible mental retardation and dwarfism—typical of congenital cretinism.

Effects on growth and calorigenesis are accompanied by a per-vasive influence on metabolism of drugs as well as carbohydrates, fats, proteins, and vitamins. Many of these changes are dependent upon or modified by activity of other hormones. Conversely, the secretion and degradation rates of virtually all other hormones, including catecholamines, cortisol, estrogens, testosterone, and insulin, are affected by thyroid status.

Many of the manifestations of thyroid hyperactivity resemble sympathetic nervous system overactivity (especially in the cardio-vascular system), although catecholamine levels are not increased. Changes in catecholamine-stimulated adenylyl cyclase activity as measured by cAMP are found with changes in thyroid activity.

Possible explanations include increased numbers of β receptors or enhanced amplification of the β-receptor signal. Other clinical symptoms reminiscent of excessive epinephrine activity (and par-tially alleviated by adrenoceptor antagonists) include lid lag and retraction, tremor, excessive sweating, anxiety, and nervousness. The opposite constellation of effects is seen in hypothyroidism (Table 38–4).

Thyroid Preparations

See the Preparations Available section at the end for a list of available preparations. These preparations may be synthetic (levothyroxine, liothyronine, liotrix) or of animal origin (desiccated thyroid).

Thyroid hormones are not effective and can be detrimental in the management of obesity, abnormal vaginal bleeding, or depres-sion if thyroid hormone levels are normal. Anecdotal reports of a beneficial effect of T₃ administered with antidepressants were not confirmed in a controlled study.

Synthetic levothyroxine is the preparation of choice for thyroid replacement and suppression therapy because of its stability, content uniformity, low cost, lack of allergenic foreign protein, easy laboratory measurement of serum levels, and long half-life (7 days), which permits once-daily administration. In addition, T₄ is converted to T₃ intracellularly; thus, administration of T₄ pro-duces both hormones. Generic levothyroxine preparations provide comparable efficacy and are more cost-effective than branded preparations.

Although liothyronine (T₃) is three to four times more potent than levothyroxine, it is not recommended for routine replace-ment therapy because of its shorter half-life (24 hours), which requires multiple daily doses; its higher cost; and the greater dif-ficulty of monitoring its adequacy of replacement by conventional laboratory tests. Furthermore, because of its greater hormone activity and consequent greater risk of cardiotoxicity, T₃ should be avoided in patients with cardiac disease. It is best used for short-term suppression of TSH. Because oral administration of T₃ is unnecessary, use of the more expensive mixture of thyroxine and liothyronine (liotrix) instead of levothyroxine is never required.

The use of desiccated thyroid rather than synthetic prepara-tions is never justified, since the disadvantages of protein antige-nicity, product instability, variable hormone concentrations, and difficulty in laboratory monitoring far outweigh the advantage of lower cost. Significant amounts of T₃ found in some thyroid extracts and liotrix may produce significant elevations in T₃ levels and toxicity. Equi-effective doses are 100 mg of desiccated thyroid, 100 mcg of levothyroxine, and 37.5 mcg of liothyronine.

The shelf life of synthetic hormone preparations is about 2 years, particularly if they are stored in dark bottles to minimize spontane-ous deiodination. The shelf life of desiccated thyroid is not known with certainty, but its potency is better preserved if it is kept dry.