Mechanism of action
Levothyroxine is a synthetic form of thyroxine (T4), the prohormone produced by the thyroid gland. After oral administration, levothyroxine is absorbed primarily in the jejunum and ileum. Approximately 80% is converted peripherally by type 1 and type 2 deiodinases to triiodothyronine (T3), the biologically active thyroid hormone.
T3 enters target cells and binds to thyroid hormone receptors (TRα and TRβ) in the nucleus. These receptors heterodimerize with retinoid X receptors and bind to thyroid response elements on DNA, modulating transcription of genes involved in metabolism, growth, and development. Thyroid hormones increase basal metabolic rate, enhance protein synthesis, promote lipolysis and gluconeogenesis, and are essential for normal CNS development in children.
Negative feedback regulation occurs at the hypothalamic and pituitary levels: circulating T3 and T4 suppress TRH and TSH secretion. In replacement therapy, exogenous levothyroxine restores euthyroid physiology and normalizes TSH levels in primary hypothyroidism.
- Levothyroxine has a 7-day half-life; steady state and TSH monitoring require 6-8 weeks after dose changes
- Correct adrenal insufficiency before starting levothyroxine to prevent adrenal crisis
- Pregnancy increases levothyroxine requirements by 25-50% due to increased TBG; check TSH each trimester
- Separate levothyroxine from calcium, iron, PPIs, and bile acid sequestrants by at least 4 hours
- In central hypothyroidism, dose to free T4 (not TSH) because TSH is unreliable
- Chronic TSH suppression <0.1 mIU/L increases risk of atrial fibrillation and osteoporosis
- Start low doses (12.5-25 mcg) in elderly and patients with coronary artery disease to avoid cardiac complications
- Myxedema coma is treated with IV levothyroxine plus hydrocortisone and aggressive supportive care
Indications
Primary hypothyroidism: Most common indication. Includes Hashimoto thyroiditis, post-thyroidectomy, radioiodine ablation, and congenital hypothyroidism.
Central hypothyroidism: Secondary (pituitary TSH deficiency) or tertiary (hypothalamic TRH deficiency) hypothyroidism.
TSH suppression therapy: Thyroid nodules, differentiated thyroid cancer (papillary, follicular) post-operatively to reduce recurrence risk.
Myxedema coma: Life-threatening decompensated hypothyroidism; IV levothyroxine is used alongside supportive care and glucocorticoids.
Off-label uses: Subclinical hypothyroidism (controversial; typically treated if TSH >10 mIU/L or symptomatic), goiter reduction.
Levothyroxine is not indicated for weight loss in euthyroid patients or as empiric therapy without biochemical confirmation of hypothyroidism.
Pharmacokinetics
Absorption: Oral bioavailability 70-80%, best absorbed on empty stomach. Food, especially fiber, calcium, and iron, reduces absorption. Peak serum levels occur 2-4 hours post-dose.
Distribution: Highly protein-bound (>99%) to thyroxine-binding globulin (TBG), transthyretin, and albumin. Only free T4 is biologically active.
Metabolism: Deiodination in liver, kidney, and other tissues produces T3 (active) and reverse T3 (inactive). Hepatic conjugation to glucuronide and sulfate metabolites occurs; some undergo enterohepatic recirculation.
Elimination: Half-life is approximately 7 days in euthyroid patients, longer in hypothyroidism, shorter in hyperthyroidism. This long half-life permits once-daily dosing and explains the 4-6 week delay to steady state after dose initiation or adjustment.
Special populations: Pregnancy increases TBG levels and often requires dose increases. Renal impairment does not significantly alter levothyroxine clearance.
Adverse effects
Most adverse effects result from excessive dosing, producing iatrogenic thyrotoxicosis.
Cardiac
- Tachycardia, palpitations, arrhythmias (especially atrial fibrillation in elderly)
- Angina pectoris, myocardial infarction (in patients with coronary artery disease)
- Increased cardiac workload and oxygen demand
Metabolic and systemic
- Weight loss, increased appetite, heat intolerance, diaphoresis
- Tremor, nervousness, anxiety, insomnia
- Osteoporosis and accelerated bone loss with chronic over-replacement, particularly in postmenopausal women
Other
- Hair loss (usually transient, may occur in first months of therapy even with appropriate dosing)
- Menstrual irregularities
- Pseudotumor cerebri in children (rare)
Hypersensitivity reactions are rare but can occur to inactive ingredients or dyes. True allergy to levothyroxine itself is extremely uncommon.
