Propylthiouracil – Uses, Dosage, Side Effects, Interactions

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Propylthiouracil is a thiourea derivative with the antithyroid property. Propylthiouracil (PTU) interferes with the oxidation of iodine possibly by interaction with peroxidase or a peroxidase-mediated complex reaction, thereby inhibiting the synthesis of thyroid hormones tri-iodothyronine (T3) and thyroxine (T4). In addition, this agent inhibits the Type I 5′-deiodinase (D1), an enzyme involved in the peripheral conversion of thyroxine to tri-iodothyronine. This results in decreased plasma triiodothyronine concentrations and decreased entrance of thyroxine into cells thereby reducing thyroid hormone activity.

Propylthiouracil is an antithyroid medication used in the therapy of hyperthyroidism and Graves disease. Propylthiouracil has been linked to serum aminotransferase elevations during therapy as well as to a clinically apparent, idiosyncratic liver injury that can be severe and even fatal.

Mechanism of Action of Propylthiouracil

Propylthiouracil binds to thyroid peroxidase and thereby inhibits the conversion of iodide to iodine. Thyroid peroxidase normally converts iodide to iodine (via hydrogen peroxide as a cofactor) and also catalyzes the incorporation of the resulting iodide molecule onto both the 3 and/or 5 positions of the phenyl rings of tyrosines found in thyroglobulin. Thyroglobulin is degraded to produce thyroxine (T4) and tri-iodothyronine (T3), which are the main hormones produced by the thyroid gland. Therefore propylthiouracil effectively inhibits the production of new thyroid hormones.

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Propylthiouracil inhibits the synthesis of thyroid hormones by interfering with the incorporation of iodine into tyrosyl residues of thyroglobulin; the drug also inhibits the coupling of these iodotyrosyl residues to form iodothyronine. Although the exact mechanism(s) has not been fully elucidated, propylthiouracil may interfere with the oxidation of iodide ion and iodotyrosyl groups. Based on limited evidence it appears that the coupling reaction is more sensitive to antithyroid agents than the iodination reaction. Propylthiouracil does not inhibit the action of thyroid hormones already formed and present in the thyroid gland or circulation nor does the drug interfere with the effectiveness of exogenously administered thyroid hormones. Patients whose thyroid gland contains a relatively high concentration of iodine (e.g., from prior ingestion or from administration during diagnostic radiologic procedures) may respond relatively slowly to antithyroid agents. Unlike methimazole, propylthiouracil inhibits the peripheral deiodination of thyroxine to triiodothyronine. Although the importance of this inhibition has not been established, propylthiouracil has a theoretical advantage compared with methimazole or carbimazole in patients with thyrotoxic crisis, since a decreased rate of conversion of circulating thyroxine to triiodothyronine may be clinically beneficial in these patients.

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Indications of Propylthiouracil

  • Used to manage hyperthyroidism which is due to an overactive thyroid gland (Grave’s disease).
  • Propylthiouracil is an antithyroid medication used in the therapy of hyperthyroidism and Graves disease. Propylthiouracil has been linked to serum aminotransferase elevations during therapy as well as to a clinically apparent, idiosyncratic liver injury that can be severe and even fatal.
  • Agents that are used to treat hyperthyroidism by reducing the excessive production of thyroid hormones.
  • Antimetabolites
  • Alcoholic Liver Damage
  • Thyroid Storm
  • Hyperthyroidism

Therapeutic Uses of Propylthiouracil

  • Antimetabolites, Antithyroid Agents
  • Propylthiouracil is indicated in the treatment of hyperthyroidism, including prior to surgery or radiotherapy, and as adjuncts in the treatment of thyrotoxicosis or thyroid storm. Propylthiouracil may be preferred over methimazole for use in thyroid storm since propylthiouracil inhibits peripheral conversion of thyroxine (T4) to triiodothyronine (T3).
  • Paradoxically propylthiouracil has been shown to reverse histological changes of alcoholic hepatitis in rats and has been proposed as a possible treatment for this condition in man.
  • Twelve-day pretreatment with PTU prevented the Tylenol-induced increase in transaminase activities. An increase in hepatic reduced glutathione levels and the prevention of inflammatory response to necrotic liver tissue appeared to be a mechanism in the protective action of hypothyroidism.
  • Propylthiouracil is used for the management of hyperthyroidism, for preoperative preparation of thyroidectomy patients, and for treatment of thyrotoxic crisis. It also may be given before or after radioactive iodine is used to treat hyperthyroidism.
  • Duration of treatment usually ranges from 6 months to 3 years, after which time thyroid function may remain normal. However, at least half of patients so treated may be expected to have recurrence 6-12 months after cessation of medication.
  • Failure of response to treatment is sometimes attributable to the improper spacing of doses since the drug is fully effective for only a few hours.

