Antithyroid Agents

Antithyroid agents are used in the management of hyperthyroidism, particularly that due to Graves’ disease. This group of medications includes the thionamides (methimazole and propylthiouracil), potassium iodide, and radioactive iodine. Thionamides are currently the preferred choice for hyperthyroid management; these drugs work by blocking thyroid hormone synthesis. Propylthiouracil also blocks the conversion of T4 to T3 and, because it less readily crosses the placenta, is the preferred therapy in the 1st trimester of pregnancy. Potassium iodide mainly works through inhibiting thyroid hormone release. Potassium iodide is most often used as a pretreatment prior to thyroid surgery or as an adjunct to hyperthyroid management. Radioactive iodine causes damage to thyroid tissue, thereby definitively reducing thyroid function.

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Overview

Pathophysiology of hyperthyroidism

  • Medical condition defined by overproduction of hormones by the thyroid gland: 
    • Triiodothyronine (T3
    • Thyroxine (T4)
  • Results in ↓ production of thyroid-stimulating hormone (TSH) by the pituitary gland.
  • Antithyroid agents may be used as treatment by blocking:
    • Thyroid hormone synthesis
    • Conversion of T4 → T3
    • Thyroid hormone release

Antithyroid medications

  • Thionamides
    • Methimazole
    • Propylthiouracil (PTU)
  • Iodides (potassium iodide)
  • Radioactive iodine

Thionamides

Pharmacodynamics

  • Thionamides inhibit thyroid hormone synthesis via blockage of: 
    • Thyroid peroxidase (TPO) reactions (oxidation of iodine)
    • Iodine organification (incorporation of iodine into thyroglobulin)
  • Thionamides do not block release of preformed hormones → takes approximately 3‒4 weeks before T4 stores are depleted
  • Additionally, PTU blocks the peripheral conversion of T4 → T3

Pharmacokinetics

Methimazole:

  • Absorption:
    • Complete
    • Variable rate
  • Distribution:
    • Accumulates in the thyroid gland
    • Crosses placenta
    • Not protein-bound
  • Metabolized in the liver
  • Excreted in the urine

Propylthiouracil:

  • Absorption: rapid
  • Distribution:
    • Accumulates in the thyroid gland
    • Crosses placenta (less so than methimazole)
    • 80%–85% protein-bound 
  • Metabolized in the liver
  • Excreted in the urine

Indications

  • Drug class of choice for maintenance therapy of hyperthyroidism.
    • Methimazole is preferred for nonpregnant individuals (has a longer half-life)
    • PTU is preferred in the 1st trimester of pregnancy.
  • Thyroid storm (in combination with other therapies)

Adverse effects

Thionamides are associated with a low incidence of severe side effects, but these may include:

  • Agranulocytosis (reversible)
  • Hepatotoxicity (fulminant hepatic necrosis can occur with PTU)
  • Aplastic anemia
  • ANCA-positive vasculitis 
  • Dermatologic reactions 
  • Lupus-like syndrome

Precautions

Considerations for thionamide management in pregnant individuals:

  • Crosses the placental barrier
    • Can accumulate in the fetal thyroid
    • PTU crosses less readily (due to protein binding)
  • Teratogenicity (more severe with methimazole, which can cause aplasia cutis)

Drug interactions

  • May ↑ myelosuppressive effect of:
    • Clozapine
    • Promazine
  • ↓ Radioactive iodine effect
  • ↓ Anticoagulant effect of warfarin

Iodides

Pharmacodynamics

  • Inhibits: 
    • Hormone release (potentially through inhibition of thyroglobulin proteolysis) → rapid improvement in symptoms
    • Iodine organification (temporary) → ↓ thyroid hormone synthesis 
  • Reduces:
    • Size of a hyperplastic thyroid gland
    • Gland vascularity

Indications

Iodine can be used for:

  • Pretreatment before thyroid surgery for Graves’ disease
  • Adjunctive therapy for hyperthyroidism (in conjunction with thionamides or radioactive iodine)
  • Thyroid storm (in combination with other therapies)
  • Prophylaxis for radioactive iodine exposure (decreases uptake in thyroid gland)

Adverse effects

  • Exacerbate hyperthyroidism symptoms (thus, should be used in conjunction with other therapy)
  • GI intolerance
  • Esophageal or mucosal injury
  • Dysgeusia

Contraindications

  • Pregnancy → fetal hypothyroidism and goiter
  • Allergy to iodine
  • Renal failure (due to the presence of potassium → hyperkalemia)

Drug interactions

  • May exacerbate hyperkalemic effect of:
    • Aliskiren
    • Angiotensin receptor blockers
    • ACEis
    • Potassium-sparing diuretics
  • ↓ Radioactive iodine effect

Radioactive Iodine

Pharmacodynamics

  • Rapidly concentrates in thyroid tissue → beta emissions → thyroid tissue damage
  • Ablates thyroid function → ↓ thyroid hormone production (occurs over 6–18 weeks)

