Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Propylthiouracil: Difference between pages

{{Short description|Medication used to treat hyperthyroidism}}

| verifiedrevid = 477853448

| synonyms = 6-''n''-propylthiouracil (PROP)

| pregnancy_AU = D

| pregnancy_AU_comment = <ref>{{cite web | title=Updates to the Prescribing Medicines in Pregnancy database | website=Therapeutic Goods Administration (TGA) | date=12 May 2022 | url=https://www.tga.gov.au/resources/resource/guidance/updates-prescribing-medicines-pregnancy-database | access-date=13 May 2022}}</ref>

| pregnancy_category =

| legal_status = Rx

| routes_of_administration = [[Oral administration|By mouth]]

| IUPHAR_ligand = 6650

| ChEBI_Ref = {{ebicite|correct|EBI}}

| C=7 | H=10 | N=2 | O=1 | S=1

| melting_point = 219

| melting_high = 221

<!-- Definition and medical uses -->

'''Propylthiouracil''' ('''PTU''') is a medication used to treat [[hyperthyroidism]].<ref name=AHFS2016/> This includes hyperthyroidism due to [[Graves' disease]] and [[toxic multinodular goiter]].<ref name=AHFS2016/> In a [[thyrotoxic crisis]] it is generally more effective than [[methimazole]].<ref name=AHFS2016/> Otherwise it is typically only used when methimazole, surgery, and [[radioactive iodine]] is not possible.<ref name=AHFS2016/> It is taken [[Oral administration|by mouth]].<ref name=AHFS2016>{{cite web|title=Propylthiouracil|url=https://www.drugs.com/monograph/propylthiouracil.html|publisher=The American Society of Health-System Pharmacists|access-date=8 December 2016|url-status=live|archive-url=https://web.archive.org/web/20161227055334/https://www.drugs.com/monograph/propylthiouracil.html|archive-date=27 December 2016}}</ref>

<!-- Side effects and mechanism -->

Common side effects include itchiness, hair loss, parotid swelling, vomiting, muscle pains, numbness, and headache.<ref name=AHFS2016/> Other severe side effects include [[liver problems]] and [[cytopenia|low blood cell counts]].<ref name=AHFS2016/> Use during pregnancy may harm the baby.<ref name=AHFS2016/> Propylthiouracil is in the [[antithyroid]] family of medications.<ref name=BNF69>{{cite book|title=British national formulary : BNF 69|date=2015|publisher=British Medical Association|isbn=9780857111562|page=493|edition=69}}</ref> It works by decreasing the amount of [[thyroid hormone]] produced by the [[thyroid gland]] and blocking the conversion of [[thyroxine]] (T4) to [[triiodothyronine]] (T3).<ref name=AHFS2016/>

<!-- History and culture -->

Propylthiouracil came into medical use in the 1940s.<ref>{{cite book| vauthors = De Groot LJ, Jameson JL |title=Endocrinology Adult and Pediatric: The Thyroid Gland|date=2010|publisher=Elsevier Health Sciences|isbn=978-0323221535|page=e202|url=https://books.google.com/books?id=vjctIKeMh3sC&pg=SL5-PA202|language=en|url-status=live|archive-url=https://web.archive.org/web/20161226215821/https://books.google.ca/books?id=vjctIKeMh3sC&pg=SL5-PA202|archive-date=2016-12-26}}</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<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>

==Side effects==

Propylthiouracil is generally well tolerated, with side effects occurring in one of every 100 patients.{{citation needed|date=January 2013}} The most common side effects are related to the skin and include rash, itching, hives, abnormal hair loss, and skin pigmentation.{{citation needed|date=January 2013}} Other common side effects are swelling, nausea, vomiting, heartburn, loss of taste, joint or muscle aches, numbness and headache, allergic reactions, and hair whitening.{{citation needed|date=January 2013}}

Its notable side effects include a risk of [[agranulocytosis]] and [[aplastic anemia]]. On 3 June 2009, the [[Food and Drug Administration (United States)|FDA]] published an alert "notifying healthcare professionals of the risk of serious liver injury, including liver failure and death, with the use of propylthiouracil."<ref>{{cite web|url=https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm162701.htm|title=Propylthiouracil (PTU)-Induced Liver Failure|publisher=[[Food and Drug Administration (United States)|FDA]]|access-date=2009-05-03|url-status=live|archive-url=https://web.archive.org/web/20090606081736/https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm162701.htm|archive-date=2009-06-06}}</ref> As a result, propylthiouracil is no longer recommended in non-pregnant adults and in children as the front line antithyroid medication.<ref name="FDA PTU Guidelines" />

