Thyroid & Antithyroid Drugs

Pharmacology of the thyroid axis is a perennial NEET PG favourite — high-yield single best answers cluster around the mechanism of PTU vs carbimazole, the drug of choice in thyroid storm and pregnancy, radioactive iodine, and agranulocytosis. These notes integrate physiology, pharmacology and clinical decision-making so you can answer both direct and clinical-vignette stems.

Quick orientation: the thyroid hormone synthesis pathway

Understanding where each drug acts is the single most efficient way to lock in this topic. The synthesis cascade in the thyroid follicular cell:

Iodide uptake (NIS / Na⁺-I⁻ symporter) → organification (iodide oxidised & bound to tyrosine on thyroglobulin, by thyroid peroxidase/TPO) → coupling of MIT + DIT → forms T3 and T4 (also by TPO) → storage in colloid as thyroglobulin → endocytosis & proteolysis → release of T4 (90%) and T3 (10%) → peripheral deiodination of T4 → active T3 (by 5′-deiodinase).

Each antithyroid agent blocks one of these steps, and naming the step is usually the answer key.

Step in synthesis	Enzyme / transporter	Drug that blocks it
Iodide trapping/uptake	Na⁺-I⁻ symporter (NIS)	Perchlorate, pertechnetate, thiocyanate
Organification + coupling	Thyroid peroxidase (TPO)	Carbimazole, methimazole, PTU (thioamides)
Hormone release from colloid	—	Iodides (Lugol's), lithium
Peripheral T4 → T3 conversion	5′-deiodinase (type I)	PTU, propranolol, glucocorticoids, ipodate, amiodarone

High-yield: PTU is the ONLY thioamide that also blocks peripheral conversion of T4 → T3 (via inhibition of D1 5′-deiodinase). This dual action makes it preferred when a rapid fall in active hormone is needed — thyroid storm.

Classification of drugs affecting the thyroid

A. Thyroid hormone preparations (replacement):

• Levothyroxine (T4) — sodium salt
• Liothyronine (T3)
• Liotrix (T4:T3 = 4:1)
• Desiccated thyroid extract (largely obsolete)

B. Antithyroid drugs:

1. Inhibitors of hormone synthesis (thioamides): carbimazole, methimazole, propylthiouracil (PTU)
2. Inhibitors of iodide trapping (ionic inhibitors): thiocyanate, perchlorate, pertechnetate
3. Inhibitors of hormone release: iodine/iodides (Lugol's iodine, potassium iodide), lithium
4. Destruction of thyroid tissue: radioactive iodine (¹³¹I)
5. Adjuvant / symptomatic: beta-blockers (propranolol), glucocorticoids, iopanoic/ipodate acid

Thyroid hormone replacement

Levothyroxine (L-T4) — the drug of choice for hypothyroidism

Levothyroxine is preferred over T3 because of its long half-life (~7 days), which gives stable plasma levels with once-daily dosing, and because peripheral tissues generate the physiologically appropriate amount of T3 by deiodination. T3 (liothyronine) has a short half-life (~1 day), causes peaks of cardiac stimulation, and is reserved for myxoedema coma (rapid action needed) and short-term suppression before thyroid cancer scanning.

Pharmacokinetics worth remembering:

• Absorbed best on an empty stomach, 30–60 min before breakfast; absorption reduced by calcium, iron, PPIs, soya, bran, cholestyramine.
• Highly protein-bound (TBG, transthyretin, albumin).
• Onset of action is slow; assess adequacy of dose by TSH after 6–8 weeks.

Dosing:

• Average adult full replacement ≈ 1.6 µg/kg/day.
• Children need higher per-kg doses; congenital hypothyroidism needs prompt, full replacement (10–15 µg/kg/day) to protect neurodevelopment.
• Elderly and those with coronary artery disease: start low (12.5–25 µg/day) and go slow to avoid precipitating angina/arrhythmia.

