Thiamazole

Last updated

Thiamazole
Methimazole.svg
Thiamazole ball-and-stick.png
Clinical data
Trade names Tapazole, others
Other namesmethimazole (USAN US)
AHFS/Drugs.com Monograph
MedlinePlus a682464
License data
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 93%
Protein binding None
Metabolism Liver
Elimination half-life 5-6 hours
Excretion Kidney
Identifiers
  • 1-Methyl-3H-imidazole-2-thione
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.000.439 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C4H6N2S
Molar mass 114.17 g·mol−1
3D model (JSmol)
Melting point 146 °C (295 °F)
Solubility in water 275 [1]  mg/mL (20 °C)
  • Cn1cc[nH]c1=S
  • InChI=1S/C4H6N2S/c1-6-3-2-5-4(6)7/h2-3H,1H3,(H,5,7) Yes check.svgY
  • Key:PMRYVIKBURPHAH-UHFFFAOYSA-N Yes check.svgY
   (verify)

Thiamazole, also known as methimazole, is a medication used to treat hyperthyroidism. [2] This includes Graves disease, toxic multinodular goiter, and thyrotoxic crisis. [2] It is taken by mouth. [2] Full effects may take a few weeks to occur. [3]

Contents

Common side effects include itchiness, hair loss, nausea, muscle pain, swelling, and abdominal pain. [2] Severe side effects may include low blood cell counts, liver failure, and vasculitis. [2] Use is not recommended during the first trimester of pregnancy due to the risk of congenital anomalies, but it may be used in the second trimester or third trimester. [4] It may be used during breastfeeding. [4] Those who developed significant side effects may also have problems with propylthiouracil. [2] Thiamazole is a cyclic thiourea derivative that works by decreasing the production of thyroid hormones. [2]

Thiamazole was approved for medical use in the United States in 1950. [2] It is on the World Health Organization's List of Essential Medicines. [5] [6] It is available as a generic medication. [2] It is also available in Europe and Asia. [7] In 2021, it was the 237th most commonly prescribed medication in the United States, with more than 1 million prescriptions. [8] [9]

Medical uses

Thiamazole is a drug used to treat hyperthyroidism such as in Graves' disease, a condition that occurs when the thyroid gland begins to produce an excess of thyroid hormone. The drug may also be taken before thyroid surgery to lower thyroid hormone levels and minimize the effects of thyroid manipulation. Additionally, thiamazole is used in the veterinary setting to treat hyperthyroidism in cats. [10]

Adverse effects

It is important to monitor any symptoms of fever or sore throat while taking thiamazole; this could indicate the development of agranulocytosis, an uncommon but severe side effect resulting from a drop in the white blood cell count (to be specific, neutropenia, a deficiency of neutrophils). A complete blood count (CBC) with differential is performed to confirm the suspicion, in which case the drug is discontinued. [11] Administration of recombinant human granulocyte colony-stimulating factor (rhG-CSF) may increase recovery.

Other known side effects include:

Interaction

Adverse effects may occur for individuals who:

Mechanism of action

Thiamazole inhibits the enzyme thyroperoxidase, which normally acts in thyroid hormone synthesis by oxidizing the anion iodide (I−) to iodine (I2), hypoiodous acid (HOI), and enzyme linked hypoiodate (EOI), facilitating iodine's addition to tyrosine residues on the hormone precursor thyroglobulin, a necessary step in the synthesis of triiodothyronine (T3) and thyroxine (T4).[ citation needed ]

It does not inhibit the action of the sodium-dependent iodide transporter located on follicular cells' basolateral membranes. Inhibition of this step requires competitive inhibitors such as perchlorate and thiocyanate.

A study has shown that it modulates secretion of CXCL10. [17]

Veterinary uses

Thiamazole is also indicated in cats to treat hyperthyroidism. [18]

Chemical properties

The cyclic thiourea derivative thiamazole is a white to matte brown crystalline powder with a characteristic odour. The boiling point is 280 °C (decomposition). Thiamazole is soluble in water, ethanol and chloroform, but hardly soluble in ether. [19]

Thiamazole acts as a free radical scavenger for radicals such as the hydroxyl radical (•OH) radical. [20] It is used as free radical scavenger in organic chemistry. [21]

Laboratory synthesis

Thiamazole has been known since 1889, [22] when it was made by a two-stage process starting from 2,2-diethoxyethaneamine, which was reacted with methyl isothiocyanate. [23]

Thiamazole synthesis route A.svg

The product of this reaction was then cyclised in an acid-catalysed reaction to form thiamazole. [23]

Manufacture

When the therapeutic potential of thiamazole was recognised in the late 1940s, a number of alternative routes were developed based, for example, on the use of 2-chloro-1,2-diethoxyethane as starting material, in a reaction with methylamine.

