Propylthiouracil
Encyclopedia
Propylthiouracil 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. Its notable side effects include a risk of agranulocytosis
.
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.
(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
.
, which shares propylthiouracil's central mechanism, but not its peripheral one.)
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
.
, 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.
A more life threatening side effect is sudden, severe, fulminant hepatic 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
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.
. 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 woman who may become pregnant. In the second and third trimester, methimazole
is preferred.
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%.
Thioamide
Thioamide 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 hyperthyroidism
Hyperthyroidism
Hyperthyroidism is the term for overactive tissue within the thyroid gland causing an overproduction of thyroid hormones . Hyperthyroidism is thus a cause of thyrotoxicosis, the clinical condition of increased thyroid hormones in the blood. Hyperthyroidism and thyrotoxicosis are not synonymous...
(including Graves' disease
Graves' disease
Graves' disease is an autoimmune disease where the thyroid is overactive, producing an excessive amount of thyroid hormones...
) by decreasing the amount of thyroid hormone
Thyroid hormone
The thyroid hormones, thyroxine and triiodothyronine , are tyrosine-based hormones produced by the thyroid gland primarily responsible for regulation of metabolism. An important component in the synthesis of thyroid hormones is iodine. The major form of thyroid hormone in the blood is thyroxine ,...
produced by the thyroid gland. Its notable side effects include a risk of agranulocytosis
Agranulocytosis
Granulopenia, also known as Agranulosis or Agranulocytosis, 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 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.
Central
PTU inhibits the enzyme thyroperoxidase, which normally acts in thyroid hormone synthesis by oxidizing the anion iodideIodide
An iodide ion is the ion I−. Compounds with iodine in formal oxidation state −1 are called iodides. This page is for the iodide ion and its salts. For information on organoiodides, see organohalides. In everyday life, iodide is most commonly encountered as a component of iodized salt,...
(I-) to iodine
Iodine
Iodine is a chemical element with the symbol I and atomic number 53. The name is pronounced , , or . The name is from the , meaning violet or purple, due to the color of elemental iodine vapor....
(I0), facilitating iodine's addition to tyrosine residues on the hormone precursor thyroglobulin
Thyroglobulin
Thyroglobulin is a 660 kDa, dimeric protein produced by and used entirely within the thyroid gland. In earlier literature, Tg was referred to as colloid....
. This is one of the essential steps in the formation of thyroxine
Thyroxine
Thyroxine, or 3,5,3',5'-tetraiodothyronine , a form of thyroid hormones, is the major hormone secreted by the follicular cells of the thyroid gland.-Synthesis and regulation:...
(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
Perchlorate
Perchlorates 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 used extensively within the pyrotechnics industry, and ammonium perchlorate is also a...
and thiocyanate
Thiocyanate
Thiocyanate is the anion [SCN]−. It is the conjugate base of thiocyanic acid. Common derivatives 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 T4 to the active form T3. (This is in contrast to methimazoleMethimazole
Methimazole is an antithyroid drug, and part of the thioamide group.-Indications:...
, 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, while the antithyroid agent methimazoleMethimazole
Methimazole is an antithyroid drug, and part of the thioamide group.-Indications:...
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
Glucuronidation
Glucuronidation is the addition of glucuronic acid to a substrate. Glucuronidation is often involved in xenobiotic metabolism of substances such as drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids...
.
Side effects
One possible side effect is agranulocytosisAgranulocytosis
Granulopenia, also known as Agranulosis or Agranulocytosis, 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.
A more life threatening side effect is sudden, severe, fulminant hepatic 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
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.
Propylthiouracil in pregnancy
Propylthiouracil is classified as Drug Class D in pregnancyPregnancy category
The pregnancy category of a pharmaceutical agent is an assessment of the risk of fetal injury due to the pharmaceutical, if it is used as directed by the mother during pregnancy. It does not include any risks conferred by pharmaceutical agents or their metabolites that are present in breast...
. 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
Methimazole
Methimazole is an antithyroid drug, and part of the thioamide group.-Indications:...
(which is also a class D) only in the first trimester of pregnancy and in woman who may become pregnant. In the second and third trimester, methimazole
Methimazole
Methimazole is an antithyroid drug, and part of the thioamide group.-Indications:...
is preferred.
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%.