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PH7.3 | PH7.3 | Thyroid Disorder Pharmacotherapy — SDL Guide — SDL Guide (Part 2)

Hyperthyroidism Drugs: Thionamides, Iodine, Beta-Blockers

The pharmacological management of hyperthyroidism uses a combination of agents targeting different aspects of the pathophysiology: synthesis inhibition (thionamides), temporary organification block (iodine/iodides), peripheral T4→T3 conversion inhibition (PTU, propranolol), and symptom control (beta-blockers).

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Thionamides — Carbimazole and PTU:
Both carbimazole (converted in vivo to methimazole — the active form) and propylthiouracil (PTU) inhibit thyroid peroxidase (TPO), blocking iodide oxidation and organification — thus stopping new thyroid hormone synthesis. Existing stored hormone continues to be released, explaining the 1–3 week delay to biochemical effect. For clinical symptom control during this lag, combine with a beta-blocker.

Critical difference — PTU's extra mechanism: PTU, unlike carbimazole, also inhibits peripheral type-1 5'-deiodinase — blocking T4→T3 conversion at peripheral tissues (liver, kidney). This provides a faster reduction in circulating T3 and is crucial in thyroid storm.

ADRs of thionamides:
- Agranulocytosis (most serious, 0.1–0.3%) — abrupt onset, reversible if caught early; WARN ALL PATIENTS to stop the drug and report immediately if they develop sore throat, fever, or oral ulcers. Check FBC if suspected — drug holiday + G-CSF if severe.
- Hepatotoxicity: PTU > carbimazole — PTU causes severe hepatitis (including fulminant hepatic failure) with long-term use, especially concerning in children and prolonged adult therapy → prefer carbimazole for maintenance; PTU restricted to 1st trimester pregnancy and thyroid storm.
- Rash, pruritus (switch to the other thionamide if minor).
- Cholestasis (rare, carbimazole).
- SLE-like syndrome (PTU, rare).

Iodine and Iodides (Lugol's Iodine): High-dose iodide transiently blocks organification via the Wolff-Chaikoff effect (iodine overload inhibits TPO-dependent organification). Additionally reduces thyroid gland vascularity (surgically useful). Uses: (1) Pre-operative preparation for thyroidectomy in Graves' disease — 10–14 days of Lugol's before surgery reduces vascularity and surgical bleeding; (2) Thyroid storm adjunct; (3) Radiation emergency prophylaxis. NOT for long-term antithyroid therapy — thyroid 'escapes' Wolff-Chaikoff effect after 1–2 weeks.

Beta-Blockers (Propranolol): Non-selective beta-blocker. Controls adrenergic symptoms of hyperthyroidism: tachycardia, tremor, anxiety, sweating, heat intolerance. Does NOT reduce thyroid hormone synthesis — purely symptomatic. Additional property: propranolol at high doses inhibits peripheral T4→T3 conversion (type-2 deiodinase, hepatic). Used as bridge therapy while thionamides take effect, and in thyroid storm.

Radioactive Iodine (¹³¹I): Oral sodium iodide-131 — concentrated in thyroid follicular cells (as iodine is) → emits beta radiation → destroys thyroid tissue. Safe, definitive outpatient treatment for Graves' disease, toxic adenoma, and toxic multinodular goitre. Onset of effect: 6–12 weeks; may cause initial transient worsening (radiation thyroiditis). Contraindications: pregnancy, breast-feeding, active Graves' ophthalmopathy (may worsen eye disease), large compressive goitre, suspected malignancy. Most patients ultimately become hypothyroid (intended in many; treated with levothyroxine).

Clinical Decision-Making: Managing Hypothyroidism and Hyperthyroidism

Sound clinical pharmacology in thyroid disease requires integrating the patient's disease type, severity, comorbidities, and special circumstances (pregnancy, planned surgery, cardiac disease) into a coherent management plan.

