Levothyroxine

Levothyroxine: A Comprehensive Overview

Levothyroxine sodium is a synthetic form of thyroxine (T4), a naturally occurring hormone produced by the thyroid gland. It is a crucial medication primarily used to treat hypothyroidism, a condition characterized by an underactive thyroid gland that doesn’t produce enough thyroid hormone. This comprehensive overview will delve into various aspects of levothyroxine, including its mechanism of action, indications, dosage and administration, pharmacokinetics, drug interactions, precautions, adverse effects, and its role in specific populations.

1. Mechanism of Action

The thyroid gland primarily secretes thyroxine (T4) and a smaller amount of triiodothyronine (T3), which is the biologically active form of the hormone. Levothyroxine, being synthetic T4, acts as a replacement or supplement for the endogenous hormone. The physiological effects of thyroid hormones are broad and impact virtually every system in the body, including metabolism, growth, and development.

1.1. Conversion to Triiodothyronine (T3)

While levothyroxine is administered as T4, its primary mechanism of action involves its conversion to T3 in peripheral tissues, mainly the liver and kidneys. This conversion is catalyzed by enzymes called deiodinases. T3 then enters the cell nucleus and binds to thyroid hormone receptors, which are nuclear proteins attached to DNA.

1.2. Genomic Effects

The binding of T3 to thyroid hormone receptors initiates genomic effects by influencing DNA transcription. This process leads to the activation or repression of specific genes, resulting in altered synthesis of messenger RNA (mRNA) and subsequent changes in the concentration of various proteins. These protein changes are responsible for the diverse metabolic and physiological effects of thyroid hormones. For instance, thyroid hormones increase basal metabolic rate by enhancing oxygen consumption and heat production. They also play a critical role in gluconeogenesis, protein synthesis, and the mobilization of glycogen stores.

1.3. Non-Genomic Effects

In addition to its genomic actions, thyroid hormones also exert non-genomic effects by interacting with plasma membrane receptors and intracellular signaling pathways. These effects can occur more rapidly than genomic actions and involve processes such as ion transport and enzyme activity.

2. Indications

Levothyroxine is primarily indicated as replacement therapy for hypothyroidism of any etiology, including:

Primary Hypothyroidism (Thyroidal): This results from a defect in the thyroid gland itself. Common causes include autoimmune thyroiditis (Hashimoto’s disease), iatrogenic hypothyroidism (after thyroidectomy or radioactive iodine treatment), congenital hypothyroidism, and iodine deficiency.
Secondary Hypothyroidism (Pituitary): This occurs when the pituitary gland fails to secrete sufficient thyroid-stimulating hormone (TSH), which is necessary to stimulate thyroid hormone production.
Tertiary Hypothyroidism (Hypothalamic): This is a rare form resulting from insufficient secretion of thyrotropin-releasing hormone (TRH) by the hypothalamus, which in turn leads to decreased TSH and thyroid hormone levels.
Beyond replacement therapy, levothyroxine may also be used for:

TSH Suppression: In some patients with thyroid cancer or benign thyroid nodules, levothyroxine may be used to suppress TSH levels, which can help to inhibit the growth of thyroid tissue.
Myxedema Coma: This is a severe, life-threatening form of hypothyroidism requiring intravenous levothyroxine administration.

3. Dosage and Administration

The dosage of levothyroxine is highly individualized and depends on various factors, including the patient’s age, weight, the severity and etiology of hypothyroidism, cardiovascular status, and concomitant medical conditions.

