What are the pharmacodynamics of levothyroxine, including its mechanisms of action?

Pharmacodynamics of Levothyroxine: Mechanism of Action

Levothyroxine exerts its physiologic actions primarily through control of DNA transcription and protein synthesis, with T3 (triiodothyronine) being the predominant active hormone that produces most physiological effects. 1

Mechanism of Action

• Levothyroxine (T4) is a synthetic form of thyroxine that diffuses into cell nuclei and binds to thyroid receptor proteins attached to DNA 1
• This hormone-nuclear receptor complex activates gene transcription and synthesis of messenger RNA and cytoplasmic proteins 1
• Although levothyroxine is administered as T4, approximately 80% of circulating T3 (the more biologically active form) is derived from T4 through deiodination in peripheral tissues 1
• T3 has approximately 4 times the biological potency of T4, making this conversion essential for full therapeutic effect 1

Pharmacokinetics Supporting Pharmacodynamic Effects

Absorption

• Oral levothyroxine absorption from the gastrointestinal tract ranges from 40% to 80%, with most absorption occurring in the jejunum and upper ileum 1
• Absorption is increased by fasting and decreased by certain foods (soybeans, dietary fiber) and malabsorption syndromes 1
• The relative bioavailability of levothyroxine tablets compared to oral solution is approximately 93% 1

Distribution

• Circulating thyroid hormones are >99% bound to plasma proteins, including:
  • Thyroxine-binding globulin (TBG)
  • Thyroxine-binding prealbumin (TBPA)
  • Albumin (TBA) 1
• Only the unbound (free) hormone is metabolically active 1
• The higher affinity of both TBG and TBPA for T4 explains the higher serum levels, slower metabolic clearance, and longer half-life of T4 (6-7 days) compared to T3 (≤2 days) 1

Metabolism

• T4 is primarily metabolized through sequential deiodination 1
• The liver is the major site of degradation for both T4 and T3, with additional T4 deiodination occurring in the kidney and other tissues 1
• Approximately 80% of the daily dose of T4 is deiodinated to yield equal amounts of T3 and reverse T3 (rT3) 1
• Thyroid hormones are also metabolized via conjugation with glucuronides and sulfates and excreted into the bile and gut where they undergo enterohepatic recirculation 1

Elimination

• Thyroid hormones are primarily eliminated by the kidneys 1
• Approximately 20% of T4 is eliminated in the stool 1
• Urinary excretion of T4 decreases with age 1

Physiological Effects

• Levothyroxine maintains normal T4 levels when a deficiency is present, exerting the same physiologic effects as endogenous T4 1
• These effects include regulation of:
  • Basal metabolic rate
  • Growth and development
  • Protein synthesis
  • Carbohydrate and lipid metabolism 2
• Levothyroxine may help mobilize hepatic fat and potentially mitigate non-alcoholic fatty liver disease (NAFLD), which is associated with hypothyroidism 3

Clinical Applications and Dosing Considerations

• For most patients with hypothyroidism, therapy can be initiated with a full replacement dosage (1.6 mcg/kg body weight) 4
• For patients <70 years without cardiac disease, the full replacement dose is approximately 1.6 mcg/kg/day 2
• For patients >70 years or with cardiac disease, a lower starting dose of 25-50 mcg/day with gradual titration is recommended to avoid cardiac complications 2
• Monitoring TSH levels every 6-8 weeks during dose titration and every 6-12 months once stable is essential to prevent both overtreatment and undertreatment 2, 5

Potential Adverse Effects Related to Pharmacodynamics

• Overtreatment with levothyroxine can lead to iatrogenic hyperthyroidism, increasing the risk for:
  • Atrial fibrillation and other cardiac arrhythmias, especially in elderly patients 1
  • Osteoporosis and fractures 5
  • Abnormal cardiac output and ventricular hypertrophy 5
• Approximately 25% of patients on levothyroxine are unintentionally maintained on doses high enough to suppress TSH completely 5

Timing of Administration and Absorption Considerations

• Levothyroxine taken at bedtime may significantly improve thyroid hormone levels compared to morning intake, as demonstrated in a randomized double-blind crossover trial 6
• Food and certain dietary supplements can significantly affect levothyroxine absorption, with coffee, soy products, fiber, calcium or iron supplements, and enteral nutrition all potentially decreasing absorption 7
• Vitamin C may enhance levothyroxine absorption, though this requires further investigation 7

Advancements in Treatment

• Novel formulations of levothyroxine are being developed to circumvent malabsorption issues and improve individualized dosing 8
• Digital therapeutics may play a future role in achieving more tailored levothyroxine therapy 8