Levothyroxine

Source: Wikipedia, the free encyclopedia.
This article is about levothyroxine as a pharmaceutical drug. For its role as a hormone, see
Thyroid hormone
.

Levothyroxine
Clinical data
Trade namesSynthroid, Levoxyl, Thyrax, others
Other names3,5,3′,5′-Tetraiodo-L-thyronine
AHFS/Drugs.comMonograph
MedlinePlusa682461
License data
Pregnancy
category
intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability40-80%[5]
MetabolismMainly in liver, kidneys, brain and muscles
Elimination half-lifeca. 7 days (in hyperthyroidism 3–4 days, in hypothyroidism 9–10 days)
ExcretionFeces and urine
Identifiers
  • (S)-2-Amino-3-[4-(4-hydroxy-3,5-diiodophenoxy)-3,5-diiodophenyl]propanoic acid
JSmol)
Melting point231 to 233 °C (448 to 451 °F) [6]
Solubility in waterSlightly 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 checkY
  • Key:XUIIKFGFIJCVMT-LBPRGKRZSA-N

Levothyroxine, also known as L-thyroxine, is a synthetic form of the

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]

Side effects from excessive doses include weight loss, trouble tolerating heat, sweating, anxiety, trouble sleeping,

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.

generic medication.[5] In 2021, it was the third most commonly prescribed medication in the United States, with more than 89 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-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

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.

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

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.

Acute massive overdose may be life-threatening; treatment should be symptomatic and supportive. Massive overdose can be associated with increased

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

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.

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

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

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

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 became the most commonly prescribed medication in the U.S., with more than 114 million prescriptions.[45][46]

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]

Common

brand names include Eltroxin, Euthyrox, Eutirox, Letrox, Levaxin, Lévothyrox, Levoxyl, L-thyroxine, Thyrax, and Thyrax Duotab in Europe; Thyrox and Thyronorm in South Asia; Unithroid, Eutirox, Synthroid, and Tirosint 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.[47] Hence it is not surprising that OWT therapy has not become popular and is very sparingly used across the globe.

References

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External links
Retrieved from "https://en.wikipedia.org/w/index.php?title=Levothyroxine&oldid=1214328274"