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{{Short description|Chemical compound}}
{{ distinguish|metamizole }}
{{Distinguish|metamizole|methazolamide|methazole}}

{{Use dmy dates|date=September 2019}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Drugbox {{Drugbox
| verifiedrevid = 459829931
| Verifiedfields = changed
| verifiedrevid = 419235587
| IUPAC_name = 1-methyl-3''H''-imidazole-2-thione
| image = Methimazole.svg | image = Methimazole.svg
| width = 150px | width = 150
| alt =
| image2 = Thiamazole ball-and-stick.png
| width2 = 250
| alt2 =
| USAN = methimazole


<!--Clinical data--> <!-- Clinical data -->
| tradename = | tradename = Tapazole, others
| Drugs.com = {{drugs.com|monograph|methimazole}} | Drugs.com = {{drugs.com|monograph|methimazole}}
| MedlinePlus = a682464 | MedlinePlus = a682464
| DailyMedID = Thiamazole
| pregnancy_category = D <small>(US)</small>
| pregnancy_category =
| routes_of_administration = ]
| ATC_prefix = H03
| ATC_suffix = BB02

| legal_AU = S4
| legal_CA = Rx-only
| legal_CA_comment =
| legal_US = Rx-only | legal_US = Rx-only
| routes_of_administration = Oral


<!--Pharmacokinetic data--> <!-- Pharmacokinetic data -->
| bioavailability = 93% | bioavailability = 93%
| protein_bound = None | protein_bound = None
| metabolism = ] | metabolism = ]
| elimination_half-life = 5-6 hours | elimination_half-life = 5-6 hours
| excretion = ] | excretion = ]


<!--Identifiers--> <!-- Identifiers -->
| IUPHAR_ligand = 6649
| CASNo_Ref = {{cascite|correct|CAS}}
| CAS_number_Ref = {{cascite|correct|??}} | CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 60-56-0 | CAS_number = 60-56-0
| ATC_prefix = H03
| ATC_suffix = BB02
| PubChem = 1349907 | PubChem = 1349907
| DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank_Ref = {{drugbankcite|correct|drugbank}}
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| KEGG_Ref = {{keggcite|correct|kegg}} | KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00401 | KEGG = D00401
| ChEBI_Ref = {{ebicite|changed|EBI}} | ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 50673 | ChEBI = 50673
| ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 1515 | ChEMBL = 1515
| synonyms =


<!--Chemical data--> <!-- Chemical data -->
| IUPAC_name = 1-Methyl-3''H''-imidazole-2-thione
| C=4 | H=6 | N=2 | S=1
| C=4 | H=6 | N=2 | S=1
| molecular_weight = 114.17 g/mol
| smiles = Cn1ccc1=S | smiles = Cn1ccc1=S
| InChI = 1/C4H6N2S/c1-6-3-2-5-4(6)7/h2-3H,1H3,(H,5,7)
| InChIKey = PMRYVIKBURPHAH-UHFFFAOYAN
| StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C4H6N2S/c1-6-3-2-5-4(6)7/h2-3H,1H3,(H,5,7) | StdInChI = 1S/C4H6N2S/c1-6-3-2-5-4(6)7/h2-3H,1H3,(H,5,7)
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| StdInChIKey = PMRYVIKBURPHAH-UHFFFAOYSA-N | StdInChIKey = PMRYVIKBURPHAH-UHFFFAOYSA-N
| melting_point = 146 | melting_point = 146
| solubility = 275<ref>{{cite web|url=http://www.drugbank.ca/drugs/DB00763|title=DrugBank: Methimazole (DB00763)|work=drugbank.ca|access-date=21 July 2015}}</ref>
| solubility = 2.75
}} }}