Pharmacokinetics

  • Absorption: readily absorbed in GI tract
  • Distribution:
    • Primarily accumulates in the thyroid gland
    • Crosses placenta
    • Not protein-bound
  • Excreted in the urine

Indications

  • Hyperthyroidism:
    • Definitive
    • Less expensive treatment
  • Toxic adenoma
  • Multinodular goiter

Adverse effects

  • Hypothyroidism:
    • Permanent
    • Caused by destruction of too much thyroid tissue
    • Requires lifelong thyroid replacement treatment
  • Radiation thyroiditis:
    • Rare
    • Causes severe thyroid pain 
  • Rebound hyperthyroidism (related to an ↑ in thyrotropin receptor antibodies (TRAbs) due to radiation)
  • Exacerbation of Graves’ ophthalmopathy 
    • Especially in smokers
    • Due to TRAbs

Contraindications

  • Pregnant or breastfeeding individuals → will destroy fetal/infant thyroid gland
  • Moderate to severe Graves’ ophthalmopathy

Precautions

Radiation precautions should be taken to reduce exposing close contacts.

Drug interactions

Medications that may ↓ the therapeutic effect of radioactive iodine:

  • Amiodarone
  • Thionamides
  • Iodine
  • Levothyroxine
  • Liothyronine

Comparison of Antithyroid Agents

The following table compares the mechanisms, indications, and adverse effects for the antithyroid medications:

Table: Comparison of antithyroid agents
MedicationMechanismIndicationsAdverse effects
MethimazoleInhibits thyroid hormone synthesis
  • Hyperthyroidism (preferred drug)
  • Thyroid storm
  • Agranulocytosis
  • Hepatotoxicity
  • Aplastic anemia
  • Vasculitis
  • Teratogenicity
PropylthiouracilInhibits conversion of T4 → T3
  • Hyperthyroidism (preferred in 1st trimester of pregnancy)
  • Thyroid storm
Potassium iodide
  • Inhibits hormone release
  • Temporary inhibition of iodine organification
  • Pretreatment before thyroid surgery
  • Hyperthyroidism
  • Thyroid storm
  • Radioactive iodine exposure prophylaxis
  • Exacerbation of hyperthyroidism
  • GI intolerance
  • Dysgeusia
Radioactive iodineInduces thyroid tissue damage → ↓ thyroid function
  • Hyperthyroidism (definitive treatment)
  • Toxic adenoma
  • Multinodular goiter
  • Hypothyroidism
  • Radiation thyroiditis
  • Rebound hyperthyroidism
  • Worsening Graves’ ophthalmopathy

References

  1. Ross, D. S. (2021). Graves hyperthyroidism in non-pregnant women. UpToDate. Retrieved July 31, 2021, from https://www.uptodate.com/contents/graves-hyperthyroidism-in-nonpregnant-adults-overview-of-treatment
  2. Ross, D.S. (2020). Thionamides in the treatment of Graves’ disease. UpToDate. Retrieved August 1, 2021, from https://www.uptodate.com/contents/thionamides-in-the-treatment-of-graves-disease
  3. Ross, D.S. (2020). Thionamides: Side effects and toxicities. UpToDate. Retrieved August 1, 2021, from https://www.uptodate.com/contents/thionamides-side-effects-and-toxicities
  4. Ross, D.S. (2020). Iodine in the treatment of hyperthyroidism. UpToDate. Retrieved August 1, 2021, from https://www.uptodate.com/contents/iodine-in-the-treatment-of-hyperthyroidism
  5. Ross, D.S. (2020). Radioiodine in the treatment of hyperthyroidism. UpToDate. Retrieved August 1, 2021, from https://www.uptodate.com/contents/radioiodine-in-the-treatment-of-hyperthyroidism
  6. Methimazole. (2017). RxList. https://www.rxlist.com/consumer_methimazole_tapazole/drugs-condition.htm
  7. Sodium iodide I-131. (2021). Medscape. https://reference.medscape.com/drug/hicon-sodium-iodide-i-131-999924#3
  8. Azizi, F. (2011). Management of hyperthyroidism during pregnancy and lactation. European Society of Endocrinology. https://eje.bioscientifica.com/view/journals/eje/164/6/871.xml
  9. Schraga, E. D., MD. (2020). Hyperthyroidism, thyroid storm, and Graves disease: practice essentials, Pathophysiology, Epidemiology. MedScape. https://emedicine.medscape.com/article/767130-overview
  10. Dong, B.J., Greenspan, F.S. (2012). Thyroid & antithyroid drugs. In: Katzung, B.G., Masters, S.B., Trevor, A.J. (Eds.), Basic & Clinical Pharmacology, 12th ed. McGraw-Hill Lange, pp. 681–696. https://pharmacomedicale.org/images/cnpm/CNPM_2016/katzung-pharmacology.pdf

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