Levothyroxine

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Levothyroxine
Levothyroxine 200.svg
Levothyroxine-from-xtal-3D-bs-17.png
Clinical data
Trade names Synthroid, Levoxyl, others
Other names3,5,3′,5′-Tetraiodo-L-thyronine
AHFS/Drugs.com Monograph
MedlinePlus a682461
License data
Pregnancy
category
Routes of
administration 		Oral, intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 40-80% [5]
Metabolism Mainly in liver, kidneys, brain and muscles
Elimination half-life ca. 7 days (in hyperthyroidism 3–4 days, in hypothyroidism 9–10 days)
Excretion Feces and urine
Identifiers
  • (S)-2-Amino-3-[4-(4-hydroxy-3,5-diiodophenoxy)-3,5-diiodophenyl]propanoic acid
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.000.093 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C15H11I4NO4
Molar mass 776.874 g·mol−1
3D model (JSmol)
Melting point 231 to 233 °C (448 to 451 °F) [6]
Solubility in water Slightly soluble (0.105 mg·mL−1 at 25 °C) [7]  mg/mL (20 °C)
  • NC(Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)C(O)=O
  • InChI=1S/C15H11I4NO4/c16-8-4-7(5-9(17)13(8)21)24-14-10(18)1-6(2-11(14)19)3-12(20)15(22)23/h1-2,4-5,12,21H, 3,20H2, (H, 22,23)/t12-/m0/s1 Yes check.svgY
  • Key:XUIIKFGFIJCVMT-LBPRGKRZSA-N

Levothyroxine, also known as L-thyroxine, is a synthetic form of the thyroid hormone thyroxine (T4). [5] [8] It is used to treat thyroid hormone deficiency (hypothyroidism), including a severe form known as myxedema coma. [5] It may also be used to treat and prevent certain types of thyroid tumors. [5] It is not indicated for weight loss. [5] Levothyroxine is taken orally (by mouth) or given by intravenous injection. [5] Levothyroxine has a half-life of 7.5 days when taken daily, so about six weeks is required for it to reach a steady level in the blood. [5]

Contents

Side effects from excessive doses include weight loss, trouble tolerating heat, sweating, anxiety, trouble sleeping, tremor, and fast heart rate. [5] Use is not recommended in people who have had a recent heart attack. [5] Use during pregnancy has been found to be safe. [5] Dosing should be based on regular measurements of thyroid-stimulating hormone (TSH) and T4 levels in the blood. [5] Much of the effect of levothyroxine is following its conversion to triiodothyronine (T3). [5]

Levothyroxine was first made in 1927. [8] It is on the World Health Organization's List of Essential Medicines. [9] Levothyroxine is available as a generic medication. [5] In 2022, it was the fourth most commonly prescribed medication in the United States, with more than 82 million prescriptions. [10] [11]

Medical use

Levothyroxine is typically used to treat hypothyroidism, [12] and is the treatment of choice for people with hypothyroidism [13] who often require lifelong thyroid hormone therapy. [14]

It may also be used to treat goiter via its ability to lower thyroid-stimulating hormone (TSH), which is considered goiter-inducing. [15] [16] Levothyroxine is also used as interventional therapy in people with nodular thyroid disease or thyroid cancer to suppress TSH secretion. [17] A subset of people with hypothyroidism treated with an appropriate dose of levothyroxine will describe continuing symptoms despite TSH levels in the normal range. [14] In these people, further laboratory and clinical evaluation is warranted, as they may have another cause for their symptoms. [14] Furthermore, reviewing their medications and possible dietary supplements is important, as several medications can affect thyroid hormone levels. [14]

Levothyroxine is also used to treat subclinical hypothyroidism, which is defined by an elevated TSH level and a normal-range free T4 level without symptoms. [14] Such people may be asymptomatic [14] and whether they should be treated is controversial. [13] One benefit of treating this population with levothyroxine therapy is preventing development of hypothyroidism. [13] As such, treatment should be taken into account for patients with initial TSH levels above 10 mIU/L, people with elevated thyroid peroxidase antibody titers, people with symptoms of hypothyroidism and TSH levels of 5–10 mIU/L, and women who are pregnant or want to become pregnant. [13] Oral dosing for patients with subclinical hypothyroidism is 1 μg/kg/day. [18]