3.1. General Administration

Levothyroxine is typically administered orally once daily, preferably on an empty stomach, 30 minutes to one hour before breakfast. This is to ensure optimal absorption.
It should be taken with a full glass of water.
Consistency in the time of administration each day is important to maintain stable hormone levels.
3.2. Starting Dose

The initial starting dose varies widely. In otherwise healthy adults with overt hypothyroidism, a common starting dose is 50 mcg per day, with adjustments made based on clinical response and thyroid function tests (TSH and free T4 levels).
In elderly patients or those with underlying cardiovascular disease, a lower starting dose (e.g., 12.5 to 25 mcg per day) is recommended to avoid cardiac stress, with gradual increases as tolerated.
For congenital hypothyroidism in neonates and infants, the starting dose is based on body weight and is typically higher to ensure normal growth and neurodevelopment.
3.3. Dosage Adjustments

Dosage adjustments are made based on periodic monitoring of TSH levels and clinical symptoms. The goal is to achieve and maintain TSH levels within the target reference range.
TSH levels are usually checked every 4 to 6 weeks after initiating therapy or making a dosage change.
Once a stable euthyroid state is achieved, monitoring may be done less frequently (e.g., annually).
3.4. Administration in Specific Populations

Pediatric Patients: Dosage is weight-based and higher relative to adults due to the importance of thyroid hormone for growth and development. Tablets can be crushed and mixed with a small amount of water for infants and young children who cannot swallow whole tablets, and administered immediately. Mixing with soy-based formula should be avoided as it can impair absorption.
Pregnant Women: Levothyroxine requirements often increase during pregnancy. TSH levels should be monitored closely, and dosage adjustments are frequently necessary to maintain optimal thyroid hormone levels for both the mother and the developing fetus.
Geriatric Patients: As mentioned earlier, a lower starting dose and slower titration are usually warranted due to increased sensitivity to the effects of thyroid hormone and a higher prevalence of cardiovascular disease.
3.5. Intravenous Administration

In cases of myxedema coma or when oral administration is not feasible, intravenous levothyroxine sodium is available. The intravenous dose is generally about 50% of the oral dose.

4. Pharmacokinetics

Understanding the pharmacokinetic properties of levothyroxine is crucial for effective management of hypothyroidism.

4.1. Absorption

Oral levothyroxine is primarily absorbed in the jejunum and upper ileum of the small intestine.
The extent of absorption varies, ranging from 40% to 80%, and is influenced by factors such as the formulation of the tablet, gastric pH, the presence of food, and gastrointestinal motility.
Absorption is generally enhanced in a fasting state, which is why it is recommended to take levothyroxine on an empty stomach.
Certain substances, including dietary fiber, calcium supplements, iron supplements, and some medications, can interfere with levothyroxine absorption.
4.2. Distribution

Once absorbed, levothyroxine is transported in the bloodstream and is highly bound (over 99%) to plasma proteins, primarily thyroxine-binding globulin (TBG), thyroxine-binding prealbumin (transthyretin), and albumin.
Only the unbound (free) hormone is biologically active and available for tissue uptake.
Conditions or medications that affect the concentration or binding affinity of these plasma proteins can influence the levels of free thyroid hormone and thus the clinical response to levothyroxine.
4.3. Metabolism

Levothyroxine is primarily metabolized in the liver through deiodination. This process converts T4 to the more active T3 and also to reverse T3 (rT3), an inactive form.
Peripheral tissues, including the kidneys, also contribute to the deiodination of T4 to T3.
4.4. Excretion

The primary route of excretion for thyroid hormones is the kidneys.
A small amount of T4 is also excreted in the feces.
The half-life of levothyroxine is relatively long, approximately 6 to 7 days in euthyroid individuals. This long half-life allows for once-daily dosing and contributes to the stability of thyroid hormone levels. However, it also means that changes in dosage may take several weeks to reach a steady state.

5. Drug Interactions

Levothyroxine can interact with a wide range of medications and certain foods, potentially affecting its absorption, metabolism, or the patient’s response.

