Thyroid and Antithyroid Drugs: Levothyroxine, Methimazole, PTU, Iodine & Radioiodine

Learning objectives

• Describe thyroid hormone synthesis, transport, conversion and nuclear-receptor action.
• Select levothyroxine or liothyronine and titrate safely in adults, older people, children and pregnancy.
• Explain how methimazole/carbimazole, propylthiouracil, iodide, radioactive iodine and beta-blockers are used in thyrotoxicosis.
• Recognise agranulocytosis, hepatotoxicity, iodine toxicity, radioiodine precautions and levothyroxine over-replacement.
• Treat myxoedema coma and thyroid storm as time-critical emergencies using a structured sequence.

1. Thyroid physiology relevant to pharmacology

Synthesis and secretion

1. Iodide is actively trapped from blood by the sodium–iodide symporter (NIS) on the basolateral thyrocyte membrane and transported toward the colloid via pendrin.
2. Thyroid peroxidase (TPO) oxidises iodide and iodinates tyrosine residues on thyroglobulin, forming MIT and DIT.
3. TPO couples two DIT residues to form thyroxine (T4), or MIT plus DIT to form triiodothyronine (T3).
4. T4 and T3 remain stored in colloid until TSH stimulates endocytosis and proteolysis of thyroglobulin.
5. Peripheral deiodinases in liver, kidney and other tissues convert T4 to active T3 or inactive reverse T3. PTU inhibits part of this peripheral conversion.

Cellular action

T3 enters target cells and binds nuclear thyroid-hormone receptors that form heterodimers with RXR. The receptor complex binds thyroid-response elements on DNA, changes messenger-RNA transcription and alters protein synthesis. Effects include increased basal metabolic rate, oxygen consumption, carbohydrate and lipid turnover, beta-adrenergic responsiveness, cardiac contractility, gut motility, growth, brain development and haemopoiesis.

2. Classification of thyroid drugs

3. Thyroid hormone replacement

3.1 Levothyroxine (L-thyroxine, T4)

Levothyroxine is the preferred long-term replacement because it has a stable half-life, reliable conversion to T3 and allows once-daily dosing.

Indications

• Primary hypothyroidism from autoimmune thyroiditis, iodine deficiency, thyroidectomy or radioiodine.
• Congenital hypothyroidism/cretinism, where early treatment prevents irreversible neurodevelopmental impairment.
• Central hypothyroidism, with dose guided by free T4 rather than TSH alone.
• TSH suppression after differentiated thyroid cancer when indicated by the oncology/endocrine plan.
• Selected non-toxic goitre or nodules—do not suppress TSH indiscriminately because atrial fibrillation and bone loss can result.

Adult dosing and titration

Administration and interactions

• Take once daily on an empty stomach, 30–60 minutes before breakfast, with a full glass of water, or consistently at bedtime separated from food.
• Separate by at least 4 hours from iron, calcium, aluminium/magnesium antacids, sucralfate, bile-acid sequestrants and high-fibre supplements.
• Proton-pump inhibitors, achlorhydria, coeliac disease and intestinal disorders may reduce absorption. Rifampicin, phenytoin, carbamazepine and phenobarbital can increase metabolism.
• Switching brands or formulations may change TSH; recheck after a switch and keep the same product when possible.
• Warfarin effect may increase as euthyroidism returns; monitor INR. Diabetes medicines may require adjustment when metabolism normalises.

Adverse effects

Excessive dosing causes iatrogenic thyrotoxicosis: tremor, anxiety, sweating, heat intolerance, diarrhoea, weight loss, tachycardia, atrial fibrillation, angina and osteoporosis. Reduce or withhold the dose and investigate TSH/free T4; urgent chest pain, syncope or arrhythmia needs emergency assessment.

3.2 Liothyronine (T3)

Liothyronine has a rapid onset and short duration. It is not routinely used for chronic hypothyroidism because rapid peaks can provoke angina, arrhythmia and bone loss. It may be used in selected severe emergencies under specialist supervision.

