Levothyroxine
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| Names | |
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| IUPAC name
(S)-2-Amino-3-[4-(4-hydroxy-3,5-diiodophenoxy)-3,5-diiodophenyl]propanoic acid
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| Other names
3,5,3',5'-Tetraiodo-L-thyronine
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| Identifiers | |
3D model (JSmol)
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| ChEBI | |
| ChEMBL | |
| ChemSpider | |
| DrugBank | |
| ECHA InfoCard | 100.000.093 |
| MeSH | Thyroxine |
PubChem CID
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| UNII | |
CompTox Dashboard (EPA)
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| Pharmacology | |
| 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 | |
| Legal status |
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| Properties | |
| C15H11I4NO4 | |
| Molar mass | 776.874 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] | |
| Related compounds | |
Related compounds
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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).
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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(D-thyroxine) was used in the past as a treatment for hypercholesterolemia (elevated cholesterol levels) but was withdrawn due to cardiac side effects.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]
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]
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.[11] 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).[12]
Patients prescribed too high a dose of levothyroxine may experience effects that mimic hyperthyroidism.[13] Overdose can result in heart palpitations, abdominal pain, nausea, anxiousness, confusion, agitation, insomnia, weight loss, and increased appetite.[14] 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.[13]
The effects of overdosing appear 6 hours to 11 days after ingestion.[14]
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,[15] 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.[16] A study of eight women suggested that coffee may interfere with the intestinal absorption of levothyroxine, though at a level less than eating bran.[17] Certain other substances can cause adverse effects that may be severe. Combination of levothyroxine with ketamine may cause hypertension and tachycardia;[18] 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
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.[13] 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. [19]
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.[20] 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.[20] Given that no increased risk of congenital abnormalities have been demonstrated in pregnant women taking levothyroxine, therapy should be continued during pregnancy.[20] 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.[20]
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.[20]
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).[20] 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.[20]
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.[20] 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.[20]
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.[20] 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]
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.[20] For oral tablets, the inability to swallow capsules serves as an additional contraindication.[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; Eutirox, Levoxyl, Synthroid, and Tirosint in North and South America; and Thyrin and Thyrolar in Bangladesh. There are also numerous generic versions.
References
- ^ Template:ChemID
- ^ Harington (1926). Biochem J. 20: 310.
{{cite journal}}: Missing or empty|title=(help) - ^ "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
Brian Springer (1995). Spin (Motion picture). Retrieved 2013-02-11.
{{cite AV media}}: Cite has empty unknown parameter:|trans_title=(help) (Wikipedia article: Spin) - ^ Vaidya B, Pearce SH (2008). "Management of hypothyroidism in adults". BMJ (Clinical research ed.). 337: a801. doi:10.1136/bmj.a801. PMID 18662921.
- ^ a b c d e Roberts CG, Ladenson PW (2004). "Hypothyroidism". The Lancet. 363: 798 of 793–803. doi:10.1016/S0140-6736(04)15696-1. PMID 15016491. Retrieved 20 April 2014.
- ^ a b c d e f g h i j k l m n o p q r s t Gaitonde DY, Rowley KD, Sweeney LB (August 1, 2012). "Hypothyroidism: An Update". American Academy of Family Physicians. 3. 86 (3): 246 of 244–251. PMID 22962987. Retrieved 20 April 2014.
- ^ Svensson J, Ericsson UB, Nilsson P, Olsson C, Jonsson B, Lindberg B, Ivarsson SA (May 2006). "Levothyroxine treatment reduces thyroid size in children and adolescents with chronic autoimmune thyroiditis". The Journal of Clinical Endocrinology and Metabolism. 91 (5): 1729–34. doi:10.1210/jc.2005-2400. PMID 16507633.
- ^ Dietlein M, Wegscheider K, Vaupel R, Schmidt M, Schicha H (2007). "Management of multinodular goiter in Germany (Papillon 2005): do the approaches of thyroid specialists and primary care practitioners differ?". Nuklearmedizin. Nuclear medicine. 46 (3): 65–75. doi:10.1160/nukmed-0068. PMID 17549317.
- ^ Mandel SJ, Brent GA, Larsen PR (1993). "Levothyroxine Therapy in Patients with Thyroid Disease". Annals of Internal Medicine. 6. 119 (6): 492 of 492–502. doi:10.7326/0003-4819-119-6-199309150-00009. PMID 8357116. Retrieved 20 April 2014.
- ^ a b c d e f g h i j k l m n o p "Levothyroxine (Lexi-Drugs)". LexiComp. Retrieved 20 April 2014.
- ^ Medscape, Hypothyroidism Treatment & Management – Author: Philip R Orlander, MD; Chief Editor: George T Griffing, MD more...
- ^ Frilling A, Liu C, Weber F (2004). "Benign multinodular goiter". Scandinavian journal of surgery : SJS : official organ for the Finnish Surgical Society and the Scandinavian Surgical Society. 93 (4): 278–81. PMID 15658668.
- ^ a b c "Synthroid (Levothyroxine Sodium) Drug Information: Uses, Side Effects, Drug Interactions and Warnings". RxList. Retrieved 2010-07-18.
- ^ a b Irizarry, Lisandro (2010-04-23). "Toxicity, Thyroid Hormone". WebMd. Retrieved 2010-10-31.
- ^ Ruth H. Michel, Patricia J. Neafsey, Laura Cox Dzurec (2004). "Self Medication Practices among Patients taking Levothyroxine". The Internet Journal of Advanced Nursing Practice. 6 (2).
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Lilja JJ, Laitinen K, Neuvonen PJ (September 2005). "Effects of grapefruit juice on the absorption of levothyroxine". Br J Clin Pharmacol. 60 (3): 337–41. doi:10.1111/j.1365-2125.2005.02433.x. PMC 1884777. PMID 16120075.
- ^ Benvenga S, Bartolone L, Pappalardo MA, Russo A, Lapa D, Giorgianni G, Saraceno G, Trimarchi F (March 2008). "Altered Intestinal Absorption of L-Thyroxine Caused by Coffee". Thyroid. 18 (3). New York: Mary Ann Liebert, Inc.: 293–301. doi:10.1089/thy.2007.0222. PMID 18341376. Retrieved 2009-05-16.
- ^ Jasek, W, ed. (2007). Austria-Codex (in German) (62nd ed.). Vienna: Österreichischer Apothekerverlag. pp. 8133–4. ISBN 978-3-85200-181-4.
- ^ "Effects of Evening vs Morning Levothyroxine Intake: A Randomized Double-blind Crossover Trial".
- ^ a b c d e f g h i j k "Novothyrox (levothyroxine sodium tablets, USP)" (PDF). Retrieved 20 April 2014.
- ^ Sherwood, Lauralee (2010). "19 The Peripheral Endocrine Glands". Human Physiology. Brooks/Cole. p. 694. ISBN 978-0-495-39184-5.
{{cite book}}:|access-date=requires|url=(help) - ^ Kendall EC (1915). "The isolation in crystalline form of the compound containing iodin, which occurs in the thyroid: Its chemical nature and physiologic activity". J. Am. Med. Assoc. 64: 2042–2043. doi:10.1001/jama.1915.02570510018005.
- ^ Kleinrock, Michael. "The Use of Medicines in the United States: Review of 2011" (PDF). IMS Institute for Healthcare Informatics. IMS Health Incorporated and Its Affiliates. Retrieved 20 April 2014.
- ^ Moore, Thomas. "Monitoring FDA MedWatch Reports: Signals for Dabigatran and Metoclopramide" (PDF). QuarterWatch. Institute for Safe Medication Practices. Retrieved 20 April 2014.