It is also used to treat myxedema coma, which is a severe form of hypothyroidism characterized by mental status changes and hypothermia. [14] As it is a medical emergency with a high mortality rate, it should be treated in the intensive-care unit [14] with thyroid hormone replacement and aggressive management of individual organ system complications. [13]

Generic levothyroxine, 25-mg oral tablet 007815180lg Generic Levothyroxine.jpg
Generic levothyroxine, 25-μg oral tablet

Dosages vary according to the age groups and the individual condition of the person, body weight, and compliance to the medication and diet. Other predictors of the required dosage are sex, body mass index, deiodinase activity (SPINA-GD), and etiology of hypothyroidism. [19] Annual or semiannual clinical evaluations and TSH monitoring are appropriate after dosing has been established. [20] Levothyroxine is taken on an empty stomach about half an hour to an hour before meals. [21] As such, thyroid replacement therapy is usually taken 30 minutes prior to eating in the morning. [14] For patients with trouble taking levothyroxine in the morning, bedtime dosing is effective, as well. [14] A study in 2015 showed greater efficacy of levothyroxine when taken at bedtime. [22] Doses of levothyroxine that normalize serum TSH may not normalize abnormal levels of LDL cholesterol and total cholesterol. [23]

Poor compliance in taking the medicine is the most common cause of elevated TSH levels in people receiving appropriate doses of levothyroxine. [14]

50 and older

For older people (over 50 years old) and people with known or suspected ischemic heart disease, levothyroxine therapy should not be initiated at the full replacement dose. [24] Since thyroid hormone increases the heart's oxygen demand by increasing heart rate and contractility, starting at higher doses may cause an acute coronary syndrome or an abnormal heart rhythm. [14]

Pregnancy and breastfeeding

Hypothyroidism is common among pregnant women. A nationwide cohort study showed that 1.39% of all pregnant women in 2010 in Denmark received a prescription of levothyroxine during pregnancy. [25] According to the U.S. Food and Drug Administration pregnancy categories, levothyroxine has been assigned category A. [24] Given that no increased risk of congenital abnormalities has been demonstrated in pregnant women taking levothyroxine, therapy should be continued during pregnancy. [24] Furthermore, therapy should be immediately administered to women diagnosed with hypothyroidism during pregnancy, as hypothyroidism is associated with a higher rate of complications, such as spontaneous abortion, preeclampsia, and premature birth. [24]

Thyroid hormone requirements increase during and last throughout pregnancy. [14] As such, pregnant women are recommended to increase to nine doses of levothyroxine each week, rather than the usual seven, as soon as their pregnancy is confirmed. [14] Repeat thyroid function tests should be done five weeks after the dosage is increased. [14]

While a minimal amount of thyroid hormones is found in breast milk, the amount does not influence infant plasma thyroid levels. [18] Furthermore, levothyroxine was not found to cause any adverse events to the infant or mother during breastfeeding. [18] As adequate concentrations of thyroid hormone are required to maintain normal lactation, appropriate levothyroxine doses should be administered during breastfeeding. [18]

Children

Levothyroxine is safe and effective for children with hypothyroidism; the goal of treatment for children with hypothyroidism is to reach and preserve normal intellectual and physical development. [24]

Contraindications

Levothyroxine is contraindicated in people with hypersensitivity to levothyroxine sodium or any component of the formulation, people with acute myocardial infarction, and people with thyrotoxicosis of any etiology. [18] Levothyroxine is also contraindicated for people with uncorrected adrenal insufficiency, as thyroid hormones may cause an acute adrenal crisis by increasing the metabolic clearance of glucocorticoids. [24] For oral tablets, the inability to swallow capsules is an additional contraindication. [18]

Side effects

Adverse events are generally caused by incorrect dosing. Long-term suppression of TSH values below normal values frequently cause cardiac side effects and contribute to decreases in bone mineral density (low TSH levels are also well known to contribute to osteoporosis). [26]