High-yield: In pregnancy, levothyroxine requirement typically increases by 25–50%. Confirm pregnancy → increase dose empirically (often 2 extra tablets/week) and titrate to trimester-specific TSH.

High-yield: Monitoring of replacement is by serum TSH in primary hypothyroidism. In central (secondary/pituitary) hypothyroidism, TSH is unreliable — titrate to free T4 in the upper-normal range.

Toxicity: overdose mimics thyrotoxicosis — palpitations, weight loss, tremor, heat intolerance, AF, osteoporosis (long-term over-replacement), and angina in CAD.

Antithyroid drugs — the thioamides

This is the most examined subsection. Carbimazole, methimazole and PTU all inhibit thyroid peroxidase (TPO), thereby blocking iodide organification and the coupling of iodotyrosines.

• Carbimazole is a prodrug, rapidly converted to methimazole (its active form) in the body. In India and the UK carbimazole is the usual choice; in the US methimazole is used directly.
• PTU additionally inhibits type I 5′-deiodinase, reducing peripheral T4 → T3 conversion.

High-yield: Because thioamides block synthesis but NOT release of preformed stored hormone, clinical improvement is delayed by 1–3 weeks until existing colloid stores are depleted.

Carbimazole/Methimazole vs Propylthiouracil — the classic comparison

Feature	Carbimazole / Methimazole	Propylthiouracil (PTU)
Mechanism	Inhibit TPO (organification + coupling)	Inhibit TPO + block peripheral T4→T3
Potency	~10× more potent	Less potent
Half-life / dosing	Long → once daily	Short → 2–3 times daily
Crosses placenta / milk	More (methimazole)	Less; more protein-bound
Preferred in pregnancy	2nd & 3rd trimester	1st trimester
Characteristic teratogenicity	Aplasia cutis, choanal/oesophageal atresia (methimazole embryopathy)	Less teratogenic (but hepatotoxic)
Major hepatotoxicity	Cholestatic	Fulminant hepatic necrosis (black-box)
Use in thyroid storm	Less ideal	Preferred

High-yield mnemonic — "PTU = Pregnancy (1st Trimester), T4→T3 block, Used in storm". Conversely methimazole/carbimazole are first-line for routine Graves' disease because of once-daily dosing and lower hepatotoxicity.

Pregnancy: a nuanced, frequently-tested point

The accepted approach: PTU in the first trimester (methimazole/carbimazole are linked to embryopathy — aplasia cutis, choanal atresia), then switch to methimazole/carbimazole from the second trimester onwards (because PTU carries a higher risk of maternal hepatotoxicity). Use the lowest effective dose to keep maternal free T4 at the upper limit of normal, since thioamides cross the placenta and can cause fetal goitre/hypothyroidism. Block-and-replace regimens are avoided in pregnancy.

Adverse effects of thioamides

• Agranulocytosis — the most feared idiosyncratic reaction (~0.1–0.5%), usually in the first 3 months. Presents as fever and sore throat. It is not reliably predicted by routine counts.
• Rash, urticaria, arthralgia (common, minor).
• Hepatotoxicity — PTU → hepatocellular necrosis (can be fatal, including in children → black-box warning); carbimazole/methimazole → cholestatic jaundice.
• ANCA-associated vasculitis (more with PTU).
• Hypothyroidism/goitre if over-treated.

High-yield: Counsel every patient starting a thioamide: "If you develop fever or sore throat, stop the drug and get an urgent total leukocyte count." Routine periodic monitoring is debated; symptom-directed CBC is the universally accepted answer. Agranulocytosis is reversible on stopping the drug; G-CSF may speed recovery.

Iodide and iodine

High-dose iodide (Lugol's iodine = iodine + potassium iodide; or saturated KI/SSKI) has several paradoxical actions:

1. Inhibits hormone release (most rapid effect — clinically improves thyrotoxicosis within 1–2 days).
2. Wolff–Chaikoff effect — acute large iodide load transiently inhibits organification and hence hormone synthesis.
3. Decreases vascularity and size of the gland — hence used for 10–14 days pre-operatively before thyroidectomy.

