Antithyroid agent

{{Short description|Hormone antagonist acting upon thyroid hormones}}

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

The main antithyroid drugs are carbimazole (in the UK), methimazole (in the US), and propylthiouracil (PTU). A less common antithyroid agent is potassium perchlorate.

==Classification based on mechanisms of action== The mechanisms of action of antithyroid drugs are not completely understood. Based on their mechanisms of action, the drugs are classified into following six classes.

===Thyroid hormone synthesis inhibitors=== These drugs probably inhibit the enzyme thyroid peroxidase ({{a.k.a}} thyroperoxidase), decreasing iodide oxidation, iodination of tyrosyl residues in thyroglobulin, and coupling of iodotyrosyl and iodothyronyl residues.<ref>{{cite book |doi=10.1016/B978-0-323-39307-2.00029-1 |quote=Thioamides inhibit thyroid peroxidase, decreasing iodide oxidation, iodination of tyrosines, and coupling of iodotyrosyl and iodothyronyl residues (see Fig. 29-3). As a result, less thyroid hormone is synthesized. Propylthiouracil also inhibits the peripheral conversion of T4 to T3. |chapter=Pituitary, Thyroid, and Parathyroid Pharmacology |title=Pharmacology and Therapeutics for Dentistry |date=2017 |last1=Galasko |first1=Gail T. |pages=417–428 |isbn=978-0-323-39307-2 }}</ref> It is thought that they inhibit the thyroperoxidase-catalyzed oxidation reactions by acting as substrates for the postulated peroxidase-iodine complex, thus competitively inhibiting the interaction with the amino acid tyrosine. The most common drugs in this class are thioamides, which include propylthiouracil, methimazole and its prodrug carbimazole.

Additionally, propylthiouracil may reduce the de-iodination of thyroxine (T4) into triiodothyronine (T3) in peripheral tissues.<ref name="pmid23883148">{{Cite journal|vauthors=Manna D, Roy G, Mugesh G |title=Antithyroid Drugs and their Analogues: Synthesis, Structure and Mechanism of Action |journal=Acc. Chem. Res. |volume= 46|issue=11 |pages=2706–15 |year=2013 |pmid=23883148| doi=10.1021/ar4001229}}</ref>

Lugol's iodine is used to temporarily block thyroid hormone synthesis before surgeries.<ref>{{Cite journal |first1=Yeşim |last1=Erbil |first2=Yasemin |last2=Ozluk |first3=Murat |last3=Giriş |first4=Artur |last4=Salmaslıoglu |first5=Halim |last5=Issever |first6=Umut |last6=Barbaros |first7=Yersu |last7=Kapran |first8=Selçuk |last8=Özarmağan |first9=Serdar |last9=Tezelman |title=Effect of Lugol Solution on Thyroid Gland Blood Flow and Microvessel Density in the Patients with Graves' Disease |journal=The Journal of Clinical Endocrinology & Metabolism |date=2007 |volume=92 |issue=6 |pages=2182–2189 |doi=10.1210/jc.2007-0229 |pmid=17389702 |doi-access=free }}</ref> It is also used to treat patients with thyroid storm or, more commonly, to reduce thyroid vascularity before thyroidectomy (surgical removal of the thyroid gland).<ref>{{cite journal |last1=Pearce |first1=Elizabeth N |title=Diagnosis and management of thyrotoxicosis |journal=BMJ |date=10 June 2006 |volume=332 |issue=7554 |pages=1369–1373 |doi=10.1136/bmj.332.7554.1369 |pmid=16763249 |pmc=1476727 }}</ref>

===Iodide uptake inhibitors=== They decrease uptake of iodide ions (I−) into follicular cells of the thyroid gland. Since their molecules have structural similarities with the iodide ion, they compete with iodide for being transported by the sodium/iodide symporter, which is a transporter protein that co-transports Na+ and I− ions. Iodide transport is a key step in the biosynthesis of the thyroid hormones T4 and T3.<ref name="Furman2017" /><ref name="Wolff1998" /> For example, potassium perchlorate competitively inhibits the active iodide transport mechanism in the thyroid gland, which has the capacity to selectively concentrate iodide against a large concentration gradient.<ref name="Furman2017">{{cite book |doi=10.1016/B978-0-12-801238-3.98053-X |chapter=Methimazole |title=Reference Module in Biomedical Sciences |date=2017 |last1=Furman |first1=B.L. |isbn=978-0-12-801238-3 }}</ref><ref name="Wolff1998">{{Cite journal |last=Wolff |first=J. |date=March 1998 |title=Perchlorate and the thyroid gland |journal=Pharmacological Reviews |volume=50 |issue=1 |pages=89–105 |doi=10.1016/S0031-6997(24)01350-4 |pmid=9549759 }}</ref>

