| Drug ID: | D203 |
| Drug Name: | Levothyroxine |
| Synonyms: |
3,3',5,5'-Tetraiodo-L-thyronine; 3,5,3',5'-Tetraiodo-L-thyronine; 4-(4-Hydroxy-3,5-diiodophenoxy)-3,5-diiodo-L-phenylalanine; L-T4; L-Thyroxine; Levothyroxin; LT4; O-(4-Hydroxy-3,5-diidophenyl)-3,5-diiodo-L-tyrosine; O-(4-Hydroxy-3,5-diiodophenyl)-3,5-diiodo-L-tyrosine; T4; Thyroxine
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| Type: | Chemical drug |
| DrugBank ID: |
DB00451
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| DrugBank Description: |
Levothyroxine is a synthetically produced form of thyroxine, a major endogenous hormone secreted by the thyroid gland. Also known as L-thyroxine or the brand name product Synthroid, levothyroxine is used primarily to treat hypothyroidism, a condition where the thyroid gland is no longer able to produce sufficient quantities of the thyroid hormones T<sub>4</sub> (tetraiodothyronine or thyroxine) and T<sub>3</sub> (triiodothyronine or ), resulting in diminished down-stream effects of these hormones. Without sufficient quantities of circulating thyroid hormones, symptoms of hypothyroidism begin to develop such as fatigue, increased heart rate, depression, dry skin and hair, muscle cramps, constipation, weight gain, memory impairment, and poor tolerance to cold temperatures.
In response to Thyroid Stimulating Hormone (TSH) release by the pituitary gland, a normally functioning thyroid gland will produce and secrete T<sub>4</sub>, which is then converted through deiodination (by type I or type II 5′-deiodinases) into its active metabolite T<sub>3</sub>. While T<sub>4</sub> is the major product secreted by the thyroid gland, T<sub>3</sub> exerts the majority of the physiological effects of the thyroid hormones; T<sub>4</sub> and T<sub>3</sub> have a relative potency of ~1:4 (T4:T3). T<sub>4</sub> and T<sub>3</sub> act on nearly every cell of the body, but have a particularly strong effect on the cardiac system. As a result, many cardiac functions including heart rate, cardiac output, and systemic vascular resistance are closely linked to thyroid status.
Prior to the development of levothyroxine, or desiccated thyroid, used to be the mainstay of treatment for hypothyroidism. However, this is no longer recommended for the majority of patients due to several clinical concerns including limited controlled trials supporting its use. Desiccated thyroid products contain a ratio of T4 to T3 of 4.2:1, which is significantly lower than the 14:1 ratio of secretion by the human thyroid gland. This higher proportion of T3 in desiccated thyroid products can lead to supraphysiologic levels of T3 which may put patients at risk of thyrotoxicosis if thyroid extract therapy is not adjusted according to the serum TSH.
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| PubChem ID: |
5819
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| CasNo: |
51-48-9
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| Repositioning for NAFLD: |
Yes
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| SMILES: |
O(c1cc(I)c(c(c1)I)O)c1c(I)cc(cc1I)C[C@@H](C(=O)O)N
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| Structure: |
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| InChiKey: |
XUIIKFGFIJCVMT-LBPRGKRZSA-N
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| Molecular Weight: |
776.872
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| DrugBank Targets: |
Thyroid hormone receptor alpha agonist; Thyroid hormone receptor beta agonist; Integrin alpha-V; Integrin beta-3
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| DrugBank MoA: |
Levothyroxine is a synthetically prepared levo-isomer of the thyroid hormone thyroxine (T<sub>4</sub>, a tetra-iodinated tyrosine derivative) that acts as a replacement in deficiency syndromes such as hypothyroidism. T<sub>4</sub> is the major hormone secreted from the thyroid gland and is chemically identical to the naturally secreted T<sub>4</sub>: it increases metabolic rate, decreases thyroid-stimulating hormone (TSH) production from the anterior lobe of the pituitary gland, and, in peripheral tissues, is converted to T<sub>3</sub>. Thyroxine is released from its precursor protein thyroglobulin through proteolysis and secreted into the blood where is it then peripherally deiodinated to form triiodothyronine (T<sub>3</sub>) which exerts a broad spectrum of stimulatory effects on cell metabolism. T<sub>4</sub> and T<sub>3</sub> have a relative potency of ~1:4.
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.