<!-- Definition and medical uses -->
'''Methimazole''' (also known as '''Tapazole''' or '''Thiamazole''' or '''MMI''') is an ] ]<ref name="pmid17389704">{{cite journal |author=Nakamura H, Noh JY, Itoh K, Fukata S, Miyauchi A, Hamada N |title=Comparison of methimazole and propylthiouracil in patients with hyperthyroidism caused by Graves' disease |journal=The Journal of clinical endocrinology and metabolism |volume=92 |issue=6 |pages=2157–62 |year=2007 |month=June |pmid=17389704 |doi=10.1210/jc.2006-2135 |url=http://jcem.endojournals.org/cgi/pmidlookup?view=long&pmid=17389704}}</ref>, and part of the ] group.
'''Thiamazole''', also known as '''methimazole''', is a medication used to treat ].<ref name=AHFS2019/> This includes ], ], and ].<ref name=AHFS2019/> It is taken by mouth.<ref name=AHFS2019>{{cite web |title=Methimazole Monograph for Professionals |url=https://www.drugs.com/monograph/methimazole.html |website=Drugs.com |publisher=American Society of Health-System Pharmacists |access-date=8 April 2019 }}</ref> Full effects may take a few weeks to occur.<ref>{{cite book | vauthors = Spina D |title=The Flesh and Bones of Medical Pharmacology E-Book |date=2008 |publisher=Elsevier Health Sciences |isbn=9780723437161 |page=74 |url=https://books.google.com/books?id=zFbsy-ugRhgC&pg=PA74 }}</ref>


<!-- Side effects and mechanism -->
==Indications==
Common side effects include itchiness, hair loss, nausea, muscle pain, swelling, and abdominal pain.<ref name=AHFS2019/> Severe side effects may include ]s, ], and ].<ref name=AHFS2019/> Use is not recommended during the ] of ] due to the risk of congenital anomalies, but it may be used in the ] or ].<ref name=Pref2019>{{cite web |title=Methimazole Use During Pregnancy |url=https://www.drugs.com/pregnancy/methimazole.html |website=Drugs.com |access-date=8 April 2019 }}</ref> It may be used during ].<ref name=Pref2019/> Those who developed significant side effects may also have problems with ].<ref name=AHFS2019/> Thiamazole is a cyclic ] derivative that works by decreasing the production of ]s.<ref name=AHFS2019/>
Methimazole is a drug used to treat ], a condition that usually occurs when the thyroid gland is producing too much thyroid hormone. It may also be taken before thyroid surgery to lower thyroid hormone levels and minimize the effects of thyroid manipulation.


<!-- History and culture -->
==Mechanism of action==
Thiamazole was approved for medical use in the United States in 1950.<ref name=AHFS2019/> It is on the ].<ref name="WHO21st">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }}</ref><ref name="WHO22nd">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 22nd list (2021) | year = 2021 | hdl = 10665/345533 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2021.02 | hdl-access=free }}</ref> It is available as a ].<ref name=AHFS2019/> It is also available in Europe and Asia.<ref>{{cite journal | vauthors = Yoshihara A, Noh J, Yamaguchi T, Ohye H, Sato S, Sekiya K, Kosuga Y, Suzuki M, Matsumoto M, Kunii Y, Watanabe N, Mukasa K, Ito K, Ito K | title = Treatment of graves' disease with antithyroid drugs in the first trimester of pregnancy and the prevalence of congenital malformation | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 97 | issue = 7 | pages = 2396–2403 | date = July 2012 | pmc = 4480840 | doi = 10.1186/1756-6614-8-S1-A12 | pmid = 22547422 | doi-access = free }}</ref> In 2021, it was the 237th most commonly prescribed medication in the United States, with more than 1{{nbsp}}million prescriptions.<ref>{{cite web | title=The Top 300 of 2021 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=14 January 2024 | archive-date=15 January 2024 | archive-url=https://web.archive.org/web/20240115223848/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title = Methimazole - Drug Usage Statistics | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Methimazole | access-date = 14 January 2024}}</ref>
Methimazole inhibits the addition of iodine to ] by the enzyme ], a necessary step in the synthesis of ] (T3) and ] (T4).


==Medical uses==
It does not inhibit the action of the sodium-dependent iodide transporter located on follicular cells' ]s. Inhibition of this step requires competitive inhibitors such as ] and ].
Thiamazole is a drug used to treat ] such as in ], a condition that occurs when the thyroid gland begins to produce an excess of ]. The drug may also be taken before thyroid surgery to lower thyroid hormone levels and minimize the effects of thyroid manipulation. {{anchor|feline}}Additionally, thiamazole is used in the veterinary setting to treat hyperthyroidism in cats.<ref name=Burch>{{cite journal | vauthors = Burch HB, Cooper DS | title = ANNIVERSARY REVIEW: Antithyroid drug therapy: 70 years later | journal = European Journal of Endocrinology | volume = 179 | issue = 5 | pages = R261-R274 | date = October 2018 | pmid = 30320502 | doi = 10.1530/EJE-18-0678 }}</ref>

