Propylthiouracil

Propylthiouracil is an antithyroid agent belonging to the pharmacological class of Thyroid Function Modulator.

Propylthiouracil is FDA-approved for the treatment of hyperthyroidism.

Propylthiouracil is rapidly absorbed through the gastrointestinal tract, concentrating in the thyroid gland, crossing the placenta, and entering breast milk. The liver extensively metabolizes it, excreting mainly via urine.

The most common side effects of Propylthiouracil include skin rash, hair loss, headache, pain (joint, nerve, or muscle pain), nausea, and paresthesia (tingling or pricking sensation).

Propylthiouracil is available as a tablet.

The molecule is available in India, the United States, Canada, the United Kingdom, Australia, Germany, France, Italy and Japan.

Propylthiouracil is an anti-thyroid agent belonging to the pharmacological class of Thyroid Function Modulator.

Propylthiouracil inhibits the conversion of iodide to iodine by binding to thyroid peroxidase. In addition to catalyzing the incorporation of the resultant iodide molecule onto the 3 and/or 5 positions of the phenol rings of tyrosines found in thyroglobulin, thyroid peroxidase typically converts iodide to iodine (using hydrogen peroxide as a cofactor). The primary hormones produced by the thyroid gland are thyroxine (T4) and tri-iodothyronine (T3), which are made through the breakdown of thyroglobulin. As a result, Propylthiouracil efficiently prevents the synthesis of thyroid hormones.

The onset of action for Propylthiouracil (PTU) generally may take several weeks (around 4 to 8 weeks) for noticeable effects after administration.

The peak plasma concentration (Cmax) of Propylthiouracil (PTU) occurs around 1-1.5 hours after oral administration.

The time taken to reach the peak plasma concentration (tmax) of Propylthiouracil is typically around 1 to 1.5 hours after oral ingestion.

• Hyperthyroidism
• Thyroid storm or thyrotoxic crisis (off-label)
• It is a preferred antithyroid drug in the first trimester of pregnancy.

In Hyperthyroidism

Propylthiouracil diminishes thyroid hormone levels and alleviates symptoms of hyperthyroidism like palpitations, anxiety, sweating, and heat intolerance. It functions by obstructing new thyroid hormone production, regulating its levels, and reducing the overactivity of the thyroid gland. Additionally, it's employed to decrease excessively high thyroid hormone levels before surgery or radioactive iodine treatment, contributing to an improved quality of life.

Off-label use of PTU in adults may be considered in certain cases, but caution is advised due to potential hepatotoxicity.

Propylthiouracil is indicated as follows:

• In patients with toxic multinodular goitre or hyperthyroidism who are intolerant of methimazole and for whom radioactive iodine therapy or surgery are not suitable forms of treatment.
• In patients who are intolerant of methimazole, to lessen hyperthyroidism symptoms before thyroidectomy or radioactive iodine therapy.
• In thyroid storm and thyrotoxicosis crisis (off-label treatment), to treat the hyperthyroidism.

Orally: Patients take Propylthiouracil orally as tablets, swallowing them whole with water, preferably at consistent times daily for optimal effectiveness, after meals, is advisable, preferably at consistent times daily. Adhering actively to these instructions is crucial, as ensuring regularity in dosage, timing, and handling potential food interactions enhances the medication's efficacy and safety profile. Ensuring strict adherence to prescribed guidelines allows for the best possible management of the condition while minimizing the risk of complications.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

Tablets: 50mg, 100mg.

Propylthiouracil is available in the form of tablets.

Dose Adjustment in Adult Patients:

300 mg taken daily at first, divided into three equal doses about eight hours apart. In extreme severity or large goitres, 400 mg daily at first; in certain circumstances, 600–900 mg daily may be needed. Maintenance (after euthyroid): 50–150 mg taken every day for one to two years is typical. Modify the dosage based on the patient's clinical response, tolerance, and thyroid condition.

Thyroid storm or thyrotoxic crisis (off-label): The American Thyroid Association suggests starting with a loading dose of 500–1000 mg of PTU, then reducing it to 250 mg every four hours. No comparative trials have been conducted, and recommendations vary greatly.

While taking Propylthiouracil, specific dietary guidelines should be followed to ensure optimal effectiveness and safety. Excessive consumption of iodine-rich foods like seaweed, seafood, and iodized salt should be avoided, as they can worsen thyroid-related issues. Opt for non-iodized salt, tea, egg whites, and specific fruits and vegetables to limit iodine intake. Ensure adequate calcium, vitamin D, zinc, iron, and selenium for optimal thyroid function. Additionally, maintaining a balanced diet with consistent Vitamin K-rich foods like leafy greens is recommended due to Propylthiouracil's impact on blood clotting. Moderating alcohol and caffeine intake and discontinuing smoking are advisable to prevent adverse health effects.

The dietary restriction should be individualized as per patient requirements.

Hypersensitivity to Propylthiouracil or any container component or ingredient in the formulation.