Too high a dose of levothyroxine causes hyperthyroidism. [21] [27] [28] Overdose can result in heart palpitations, abdominal pain, nausea, anxiousness, confusion, agitation, insomnia, weight loss, and increased appetite. [29] [27] Allergic reactions to the drug are characterized by symptoms such as difficulty breathing, shortness of breath, or swelling of the face and tongue. Acute overdose may cause fever, hypoglycemia, heart failure, coma, and unrecognized adrenal insufficiency.[ citation needed ]

Acute massive overdose may be life-threatening; treatment should be symptomatic and supportive. Massive overdose can be associated with increased sympathetic activity, thus may require treatment with beta-blockers. [21]

The effects of overdosing appear 6 hours to 11 days after ingestion. [29]

Interactions

Many foods and other substances can interfere with absorption of thyroxine. Substances that reduce absorption are aluminium- and magnesium-containing antacids, simethicone, sucralfate, cholestyramine, colestipol, and polystyrene sulfonate. Sevelamer with calcium carbonate may decrease the bioavailability of levothyroxine. [30] Grapefruit juice may delay the absorption of levothyroxine, but based on a study of 10 healthy people aged 20–30 (eight men, two women), it may not have a significant effect on bioavailability in young adults. [31] [32] A study of eight women suggested that coffee may interfere with the intestinal absorption of levothyroxine, though at a level less than eating bran. [33] Certain other substances can cause adverse effects that may be severe. Combination of levothyroxine with ketamine may cause hypertension and tachycardia; [34] and tricyclic and tetracyclic antidepressants increase its toxicity. Soy, walnuts, fiber, calcium supplements, and iron supplements can also adversely affect absorption. [31] A study found that cow's milk reduces levothyroxine absorption. [35]

To minimize interactions, a manufacturer of levothyroxine recommends after taking it, waiting 30 minutes to one hour before eating or drinking anything that is not water. They further recommend to take it in the morning on an empty stomach. [31]

Chemistry

Levothyroxine is a synthetic form of thyroxine (T4), which is secreted by the thyroid gland. Levothyroxine and thyroxine are chemically identical: natural thyroxine is also in the "levo" chiral form, the difference is only in terminological preference. T4 is biosynthesized from tyrosine. Approximately 5% of the US population suffers from over- or underproduction of T4 and T3. See Thyroid hormones § Thyroid metabolism for more information on its biosynthesis.[ citation needed ]

Industrially, levothyroxine is made by chemical synthesis. Tyrosine is a common starting material. [36] The produced hormone is incorporated into drugs as its sodium salt, levothyroxine sodium. Solid drugs such as tablets contain the pentahydrate form of the salt. [37]

Dextrothyroxine is the mirror form of levothryoxine with the opposite, non-natural chirality.

Mechanism of action

T4 is a prohormone; that is, T4 is a precursor to the hormone T3. Whereas T4 is a tetraiodide, T3 is a triiodide, triiodothyronine. The T4 → T3 conversion is mediated by the selenoenzyme iodothyronine deiodinase. T3-thyroxine is a unique example of an iodine compound that is essential for human health. [38] [39] T3 binds to thyroid receptor proteins in the cell nucleus and causes metabolic effects through the control of DNA transcription and protein synthesis. [24]

Pharmacokinetics

Absorption of orally administered levothyroxine from the gastrointestinal tract ranges from 40 to 80%, with the majority of the drug absorbed from the jejunum and upper ileum. [24] Levothyroxine absorption is increased by fasting and decreased in certain malabsorption syndromes, by certain foods, and with age. The bioavailability of the drug is decreased by dietary fiber. [24]

Greater than 99% of circulating thyroid hormones are bound to plasma proteins including thyroxine-binding globulin, transthyretin (previously called thyroxine-binding prealbumin), and albumin. [18] Only free hormone is metabolically active. [18]

The primary pathway of thyroid hormone metabolism is through sequential deiodination. [24] The liver is the main site of T4 deiodination, and along with the kidneys, are responsible for about 80% of circulating T3. [40] In addition to deiodination, thyroid hormones are also excreted through the kidneys and metabolized through conjugation and glucuronidation and excreted directly into the bile and the gut, where they undergo enterohepatic recirculation. [18]

