Levothyroxine

Thyroid Hormone Replacement; Hormone Replacement Therapy. Specifically, it's a synthetic T4 hormone.

Levothyroxine is a synthetic form of thyroxine (T4), the primary hormone produced by the thyroid gland. After absorption, T4 is converted to its active form, triiodothyronine (T3), primarily in the liver and peripheral tissues via deiodination. T3 then enters target cells and binds to thyroid hormone receptors (TRs) in the nucleus. This binding modulates gene expression, influencing a wide range of physiological processes including metabolism, growth, and development. The net effect is to increase basal metabolic rate, stimulate protein synthesis, and enhance the effects of catecholamines.

Absorption: • Absorption occurs primarily in the small intestine and is highly variable, influenced by factors such as food, gastric pH, and concomitant medications. Absorption can be reduced by 30-70% when taken with food. Distribution: • Levothyroxine is highly protein-bound (approximately 99.97%) to thyroxine-binding globulin (TBG), albumin, and transthyretin. Only a small fraction of circulating T4 is unbound and biologically active. Metabolism: • Primarily metabolized in the liver and kidneys via deiodination to form T3, the active form. It also undergoes glucuronidation and sulfation. Excretion: • A small amount of unchanged levothyroxine and its metabolites are excreted in the bile and feces. The majority of metabolites are excreted in the urine. Half-life: • Approximately 6-8 days for T4. T3 has a shorter half-life of approximately 1 day. However, due to the T4 to T3 conversion and tissue binding, the physiological effects of levothyroxine can last for several weeks.

Levothyroxine increases basal metabolic rate, oxygen consumption, and heat production. It affects nearly every physiological system in the body, including the cardiovascular, neurological, and skeletal systems. It promotes growth and development, particularly in children. Thyroid hormone also influences carbohydrate, protein, and fat metabolism, and increases the number of beta-adrenergic receptors in the heart.

• Hypothyroidism: Treatment of all causes of hypothyroidism, including primary hypothyroidism (thyroid gland failure), secondary hypothyroidism (pituitary gland failure), and post-surgical hypothyroidism. • Thyroid Suppression Therapy: Suppression of thyroid stimulating hormone (TSH) in patients with well-differentiated thyroid cancer after thyroidectomy. • Diagnostic Use: Diagnostic suppression test for suspected thyroid disorders. • Pituitary TSH Suppression: Treatment of subclinical hypothyroidism with elevated TSH levels.

Absolute: • Untreated adrenal insufficiency: Levothyroxine can exacerbate symptoms of adrenal insufficiency. • Acute myocardial infarction: Levothyroxine can increase myocardial oxygen demand and worsen cardiac ischemia. Relative: • Cardiac arrhythmias: Levothyroxine can worsen pre-existing arrhythmias. • Hyperthyroidism: Levothyroxine should not be used in patients with hyperthyroidism. • Significant cardiovascular disease: Use with caution and lower starting doses in patients with angina or severe heart failure.

Hypothyroidism: Initial dosing is individualized based on factors like age, weight, severity of hypothyroidism, and cardiac status. • Adults: Starting dose typically 25-75 mcg/day, with adjustments based on TSH levels. • Elderly: Lower starting doses (e.g., 12.5-25 mcg/day) are recommended due to increased sensitivity. • Children: Dosing is based on weight and age, typically starting at 10-15 mcg/kg/day. Thyroid Cancer Suppression: Dosage is determined by the oncologist based on the individual’s risk stratification and TSH goal. Administration: Levothyroxine should be taken on an empty stomach, at least 30-60 minutes before breakfast, with water. Consistency in administration is crucial.

Pediatric: Dosing requires careful titration based on growth and development parameters, as well as TSH levels. Congenital hypothyroidism requires early and consistent treatment to prevent neurological damage. Geriatric: Patients are more susceptible to cardiac effects; initiate therapy with lower doses and titrate slowly. Renal impairment: No significant dosage adjustment is typically needed, but monitor closely for signs of toxicity. Hepatic impairment: May require lower starting doses and slower titration due to altered protein binding and metabolism.