5.1. Substances Affecting Levothyroxine Absorption

Several substances can decrease the absorption of levothyroxine from the gastrointestinal tract if taken concurrently or too close in time:

Antacids: Especially those containing aluminum hydroxide, magnesium hydroxide, or calcium carbonate.
Calcium Supplements: Calcium carbonate and calcium citrate.
Iron Supplements: Ferrous sulfate, ferrous gluconate.
Cholestyramine and Colestipol: Bile acid sequestrants.
Sucralfate: A mucosal protectant.
Proton Pump Inhibitors (PPIs): Such as omeprazole, lansoprazole, and esomeprazole, may slightly reduce absorption.
Histamine H2-Receptor Antagonists: Such as ranitidine and famotidine, may also have a minor effect.
Phosphate Binders: Such as sevelamer and lanthanum carbonate.
Orlistat: A weight-loss medication that inhibits fat absorption.
Certain Foods: Soybean flour, cottonseed meal, walnuts, and dietary fiber can impair absorption. Grapefruit and grapefruit juice may also have an effect.
It is generally recommended to administer levothyroxine at least 4 hours before or after these substances.

5.2. Substances Affecting Levothyroxine Metabolism and Thyroid Hormone Levels

Amiodarone: An antiarrhythmic drug that can inhibit the peripheral conversion of T4 to T3 and may lead to either hypo- or hyperthyroidism.
Phenytoin, Carbamazepine, and Rifampin: These drugs can increase the hepatic metabolism of thyroid hormones, potentially leading to decreased levothyroxine efficacy and requiring a higher dose.
Estrogens (including oral contraceptives): Can increase TBG levels, leading to higher total T4 and T3 but often maintaining normal free hormone levels. However, some women may require a slight increase in levothyroxine dosage.
Anabolic Steroids and Androgens: Can decrease TBG levels, potentially lowering total T4 and T3 but usually not affecting free hormone levels significantly.
5.3. Effects of Levothyroxine on Other Drugs

Oral Anticoagulants (e.g., Warfarin): Levothyroxine can enhance the effect of oral anticoagulants, increasing the risk of bleeding. Monitoring of coagulation parameters (INR) is essential, and the anticoagulant dose may need to be adjusted.
Antidiabetic Agents (Insulin and Oral Hypoglycemics): Thyroid hormone can affect glucose metabolism. In hypothyroid patients starting levothyroxine, the requirements for insulin or oral antidiabetic drugs may change, necessitating careful monitoring of blood glucose levels and potential dosage adjustments.
Digitalis Glycosides (e.g., Digoxin): Levothyroxine may reduce the serum levels of digitalis glycosides, potentially decreasing their therapeutic effect.
Beta-Adrenergic Blocking Agents (Beta-Blockers): The effects of some beta-blockers may be altered when a hypothyroid patient becomes euthyroid.
Tricyclic Antidepressants: Concurrent use may increase the therapeutic and toxic effects of both drugs, possibly due to increased sensitivity to catecholamines.
Sympathomimetic Agents (e.g., Decongestants): Levothyroxine can increase the sensitivity to sympathomimetic amines, potentially increasing the risk of cardiovascular side effects.
Ketamine: Marked hypertension and tachycardia have been reported with concomitant administration of levothyroxine and ketamine.

6. Precautions

Certain medical conditions and situations require careful consideration and monitoring when using levothyroxine.

Cardiovascular Disease: In patients with pre-existing cardiovascular disease, levothyroxine should be initiated at a low dose with gradual titration to avoid precipitating angina, arrhythmias, or myocardial infarction due to increased metabolic demand on the heart.
Adrenal Insufficiency: Untreated adrenal insufficiency can be exacerbated by thyroid hormone replacement. An adrenal crisis may occur. Therefore, adrenal insufficiency should be corrected with glucocorticoid therapy before starting levothyroxine.
Diabetes Mellitus: As mentioned in drug interactions, levothyroxine can affect glycemic control, requiring careful monitoring and potential adjustment of antidiabetic medication dosages.
Osteoporosis: Overtreatment with levothyroxine, leading to hyperthyroidism, can accelerate bone resorption and decrease bone mineral density, increasing the risk of osteoporosis and fractures, particularly in postmenopausal women. The lowest effective dose should be used.
Myxedema Coma: Oral levothyroxine is not recommended for the treatment of myxedema coma, which requires intravenous administration.
Allergies: Patients with known hypersensitivity to levothyroxine or any of the inactive ingredients in the formulation should avoid its use.
Pregnancy and Breastfeeding: Levothyroxine is generally considered safe during pregnancy and breastfeeding, but dosage adjustments are often necessary during pregnancy. Thyroid hormone is excreted in breast milk in low concentrations, and adverse effects on the infant are unlikely at therapeutic maternal doses. However, monitoring of thyroid function in both the mother and the infant may be warranted.
Switching Brands: Different formulations of levothyroxine may have slightly different bioavailability. Switching between brands is generally not recommended unless clinically necessary, and if a switch is made, close monitoring of TSH levels and clinical response is advisable, as dosage adjustments may be needed.