Half-life elimination is 6–7 days for people with normal lab results; 9–10 days for people with hypothyroidism; 3–4 days for people with hyperthyroidism. [18] Thyroid hormones are primarily eliminated by the kidneys (about 80%), with urinary excretion decreasing with age. [18] The remaining 20% of T4 is eliminated in the stool. [18]

History

Thyroxine was first isolated in pure form in 1914 at the Mayo Clinic by Edward Calvin Kendall from extracts of hog thyroid glands. [41] The hormone was synthesized in 1927 by British chemists Charles Robert Harington and George Barger. [42]

Society and culture

Economics

A 30 tablet blister pack package of generic Euthyrox (levothyroxine) manufactured by Merck KGaA and marketed by Provell Pharmaceuticals in the US Generic Euthyrox.jpg
A 30 tablet blister pack package of generic Euthyrox (levothyroxine) manufactured by Merck KGaA and marketed by Provell Pharmaceuticals in the US

As of 2011, levothyroxine was the second-most commonly prescribed medication in the U.S., [43] with 23.8 million prescriptions filled each year. [44]

In 2016, it was the most commonly prescribed medication in the US, with more than 114 million prescriptions. [11]

Available forms

Levothyroxine for systemic administration is available as an oral tablet, an intramuscular injection, and as a solution for intravenous infusion. [18] Furthermore, it is available as both brand-name and generic products. [14] While the FDA approved the use of generic levothyroxine for brand-name levothyroxine in 2004, the decision was met with disagreement by several medical associations. [14] The American Association of Clinical Endocrinologists (AACE), the Endocrine Society, and the American Thyroid Association did not agree with the FDA that brand-name and generic formulations of levothyroxine were bioequivalent. [14] As such, people were recommended to be started and kept on either brand-name or generic levothyroxine formulations and not changed back and forth from one to the other. [14] For people who do switch products, their TSH and free T4 levels should be tested after six weeks to check that they are within normal range. [14]

Brand names include Eltroxin, Euthyrox, Eutirox, Letrox, Levaxin, Lévothyrox, Levoxyl, L-thyroxine, Thyrax, and Thyrax Duotab in Europe; Thyrox and Thyronorm in South Asia; Euthyrox, Levoxyl, Synthroid, Tirosint, and Unithroid in North and South America; and Thyrin and Thyrolar in Bangladesh. Numerous generic versions also are available. [5]

The related drug dextrothyroxine (D-thyroxine) was used in the past as a treatment for hypercholesterolemia (elevated cholesterol levels), but was withdrawn due to cardiac side effects.[ citation needed ] Once weekly thyroxine (OWT) preparations are also available for clinical use. A recent meta-analysis published by Dutta et al. involving data from 4 studies (294 patients) showed that OWT is associated with less efficient control of hypothyroidism, risks of supraphysiologic elevation of thyroid hormone levels along with transient echocardiographic changes in some patients following 2-4 h of thyroxine intake. [45] Hence it is not surprising that OWT therapy has not become popular and is very sparingly used across the globe.

Related Research Articles

<span class="mw-page-title-main">Hyperthyroidism</span> Clinical syndrome caused by excessive thyroid hormone

Hyperthyroidism is the condition that occurs due to excessive production of thyroid hormones by the thyroid gland. Thyrotoxicosis is the condition that occurs due to excessive thyroid hormone of any cause and therefore includes hyperthyroidism. Some, however, use the terms interchangeably. Signs and symptoms vary between people and may include irritability, muscle weakness, sleeping problems, a fast heartbeat, heat intolerance, diarrhea, enlargement of the thyroid, hand tremor, and weight loss. Symptoms are typically less severe in the elderly and during pregnancy. An uncommon but life-threatening complication is thyroid storm in which an event such as an infection results in worsening symptoms such as confusion and a high temperature; this often results in death. The opposite is hypothyroidism, when the thyroid gland does not make enough thyroid hormone.

<span class="mw-page-title-main">Thyroid</span> Endocrine gland in the neck; secretes hormones that influence metabolism

The thyroid, or thyroid gland, is an endocrine gland in vertebrates. In humans, it is a butterfly-shaped gland located in the neck below the Adam's apple. It consists of two connected lobes. The lower two thirds of the lobes are connected by a thin band of tissue called the isthmus. Microscopically, the functional unit of the thyroid gland is the spherical thyroid follicle, lined with follicular cells (thyrocytes), and occasional parafollicular cells that surround a lumen containing colloid.

