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Propylthiouracil

propylthiouracil, propylthiouracil side effects
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

Common side effects include itchiness, hair loss, swelling, vomiting, muscle pains, numbness, and headache Other severe side effects include liver problems and low blood cell counts Use during pregnancy may harm the baby Propylthiouracil is in the antithyroid family of medications It works by decreasing the amount of thyroid hormone produced by the thyroid gland and blocking the conversion of thyroxine T4 to triiodothyronine T3

Propylthiouracil came into medical use in the 1940s It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system The wholesale cost in the developing world is about 362 USD a month In the United Kingdom a month costs the NHS about 5251 pounds In the United States the wholesale price is 3834 USD per month

Contents

  • 1 Side effects
    • 11 Pregnancy
  • 2 Mechanism of action
    • 21 Thyroid
    • 22 T3/T4 target tissues
  • 3 Pharmacokinetics
  • 4 Chemical synthesis
  • 5 History
  • 6 See also
  • 7 References
  • 8 External links

Side effects

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

Its notable side effects include a risk of agranulocytosis and aplastic anemia 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" As a result, propylthiouracil is no longer recommended in non-pregnant adults and in children as the front line antithyroid medication

One possible side effect is agranulocytosis, 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

Other life-threatening side effect is sudden, severe, fulminant liver 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

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 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

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%

Mechanism of action

Thyroid

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

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

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

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

History

It was approved by the US Food and Drug Administration in 1947

See also

  • Phenylthiocarbamide
  • Supertaster
  • TAS2R38
  • Methylthiouracil

References

  1. ^ a b c d e f g h i "Propylthiouracil" The American Society of Health-System Pharmacists Archived from the original on 27 December 2016 Retrieved 8 December 2016 
  2. ^ a b British national formulary : BNF 69 69 ed British Medical Association 2015 p 493 ISBN 9780857111562 
  3. ^ Groot, Leslie J De; Jameson, J Larry 2010 Endocrinology Adult and Pediatric: The Thyroid Gland Elsevier Health Sciences p e202 ISBN 032322153X Archived from the original on 2016-12-26 
  4. ^ "WHO Model List of Essential Medicines 19th List" PDF World Health Organization April 2015 Archived PDF from the original on 13 December 2016 Retrieved 8 December 2016 
  5. ^ "Propylthiouracil" International Drug Price Indicator Guide Retrieved 8 December 2016 
  6. ^ "NADAC as of 2016-12-21 | DataMedicaidgov" Centers for Medicare and Medicaid Services Archived from the original on 24 December 2016 Retrieved 26 December 2016 
  7. ^ "Propylthiouracil PTU-Induced Liver Failure" FDA Archived from the original on 2009-06-06 Retrieved 2009-05-03 
  8. ^ 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 19 7: 673–4 doi:101089/thy20090169 PMID 19583480 
  9. ^ 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 doi:103904/kjim2005204335 PMID 16491833 Archived from the original on 2008-12-22 
  10. ^ "propylthiouracil" Onlineepocratescom Archived from the original on 2013-12-03 Retrieved 2013-11-29 
  11. ^ Fumarola, A; Di Fiore, A; Dainelli, M; Grani, G; Carbotta, G; Calvanese, A Jun 2011 "Therapy of hyperthyroidism in pregnancy and breastfeeding" Obstetrical & gynecological survey 66 6: 378–85 doi:101097/OGX0b013e31822c6388 PMID 21851752 
  12. ^ "Propylthiouracil: Drug safety during pregnancy and breastfeeding" Drugsafetysitecom Archived from the original on 2013-12-05 Retrieved 2013-11-29 
  13. ^ Boron, WF & Boulpaep, EL 2005 Medical Physiology, Updated Edition Elsevier Saunders, Philadelphia, PA
  14. ^ Abalovich M, Amino N, Barbour LA, et al August 2007 "Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society Clinical Practice Guideline" J Clin Endocrinol Metab 92 8 Suppl: S1–47 doi:101210/jc2007-0141 PMID 17948378 
  15. ^ 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 12: 2197–2200 doi:101021/ja01228a042 

External links

  • "Clinical Pharmacology Online Database" Archived from the original on 2007-12-16 

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Propylthiouracil


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