Pharmacology, Indications, Adverse Reactions, and Drug Interactions of Levothyroxine and Antithyroid Drugs
Levothyroxine (Synthetic Thyroxine)
Pharmacology
Levothyroxine (L-T4) is a synthetic form of thyroxine with a long half-life that allows once-daily administration and maintains stable serum levels even if occasional doses are missed 1. The drug undergoes extrathyroidal conversion to triiodothyronine (T3), which normally provides 80% of daily T3 production, offering protective value during illness 1. After oral administration, levothyroxine requires approximately 6 weeks to reach a new equilibrium following dose adjustments 1.
The mean replacement dose is 1.6 mcg/kg per day, resulting in serum free T4 concentrations in the upper half of the normal reference range 1. This slightly elevated free T4 is necessary because the thyroid gland normally contributes 20% of daily T3 production directly, which must now be generated from T4 conversion 1. Daily maintenance doses vary widely between 75 and 250 mcg depending on individual factors 1.
Indications
Levothyroxine is the drug of choice for treating hypothyroidism, including overt hypothyroidism (elevated TSH with low free T4) and subclinical hypothyroidism with TSH >10 mIU/L 2. Treatment is indicated regardless of symptoms when TSH exceeds 10 mIU/L, as this carries approximately 5% annual risk of progression to overt hypothyroidism 2.
For thyroid cancer patients, levothyroxine serves dual purposes: hormone replacement and TSH suppression therapy 3. TSH suppressive treatment benefits high-risk thyroid cancer patients by decreasing progression of metastatic disease and reducing cancer-related mortality 3. Target TSH levels vary by risk stratification: 0.5-2 mIU/L for low-risk patients with excellent response, 0.1-0.5 mIU/L for intermediate-to-high risk patients, and <0.1 mIU/L for structural incomplete response 2.
Dosing Considerations
**For patients <70 years without cardiac disease, start with full replacement dose of approximately 1.6 mcg/kg/day** 2. However, for patients >70 years or with cardiac disease/multiple comorbidities, start with 25-50 mcg/day and titrate gradually by 12.5-25 mcg every 6-8 weeks 2. This conservative approach prevents unmasking cardiac ischemia or precipitating arrhythmias 2.
Monitor TSH every 6-8 weeks during dose titration until target range (0.5-4.5 mIU/L) is achieved 2. Once stable, repeat testing every 6-12 months or if symptoms change 2. Free T4 can help interpret ongoing abnormal TSH levels during therapy, as TSH may take longer to normalize 2.
Adverse Reactions
The primary adverse effects of levothyroxine result from overtreatment rather than the medication itself 2. Approximately 25% of patients on levothyroxine are unintentionally maintained on doses sufficient to fully suppress TSH, increasing serious complication risks 2.
Cardiovascular complications: TSH suppression <0.1 mIU/L increases atrial fibrillation risk 3-5 fold, especially in patients ≥60 years 2. Prolonged suppression is associated with increased cardiovascular mortality, abnormal cardiac output, and ventricular hypertrophy 2.
Bone health: TSH suppression causes significant bone mineral density loss in postmenopausal women, increasing fracture risk 2. Women >65 years with TSH ≤0.1 mIU/L have markedly increased risk of hip and spine fractures 2.
Metabolic effects: Overtreatment creates a hypermetabolic state that can paradoxically manifest as fatigue in elderly patients 2.
Drug Interactions
Several medications interfere with levothyroxine absorption or metabolism, necessitating dose adjustments 1. Iron supplements, calcium supplements, and antacids must be taken at least 4 hours apart from levothyroxine 2.
Pregnancy increases levothyroxine requirements by 25-50% above pre-pregnancy doses, requiring proactive dose adjustments for proper fetal neurologic development 2. For women with pre-existing hypothyroidism, increase the dose by 25-50% immediately upon pregnancy confirmation 2.
Tyrosine kinase inhibitors (TKIs) commonly increase serum TSH, probably due to interference in thyroid hormone metabolism, often requiring adjustment of levothyroxine therapy 3.
Critical Safety Considerations
Before initiating levothyroxine in patients with suspected central hypothyroidism or concurrent adrenal insufficiency, always start corticosteroids at least 1 week prior to thyroid hormone replacement 2. Starting thyroid hormone before adequate glucocorticoid coverage can precipitate life-threatening adrenal crisis 2. Measure morning cortisol and ACTH to exclude adrenal insufficiency before treatment 2.
Clinical Vignette: Levothyroxine
A 45-year-old woman presents with fatigue, weight gain of 15 pounds over 6 months, cold intolerance, and constipation. Laboratory testing reveals TSH 18.4 mIU/L (normal 0.45-4.5) and free T4 0.6 ng/dL (normal 0.9-1.9). She has no cardiac history.
Management: This represents overt primary hypothyroidism requiring immediate levothyroxine initiation 2. Before starting treatment, obtain morning cortisol and ACTH to exclude adrenal insufficiency 2. Given her age <70 years and absence of cardiac disease, start levothyroxine at full replacement dose of approximately 1.6 mcg/kg/day (roughly 100-125 mcg daily for a 70 kg woman) 2. Recheck TSH and free T4 in 6-8 weeks, adjusting dose by 12.5-25 mcg increments until TSH reaches 0.5-4.5 mIU/L 2. Once stable, monitor TSH annually 2.