The thyroid hormones have been shown to exert both genomic and non-genomic effects. They exert their genomic effects by diffusing into the cell nucleus and binding to thyroid hormone receptors in DNA regions called thyroid hormone response elements (TREs) near genes. This complex of T<sub>4</sub>, T<sub>3</sub>, DNA, and other coregulatory proteins causes a conformational change and a resulting shift in transcriptional regulation of nearby genes, synthesis of messenger RNA, and cytoplasmic protein production. For example, in cardiac tissues T<sub>3</sub> has been shown to regulate the genes for α- and β-myosin heavy chains, production of the sarcoplasmic reticulum proteins calcium-activated ATPase (Ca2+-ATPase) and phospholamban, β-adrenergic receptors, guanine-nucleotide regulatory proteins, and adenylyl cyclase types V and VI as well as several plasma-membrane ion transporters, such as Na+/K+–ATPase, Na+/Ca2+ exchanger, and voltage-gated potassium channels, including Kv1.5, Kv4.2, and Kv4.3. As a result, many cardiac functions including heart rate, cardiac output, and systemic vascular resistance are closely linked to thyroid status.
The non-genomic actions of the thyroid hormones have been shown to occur through binding to a plasma membrane receptor integrin aVb3 at the Arg-Gly-Asp recognition site. From the cell-surface, T<sub>4</sub> binding to integrin results in down-stream effects including activation of mitogen-activated protein kinase (MAPK; ERK1/2) and causes subsequent effects on cellular/nuclear events including angiogenesis and tumor cell proliferation.
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| DrugBank Pharmacology: |
Oral levothyroxine is a synthetic hormone that exerts the same physiologic effect as endogenous T<sub>4</sub>, thereby maintaining normal T<sub>4</sub> levels when a deficiency is present.
Levothyroxine has a narrow therapeutic index and is titrated to maintain a euthyroid state with TSH (thyroid stimulating hormone) within a therapeutic range of 0.4–4.0 mIU/L. Over- or under-treatment with levothyroxine may have negative effects on growth and development, cardiovascular function, bone metabolism, reproductive function, cognitive function, emotional state, gastrointestinal function and glucose and lipid metabolism. The dose of levothyroxine should be titrated slowly and carefully and patients should be monitored for their response to titration to avoid these effects. TSH levels should be monitored at least yearly to avoid over-treating with levothyroxine which can result in hyperthyroidism (TSH <0.1mIU/L) and symptoms of increased heart rate, diarrhea, tremor, hypercalcemia, and weakness to name a few.
As many cardiac functions including heart rate, cardiac output, and systemic vascular resistance are closely linked to thyroid status, over-treatment with levothyroxine may result in increases in heart rate, cardiac wall thickness, and cardiac contractility and may precipitate angina or arrhythmias, particularly in patients with cardiovascular disease and in elderly patients. In populations with any cardiac concerns, levothyroxine should be initiated at lower doses than those recommended in younger individuals or in patients without cardiac disease. Patients receiving concomitant levothyroxine and sympathomimetic agents should be monitored for signs and symptoms of coronary insufficiency. If cardiac symptoms develop or worsen, reduce the levothyroxine dose or withhold for one week and restart at a lower dose.
Increased bone resorption and decreased bone mineral density may occur as a result of levothyroxine over-replacement, particularly in post-menopausal women. The increased bone resorption may be associated with increased serum levels and urinary excretion of calcium and phosphorous, elevations in bone alkaline phosphatase and suppressed serum parathyroid hormone levels. Administer the minimum dose of levothyroxine that achieves the desired clinical and biochemical response to mitigate this risk.
Addition of levothyroxine therapy in patients with diabetes mellitus may worsen glycemic control and result in increased antidiabetic agent or insulin requirements. Carefully monitor glycemic control after starting, changing or discontinuing levothyroxine.
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| DrugBank Indication: |
Levothyroxine is indicated as replacement therapy in primary (thyroidal), secondary (pituitary) and tertiary (hypothalamic) congenital or acquired hypothyroidism. It is also indicated as an adjunct to surgery and radioiodine therapy in the management of thyrotropin-dependent well-differentiated thyroid cancer.
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| Targets: |
THRA agonist; THRB agonist
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| Therapeutic Category: |
Anti-fibrosis
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| Clinical Trial Progress: |
Phase 2 terminated (NCT03281083: Difficult recruitment and end of funding.)
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| Latest Progress: |
Under clinical trials
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