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Monday, August 11, 2025

Antithyroid agents


Introduction

  • Antithyroid agents are drugs that reduce thyroid hormone synthesis or modify peripheral effects of thyroid hormones.

  • Primarily used in the management of hyperthyroidism, especially in Graves’ disease, toxic multinodular goiter, and toxic adenoma.

  • Can be used as definitive therapy, in preparation for surgery, or as a bridge to radioactive iodine treatment.

  • Classes include thioamides, iodine-containing agents, radioactive iodine, and adjunctive medications.

Classification

1. Thioamides (Thioureylene derivatives)

  • Propylthiouracil (PTU)

  • Methimazole (MMI)

  • Carbimazole (prodrug of methimazole; used in some countries)

2. Iodine-Containing Agents

  • Potassium iodide (Lugol’s solution, saturated solution of potassium iodide – SSKI)

  • Iodinated contrast agents (e.g., iopanoic acid – rarely used)

3. Radioactive Iodine (¹³¹I)

  • Oral sodium iodide-131.

4. Adjunctive Agents

  • Beta-adrenergic blockers (e.g., propranolol) – symptom control.

  • Glucocorticoids – in thyroid storm, ophthalmopathy.

  • Cholestyramine – binds thyroid hormones in gut, enhances clearance.

Mechanisms of Action

Thioamides

  • Inhibit thyroid peroxidase (TPO), blocking organification of iodide and coupling of iodotyrosines.

  • PTU also inhibits peripheral conversion of thyroxine (T₄) to triiodothyronine (T₃) by blocking type 1 deiodinase.

Iodine-containing agents

  • High doses acutely inhibit release of thyroid hormones from the gland (Wolff–Chaikoff effect).

  • Reduce gland vascularity preoperatively.

Radioactive iodine

  • Taken up selectively by thyroid follicular cells.

  • Beta emissions cause localized tissue destruction over weeks.

Adjunctive agents

  • Beta-blockers: block adrenergic symptoms; propranolol also reduces peripheral T₄→T₃ conversion.

  • Glucocorticoids: decrease T₄→T₃ conversion and treat autoimmune inflammation.

  • Cholestyramine: interrupts enterohepatic circulation of thyroid hormones.

Clinical Indications

Thioamides

  • Graves’ disease (first-line in many young patients and pregnancy).

  • Toxic multinodular goiter or adenoma (short-term before definitive therapy).

  • Thyroid storm (PTU preferred early).

Iodine-containing agents

  • Preoperative preparation to reduce gland vascularity.

  • Acute inhibition of hormone release in thyroid storm (given after thioamides).

  • Radiation emergencies (potassium iodide to block radioactive iodine uptake).

Radioactive iodine

  • Definitive treatment of Graves’ disease, toxic multinodular goiter, or adenoma in non-pregnant adults.

Adjuncts

  • Symptom control while waiting for thioamide effect.

  • Thyroid storm management (beta-blockers, glucocorticoids, bile acid sequestrants).

Pharmacokinetics

Methimazole

  • Potent, long half-life (~6–13 hours), allowing once-daily dosing.

  • Crosses placenta and appears in breast milk.

Propylthiouracil

  • Shorter half-life (~1–2 hours) – multiple daily doses needed.

  • Greater protein binding; crosses placenta.

Potassium iodide

  • Rapid onset (within 24 hours for hormone release inhibition).

Radioactive iodine

  • Oral absorption; concentrated in thyroid.

  • Effects seen after weeks; full response in 2–3 months.

Adverse Effects

Thioamides

  • Minor: rash, pruritus, arthralgia, mild GI upset.

  • Major: agranulocytosis (rare, abrupt onset), hepatotoxicity (especially PTU – risk of fulminant hepatic failure), vasculitis (ANCA-associated).

Iodine-containing agents

  • Metallic taste, salivary gland swelling, rash.

  • Iodism (chronic iodine toxicity): burning mouth/throat, sore teeth/gums, GI upset.

  • Rare angioedema, anaphylaxis.

Radioactive iodine

  • Hypothyroidism (most patients within months–years).

  • Radiation thyroiditis.

  • Contraindicated in pregnancy and breastfeeding.

Adjuncts

  • Beta-blockers: bradycardia, hypotension, bronchospasm.

  • Glucocorticoids: systemic corticosteroid adverse effects if used long term.

Contraindications

Thioamides

  • History of severe hypersensitivity reactions to the drug.

  • Previous agranulocytosis with thioamides.

Iodine-containing agents

  • Pregnancy (except in radiation emergencies).

  • Iodine hypersensitivity (rare).

Radioactive iodine

  • Pregnancy, breastfeeding.

  • Severe uncontrolled thyrotoxicosis without prior stabilization.

Precautions

  • Monitor full blood count if symptoms suggest agranulocytosis (fever, sore throat).

  • Monitor liver function (especially with PTU).

  • Monitor thyroid function tests periodically to avoid overtreatment and hypothyroidism.

Drug Interactions

Thioamides

  • Potentiate effects of warfarin (by reducing catabolism of clotting factors).

  • Additive bone marrow suppression with other myelosuppressives.

Iodine-containing agents

  • May interact with lithium (both reduce thyroid hormone release).

Radioactive iodine

  • Avoid iodine-containing medications before therapy (interferes with uptake).

Special Populations

Pregnancy

  • PTU preferred in the first trimester (lower teratogenic risk than methimazole).

  • Methimazole preferred in later trimesters due to PTU hepatotoxicity risk.

Lactation

  • Low-dose methimazole or PTU acceptable; monitor infant thyroid function.

Pediatrics

  • Thioamides used as first-line; radioactive iodine avoided except in select adolescents.

Future Directions

  • Development of targeted immunomodulators for autoimmune hyperthyroidism.

  • Long-acting thioamide formulations to improve adherence.

  • Safer iodine organification inhibitors with reduced side effect profiles.




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