• Oral chronic use: products and local guidance vary; if used, very low divided doses are titrated cautiously with specialist monitoring.
• Myxoedema coma: IV liothyronine may be added to IV levothyroxine in selected patients, but high doses increase arrhythmia and mortality risk. Typical specialist ranges are a 5–20 microgram loading dose followed by 2.5–10 micrograms every 8 hours, using lower doses in older patients or coronary disease.
• Adverse effects: palpitations, tachycardia, atrial fibrillation, angina, heart failure, tremor, insomnia and osteoporosis.

4. Antithyroid thioamides

Mechanism

Methimazole, carbimazole and PTU concentrate in the thyroid and inhibit TPO-catalysed oxidation of iodide, organification of tyrosine and coupling of MIT/DIT. They do not destroy stored hormone, so clinical improvement usually takes 1–2 weeks or more. PTU additionally inhibits peripheral conversion of T4 to T3.

Adverse effects and patient warning

• Common: nausea, metallic taste, headache, rash, pruritus, arthralgia and gastrointestinal upset.
• Agranulocytosis: fever, sore throat, mouth ulcers or infection. Stop the drug immediately, obtain urgent full blood count and do not restart the thioamide if true agranulocytosis is confirmed without specialist direction.
• Hepatotoxicity: jaundice, dark urine, pale stool, severe pruritus, right-upper-quadrant pain or unusual fatigue require immediate liver tests and stopping the suspected drug.
• Rare pancreatitis, aplastic anaemia, thrombocytopenia and ANCA-associated vasculitis can occur, more often with PTU.
• Over-treatment produces hypothyroidism and goitre due to increased TSH; titrate using free T4/T3 and clinical response, not symptoms alone.

Pregnancy

Radioactive iodine is contraindicated in pregnancy. Methimazole/carbimazole is generally avoided in the first trimester because of embryopathy; PTU is commonly preferred early, then many protocols switch to methimazole after the first trimester to reduce maternal liver risk. Use the lowest dose that controls free T4 and specialist obstetric-endocrine monitoring.

5. Iodine and iodides

Mechanism and uses

Large iodide doses produce the acute Wolff–Chaikoff effect: they inhibit iodide organification and rapidly reduce thyroid-hormone release. They also decrease gland vascularity and can make thyroidectomy safer. Escape from the effect occurs after roughly 10–14 days, so iodide is not usually long-term monotherapy.

• Preoperative Graves disease: Lugol solution or saturated potassium iodide for about 7–10 days under endocrinology/surgical direction.
• Thyroid storm: give iodide only after a thioamide, usually at least one hour later, so newly trapped iodine is not used as substrate for synthesis.
• Radiation prophylaxis: potassium iodide protects the thyroid from radioactive iodine exposure only in specific public-health emergencies and is not a general thyroid medicine.

Chronic high-dose iodide can cause hypothyroidism, goitre or iodine-induced hyperthyroidism, especially in multinodular glands. Avoid casual use in pregnancy, renal disease or iodide hypersensitivity.

6. Radioactive iodine (I-131)

Oral sodium iodide I-131 is actively concentrated by thyroid tissue. Beta particles damage follicular cells within a short range; tissue is gradually replaced by fibrosis. It is used for Graves disease, toxic multinodular goitre and selected differentiated thyroid cancers.

• Response: improvement may begin after several weeks and become clearer over 2–3 months; hypothyroidism is an expected long-term outcome and is treated with levothyroxine.
• Contraindications: pregnancy and breastfeeding; avoid in children/young people unless specialist indications justify it. Defer if thyroid cancer risk or compressive goitre requires surgery.
• Precautions: follow radiation-safety instructions for distance, hygiene, sleeping arrangements and contact with children/pregnant people. Antithyroid drugs and iodinated contrast can reduce uptake; coordinate withholding/restarting.
• Risks: transient thyroiditis, neck pain, temporary hormone release and rare precipitation of thyroid storm; beta-blockade and pretreatment thioamide may be considered in high-risk patients.

7. Beta-blockers for symptomatic thyrotoxicosis

Propranolol, atenolol or other beta-blockers reduce tremor, palpitations, anxiety and tachycardia while definitive therapy takes effect. Propranolol at higher doses modestly reduces T4-to-T3 conversion.

