Levothyroxine, also known as -thyroxine, is a synthetic form of the
thyroid hormone thyroxine (T
4).
[ It is used to treat thyroid hormone deficiency (hypothyroidism), including a severe form known as myxedema coma.][ It may also be used to treat and prevent certain types of thyroid tumors.][ It is not indicated for ]weight loss
Weight loss, in the context of medicine, health, or physical fitness, refers to a reduction of the total body mass, by a mean loss of fluid, body fat (adipose tissue), or lean mass (namely bone mineral deposits, muscle, tendon, and other conn ...
.[ Levothyroxine is taken orally (by mouth) or given by intravenous injection.][ Levothyroxine has a ]half-life Half-life is a mathematical and scientific description of exponential or gradual decay.
Half-life, half life or halflife may also refer to:
Film
* Half-Life (film), ''Half-Life'' (film), a 2008 independent film by Jennifer Phang
* ''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.[
Side effects from excessive doses include weight loss, trouble tolerating heat, sweating, anxiety, trouble sleeping, ]tremor
A tremor is an involuntary, somewhat rhythmic muscle contraction and relaxation involving neural oscillations, oscillations or twitching movements of one or more body parts. It is the most common of all involuntary movements and can affect the h ...
, and fast heart rate.[ Use is not recommended in people who have had a recent ]heart attack
A myocardial infarction (MI), commonly known as a heart attack, occurs when Ischemia, blood flow decreases or stops in one of the coronary arteries of the heart, causing infarction (tissue death) to the heart muscle. The most common symptom ...
.[ Use during ]pregnancy
Pregnancy is the time during which one or more offspring gestation, gestates inside a woman's uterus. A multiple birth, multiple pregnancy involves more than one offspring, such as with twins.
Conception (biology), Conception usually occurs ...
has been found to be safe.[ Dosing should be based on regular measurements of thyroid-stimulating hormone (TSH) and T4 levels in the blood.][ Much of the effect of levothyroxine is following its conversion to triiodothyronine (T3).]
Levothyroxine was first made in 1927. It is on the World Health Organization's List of Essential Medicines. Levothyroxine is available as a generic medication.[ In 2022, it was the fourth most commonly prescribed medication in the United States, with more than 82million prescriptions.]
Medical uses
Levothyroxine is typically used to treat hypothyroidism, and is the treatment of choice for people with hypothyroidism who often require lifelong thyroid hormone therapy.
It may also be used to treat goiter via its ability to lower thyroid-stimulating hormone (TSH), which is considered goiter-inducing. Levothyroxine is also used as interventional therapy in people with nodular thyroid disease or thyroid cancer
Thyroid cancer is cancer that develops from the tissues of the thyroid gland. It is a disease in which cells grow abnormally and have the potential to spread to other parts of the body. Symptoms can include swelling or a lump in the neck, ...
to suppress TSH secretion. A subset of people with hypothyroidism treated with an appropriate dose of levothyroxine will describe continuing symptoms despite TSH levels in the normal range. In these people, further laboratory and clinical evaluation is warranted, as they may have another cause for their symptoms. Furthermore, reviewing their medications and dietary supplements is important, as several medications can affect thyroid hormone levels.
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. Such people may be asymptomatic and whether they should be treated is controversial. One benefit of treating this population with levothyroxine therapy is preventing the development of hypothyroidism. 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. Oral dosing for patients with subclinical hypothyroidism is 1 μg/kg/day.
It is also used to treat myxedema coma, which is a severe form of hypothyroidism characterized by mental status changes and hypothermia. As it is a medical emergency with a high mortality rate, it should be treated in the intensive-care unit with thyroid hormone replacement and aggressive management of individual organ system complications.
Dosages vary according to the age groups and the individual condition of the person, body weight, and compliance with the medication and diet. Other predictors of the required dosage are sex, body mass index
Body mass index (BMI) is a value derived from the mass (Mass versus weight, weight) and height of a person. The BMI is defined as the human body weight, body mass divided by the square (algebra), square of the human height, body height, and is ...
, deiodinase activity (SPINA-GD), and etiology of hypothyroidism. Annual or semiannual clinical evaluations and TSH monitoring are appropriate after dosing has been established. Levothyroxine is taken on an empty stomach about half an hour to an hour before meals. As such, thyroid replacement therapy is usually taken 30 minutes prior to eating in the morning. For patients with trouble taking levothyroxine in the morning, bedtime dosing is effective, as well. A study in 2015 showed greater efficacy of levothyroxine when taken at bedtime. Doses of levothyroxine that normalize serum TSH may not normalize abnormal levels of LDL cholesterol and total cholesterol.