7. Adverse Effects

Levothyroxine is generally well-tolerated when the dosage is appropriately adjusted to achieve a euthyroid state. Adverse effects are usually associated with either undertreatment (hypothyroidism) or overtreatment (hyperthyroidism).

7.1. Symptoms of Undertreatment (Hypothyroidism)

These occur when the levothyroxine dose is too low and the patient remains hypothyroid. Symptoms can include:

Fatigue, lethargy
Weight gain
Cold intolerance
Constipation
Dry skin and hair
Muscle weakness
Depression
Slow heart rate
Impaired memory and concentration
7.2. Symptoms of Overtreatment (Hyperthyroidism)

These occur when the levothyroxine dose is too high, leading to excessive thyroid hormone levels. Symptoms can include:

Palpitations, rapid heart rate
Anxiety, nervousness, irritability
Insomnia
Tremors
Sweating, heat intolerance
Weight loss
Diarrhea
Increased appetite
Hair loss
Menstrual irregularities
7.3. Less Common but Serious Adverse Effects

Cardiac Adverse Reactions: Especially in elderly patients and those with underlying cardiovascular disease, overtreatment can lead to arrhythmias, angina, myocardial infarction, and even death.
Decreased Bone Mineral Density: Long-term suppression of TSH with high doses of levothyroxine can increase bone resorption and the risk of osteoporosis.
Thyroid Storm: A rare but life-threatening condition resulting from severe hyperthyroidism, which can be precipitated by excessive levothyroxine dosage.
Hypersensitivity Reactions: Although rare, allergic reactions such as rash, urticaria, and angioedema can occur.

8. Use in Specific Populations (Reiterated)

Pediatric Use: Crucial for normal growth and development. Monitoring for clinical and laboratory response is essential. Over-treatment should be avoided due to potential effects on bone maturation and growth.
Geriatric Use: Increased risk of cardiac adverse reactions necessitates lower starting doses and slower titration.
Pregnancy: Dosage requirements often increase. Careful monitoring of TSH is crucial for both maternal and fetal well-being.
Lactation: Generally considered safe at usual therapeutic doses.

9. Overdosage

Signs and symptoms of levothyroxine overdose are those of hyperthyroidism and may include rapid heartbeat, palpitations, nervousness, irritability, tremors, sweating, diarrhea, and excessive hunger. Massive overdose may result in more severe symptoms such as hyperthermia, tachycardia, arrhythmias, hypotension, seizures, and coma.

Management of overdose is primarily symptomatic and supportive. Beta-blockers may be used to control adrenergic effects such as tachycardia and tremors. In cases of recent ingestion, activated charcoal may be considered to reduce absorption. Extreme caution is warranted in patients with cardiac disease, as increased thyroid hormone levels can exacerbate their condition.

10. Conclusion

Levothyroxine is a cornerstone in the management of hypothyroidism, effectively replacing or supplementing endogenous thyroid hormone. Its proper use requires careful individualization of dosage based on clinical assessment and thyroid function tests, along with consideration of potential drug interactions and precautions. While generally safe and well-tolerated, both under- and overtreatment can lead to adverse effects. Ongoing monitoring and communication between the patient and healthcare provider are essential to ensure optimal therapeutic outcomes and maintain a euthyroid state, thereby improving the patient’s quality of life and overall well-being. The long-term nature of thyroid hormone replacement therapy underscores the importance of patient education regarding proper administration, potential interactions, and the signs and symptoms of both hypo- and hyperthyroidism.