Levothyroxine

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This article is about levothyroxine as a pharmaceutical drug. For its role as a hormone, see Thyroid hormone.
Levothyroxine
Levothyroxine 200.svg
Levothyroxine 3D ball.png
Names
IUPAC name
(S)-2-Amino-3-[4-(4-hydroxy-3,5-diiodophenoxy)-3,5-diiodophenyl]propanoic acid
Other names
3,5,3',5'-Tetraiodo-L-thyronine
Identifiers
51-48-9 YesY
ChEBI CHEBI:18332 YesY
ChEMBL ChEMBL1624 YesY
ChemSpider 5614 YesY
DrugBank DB00451 YesY
2635
Jmol 3D model Interactive image
MeSH Thyroxine
PubChem 5819
UNII Q51BO43MG4 N
  • 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 YesY
    Key: XUIIKFGFIJCVMT-LBPRGKRZSA-N YesY
  • InChI=1/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
    Key: XUIIKFGFIJCVMT-LBPRGKRZBS
  • NC(Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)C(O)=O
Properties
C15H11I4NO4
Molar mass 776.87 g·mol−1
Melting point 231 to 233 °C (448 to 451 °F; 504 to 506 K) [2]
Slightly soluble (0.105 mg·l−1 at 25 °C) [1]
Pharmacology
ATC code H03AA01
Legal status
  • ℞ (Prescription only)
  • US: A (No risk in human studies)
Oral, intravenous
Pharmacokinetics:
~100%
Mainly in liver, kidneys, brain and muscles
ca. 7 days (in hyperthyroidism 3–4 days, in hypothyroidism 9–10 days)
Through feces and urine
Vapor pressure {{{value}}}
Related compounds
Related compounds
 Triiodothyronine (tri-iodated)
Thyronine (without iodine)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
N verify (what is YesYN ?)
Infobox references

Levothyroxine (INN, USAN) or L-thyroxine is a synthetic thyroid hormone that is chemically identical to thyroxine (T4), which is naturally secreted by the follicular cells of the thyroid gland. It is used to treat thyroid hormone deficiency, and occasionally to prevent the recurrence of thyroid cancer. Like its naturally secreted counterpart, levothyroxine is a chiral compound in the L-form. 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(D-thyroxine) was used in the past as a treatment for hypercholesterolemia (elevated cholesterol levels) but was withdrawn due to cardiac side effects.

It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.[3]

Medical uses

Levothyroxine is typically used to treat hypothyroidism,[4] and is the treatment of choice for patients with hypothyroidism,[5] who often require lifelong thyroid hormone therapy.[6] It may also be used to treat goiter via its ability to lower thyroid-stimulating hormone (TSH), a hormone that is considered goiter-inducing.[7][8] Levothyroxine is also used as interventional therapy in patients with nodular thyroid disease or thyroid cancer to suppress thyroid-stimulating hormone (TSH) secretion.[9]

Contraindications

Levothyroxine is contraindicated in patients with hypersensitivity to levothyroxine sodium or any component of the formulation, patients with acute myocardial infarction, and patients with thyrotoxicosis of any etiology.[10] Levothyroxine is also contraindicated in patients with uncorrected adrenal insufficiency, as thyroid hormones may cause an acute adrenal crisis by increasing the metabolic clearance of glucocorticoids.[11] For oral tablets, the inability to swallow capsules serves as an additional contraindication.[10]

Adverse effects

Dosing, which is generally straightforward, must be controlled to achieve free T4 and free T3 levels within the normal reference range and elimination of hypothyroid and hyperthyroid symptoms. Once patients are stabilized annual or semiannual clinical evaluations and TSH monitoring are appropriate.[12] Long-term suppression of TSH values below normal values will frequently cause cardiac side-effects and contribute to decreases in bone mineral density (low TSH levels are also well known to contribute to osteoporosis).[13]

Patients prescribed too high a dose of levothyroxine may experience effects that mimic hyperthyroidism.[14] Overdose can result in heart palpitations, abdominal pain, nausea, anxiousness, confusion, agitation, insomnia, weight loss, and increased appetite.[15] 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 sympathetic activity and thus require treatment with beta-blockers.[14]

The effects of overdosing appear 6 hours to 11 days after ingestion.[15]

