Anti Hyperthyroidism drugs
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Anti-Hyperthyroidism Drugs
Overview
Hyperthyroidism (thyrotoxicosis) is treated by three main strategies: pharmacological inhibition of thyroid hormone synthesis/release, radioactive iodine ablation, and surgery. Drugs used span several classes with distinct mechanisms.
1. Thionamides (Thioureylenes) - The Primary Pharmacological Class
These are the mainstay oral antithyroid drugs.
Agents
| Drug | Notes |
|---|---|
| Methimazole (MMI) | Preferred agent in most situations |
| Propylthiouracil (PTU) | Reserved for specific indications |
| Carbimazole | Pro-drug of methimazole; used in Europe/UK |
Mechanism of Action
Thionamides inhibit thyroid hormone synthesis by two mechanisms:
- Inhibition of thyroid peroxidase (TPO) - block organification of iodide (incorporation of iodine into tyrosyl residues of thyroglobulin) and block coupling of iodotyrosines (MIT + DIT) to form T3 and T4
- Immunosuppressive effect - reduce levels of thyroid-stimulating immunoglobulins in Graves' disease
PTU has an additional mechanism not shared by methimazole: it inhibits peripheral 5'-deiodinase (D1), blocking conversion of T4 to the more active T3 in extrathyroidal tissues. This makes PTU the preferred drug in thyroid storm where rapid reduction of active hormone levels is needed.
Goodman & Gilman's The Pharmacological Basis of Therapeutics, p. 2566
Pharmacokinetics Comparison
| Parameter | PTU | Methimazole |
|---|---|---|
| Plasma protein binding | ~75% | Nil |
| Plasma t½ | ~75 min | ~4-6 hours |
| Volume of distribution | ~0.4 L/kg | ~0.7 L/kg |
| Dosing frequency | 3-4 times/day | Once or twice daily |
| Transplacental passage | Low | Low (but higher than PTU) |
| Levels in breast milk | Low | Low |
| Thyroid concentration | Yes | Yes |
Goodman & Gilman's, Table 47-5
Doses
- Methimazole: 15-40 mg/day as starting dose (single daily dose)
- PTU: 100 mg every 8 hours; if >300 mg/day needed, dose every 4-6 hours
- Response is typically seen in 3-6 weeks; euthyroidism achieved within ~12 weeks
- Once euthyroid, dose is reduced but continued (not stopped, to avoid Graves exacerbation)
Therapeutic Uses
- Definitive treatment of Graves' disease awaiting spontaneous remission
- Long-term therapy in patients who decline radioiodine or surgery
- Pre-operative preparation (render patient euthyroid before thyroidectomy)
- Adjunct to radioiodine (hasten recovery while radiation takes effect)
Drug of Choice: Methimazole vs. PTU
| Situation | Preferred Drug |
|---|---|
| Graves' disease (general) | Methimazole |
| Thyroid storm | PTU (also inhibits T4→T3 conversion) |
| 1st trimester pregnancy | PTU (methimazole associated with embryopathy - aplasia cutis, choanal atresia) |
| 2nd/3rd trimester pregnancy | Switch back to Methimazole (PTU risk of hepatotoxicity) |
| Breastfeeding | Both are acceptable; PTU traditionally preferred (lower milk levels), though methimazole is also used |
Katzung's Basic and Clinical Pharmacology, 16th Edition
Adverse Effects
Common:
- Rash, urticaria, pruritus (~5%)
- Arthralgia, fever
- Mild transient leukopenia
Serious/Rare:
- Agranulocytosis (~0.2-0.5%) - most feared complication; onset usually within first 3 months; patients must be warned to report sore throat/fever immediately
- Hepatotoxicity: PTU can cause severe fulminant hepatic necrosis (rare but fatal) - this is a key reason methimazole is now preferred. Methimazole causes cholestatic jaundice (milder)
- Vasculitis (ANCA-positive) - more with PTU
- Aplastic anemia (rare)
- Hypoprothrombinemia, bleeding
- Drug-induced lupus
2. Ionic Inhibitors (Competitive Inhibitors of Iodide Uptake)
These drugs competitively inhibit the sodium-iodide symporter (NIS), blocking iodine uptake by the thyroid.
Agents
- Perchlorate (ClO₄⁻) - most potent; risk of aplastic anemia limits use
- Thiocyanate (SCN⁻)
- Pertechnetate
These are rarely used clinically today. Perchlorate occasionally used to treat amiodarone-induced hyperthyroidism.
