Levothyroxine

Levothyroxine replaces deficient endogenous thyroxine, restoring normal metabolic, cardiovascular, neurodevelopmental, and reproductive function. It is a narrow-therapeutic-index drug, titrated against serum TSH to achieve a euthyroid state.

Mechanism of Action

• Genomic effect: levothyroxine (T4) is a prohormone that is peripherally deiodinated by type I and type II 5′-deiodinases to triiodothyronine (T3), the active hormone. T3 enters the cell nucleus and binds thyroid hormone receptors α (THRA) and β (THRB), which heterodimerise with retinoid X receptors on thyroid hormone response elements (TREs) in DNA, modulating transcription of target genes including those for cardiac myosin heavy chains, Na⁺/K⁺-ATPase, β-adrenergic receptors, and sarcoplasmic Ca²⁺-ATPase.
• Non-genomic effect: T4 binds integrin αVβ3 at the plasma membrane (Arg-Gly-Asp recognition site), activating MAPK (ERK1/2) signalling and producing angiogenic and proliferative effects.
• Net physiology: increases basal metabolic rate, stimulates cardiac output and heart rate, supports normal CNS development in infants, regulates lipid and glucose metabolism, and is required for normal growth in children.
• TSH feedback: rising free T4 (and downstream T3) suppresses hypothalamic TRH and pituitary TSH secretion, completing the negative-feedback loop.

Pharmacokinetics

• Absorption: oral bioavailability 40–80%, predominantly from jejunum and upper ileum. Absorption is decreased by fasting state disruption, malabsorption syndromes (coeliac disease, H. pylori gastritis, post-bariatric surgery), aging, and concurrent food — particularly soy, fibre, coffee, and dairy. Many drugs and minerals (calcium, iron, magnesium, aluminium, bile-acid sequestrants, proton pump inhibitors, sucralfate) form insoluble chelates and reduce absorption.
• Protein binding: greater than 99% — to thyroxine-binding globulin (TBG), transthyretin (TBPA), and albumin. Only the small free fraction is metabolically active.
• Metabolism: peripheral deiodination of T4 to T3 (active, ~80% of circulating T3 is peripherally derived) and to reverse T3 (calorigenically inactive). Hepatic conjugation to glucuronides and sulfates with enterohepatic recirculation.
• Half-life: T4 ≈ 6–7 days; T3 ≈ 1–2 days. Long T4 half-life supports once-daily oral dosing and forgives occasional missed doses.
• Excretion: hepatic and renal; ~20% of T4 eliminated in stool as conjugates and unchanged drug; urinary excretion declines with age.

• Primary, secondary, and tertiary hypothyroidism (congenital or acquired) — lifelong replacement therapy.
• Congenital hypothyroidism in neonates and infants — early treatment is essential for normal neurodevelopment.
• TSH suppression as adjunct to surgery and radioiodine in differentiated (papillary and follicular) thyroid carcinoma.
• Euthyroid (non-toxic) goitre — to reduce goitre size and to prevent recurrence after thyroidectomy in iodine-replete regions.
• Myxoedema coma — intravenous formulation in critical care.

• Hypersensitivity to levothyroxine or any excipient.
• Untreated thyrotoxicosis of any aetiology.
• Untreated adrenal insufficiency — treat adrenal insufficiency first to avoid precipitating an adrenal crisis.
• Untreated pituitary insufficiency (in central hypothyroidism, exclude or treat concomitant secondary adrenal insufficiency before starting).
• Acute myocardial infarction, acute myocarditis, acute pancarditis — initiation deferred until clinically stable.

Most adverse effects reflect over-replacement (iatrogenic thyrotoxicosis) rather than intrinsic drug toxicity. With correct titration to TSH within range, levothyroxine is well tolerated.

Common (≥1/100 to <1/10) — usually signs of over-replacement: palpitations, tachycardia, tremor, anxiety, insomnia, heat intolerance, sweating, weight loss, diarrhoea, headache.

Uncommon (≥1/1,000 to <1/100): hair loss (usually transient, early in therapy), menstrual irregularity, allergic skin reactions to excipients (rash, urticaria), muscle cramps.

Rare (<1/1,000): angina or arrhythmia in patients with underlying coronary disease, pseudotumour cerebri (idiopathic intracranial hypertension — described particularly in children), slipped capital femoral epiphysis (in children on supraphysiologic doses), seizures (very rare).

Long-term over-replacement risks: atrial fibrillation (particularly in elderly), accelerated bone loss and increased fracture risk in postmenopausal women, worsening glycaemic control in diabetes.