High-yield — Wolff–Chaikoff effect: A large dose of iodide autoregulates the gland by transiently shutting down organification. The gland normally "escapes" in ~10 days (downregulation of NIS). Failure to escape → iodide-induced hypothyroidism (relevant with amiodarone, in neonates, and in autoimmune thyroiditis). The opposite — iodide-induced hyperthyroidism in a nodular gland — is the Jod-Basedow phenomenon.

High-yield — timing rule: Always give the thioamide BEFORE iodine in preparation for surgery. Giving iodine first to an untreated patient can load the gland with substrate (Jod-Basedow) and worsen thyrotoxicosis.

Lithium also blocks hormone release and can be used in patients allergic to iodine, but is rarely first-line.

Radioactive iodine (¹³¹I)

¹³¹I is concentrated by the NIS, emits β-particles (path length ~1–2 mm) that destroy follicular cells, with a physical half-life of ~8 days.

• Definitive therapy for Graves' disease and toxic nodular goitre, and for thyroid cancer ablation (higher doses).
• Simple, outpatient, avoids surgery; effect takes 6–12 weeks.
• Hypothyroidism is the expected, near-inevitable end-result — patients should be counselled that lifelong levothyroxine is likely.

Absolute contraindications: pregnancy and lactation (crosses placenta, destroys fetal thyroid after ~10–12 weeks gestation). Pregnancy must be excluded; avoid conception for ~6 months after. Relative caution: active/moderate-severe Graves' ophthalmopathy (RAI can worsen orbitopathy — pre-treat with steroids, or prefer thioamides/surgery), young children.

High-yield: Pre-treatment with thioamides before RAI is sometimes used in elderly/cardiac patients to deplete hormone stores and prevent post-RAI thyroiditis flare; thioamides are stopped ~3–5 days before the dose so as not to block uptake.

Beta-blockers — symptomatic control

Propranolol controls the adrenergic features of thyrotoxicosis (tachycardia, tremor, anxiety, palpitations) within hours and is part of every thyroid-storm protocol. Propranolol (non-selective, lipophilic) is favoured because at high doses it also modestly inhibits peripheral T4 → T3 conversion. It does NOT treat the underlying hyperthyroidism. Use cardioselective agents (atenolol/metoprolol) if there is bronchospasm risk; verapamil/diltiazem if beta-blockers are contraindicated.

Thyroid storm — the integrated answer

Thyroid storm is a life-threatening decompensated thyrotoxicosis; management combines drugs that hit every step. Remember the sequence:

1. Beta-blocker (propranolol) — control adrenergic surge (also ↓T4→T3).
2. PTU (loading dose) — blocks synthesis and peripheral conversion — preferred thioamide here.
3. Iodine (Lugol's / SSKI) — given at least 1 hour AFTER the thioamide — blocks hormone release.
4. Glucocorticoids (hydrocortisone/dexamethasone) — inhibit T4→T3 conversion and treat relative adrenal insufficiency.
5. Supportive: cooling, fluids, treat precipitant (infection, surgery), paracetamol for fever.

High-yield: Avoid aspirin/salicylates for fever in thyroid storm — they displace thyroid hormone from TBG and raise free hormone. Use paracetamol instead.

High-yield — the "block sequence" in storm: PTU first → wait ≥1 hr → then iodine. Drugs that block T4→T3: PTU, propranolol, glucocorticoids, ipodate/iopanoic acid, amiodarone (mnemonic "PIGPA" / "Stop the conversion: PTU, Propranolol, Prednisolone-type steroids, iodinated contrast").

Amiodarone and the thyroid (high-yield aside)

Amiodarone is ~37% iodine by weight and is a classic exam trap:

• Inhibits peripheral T4→T3 conversion (→ ↑T4, ↑rT3, ↓T3) — euthyroid pattern changes.
• Amiodarone-induced hypothyroidism (AIT type via Wolff–Chaikoff) — common in iodine-replete areas; treat with levothyroxine, often continue amiodarone.
• Amiodarone-induced thyrotoxicosis (AIT): Type 1 (iodine-induced excess synthesis in nodular gland — treat with thioamides) vs Type 2 (destructive thyroiditis — treat with glucocorticoids).

