Propylthiouracil
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| Non-proprietary name | Propylthiouracil | |||||||||||||||||||||
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| Molecular formula | C 7 H 10 N 2 OS | |||||||||||||||||||||
| Brief description |
white, finely crystalline, almost odorless powder |
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| Mechanism of action |
Iodization inhibitor |
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| properties | ||||||||||||||||||||||
| Molar mass | 170.23 g · mol -1 | |||||||||||||||||||||
| Physical state |
firmly |
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| Melting point |
219 ° C |
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| pK s value |
8.3 |
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| solubility |
Slightly soluble in water (1200 mg · l −1 at 25 ° C) in alkaline solutions |
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| As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions . | ||||||||||||||||||||||
Propylthiouracil (PTU) is a thiourea - derivative and belongs to the group of anti-thyroid drugs , which for the symptomatic treatment of morbid overactive thyroid ( hyperthyroidism be used).
Clinical information
Application areas (indications)
The hyperthyroidism as a disease comprises a number of different diseases which are characterized by a Hyper metabolism and increased serum levels of thyroid hormones. Thyrostatic drugs of the thiourea type are used to treat hyperthyroidism - especially in Graves 'disease ( Graves' disease ) - for preoperative therapy before subtotal goiter resection , before and after radioiodine therapy and in doses of 900 to 1200 mg / day orally or via the gastric tube Supportive measure ( adjuvant therapy ) is indicated in the event of a thyrotoxic crisis (= acute, life-threatening exacerbation of hyperthyroidism).
Contraindications (contraindications)
Therapy with the drug is contraindicated in cases of hypersensitivity to propylthiouracil, existing agranulocytosis or severe hematopoiesis disorders , severe liver insufficiency and thyroid carcinoma. A contraindication is a retrosternal goiter due to the risk of compression of the trachea by increasing the volume of the gland.
Drug interactions
The thyrostatic effect of propylthiouracil is influenced by the parallel administration of thyroxine and can be significantly reduced and delay the onset of euthyroidism if iodine - containing X - ray contrast media or other iodine-containing drugs have been administered beforehand or at the same time. The free effective fraction of coumarin derivatives can increase during therapy with propylthiouracil. The drug is also an antagonist of vitamin K , the effect of anticoagulants can be intensified, so that the INR must be closely monitored as part of the treatment. In vitro studies show a significant increase in the free fraction of propylthiouracil in the serum with warfarin , acetylsalicylic acid and phenylbutazone . This reaction was not observed with phenytoin , nortriptyline and phenazone .
Use during pregnancy and breastfeeding
Hyperthyroidism during pregnancy is associated with increased rates of miscarriage , stillbirth and malformations. Also leading maternal hypothyroidism to increased rates of miscarriage. The rate of malformations during therapy with propylthiouracil does not differ from the spontaneous rate. Fetal hormone production begins in the 10th to 14th week of pregnancy. The dosage of propylthiouracil must be selected as low as possible in order to avoid an abortion, hypothyroidism and goiter in the fetus or newborn. In the last trimester of pregnancy there is often a spontaneous improvement in hyperthyroidism. Mild hyperthyroidism is better tolerated than hypothyroidism by the pregnant woman and the fetus.
During breastfeeding , propylthiouracil is considered the drug of choice if there are strict indications , as the concentration in breast milk is no more than one tenth of the maternal serum concentration. However, isolated cases of hypothyroidism in infants have been described. Particularly careful monitoring of mother and child is required during pregnancy and breastfeeding. The TSH levels should be very low or not measurable, and the parameters of the free thyroid hormones should be in the upper normal range. A combination of propylthiouracil with thyroxine during pregnancy and breastfeeding is obsolete.
Adverse drug effects
Most side effects are dose-dependent and are therefore mainly observed in the first few weeks of treatment and especially in the event of an overdose. Lighter reactions often regress even if thyrostatic therapy is continued. With normal doses of Propylthiouracil, the following adverse drug effects can occur:
- Uncommon: arthralgia , drug eruption , gastrointestinal complaints , hives (urticaria)
- Rare: agranulocytosis , hepatotoxicity
- Very rare: allergic reaction , drug fever , liver dysfunction , lymphadenopathy , thrombocytopenia , vasculitis
- Extremely rare: alopecia , angiitis , positive Coombs test , Dysosmie (impaired sense of smell), disturbance of erythropoiesis , impaired sense of taste , hemolysis , idiopathic interstitial pneumonia , lupus erythematosus , neuromuscular disorders , polyarteritis nodosa , peripheral edema , acute arthritis , nausea , vertigo , Vomit
- Possible: leukocytopenia , protrusio bulbi , goiter formation in the newborn, thyrotoxic crisis
Propylthiouracil has been shown to be carcinogenic in animal experiments .