Besides perchlorates, other examples of iodide uptake inhibitors include pertechnetates, thiocyanates, nitrates.<ref>{{cite journal |last1=Mervish |first1=Nancy A. |last2=Pajak |first2=Ashley |last3=Teitelbaum |first3=Susan L. |last4=Pinney |first4=Susan M. |last5=Windham |first5=Gayle C. |last6=Kushi |first6=Lawrence H. |last7=Biro |first7=Frank M. |last8=Valentin-Blasini |first8=Liza |last9=Blount |first9=Benjamin C. |last10=Wolff |first10=Mary S. |title=Thyroid Antagonists (Perchlorate, Thiocyanate, and Nitrate) and Childhood Growth in a Longitudinal Study of U.S. Girls |journal=Environmental Health Perspectives |date=April 2016 |volume=124 |issue=4 |pages=542–549 |doi=10.1289/ehp.1409309 |pmc=4829993 |pmid=26151950 |bibcode=2016EnvHP.124..542M }}</ref>

These drugs are no longer used due to high toxicity and adverse effects.<ref>{{Cite journal |last1=Wyngaarden |first1=J. B. |last2=Stanbury |first2=J. B. |last3=Rapp |first3=B. |date=May 1953 |title=The effects of iodine, perchlorate, thiocyanate, and nitrate administration upon the iodide concentrating mechanism of the rat thyroid |journal=Endocrinology |volume=52 |issue=5 |pages=568–574 |doi=10.1210/endo-52-5-568 |pmid=13060263 }}</ref><ref>{{Cite journal |last1=Serrano-Nascimento |first1=Caroline |last2=Nunes |first2=Maria Tereza |date=2022 |title=Perchlorate, nitrate, and thiocyanate: Environmental relevant NIS-inhibitors pollutants and their impact on thyroid function and human health |journal=Frontiers in Endocrinology |volume=13 |doi=10.3389/fendo.2022.995503 |pmid=36339434 |pmc=9633673 |doi-access=free }}</ref>

===Thyroid hormone release inhibitors=== They inhibit release (secretion) of thyroid hormones by the thyroid gland. The most studied drug in this class is lithium, which inhibits thyroid hormone secretion by inhibiting iodotyrosine coupling, thyroidal iodide uptake, and alteration in structure of thyroglobulin,<ref>{{Cite journal |last=Lazarus |first=J.h. |date=October 1998 |title=The Effects of Lithium Therapy on Thyroid and Thyrotropin-Releasing Hormone |journal=Thyroid |volume=8 |issue=10 |pages=909–913 |doi=10.1089/thy.1998.8.909 |pmid=9827658 }}</ref> a protein which acts as a substrate for the synthesis of thyroid hormones and storage of inactive forms of T3, T4 and iodine within the lumen of thyroid follicular cells.<ref>{{cite web|url=https://www.ncbi.nlm.nih.gov/gene/7038|title=TG thyroglobulin [Homo sapiens (human)] – Gene – NCBI|website=National Center for Biotechnology Information (NCBI)|access-date=2019-09-16}}</ref> Since lithium is neither metabolized nor protein-bound, its bioavailability usually is close to 100%.<ref>{{cite journal |last1=Ware |first1=Kenric |last2=Tillery |first2=Erika |last3=Linder |first3=Lauren |title=General pharmacokinetic/pharmacodynamic concepts of mood stabilizers in the treatment of bipolar disorder |journal=Mental Health Clinician |date=January 2016 |volume=6 |issue=1 |pages=54–61 |doi=10.9740/mhc.2016.01.054 |pmid=29955448 |pmc=6009247 }}</ref> Hence, there are risks of serious side effects such as lithium toxicity, hypothyroidism, and diabetes insipidus.<ref name=AHFS2015>{{cite web|title=Lithium Salts|url=https://www.drugs.com/monograph/lithium-salts.html|publisher=The American Society of Health-System Pharmacists|access-date=1 December 2015|url-status=live|archive-url=https://web.archive.org/web/20151208101020/http://www.drugs.com/monograph/lithium-salts.html|archive-date=8 December 2015}}</ref>

===Excess iodine=== Excessive iodine intake can temporarily inhibit production of thyroid hormones. This occurs because of the Wolff-Chaikoff effect, which is a phenomenon of rejection of large quantities of iodine by the thyroid gland, therefore preventing it from synthesizing large quantities of thyroid hormones.<ref>{{cite journal |last1=Markou |first1=K. |last2=Georgopoulos |first2=N. |last3=Kyriazopoulou |first3=V. |last4=Vagenakis |first4=A.G. |title=Iodine-Induced Hypothyroidism |journal=Thyroid |date=May 2001 |volume=11 |issue=5 |pages=501–510 |doi=10.1089/105072501300176462 |pmid=11396709 }}</ref>

