Thyroid Agents

Thyroid function runs on a feedback loop, the hypothalamic–pituitary–thyroid (HPT) axis. The hypothalamus releases TRH, which tells the pituitary to release TSH (thyroid-stimulating hormone), which tells the thyroid to make T4 and T3. T4 is the main circulating hormone; tissues convert about half of it into the more active T3. When thyroid hormone is plentiful, it feeds back to shut off TRH and TSH — a self-regulating thermostat.

That feedback is why TSH is the lab you titrate to, and it moves in the opposite direction of thyroid status. A high TSH means the pituitary is "shouting" for more hormone — the patient is under-replaced / hypothyroid. A low TSH means feedback has switched it off — the patient is over-replaced / hyperthyroid. Thyroid hormone itself sets the basal metabolic rate of nearly every tissue, so it acts like the body’s metabolic accelerator: heart rate, heat production, gut motility, and mental speed all rise and fall with it.

Hypothyroidism — too little hormone — slows everything: fatigue, cold intolerance, weight gain, bradycardia, constipation, dry skin. The fix is replacement with levothyroxine, synthetic T4 that the body converts to T3 and uses to restore a normal metabolic rate. Because it has a long half-life and a narrow therapeutic index, the dose is fine-tuned to the TSH over weeks.

Hyperthyroidism (often Graves disease) — too much hormone — speeds everything up: heat intolerance, weight loss despite a good appetite, tachycardia and palpitations (even atrial fibrillation), tremor, anxiety. The fix is an antithyroid drug — methimazole (first-line) or propylthiouracil (PTU) — which block thyroid peroxidase, the enzyme that builds thyroid hormone. PTU has a second action: it also blocks the peripheral conversion of T4 to T3, which is why it may be an effective treatment for thyroid storm. A key teaching point: antithyroid drugs stop new synthesis but don’t remove hormone already stored in the gland, so the clinical effect takes weeks as the reserve is used up.

Sodium iodide I-131 (radioactive iodine, RAI) is handled by the thyroid exactly like dietary iodide: the sodium-iodide symporter concentrates it in follicular cells and thyroid peroxidase binds it into thyroglobulin, which traps it in the gland — and its beta emission then destroys the tissue that took it up. It treats hyperthyroidism and selected thyroid cancers, and the usual long-term result is hypothyroidism that may need lifelong thyroid hormone. It is contraindicated in pregnancy (it crosses the placenta and can cause severe, irreversible neonatal hypothyroidism) and in breastfeeding (it concentrates in the lactating breast). In the days after treatment, radiation thyroiditis can release stored hormone and worsen hyperthyroidism, even to thyroid storm; stable iodide, thyroid hormone and antithyroid drugs all reduce its uptake, so they are stopped beforehand.

Potassium iodide (KI) works the other way: a dose of stable iodide floods the thyroid so radioactive iodine cannot get in. The FDA-approved OTC tablets (IOSAT, ThyroSafe) are thyroid-blocking medicines for a nuclear radiation emergency only — taken when public officials say, once every 24 hours, alongside other protective measures; each dose protects for about 24 hours. Pharmacologic iodide also has short-term uses in severe hyperthyroidism that come from clinical references, not from these labels: it acutely blocks thyroid hormone release, and a saturated KI solution (SSKI) or Lugol’s iodine is given before surgery for Graves disease or toxic multinodular goiter to reduce gland vascularity and blood loss. When iodide is used with a thionamide, it is given at least an hour after the thionamide, so the new iodine is not used to make more hormone.

Because these drugs move the metabolic thermostat, the main adverse effects are simply overshoot. Too much levothyroxine produces iatrogenic hyperthyroidism: palpitations, insomnia, tremor, heat intolerance, and weight loss — and, particularly in the elderly or in coronary artery disease, angina, arrhythmia, and atrial fibrillation, because the faster, harder heart demands more oxygen. Chronic over-replacement also accelerates bone loss. Conversely, too much antithyroid drug tips the patient back into hypothyroidism.

Two idiosyncratic dangers of the antithyroid drugs are not clearly dose-dependent: agranulocytosis (a sudden loss of infection-fighting white cells — the reason patients must report a sore throat or fever at once) and hepatotoxicity — likely an immunological reaction to a drug metabolite — severe enough that PTU carries a boxed warning for liver failure. The thyroid hormones’ own boxed warning (levothyroxine, liothyronine) is different — it warns that thyroid hormone must never be used for weight loss, because in a euthyroid person the doses needed to affect weight are toxic.