It acts at ].<ref name="pmid17911406">{{cite journal |author=Crescioli C, Cosmi L, Borgogni E, ''et al.'' |title=Methimazole inhibits CXC chemokine ligand 10 secretion in human thyrocytes |journal=J. Endocrinol. |volume=195 |issue=1 |pages=145–55 |year=2007 |month=October |pmid=17911406 |doi=10.1677/JOE-07-0240 |url=http://joe.endocrinology-journals.org/cgi/pmidlookup?view=long&pmid=17911406}}</ref>


==Adverse effects== ==Adverse effects==
It is important to monitor any symptoms of fever or sore throat while taking thiamazole; this could indicate the development of ], an uncommon but severe side effect resulting from a drop in the ] count (to be specific, ], a deficiency of ]). A complete blood count (CBC) with differential is performed to confirm the suspicion, in which case the drug is discontinued.<ref>{{cite journal | vauthors = Fumarola A, Di Fiore A, Dainelli M, Grani G, Calvanese A | title = Medical treatment of hyperthyroidism: state of the art | journal = Experimental and Clinical Endocrinology & Diabetes | volume = 118 | issue = 10 | pages = 678–684 | date = November 2010 | pmid = 20496313 | doi = 10.1055/s-0030-1253420 }}</ref> Administration of recombinant human ] (rhG-CSF) may increase recovery.
{{unreferenced-section|date=November 2011}}
It is important to monitor any symptoms of fever or sore throat while taking methimazole; this could indicate the development of ], an uncommon but severe side effect resulting from a drop in the ] count (to be specific, ], a deficiency of neutrophils). A complete blood count (CBC) with differential is performed to confirm the suspicion, in which case the drug is discontinued. Administration of recombinant human ] (rhG-CSF) may increase recovery.


Other side effects include Other known side effects include:
*skin rash *skin rash
*itching *itching
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*abnormal sensations (tingling, prickling, burning, tightness, and pulling) *abnormal sensations (tingling, prickling, burning, tightness, and pulling)
*swelling *swelling
*joint and muscle pain *] and ]
*drowsiness *drowsiness
*dizziness *dizziness
*decreased white blood cells *decreased platelet count (])
*] (prenatal exposure)
*decreased platelet
*] (prenatal exposure) * ] (prenatal exposure)
* ] (prenatal exposure during the first trimester of ])
*acute pancreatitis<ref>{{cite journal | vauthors = Pecere A, Caputo M, Sarro A, Ucciero A, Zibetti A, Aimaretti G, Marzullo P, Barone-Adesi F | title = Methimazole Treatment and Risk of Acute Pancreatitis: A Population-based Cohort Study | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 105 | issue = 12 | pages = e4527–e4530 | date = December 2020 | pmid = 32813014 | doi = 10.1210/clinem/dgaa544 | s2cid = 221181752 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Brix TH, Lund LC, Henriksen DP, Folkestad L, Bonnema SJ, Hallas J, Hegedüs L | title = Methimazole and risk of acute pancreatitis | journal = The Lancet. Diabetes & Endocrinology | volume = 8 | issue = 3 | pages = 187–189 | date = March 2020 | pmid = 32035032 | doi = 10.1016/s2213-8587(20)30025-5 | doi-access = free }}</ref><ref>{{cite web | id = EMA/PRAC/826440/2018 | url = https://www.ema.europa.eu/en/documents/prac-recommendation/prac-recommendations-signals-adopted-26-29-november-2018-prac-meeting_en.pdf | title = PRAC recommendations on signals | author = Pharmacovigilance Risk Assessment Committee (PRAC) | publisher = European Medicines Agency | date = 4 January 2019 }}</ref>