Key differentials & decision points

Clinical setting	Preferred drug/strategy
Routine Graves' disease, non-pregnant	Carbimazole/methimazole (once daily)
1st-trimester pregnancy hyperthyroidism	PTU
2nd/3rd-trimester pregnancy	Methimazole/carbimazole
Thyroid storm	PTU + propranolol + iodine + steroids
Pre-thyroidectomy preparation	Thioamide → then Lugol's iodine 10–14 days
Definitive cure, non-pregnant, no severe eye disease	Radioactive ¹³¹I
Hypothyroidism (all causes)	Levothyroxine
Myxoedema coma	IV levothyroxine ± liothyronine + hydrocortisone
Amiodarone-induced thyrotoxicosis type 2	Glucocorticoids

Recently asked / exam angle

• Which antithyroid drug inhibits peripheral conversion of T4 to T3? → Propylthiouracil (and propranolol, steroids, ipodate). Classic single-best-answer.
• Drug of choice for hyperthyroidism in first trimester of pregnancy? → PTU.
• Mechanism of action of carbimazole? → inhibition of thyroid peroxidase (organification & coupling).
• Wolff–Chaikoff vs Jod–Basedow — match the phenomenon: large iodide load → transient hypo (Wolff–Chaikoff); iodine excess in nodular goitre → hyper (Jod–Basedow).
• Most serious adverse effect of carbimazole/PTU? → agranulocytosis (fever + sore throat). PTU additionally → fulminant hepatotoxicity (black box).
• Contraindication to radioactive iodine? → pregnancy/lactation; caution in active orbitopathy.
• Why levothyroxine over T3 for replacement? → long half-life, stable levels, peripheral autoregulation of T3.
• Why give thioamide before iodine pre-op? → prevent Jod–Basedow / worsening thyrotoxicosis; also prevents using iodine as substrate.
• Carbimazole is a prodrug of? → methimazole.
• Antithyroid drug causing aplasia cutis in fetus? → methimazole/carbimazole.
• Image/clinical vignette: post-RAI worsening of eye signs → answer relates to Graves' ophthalmopathy flare, prevented by steroids.

Rapid revision

1. Levothyroxine (T4) = drug of choice for hypothyroidism; dose ~1.6 µg/kg/day; monitor with TSH at 6–8 weeks; take empty stomach.
2. Thioamides (carbimazole, methimazole, PTU) block thyroid peroxidase → inhibit organification & coupling.
3. Only PTU additionally blocks peripheral T4 → T3 conversion (5′-deiodinase).
4. Carbimazole is a prodrug → methimazole; once-daily dosing; first-line for routine Graves'.
5. PTU = first trimester pregnancy + thyroid storm; risk of fulminant hepatic necrosis.
6. Methimazole/carbimazole teratogenicity = aplasia cutis, choanal/oesophageal atresia.
7. Most feared thioamide toxicity = agranulocytosis → stop drug, check TLC if fever/sore throat.
8. Iodides (Lugol's) inhibit hormone release (fastest action) + reduce gland vascularity → used pre-thyroidectomy 10–14 days, after a thioamide.
9. Wolff–Chaikoff = iodide-induced transient hypothyroidism; Jod–Basedow = iodide-induced hyperthyroidism in nodular gland.
10. Radioactive ¹³¹I (β-emitter) = definitive cure; contraindicated in pregnancy/lactation; expect resultant hypothyroidism; caution in active ophthalmopathy.
11. Propranolol controls adrenergic symptoms + modestly ↓T4→T3; does not cure hyperthyroidism.
12. Thyroid storm: propranolol + PTU + iodine (≥1 hr after PTU) + glucocorticoids + supportive; use paracetamol not aspirin for fever.