Antithyroid Drugs (Methimazole and Propylthiouracil)
Pharmacology
Methimazole (MMI) and propylthiouracil (PTU) inhibit thyroid hormone synthesis at different steps 4. Their primary mechanism involves blocking thyroid peroxidase, preventing iodination of tyrosine residues and coupling of iodotyrosines to form T3 and T4 4. PTU additionally inhibits peripheral conversion of T4 to T3, providing an extra mechanism of action 4.
Methimazole has a longer half-life allowing once-daily dosing, while PTU requires administration every 6 hours due to its shorter half-life 4. Both drugs cross the placenta and are present in breast milk, though at levels generally considered safe for breastfeeding 4.
Indications
Antithyroid drugs serve as primary treatment for Graves' disease hyperthyroidism (long-term therapy: 1-2 years) or as preparative therapy before radioiodine treatment or surgery (short-term therapy: weeks to months) 4.
The starting dose of methimazole is typically 10-30 mg as a single daily dose, while PTU starts at 100-300 mg every 6 hours 4. Methimazole is the drug of choice for most patients because major side effects are less common, it can be used as single daily dose, it's less expensive and more available 4.
Special Population: Pregnancy
For hyperthyroidism in pregnancy, PTU is the drug of choice in the first trimester 4, 5. Methimazole use in the first trimester is associated with aplasia cutis and choanal/esophageal atresia 4. The odds of birth defects during the first trimester are higher with MMI/CMZ than with PTU (OR 1.29,95% CI 1.09-1.53) 5.
However, switch to methimazole after the first trimester because PTU carries greater risk of severe hepatotoxicity 5. Both drugs have similar placental transfer kinetics and therapeutic efficacy 4. Neither drug contraindicates breastfeeding 4.
Adverse Reactions
Hepatotoxicity
PTU causes significantly more liver injury than methimazole 5. The odds of liver function injury are 2.4 times higher with PTU than MMI/CMZ (OR 2.40,95% CI 1.16-4.96) 5. The odds of elevated transaminases are nearly 4 times higher with PTU (OR 3.96,95% CI 2.49-6.28) 5.
Hematologic Effects
Agranulocytosis is a rare but serious complication of both drugs, with no significant difference in incidence between PTU and methimazole 5. Patients should be instructed to immediately report fever, sore throat, or other signs of infection 4.
Dermatologic Reactions
Rash and urticaria occur with both drugs at similar rates 5. No significant between-group differences were found in odds of rash or urticaria 5.
Teratogenic Effects
Methimazole carries higher risk of congenital anomalies in the first trimester, while PTU has no established association with birth defects 4, 5. This risk profile reverses after the first trimester when PTU's hepatotoxicity risk becomes more concerning 5.
Drug Interactions
Antithyroid drugs do not have major documented drug-drug interactions, but their effects on thyroid hormone levels can influence the metabolism of other medications 4. As thyroid status normalizes, adjustments may be needed for drugs with narrow therapeutic indices 4.
Monitoring Requirements
Regular monitoring of thyroid function tests (TSH, free T3, free T4) is essential during antithyroid drug therapy 6. For patients with autonomously functioning thyroid nodules treated with thermal ablation, measure TSH, free T3, and free T4 at 3,6, and 12 months during the first year, then every 6 months once TSH control is achieved 6.
Clinical Vignette: Antithyroid Drugs
A 28-year-old woman at 8 weeks gestation presents with palpitations, heat intolerance, and weight loss. She has a diffuse goiter. TSH is <0.01 mIU/L, free T4 is 3.2 ng/dL (normal 0.9-1.9), and free T3 is elevated. TSH receptor antibodies are positive, confirming Graves' disease.
Management: This pregnant patient with Graves' disease requires immediate antithyroid drug therapy 4. Start propylthiouracil 100-150 mg every 8 hours because she is in the first trimester 4, 5. PTU is preferred over methimazole in early pregnancy due to lower risk of congenital anomalies 4, 5. Monitor thyroid function every 2-4 weeks, adjusting PTU dose to maintain free T4 in the upper normal range 4. Plan to switch to methimazole after the first trimester (around 16 weeks) to reduce hepatotoxicity risk 5. Educate the patient to immediately report fever, sore throat, or jaundice 4. Both drugs are compatible with breastfeeding 4.
Combination Therapy Considerations
A small subset of hypothyroid patients on levothyroxine monotherapy continue to complain of tiredness, lack of energy, cognitive disorders, and mood disturbances despite biochemical euthyroidism 1. Animal studies indicate that only the combination of T4 and T3 replacement ensures euthyroidism in all tissues 1.
One study showed that substituting 50 mcg of levothyroxine with 12.5 mcg T3 significantly improved psychometric scores in hypothyroid patients 1. However, another double-blind randomized controlled trial found that adding T3 to T4 did not improve depressive symptoms better than T4 alone 7. Current evidence does not support routine use of combined T3 and T4 therapy, though it may benefit select patients 7.
A novel approach using triiodothyronine sulfate (T3S) combined with L-T4 showed promise in maintaining normal T3 levels with restoration of physiological FT4/FT3 ratio and no adverse events 8. Twelve patients judged the L-T4+T3S treatment better than L-T4 alone, while no patient preferred L-T4 over the combined treatment 8.