Propylthiouracil

Approved Indications:

• Hyperthyroidism (e.g., Graves' disease):
  Used to treat overactive thyroid gland, particularly in patients who cannot tolerate methimazole or radioactive iodine therapy.
• Thyrotoxic Crisis (Thyroid Storm):
  Acute management of life-threatening thyrotoxicosis; suppresses thyroid hormone synthesis and conversion.
• Preoperative Preparation for Thyroidectomy:
  To induce a euthyroid state before surgical thyroid removal.
• Preparation Before Radioactive Iodine Therapy:
  Temporarily used to control hyperthyroid symptoms prior to radioactive iodine ablation.

Important Off-Label (Clinically Accepted) Uses:

• First Trimester of Pregnancy (Hyperthyroidism):
  Preferred over methimazole due to lower risk of teratogenic effects.
• Amiodarone-Induced Thyrotoxicosis (Type 1):
  May be used in iodine-induced hyperthyroidism when antithyroid therapy is required.

Route: Oral (tablets)
Form: 50 mg tablets

Adults:

• Initial treatment of hyperthyroidism:
  100–150 mg orally every 8 hours (total 300–450 mg/day in divided doses).
  In severe cases, doses may reach 600–900 mg/day.
• Maintenance dose:
  50–150 mg/day in divided doses, adjusted per thyroid hormone levels.
• Thyroid storm:
  Initial loading dose: 600–1000 mg PO once, then
  200–300 mg PO every 4–6 hours.

Pregnancy (1st Trimester):

• 50–150 mg/day in divided doses; lowest effective dose is recommended.
• Switch to methimazole in 2nd and 3rd trimesters to reduce hepatotoxicity risk.

Pediatric Patients:

• Initial dose:
  5–7 mg/kg/day orally in 3 divided doses.
• Maintenance dose:
  2–4 mg/kg/day based on response and lab parameters.

Elderly:

• Start at the lower end of the adult dosage range due to increased sensitivity.

Renal Impairment:

• No specific dose adjustment required, but monitor closely for accumulation.

Hepatic Impairment:

• Use cautiously. Contraindicated in active severe liver disease.
• Baseline and periodic liver function tests are essential.

Propylthiouracil (PTU) inhibits thyroid peroxidase, the enzyme responsible for catalyzing the iodination of tyrosine residues and the coupling of iodotyrosines during thyroid hormone synthesis (T3 and T4). This action reduces the formation of thyroid hormones within the gland. Additionally, PTU uniquely inhibits peripheral conversion of thyroxine (T4) to triiodothyronine (T3) by blocking the enzyme 5'-deiodinase, making it particularly useful in rapidly reducing thyroid hormone activity in thyrotoxic crisis.

• Absorption: Rapid and efficient after oral administration.
• Bioavailability: Approximately 50–80% (variable due to first-pass metabolism).
• Distribution: Widely distributed, including intrathyroidal accumulation.
• Protein Binding: Approximately 80–90%.
• Metabolism: Hepatic conjugation via glucuronidation.
• Active Metabolites: None clinically significant.
• Elimination:
• Renal (primarily as inactive glucuronide conjugates)
• Minimal unchanged drug excreted
• Half-life: 1–2 hours (short), but prolonged pharmacodynamic effect due to intrathyroidal retention.
• Onset of action: 24–36 hours
• Duration of effect: 12–24 hours after single dose

• Pregnancy:
• FDA classification: No longer categorized (previously Category D).
• Clinical guidance:
• Preferred drug in the first trimester of pregnancy due to lower risk of fetal malformations compared to methimazole.
• Switch to methimazole in the 2nd and 3rd trimesters to reduce risk of maternal liver toxicity.
• Lactation:
• Excreted in small quantities into breast milk.
• Generally compatible with breastfeeding at doses ≤300 mg/day.
• Monitor infant thyroid function if used during lactation.
• Caution:
  Use only when clearly needed. Monitor maternal and fetal thyroid function closely during therapy.

• Primary Class: Antithyroid Agent
• Subclass: Thioamide (also includes methimazole)

• Known hypersensitivity to propylthiouracil or any tablet components
• History of serious adverse reactions (e.g., agranulocytosis, fulminant hepatitis) to PTU
• Pre-existing severe hepatic impairment
• Use during 2nd and 3rd trimesters of pregnancy (relative; methimazole preferred)
• Neonates and infants (only under expert supervision due to hepatotoxicity risk)

• Boxed Warning (Black Box):
• Severe hepatotoxicity, including liver failure and death, reported in adults and children.
• Use only when methimazole is not appropriate (e.g., 1st trimester pregnancy or thyroid storm).
• Agranulocytosis:
• Serious risk; typically occurs within 90 days of treatment.
• Discontinue immediately if sore throat, fever, or infection symptoms develop.
• Vasculitis and ANCA-associated syndromes:
• PTU has been linked to vasculitis, glomerulonephritis, and lupus-like reactions.
• Monitoring:
• Baseline and periodic CBC, LFTs, and thyroid panel (TSH, Free T4, T3)
• Educate patients on signs of liver injury and infection
• Pediatric Risk:
• Not first-line for children due to increased hepatotoxicity risk

Common:

• Dermatologic: Rash, urticaria, pruritus
• Gastrointestinal: Nausea, vomiting, epigastric pain
• Musculoskeletal: Arthralgia, joint pain
• Neurologic: Headache, dizziness

Serious/Rare:

• Hepatic: Hepatitis, hepatic necrosis, liver failure
• Hematologic: Agranulocytosis, leukopenia, aplastic anemia
• Immunologic: ANCA-positive vasculitis, lupus-like syndrome
• Renal: Interstitial nephritis
• Others: Fever, lymphadenopathy

Onset:

• Common side effects: within days to weeks
• Agranulocytosis and hepatotoxicity: often within the first 2–3 months

Dose-dependence:

• Rash and GI upset may be dose-related
• Serious effects not necessarily dose-dependent

• Warfarin (and other anticoagulants):
  PTU may reduce anticoagulant effect by altering vitamin K-dependent clotting factor metabolism.
• Beta-Blockers (e.g., propranolol):
  Often co-prescribed to manage adrenergic symptoms of hyperthyroidism; additive effect.
• Digitalis glycosides:
  Dose may need adjustment as thyroid status changes; hyperthyroidism increases clearance of digoxin.
• Theophylline:
  Reduced clearance when thyroid hormone levels decrease; monitor levels.
• Enzyme Systems:
  Not a major substrate of CYP450 enzymes; metabolized via hepatic glucuronidation.

• FDA Black Box Reaffirmed (2021–2023):
• Severe liver injury risk confirmed; PTU use limited to thyroid storm or early pregnancy.
• Routine use discouraged unless methimazole is contraindicated.
• ATA Guidelines (2023):
• Methimazole remains first-line for most hyperthyroid patients.
• PTU reserved for:
• First trimester of pregnancy
• Thyroid storm
• Methimazole intolerance
• Pediatric Use Updated:
• PTU should not be used as first-line therapy in children due to increased risk of acute liver failure.

• Temperature: Store at 20°C to 25°C (68°F to 77°F); excursions allowed between 15°C–30°C
• Humidity: Protect from moisture
• Light: Store in a dry, dark container
• Handling:
• No refrigeration or reconstitution required
• Keep tightly closed in original container
• Do not use if tablet shows discoloration or damage