Adverse effects are minimized by initiating therapy at low doses (especially in elderly and those with cardiac disease) and titrating based on TSH levels every 6-8 weeks.
Contraindications and warnings
Absolute contraindications:
- Uncorrected adrenal insufficiency: Thyroid hormone increases cortisol metabolism; initiating levothyroxine without glucocorticoid replacement can precipitate adrenal crisis
- Acute myocardial infarction
- Untreated thyrotoxicosis
Cardiovascular disease: Use caution and start at low doses in patients with coronary artery disease, angina, arrhythmias, or heart failure. Levothyroxine increases myocardial oxygen demand and may precipitate ischemia or arrhythmias.
Osteoporosis: Long-term suppressive therapy (TSH <0.1 mIU/L) accelerates bone loss. Monitor bone density in at-risk patients.
Diabetes mellitus: Thyroid hormones increase glucose metabolism; may require adjustment of antidiabetic medications.
Pregnancy: Hypothyroidism in pregnancy is associated with adverse fetal outcomes. Levothyroxine requirements typically increase by 25-50% during pregnancy due to increased TBG. TSH should be monitored each trimester. The drug is pregnancy category A (safe).
Elderly: Increased sensitivity to thyroid hormones. Start at lower doses (12.5-25 mcg daily) to avoid cardiac complications.
Switching formulations: Different levothyroxine products may not be bioequivalent. Advise patients to use the same brand consistently; recheck TSH 6-8 weeks after any formulation change.
Drug interactions
Decreased levothyroxine absorption
- Calcium, iron, magnesium supplements: Separate administration by at least 4 hours
- Proton pump inhibitors, H2 blockers: Reduced gastric acidity impairs absorption
- Bile acid sequestrants (cholestyramine, colesevelam): Bind levothyroxine; separate by 4-6 hours
- Sucralfate, aluminum hydroxide antacids: Separate by at least 4 hours
- Soy, fiber, coffee: May reduce absorption
Increased levothyroxine metabolism
- Rifampin, phenytoin, carbamazepine, phenobarbital: Hepatic enzyme inducers increase T4 clearance
- Sertraline, other SSRIs: May increase levothyroxine requirements in hypothyroid patients
Altered protein binding
- Estrogens, oral contraceptives, pregnancy: Increase TBG, raising total T4 but not necessarily free T4; may require dose increase
- Androgens, glucocorticoids: Decrease TBG
Warfarin
Thyroid hormones enhance warfarin's anticoagulant effect by increasing catabolism of vitamin K-dependent clotting factors. Monitor INR closely when initiating or adjusting levothyroxine.
Sympathomimetics
Thyroid hormones potentiate effects of catecholamines; combined use increases risk of coronary insufficiency and arrhythmias.
Amiodarone
Contains iodine and inhibits peripheral conversion of T4 to T3. Can cause both hypothyroidism and thyrotoxicosis. Complex interaction requiring careful monitoring.
Clinical pearls
Take on empty stomach: Administer 30-60 minutes before breakfast or at bedtime (3+ hours after last meal) for consistent absorption. Consistency is more important than timing.
Steady state and monitoring: Due to 7-day half-life, TSH should be checked 6-8 weeks after initiation or dose change. Target TSH 0.5-2.5 mIU/L in most patients; lower targets (0.1-0.5) for thyroid cancer suppression.
Pregnancy: Check TSH as soon as pregnancy is confirmed. Most women need 25-50% dose increase. Target first-trimester TSH <2.5 mIU/L.
Subclinical hypothyroidism: TSH 4.5-10 mIU/L with normal free T4. Treatment is individualized; consider if symptomatic, positive TPO antibodies, goiter, or planning pregnancy.
