What is the recommended first‑line therapy for overt hyperthyroidism in adults?

First-Line Therapy for Overt Hyperthyroidism in Adults

Methimazole is the recommended first-line antithyroid drug for treating overt hyperthyroidism in adults, except during the first trimester of pregnancy when propylthiouracil is preferred. 1

Initial Treatment Selection

Methimazole should be initiated as the primary antithyroid medication due to its superior efficacy and safety profile compared to propylthiouracil 1. The American College of Physicians explicitly recommends methimazole as the preferred first-line agent 1.

Starting Dose Strategy

• For severe hyperthyroidism (free T4 ≥7 ng/dL): Start methimazole 30 mg daily as a single dose 2
• For mild to moderate hyperthyroidism (free T4 <7 ng/dL): Start methimazole 15 mg daily as a single dose 2
• Methimazole 30 mg/day normalizes free T4 more effectively than propylthiouracil 300 mg/day in severe cases (96.5% vs 78.3% at 12 weeks) 2

Why Methimazole Over Propylthiouracil

• Propylthiouracil is reserved only for specific situations: patients intolerant to methimazole and first trimester of pregnancy, due to its potential to cause severe liver problems 1
• Methimazole has a lower frequency of adverse effects, particularly mild hepatotoxicity, compared to propylthiouracil 2
• Methimazole can be administered as a single daily dose, improving adherence, whereas propylthiouracil requires multiple daily doses 3

Immediate Symptomatic Management

Beta-blockers should be initiated concurrently with methimazole to provide immediate symptomatic relief while awaiting thyroid hormone normalization 1, 4.

• Atenolol 25-50 mg daily or propranolol are the preferred agents for controlling tachycardia, tremor, and anxiety 1
• Target heart rate <90 bpm if blood pressure allows 1
• Beta-blockers are particularly important for patients with cardiac disease, as hyperthyroidism causes increased cardiac output and reduced systemic vascular resistance 1
• Dose reduction of beta-blockers is needed once euthyroid state is achieved 1

Monitoring During Initial Treatment

• Check free T4 or free T3 index every 2-4 weeks during initial treatment to guide dose adjustments 1
• The goal is to maintain free T4/T3 in the high-normal range using the lowest effective dose 1
• Do not use TSH to guide initial therapy, as TSH may remain suppressed for months even after achieving euthyroidism 1

Dose Adjustment Algorithm

• If free T4/T3 remains elevated: Continue current methimazole dose 1
• If free T4/T3 is in the high-normal range: Maintain current dose 1
• If free T4/T3 drops below normal: Reduce methimazole dose or discontinue temporarily 1

Critical Safety Monitoring

All patients on thioamides require vigilant monitoring for life-threatening adverse effects that typically occur within the first 3 months 1.

Agranulocytosis

• Presents with sore throat and fever 1
• Requires immediate CBC and drug discontinuation 1
• Occurs most commonly in the first 3 months of treatment 1

Hepatotoxicity

• Monitor for fever, nausea, vomiting, right upper quadrant pain, dark urine, and jaundice 1
• Immediate drug discontinuation if suspected 1
• Propylthiouracil carries higher hepatotoxicity risk than methimazole 1

Vasculitis

• Can be life-threatening 1
• Watch for skin changes, hematuria, or respiratory symptoms 1

Special Populations

Pregnancy

• First trimester: Switch to propylthiouracil due to methimazole's association with congenital anomalies 1, 3
• After first trimester: Switch back to methimazole 1
• Both drugs are compatible with breastfeeding 1
• Pregnancy must be avoided for 4 months following radioactive iodine administration 1, 5

Elderly and Cardiac Disease

• Beta-blockers are especially important for rate control in hyperthyroid patients with cardiac disease 1
• Atrial fibrillation occurs in 5-15% of hyperthyroid patients, more frequently in those over 60 years 1
• Anticoagulation should be guided by CHA₂DS₂-VASc risk factors, not solely by presence of hyperthyroidism 1

Definitive Treatment Considerations

While antithyroid drugs are first-line therapy, definitive treatment options include radioactive iodine (I-131) ablation and surgery 5, 4.

• Radioactive iodine is absolutely contraindicated in pregnancy and breastfeeding 1
• Radioactive iodine may worsen Graves' ophthalmopathy 1, 5
• Surgery (subtotal or near-total thyroidectomy) has limited but specific roles, particularly for large goiters causing compressive symptoms 5

Common Pitfalls to Avoid

• Never reduce methimazole based solely on suppressed TSH while free T4 remains elevated or high-normal, as this leads to inadequate treatment and recurrent hyperthyroidism 1
• Do not use antithyroid drugs for destructive thyroiditis, which is self-limited and requires only beta-blockers for symptomatic relief 1
• Avoid starting full replacement doses in elderly patients with cardiac disease, as this can unmask or worsen cardiac ischemia 1
• Never attempt cardioversion in thyrotoxic patients without first achieving euthyroid state, as antiarrhythmic drugs and cardioversion are generally unsuccessful while thyrotoxicosis persists 1

Treatment Duration

• Typical course is 12-18 months for Graves' disease with a view to inducing long-term remission 5
• Antithyroid drugs will not "cure" hyperthyroidism associated with toxic nodular goiter 5
• For toxic nodular goiter, radioiodine is the treatment of choice 5