Propylthiouracil

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Propylthiouracil
Propylthiouracil.svg
Propylthiouracil-3D-balls.png
Clinical data
Other names6-n-propylthiouracil (PROP)
AHFS/Drugs.com Monograph
MedlinePlus a682465
Pregnancy
category
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
  • US: WARNING [2]
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 80%-95%
Metabolism ?
Elimination half-life 2 hours
Excretion ?
Identifiers
  • 6-propyl-2-sulfanylpyrimidin-4-one
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.000.095 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C7H10N2OS
Molar mass 170.23 g·mol−1
3D model (JSmol)
Melting point 219 to 221 °C (426 to 430 °F)
  • S=C1N/C(=C\C(=O)N1)CCC
  • InChI=1S/C7H10N2OS/c1-2-3-5-4-6(10)9-7(11)8-5/h4H,2-3H2,1H3,(H2,8,9,10,11) Yes check.svgY
  • Key:KNAHARQHSZJURB-UHFFFAOYSA-N Yes check.svgY
   (verify)

Propylthiouracil (PTU) is a medication used to treat hyperthyroidism. [3] This includes hyperthyroidism due to Graves' disease and toxic multinodular goiter. [3] In a thyrotoxic crisis it is generally more effective than methimazole. [3] Otherwise it is typically only used when methimazole, surgery, and radioactive iodine is not possible. [3] It is taken by mouth. [3]

Contents

Common side effects include itchiness, hair loss, parotid swelling, vomiting, muscle pains, numbness, and headache. [3] Other severe side effects include liver problems and low blood cell counts. [3] Use during pregnancy may harm the baby. [3] Propylthiouracil is in the antithyroid family of medications. [4] It works by decreasing the amount of thyroid hormone produced by the thyroid gland and blocking the conversion of thyroxine (T4) to triiodothyronine (T3). [3]

Propylthiouracil came into medical use in the 1940s. [5] It is on the World Health Organization's List of Essential Medicines. [6]

Side effects

Propylthiouracil is generally well tolerated, with side effects occurring in one of every 100 patients.[ citation needed ] The most common side effects are related to the skin and include rash, itching, hives, abnormal hair loss, and skin pigmentation.[ citation needed ] 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 ]

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." [7] As a result, propylthiouracil is no longer recommended in non-pregnant adults and in children as the front line antithyroid medication. [8]

One possible side effect is agranulocytosis, [9] 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. [8]

Pregnancy

Propylthiouracil is classified as 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. [10] 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. [8]

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. [11] The incidence of fetal goiter after PTU treatment in reported cases is approximately 12%.

Mechanism of action

Thyroid

Thyroid hormone synthesis, with the oxidation step labeled at center-left. Thyroid hormone synthesis.png
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). [12]

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. [13]

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. [14]

Propylthiouracil rxn.png

Role in taste

Propylthiouracil, together with phenylthiocarbamide (PTC), are known to have bitter taste. [15] However, it seems the 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. [15]

History

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

Related Research Articles

<span class="mw-page-title-main">Hyperthyroidism</span> Endocrine neck-gland secretes excess hormones affecting metabolism

Hyperthyroidism is the condition that occurs due to excessive production of thyroid hormones by the thyroid gland. Thyrotoxicosis is the condition that occurs due to excessive thyroid hormone of any cause and therefore includes hyperthyroidism. Some, however, use the terms interchangeably. Signs and symptoms vary between people and may include irritability, muscle weakness, sleeping problems, a fast heartbeat, heat intolerance, diarrhea, enlargement of the thyroid, hand tremor, and weight loss. Symptoms are typically less severe in the elderly and during pregnancy. An uncommon but life-threatening complication is thyroid storm in which an event such as an infection results in worsening symptoms such as confusion and a high temperature; this often results in death. The opposite is hypothyroidism, when the thyroid gland does not make enough thyroid hormone.