Interactions

There are foods and other substances that can interfere with absorption of thyroxine. Examples include calcium and iron supplements taken within four hours of levothyroxine,[16] as well as soy products within three hours of the medication. Other substances that reduce absorption are aluminium and magnesium containing antacids, simethicone, sucralfate, cholestyramine, colestipol, and polystyrene sulfonate. Grapefruit juice may delay the absorption of levothyroxine, but based on a study of 10 healthy people aged 20–30 (8 men, 2 women) it may not have a significant effect on bioavailability in young adults.[17] A study of eight women suggested that coffee may interfere with the intestinal absorption of levothyroxine, though at a level less than eating bran.[18] Certain other substances can cause adverse effects that may be severe. Combination of levothyroxine with ketamine may cause hypertension and tachycardia;[19] and tricyclic and tetracyclic antidepressants increase its toxicity. On the other hand, lithium can cause hyperthyroidism (but most often hypothyroidism) by affecting iodine metabolism of the thyroid itself and thus inhibits synthetic levothyroxine as well.[citation needed]

Dosage

Generic levothyroxine, 25 µg oral tablet

Dosages vary according to the age groups and the individual condition of the patient, body weight and compliance to the medication and diet. Monitoring of the patient's condition and adjustment of the dosage is periodical and necessary. Levothyroxine is taken on an empty stomach approximately half an hour to an hour before meals.[14] As such, thyroid replacement therapy is usually taken 30 minutes prior to eating in the morning.[6] For patients with trouble taking levothyroxine in the morning, bedtime dosing is effective as well.[6] A recent study published in JAMA showed greater efficacy of levothyroxine when taken at bedtime.[20]

Poor compliance to thyroid replacement therapy is the most common cause of elevated TSH levels in patients receiving appropriate doses of levothyroxine.[6]

Elderly

For older patients (over 50 years old) and patients with known or suspected ischemic heart disease, levothyroxine therapy should not be initiated at the full replacement dose.[11] Since thyroid hormone increases myocardial oxygen demand by increasing heart rate and contractility, starting at higher doses may cause acute coronary syndrome or an arrhythmia.[6]

Pregnancy

According to the U.S. Food and Drug Administration pregnancy categories, levothyroxoine has been assigned Pregnancy Category A.[11] Given that no increased risk of congenital abnormalities have been demonstrated in pregnant women taking levothyroxine, therapy should be continued during pregnancy.[11] 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.[11]

Thyroid hormone requirements increase during and last throughout pregnancy.[6] As such, it is recommended that pregnant women increase to nine doses of levothyroxine each week, rather than the usual seven, as soon as their pregnancy is confirmed.[6] Repeat thyroid function tests should be done five weeks after the dosage is increased.[6]

Breastfeeding

While a minimal amount of thyroid hormones are found in breast milk, the amount does not influence infant plasma thyroid levels.[10] Furthermore, levothyroxine was not found to cause any adverse events to the infant or mother during breastfeeding.[10] As adequate concentrations of thyroid hormone are required to maintain normal lactation, it is recommended that appropriate levothyroxine doses be administered during breastfeeding.[10]

Persistent symptoms

A subset of patients with hypothyroidism treated with an appropriate dose of levothyroxine will describe continuing symptoms despite TSH levels in the normal range.[6] In these patients, further laboratory and clinical evaluation is warranted as they may have another cause for their symptoms.[6] Furthermore, it is important to review their medications and possible dietary supplements as several medications can affect thyroid hormone levels in patients on levothyroxine therapy.[6]

Subclinical hypothyroidism

Subclinical hypothyroidism is defined by an elevated TSH level and a normal-range free T4 level without symptoms.[6] Such patients may be asymptomatic[6] and whether they should be treated is controversial.[5] One benefit of treating this population with levothyroxine therapy is preventing patients' development of hypothyroidism.[5] As such, it is recommended that treatment should be taken into account for patients with initial TSH levels > 10 mIU/L, patients with elevated thyroid peroxidase antibody titers, patients with symptoms of hypothyroidism and TSH levels between 5–10 mIU/L, and patients who are pregnant or want to become pregnant.[5] Oral dosing for patients with subclinical hypothyroidism is 1 µg/kg/day.[10]

Myxedema coma

Myxedema coma is a severe form of hypothyroidism characterized by mental status changes and hypothermia.[6] As it is a medical emergency with a high mortality rate, patients should be treated in the intensive care unit[6] with thyroid hormone replacement and aggressive management of individual organ system complications.[5] For patients with myxedema coma, 200–500 µg IV of levothyroxine should be administered, followed by 100–300 µg the next day if necessary.[10] Smaller doses should be taken into account for patients with cardiovascular disease.[10]

Children

Levothyroxine dosing in the pediatric population varies with age and body weight. Doses should be adjusted based on an individual patient's clinical and laboratory results.[10] The goal of treatment for pediatric patients with hypothyroidism is to reach and preserve normal intellectual and physical development.[11]

