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Mechanism of Action
Thyroid hormones exert their physiologic actions through control of DNA transcription and protein synthesis. Triiodothyronine (T3) and L-thyroxine (T4) diffuse into the cell nucleus and bind to thyroid receptor proteins attached to DNA. This hormone nuclear receptor complex activates gene transcription and synthesis of messenger RNA and cytoplasmic proteins.
The physiological actions of thyroid hormones are produced predominantly by T3, the majority of which (approximately 80%) is derived from T4 by deiodination in peripheral tissues.
Thyroid hormone synthesis and secretion is regulated by the hypothalamic-pituitary-thyroid axis. Thyrotropin-releasing hormone (TRH) released from the hypothalamus stimulates secretion of thyrotropin-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 decrease. When thyroid hormone levels decrease, TRH and TSH secretion increase.
TSH, along with T4 levels and other laboratory and clinical data, is primarily used for both the diagnosis of hypothyroidism and evaluation of levothyroxine therapy adequacy [Dosage and Administration (2.4)]. There are drugs known to affect thyroid hormones and TSH levels by various mechanisms. Some drugs may cause a transient decrease in TSH secretion without hypothyroidism: dopamine ( > 1 mcg per kg per min), glucocorticoids (hydrocortisone > 100 mg per day or equivalent) and octreotide ( > 100 mcg per day).
Thyroid hormones regulate multiple metabolic processes and play an essential role in normal growth and development, and normal maturation of the central nervous system and bone. The metabolic actions of thyroid hormones include augmentation of cellular respiration and thermogenesis, as well as metabolism of proteins, carbohydrates, and lipids. The protein anabolic effects of thyroid hormones are essential to normal growth and development.
Absorption of orally administered T4 from the gastrointestinal (GI) tract ranges from 40% to 80%. The majority of the levothyroxine dose is absorbed from the jejunum and upper ileum. The relative bioavailability of TIROSINT capsules compared to another marketed levothyroxine sodium tablet, is approximately 103%. T4 absorption is increased by fasting, and decreased in malabsorption syndromes and by certain foods such as soybeans. Dietary fiber decreases the bioavailability of T4. Absorption may also decrease with age. In addition, many drugs and foods affect T4 absorption. [See DRUG INTERACTIONS]
Circulating thyroid hormones are greater than 99% bound to plasma proteins, including thyroxine-binding globulin (TBG), thyroxine-binding prealbumin (TBPA), and thyroxine-binding albumin (TBA), whose capacities and affinities vary 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 [See DRUG INTERACTIONS].
T4 is slowly eliminated. The major pathway of thyroid hormone metabolism is through sequential deiodination. Approximately 80% 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 80% of the daily dose of T4 is deiodinated to yield equal amounts of T3 and reverse T3 (r T3). T3 and r T3 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 20% of T4 is eliminated in the stool. Urinary excretion of T4 decreases with age.
Table 6: Pharmacokinetic
Parameters of Thyroid Hormones in Euthyroid Patients
|Hormone||Ratio in Thyroglobulin||Biologic Potency||Half-Life (Days)||Protein Binding (%)2|
|T4||10 – 20||1||6 – 71||99.96|
T3: Liothyronine (Triiodothyronine)
13 – 4 days in hyperthyroidism, 9 – 10 days in hypothyroidism.
2Includes TBG, TBPA and TBA.
Animal Toxicology and/or Pharmacology
No animal toxicology studies have been conducted with Levothyroxine Sodium.
Last reviewed on RxList: 3/14/2012
This monograph has been modified to include the generic and brand name in many instances.
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