Levothyroxine

Generic Name: Levothyroxine sodium
Pharmacological Class: Synthetic thyroid hormone (T4)
Therapeutic Class: Thyroid hormone replacement
ATC Code: H03AA01
Regulatory Status: Prescription-only medicine
Common Brand Names: Eltroxin, Euthyrox, Synthroid, Levothroid, Eltroxin, Levoxyl, Thyronorm, Euthyrox, Unithroid

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Chemical and Pharmacological Properties

• Chemical Structure: Synthetic form of thyroxine (T4), a naturally occurring thyroid hormone

• Molecular Formula: C15H11I4NO4

• Molecular Weight: 776.87 g/mol

• Bioequivalence Warning: Levothyroxine preparations are not all therapeutically equivalent; prescribers are advised to maintain patients on a consistent brand

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Mechanism of Action

Levothyroxine is a synthetic isomer of endogenous thyroxine (T4). After oral administration, it is absorbed in the small intestine and converted peripherally to the more biologically active triiodothyronine (T3). T3 then:

• Binds to thyroid hormone receptors in the nucleus

• Regulates gene transcription and protein synthesis

• Modulates metabolism, growth, and development

Thyroid hormones affect nearly every organ system, particularly influencing basal metabolic rate, oxygen consumption, thermogenesis, and lipid/carbohydrate metabolism.

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Indications

1. Hypothyroidism (primary, secondary, or tertiary):

   • Congenital or acquired

   • Hashimoto’s thyroiditis

   • Post-thyroidectomy or radioiodine ablation

   • Secondary hypothyroidism due to pituitary or hypothalamic disease

2. Goiter:

   • Management of benign euthyroid goiter

   • Suppressive therapy to prevent enlargement

3. Thyroid cancer (adjunctive):

   • Used to suppress TSH levels post-thyroidectomy in differentiated thyroid cancers

4. Thyroid-stimulating hormone (TSH) suppression testing (rare):

   • To aid in the diagnosis of mild hyperthyroidism

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Dosage and Administration

General Principles:

• Administer once daily on an empty stomach, ideally 30 to 60 minutes before breakfast

• Consistency is key – patients should always take it at the same time of day with the same conditions (e.g., fasting)

• Oral bioavailability is reduced by food, calcium, iron, soy, coffee, antacids

Adult Dosing:

• Hypothyroidism (full replacement):

  • Healthy adults <50 years: Start with 1.6 mcg/kg/day

  • Elderly or those with cardiovascular disease: Start with 12.5–25 mcg/day and titrate every 6–8 weeks

  • Maintenance: Usually 100–125 mcg/day for adults

• Subclinical hypothyroidism:

  • 25–75 mcg/day depending on TSH levels and symptoms

• Thyroid cancer suppression:

  • Higher doses aiming for low TSH levels (e.g., <0.1 mIU/L)

Pediatric Dosing:

• Neonates and infants: 10–15 mcg/kg/day

• Children (by weight and age): 4–6 mcg/kg/day at 1–5 years; 2–4 mcg/kg/day at 6–12 years

Monitoring Parameters:

• TSH and Free T4 levels every 6–8 weeks after initiation or dose adjustment

• Annual TSH checks once stable

• Monitor for signs of under- or over-treatment

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Pharmacokinetics

• Absorption: ~40–80% bioavailability; peaks in 2–4 hours

• Distribution: High protein binding (>99%, mainly to thyroxine-binding globulin, TBG)

• Metabolism: Peripheral deiodination to T3 (active) and reverse T3 (inactive)

• Half-life: ~6–7 days (shortened in hyperthyroid state, prolonged in hypothyroidism)

• Elimination: Renal (80%) and fecal routes

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Contraindications

• Known hypersensitivity to levothyroxine or excipients

• Untreated thyrotoxicosis

• Acute myocardial infarction

• Uncorrected adrenal insufficiency

• Thyrotoxicosis (e.g., uncontrolled Graves’ disease)

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Special Warnings and Precautions

1. Cardiovascular Risk:

   • Excess dosing may induce angina, arrhythmias, heart failure

   • Use caution in ischemic heart disease and elderly patients

2. Adrenal Insufficiency:

   • Must be treated before initiating levothyroxine to avoid adrenal crisis

3. Bone Loss:

   • Long-term over-replacement may lead to reduced bone mineral density, especially in postmenopausal women

4. Weight Loss Abuse:

   • Not approved for obesity or weight loss; misuse can cause serious toxicity

5. Malabsorption:

   • Common in celiac disease, atrophic gastritis, H. pylori infection, or post-bariatric surgery

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Adverse Effects

Properly dosed levothyroxine is generally well-tolerated. Adverse effects usually arise from over- or under-dosing.

Signs of Overdose (Hyperthyroid symptoms):

• Palpitations

• Tachycardia or arrhythmia

• Anxiety, tremor, insomnia

• Weight loss despite normal appetite

• Menstrual irregularities

• Heat intolerance

• Diarrhea

• Osteopenia or fractures (with long-term excess)

Signs of Under-treatment (Hypothyroid symptoms):

• Fatigue

• Constipation

• Depression

• Bradycardia

• Cold intolerance

• Dry skin, hair loss

• Menstrual irregularities

• Poor concentration

Allergic reactions:

• Rare, often due to inactive ingredients (e.g., dyes, lactose)

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Drug Interactions

Drugs that reduce levothyroxine absorption:

• Iron supplements (ferrous sulfate)

• Calcium carbonate

• Aluminum hydroxide (antacids)

• Sucralfate

• Proton pump inhibitors (omeprazole)

• Bile acid sequestrants (cholestyramine)

• Soy and fiber-rich foods

Drugs affected by levothyroxine:

• Warfarin: Enhances anticoagulant effect (↑ INR)

• Insulin and antidiabetics: May require dose adjustment as metabolism increases

• Digoxin: Decreased serum digoxin concentration

Drugs that alter thyroid hormone metabolism:

• Rifampin, carbamazepine, phenytoin (↑ hepatic metabolism)

• Estrogen (↑ TBG levels; may need dose increase)

• Amiodarone (inhibits T4 → T3 conversion; contains iodine)

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Use in Pregnancy and Lactation

Pregnancy:

• Category A (safe)

• Thyroxine demand increases in pregnancy (due to increased TBG)

• Dose often needs to be increased by 30–50% during pregnancy

• Hypothyroidism during pregnancy is associated with miscarriage, preeclampsia, and cognitive impairment in the fetus

Lactation:

• Excreted in small amounts in breast milk

• Considered safe; no known adverse effects in nursing infants

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Overdose and Toxicity

Acute Overdose:

• Symptoms may be delayed by several days

• Agitation, hyperthermia, tachycardia, tremor

• Severe: atrial fibrillation, seizures, cardiac arrest

Chronic Overdose:

• Osteoporosis

• Cardiac hypertrophy and dysfunction

• Menstrual disturbances

• Psychiatric symptoms (e.g., mania, anxiety)

Treatment:

• Supportive therapy

• Beta-blockers (e.g., propranolol) for symptom control

• Cholestyramine or activated charcoal to reduce absorption (if recent ingestion)

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Patient Counseling Points

• Take on an empty stomach, 30–60 minutes before breakfast

• Take separately from calcium, iron, antacids, or soy products by at least 4 hours

• Consistency in brand and timing is essential for stable hormone levels

• Do not discontinue or change dose without consulting a doctor

• Monitoring of TSH and Free T4 is essential after dose changes

• Notify healthcare provider if symptoms of over- or under-replacement occur

• Store at room temperature, protected from light and moisture

• Alert dentist or other physicians to levothyroxine therapy due to interaction potential