indication

For use alone or in combination with antithyroid agents to treat hypothyroidism, goiter, chronic lymphocytic thyroiditis, myxedema coma, and stupor.

pharmacology

Levothyroxine (T₄) is a synthetically prepared levo isomer of thyroxine, the major hormone secreted from the thyroid gland. Thyroxine is released from thyroglobulin by proteolysis and secreted into the blood. Thyroxine is peripherally deiodinated to form triiodothyronine (T₃) which exerts a broad spectrum of stimulatory effects on cell metabolism. Thyroid hormone increases the metabolic rate of cells of all tissues in the body. In the fetus and newborn, thyroid hormone is important for the growth and development of all tissues including bones and the brain. In adults, thyroid hormone helps to maintain brain function, food metabolism, and body temperature, among other effects. The symptoms of thyroid deficiency relieved by levothyroxine include slow speech, lack of energy, weight gain, hair loss, dry thick skin and unusual sensitivity to cold.

mechanism of action

Levothyroxine acts like the endogenous thyroid hormone thyroxine (T₄, a tetra-iodinated tyrosine derivative). In the liver and kidney, T₄ is converted to T₃, the active metabolite. In order to increase solubility, the thyroid hormones attach to thyroid hormone binding proteins, thyroxin-binding globulin, and thyroxin-binding prealbumin (transthyretin). Transport and binding to thyroid hormone receptors in the cytoplasm and nucleus then takes place. Thus by acting as a replacement for natural thyroxine, symptoms of thyroxine deficiency are relieved.

toxicity

LD₅₀=20 mg/kg (orally in rat). Hypermetabolic state indistinguishable from thyrotoxicosis of endogenous origin. Symptoms of thyrotoxicosis include weight loss, increased appetite, palpitations, nervousness, diarrhea, abdominal cramps, sweating, tachycardia, increased pulse and blood pressure, cardiac arrhythmias, tremors, insomnia, heat intolerance, fever, and menstrual irregularities.

biotransformation

Approximately 70% of secreted T₄ is deiodinated to equal amounts of T₃ and reverse triiodothyronine (rT₃), which is calorigenically inactive. Elimination of T₄ and T₃ involves hepatic conjugation to glucuronic and sulfuric acids. The hormones undergo enterohepatic circulation as conjugates are hydrolyzed in the intestine and reabsorbed. Conjugated compounds that reach the colon are hydrolyzed and eliminated as free compounds in the feces. Other minor T₄ metabolites have been identified.

absorption

Bioavailability varies from 48% to 80%. Human studies have confirmed the importance of an intact jejunum and ileum for levothyroxine absorption and have shown some absorption from the duodenum.

half life

T₄, 6 to 7 days. T₃, 1 to 2 days.

route of elimination

Thyroid hormones are primarily eliminated by the kidneys.

drug interactions

Acenocoumarol: The thyroid hormone, levothyroxine, increase the anticoagulant effect of acenocoumarol.

Anisindione: The thyroid hormone, levothyroxine, increase the anticoagulant effect of anisindione.

Calcium: Calcium decreases absorption of levothyroxine

Calcium Acetate: Calcium salts such as calcium acetate may diminish the therapeutic effect of thyroid products such as levothyroxine. Separate the doses of the thyroid product and the oral calcium supplement by at least 4 hours. Monitor for decreased therapeutic effects of thyroid products if an oral calcium supplement is initiated/dose increased, or increased effects if an oral calcium supplement is discontinued/dose decreased.

Calcium Chloride: Calcium salts such as calcium chloride may diminish the therapeutic effect of thyroid products such as levothyroxine. Separate the doses of the thyroid product and the oral calcium supplement by at least 4 hours. Monitor for decreased therapeutic effects of thyroid products if an oral calcium supplement is initiated/dose increased, or increased effects if an oral calcium supplement is discontinued/dose decreased.

Cholestyramine: The resin, cholestyramine, decreases the absorption of the thyroid hormone, levothyroxine.

Colestipol: The resin, colestipol, decreases the absorption of the thyroid hormone, levothyroxine.

Dicumarol: The thyroid hormone, levothyroxine, increase the anticoagulant effect of dicumarol.

Digoxin: The thyroid hormone, levothyroxine, decreases the effect of digoxin.

Iron: Iron decreases absorption of levothyroxine

Iron Dextran: Iron decreases the absorption of levothyroxine

Raloxifene: Raloxifene decreases absorption of levothyroxine

Sucralfate: Sucralfate decreases the effect of levothyroxine

Warfarin: Levothyroxine may contribute to the anticoagulant effect of warfarin by increasing the metabolism of vitamin K-dependent clotting factors. Monitor for changes in prothrombin time and anticoagulant effects if levothyroxine is initiated, discontinued or dose changed.