Thyroid Hormone Physiology and Pharmacokinetics
Axis, biosynthesis, deiodinases, receptors, and drug interactions
Hypothalamic-Pituitary-Thyroid Axis
Hypothalamus
Thyrotropin-releasing hormone released
→
Pituitary
Thyroid-stimulating hormone secreted
→
Thyroid
T4 and T3 synthesized and secreted
→
Feedback
T3 suppresses thyroid-stimulating hormone at pituitary
Biosynthesis Steps and Drug Targets
Step 1
Sodium-Iodide Symporter
  • Concentrates iodide 20–40× plasma
  • Basis for radioactive iodine uptake
  • Inhibited by perchlorate
Steps 2–3
Thyroid Peroxidase
  • Organification of iodide onto thyroglobulin
  • Coupling to form T4 and T3
  • Blocked by methimazole and propylthiouracil
Regulation
Wolff-Chaikoff Effect
  • Iodide excess transiently blocks organification
  • Exploited by Lugol's iodine and potassium iodide
  • Escape occurs in days via symporter downregulation
Deiodinase Isoforms
Type 1
D1 — Peripheral Tissues
  • Liver, kidney, skeletal muscle
  • T4 → T3 (peripheral conversion)
  • Inhibited by propylthiouracil, amiodarone
Type 2
D2 — Brain and Pituitary
  • Pituitary, brain, heart
  • Local T4 → T3 for thyroid-stimulating hormone feedback
  • Upregulated in hypothyroidism
Type 3
D3 — Placenta / Fetus
  • Inactivates T4 and T3 to reverse T3
  • Protects fetus from excess thyroid hormone
  • Upregulated in critical illness (sick euthyroid)
Key Drug Interactions
Absorption Reducers
Separate by ≥4 Hours
  • Calcium, iron, antacids
  • Cholestyramine, sucralfate
  • Proton pump inhibitors (raise gastric pH)
Metabolism Inducers
Require Dose Increase
  • Rifampin — hepatic enzyme induction
  • Phenytoin, carbamazepine, phenobarbital
  • Dose increase 20–50%; recheck thyroid-stimulating hormone
Amiodarone: Multiple Mechanisms

37% iodine by weight → massive iodine load • Inhibits type 1 deiodinase → raises reverse T3, lowers T3 • Can cause hypothyroidism (most common) or thyrotoxicosis (type 1: iodine-driven; type 2: destructive thyroiditis) • Check thyroid function before starting and every 6 months.