One possible side effect is [[agranulocytosis]],<ref name="pmid16491833">{{cite journal | vauthors = Cho YY, Shon HS, Yoon HD | title = Management of a pregnant patient with Graves' disease complicated by propylthiouracil induced agranulocytosis | journal = The Korean Journal of Internal Medicine | volume = 20 | issue = 4 | pages = 335–338 | date = December 2005 | pmid = 16491833 | pmc = 3891081 | doi = 10.3904/kjim.2005.20.4.335 | url = http://www.kaim.or.kr/journal/view2.php?year=2005&vol=20&no=4&page=335 | url-status = dead | archive-url = https://web.archive.org/web/20081222032028/http://www.kaim.or.kr/journal/view2.php?year=2005&vol=20&no=4&page=335 | archive-date = 2008-12-22 }}</ref> a decrease of white blood cells in the blood. Symptoms and signs of agranulocytosis include infectious lesions of the throat, the gastrointestinal tract, and skin with an overall feeling of illness and fever. A decrease in blood platelets (thrombocytopenia) also may occur. Since platelets are important for the clotting of blood, thrombocytopenia may lead to problems with excessive bleeding. Side effects are suspected and the drug is sometimes discontinued if the patient complains of recurrent episodes of sore throat.

Another life-threatening side effect is sudden, severe, [[fulminant liver failure]] resulting in death or the need for a liver transplantation, which occurs in up to 1 in 10,000 people taking propylthiouracil. Unlike agranulocytosis which most commonly occurs in the first three months of therapy, this side effect may occur at any time during treatment.<ref name="FDA PTU Guidelines">{{cite journal | vauthors = Bahn RS, Burch HS, Cooper DS, Garber JR, Greenlee CM, Klein IL, Laurberg P, McDougall IR, Rivkees SA, Ross D, Sosa JA, Stan MN | display-authors = 6 | 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 | journal = Thyroid | volume = 19 | issue = 7 | pages = 673–674 | date = July 2009 | pmid = 19583480 | doi = 10.1089/thy.2009.0169 }}</ref>

===Pregnancy===

Propylthiouracil is classified as [[Pregnancy category|Drug Class D in pregnancy]]. Class D signifies there is positive evidence of human fetal risk. The maternal benefit may outweigh fetal risk in life-threatening situations.<ref name="Epocrates">{{cite web |url=https://online.epocrates.com/u/10a278?src=PK |title=propylthiouracil |publisher=Online.epocrates.com |access-date=2013-11-29 |url-status=live |archive-url=https://web.archive.org/web/20131203015017/https://online.epocrates.com/u/10a278?src=PK |archive-date=2013-12-03 }}</ref> PTU is preferred over [[methimazole]] (which is also a class D) only in the first trimester of pregnancy and in women who may become pregnant because of the increased risk of teratogenicity of methimazole during critical organogenesis. In the second and third trimester, this risk is diminished and [[methimazole]] is preferred to avoid the risk of liver complications from PTU in the mother.<ref name="FDA PTU Guidelines" />

The primary effect on the fetus from transplacental passage of PTU is the production of a mild hypothyroidism when the drug is used close to term. This usually resolves within a few days without treatment. The hypothyroid state may be observed as a goiter in the newborn, and is the result of increased levels of fetal pituitary thyrotropin.<ref>{{cite journal | vauthors = Fumarola A, Di Fiore A, Dainelli M, Grani G, Carbotta G, Calvanese A | title = Therapy of hyperthyroidism in pregnancy and breastfeeding | journal = Obstetrical & Gynecological Survey | volume = 66 | issue = 6 | pages = 378–385 | date = June 2011 | pmid = 21851752 | doi = 10.1097/OGX.0b013e31822c6388 | s2cid = 28728514 }}</ref> The incidence of fetal goiter after PTU treatment in reported cases is approximately 12%.

==Mechanism of action==

===Thyroid===

[[File:Thyroid hormone synthesis.png|thumb|[[Thyroid hormone synthesis]], with the oxidation step labeled at center-left.]]

