Thyroid Inhibitors

1. Thioamides (antithyroid drugs)
2. Ionic inhibitors
3. High-dose iodine
4. Radioactive iodine (¹³¹I)

1. Thioamides

Drugs

• Methimazole (MMI) - first-line in most adults and children; ~10x more potent than PTU
• Propylthiouracil (PTU) - reserved for specific indications (see below)
• Carbimazole - prodrug of methimazole, used in the UK; converted to methimazole after absorption

Mechanism of Action

1. Organification - incorporation of iodine into tyrosyl residues of thyroglobulin (forming MIT and DIT)
2. Coupling - joining of iodotyrosyl residues to form T3 and T4

These drugs deplete stored hormone as thyroglobulin is hydrolyzed and hormones already formed continue to be released - so onset of clinical effect takes several weeks.

• Goodman & Gilman, p. 970

Pharmacokinetics

Clinical Indications

• Graves' disease (primary treatment or pre-surgical)
• Toxic nodular goiter
• Pre-operative preparation before thyroidectomy
• Adjunct before/after radioactive iodine
• Thyroid storm (PTU preferred)

PTU Preferred Situations

• First trimester of pregnancy (methimazole associated with "methimazole embryopathy": aplasia cutis, choanal atresia)
• Thyroid storm (additional T4-to-T3 conversion block)
• Adverse reaction to methimazole (excluding agranulocytosis/hepatitis)

Due to a black box warning about severe hepatitis, PTU should be reserved for use only during the first trimester of pregnancy, in thyroid storm, and when patients are intolerant of methimazole.

• Katzung, p. 1085

Adverse Effects

• Rash, urticaria, pruritus (~5%)
• Arthralgia, myalgia
• Fever, GI disturbance

• Agranulocytosis (0.1-0.5%) - most feared; usually in the first 3 months; patients must be warned to report sore throat or fever immediately
• Hepatotoxicity - PTU causes hepatocellular damage (black box warning, can be fatal); methimazole causes cholestatic pattern
• ANCA-associated vasculitis - mainly PTU
• Aplastic anemia - rare
• Both drugs cross the placenta and can cause fetal hypothyroidism and goiter

2. Ionic Inhibitors

Perchlorate (ClO4-) blocks the entrance of iodide into the thyroid by competitively inhibiting the NIS and can itself be transported by NIS into the thyroid gland. NIS inhibitors (perchlorate, thiocyanate, nitrate) are additive in inhibiting iodine uptake.

• Goodman & Gilman, p. 972

3. High-Dose Iodine (Wolff-Chaikoff Effect)

• Limits its own transport (NIS downregulation)
• Transiently inhibits organification - the Wolff-Chaikoff effect: high intrathyroidal iodide inhibits TPO
• Inhibits hormone release - the most clinically important acute effect; reduces vascularity of the gland
• Escape occurs after 1-2 weeks as the thyroid adapts (via reduced NIS expression), so iodide alone is not adequate for sustained treatment

Preparations

• Lugol's solution - 8% iodine + 19% potassium iodide; ~8 mg iodide per drop
• Saturated solution of potassium iodide (SSKI/KISS) - 50 mg iodide per drop

Clinical Uses

• Thyroid storm: given after the first dose of PTU/methimazole (never before, to avoid providing substrate for hormone synthesis)
• Pre-operative preparation (Plummer's iodine): reduces vascularity and firmness of the gland before thyroidectomy; given for 7-14 days pre-op
• Radiation emergency: potassium iodide blocks radioactive iodine uptake (protective)
• Neonatal Graves disease: Lugol's solution 1 drop every 8 hours

4. Radioactive Iodine (¹³¹I)

Mechanism

• ¹³¹I behaves chemically identical to stable ¹²⁷I - it is trapped and organified by the thyroid
• Emits beta (β) particles (main therapeutic effect - destroys follicular cells) and gamma rays
• t½ = 8 days; >99% of radiation is expended within 56 days
• Destruction is highly selective - adjacent tissues receive minimal damage

Indications

• Hyperthyroidism in older patients or those with cardiac disease (clearest indication)
• Graves disease that persists or recurs after subtotal thyroidectomy
• Prolonged antithyroid drug treatment without remission
• Toxic nodular goiter
• Thyroid ablation after thyroid cancer surgery
• Treatment of metastatic differentiated thyroid cancer

Dosing

• Usual dose: 4-15 mCi total; targeting delivery of 8 mCi to the thyroid based on 24-h radioiodine uptake
• 80% of patients cured with a single dose; ~20% need a second dose

Contraindications

• Pregnancy (absolute) - causes fetal hypothyroidism
• Breastfeeding
• Children (relative - most centers avoid)

Consequence

• Hypothyroidism in a large proportion of patients over time (the main long-term adverse effect); patients require lifelong levothyroxine replacement

5. Adjunct / Peripheral Inhibitors

6. Drugs That Disrupt Thyroid Hormone Synthesis/Metabolism (Summary Table)

Thyroid Storm - Treatment Protocol

1. PTU (large doses) - blocks synthesis AND peripheral conversion
2. Iodide (Lugol's or SSKI) - given 1 hour AFTER PTU - blocks release
3. Beta-blocker (propranolol) - controls adrenergic symptoms
4. Glucocorticoids - inhibit Dio1, treat adrenal insufficiency
5. Treat precipitating cause
6. Supportive care (IV fluids, cooling, antipyretics)

• Goodman & Gilman's The Pharmacological Basis of Therapeutics, pp. 970-973
• Katzung's Basic and Clinical Pharmacology, 16th Ed., pp. 1085-1092
• Recent evidence: PMID 40891035 (mortality comparison: drugs vs RAI vs surgery, 2025 network meta-analysis), PMID 40745151 (agranulocytosis dose-risk, 2025 meta-analysis), PMID 38195966 (perchlorates in hyperthyroidism, 2024 systematic review)