Warnings

Liver Toxicity

Liver injury, liver failure, and fatalities were observed in pregnant women treated with Propylthiouracil. In-utero exposure led to newborn death and liver failure. Pregnant women taking Propylthiouracil should be alerted to potential liver damage risks for both mother and fetus. Propylthiouracil crosses the placenta, causing fetal goitre and cretinism. Alternative antithyroid medications after the first trimester might be recommended.

Pregnancy

During pregnancy, propylthiouracil treatment in women has led to liver injuries, including failure and fatalities. In-utero exposure resulted in newborn death and liver failure. Women taking Propylthiouracil during pregnancy should be cautioned about potential liver damage risks for both mother and fetus. Propylthiouracil crosses the placenta and causes fetal goitre and cretinism. Considering an alternative antithyroid medication after the first trimester might be advisable.

Agranulocytosis

Propylthiouracil therapy may cause agranulocytosis in around 0.2% to 0.5% of patients, posing a potentially life-threatening side effect. Agranulocytosis typically arises within the initial 3 months of treatment. Patients must promptly report any symptoms hinting at agranulocytosis, such as fever or sore throat. Additionally, leukopenia, thrombocytopenia, and aplastic anemia (pancytopenia) may manifest. If suspected of experiencing agranulocytosis, interstitial pneumonitis, aplastic anemia (pancytopenia), ANCA-positive vasculitis, hepatitis, fever, or exfoliative dermatitis, Propylthiouracil should be discontinued, and the patient's bone marrow indices obtained.

Hypothyroidism

Routine monitoring of TSH and free T4 levels is essential with Propylthiouracil due to the potential for causing hypothyroidism. Administered to pregnant women, it readily crosses placental membranes, leading to fetal goitre and cretinism.

Precautions

• Patients on Propylthiouracil should monitor and report liver dysfunction symptoms, ensuring timely liver function tests if these arise. Immediately reporting signs like sore throat, fever, headache, or skin issues necessitates prompt white blood cell checks for agranulocytosis. Exercise caution when combining Propylthiouracil with drugs linked to agranulocytosis.
• Patients taking an antithyroid drug should inform the physician promptly upon pregnancy or intention to conceive. Immediately reporting symptoms like sore throat, skin issues, fever, headache, malaise, or signs of liver issues is essential.

• Regular prothrombin time monitoring is advised due to Propylthiouracil's potential for hypoprothrombinemia and bleeding, especially before surgery. Periodic thyroid function tests are essential for proper dosage adjustment.

It is unsafe to consume alcohol.

It's safe to use during breastfeeding.

It is considered relatively safe, particularly when compared to methimazole, another antithyroid drug.

Limit iodine-rich foods; ensure nutrients; balance diet; avoid smoking and alcohol.

The adverse reactions related to Propylthiouracil can be categorized as:

• Common Adverse Effects: Skin rashes, itching, and gastrointestinal (GI) disturbances such as nausea, vomiting, and stomach upset.
• Less Common Adverse Effects: Liver problems manifesting as jaundice, dark urine, or persistent fatigue.
• Rare Adverse Effects: Serious hypersensitivity reactions (e.g., Stevens-Johnson syndrome and toxic epidermal necrolysis), agranulocytosis.

Reports on post-marketing

Severe liver injury, including hepatic failure requiring liver transplantation or death, has been reported (pediatric population).

The clinically relevant drug interactions of Propylthiouracil are briefly summarized here.

• Oral anticoagulants: Propylthiouracil may inhibit vitamin K activity, increasing the activity of oral anticoagulants like warfarin. Therefore, extra monitoring of PT/INR should be taken into consideration, particularly before surgical procedures.
• Beta-adrenergic blocking agents: A high extraction ratio beta-blocker may be cleared more readily in cases of hyperthyroidism. When a patient with hyperthyroidism becomes euthyroid, a lower dosage of beta-adrenergic blockers might be required.
• Digitalis glycosides: When hyperthyroid patients on a stable digitalis glycoside regimen become euthyroid, serum digitalis levels may rise; a lower dosage of digitalis glycosides may be required.
• Theophylline: When hyperthyroid patients on a stable theophylline regimen become euthyroid, theophylline clearance may decrease; a lower dose of theophylline may be required.

The common side effects of Propylthiouracil include skin rash, hair loss, headache, stomach upset, pain (joint, nerve, or muscle pain), nausea, and paresthesia (tingling or pricking sensation).

• Pregnancy

Pregnancy Category D (FDA): Use in situations where there is no safer medication available and life is in danger. Evidence that human fetal risk exists.

Pregnant women with untreated or insufficiently treated Graves' disease are more likely to experience unfavorable outcomes like maternal heart failure, spontaneous abortion, preterm birth, stillbirth, and fetal or neonatal hyperthyroidism.