<span class="mw-page-title-main">Thyroid</span> Endocrine gland in the neck; secretes hormones that influence metabolism

The thyroid, or thyroid gland, is an endocrine gland in vertebrates. In humans, it is in the neck and consists of two connected lobes. The lower two thirds of the lobes are connected by a thin band of tissue called the isthmus (pl.: isthmi). The thyroid gland is a butterfly-shaped gland located in the neck below the Adam's apple. Microscopically, the functional unit of the thyroid gland is the spherical thyroid follicle, lined with follicular cells (thyrocytes), and occasional parafollicular cells that surround a lumen containing colloid. The thyroid gland secretes three hormones: the two thyroid hormones – triiodothyronine (T3) and thyroxine (T4) – and a peptide hormone, calcitonin. The thyroid hormones influence the metabolic rate and protein synthesis and growth and development in children. Calcitonin plays a role in calcium homeostasis. Secretion of the two thyroid hormones is regulated by thyroid-stimulating hormone (TSH), which is secreted from the anterior pituitary gland. TSH is regulated by thyrotropin-releasing hormone (TRH), which is produced by the hypothalamus.

<span class="mw-page-title-main">Graves' disease</span> Autoimmune endocrine disease

Graves' disease, also known as toxic diffuse goiter, is an autoimmune disease that affects the thyroid. It frequently results in and is the most common cause of hyperthyroidism. It also often results in an enlarged thyroid. Signs and symptoms of hyperthyroidism may include irritability, muscle weakness, sleeping problems, a fast heartbeat, poor tolerance of heat, diarrhea and unintentional weight loss. Other symptoms may include thickening of the skin on the shins, known as pretibial myxedema, and eye bulging, a condition caused by Graves' ophthalmopathy. About 25 to 30% of people with the condition develop eye problems.

<span class="mw-page-title-main">Iodothyronine deiodinase</span> Class of enzymes

Iodothyronine deiodinases (EC 1.21.99.4 and EC 1.21.99.3) are a subfamily of deiodinase enzymes important in the activation and deactivation of thyroid hormones. Thyroxine (T4), the precursor of 3,5,3'-triiodothyronine (T3) is transformed into T3 by deiodinase activity. T3, through binding a nuclear thyroid hormone receptor, influences the expression of genes in practically every vertebrate cell. Iodothyronine deiodinases are unusual in that these enzymes contain selenium, in the form of an otherwise rare amino acid selenocysteine.

Thyroid-stimulating hormone (also known as thyrotropin, thyrotropic hormone, or abbreviated TSH) is a pituitary hormone that stimulates the thyroid gland to produce thyroxine (T4), and then triiodothyronine (T3) which stimulates the metabolism of almost every tissue in the body. It is a glycoprotein hormone produced by thyrotrope cells in the anterior pituitary gland, which regulates the endocrine function of the thyroid.

<span class="mw-page-title-main">Triiodothyronine</span> Chemical compound

Triiodothyronine, also known as T3, is a thyroid hormone. It affects almost every physiological process in the body, including growth and development, metabolism, body temperature, and heart rate.

<span class="mw-page-title-main">Levothyroxine</span> Thyroid hormone

Levothyroxine, also known as L-thyroxine, is a synthetic form of the thyroid hormone thyroxine (T4). It is used to treat thyroid hormone deficiency (hypothyroidism), including a severe form known as myxedema coma. It may also be used to treat and prevent certain types of thyroid tumors. It is not indicated for weight loss. Levothyroxine is taken orally (by mouth) or given by intravenous injection. Levothyroxine has a half-life of 7.5 days when taken daily, so about six weeks is required for it to reach a steady level in the blood.

<span class="mw-page-title-main">Wolff–Chaikoff effect</span> Effect of iodine on the thyroid

The Wolff–Chaikoff effect is a presumed reduction in thyroid hormone levels caused by ingestion of a large amount of iodine.

<span class="mw-page-title-main">Thiamazole</span> Chemical compound

Thiamazole, also known as methimazole, is a medication used to treat hyperthyroidism. This includes Graves disease, toxic multinodular goiter, and thyrotoxic crisis. It is taken by mouth. Full effects may take a few weeks to occur.

