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Propylthiouracil: Carcinogenic Potency Database potency.berkeley.edu |
Propylthiouracil (PTU) or 6-N-Propylthiouracil (PROP) is a thioamide drug used to treat hyperthyroidism (including Graves disease) by decreasing the amount of thyroid hormone produced by the thyroid gland.[1] Its notable side effects include a risk of agranulocytosis. On June 3, 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."[2]
[edit] HistoryIt was approved by the United States Food and Drug Administration in 1947. It is used to study the genetics of bitter perception with supertasters.[3] [edit] Mode of action[edit] CentralPTU inhibits the enzyme thyroperoxidase, which normally acts in thyroid hormone synthesis to add iodide to the tyrosine residues on the hormone precursor thyroglobulin, thus forming thyroxine. Notably, 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. [edit] PeripheralPTU 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.) [edit] PharmacokineticsAdministration 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. As a result, there is little placental transfer or distribution to breast milk. In contrast, the antithyroid agent methimazole has higher levels of both placental transfer and breast milk distribution and is therefore contraindicated in pregnant/lactating females. 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, the remaining fraction undergoing extensive hepatic metabolism via glucuronidation. [edit] Side effectsOne possible side effect is agranulocytosis,[4] 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. Propylthiouracil (PTU) is generally well-tolerated with side effects occurring in 1 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. [edit] Propylthiouracil in PregnancyPropylthiouracil is classified as Drug Class D in pregnancy. Class D signifies that there is positive evidence of human fetal risk. Maternal benefit may outweigh fetal risk in life-threatening situations. [5] 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. Clinically, 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%. [6] [edit] References
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