<span class="mw-page-title-main">Graves' disease</span> Autoimmune endocrine disease

Graves' disease, also known as toxic diffuse goiter or Basedow’s disease, is an autoimmune disease that affects the thyroid. It frequently results in and is the most common cause of hyperthyroidism. It also often results in an enlarged thyroid. Signs and symptoms of hyperthyroidism may include irritability, muscle weakness, sleeping problems, a fast heartbeat, poor tolerance of heat, diarrhea and unintentional weight loss. Other symptoms may include thickening of the skin on the shins, known as pretibial myxedema, and eye bulging, a condition caused by Graves' ophthalmopathy. About 25 to 30% of people with the condition develop eye problems.

<span class="mw-page-title-main">Hypothyroidism</span> Insufficient production of thyroid hormones by the thyroid gland

Hypothyroidism is a disorder of the endocrine system in which the thyroid gland does not produce enough thyroid hormones. It can cause a number of symptoms, such as poor ability to tolerate cold, extreme fatigue, muscle aches, constipation, slow heart rate, depression, and weight gain. Occasionally there may be swelling of the front part of the neck due to goitre. Untreated cases of hypothyroidism during pregnancy can lead to delays in growth and intellectual development in the baby or congenital iodine deficiency syndrome.

<span class="mw-page-title-main">Congenital hypothyroidism</span> Thyroid hormone deficiency present at birth

Congenital hypothyroidism (CH) is thyroid hormone deficiency present at birth. If untreated for several months after birth, severe congenital hypothyroidism can lead to growth failure and permanent intellectual disability. Infants born with congenital hypothyroidism may show no effects, or may display mild effects that often go unrecognized as a problem. Significant deficiency may cause excessive sleeping, reduced interest in nursing, poor muscle tone, low or hoarse cry, infrequent bowel movements, significant jaundice, and low body temperature.

Thyroid-stimulating hormone (also known as thyrotropin, thyrotropic hormone, or abbreviated TSH) is a pituitary hormone that stimulates the thyroid gland to produce thyroxine (T4), and then triiodothyronine (T3) which stimulates the metabolism of almost every tissue in the body. It is a glycoprotein hormone produced by thyrotrope cells in the anterior pituitary gland, which regulates the endocrine function of the thyroid.

<span class="mw-page-title-main">Triiodothyronine</span> Chemical compound

Triiodothyronine, also known as T3, is a thyroid hormone. It affects almost every physiological process in the body, including growth and development, metabolism, body temperature, and heart rate.

<span class="mw-page-title-main">Hashimoto's thyroiditis</span> Autoimmune disease

Hashimoto's thyroiditis, also known as chronic lymphocytic thyroiditis, Hashimoto's disease, and autoimmune thyroiditis is an autoimmune disease in which the thyroid gland is gradually destroyed.

<span class="mw-page-title-main">Propylthiouracil</span> Medication used to treat hyperthyroidism

Propylthiouracil (PTU) is a medication used to treat hyperthyroidism. This includes hyperthyroidism due to Graves' disease and toxic multinodular goiter. In a thyrotoxic crisis it is generally more effective than methimazole. Otherwise it is typically only used when methimazole, surgery, and radioactive iodine is not possible. It is taken by mouth.

<span class="mw-page-title-main">Thyroid disease</span> Medical condition

Thyroid disease is a medical condition that affects the function of the thyroid gland. The thyroid gland is located at the front of the neck and produces thyroid hormones that travel through the blood to help regulate many other organs, meaning that it is an endocrine organ. These hormones normally act in the body to regulate energy use, infant development, and childhood development.

<span class="mw-page-title-main">Carbimazole</span> Medication used for hyperthyroidism

Carbimazole (brand names Neo-Mercazole, Anti-Thyrox, etc.) is used to treat hyperthyroidism. Carbimazole is a pro-drug as after absorption it is converted to the active form, methimazole. Methimazole prevents thyroid peroxidase enzyme from iodinating and coupling the tyrosine residues on thyroglobulin, hence reducing the production of the thyroid hormones T3 and T4 (thyroxine).