Central hypothyroidism: Do not use TSH to guide therapy (TSH is inappropriately normal or low). Dose to free T4 level in upper half of reference range.
Myxedema coma: Medical emergency. Give IV levothyroxine loading dose plus hydrocortisone (to cover possible adrenal insufficiency), supportive care, and treat precipitating factors.
Brand vs. generic: The FDA considers levothyroxine products bioequivalent if they are within 95-105% of labeled potency, but this 10% range can be clinically significant in sensitive patients. Many endocrinologists recommend brand consistency.
Over-treatment consequences: Chronic TSH suppression (<0.1 mIU/L) increases risk of atrial fibrillation (especially age >60) and osteoporotic fractures.
Do not use for weight loss: Levothyroxine in euthyroid patients causes muscle loss, not fat loss, and risks cardiac complications.
Practice questions
1. A 68-year-old woman with newly diagnosed hypothyroidism (TSH 18 mIU/L) and a history of coronary artery disease is started on levothyroxine. Three weeks later, she develops worsening chest pain with exertion. ECG shows ST-segment depression in leads II, III, and aVF. Which of the following is the most appropriate next step?
2. A 32-year-old woman with Hashimoto thyroiditis has been stable on levothyroxine 100 mcg daily for 2 years. She now presents at 8 weeks gestation. Her TSH is 4.8 mIU/L (reference 0.5-5.0). What is the most appropriate management?
3. A 45-year-old man with hypothyroidism on levothyroxine 125 mcg daily for 6 months reports persistent fatigue. Labs show TSH 0.8 mIU/L (normal 0.5-5.0), free T4 1.2 ng/dL (normal 0.8-1.8). He mentions taking a calcium supplement with breakfast when he takes his levothyroxine. What is the most likely explanation for his symptoms?
Frequently asked questions
How does levothyroxine work?
Levothyroxine is synthetic T4 that is converted peripherally to active T3, which binds nuclear thyroid receptors and regulates gene transcription. This increases basal metabolic rate, promotes protein synthesis, and restores normal metabolism in hypothyroid patients. Its long half-life of 7 days allows once-daily dosing but requires 6-8 weeks to reach steady state.
What are the side effects of levothyroxine?
Most side effects result from excessive dosing causing iatrogenic hyperthyroidism: tachycardia, palpitations, atrial fibrillation, angina, weight loss, tremor, anxiety, insomnia, and heat intolerance. Chronic over-replacement increases risk of osteoporosis and fractures. Proper dosing guided by TSH monitoring minimizes adverse effects. Hair loss may occur transiently even with appropriate dosing.
When should I take levothyroxine?
Take levothyroxine on an empty stomach, ideally 30-60 minutes before breakfast or at bedtime at least 3 hours after the last meal. This maximizes absorption. Separate from calcium, iron, multivitamins, antacids, and coffee by at least 4 hours. Consistency in timing and formulation is more important than the specific time of day chosen.
Levothyroxine vs liothyronine — what is the difference?
Levothyroxine is synthetic T4 with a 7-day half-life, allowing once-daily dosing and stable hormone levels. Liothyronine is synthetic T3 with a 24-hour half-life, causing more fluctuation. Levothyroxine is first-line because it mimics normal physiology (most T3 comes from peripheral T4 conversion) and provides steady hormone levels. Liothyronine is reserved for myxedema coma or rare cases of conversion defects.
Why does levothyroxine dose increase in pregnancy?
Pregnancy increases thyroxine-binding globulin (TBG) levels due to estrogen, which binds more thyroid hormone and reduces free T4 available to tissues. Additionally, placental deiodinases metabolize T4, and fetal needs increase thyroid hormone demand. Most pregnant women require a 25-50% dose increase. TSH should be checked each trimester with a target below 2.5 mIU/L in the first trimester.
Conditions it is used for
Related drugs
Sources and further reading
DailyMed (FDA labels)StatPearls (NCBI Bookshelf)MedlinePlusWHO ATC/DDD index: H03AA01
Educational content for medical students, prepared by the WhiteCoat Pro editorial team with AI assistance; every page is reviewed by a second AI model for factual errors. It is not medical advice and does not replace the product label, local guidelines or a clinician.