Poor compliance in taking the medicine is the most common cause of elevated TSH levels in people receiving appropriate doses of levothyroxine.
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. 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.
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. According to the U.S. Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...
pregnancy categories, levothyroxine has been assigned category A. Given that no increased risk of congenital abnormalities has been demonstrated in pregnant women taking levothyroxine, therapy should be continued during pregnancy. Furthermore, treatment 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.
Thyroid hormone requirements increase during and last throughout pregnancy. 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. Repeat thyroid function tests should be done five weeks after the dosage is increased.
While a minimal amount of thyroid hormones is found in breast milk, the amount does not influence infant plasma thyroid levels. Furthermore, levothyroxine was not found to cause any adverse events to the infant or mother during breastfeeding. Since adequate thyroid hormone concentrations are required to maintain normal lactation, appropriate levothyroxine doses should be administered during breastfeeding.
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.
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. 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. For oral tablets, the inability to swallow capsules is an additional contraindication.
Side effects
Adverse events are generally caused by incorrect dosing. Long-term suppression of TSH values below normal values frequently causes cardiac side effects and contributes to decreases in bone mineral density (low TSH levels are also well known to contribute to osteoporosis
Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to more porous bone, and consequent increase in Bone fracture, fracture risk.
It is the most common reason f ...
).
Too high a dose of levothyroxine causes hyperthyroidism. Overdose can result in heart palpitations
Palpitations occur when a person becomes aware of their heartbeat. The heartbeat may feel hard, fast, or uneven in their chest.
Symptoms include a very fast or irregular heartbeat. Palpitations are a sensory symptom. They are often described as ...
, abdominal pain, nausea, anxiousness, confusion, agitation, insomnia
Insomnia, also known as sleeplessness, is a sleep disorder where people have difficulty sleeping. They may have difficulty falling asleep, or staying asleep for as long as desired. Insomnia is typically followed by daytime sleepiness, low ene ...
, weight loss, and increased appetite. 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
Fever or pyrexia in humans is a symptom of an anti-infection defense mechanism that appears with Human body temperature, body temperature exceeding the normal range caused by an increase in the body's temperature Human body temperature#Fever, s ...
, hypoglycemia
Hypoglycemia (American English), also spelled hypoglycaemia or hypoglycæmia (British English), sometimes called low blood sugar, is a fall in blood sugar to levels below normal, typically below 70 mg/dL (3.9 mmol/L). Whipple's tria ...
, heart failure
Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome caused by an impairment in the heart's ability to Cardiac cycle, fill with and pump blood.
Although symptoms vary based on which side of the heart is affected, HF ...
, coma
A coma is a deep state of prolonged unconsciousness in which a person cannot be awakened, fails to Nociception, respond normally to Pain, painful stimuli, light, or sound, lacks a normal Circadian rhythm, sleep-wake cycle and does not initiate ...
, and unrecognized adrenal insufficiency.
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.
The effects of overdosing appear 6 hours to 11 days after ingestion.
Interactions
Many foods and other substances can interfere with the absorption of thyroxine. Substances that reduce absorption are aluminium
Aluminium (or aluminum in North American English) is a chemical element; it has chemical symbol, symbol Al and atomic number 13. It has a density lower than that of other common metals, about one-third that of steel. Aluminium has ...
- and magnesium
Magnesium is a chemical element; it has Symbol (chemistry), symbol Mg and atomic number 12. It is a shiny gray metal having a low density, low melting point and high chemical reactivity. Like the other alkaline earth metals (group 2 ...
-containing antacids, simethicone
Simeticone (International Nonproprietary Name, INN), also known as simethicone (United States Adopted Name, USAN), is an anti-foaming agent used to reduce bloating, discomfort or pain caused by excessive gas.
Medical uses
Simeticone is used to ...