The patient should be informed of the uncommon risk of liver damage to the mother and fetus if Propylthiouracil is used during pregnancy or if the patient gets pregnant while taking the medication. It is crucial to administer a sufficient, but not an excessive, dose of Propylthiouracil during pregnancy because it can cause cretinism and goitre in the developing fetus and cross placental membranes. It's common for thyroid dysfunction in pregnant women to lessen as the pregnancy goes on, which means a dosage reduction might be feasible. Sometimes, antithyroid medication can be stopped weeks or months before childbirth.

During the first trimester of pregnancy, Propylthiouracil may be the better medication because methimazole may be linked to the infrequent development of fetal abnormalities. In the second and third trimesters of pregnancy, switching from Propylthiouracil to methimazole may be preferable due to the possibility of hepatotoxicity in mothers.

Nursing Mothers

As a result of the small amount of Propylthiouracil in breast milk, the nursing infant is probably exposed to doses that are not harmful. Using 400 mg of Propylthiouracil orally, nine nursing women participated in one study. During the four hours following medication administration, the average amount of Propylthiouracil excreted was 0.025% of the dose.

• Pediatric Use

As per FDA, the safety and efficacy of Propylthiouracil in Pediatric patients have not been established.

However, when using this population, utmost caution should be taken.

Dose Adjustment in Pediatric Patients:

6 to10 years: 50 to 150 mg daily

For more than 10 years, 150 to 300 mg daily.

Doses are usually given in 3 divided doses daily at approximately 8-hour intervals.

• Geriatrics (> 65 years old)

As per the FDA, the safety and efficacy of Propylthiouracil in elderly patients above 65 have not been extensively studied or established.

Insufficient data from propylthiouracil studies involve subjects aged 65 or older. Clinical experience hasn't shown differences between elderly and younger patients. Caution in dose selection for elderly patients is essential, considering potential hepatic, renal, or cardiac function declines and other concurrent medical conditions or medications.

Dose Adjustment in Kidney Impairment Patients:

GFR less than 10 mL/min: Reduce dose by 50%.

GFR 10 to 50 mL/min: Reduce dose by 25%.

Dose Adjustment in Hepatic Impairment Patients:

Hepatic Impairment: Dosage adjustment may be required.

The physician should be vigilant about the knowledge pertaining to the identification and treatment of overdosage of Propylthiouracil.

Signs and Symptoms

Overconsumption of Propylthiouracil could lead to epigastric distress, nausea, agranulocytosis, pancytopenia, vomiting, hypothyroidism, oedema fever, headache, arthralgia, and pruritus.

Management

There is no specific antidote or treatment for overdosage of Propylthiouracil, so treatment typically involves symptomatic and supportive measures. Gastric lavage or induced vomiting could be considered if the ingestion occurred within an hour, followed by the administration of activated charcoal to reduce further absorption of the drug from the gastrointestinal tract. Continuous monitoring of cardiac function, blood pressure, respiratory status, and electrolyte balance is essential.

Patients presenting with severe symptoms or complications may require intensive care support. Intravenous fluids (IV) may be administered to maintain hydration and support kidney function, while electrolyte imbalances should be corrected promptly.Close monitoring of liver function, including liver enzymes and bilirubin levels, is crucial due to the potential for hepatotoxicity following an overdose. In cases of severe liver injury, liver transplant evaluation might be necessary.Timely medical intervention plays a crucial role in managing Propylthiouracil overdose, ensuring careful monitoring and proper care to address symptoms and prevent complications.

Pharmacodynamics

Grave's disease most frequently causes hyperthyroidism. This is an autoimmune condition in which the body's antibodies bind to thyroid-stimulating hormone receptors found in thyroid gland cells, causing an excess of thyroid hormone to be produced. Iodine and a protein known as thyroglobulin are combined with an enzyme known as peroxidase to form the two thyroid hormones produced by the thyroid gland: thyroxine (T4) and triiodothyronine (T3). PTU prevents iodine and peroxidase from interacting generally with thyroglobulin to generate T4 and T3. This action reduces the production of thyroid hormone. PTU also decreases thyroid hormone activity because it obstructs the conversion of T4 to T3, which is more potent than T4. Propylthiouracil's functions and applications are similar to those of methimazole.

Pharmacokinetics:

• Absorption: The gastrointestinal tract rapidly and effectively absorbs Propylthiouracil upon oral intake, showcasing a bioavailability ranging from 50% to 75%. Peak plasma concentrations are approximately achieved within 1 to 2 hours post-administration.
• Distribution: This medication concentrates notably in the thyroid gland, crosses the placental barrier, potentially affecting the fetus, and enters breast milk. Approximately 80-85% of the drug in plasma binds to proteins, influencing its systemic distribution.
• Metabolism: Extensive hepatic metabolism occurs via glucuronidation, transforming Propylthiouracil into a glucuronic acid conjugate in the liver.
• Excretion: The drug undergoes primarily renal excretion, with about 35% eliminated via urine, predominantly in its metabolized form. The elimination half-life averages around 1 to 2 hours, indicating a relatively short duration of action.

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