Contraindications of Propylthiouracil

  • a condition with low thyroid hormone levels
  • a type of blood disorder with a decrease in all types of blood cells called pancytopenia
  • decreased function of bone marrow
  • decreased blood platelets
  • very low levels of granulocytes
  • a type of white blood cell
  • low levels of white blood cells
  • a type of inflammation of the lung called interstitial pneumonitis
  • acute liver failure
  • damage to the liver and inflammation
  • the high amount of bilirubin in the blood
  • abnormal liver function tests
  • pregnancy
  • an autoimmune disease affecting small blood vessels in the body called ANCA-positive vasculitis
  • Allergies to Thiourea Antithyroid  and Thiouracil Analogues
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Dosage of Propylthiouracil

Hyperthyroidism

  • Initial dose – 100 mg orally every 8 hours
  • Maintenance dose – 100 to 150 mg orally daily administered in 3 equally divided doses approximately every 8 hours
  • For patients with severe hyperthyroidism, very large goiters, or both, the initial dose may be increased to 400 mg, or for the occasional patient, up to 600 to 900 mg daily initially (administered in 3 equally divided doses at approximately 8-hour intervals).
  • For patients with severe hyperthyroidism, very large goiters, or both, the initial dose may be increased to 400 mg, or for the occasional patient, up to 600 to 900 mg daily initially (administered in 3 equally divided doses at approximately 8-hour intervals).

Thyroid Storm

  • Initial dose – 100 mg orally every 8 hours
  • Maintenance dose – 100 to 150 mg orally daily administered in 3 equally divided doses approximately every 8 hours.

Pediatric Dose for Hyperthyroidism

6 years or older

  • Initial dose: 50 mg orally daily in 3 equally divided doses approximately every 8 hours
  • Carefully titrate based on clinical response and evaluation of TSH and free T4 levels

6 to 10 years of age

  • Initial dose: 50 to 150 mg orally daily in 3 equally divided doses approximately every 8 hours

10 years or older

  • Initial dose: 150 to 300 mg orally daily in 3 equally divided doses approximately every 8 hours
  • Maintenance dose: 50 mg orally twice a day when euthyroid

Side Effects of Propylthiouracil

More common

  • Black, tarry stools
  • chest pain
  • cough
  • fever
  • painful or difficult urination
  • shortness of breath
  • sore throat
  • sores, ulcers, or white spots on the lips or in the mouth
  • swollen glands
  • unusual bleeding or bruising
  • unusual tiredness or weakness

Less common

  • Dark-colored urine
  • a general feeling of discomfort, illness, or weakness
  • headache
  • light-colored stools
  • nausea or vomiting
  • stomach pain, continuing
  • upper right abdominal or stomach pain
  • yellow eyes and skin
  • backache
  • numbness or tingling of fingers, toes, or face
  • pain, swelling, or redness in joints
  • signs of clotting problems (e.g., unusual nosebleeds, bruising, blood in urine, coughing blood,  bleeding gums, cuts that don’t stop bleeding)
  • signs of infection (symptoms may include fever or chills, severe diarrhea, shortness of breath, prolonged dizziness, headache, stiff neck, weight loss, or listlessness)
  • signs of kidney problems (e.g., increased urination at night, decreased urine production, blood in the urine, change of urine color)
  • skin rash
  • swelling of feet or lower legs
  • symptoms of liver problems (such as yellow eyes or skin, abdominal pain, pale stools, dark urine, itching, nausea, or fatigue)
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Rare

  • Abdominal or stomach pain
  • agitation
  • bleeding gums
  • bleeding under the skin
  • blood in the urine or stools
  • bloody or cloudy urine
  • burning, crawling, itching, numbness, prickling, “pins and needles”, or tingling feelings
  • coma
  • confusion
  • cough or hoarseness
  • cracks in the skin
  • decreased urine output
  • depression

Drug Interactions of Propylthiouracil

There may be an interaction between propylthiouracil and any of the following:

  • Bacillus Calmette-Guérin (BCG)
  • beta-blockers (e.g., atenolol, metoprolol, propranolol)
  • clozapine
  • deferiprone
  • medications that contain iodine
  • aspirin
  • zolpidem
  • aspirin
  • lorazepam
  • loratadine
  • Fish Oil (omega-3 polyunsaturated fatty acids)
  • ibuprofen
  • atorvastatin
  • methimazole
  • metoprolol
  • acetaminophen
  • clopidogrel
  • propranolol
  • pantoprazole
  • montelukast
  • levothyroxine
  • valproic acid
  • Vitamin B12 (cyanocobalamin)
  • Vitamin C (ascorbic acid)
  • Vitamin D3 (cholecalciferol)
  • theophyllines (e.g., aminophylline, oxtriphylline, theophylline)
  • warfarin

Pregnancy Category of Propylthiouracil

Pregnancy

This medication should not be used during pregnancy unless the benefits outweigh the risks. If you become pregnant while taking this medication, contact your doctor immediately.

Lactation

This medication passes into breast milk. If you are a breast-feeding mother and are taking propylthiouracil, it may affect your baby. Talk to your doctor about whether you should continue breast-feeding.

References

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