===Iodine radiopharmaceuticals=== {{main|Isotopes of iodine|radiopharmaceutical}} They are radioisotopes of iodine. In small doses, when they are taken up by overactive thyroid follicular cells, they emit small amounts of beta radiation that destroys not all, but many thyroid follicular cells, thereby reducing thyroid hormone production.<ref name="I-131 DrugBank">{{Cite web |title=Iodide I-131 |url=https://go.drugbank.com/drugs/DB09293 |access-date=2023-10-03 |website=go.drugbank.com}}</ref> This is a form of targeted therapy for hyperthyroidism. Since even low levels of ionizing radiation are highly mutagenic and can cause cancer,<ref>{{cite journal |last1=Zelensky |first1=Alex N. |last2=Schoonakker |first2=Mascha |last3=Brandsma |first3=Inger |last4=Tijsterman |first4=Marcel |last5=van Gent |first5=Dik C. |last6=Essers |first6=Jeroen |last7=Kanaar |first7=Roland |title=Low dose ionizing radiation strongly stimulates insertional mutagenesis in a γH2AX dependent manner |journal=PLOS Genetics |date=16 January 2020 |volume=16 |issue=1 |article-number=e1008550 |doi=10.1371/journal.pgen.1008550 |pmc=6964834 |pmid=31945059 |doi-access=free }}</ref> less toxic iodine isotopes such as iodine-123<ref>{{cite book |last1=Pappaconstantinou |first1=Mary |last2=Heston |first2=Thomas F. |last3=Tran |first3=Huyen D. |title=StatPearls |date=2025 |publisher=StatPearls Publishing |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK559314/ |chapter=I-123 Uptake |pmid=32644740 }}</ref> are more commonly used in nuclear imaging, while iodine-131 is used for its cytolytic (cell-destroying) effects in hyperthyroidism and thyroid tumors.<ref name="I-131 DrugBank" />

===Thyroid hormone receptor antagonists=== Also called TR antagonists, they inhibit action of thyroid hormones by blocking TR receptors (thyroid hormone receptors). Antagonist 1-850 and its derivatives have been found to be coactivator interaction inhibitors, which interfere with the interaction between TR receptors and coactivator proteins such as nuclear hormone receptor coregulator (NRC). As a result, the receptors are unable to recruit coactivators, causing stoppage of transcription of target genes, thereby preventing activation of TR receptors, ultimately leading to inhibition of effects of thyroid hormones because they can bind to only inactive TR receptors, and these receptors can't be activated in presence of TR antagonists.<ref name="Schapira2003">{{cite journal |last1=Schapira |first1=Matthieu |last2=Raaka |first2=Bruce M. |last3=Das |first3=Sharmistha |last4=Fan |first4=Li |last5=Totrov |first5=Maxim |last6=Zhou |first6=Zhiguo |last7=Wilson |first7=Stephen R. |last8=Abagyan |first8=Ruben |last9=Samuels |first9=Herbert H. |title=Discovery of diverse thyroid hormone receptor antagonists by high-throughput docking |journal=Proceedings of the National Academy of Sciences |date=10 June 2003 |volume=100 |issue=12 |pages=7354–7359 |doi=10.1073/pnas.1131854100 |pmc=165879 |pmid=12777627 |bibcode=2003PNAS..100.7354S |doi-access=free }}</ref> Antagonist 1-850 has also been found to inhibit binding of [125I]T3{{efn|[125I]T3 is a radiopharmaceutical formulation of triiodothyronine having iodine-125 atoms instead of iodine.}} to TRs in intact GH4 cells.<ref name="Schapira2003" />

==Adverse effects== The most dangerous side effect is agranulocytosis (1/250, more in PTU); this is an idiosyncratic reaction which generally resolves on cessation of drug. It occurs in about 0.2 to 0.3% of cases treated with antithyroid drugs.<ref>{{Cite journal |last1=Zambrana |first1=J. |last2=Zambrana |first2=F. |last3=Neto |first3=F. |last4=Gonçalves |first4=A. |last5=Zambrana |first5=F. |last6=Ushirohira |first6=J. |year=2005 |title=Agranulocytosis with tonsillitis associated with methimazole therapy |journal=Brazilian Journal of Otorhinolaryngology |volume=71 |issue=3 |pages=374–377 |doi=10.1016/S1808-8694(15)31339-2 |pmid=16446945 |pmc=9450596 |doi-access=free}}</ref> Other side effects include granulocytopenia (dose dependent, which improves on cessation of the drug) and aplastic anemia, and in case of propylthiouracil, severe, fulminant liver failure.<ref name="FDA PTU Guidelines">{{cite journal | last1=Bahn | first1=RS | last2=Burch | first2=HS | last3=Cooper | first3=DS | last4=Garber | first4=JR | last5=Greenlee | first5=CM | last6=Klein | first6=IL | last7=Laurberg | first7=P | last8=McDougall | first8=IR | last9=Rivkees | first9=SA | display-authors=8| title=The Role of Propylthiouracil in the Management of Graves' Disease in Adults: report of a meeting jointly sponsored by the American Thyroid Association and the Food and Drug Administration. | pmid=19583480 | name-list-style=vanc | journal=Thyroid | doi=10.1089/thy.2009.0169 | volume=19 | issue=7 |date=July 2009 | pages=673–4}}</ref> Patients on these medications should see a doctor if they develop sore throat or fever.