PTU inhibits the enzyme [[thyroperoxidase]], which normally acts in thyroid hormone synthesis by oxidizing the anion [[iodide]] (I⁻) to [[iodine]] (I⁰), facilitating iodine's addition to tyrosine residues on the hormone precursor [[thyroglobulin]]. This is one of the essential steps in the formation of [[thyroxine]] (T4).<ref>{{cite book | vauthors = Boron WF, Boulpaep EL | date = 2005 | title = Medical Physiology | edition = Updated | publisher = Elsevier Saunders | location = Philadelphia, PA }}</ref>

PTU 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]].

=== T3/T4 target tissues ===

PTU also acts by inhibiting the enzyme 5'-deiodinase ([[tetraiodothyronine 5' deiodinase]]), which converts T₄ to the more active form T₃. (This is in contrast to [[methimazole]], which shares propylthiouracil's central mechanism, but not its peripheral one.)

It is important to recognize that these enzymes only work on the conjugated tyrosine molecules of T3 and T4: a completely different enzyme family is responsible for the deiodinase activity of iodized single tyrosine molecules within the thyroid follicular cells. For information on that enzyme family, see [[Iodotyrosine deiodinase]].

==Pharmacokinetics==

The administration is oral, with peak serum concentrations occurring in one hour, and actively concentrated to the thyroid gland. Depending on several patient variables, however, euthyroid status may not be achieved until 2–4 months after treatment initiation. Of note, the drug is approximately 70% protein-bound and significantly ionized at normal physiologic pH, while the antithyroid agent [[methimazole]] is substantially less protein bound. However, both are equally transferred across the placenta.<ref name="ESCPG">{{cite journal | vauthors = Abalovich M, Amino N, Barbour LA, Cobin RH, De Groot LJ, Glinoer D, Mandel SJ, Stagnaro-Green A | display-authors = 6 | title = Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society Clinical Practice Guideline | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 92 | issue = 8 Suppl | pages = S1-47 | date = August 2007 | pmid = 17948378 | doi = 10.1210/jc.2007-0141 | doi-access = free }}</ref>

The plasma half-life is one hour and is not altered appreciably by the thyroid status of the patient. Due to the concentration in the thyroid, however, dosing intervals may last 8 hours or longer. Less than 10% of the drug is excreted unchanged, with the remaining fraction undergoing extensive hepatic metabolism via [[glucuronidation]].

==Chemical synthesis==

Propylthiouracil can be prepared from [[ethyl 3-oxohexanoate]] and [[thiourea]].<ref>{{cite journal | vauthors = Anderson GW, Halverstadt IF | title = Studies in chemotherapy; antithyroid compounds; synthesis of 5- and 6-substituted 2-thiouracils from beta-oxoesters and thiourea | journal = Journal of the American Chemical Society | volume = 67 | issue = 12 | pages = 2197–2200 | date = December 1945 | pmid = 21005687 | doi = 10.1021/ja01228a042 }}</ref>

:[[File:Propylthiouracil rxn.png|500px]]

:

== Role in taste ==

Propylthiouracil, together with [[phenylthiocarbamide]] (PTC), are known to have bitter taste.<ref name=":0">{{cite journal | vauthors = Bufe B, Breslin PA, Kuhn C, Reed DR, Tharp CD, Slack JP, Kim UK, Drayna D, Meyerhof W | display-authors = 6 | title = The molecular basis of individual differences in phenylthiocarbamide and propylthiouracil bitterness perception | journal = Current Biology | volume = 15 | issue = 4 | pages = 322–327 | date = February 2005 | pmid = 15723792 | pmc = 1400547 | doi = 10.1016/j.cub.2005.01.047 }}</ref> However, it seems the [[Taster (genetics)|propensity for tasting]] these compounds is genetically based and the bitter taste is likely to be engendered by the [[thiocyanate]] moiety, also present in PTC.<ref name=":0" />

==History==

It was approved by the United States [[Food and Drug Administration]] in 1947.

== References ==

{{Reflist}}

== External links ==

{{Commons category|Propylthiouracil}}

* {{cite web | url = https://druginfo.nlm.nih.gov/drugportal/name/propylthiouracil | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Propylthiouracil }}

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