Available forms

Levothyroxine for systemic administration is available as an oral tablet, an intramuscular injection, and as a solution for intravenous infusion.[10] Furthermore, levothyroxine is available as both brand-name and generic products.[6] While the United States Food and Drug Administration (FDA) approved the use of generic levothyroxine for brand-name levothyroxine in 2004, the decision was met with disagreement by several medical associations.[6] 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.[6] As such, it was recommended that patients be started and kept on either brand-name or generic levothyroxine formulations and not changed back and forth from one to the other.[6] For patients who do switch products, it is recommended that their TSH and free T4 levels be tested after six weeks to check that they are within normal range.[6]

Mechanism of action

Levothyroxine is a synthetic form of thyroxine (T4), an endogenous hormone secreted by the thyroid gland, which is converted to its active metabolite, L-triiodothyronine (T3).[11] T4 and T3 bind to thyroid receptor proteins in the cell nucleus and cause metabolic effects through the control of DNA transcription and protein synthesis.[11]

Pharmacokinetics

Absorption

Absorption of orally administered levothyroxine from the gastrointestinal tract ranges from 40–80%, with the majority of the drug absorbed from the jejunum and upper ileum.[11] 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.[11]

Distribution

Greater than 99% of circulating thyroid hormones are bound to plasma proteins including thyroxine-binding globulin, thyroxine-binding prealbumin, and albumin.[10] Only free hormone is metabolically active.[10]

Metabolism

The primary pathway of thyroid hormone metabolism is through sequential deiodination.[11] The liver is the main site of T4 deiodination, and along with the kidneys are responsible for about 80% of circulating T3.[21] 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.[10]

Elimination

Half-life elimination is 6–7 days for euthyroid patients; 9–10 days for hypothyroid patients; 3–4 days for hyperthyroid patients.[10] Thyroid hormones are primarily eliminated by the kidneys (approximately 80%), with urinary excretion decreasing with age.[10] The remaining 20% of T4 eliminated in the stool.[10]

History

Thyroxine was first isolated in pure form in 1914 at the Mayo Clinic by Edward Calvin Kendall from extracts of hog thyroid glands.[22] The hormone was synthesized in 1927 by British chemists Charles Robert Harington and George Barger.

Economics

Levothyroxine is the second most commonly prescribed medication in the United States,[23] with 23.8 million prescriptions filled each year.[24]

Brand names

Common brand names include Eltroxin, Euthyrox, Letrox, Levaxin, L-thyroxine, Thyrax, and Thyrax Duotab in Europe; Thyrox, Thyronorm in South Asia; Unithroid, Eutirox, Levoxyl, Synthroid, and Tirosint in North and South America; and Thyrin and Thyrolar in Bangladesh. There are also numerous generic versions.

References

  1. ↑ Levothyroxine in the ChemIDplus database
  2. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  3. ↑ Lua error in package.lua at line 80: module 'strict' not found. Lua error in package.lua at line 80: module 'strict' not found. (Wikipedia article: Spin)
  4. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  5. ↑ 5.0 5.1 5.2 5.3 5.4 Lua error in package.lua at line 80: module 'strict' not found.
  6. ↑ 6.00 6.01 6.02 6.03 6.04 6.05 6.06 6.07 6.08 6.09 6.10 6.11 6.12 6.13 6.14 6.15 6.16 6.17 6.18 6.19 Lua error in package.lua at line 80: module 'strict' not found.
  7. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  8. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  9. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  10. ↑ 10.00 10.01 10.02 10.03 10.04 10.05 10.06 10.07 10.08 10.09 10.10 10.11 10.12 10.13 10.14 10.15 Lua error in package.lua at line 80: module 'strict' not found.
  11. ↑ 11.00 11.01 11.02 11.03 11.04 11.05 11.06 11.07 11.08 11.09 11.10 Lua error in package.lua at line 80: module 'strict' not found.
  12. ↑ Medscape, Hypothyroidism Treatment & Management – Author: Philip R Orlander, MD; Chief Editor: George T Griffing, MD more...
  13. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  14. ↑ 14.0 14.1 14.2 Lua error in package.lua at line 80: module 'strict' not found.
  15. ↑ 15.0 15.1 Lua error in package.lua at line 80: module 'strict' not found.
  16. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  17. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  18. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  19. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  20. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  21. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  22. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  23. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  24. ↑ Lua error in package.lua at line 80: module 'strict' not found.

External links

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