The most common side effects are rash and peripheral neuritis.<ref>{{cite journal |last1=Pal |first1=Partha |last2=Ray |first2=Sayantan |last3=Biswas |first3=Kaushik |last4=Maiti |first4=Animesh |last5=Mukhopadhyay |first5=Deep |last6=George |first6=Rintu |last7=Mukherjee |first7=Debabrata |title=Thyrotoxic neuropathy; an under recognized condition: A clinical vignette |journal=Thyroid Research and Practice |date=2014 |volume=11 |issue=3 |page=118 |doi=10.4103/0973-0354.138559 |doi-access=free }}</ref> These drugs also cross the placenta and are secreted in breast milk.<ref>{{cite journal |last1=Kampmann |first1=Jens P. |last2=Hansen |first2=J. Mølholm |title=Clinical Pharmacokinetics of Antithyroid Drugs |journal=Clinical Pharmacokinetics |date=1981 |volume=6 |issue=6 |pages=401–428 |doi=10.2165/00003088-198106060-00001 |pmid=6172233 }}</ref>

==Graves' disease== In Graves' disease, treatment with antithyroid medications must be given for six months to two years, in order to be effective. Even then, upon cessation of the drugs, the hyperthyroid state may recur. Side effects of the antithyroid medications include a potentially fatal reduction in the level of white blood cells.

A randomized control trial testing single dose treatment for Graves' found methimazole achieved euthyroidism (normal thyroid function that occurs within normal serum levels of TSH and T4{{fact|date=June 2025}}) more effectively after 12 weeks than did propylthiouracil (77.1% on methimazole 15 mg vs 19.4% in the propylthiouracil 150 mg groups).<ref name="pmid11298092">{{cite journal |last1=Homsanit |first1=Mayuree |last2=Sriussadaporn |first2=Sutin |last3=Vannasaeng |first3=Sathit |last4=Peerapatdit |first4=Thavatchai |last5=Nitiyanant |first5=Wannee |last6=Vichayanrat |first6=Apichati |title=Efficacy of single daily dosage of methimazole vs. propylthiouracil in the induction of euthyroidism |journal=Clinical Endocrinology |date=March 2001 |volume=54 |issue=3 |pages=385–390 |doi=10.1046/j.1365-2265.2001.01239.x |pmid=11298092 }}</ref> But generally both drugs are considered equivalent.

A study has shown no difference in outcome for adding thyroxine to antithyroid medication and continuing thyroxine versus placebo after antithyroid medication withdrawal. However, two markers were found that can help predict the risk of recurrence. These two markers are an elevated level of thyroid stimulating hormone receptor antibodies (TSHR-Ab) and smoking. A positive TSHR-Ab at the end of antithyroid drug treatment increases the risk of recurrence to 90% (sensitivity 39%, specificity 98%), a negative TSHR-Ab at the end of antithyroid drug treatment is associated with a 78% chance of remaining in remission. Smoking was shown to have an impact independent to a positive TSHR-Ab.<ref name="pmid11331213">{{Cite journal|vauthors=Glinoer D, de Nayer P, Bex M |title=Effects of l-thyroxine administration, TSH-receptor antibodies and smoking on the risk of recurrence in Graves' hyperthyroidism treated with antithyroid drugs: a double-blind prospective randomized study |journal=Eur. J. Endocrinol. |volume=144 |issue=5 |pages=475–83 |year=2001 |pmid=11331213| doi=10.1530/eje.0.1440475|doi-access=free |hdl=2078.1/42755 |hdl-access=free }}</ref>

Competitive antagonists of thyroid stimulating hormone receptors are currently being investigated as a possible treatment for Grave's disease.

==Notes== {{notelist}}

==References== {{Reflist}}

==External links== * {{MeshName|Antithyroid agents}}

Category:Antithyroid drugs