<span class="mw-page-title-main">Thyroid disease</span> Medical condition

Thyroid disease is a medical condition that affects the function of the thyroid gland. The thyroid gland is located at the front of the neck and produces thyroid hormones that travel through the blood to help regulate many other organs, meaning that it is an endocrine organ. These hormones normally act in the body to regulate energy use, infant development, and childhood development.

<span class="mw-page-title-main">Carbimazole</span> Medication used for hyperthyroidism

Carbimazole (brand names Neo-Mercazole, Anti-Thyrox, etc.) is used to treat hyperthyroidism. Carbimazole is a pro-drug as after absorption it is converted to the active form, methimazole. Methimazole prevents thyroid peroxidase enzyme from iodinating and coupling the tyrosine residues on thyroglobulin, hence reducing the production of the thyroid hormones T3 and T4 (thyroxine).

<span class="mw-page-title-main">Toxic multinodular goitre</span> Medical condition

Toxic multinodular goiter (TMNG), also known as multinodular toxic goiter (MNTG), is an active multinodular goiter associated with hyperthyroidism.

Thyroid storm is a rare but severe and life-threatening complication of hyperthyroidism. It occurs when an overactive thyroid leads to hypermetabolism, which can cause death from cardiac arrest or multiple organ failure.

Goitrogens are substances that disrupt the production of thyroid hormones. This triggers the pituitary to release thyroid-stimulating hormone (TSH), which then promotes the growth of thyroid tissue, eventually leading to goiter.

<span class="mw-page-title-main">Reverse triiodothyronine</span> Chemical compound

Reverse triiodothyronine (3,3′,5′-triiodothyronine, reverse T3, or rT3) is an isomer of triiodothyronine (3,5,3′ triiodothyronine, T3).

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

Euthyroid sick syndrome (ESS) is a state of adaptation or dysregulation of thyrotropic feedback control wherein the levels of T3 and/or T4 are abnormal, but the thyroid gland does not appear to be dysfunctional. This condition may result from allostatic responses of hypothalamus-pituitary-thyroid feedback control, dyshomeostatic disorders, drug interferences, and impaired assay characteristics in critical illness.

<span class="mw-page-title-main">Thyroid hormones</span> Hormones produced by the thyroid gland

Thyroid hormones are any hormones produced and released by the thyroid gland, namely triiodothyronine (T3) and thyroxine (T4). They are tyrosine-based hormones that are primarily responsible for regulation of metabolism. T3 and T4 are partially composed of iodine, derived from food. A deficiency of iodine leads to decreased production of T3 and T4, enlarges the thyroid tissue and will cause the disease known as simple goitre.

<span class="mw-page-title-main">Iopanoic acid</span> Chemical compound

Iopanoic acid is an iodine-containing radiocontrast medium used in cholecystography. Both iopanoic acid and ipodate sodium are potent inhibitors of thyroid hormone release from thyroid gland, as well as of peripheral conversion of thyroxine (T4) to triiodothyronine (T3). These compounds inhibit 5'deiodinase (5'DID-1 and 5'DID-2) enzymes, which catalyse T4-T3 conversion in the thyroid cell, liver, kidney, skeletal muscle, heart, brain, pituitary. This accounts for the dramatic improvement in both subjective and objective symptoms of hyperthyroidism, particularly when they are used as an adjunctive therapy with thioamides (propylthiouracil, carbimazole). They can be used in the treatment of patients with severe thyrotoxicosis (thyroid storm) and significant morbidity (e.g., myocardial infarction, or stroke) for rapid control of elevated plasma triiodothyronine concentrations. The use of iopanoic acid for treatment of thyrotoxicosis has been discontinued in the United States.