Thiamazole synthesis route B.svg

The resulting intermediate can be treated with potassium thiocyanate in the presence of acid to give thiamazole. [23]

History

Surgery was used to treat hyperthyroidism until the advent of drug therapies in the 1940s. In 1942, thiourea was used by Edwin B. Astwood to treat a patient with the condition. He later published evidence that thiouracil was more effective and began a search for analogues with higer potency and less toxicity. [10] [24] In 1949 he published his work on thiamazole which showed its superiority to previous therapies. [10] The compound had been known since 1889, [22] [23] and was developed as a drug by Eli Lilly and Company under the trade name Tapazole. [25]

Related Research Articles

<span class="mw-page-title-main">Hyperthyroidism</span> Endocrine neck-gland secretes excess hormones affecting metabolism

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">Graves' disease</span> Autoimmune endocrine disease

Graves' disease, also known as toxic diffuse goiter, 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> Endocrine disease

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, a feeling of tiredness, 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">Levothyroxine</span> Thyroid hormone

Levothyroxine, also known as L-thyroxine, is a synthetic form of the thyroid hormone thyroxine (T4). 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. Levothyroxine is taken orally (by mouth) or given by intravenous injection. 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.

Edwin Bennett Astwood was a Bermudian-American physiologist and endocrinologist: his research on endocrine system led to treatments for hyperthyroidism, first published in 1943 in what has subsequently been called a "landmark" paper. In 1949 he showed that methimazole was superior to alternative therapies for Graves' disease and this became a standard treatment for the condition.

<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">Wolff–Chaikoff effect</span> Effect of iodine on the thyroid

The Wolff–Chaikoff effect is a presumed reduction in thyroid hormone levels caused by ingestion of a large amount of iodine.

<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">Toxic multinodular goitre</span> Medical condition

Toxic multinodular goiter (TMNG), also known as multinodular toxic goiter (MNTG), is an active multinodular goiter associated with hyperthyroidism.

Thyroid storm is a rare but severe and life-threatening complication of hyperthyroidism. It occurs when an overactive thyroid leads to hypermetabolism, which can cause death from cardiac arrest or multiple organ failure.

<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.

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

Ethionamide is an antibiotic used to treat tuberculosis. Specifically it is used, along with other antituberculosis medications, to treat active multidrug-resistant tuberculosis. It is no longer recommended for leprosy. It is taken by mouth.

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

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

<span class="mw-page-title-main">2-Thiouracil</span> Chemical compound

2-Thiouracil is a chemical derivative of uracil in which the oxygen atom in the 2-position of the ring is substituted by sulfur.

<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.

The signs and symptoms of Graves' disease generally result from the direct and indirect effects of hyperthyroidism, although they can also be caused by other thyroidal conditions, such as Graves' ophthalmopathy, goitre and pretibial myxedema. These clinical manifestations can involve virtually every system in the body.

<span class="mw-page-title-main">Dulaglutide</span> Diabetes medication

Dulaglutide, sold under the brand name Trulicity among others, is a medication used for the treatment of type 2 diabetes in combination with diet and exercise. It is also approved in the United States for the reduction of major adverse cardiovascular events in adults with type 2 diabetes who have established cardiovascular disease or multiple cardiovascular risk factors. It is a once-weekly injection.