Pharmacological properties
Mechanism of action (pharmacodynamics)
Propylthiouracil is a thiourea - derivative and belongs as Iodisationshemmer to the group of anti-thyroid drugs , which the thyroid peroxidase (thyroid peroxidase) competitively inhibit and thus on the one hand the oxidation of iodide to elemental iodine (Iodisation) and as a result, the incorporation of iodine into the tyrosyl residues of thyroglobulin and prevent their combination to T 3 or T 4 . Propylthiouracil in high doses inhibits the peripheral deiodination of thyroxine to triiodothyronine by deiodase D1. This mechanism is independent of iodine. It only takes effect after 1–2 weeks, when the hormone stores in the thyroid are exhausted.
Absorption and distribution in the body (pharmacokinetics)
Propylthiouracil is well and rapidly absorbed after oral administration; simultaneous consumption of food has no effect on absorption . The absolute bioavailability is about 80% and maximum serum levels are reached after 1 to 2 hours. The plasma protein binding is 75%, the distribution volume 0.4 L / kg. Propylthiouracil accumulates insignificantly in the thyroid gland. Contrary to what was originally believed, propylthiouracil was later shown to cross the placenta as well as thiamazole . In contrast, the concentration of propylthiouracil in breast milk is lower than in plasma. The milk to plasma concentration ratio is about 0.1 for propylthiouracil and about 1.0 for thiamazole. Most of the metabolism of propylthiouracil takes place in the liver. More than 65% of it is glucuronidated, i.e. reacted with glucuronic acid and further S-methylated and sulfated. The metabolites are not or only weakly active. The elimination is mainly renal , about 60% in the form of metabolites, about 10% is eliminated unchanged. The plasma half-life of propylthiouracil is short at around 2 hours, so the daily dose must be divided into up to 6 individual doses. In the thyroid gland, the active ingredient is desulfurized to propyluracil; the sulfur is oxidized to sulfate .
Application in veterinary medicine
Propylthiouracil is rarely used in the preoperative preparation for a thyroidectomy in feline hyperthyroidism in domestic cats . Because of the possible mild to serious side effects ( thrombocytopenia and hemolytic anemia ), the drug should only be used for a short time. In the veterinary medicine is thiamazole , however, the drug of choice, propylthiouracil to (inhibition of peripheral conversion of T an advantage in the treatment of serious hyperthyroidism by achieving a rapid clinical success 4 to T 3 ) have.
Law
"According to § 1 in conjunction with Appendix 1 of the ordinance on substances with a pharmacological effect, the use of" substances with a thyrostatic effect such as thiouracils , thioimidazoles , thiohydantoins for equidae , cattle, pigs, sheep, goats, rabbits, poultry, haired game and game birds for all areas of application "excluded. Therefore, there are no maximum permitted levels; Proof of residues leads to criminal prosecution regardless of the level of the finding. The misuse of thyreostatics as fattening aids is monitored within the framework of the National Residue Control Plan. "
Individual evidence
- ↑ Data sheet 4-propyl-2-thiouracil (PDF) from Merck , accessed on January 28, 2008.
- ↑ a b c Entry on propylthiouracil in the ChemIDplus database of the United States National Library of Medicine (NLM) .
- ↑ a b c d e f g h i Entry on Propylthiouracil. In: Römpp Online . Georg Thieme Verlag, accessed on July 26, 2019.
- ↑ a b Entry on propylthiouracil in the GESTIS substance database of the IFA , accessed on February 13, 2017(JavaScript required) .
- ↑ Leslie J. De Groot, et al. The Hormone Foundation's Patient Guide to the Management of Maternal Hyperthyroidism Before, During and After Pregnancy The Journal of Clinical Endocrinology and Metabolism Vol. 92, No. 9 0, 2007.
- ↑ Propycil® specialist information in the Swiss drug compendium . February 4, 2008.
- ↑ JT Hardee: Propylthiouracil-Induced Hepatotoxicity , West J Med. 1996 September; 165 (3): 144-147; PMC 1303726 (free full text, PDF).
- ^ SJ Stankus, NT Johnson: Propylthiouracil-induced hypersensitivity vasculitis presenting as respiratory failure. In: Chest. Volume 102, Number 5, November 1992, pp. 1595-1596, PMID 1424898 .
- ↑ Cynthia M. et al .: The Merck Veterinary Manual (Merck Veterinary Manual) . Sons, John Wiley &, ISBN 978-0-911910-50-6 .
- ^ Trepanier LA .: The use of antithyroid drugs in the medical management of feline hyperthyroidism. : Probl Vet Med. 1990 Dec; 2 (4): 668-82, PMID 1724620 .
- ↑ National Residue Control Plan for Food of Animal Origin ( Memento of September 27, 2014 in the Internet Archive ).
Trade names
Prothiucil (A), Propycil (D, CH)
literature
- Heinz Lüllmann, Klaus Mohr, Lutz Hein: Pharmacology and Toxicology . 16th edition. Thieme, Stuttgart 2006, ISBN 3-13-368516-3 .
- Thomas Karow, Ruth Lang-Roth: General and special pharmacology and toxicology . 16th edition. 2008.
Web links
- Vetpharm entry for propylthiouracil , accessed December 3, 2011.
- FDA: Propylthiouracil - Professional Information