8. Myxoedema coma: emergency replacement

Myxoedema coma is decompensated severe hypothyroidism with altered mental status, hypothermia, bradycardia, hypotension, hypoventilation, hyponatraemia or hypoglycaemia. Treat clinically; do not delay for a thyroid assay when the presentation is convincing.

1. Airway and ventilation support, cautious warming, glucose correction, treatment of infection and careful fluid/electrolyte management.
2. Give stress-dose hydrocortisone (for example, 100 mg IV every 8 hours) until adrenal insufficiency is excluded, because thyroid hormone can precipitate adrenal crisis.
3. IV levothyroxine loading commonly 200–400 micrograms, using lower doses in older people, small body size or coronary disease, followed by about 1.6 micrograms/kg/day reduced to roughly 75% while IV.
4. Selected severe cases receive liothyronine 5–20 micrograms IV loading then 2.5–10 micrograms every 8 hours; avoid high doses due to arrhythmia and myocardial ischaemia.
5. Monitor ECG, temperature, blood pressure, sodium, glucose, cortisol, free T4/T3 and clinical response in ICU-level care.

9. Thyroid storm: emergency sequence

Thyroid storm is decompensated thyrotoxicosis with fever, marked tachycardia/arrhythmia, CNS disturbance, gastrointestinal/hepatic dysfunction or heart failure. Search for infection, surgery, trauma, myocardial infarction, iodine exposure or antithyroid-drug interruption.

1. Resuscitation: oxygen/ventilation, IV access, cooling, fluids, glucose, ECG and treatment of the trigger.
2. Beta-blockade: propranolol 60–80 mg orally every 4–6 hours or titratable esmolol in ICU; avoid non-selective blockade in severe asthma, shock or decompensated heart failure.
3. Thioamide: PTU 500–1,000 mg loading then 250 mg every 4 hours is a common emergency regimen; methimazole 20 mg every 4–6 hours is an alternative when PTU is unsuitable. Use a local protocol.
4. Iodide: give Lugol/SSKI at least one hour after the thioamide—never before unless a specialist directs it.
5. Corticosteroid: hydrocortisone 100 mg IV every 8 hours or equivalent to reduce T4-to-T3 conversion and cover relative adrenal insufficiency.
6. Consider cholestyramine, plasmapheresis or urgent thyroidectomy for refractory cases with specialist input.

10. Monitoring

11. Important interactions

• Calcium, iron, sucralfate, antacids, bile-acid sequestrants and fibre reduce levothyroxine absorption; separate by at least four hours.
• Rifampicin, carbamazepine, phenytoin and phenobarbital increase thyroid-hormone metabolism; TSH may rise.
• Warfarin sensitivity may change as thyroid status changes; check INR.
• Iodinated contrast and amiodarone supply large iodine loads and can cause hypo- or hyperthyroidism; check thyroid history before exposure.
• Beta-blockers can mask adrenergic hypoglycaemia warning signs; monitor diabetic patients more closely.
• Antithyroid drugs and radioiodine have opposing treatment goals; coordinate stopping/restarting rather than alternating without a plan.

12. Clinical cases

13. High-yield points

• T4 is the stable replacement hormone; T3 is more potent and faster but more arrhythmogenic.
• Levothyroxine is taken fasting and separated from iron/calcium by at least four hours.
• Methimazole/carbimazole inhibit synthesis; PTU also inhibits peripheral T4-to-T3 conversion but has severe hepatic toxicity.
• Fever or sore throat on a thioamide means possible agranulocytosis: stop and check CBC urgently.
• Iodide acts rapidly but transiently; give after a thioamide in thyroid storm.
• I-131 destroys thyroid tissue and is contraindicated in pregnancy and breastfeeding.
• Beta-blockers control symptoms but do not correct hormone synthesis.
• Myxoedema coma requires thyroid hormone plus hydrocortisone and supportive care; thyroid storm requires beta-blocker, thioamide, delayed iodide, steroid and resuscitation.

14. Sources and further reading

• Supplied SlideShare: Thyroid & antithyroid drug.
• Supplied SlideShare: Thyroid drugs.
• DailyMed: levothyroxine sodium.
• DailyMed: methimazole.
• DailyMed: propylthiouracil.
• DailyMed: potassium iodide.
• DailyMed: sodium iodide I-131.
• NCBI: myxoedema coma review.