==Drug interactions== == Interaction ==
Adverse effects may occur for individuals who: Adverse effects may occur for individuals who:
*Take ]s ('blood thinners') such as warfarin (Coumadin), ] medications, digoxin (Lanoxin), theophylline (Theobid, Theo-Dur), and vitamins *Take ]s ('blood thinners') such as ] (Coumadin),<ref>{{cite journal | vauthors = Busenbark LA, Cushnie SA | title = Effect of Graves' disease and methimazole on warfarin anticoagulation | journal = The Annals of Pharmacotherapy | volume = 40 | issue = 6 | pages = 1200–1203 | date = June 2006 | pmid = 16735660 | doi = 10.1345/aph.1G422 }}</ref> ] medications, ] (Lanoxin), ] (Theobid, Theo-Dur), and vitamins
*Have ever had any blood disease, such as decreased white blood cells (leukopenia), decreased platelets (thrombocytopenia), or aplastic anemia, or liver disease (hepatitis, jaundice) *Have ever had any blood disease, such as decreased white blood cells (leukopenia), decreased platelets (thrombocytopenia) or aplastic anemia, or liver disease (hepatitis, jaundice)<ref>{{Cite web |title=Methimazole (Oral Route) Precautions | work = Mayo Clinic |url=https://www.mayoclinic.org/drugs-supplements/methimazole-oral-route/precautions/drg-20073004#:~:text=In%20very%20rare%20situations,%20methimazole,necessary%20for%20proper%20blood%20clotting. |access-date=2024-03-31 }}</ref>
*Are pregnant, or going to become pregnant, or are breast-feeding. An alternative anti-thyroid drug, ], is often substituted during pregnancy or breast-feeding. If pregnancy occurs while taking methimazole, switching to propylthiouracil may be an alternative. Early studies suggested that methimazole may harm the fetus; however, more recent studies suggest this may not be the case.{{citation needed|date=June 2011}}
*Are going to have surgery, including dental surgery.


==See also== ==Mechanism of action==
Thiamazole inhibits the enzyme ], which normally acts in thyroid hormone synthesis by oxidizing the anion iodide (I<sup>−</sup>) to iodine (I<sub>2</sub>), hypoiodous acid (HOI), and enzyme linked hypoiodate (EOI), facilitating iodine's addition to tyrosine residues on the hormone precursor ], a necessary step in the synthesis of ] (T<sub>3</sub>) and ] (T<sub>4</sub>).{{Cn|date=July 2023}}
*]


It does not inhibit the action of the sodium-dependent iodide transporter located on follicular cells' ]s. Inhibition of this step requires competitive inhibitors such as ] and ].
==References==
{{reflist}}


A study has shown that it modulates secretion of ].<ref name="pmid17911406">{{cite journal | vauthors = Crescioli C, Cosmi L, Borgogni E, Santarlasci V, Gelmini S, Sottili M, Sarchielli E, Mazzinghi B, Francalanci M, Pezzatini A, Perigli G, Vannelli GB, Annunziato F, Serio M | title = Methimazole inhibits CXC chemokine ligand 10 secretion in human thyrocytes | journal = The Journal of Endocrinology | volume = 195 | issue = 1 | pages = 145–155 | date = October 2007 | pmid = 17911406 | doi = 10.1677/JOE-07-0240 | doi-access = free }}</ref>

==Chemical properties==
The cyclic ] derivative thiamazole is a white to matte brown crystalline powder with a characteristic odour. The boiling point is 280&nbsp;°C (]). Thiamazole is soluble in water, ethanol and chloroform, but hardly soluble in ether.<ref name="RÖMPP Online">{{RömppOnline|Name=Thiamazol |Datum=10. November 2014 |ID=RD-20-01333 }}</ref>

Thiamazole acts as a ] for radicals such as the ] (<sup>•</sup>OH) radical.<ref>{{Cite journal| vauthors = Taylor JJ, Willson RL, Kendall-Taylor P |date=1984-10-29|title=Evidence for direct interactions between methimazole and free radicals|journal=FEBS Letters|volume=176|issue=2|pages=337–340|doi=10.1016/0014-5793(84)81192-8|s2cid=86322153|doi-access=}}</ref> It is used as free radical scavenger in ].<ref>{{Citation |title=Inhibition of amine oxide |url=https://patents.google.com/patent/CN102741310B/en |date=2010-12-30 |access-date=2019-04-14}}</ref>

===Laboratory synthesis===
Thiamazole has been known since 1889,<ref name=Wohl>{{cite journal | vauthors = Wohl A, Marckwald W |doi=10.1002/cber.188902201280 |title=Ueber Condensations-producte aus Amidoacetal. (II.) |date=1889 |journal=Berichte der Deutschen Chemischen Gesellschaft |language=de |volume=22 |pages=1353–1362 |url=https://zenodo.org/record/1903041 }}</ref> when it was made by a two-stage process starting from 2,2-diethoxyethaneamine, which was reacted with ].<ref name=Baranov>{{cite journal | vauthors = Baranov VV, Galochkin AA, Kravchenko AN |doi=10.1007/s11172-023-3983-y |title=A novel approach to the synthesis of methimazole | date = August 2023 |journal=Russian Chemical Bulletin |volume=72 |issue=8 |pages=1946–1949 }}</ref>
:]
The product of this reaction was then ] in an acid-catalysed reaction to form thiamazole.<ref name=Baranov/>