References

  1. ↑ "DrugBank: Methimazole (DB00763)". drugbank.ca. Retrieved 21 July 2015.
  2. 1 2 3 4 5 6 7 8 9 "Methimazole Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Retrieved 8 April 2019.
  3. ↑ Spina D (2008). The Flesh and Bones of Medical Pharmacology E-Book. Elsevier Health Sciences. p. 74. ISBN   9780723437161.
  4. 1 2 "Methimazole Use During Pregnancy". Drugs.com. Retrieved 8 April 2019.
  5. ↑ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl: 10665/325771 . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  6. ↑ World Health Organization (2021). World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. hdl: 10665/345533 . WHO/MHP/HPS/EML/2021.02.
  7. ↑ Yoshihara A, Noh J, Yamaguchi T, Ohye H, Sato S, Sekiya K, et al. (July 2012). "Treatment of graves' disease with antithyroid drugs in the first trimester of pregnancy and the prevalence of congenital malformation". The Journal of Clinical Endocrinology and Metabolism. 97 (7): 2396–2403. doi: 10.1186/1756-6614-8-S1-A12 . PMC   4480840 . PMID   22547422.
  8. ↑ "The Top 300 of 2021". ClinCalc. Archived from the original on 15 January 2024. Retrieved 14 January 2024.
  9. ↑ "Methimazole - Drug Usage Statistics". ClinCalc. Retrieved 14 January 2024.
  10. 1 2 3 Burch, Henry B.; Cooper, David S. (2018). "Antithyroid drug therapy: 70 years later". European Journal of Endocrinology. 179 (5): R261–R274. doi:10.1530/EJE-18-0678. PMID   30320502.
  11. ↑ Fumarola A, Di Fiore A, Dainelli M, Grani G, Calvanese A (November 2010). "Medical treatment of hyperthyroidism: state of the art". Experimental and Clinical Endocrinology & Diabetes. 118 (10): 678–684. doi:10.1055/s-0030-1253420. PMID   20496313.
  12. ↑ Pecere A, Caputo M, Sarro A, Ucciero A, Zibetti A, Aimaretti G, et al. (December 2020). "Methimazole Treatment and Risk of Acute Pancreatitis: A Population-based Cohort Study". The Journal of Clinical Endocrinology and Metabolism. 105 (12): e4527–e4530. doi: 10.1210/clinem/dgaa544 . PMID   32813014. S2CID   221181752.
  13. ↑ Brix TH, Lund LC, Henriksen DP, Folkestad L, Bonnema SJ, Hallas J, Hegedüs L (March 2020). "Methimazole and risk of acute pancreatitis". The Lancet. Diabetes & Endocrinology. 8 (3): 187–189. doi: 10.1016/s2213-8587(20)30025-5 . PMID   32035032.
  14. ↑ Pharmacovigilance Risk Assessment Committee (PRAC) (4 January 2019). "PRAC recommendations on signals" (PDF). European Medicines Agency. EMA/PRAC/826440/2018.
  15. ↑ Busenbark, Laura A.; Cushnie, Sally A. (May–June 2006). "Effect of Graves' disease and methimazole on warfarin anticoagulation". The Annals of Pharmacotherapy. 40 (6). doi:10.1345/aph.1G422. ISSN   1060-0280. PMID   16735660 – via Sage Journals.
  16. ↑ "Methimazole (Oral Route) Precautions - Mayo Clinic". www.mayoclinic.org. Retrieved 31 March 2024.
  17. ↑ Crescioli C, Cosmi L, Borgogni E, Santarlasci V, Gelmini S, Sottili M, et al. (October 2007). "Methimazole inhibits CXC chemokine ligand 10 secretion in human thyrocytes". The Journal of Endocrinology. 195 (1): 145–155. doi: 10.1677/JOE-07-0240 . PMID   17911406.
  18. ↑ "Managing hyperthyroidism in cats." by S Caney, Veterinary Times 2012 Vol.42 No.46 pp.12-15
  19. ↑ Entry on Thiamazol . at: Römpp Online . Georg Thieme Verlag, retrieved 10. November 2014.
  20. ↑ Taylor JJ, Willson RL, Kendall-Taylor P (29 October 1984). "Evidence for direct interactions between methimazole and free radicals". FEBS Letters. 176 (2): 337–340. doi:10.1016/0014-5793(84)81192-8. S2CID   86322153.
  21. ↑ Inhibition of amine oxide, 30 December 2010, retrieved 14 April 2019
  22. 1 2 Wohl, A.; Marckwald, W. (1889). "Ueber Condensations-producte aus Amidoacetal. (II.)". Berichte der Deutschen Chemischen Gesellschaft (in German). 22: 1353–1362. doi:10.1002/cber.188902201280.
  23. 1 2 3 4 Baranov, V. V.; Galochkin, A. A.; Kravchenko, A. N. (2023). "A novel approach to the synthesis of methimazole". Russian Chemical Bulletin. 72 (8): 1946–1949. doi:10.1007/s11172-023-3983-y.
  24. ↑ Astwood, E. B. (1984). "Landmark article May 8, 1943: Treatment of hyperthyroidism with thiourea and thiouracil. By E.B. Astwood". JAMA: The Journal of the American Medical Association. 251 (13): 1743–1746. doi:10.1001/jama.251.13.1743. PMID   6422063.
  25. ↑ Davidson, L. A. G. (1953). "Methimazole in Treatment of Thyrotoxicosis". BMJ. 2 (4849): 1300–1303. doi:10.1136/bmj.2.4849.1300. PMC   2030295 . PMID   13106417.
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