Antithyroid Drug

Aka: Antithyroid Drug, Thioamide, Thionamide

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II. Indications

  1. Methimazole is the preferred first-line Thionamide (over PTU) in most cases due to lower hepatotoxicity
  2. Reasons to use Propylthiouracil (PTU) instead of Methimazole
    1. Lactation
    2. Pregnancy (both PTU and Methimazole are Category D)
      1. Use Propylthiouracil (PTU) in first trimester
      2. Use Methimazole in second and third trimester
  3. Thionamide indications
    1. Hyperthyroidism in children and adolescents
    2. Hyperthyroidism in Pregnancy (first trimester for PTU, Methimazole after)
    3. Severe Grave's Disease (e.g. Thyroid Storm)
    4. Subclinical Hyperthyroidism

III. Mechanism

  1. Thionamides block T3 and T4 synthesis (by inhibiting Thyroid peroxidase)
    1. Thyroid peroxidase normally converts inorganic Iodide ions to organic Iodine
    2. Organic Iodine is required for Thyroxine synthesis
  2. Propylthiouracil also blocks T4 to T3 conversion in peripheral tissue

IV. Medications: Methimazole (Tapazole)

  1. Preferred first-line agent
  2. Target dose to Free T4 high end of normal range
  3. Avoid in first trimester due to congenital defect risk
    1. Esophageal atresia
    2. Choanal Atresia
    3. Aplasia cutis
    4. Abdominal wall defects
    5. Ventricular Septal Defect
  4. Advantages over Propylthiouracil (PTU)
    1. Once daily dosing
    2. Decreases T4 and T3 levels more rapidly
    3. Much safer than PTU
      1. Lower risk of Agranulocytosis at moderate doses
      2. Does not carry the same liver toxicity risk as PTU
  5. Dosing: Adults with Hyperthyroidism
    1. Start
      1. Subclinical Hyperthyroidism: 5 mg orally daily
      2. Mild Hyperthyroidism: 5 mg orally three times daily
      3. Moderate Hyperthyroidism: 10 mg orally three times daily
      4. Severe Hyperthyroidism: 20 mg orally three times daily
    2. Maintenance
      1. Titrate Methimazole dose down after 4 to 6 weeks
      2. Reduce dose to 5-10 mg per day
      3. Goal: maintain normal Thyroid function
      4. Range: 5 to 30 mg/day
  6. Dosing: Children with Hyperthyroidism
    1. Target dose to Free T4 high end of normal range
    2. Start: 0.4 mg/kg/day divided every 8 hours orally
    3. Maximum: 30 mg/day
    4. Maintenance
      1. Titrate Methimazole dose down after 4 to 6 weeks
      2. Reduce dose to 50% of starting dose (e.g. 0.2 mg/kg/day divided every 8 hours)
      3. Goal: maintain normal Thyroid function

V. Medications: Propylthiouracil (PTU)

  1. Target dose to Free T4 high end of normal range
  2. Indications (reasons to use PTU instead of Methimazole)
    1. Lactation
    2. Pregnancy (both PTU and Methimazole are Category D)
      1. Use PTU in first trimester
      2. Use Methimazole in second and third trimester
  3. Hyperthyroidism in Adults
    1. Start
      1. Subclinical Hyperthyroidism: 50 to 100 mg orally divided three times daily
      2. Moderate Hyperthyroidism: 100 to 150 mg orally three times daily
      3. Severe Hyperthyroidism: 200 to 400 mg orally three times daily
    2. Maintenance
      1. Titrate Propylthiouracil (PTU) dose down after 4 to 6 weeks
      2. Goal: maintain normal Thyroid function
      3. Dose: reduce to 50-100 mg/day in divided doses
    3. Thyroid Storm
      1. See Thyroid Storm for full protocol (Beta Blockers, Thionamides, Iodine, Glucocorticoids)
      2. Load 500 to 1000 mg PO, PR, or per NG
      3. Maintenance 200 to 250 mg (up to 400 mg) every 4 hours PO, PR, or per NG
  4. Hyperthyroidism in Children
    1. Start
      1. Age >10 years old: 50 to 100 mg orally three times daily
      2. Age 6 to 10 years: 50 mg orally three times daily
      3. Age <6 years (NOT FDA approved): 5 to 7 mg/kg/day divided every 8 hours
    2. Maintenance
      1. Titrate Propylthiouracil (PTU) dose down after 4 to 6 weeks
      2. Goal: maintain normal Thyroid function
      3. Dose: reduce to 1/3 to 1/2 of initial dose

VI. Adverse effects (3 per 1000 patients)

  1. Drug-Induced Agranulocytosis (more common with PTU)
    1. Risk increases over age 40 years
    2. Occurs in 0.17% of those on Methimazole
    3. Presentation: Infection (e.g. Pharyngitis)
    4. Course
      1. Resolves within 2-3 weeks after drug stopped
      2. Severe, refractory course may occur
    5. Contraindication to further Antithyroid Drugs
  2. Jaundice
    1. Cholestatic Jaundice
    2. Occurs more commonly with Methimazole
  3. Hepatitis
    1. Occurs with both Methimazole and Propylthiouracil (PTU)
      1. However, PTU is higher risk of liver injury, making Methimazole preferred in most cases
    2. Methimazole associated hepatitis
      1. Incidence: 3.17 per 1000 person-years
      2. Acute Hepatic Failure: 0.32 per 1000 person-years
    3. Propylthiouracil (PTU) is associated with severe liver injury
      1. Adults: 1 in 10,000
      2. Children: 1 in 2,000
  4. Vasculitis
  5. Lupus-Like Syndrome
  6. Aplastic Anemia
  7. Rash or Pruritus
    1. Switch from PTU to Methimazole if severe
  8. Arthralgia or Polyarthritis
  9. Fever
  10. Congenital abnormalities possible with Methimazole

VII. Monitoring

  1. Repeat examination every 3 months
  2. Pregnancy Test before starting therapy
  3. Lab Testing while on antithyroid medications: Monthly for 6 to 12 months
    1. Complete Blood Count (CBC)
      1. Obtain at baseline
      2. Repeat if Pharyngitis or fever occur (need not be done without symptoms or signs)
    2. Liver Function Tests
      1. Obtain at baseline and if symptoms develop
    3. Thyroid Function Tests (baseline, then every 4-8 weeks, then after stabilizing, every 3 months)
      1. Thyroid Stimulating Hormone (TSH) after stabilizing, once on every 3 month schedule
      2. Free T4
      3. Free T3
  4. Lab Testing after completing antithyroid medications
    1. Obtain Thyroid Function Tests every 1-3 months for 6-12 months
  5. Indications to discontinue medication (via taper)
    1. Total treatment course of 12-18 months AND
    2. TSH normalized for 6-12 months
  6. Indications to consider Thyroid ablation
    1. Inadequate suppression at 12 months from initiation

VIII. Efficacy: Predictors of Relapse (occurs in 30-70% of cases within first year)

  1. Tobacco Abuse
  2. Large Goiter
  3. Thyroid Stmulating Antibody high at end of treatment

IX. References

  1. Kravets (2016) Am Fam Physician 93(5): 363-70 [PubMed]

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