Propylthiouracil (PTU)

Propylthiouracil (thiocarbamide) is an antithyroid drug. The drug is a common therapeutic choice for the following:

• Hyperthyroidism treatment
• Used if methimazole or radioactive iodine treatment is contraindicated or as an alternative treatment option in a patient with Graves disease or toxic multinodular goiter[1]
• Used before thyroidectomy or radioactive iodine therapy to treat hyperthyroidism
• In thyroid storm and thyrotoxicosis crisis (off label treatment), to treat the hyperthyroidism.
• It is a preferred antithyroid drug in the first trimester of pregnancy

Propylthiouracil inhibits the production of new thyroid hormone in the thyroid gland.[2] It acts by inhibiting the enzyme thyroid peroxidase, which usually functions to convert iodide to iodine molecule and incorporate the iodine molecule into amino acid tyrosine. Hence, DIT (diiodotyrosine) or MIT (monoiodotyrosine) does not get produced, which are the main constituents in the production of thyroxine (T4) and triiodothyronine (T3).[3] Peripherally, it acts by inhibiting the conversion of T4 to T3. It has effects on the existing thyroid hormones stored in the thyroid gland or circulating in the blood.

The available propylthiouracil tablet has 50 mg of the drug, and storage should be at room temperature. Dosage is as follows:

• Adults: Propylthiouracil is administered orally, initially as 300 mg/day in three divided doses every 8 hours (may reach up to 600 to 900 mg/day). The general maintenance dose after the initial treatment is 100 to 150 mg/day. The dose is adjusted to maintain normal TSH, T3, and T4 levels.
  • Graves disease (off label): PTU can be started as an initial dose of 50 to 150 mg three times a day 
  • Thyrotoxic crisis/thyroid storm (off-label): The American Thyroid Association recommends 500 to 1000 mg as a loading dose of PTU, which can be followed by 250 mg every 4 hours. Recommendations are widely variable, and comparative trials have not taken place.[4]
  • Pediatric: Due to severe liver toxicity reported with the use of PTU, it is no longer approved by the United States Food and Drug Administration (FDA) in pediatric patients. 
  •  Geriatric: Clinical studies incorporating the effects of PTU in patients over 65 years are lacking. PTU should be used cautiously in the geriatric age group, owing to an increased likelihood of co-morbidities and declined organ function in the elderly.

Pharmacokinetics

• Absorption: 75%
• Distribution: 80 to 85% of the drug is bound to plasma proteins (lipoproteins and albumin are the major binding proteins), Vd 0.4 L/kg. It concentrates in the thyroid gland.
• Onset: 24 to 36 hours are necessary for a significant therapeutic effect.  
• Duration: 12 to 24 hours
• Half-life elimination: 1 hour approximately 
• Metabolism: PTU primarily undergoes metabolism in the liver to glucuronides or inorganic sulfates.
• Elimination: 35% gets excreted as metabolites in the urine.

Propylthiouracil and patient population groups:

• Pediatric population: PTU has been associated with liver injury in both adult and pediatric populations, whereas no case reports suggest liver injury with methimazole in the pediatric population. Hence, PTU is not for use in the pediatric population.[5]
• Renal impairment: Dose adjustment is not required.
• Hepatobiliary disease: PTU causes liver injury; hence, it is not used in patients with liver impairment. However, the manufacturer's label does not require dosage adjustment. 
• Pregnant: PTU is a pregnancy category D drug. PTU can cross the placenta and can cause fetal cretinism and goiter. Methimazole causes fetal anatomical abnormalities; hence, if it is necessary to use antithyroid drugs in pregnancy, PTU is preferred in the first trimester with the lowest possible drug dose usage. Due to the increased reported risk of maternal hepatotoxicity from PTU, methimazole is the therapeutic choice in the second and third trimesters.[6][7]
• Breastfeeding: PTU is excreted in breast milk in small amounts and delivered to infants. There are no clear-cut recommendations for its use in nursing. (AAP suggests it is compatible with nursing while AAFP says it is safe with nursing).[8]

Drug Interactions:

• Coumarins (oral): PTU inhibits vitamin K activity and hence increases the effects of oral anticoagulants. Therefore, PT/INR monitoring is necessary for such patients.
• Beta-blockers, digitalis, and theophylline: In a patient with hyperthyroidism, there is an increased clearance of these drugs. When the patient becomes euthyroid, a decrease in the dose of beta-blockers and theophylline is required.

• Acute liver injury: Reported cases have shown PTU to be associated with acute liver failure and death. PTU has a black box warning for this issue. There are cases reported in pregnancy, adults, and children. Hence, caution is necessary with its use, especially in the first six months of the start of therapy. Since the onset is unpredictable and variable, regular monitoring is not a recommendation. Educate the patient regarding the potential symptoms to come and visit the physician for anorexia, pruritis, right upper quadrant pain, nausea, vomiting, light-colored stool, dark urine. Stop the drug at the first appearance of these symptoms and perform laboratory tests: biochemical (bilirubin, alkaline phosphatase) and hepatocellular injury markers (AST, ALT).[9]

• Hypothyroidism: PTU can lead to hypothyroidism- weight gain, constipation, or drowsiness. Hence, routine monitoring of TSH and T4 is necessary to maintain the euthyroid state.

• ANCA-associated vasculitis: There have been multiple reported studies in which PTU-treated patients developed small vessel vasculitis and positivity to proteinase-3 or myeloperoxidase. Symptoms include- fever, weight loss, myalgia, arthralgia, paraesthesia. Idiosyncratic reactions like this usually start within weeks of drug initiation but have been found to occur years later as well. Most patients responded to drug withdrawal, immunosuppressants, and substitution with other thioamide drugs for hyperthyroid symptom control. Complications included: leukoclastic vasculitis, glomerulonephritis (crescenteric or rapidly progressive), alveolar/pulmonary hemorrhage, cerebral angiitis, or ischemic colitis.[10]

• Hypersensitivity: Reports of severe hypersensitivity reactions like Steven Johnson Syndrome, toxic epidermal necrolysis, urticaria, have been described. 

• Agranulocytosis: This is a potentially life-threatening occurrence with PTU in 0.2 to 0.5 % of patients. The patients should receive instruction to report any symptoms suggestive of pancytopenia – fever, sore throat, interstitial pneumonitis. The risk is at its highest in the first three months of treatment[11].
• Potential teratogenicity: PTU was a Category D drug for pregnancy under the old FDA system. 

Other reported side effects in case reports/case series [12][13][12]:

• Dermatologic: erythema nodosum, exfoliative dermatitis, urticaria, skin ulcers, skin rash, alopecia, Stevens-Johnson syndrome, toxic epidermal necrolysis
• Renal: acute kidney injury, acute interstitial nephritis
• Gastrointestinal: loss of taste, taste perversion, nausea, vomiting, stomach pain, sialadenopathy
• Neurological: neuritis, headache, paresthesia, drowsiness, vertigo
• Hematological: lymphadenopathy, splenomegaly, leukopenia, aplastic anemia, lymphadenopathy, hemorrhage, hypoprothrombinemia
• Respiratory: pulmonary alveolar hemorrhage, interstitial pneumonitis
• Drug fever
• Lupus-like syndrome

Observed adverse reactions in laboratory animals:

• Carcinogenesis: pituitary adenomas, thyroid hyperplasia, and carcinoma after more than one year of continuous PTU usage.
• Infertility

• Previous history of hypersensitivity to PTU or any of its drug components