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Propylthiouracil Systematic (IUPAC) name 6-propyl-2-sulfanylpyrimidin-4-one Identifiers CAS number 51-52-5 ATC code H03BA02 PubChem CID 657298 DrugBank APRD00297 ChemSpider 571424 Y UNII 721M9407IY Y KEGG D00562 Y ChEMBL CHEMBL1518 Y Chemical data Formula C7H10N2OS  Mol. mass 170.233 g/mol SMILES eMolecules & PubChem InChI InChI=1S/C7H10N2OS/c1-2-3-5-4-6(10)9-7(11)8-5/h4H,2-3H2,1H3,(H2,8,9,10,11) Y Key: KNAHARQHSZJURB-UHFFFAOYSA-N Y Pharmacokinetic data Bioavailability 80%-95% Metabolism  ? Half-life 2 hours Excretion  ? Therapeutic considerations Pregnancy cat. D Legal status  ? Routes Oral  Y(what is this?)  (verify) Propylthiouracil (PTU) or 6-n-Propylthiouracil[1] (PROP) is a thioamide drug used to treat hyperthyroidism (including Graves' disease) by decreasing the amount of thyroid hormone produced by the thyroid gland.[2] Its notable side effects include a risk of agranulocytosis. On 3 June 2009, the FDA published an alert "notifying healthcare professionals of the risk of serious liver injury, including liver failure and death, with the use of propylthiouracil."[3] As a result, propylthiouracil is no longer recommended in non-pregnant adults and in children as the front line antithyroid medication[4]. Contents 1 History 2 Mode of action 2.1 Central 2.2 Peripheral 3 Pharmacokinetics 4 Side effects 5 Propylthiouracil in pregnancy 6 Chemical structure 7 References 8 External links History It was approved by the US Food and Drug Administration in 1947. Mode of action Central 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).[5] 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. Peripheral PTU also acts by inhibiting the enzyme 5'-deiodinase (tetraiodothyronine 5' deiodinase), which converts T4 to the active form T3. (This is in contrast to methimazole, which shares propylthiouracil's central mechanism, but not its peripheral one.) Pharmacokinetics 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.[6] 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. Side effects One possible side effect is agranulocytosis,[7] 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. A more life threatening side effect is sudden, severe, fulminant hepatic failure resulting in death or 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 [4] Propylthiouracil is generally well-tolerated, with side effects occurring in one of every 100 patients. The most common side effects are related to the skin, and include rash, itching, hives, abnormal hair loss, and skin pigmentation. Other common side effects are swelling, nausea, vomiting, heartburn, loss of taste, joint or muscle aches, numbness and headache, allergic reactions, and hair whitening. Propylthiouracil in pregnancy Propylthiouracil is classified as Drug Class D in pregnancy. Class D signifies there is positive evidence of human fetal risk. Maternal benefit may outweigh fetal risk in life-threatening situations.[8] PTU is preferred over methimazole (which is also a class D) only in the first trimester of pregnancy and in woman who may become pregnant. In the second and third trimester, methimazole is preferred[4]. 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. The incidence of fetal goiter after PTU treatment in reported cases is approximately 12%.[9] Chemical structure Anderson, George W.; Halverstadt, I. F.; Miller, Wilbur H.; Roblin, Richard O. (1945). "Studies in Chemotherapy. X. Antithyroid Compounds. Synthesis of 5- and 6- Substituted 2-Thiouracils from β-Oxoesters and Thiourea". Journal of the American Chemical Society 67: 2197. doi:10.1021/ja01228a042.  References ^ The letter "n" should be a lower case letter, as it describes the nature of the propyl substituent as normal, rather than its position on one of the ring nitrogens. Thereby, the position already is marked by the "6". ^ Nakamura H, Noh JY, Itoh K, Fukata S, Miyauchi A, Hamada N (June 2007). "Comparison of methimazole and propylthiouracil in patients with hyperthyroidism caused by Graves' disease". The Journal of clinical endocrinology and metabolism 92 (6): 2157–62. doi:10.1210/jc.2006-2135. PMID 17389704.  ^ "Propylthiouracil (PTU)-Induced Liver Failure". FDA. Retrieved 2009-05-03.  ^ a b c Bahn RS, Burch HS, Cooper DS, et al. (July 2009) 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, Thyroid. Jul 2009;19(7):673-674. PMID: 19583480. ^ Boron, WF & Boulpaep, EL. 2005. Medical Physiology, Updated Edition. Elsevier Saunders, Philadelphia, PA ^ Abalovich M, Amino N, Barbour LA, et al. (Aug 2007) Endocrine Society Clinical Practice Guidelines. J Clin Endocrinol Metab. Aug 2007;92(8 Suppl):S1-47. PMID: 17948378 ^ Cho YY, Shon HS, Yoon HD (December 2005). "Management of a pregnant patient with Graves' disease complicated by propylthiouracil induced agranulocytosis". The Korean journal of internal medicine 20 (4): 335–8. PMID 16491833.  ^ propylthiouracil ^ Propylthiouracil: Drug safety during pregnancy and breastfeeding / DRUGSAFETYSITE.COM External links "Clinical Pharmacology Online Database".  v · d · eThyroid therapy (H03) Thyroid hormones Levothyroxine# • Liothyronine • Tiratricol • Thyroid gland preparations Antithyroid preparations Thyroid peroxidase inhibitors (thioamide) Thiouracils: Propylthiouracil# • Methylthiouracil • Benzylthiouracil Sulfur-containing imidazole derivatives: Carbimazole • Methimazole Block conversion of T4 to T3 Propylthiouracil# • Ipodate Sodium-iodide symporter inhibitor Perchlorate (Potassium perchlorate) • Pertechnetate (Sodium pertechnetate) Other Diiodotyrosine • Dibromotyrosine #WHO-EM. ‡Withdrawn from market. Clinical trials: †Phase III. §Never to phase III M: END anat/phys/devp/cell/horm noco(d)/cong/tumr, sysi/epon proc, drug (A10/H1/H2/H3/H5)