, sucralfate, cholestyramine, colestipol, and polystyrene sulfonate. Sevelamer with calcium carbonate
Calcium carbonate is a chemical compound with the chemical formula . It is a common substance found in Rock (geology), rocks as the minerals calcite and aragonite, most notably in chalk and limestone, eggshells, gastropod shells, shellfish skel ...
may decrease the bioavailability of levothyroxine. 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. A study of eight women suggested that coffee may interfere with the intestinal absorption of levothyroxine, though at a level less than eating bran. Certain other substances can cause adverse effects that may be severe. Combination of levothyroxine with ketamine
Ketamine is a cyclohexanone-derived general anesthetic and NMDA receptor antagonist with analgesic and hallucinogenic properties, used medically for anesthesia, depression, and pain management. Ketamine exists as its S- (esketamine) a ...
may cause hypertension
Hypertension, also known as high blood pressure, is a Chronic condition, long-term Disease, medical condition in which the blood pressure in the artery, arteries is persistently elevated. High blood pressure usually does not cause symptoms i ...
and tachycardia; and tricyclic and tetracyclic antidepressants increase its toxicity. Soy, walnuts, fiber
Fiber (spelled fibre in British English; from ) is a natural or artificial substance that is significantly longer than it is wide. Fibers are often used in the manufacture of other materials. The strongest engineering materials often inco ...
, calcium supplements, and iron supplements can also adversely affect absorption. A study found that cow's milk
Milk is a white liquid food produced by the mammary glands of lactating mammals. It is the primary source of nutrition for young mammals (including breastfed human infants) before they are able to digest solid food. Milk contains many nutr ...
reduces levothyroxine absorption.
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 taking it in the morning on an empty stomach.
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 for more information on its biosynthesis.
Industrially, levothyroxine is made by chemical synthesis. Tyrosine is a common starting material. 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.
Dextrothyroxine is the mirror form of levothyroxine with the opposite, non-natural chirality.
Mechanism of action
T4 is a prohormone; T4 is a precursor to the hormone T3. T4 is a tetraiodide, T3 is a triiodide, triiodothyronine. The selenoenzyme iodothyronine deiodinase mediates the T4 → T3 conversion. T3-thyroxine is a unique example of an iodine compound essential for human health. T3 binds to thyroid receptor proteins in the cell nucleus
The cell nucleus (; : nuclei) is a membrane-bound organelle found in eukaryote, eukaryotic cell (biology), cells. Eukaryotic cells usually have a single nucleus, but a few cell types, such as mammalian red blood cells, have #Anucleated_cells, ...
and causes metabolic effects through the control of DNA transcription and protein synthesis.
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
The jejunum is the second part of the small intestine in humans and most higher vertebrates, including mammals, reptiles, and birds. Its lining is specialized for the absorption by enterocytes of small nutrient molecules which have been pr ...
and upper ileum
The ileum () is the final section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear and the terms posterior intestine or distal intestine may ...
. Levothyroxine absorption is increased by fasting and decreased in certain malabsorption syndromes, by certain foods, and with age. Dietary fiber decreases the bioavailability of the drug.
Greater than 99% of circulating thyroid hormones are bound to plasma proteins including thyroxine-binding globulin, transthyretin (previously called thyroxine-binding prealbumin), and albumin. Only free hormone is metabolically active.
The primary pathway of thyroid hormone metabolism is through sequential deiodination. The liver is the main site of T4 deiodination, and along with the kidneys, are responsible for about 80% of circulating T3. 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.
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. Thyroid hormones are primarily eliminated by the kidneys (about 80%), with urinary excretion decreasing with age. The remaining 20% of T4 is eliminated in the stool.
History
Thyroxine was first isolated in pure form in 1914 at the Mayo Clinic by Edward Calvin Kendall from extracts of hog thyroid glands. The hormone was synthesized in 1927 by British chemists Charles Robert Harington and George Barger.
Society and culture
Economics
, levothyroxine was the second-most commonly prescribed medication in the U.S., with 23.8 million prescriptions filled each year.
In 2022, it was the fourth most commonly prescribed medication in the United States, with more than 82million prescriptions.
Available forms
Levothyroxine for systemic administration is available as an oral tablet, an intramuscular injection, and as a solution for intravenous infusion. Furthermore, it is available as both brand-name and generic products. 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. 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. 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. For people who do switch products, their TSH and free T4 levels should be tested after six weeks to check that they are within the normal range.
Brand names include Eltroxin, Euthyrox, Eutirox, Letrox, Levaxin, Lévothyrox, Levoxyl, -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.[
]
Research
A meta-analysis published in 2021 found that once weekly thyroxine is associated with less efficient control of hypothyroidism at six weeks.
References
External links
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{{Authority control
Drugs developed by AbbVie
Hormones of the hypothalamus-pituitary-thyroid axis
Hormones of the thyroid gland
Iodinated tyrosine derivatives
Drugs developed by Merck
Drugs developed by Pfizer
Wikipedia medicine articles ready to translate
Thyroid hormone receptor agonists
World Health Organization essential medicines
Iodine-containing natural products
Organoiodides
1914 in science
1914 in the United States