Hypothyroidism management:
- Overt hypothyroidism (elevated TSH + low free T4, symptomatic): Levothyroxine 1.6 mcg/kg/day starting dose in young healthy adults. Start low (12.5–50 mcg/day) in elderly (>60 years) and those with cardiac disease — rapid T3 increase can precipitate angina, AF, acute MI. Uptitrate every 6–8 weeks guided by TSH.
- Subclinical hypothyroidism (raised TSH, normal free T4): Treatment debated. Generally treat if TSH >10 mIU/L, or if symptomatic, or in pregnancy. TREAT trial showed levothyroxine did NOT improve QoL in older adults with subclinical hypothyroidism — individualize.
- Myxoedema coma: IV liothyronine (300–400 mcg loading dose) — most rapid T3 delivery when peripheral conversion is impaired; concurrent IV hydrocortisone (relative adrenal insufficiency common), rewarming, supportive care.

Hyperthyroidism management:

Choice of treatment modality for Graves' disease:
1. Antithyroid drugs (carbimazole/PTU): First-line for most patients; remission rate ~50% after 12–18 months; relapse common (30–40% within 2 years). Preferred in: pregnancy, mild disease, young patients seeking euthyroidism without radiation.
2. Radioactive iodine (¹³¹I): Preferred in: older patients, relapsed Graves', toxic multinodular goitre, toxic adenoma. Contraindicated in pregnancy. Results in hypothyroidism in most cases — this is planned and acceptable.
3. Thyroidectomy (subtotal): Preferred in: large goitre (compressive symptoms), co-existing suspected thyroid malignancy, severe Graves' ophthalmopathy where rapid euthyroidism is needed, patient preference, or failure of medical therapy. Pre-operative preparation: carbimazole to achieve euthyroidism, then Lugol's iodine 10–14 days before surgery (reduces vascularity and surgical bleeding).

Thyroid storm management (thyrotoxic crisis — life-threatening emergency):
1. PTU 200 mg 6-hourly (blocks synthesis AND peripheral T4→T3 conversion) — first choice because of dual mechanism
2. After PTU loading: Lugol's iodine (1 hour AFTER PTU — if given before PTU, will provide iodine substrate for ongoing synthesis)
3. Propranolol IV — heart rate control, additional T4→T3 conversion inhibition
4. Hydrocortisone — adrenal axis support (stress response); also inhibits T4→T3 conversion
5. Treat precipitating cause (infection, surgery, iodine load)

Graves' Disease Management Algorithm

Self-Assessment: Thyroid Drug Scenarios

Test your integration of thyroid pharmacology with these scenarios:

Scenario A: A 32-year-old woman with Graves' hyperthyroidism is 7 weeks pregnant. Her free T4 is 3.8 ng/dL (very elevated). What drug do you start, at what dose range, and what do you tell her about the drug holiday at 13 weeks?
Answer: PTU — preferred in 1st trimester (carbimazole teratogenicity). Starting dose typically 100–150 mg TDS, titrated to lowest effective dose. At 13 weeks, switch to carbimazole (PTU hepatotoxicity risk increases with duration). Inform that both drugs cross the placenta and can cause fetal hypothyroidism — use the lowest effective dose. Breastfeeding: low-dose carbimazole is preferred (less breast milk transfer than PTU).

Scenario B: A 50-year-old man with toxic nodular goitre and persistent hyperthyroidism despite 18 months of carbimazole. No ophthalmopathy. He refuses surgery. TSH <0.01, free T4 elevated. What do you recommend?
Answer: Radioactive iodine (¹³¹I) — standard for non-pregnant adult with relapsed or persistent hyperthyroid nodular disease. Pre-treat with carbimazole if severely thyrotoxic, stop carbimazole 3–5 days before radioiodine (to allow iodine uptake). Warn that hypothyroidism is likely (plan levothyroxine). Monitor TSH at 6 weeks, 3 months, 6 months.

Scenario C: Why is Lugol's iodine given AFTER PTU in thyroid storm, not before?
Answer: If iodine is given before thionamide, the thyroid uses the excess iodide as substrate for more T4/T3 synthesis ('iodide escape' from the Wolff-Chaikoff effect can take longer than the storm). PTU must first block TPO so no new hormone synthesis occurs; only then does Lugol's iodine addition safely exploit the Wolff-Chaikoff block on organification without providing substrate for synthesis.