Thyroid disease in pregnancy can affect the health of the mother as well as the child before and after delivery. Thyroid disorders are prevalent in women of child-bearing age and for this reason commonly present as a pre-existing disease in pregnancy, or after childbirth. Uncorrected thyroid dysfunction in pregnancy has adverse effects on fetal and maternal well-being. The deleterious effects of thyroid dysfunction can also extend beyond pregnancy and delivery to affect neurointellectual development in the early life of the child. Due to an increase in thyroxine binding globulin, an increase in placental type 3 deioidinase and the placental transfer of maternal thyroxine to the fetus, the demand for thyroid hormones is increased during pregnancy. The necessary increase in thyroid hormone production is facilitated by high human chorionic gonadotropin (hCG) concentrations, which bind the TSH receptor and stimulate the maternal thyroid to increase maternal thyroid hormone concentrations by roughly 50%. If the necessary increase in thyroid function cannot be met, this may cause a previously unnoticed (mild) thyroid disorder to worsen and become evident as gestational thyroid disease. Currently, there is not enough evidence to suggest that screening for thyroid dysfunction is beneficial, especially since treatment thyroid hormone supplementation may come with a risk of overtreatment. After women give birth, about 5% develop postpartum thyroiditis which can occur up to nine months afterwards. This is characterized by a short period of hyperthyroidism followed by a period of hypothyroidism; 20–40% remain permanently hypothyroid.

References

  1. ↑ "Updates to the Prescribing Medicines in Pregnancy database". Therapeutic Goods Administration (TGA). 12 May 2022. Retrieved 13 May 2022.
  2. ↑ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA . Retrieved 22 Oct 2023.
  3. 1 2 3 4 5 6 7 8 9 "Propylthiouracil". The American Society of Health-System Pharmacists. Archived from the original on 27 December 2016. Retrieved 8 December 2016.
  4. ↑ British national formulary : BNF 69 (69 ed.). British Medical Association. 2015. p. 493. ISBN   9780857111562.
  5. ↑ De Groot LJ, Jameson JL (2010). Endocrinology Adult and Pediatric: The Thyroid Gland. Elsevier Health Sciences. p. e202. ISBN   978-0323221535. Archived from the original on 2016-12-26.
  6. ↑ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl: 10665/325771 . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  7. ↑ "Propylthiouracil (PTU)-Induced Liver Failure". FDA. Archived from the original on 2009-06-06. Retrieved 2009-05-03.
  8. 1 2 3 Bahn RS, Burch HS, Cooper DS, Garber JR, Greenlee CM, Klein IL, 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): 673–674. doi:10.1089/thy.2009.0169. 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): 335–338. doi:10.3904/kjim.2005.20.4.335. PMC   3891081 . PMID   16491833. Archived from the original on 2008-12-22.
  10. ↑ "propylthiouracil". Online.epocrates.com. 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 (June 2011). "Therapy of hyperthyroidism in pregnancy and breastfeeding". Obstetrical & Gynecological Survey. 66 (6): 378–385. doi:10.1097/OGX.0b013e31822c6388. PMID   21851752. S2CID   28728514.
  12. ↑ Boron WF, Boulpaep EL (2005). Medical Physiology (Updated ed.). Philadelphia, PA: Elsevier Saunders.
  13. ↑ Abalovich M, Amino N, Barbour LA, Cobin RH, De Groot LJ, Glinoer D, et al. (August 2007). "Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society Clinical Practice Guideline". The Journal of Clinical Endocrinology and Metabolism. 92 (8 Suppl): S1-47. doi: 10.1210/jc.2007-0141 . PMID   17948378.
  14. ↑ Anderson GW, Halverstadt IF (December 1945). "Studies in chemotherapy; antithyroid compounds; synthesis of 5- and 6-substituted 2-thiouracils from beta-oxoesters and thiourea". Journal of the American Chemical Society. 67 (12): 2197–2200. doi:10.1021/ja01228a042. PMID   21005687.
  15. 1 2 Bufe B, Breslin PA, Kuhn C, Reed DR, Tharp CD, Slack JP, et al. (February 2005). "The molecular basis of individual differences in phenylthiocarbamide and propylthiouracil bitterness perception". Current Biology. 15 (4): 322–327. doi:10.1016/j.cub.2005.01.047. PMC   1400547 . PMID   15723792.
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