Antithyroid drugs
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"antithyroid drugs" AND hyperthyroidism
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Antithyroid Drugs
Antithyroid drugs reduce thyroid hormone synthesis or release and are used primarily in hyperthyroidism (Graves disease, toxic nodular goiter, thyroid storm). The main classes are thioamides, iodine/iodide preparations, and radioiodine (as an adjunct). Beta-blockers and perchlorate are used as adjuncts.
1. Classification
| Class | Drugs |
|---|---|
| Thioamides | Propylthiouracil (PTU), Methimazole, Carbimazole (prodrug of methimazole) |
| Iodine/Iodides | Lugol's solution, SSKI (saturated solution of potassium iodide) |
| Radioactive iodine | ¹³¹I (iodine-131) |
| Ionic inhibitors | Perchlorate, Thiocyanate, Pertechnetate |
| Adjuncts | Propranolol, Lithium, Cholestyramine |
2. Thioamides - The Primary Antithyroid Drugs
Chemistry & Structure
Thioamides (thioureylenes) belong to the family of thioamides. PTU is the prototype. Methimazole is 1-methyl-2-mercaptoimidazole. Carbimazole (used in Europe) is a carbethoxy derivative that is converted to methimazole after absorption. - Goodman & Gilman's, p. 970
Mechanism of Action
Both PTU and methimazole:
- Inhibit thyroid peroxidase (TPO) - block the oxidation and organification of iodide, preventing incorporation of iodine into tyrosyl residues of thyroglobulin (blocking MIT and DIT synthesis)
- Block the coupling reaction - prevent condensation of iodotyrosines (MIT + DIT) to form T3 and T4
- May have immunosuppressive effects - blunting the autoimmune process in Graves disease (this may contribute to durable remissions) - Goldman-Cecil, p. 2438
PTU additionally:
- Inhibits type 1 deiodinase in peripheral tissues, blocking conversion of T4 → T3
- This makes PTU preferable in thyroid storm (where rapid T3 reduction is critical) - Goodman & Gilman's, p. 970
Important note: These drugs block new hormone synthesis but do not release stored hormone. Clinical effect is delayed until stored thyroid hormone is depleted - typically 3-6 weeks.
Pharmacokinetics
| Property | PTU | Methimazole |
|---|---|---|
| Plasma protein binding | ~75% | Negligible |
| Plasma half-life (t½) | ~75 min | ~4-6 hours |
| Duration of action (100 mg PTU) | 2-3 hours | Up to 24 hours |
| Dosing frequency | 2-3 times daily | Once daily |
| Placental transfer | Less (due to protein binding) | More |
| Breast milk | Less | More |
| Volume of distribution | Smaller | Larger |
Methimazole concentrates in the thyroid and has a longer intrathyroidal t½. Its long duration allows once-daily dosing, improving adherence. - Goodman & Gilman's, p. 970
Doses
- Methimazole: Starting dose 15-40 mg/day (once daily). Equivalent: 30 mg methimazole ≈ 400 mg PTU
- PTU: Starting dose 100 mg every 8 hours. For severe cases: up to 500-600 mg/day in divided doses every 4-6 hours
- Once euthyroidism is achieved (usually 12 weeks), doses are titrated down - Goodman & Gilman's, p. 971
Drug of Choice (DOC)
Methimazole is the DOC for most hyperthyroid states because:
- Once-daily dosing (better compliance)
- Longer duration of action
- Less hepatotoxic than PTU
- Equally effective
PTU is preferred in:
- Thyroid storm - rapid T3 lowering needed (due to peripheral T4→T3 inhibition)
- First trimester of pregnancy - PTU has less placental transfer; methimazole is associated with "methimazole embryopathy" (aplasia cutis, choanal atresia, esophageal atresia)
- Methimazole hypersensitivity
After the first trimester, therapy can be switched back to methimazole. - Goldman-Cecil, p. 2438
Therapeutic Uses
- Definitive long-term treatment of Graves disease - to induce remission (12-18 months; remission if TRAb levels normalize)
- Pre-surgical preparation - render patient euthyroid before thyroidectomy
- Adjunct to radioactive iodine - hasten recovery while awaiting radiation effect
- Patients who refuse surgery or RAI - Goodman & Gilman's, p. 971
Response to Treatment
Thyrotoxicosis usually improves within 3-6 weeks. Rate depends on:
- Dose given
- Size of goiter
- Pretreatment T3 levels
- Quantity of stored hormone
- Rate of hormone turnover
TSH may remain suppressed for weeks even after T4/T3 normalize - do not use TSH alone to follow acute regression. Follow free T4 and total/free T3 every 2-4 months initially. - Goldman-Cecil, p. 2439
In Graves disease: if TRAb levels normalize after 12-18 months, remission is likely and drugs can be stopped. If TRAb remains elevated, consider RAI or surgery. - Goldman-Cecil, p. 2439
3. Adverse Effects of Thioamides
Minor (1-5% incidence)
- Rash / urticaria - most common; treat with antihistamine or switch to the other drug
- Arthralgia, fever, GI intolerance, headache, nausea
Major / Serious
| Adverse Effect | Details |
|---|---|
| Agranulocytosis | 0.1-0.5% incidence (1 in 1000); usually in first weeks-months; idiosyncratic but more common with older patients and higher doses; can be fatal if unrecognized |
| Fulminant hepatic necrosis | Rare but devastating; primarily PTU; ~1 in 10,000 adults, 1 in 2,000 children; main reason PTU is no longer the DOC; can require liver transplant |
| Methimazole hepatitis | Methimazole more commonly causes cholestasis or mild hepatitis rather than necrosis |
| Aplastic anemia | Very rare |
| Drug-induced lupus | Rare |
| Teratogenicity | Methimazole: embryopathy (aplasia cutis, choanal/esophageal atresia); PTU safer in 1st trimester |
Warning for agranulocytosis: Routine neutrophil monitoring is not recommended because of the rapid, idiosyncratic onset. Instead, patients must be instructed to:
- Stop the drug immediately if they develop fever, sore throat, or signs of infection
- Seek medical attention for CBC
- If confirmed, neither thioamide should ever be re-administered
- Management: hospitalization, broad-spectrum antibiotics, G-CSF - Goldman-Cecil, p. 2438
4. Iodine and Iodide Preparations
Mechanism of Action
High-dose iodine works via the Wolff-Chaikoff effect:
- Large doses of iodide transiently inhibit organification of iodide (inhibit TPO)
- Also inhibit thyroid hormone release from the gland
- Additionally reduces thyroid vascularity and gland size (useful preoperatively)
Escape phenomenon: After 10-14 days of continued iodide, the thyroid escapes inhibition, so iodide must not be used as sole long-term treatment.