• Reduced absorption (separate dosing by ≥4 hours): calcium carbonate, ferrous sulfate and other iron salts, aluminium-containing antacids, sevelamer, lanthanum carbonate, bile-acid sequestrants (cholestyramine, colestipol, colesevelam), sucralfate, proton pump inhibitors (reduce gastric acid required for tablet dissolution), orlistat, raloxifene, soy products.
• Increased TBG and total T4 (free T4 typically unchanged but dose adjustment may be needed): oestrogens (oral contraceptives, oral HRT), tamoxifen, raloxifene, methadone, mitotane, 5-fluorouracil, capecitabine, heroin.
• Decreased TBG / displaced from binding (may decrease total but not free T4): androgens, anabolic steroids, glucocorticoids, slow-release nicotinic acid.
• Accelerated metabolism (induce CYP/conjugation, often require dose increase): phenytoin, carbamazepine, phenobarbital, rifampicin, primidone, sertraline.
• Anticoagulants: levothyroxine enhances the anticoagulant effect of warfarin and other vitamin-K antagonists — closer INR monitoring is required when initiating, titrating, or stopping.
• Insulin and oral antidiabetics: levothyroxine may worsen glycaemic control; doses of antidiabetic agents may require upward adjustment.
• Sympathomimetics: additive cardiac stimulation; risk of arrhythmia and coronary insufficiency.
• Ketamine: case reports of marked hypertension and tachycardia during anaesthesia.

Take once daily on an empty stomach, ideally 30–60 minutes before breakfast, with water only. Separate from interacting foods, supplements, and medicines by at least 4 hours.

Adults with Primary Hypothyroidism

• Healthy adults <50 years, no cardiac disease: typically initiate at full replacement dose, approximately 1.6 mcg/kg ideal body weight per day (often 100–125 mcg daily).
• Adults ≥50 years or with cardiovascular disease: initiate at 25–50 mcg daily and titrate upward in 12.5–25 mcg increments every 4–6 weeks based on TSH.
• TSH monitoring: recheck 6–8 weeks after initiation or dose change, then annually once stable. Target TSH typically 0.4–4.0 mIU/L (lower in pregnancy and selected oncology indications).

Pregnancy

Requirements typically increase by 25–50% from the first trimester. Confirm pregnancy testing early; pre-empt by increasing dose by ~2 tablets per week as soon as pregnancy is confirmed and recheck TSH every 4 weeks during the first half of pregnancy. Target TSH per trimester-specific reference range.

Differentiated Thyroid Cancer

TSH suppression target depends on recurrence risk — low (TSH 0.5–2.0 mIU/L), intermediate (0.1–0.5), or high (<0.1). Doses are typically higher than physiologic replacement (~2.0–2.2 mcg/kg/day).

Paediatric

Weight-based dosing, highest per kg in neonates (10–15 mcg/kg/day) and decreasing with age. Congenital hypothyroidism requires immediate initiation to preserve cognitive development.

Renal and Hepatic Impairment

No specific dose adjustment is required for renal or hepatic dysfunction.

Missed Dose

Take as soon as remembered the same day. If close to the next dose, skip and resume the normal schedule. Do not double up. Occasional missed doses are well tolerated given the long half-life.

Brand Switching

Levothyroxine is a narrow-therapeutic-index drug. Switching between brands or between branded and generic formulations can alter exposure; if a switch is unavoidable, recheck TSH 6–8 weeks afterward.

Elderly

Start low (12.5–25 mcg/day) and titrate slowly to avoid precipitating angina, arrhythmia, or heart failure. The target TSH in older adults may be slightly higher than in younger patients (e.g. up to 6 mIU/L in those over 70).

Pregnancy and Breastfeeding

• Pregnancy: continue and increase dose as above; untreated maternal hypothyroidism is harmful to fetal neurodevelopment.
• Breastfeeding: compatible with breastfeeding; physiologic amounts are transferred in milk.

Adrenal Insufficiency

Always exclude or treat adrenal insufficiency before starting levothyroxine in patients with hypopituitarism or autoimmune polyendocrine syndromes — precipitating an adrenal crisis can be life-threatening.

Effect on Driving

No relevant effect on the ability to drive or operate machinery once euthyroid; symptomatic hypothyroidism or thyrotoxicosis from incorrect dosing may impair concentration.

Store below 25°C in the original packaging to protect from light and moisture. Liquid formulations and reconstituted intravenous solutions follow brand-specific instructions; some oral solutions and soft-gel capsules require additional moisture protection.

Typically 2 years for tablets and soft-gel capsules; brand-specific. Do not use after the expiry date printed on the packaging.

Prescription required (Rx).