<span class="mw-page-title-main">Liothyronine</span> Chemical compound

Liothyronine is a manufactured form of the thyroid hormone triiodothyronine (T3). It is most commonly used to treat hypothyroidism and myxedema coma. It can be taken by mouth or by injection into a vein.

Thyroid function tests (TFTs) is a collective term for blood tests used to check the function of the thyroid. TFTs may be requested if a patient is thought to suffer from hyperthyroidism or hypothyroidism, or to monitor the effectiveness of either thyroid-suppression or hormone replacement therapy. It is also requested routinely in conditions linked to thyroid disease, such as atrial fibrillation and anxiety disorder.

Desiccated thyroid extract (DTE), is thyroid gland that has been dried and powdered for medical use. It is used to treat hypothyroidism, but less preferred than levothyroxine. It is taken by mouth. Maximal effects may take up to three weeks to occur.

<span class="mw-page-title-main">Hypothalamic–pituitary–thyroid axis</span> Part of the neuroendocrine system

The hypothalamic–pituitary–thyroid axis is part of the neuroendocrine system responsible for the regulation of metabolism and also responds to stress.

An antithyroid agent is a hormone inhibitor acting upon thyroid hormones.

Euthyroid sick syndrome (ESS) is a state of adaptation or dysregulation of thyrotropic feedback control wherein the levels of T3 and/or T4 are abnormal, but the thyroid gland does not appear to be dysfunctional. This condition may result from allostatic responses of hypothalamus-pituitary-thyroid feedback control, dyshomeostatic disorders, drug interferences, and impaired assay characteristics in critical illness.

<span class="mw-page-title-main">Thyroid hormones</span> Hormones produced by the thyroid gland

Thyroid hormones are any hormones produced and released by the thyroid gland, namely triiodothyronine (T3) and thyroxine (T4). They are tyrosine-based hormones that are primarily responsible for regulation of metabolism. T3 and T4 are partially composed of iodine, derived from food. A deficiency of iodine leads to decreased production of T3 and T4, enlarges the thyroid tissue and will cause the disease known as simple goitre.

Thyroid disease in pregnancy can affect the health of the mother as well as the child before and after delivery. Thyroid disorders are prevalent in women of child-bearing age and for this reason commonly present as a pre-existing disease in pregnancy, or after childbirth. Uncorrected thyroid dysfunction in pregnancy has adverse effects on fetal and maternal well-being. The deleterious effects of thyroid dysfunction can also extend beyond pregnancy and delivery to affect neurointellectual development in the early life of the child. Due to an increase in thyroxine binding globulin, an increase in placental type 3 deioidinase and the placental transfer of maternal thyroxine to the fetus, the demand for thyroid hormones is increased during pregnancy. The necessary increase in thyroid hormone production is facilitated by high human chorionic gonadotropin (hCG) concentrations, which bind the TSH receptor and stimulate the maternal thyroid to increase maternal thyroid hormone concentrations by roughly 50%. If the necessary increase in thyroid function cannot be met, this may cause a previously unnoticed (mild) thyroid disorder to worsen and become evident as gestational thyroid disease. Currently, there is not enough evidence to suggest that screening for thyroid dysfunction is beneficial, especially since treatment thyroid hormone supplementation may come with a risk of overtreatment. After women give birth, about 5% develop postpartum thyroiditis which can occur up to nine months afterwards. This is characterized by a short period of hyperthyroidism followed by a period of hypothyroidism; 20–40% remain permanently hypothyroid.

Kent Holtorf is an American physician and entrepreneur practicing in Los Angeles, California. He is a board examiner of the American Board of Anti-Aging Medicine (ABAAM), which is not recognized by established medical organizations. He is the founder and medical director of Holtorf Medical Group, a practice with five centers that offer treatment for conditions including fibromyalgia, adrenal fatigue, complex endocrine dysfunction, hypothyroidism, age management, chronic fatigue syndrome, low libido, chronic Lyme disease, migraines, PMS, perimenopause and menopause. His practice focuses on alternative therapies that are not recognised as effective. He has been criticized in the media for his controversial views on topics like bioidentical hormone replacement therapy and vaccines.

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