Preparations
- Lugol's solution (5% iodine + 10% potassium iodide) - 5-10 drops 3x/day
- SSKI (saturated solution of potassium iodide) - 1-5 drops 3x/day
Uses
- Preoperative preparation for thyroidectomy (with antithyroid drugs) - reduces vascularity and bleeding
- Adjunct in thyroid storm (given after PTU/methimazole to avoid feeding stored iodine to synthesis)
- Short-term treatment in intolerance to thioamides
5. Ionic Inhibitors (Competitive Anion Inhibitors)
Mechanism: Inhibit the sodium-iodide symporter (NIS) - block active iodide transport into thyroid follicular cells. They compete with iodide for uptake.
- Perchlorate (ClO₄⁻): Used occasionally for Graves disease or to prevent thyroid uptake of iodine in amiodarone-induced thyrotoxicosis; rare risk of aplastic anemia limits use
- Thiocyanate (SCN⁻): Dietary goitrogens in certain foods (e.g., cabbage)
- Pertechnetate (TcO₄⁻): Used in thyroid scanning, not therapy
6. Radioactive Iodine (¹³¹I)
- Concentrated by the thyroid, emits beta radiation → destroys follicular cells
- Primary definitive treatment for Graves disease in adults in the USA
- Leads to hypothyroidism in most patients over time → lifelong levothyroxine required
- Not suitable in pregnancy (contraindicated), active ophthalmopathy (may worsen), or suspected thyroid cancer
7. Adjunct Agents
| Drug | Mechanism | Use |
|---|---|---|
| Propranolol (beta-blocker) | Blocks sympathetic effects (tachycardia, tremor, anxiety); inhibits peripheral T4→T3 conversion at high doses | Symptomatic relief in all forms of hyperthyroidism; thyroid storm |
| Lithium | Blocks thyroid hormone release (similar to iodide) | Short-term control in patients intolerant to thioamides and iodine |
| Cholestyramine | Enhances fecal excretion of T4 via enterohepatic circulation | Adjunct in severe/refractory hyperthyroidism |
| Dexamethasone | Inhibits T4→T3 conversion; inhibits thyroid hormone secretion | Thyroid storm |
8. Special Situations
Thyroid Storm
Drug regimen (in order of administration to prevent iodine feeding synthesis):
- PTU (large doses, 500-1000 mg loading then 250 mg q4h) - blocks synthesis AND T4→T3 conversion
- Iodide (1 hour after PTU) - blocks hormone release
- Propranolol - controls adrenergic symptoms
- Dexamethasone - inhibits conversion and secretion
Pregnancy
- 1st trimester: PTU (less teratogenic)
- 2nd-3rd trimester: Switch to methimazole (less hepatotoxic)
- Use lowest effective doses; monitor fetal thyroid function
- Target: maintain free T4 at or slightly above upper limit of normal
Graves Disease Remission
After 12-18 months of thioamide therapy: check TRAb (TSH receptor antibody). Remission rate approximately 30-50%. Predictors of remission: small goiter, mild disease, declining TRAb. - Goldman-Cecil, p. 2439
9. Summary Comparison: PTU vs. Methimazole
| Feature | PTU | Methimazole |
|---|---|---|
| Mechanism | Blocks TPO + T4→T3 conversion | Blocks TPO only |
| t½ | 75 min | 4-6 hours |
| Dosing | 2-3 times/day | Once daily |
| Protein binding | 75% (less crosses placenta) | Nil |
| DOC for Graves | No | Yes |
| DOC in thyroid storm | Yes | No |
| DOC in 1st trimester | Yes | No |
| Hepatotoxicity | Fulminant necrosis (rare but fatal) | Cholestasis/mild hepatitis |
| Dose equivalence | 400 mg = | 30 mg |
Recent Evidence (PubMed, 2024-2026)
- A 2025 meta-analysis (PMID 40745151) examined agranulocytosis risk and found a dose-dependent risk relationship with antithyroid drugs.
- A 2025 network meta-analysis (PMID 40891035) compared mortality across antithyroid drugs, RAI, and surgery - providing updated comparative safety data.
- A 2025 meta-analysis of RCTs (PMID 40745639) compared thyroidectomy vs. antithyroid drugs in Graves disease.
No evidence found that contradicts the established pharmacological principles in the textbooks above.
Sources: Katzung's Basic & Clinical Pharmacology 16th Ed., Goodman & Gilman's Pharmacological Basis of Therapeutics, Goldman-Cecil Medicine.
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