Propylthiouracil (
PTU) or
6-N-Propylthiouracil (PROP) is a
thioamideThioamide is a functional group with the general structure R-CS-NR'R, where R, R', and R are organic groups. They are analogous to amides but they exhibit greater multiple bond character along the C-N bond, resulting in a larger rotational barrier...
drug used to treat
hyperthyroidismHyperthyroidism is the term for overactive tissue within the thyroid gland,resulting in overproduction and thus an excess of circulating free thyroid hormones: thyroxine , triiodothyronine , or both...
(including Graves disease) by decreasing the amount of
thyroid hormoneThe thyroid hormones, thyroxine and triiodothyronine , are tyrosine-based hormones produced by the thyroid gland. An important component in the synthesis of thyroid hormones is iodine. The major form of thyroid hormone in the blood is thyroxine , which has a longer half life than T3...
produced by the thyroid gland. Its notable side effects include a risk of
agranulocytosisAgranulocytosis, also known as agranulosis, is an acute condition involving a severe and dangerous leukopenia, most commonly of neutrophils, causing a neutropenia in the circulating blood. It represents a severe lack of one major class of infection-fighting white blood cells...
.
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."
It was approved by the
United StatesThe United States of America is a federal constitutional republic comprising fifty states and a federal district...
Food and Drug AdministrationThe Food and Drug Administration is a Government agency of the United States Department of Health and Human Services and is responsible for regulating and supervising the safety of foods, tobacco products, dietary supplements, Medication drugs, vaccines, Biopharmaceutical, blood transfusion,...
in 1947.
Propylthiouracil (
PTU) or
6-N-Propylthiouracil (PROP) is a
thioamideThioamide is a functional group with the general structure R-CS-NR'R, where R, R', and R are organic groups. They are analogous to amides but they exhibit greater multiple bond character along the C-N bond, resulting in a larger rotational barrier...
drug used to treat
hyperthyroidismHyperthyroidism is the term for overactive tissue within the thyroid gland,resulting in overproduction and thus an excess of circulating free thyroid hormones: thyroxine , triiodothyronine , or both...
(including Graves disease) by decreasing the amount of
thyroid hormoneThe thyroid hormones, thyroxine and triiodothyronine , are tyrosine-based hormones produced by the thyroid gland. An important component in the synthesis of thyroid hormones is iodine. The major form of thyroid hormone in the blood is thyroxine , which has a longer half life than T3...
produced by the thyroid gland. Its notable side effects include a risk of
agranulocytosisAgranulocytosis, also known as agranulosis, is an acute condition involving a severe and dangerous leukopenia, most commonly of neutrophils, causing a neutropenia in the circulating blood. It represents a severe lack of one major class of infection-fighting white blood cells...
.
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."
History
It was approved by the
United StatesThe United States of America is a federal constitutional republic comprising fifty states and a federal district...
Food and Drug AdministrationThe Food and Drug Administration is a Government agency of the United States Department of Health and Human Services and is responsible for regulating and supervising the safety of foods, tobacco products, dietary supplements, Medication drugs, vaccines, Biopharmaceutical, blood transfusion,...
in 1947. It is used to study the genetics of
bitterBitter can refer to:* Bitterness, one of the five basic tastes* Bitter , a kind of ale particularly popular in Britain* Bitters, an herbal preparation now used mostly in cocktails* Bitter Cars, a German car company...
perception with supertasters.
Central
PTU inhibits the enzyme thyroperoxidase, which normally acts in thyroid hormone synthesis to add
iodideAn iodide ion is an iodine atom with a −1 charge. Compounds with iodine in formal oxidation state −1 are called iodides. This can include ionic compounds such as caesium iodide or covalent compounds such as phosphorus triiodide. This is the same naming scheme as is seen with chlorides...
to the tyrosine residues on the hormone precursor
thyroglobulinThyroglobulin is a 660 kDa, dimeric protein produced by and used entirely within the thyroid gland. In earlier literature, Tg was referred to as "colloid"....
, thus forming
thyroxineThyroxine, or 3,5,3',5'-tetraiodothyronine , a form of thyroid hormones is the major hormone secreted by the follicular cells of the thyroid gland. Thyroxine is synthesized via the iodination and covalent bonding of the phenyl portions of tyrosine residues found in an initial peptide,...
.
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
perchloratePerchlorates are the salts derived from perchloric acid . They occur both naturally and through manufacturing. They have been used as a medicine for more than 50 years to treat thyroid gland disorders. They are also used as an oxidizer in rocket fuel and explosives and can be found in airbags...
and
thiocyanateThiocyanate is the anion [SCN]
− and the conjugate base of thiocyanic acid. Common compounds include the colourless salts potassium thiocyanate and sodium thiocyanate. Organic compounds containing the functional group SCN are also called thiocyanates...
.
Peripheral
PTU also acts by inhibiting the enzyme 5'-deiodinase (tetraiodothyronine 5' deiodinase), which converts T
4 to the active form T
3. (This is in contrast to
methimazoleMethimazole is an antithyroid drug, and part of the thioamide group.-Indications:Methimazole is a drug used to treat hyperthyroidism, a condition that usually occurs when the thyroid gland is producing too much thyroid hormone...
, 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. As a result, there is little placental transfer or distribution to breast milk. In contrast, the antithyroid agent
methimazoleMethimazole is an antithyroid drug, and part of the thioamide group.-Indications:Methimazole is a drug used to treat hyperthyroidism, a condition that usually occurs when the thyroid gland is producing too much thyroid hormone...
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.
Side effects
One possible side effect is
agranulocytosisAgranulocytosis, also known as agranulosis, is an acute condition involving a severe and dangerous leukopenia, most commonly of neutrophils, causing a neutropenia in the circulating blood. It represents a severe lack of one major class of infection-fighting white blood cells...
, 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.
Propylthiouracil in Pregnancy
Propylthiouracil 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.
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%.