3. Iodine and Iodide Compounds
Mechanism: Wolff-Chaikoff Effect
High doses of iodide paradoxically inhibit thyroid hormone synthesis and release (acute inhibitory effect). At very high iodine concentrations, organification is blocked temporarily.
Agents
- Lugol's solution (5% iodine + 10% KI)
- Saturated solution of potassium iodide (SSKI)
- Potassium iodide
Uses
- Pre-operative preparation - given 10-14 days before thyroid surgery (reduces gland vascularity and firmness, making surgery safer)
- Thyroid storm - given AFTER thionamides (PTU must be given first, at least 1 hour before iodine, to prevent iodine from being used to synthesize more hormone)
- Radiation emergency - block thyroid uptake of radioactive iodine
- Acute management of severe thyrotoxicosis
Key Note: "Escape" Phenomenon
The Wolff-Chaikoff effect is transient; the thyroid "escapes" after 10-14 days. Thus, iodide cannot be used long-term as the sole antithyroid agent.
4. Radioactive Iodine (¹³¹I)
While not a "drug" in the classic sense, ¹³¹I is a definitive medical treatment.
- Mechanism: Taken up by thyroid follicular cells, emits beta radiation causing gradual destruction of thyroid tissue
- Onset: Effects seen over weeks to months; definitive effect in 2-3 months
- Contraindications: Pregnancy, breastfeeding, active Graves' ophthalmopathy (can worsen)
- Complication: May cause transient exacerbation of thyrotoxicosis (radiation thyroiditis, within 1-2 weeks); can rarely precipitate thyroid storm - pre-treat with thionamides for high-risk patients
- Most patients become hypothyroid eventually and require lifelong levothyroxine
5. Beta-Adrenergic Blockers (Adjunctive Therapy)
Beta-blockers do NOT reduce thyroid hormone synthesis but are used to control adrenergic symptoms of hyperthyroidism.
Mechanism
- Block peripheral effects of excess thyroid hormone (tachycardia, tremor, anxiety, sweating, heat intolerance)
- Propranolol (non-selective) also inhibits peripheral T4→T3 conversion at high doses
Agents and Uses
| Drug | Notes |
|---|---|
| Propranolol | Non-selective; inhibits T4→T3 conversion; most commonly used |
| Atenolol | Cardioselective; once daily |
| Metoprolol | Cardioselective |
- Used as bridge therapy while thionamides take effect
- Essential in thyroid storm management
- Dose: Propranolol 20-80 mg every 4-6 hours in thyroid storm
6. Thyroid Storm: Drug Protocol
Thyroid storm requires urgent, sequential drug therapy (order matters):
- PTU 200-400 mg every 4-6 hours (blocks synthesis + T4→T3 conversion)
- Lugol's iodine or SSKI - given 1 hour AFTER PTU (to prevent iodine fueling new synthesis)
- Propranolol 60-80 mg every 4-6 hours (control adrenergic symptoms)
- Hydrocortisone 100 mg every 8 hours (blocks T4→T3 conversion, treats relative adrenal insufficiency)
- Cholestyramine - binds thyroid hormones in gut, reduces enterohepatic circulation
Tintinalli's Emergency Medicine; Goldman-Cecil Medicine; Goodman & Gilman's
Summary Table
| Drug Class | Example Agents | Mechanism | Key Use |
|---|---|---|---|
| Thionamides | Methimazole, PTU, Carbimazole | Inhibit TPO; block T4 synthesis | First-line therapy |
| Ionic inhibitors | Perchlorate | Block NIS (iodide uptake) | Amiodarone-induced hyperthyroidism |
| Iodides | Lugol's, SSKI | Wolff-Chaikoff effect; reduce vascularity | Pre-op prep, thyroid storm |
| Radioactive iodine | ¹³¹I | Radiation destruction of thyroid | Definitive therapy |
| Beta-blockers | Propranolol, Atenolol | Block adrenergic symptoms ± T4→T3 | Symptomatic control, thyroid storm |
| Corticosteroids | Hydrocortisone | Block T4→T3; anti-inflammatory | Thyroid storm, Graves' ophthalmopathy |
Recent Evidence Note: A 2025 meta-analysis (PMID: 40745151) examined the dose-risk relationship for agranulocytosis with antithyroid drugs, confirming the importance of careful dosing. A 2025 network meta-analysis (PMID: 40891035) on mortality risks comparing antithyroid drugs, radioactive iodine, and surgery found no significant mortality difference between the three definitive treatment modalities.
Sources: Goodman & Gilman's Pharmacological Basis of Therapeutics | Katzung's Basic and Clinical Pharmacology 16th Ed. | Goldman-Cecil Medicine | Tintinalli's Emergency Medicine
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