This paper explores two medication derivatives used in the treatment of hypothyroidism from research conducted by the American Thyroid Association, Journal of the American Medical Association, Kings Pharmaceuticals, Forest Laboratories, and Abbott Laboratories. The standard therapy for patients with primary hypothyroidism and secondary hypothyroidism is replacement with synthetic tetraiodothyronine (T4), which undergoes a chemical reaction removing an iodine in the conversion to triiodothyronine (T4), the active form of thyroid hormone. Hypothyroidism requires life-long treatment, and is treated with thyroid hormone drugs, either hormonal arrangements derived from animal thyroid or synthetic arrangements containing levothyroxine (an L-isomer of T4) sodium or liothyronine (an L-isomer of T3) sodium or both. Thyroid hormone replacement therapy in patients with hypothyroidism is treated with the use of pharmaceutical treatments such Levoxyl (Synthroid), Thyroral, Cytomel, or Armour Thyroid. In addition, the absorption, distribution, metabolism, and elimination of these compounds will be discussed.
Keywords: tetraiodothyronine, levothyroxine, liothyronine, triiodothyronine
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The Pharmacology of Hypothyroidism:
An Overview of Thyroid Hormone Replacement Therapy Medications
The thyroid gland is a butterfly-shaped endocrine gland located in the front part of the neck. The thyroid makes the thyroid hormones that control a multitude of metabolic processes, playing an essential role in human growth and development, the development of the central nervous system, and maturation of bone. The metabolic actions of thyroid hormones include regulation of cellular respiration and thermogenesis, in addition to metabolism of proteins, carbohydrates, and lipids. A shortage of thyroid hormones in humans and other vertebrates is denoted as hypothyroidism. This occurs if an iodine-deficiency exists or if the pituitary gland does not create enough thyroid-stimulating hormone (TSH) to stimulate the thyroid gland to generate a sufficient amount of tetraiodothyronine and triiodothyronine for normal bodily function. Thyroid hormone replacement therapy in patients with hypothyroidism is treated with the use of synthetic or natural hormonal arrangements such Levoxyl (Synthroid), Thyroral, Cytomel, or Armour Thyroid.
The mechanisms in which thyroid hormones exercise their physiologic influence are not well understood. It is thought that their most important effects are exercised through the control of DNA transcription and translation to create proteins. The hormones, normally produced by the thyroid, T4 and T3 diffuse into the cell nucleus and bind to thyroid receptor proteins attached to DNA. This hormone nuclear receptor complex activates gene transcription, the synthesis of mRNA, and the ribosomes. These hormones increase oxygen utilization by the tissues of the body, increase the basal metabolic rate, and the metabolism of carbohydrates, lipids, and proteins. Thus, they exert a strong control on every organ system in the body and are of particular importance in the development of the central nervous system.
In tissues, deiodinases can either activate or inactivate thyroid hormones. Activation occurs by conversion of T4 to the active hormone T3 through the removal of an iodine atom on the outer ring. Inactivation of thyroid hormones occurs by removal of an iodine atom on the inner ring, which converts tetraiodothyronine to the inactive reverse triiodothyronine, or which converts the active triiodothyronine to the inactive diiodothyronine (T2). The major part of tetraiodothyronine deiodination occurs within the cells. As T4 and T3 levels drop within the body, treatment will need to be involved in the regulation of the thyroid hormones for normal metabolism and body maturation.
Figure 1.1: Iodothyrinone Deiodinase
Hypothyroidism requires life-long treatment, and is treated with thyroid hormone drugs, either natural or synthetic arrangements containing tetraiodothyronine or levothyroxine sodium or triiodothyronine or liothyronine sodium or both. T4 and T3 are produced in the human thyroid gland by the iodination and pairing of the amino acid tyrosine. T4 contains four iodine atoms and is formed by the pairing of two molecules of diiodotyrosine. T3 contains three atoms of iodine and is formed by the pairing of one molecule of diiodotyrosine with one molecule of monoiodotyrosine. Both hormones are stored in the thyroid colloid as thyroglobulin.
