How does methimazole work?

Mechanism of Action of Methimazole

Methimazole works primarily by inhibiting thyroid hormone synthesis through blocking thyroid peroxidase-mediated iodination of tyrosine residues in thyroglobulin, which is an essential step in the production of thyroxine (T4) and triiodothyronine (T3). 1, 2

Primary Mechanisms

• Inhibition of Thyroid Hormone Synthesis:

  • Methimazole contains a thiourea moiety within a heterocyclic structure that interferes with thyroid peroxidase (TPO) 2
  • It blocks the TPO-catalyzed iodination of tyrosine residues in thyroglobulin, preventing the formation of thyroid hormones 1, 2
  • Unlike propylthiouracil (PTU), methimazole does NOT block the peripheral conversion of T4 to T3 3, 2

• Pharmacokinetic Properties:

  • Readily absorbed in the gastrointestinal tract
  • Metabolized in the liver
  • Excreted in the urine 1
  • Has a longer half-life than PTU, allowing for once-daily dosing 3

Secondary Mechanisms

Methimazole also exhibits additional effects that contribute to its therapeutic action:

1. Antioxidant Properties:

   • Rapidly eliminates H₂O₂ produced during thyroid hormone synthesis 4
   • Facilitates electron transfer from NADPH to H₂O₂ using thioredoxin or glutathione 4
   • Functions similarly to peroxiredoxin or glutathione peroxidase 4

2. Immunomodulatory Effects:

   • Inhibits the interferon-gamma (IFN-γ) signaling pathway in thyroid cells 4
   • Modulates the function of transcription factor STAT1 4
   • Prevents IFN-γ and H₂O₂-mediated inactivation of phosphatases 4
   • These effects may help explain its efficacy in Graves' disease beyond hormone synthesis inhibition

3. Transcriptional Regulation:

   • Inhibits thyroid hormone receptor (TR)-mediated transcription 5
   • Recruits nuclear corepressors to the thyroid hormone receptor in the absence of T3 5
   • May decrease growth hormone release stimulated by T3 5

Important Clinical Considerations

• Methimazole does NOT inactivate existing thyroid hormones that are already stored in the thyroid or circulating in the blood 1
• It does NOT interfere with the effectiveness of exogenously administered thyroid hormones 1
• At therapeutic concentrations, methimazole can paradoxically increase TPO mRNA and cellular TPO activity, although it inhibits the TPO-H₂O₂-mediated catalytic reaction 6

Comparison with Propylthiouracil (PTU)

• Both drugs inhibit thyroid hormone synthesis, but through slightly different mechanisms 2
• PTU has the additional effect of blocking peripheral conversion of T4 to T3, which methimazole lacks 3, 2
• Methimazole has a longer half-life, allowing for once-daily dosing compared to multiple daily doses required for PTU 3
• PTU is preferred in the first trimester of pregnancy due to lower risk of congenital malformations, while methimazole is associated with lower risk of severe liver injury 3

Understanding methimazole's mechanism of action helps explain its effectiveness in treating hyperthyroidism, particularly Graves' disease, where both its hormone synthesis inhibition and immunomodulatory effects contribute to clinical improvement.