===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 ] as starting material, in a reaction with ].
:]
The resulting intermediate can be treated with ] in the presence of acid to give thiamazole.<ref name=Baranov/>

==History==
Surgery was used to treat hyperthyroidism until the advent of drug therapies in the 1940s. In 1942, ] was used by ] to treat a patient with the condition. He later published evidence that ] was more effective and began a search for analogues with higher potency and less toxicity.<ref name=Burch/><ref>{{cite journal |doi=10.1001/jama.251.13.1743 |title=Landmark article May 8, 1943: Treatment of hyperthyroidism with thiourea and thiouracil. By E.B. Astwood |date=1984 |last1=Astwood |first1=E. B. |journal=JAMA: The Journal of the American Medical Association |volume=251 |issue=13 |pages=1743–1746 |pmid=6422063 }}</ref> In 1949 he published his work on thiamazole which showed its superiority to previous therapies.<ref name=Burch/> The compound had been known since 1889,<ref name=Wohl/><ref name=Baranov/> and was developed as a drug by ] under the trade name Tapazole.<ref>{{cite journal |doi=10.1136/bmj.2.4849.1300 |title=Methimazole in Treatment of Thyrotoxicosis |date=1953 |last1=Davidson |first1=L. A. G. |journal=BMJ |volume=2 |issue=4849 |pages=1300–1303 |pmid=13106417 |pmc=2030295 }}</ref>

==Veterinary uses==
Thiamazole is commonly used in cats to treat hyperthyroidism.<ref name="endo">{{cite book |author1-first=J. Catherine |author1-last=Scott-Moncrieff |editor1-last=Feldman | editor1-first=Edward C. | editor2-last=Nelson | editor2-first=Richard W. | editor3-last=Reusch | editor3-first=Claudia | editor4-last=Scott-Moncrieff | editor4-first=J. Catharine |title=Canine and feline endocrinology |date=2015 |publisher=Elsevier Saunders |location=St. Louis, Missouri |isbn=978-1-4557-4456-5 |edition=Fourth |url=http://www.sciencedirect.com/book/9781455744565/canine-and-feline-endocrinology |chapter=Feline Hyperthyroidism| publication-place=St. Louis, Missouri | pages=172–177}}</ref>

Despite 20% of cats treated with thiamazole testing positive for ] ] and ], neither condition is associated with thiamazole in cats.<ref name="endo"/>

] also occurs in a small but notable amount of cats treated with thiamazole.<ref name="endo"/>

In July 2024, the US ] (FDA) approved Felanorm, the first generic methimazole oral solution for the treatment of hyperthyroidism in cats.<ref name="FDA 20240709">{{cite web | title=FDA Approves First Generic Methimazole for Treating Hyperthyroidism in Cats | website=U.S. ] (FDA) | date=9 July 2024 | url=https://www.fda.gov/animal-veterinary/cvm-updates/fda-approves-first-generic-methimazole-treating-hyperthyroidism-cats | access-date=21 December 2024}} {{PD-notice}}</ref><ref name="Recent Animal Drug Approvals">{{cite web | title=Recent Animal Drug Approvals | website=U.S. ] (FDA) | date=2 December 2024 | url=https://www.fda.gov/animal-veterinary/approved-animal-drug-products-green-book/recent-animal-drug-approvals | access-date=21 December 2024 }} {{PD-notice}}</ref><ref>https://animaldrugsatfda.fda.gov/adafda/app/search/public/document/downloadFoi/15625</ref> Felanorm contains the same active ingredient (methimazole) as the approved brand name drug product, Felimazole Coated Tablets, which were first approved in May 2009.<ref name="FDA 20240709" /> In addition, the FDA determined that Felanorm contains no inactive ingredients that may significantly affect the bioavailability of the active ingredient.<ref name="FDA 20240709" /> Felanorm is sponsored by Norbrook Laboratories based in the United Kingdom.<ref name="FDA 20240709" />

== References ==
{{Reflist}}

{{Sulfur compounds}}
{{Thyroid therapy}} {{Thyroid therapy}}
{{Thyroid hormone receptor modulators}}
{{Portal bar | Medicine}}


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