Thyroid hormone preparations are of two categories, the natural hormonal arrangements derived from animal thyroid and synthetic arrangements. Natural arrangements include desiccated thyroid and thyroglobulin. Desiccated thyroid is derived from domesticated animals such as porcine thyroid and bovine thyroid, and the thyroglobulin is derived from the thyroid glands of the pig. â€œThe United States Pharmacopeia (USP) has standardized the total iodine content of natural preparations. Thyroid USP contains not less than (NLT) 0.17 percent and not more than (NLT) 0.23 percent iodine and thyroglobulin contains not less than (NLT) 0.7 percent of organically bound iodine. Iodine content is only and indirect indicator of true hormonal biological activity.â€Â
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Thyroid hormone synthesis and secretion is regulated by the hypothalamic-pituitary-thyroid axis. Thyrotropin-releasing hormone (TRH) released from the hypothalamus stimulates secretion of thyroid-stimulating hormone (TSH), from the anterior pituitary. TSH, in turn, is the physiologic stimulus for the synthesis and secretion of thyroid hormones, T4 and T3, by the thyroid gland. Circulating serum T3 and T4 levels exert a feedback effect on both TRH and TSH secretion. When serum T3 and T4 levels increase, TRH and TSH secretion decreases. When thyroid hormone levels decrease, TRH and TSH secretion increase. The physiologic actions of thyroid hormones are produced predominately by T3, the majority of which is derived from T4 by deiodination in the tissues.
Figure 1.2: Thyroid-Releasing Hormone
Figure 1.2: L-isomers of Tetraiodothyronine and Triiodothyronine
Of the drugs, levothyroxine sodium is an effective method in the suppression of pituitary TSH secretion in the treatment or prevention of various types of euthyroid goiters, including thyroid nodules, Hashimotoâ€™s thyroiditis, multinodular goiter and, as adjunctive therapy in the management of thyrotropin-dependent well-differentiated thyroid cancer. However, the abosrtoption, distribution, metabolism, and elimination differ between the T4 and T3 medications. Research conducted by scientists in the field is still inconclusive of which of the two is more indicative of treating hypothyroidism.
The absorption of orally administered T4 from the gastrointestinal tract ranges from about forty to eighty percent, the majority of the levothyroxine dose is absorbed from the jejunum and upper ileum. The relative bioavailability of levothyroxine sodium tablets, compared to an equal nominal dose of oral levothyroxine sodium solution, is approximately ninety-eight percent. T4 absorption is increased by fasting, and decreased in improper absorption syndromes and by certain foods such as soy milk, bean curd, and other soy products. Dietary fiber decreases bioavailability of T4. Absorption may also decrease with age. In addition, many drugs and foods affect T4 absorption.
Circulating thyroid hormones are greater than ninety-nine percent bound to plasma proteins, including thyroxine-binding globulin (TBG), thyroxine-binding prealbumin (TBPA), and albumin (TBA), whose faculties and effects diverge for each hormone. The higher affinity of both TBG and TBPA for T4 partially explains the higher serum levels, slower metabolic clearance, and longer half-life of T4 compared to T3. Protein-bound thyroid hormones exist in reverse equilibrium with small amounts of free hormone. Only unbound hormone is metabolically active. Many drugs and physiologic conditions affect the binding of thyroid hormones to serum proteins. Thyroid hormones do not readily cross the placental barrier.
T4 is slowly eliminated. The major pathway of thyroid hormone metabolism is through sequential deiodination. Approximately eighty-percent of circulating T3 is derived from peripheral T4 by monodeiodination. The liver is the major site of degradation for both T4 and T3, with T4 deiodination also occurring at a number of additional sites, including the kidney and other tissues. Approximately eighty percent of the daily dose of T4 is deiodinated to yield equal amounts of T3 and rT3. T3 and rT3 are further deiodinated to diiodothyronine. Thyroid hormones are also metabolized via conjugation with glucuronides and sulfates and excreted directly into the bile and gut where they undergo enterohepatic recirculation.
Thyroid hormones are primarily eliminated by the kidneys. A portion of the conjugated hormone reaches the colon unchanged and is eliminated in the feces. Approximately twenty percent of T4 is eliminated in the stool. Urinary excretion of T4 decreases with age.
Whereas, T3 is not firmly bound to serum protein, it is readily available to body tissues. The onset of activity of liothyronine sodium is rapid, occurring within a few hours. Maximum pharmacologic response occurs within 2 or 3 days, providing early clinical response. The biological half-life is about 2-1/2 days. T3 is almost totally absorbed, 95 percent in 4 hours. The hormones contained in the natural preparations are absorbed in a manner similar to the synthetic hormones.
Liothyronine sodium has a rapid cutoff of activity which permits quick dosage adjustment and facilitates control of the effects of over dosage, should they occur. The higher affinity of T4 for both TBG and TBPA as compared to triiodothyronine partially explains the higher serum levels and longer half-life of the former hormone. Both protein-bound hormones exist in reverse equilibrium with minute amounts of free hormone, the latter accounting for the metabolic activity.
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Figure 1.4 Liothyronine sodium