Common (>10%): • Anxiety, nervousness, irritability • Weight loss • Increased appetite • Heat intolerance • Sweating • Tremor Serious (<1%): • Cardiac arrhythmias (especially in patients with pre-existing heart disease) • Myocardial infarction • Angina pectoris • Adrenal insufficiency (when coexisting adrenal insufficiency is unmasked) • Exacerbation of hypercalcemia

• Calcium supplements/Antacids (containing aluminum or magnesium): Decrease absorption of levothyroxine. Administer levothyroxine at least 4 hours apart. • Iron supplements: Decrease absorption of levothyroxine. Administer levothyroxine at least 4 hours apart. • Cholestyramine/Colestipol: Bind to levothyroxine in the gut, reducing absorption. • Warfarin: Levothyroxine can increase the effects of warfarin, increasing the risk of bleeding. • Digoxin: Levothyroxine may increase digoxin levels, potentially leading to toxicity. • SSRIs: May interfere with T4 to T3 conversion.

• Cardiac Effects: Levothyroxine can worsen or precipitate cardiac arrhythmias and angina, particularly in patients with pre-existing cardiovascular disease. Monitor cardiac status closely. • Adrenal Insufficiency: Levothyroxine can exacerbate underlying adrenal insufficiency. Assess adrenal function before starting therapy. • Myxedema Coma: Abrupt discontinuation of levothyroxine can precipitate myxedema coma, a life-threatening condition. Do not discontinue abruptly. • Impaired Fertility: Hypothyroidism and its treatment can affect fertility.

Pregnancy: Levothyroxine is generally considered safe during pregnancy. Thyroid hormone requirements often increase during pregnancy, necessitating dosage adjustments. Adequate thyroid hormone levels are crucial for fetal neurodevelopment. FDA Pregnancy Category A. Lactation: Levothyroxine is excreted in breast milk, but the amount is usually insufficient to cause harm to the infant. Monitor the infant for signs of hyperthyroidism.

• TSH levels: Primary monitoring parameter to assess treatment efficacy. Levels should be checked 6-8 weeks after initiation or dosage adjustments. • Free T4 levels: Can be used to assess thyroid hormone status, particularly when TSH levels are discordant with clinical symptoms. • Clinical assessment: Monitor for symptoms of hyper- or hypothyroidism (e.g., heart rate, weight, energy levels).

• Adherence: Emphasize the importance of taking levothyroxine consistently on an empty stomach, at the same time each day. • Drug Interactions: Advise patients to inform their healthcare provider of all medications they are taking, including over-the-counter drugs and supplements. • Symptoms to Report: Instruct patients to report any symptoms of hyper- or hypothyroidism (e.g., palpitations, weight changes, anxiety, fatigue). • Lifelong Therapy: Explain that hypothyroidism usually requires lifelong treatment with levothyroxine.

Store at room temperature, protected from light and moisture. Keep out of reach of children.

• Absorption Variability: Be aware of factors affecting levothyroxine absorption (food, medications, gastrointestinal disorders) and counsel patients accordingly. • TSH Goal: Individualize TSH goals based on patient factors such as age, cardiovascular status, and pregnancy status. • Generic Substitution: While generally acceptable, be aware that different generic formulations may have slightly different bioavailability, potentially requiring dosage adjustments.

• American Thyroid Association (ATA) Guidelines for the Management of Hypothyroidism: https://www.thyroid.org/professionals/clinical-practice-guidelines/ • Jameson JL, et al. Principles of Adult Endocrinology. 4th ed. New York, NY: McGraw-Hill; 2018. • Lexicomp. Levothyroxine. Wolters Kluwer Health, Inc. [Accessed October 26, 2023]