THYRION-50

Indications

• Hypothyroidism
• Thyroid hormone replacement therapy
• Goiter (as part of treatment)
• Thyroid cancer (in certain cases)

Dosage

Children: For children, dosing is determined by age and weight, and specific guidance should be referred from the BNF for Children.

Adults: The initial dose for adults varies based on clinical circumstances and should be titrated according to TSH levels. Typically, a starting dose is around 50-100 micrograms daily, adjusted as necessary.

Mechanism of action

Levothyroxine acts as a replacement for the deficient thyroid hormone T4 in conditions like hypothyroidism. It increases metabolic rate by decreasing thyroid-stimulating hormone (TSH) production from the pituitary gland and is converted to triiodothyronine (T3) in peripheral tissues, which has more potent metabolic effects. This hormone regulates numerous biochemical pathways that influence growth, metabolism, and overall energy levels in the body.

Pharmacodynamics

Levothyroxine maintains normal T4 levels in individuals with deficiency, exerting physiological effects similar to endogenous T4. It has a narrow therapeutic index, necessitating careful dose titration to achieve a euthyroid state, typically monitored via TSH levels. Over-treatment can lead to hyperthyroid symptoms, whereas under-treatment can cause symptoms of hypothyroidism. Regular monitoring is essential to avoid adverse effects on growth, cardiac function, and metabolism.

Pharmacokinetics

Levothyroxine is well-absorbed from the gastrointestinal tract, with peak plasma concentrations occurring approximately 2 to 4 hours post-administration. It has a long half-life, allowing for once-daily dosing, and is metabolized in the liver and other tissues, with a significant portion excreted as metabolites in urine. The pharmacokinetics can be affected by various factors including age, weight, gastrointestinal health, and interactions with other medications.

Adverse effects

• Increased heart rate
• Diarrhea
• Tremors
• Hypercalcemia
• Weakness
• Weight loss
• Heat intolerance
• Increased appetite

Interactions

• voxilaprevir with sofosbuvir and velpatasvir: Severe (increases absorption)
• oral antacids: Unknown (decreases absorption)
• apalutamide: Unknown (decreases exposure)
• oral calcium salts: Unknown (decreases absorption)
• ritonavir: Unknown (decreases concentration)
• oral iron: Unknown (decreases absorption)
• sucralfate: Unknown (decreases absorption)

Precautions

• Monitor thyroid-stimulating hormone (TSH) levels regularly to maintain a euthyroid state
• Titration of dose should be done slowly and carefully to avoid over- or under-treatment
• Patients should be monitored for responses to titration to prevent negative effects on growth, cardiovascular function, and metabolism

Pregnancy

Levothyroxine is considered safe during pregnancy; however, dosages may need to be adjusted to maintain normal thyroid hormone levels.

Breast-feeding

Levothyroxine is excreted in breast milk but in amounts that are not expected to harm a nursing infant; monitoring is recommended.

Storage

Store at room temperature, away from moisture and heat. Keep out of reach of children.

Formulations

• Tablets
• Oral solution

Indications

• Primary hypothyroidism
• Subclinical hypothyroidism
• Secondary hypothyroidism due to pituitary disease
• Congenital hypothyroidism
• Thyroid hormone replacement in patients with thyroidectomy
• Management of myxedema coma (in emergency settings)
• Hypothyroidism in patients with cardiac disease (with caution)

Dosage

Adults: Initially 1.6 micrograms/kg once daily, adjusted according to response, round dose to the nearest 25 micrograms. For the elderly, initially 25–50 micrograms once daily, adjusted in steps of 25 micrograms every 4 weeks

Mechanism of action

Levothyroxine sodium acts as a replacement for endogenous thyroxine, binding to thyroid hormone receptors in the nucleus of cells. This initiates the transcription of genes that regulate various metabolic processes, including protein synthesis, carbohydrate metabolism, and lipid metabolism. The increase in metabolic rate enhances the overall physiological processes in the body, promoting normal growth and development.

Pharmacodynamics

The pharmacodynamic effects of levothyroxine sodium include increased basal metabolic rate, enhancement of gluconeogenesis and glycogenolysis, and promotion of protein synthesis. It also plays a vital role in the development of the central nervous system and regulates the metabolism of carbohydrates and fats. The effects are dose-dependent, with higher doses leading to more pronounced effects on metabolism.

Pharmacokinetics

Levothyroxine sodium is well-absorbed from the gastrointestinal tract, with peak plasma concentrations occurring within 2 to 4 hours after oral administration. It has a half-life of approximately 6 to 7 days, allowing for once-daily dosing. The drug is extensively bound to plasma proteins, primarily thyroxine-binding globulin, and is metabolized predominantly in the liver. Renal impairment may prolong its half-life, necessitating dose adjustments in patients with compromised renal function.

Adverse effects

• Hyperthyroidism
• Allergic reactions
• Cardiac arrhythmias
• Osteoporosis
• Weight loss
• Nervousness
• Insomnia
• Menstrual irregularities
• Heat intolerance
• Tremors

Interactions

• Anticoagulants (e.g., warfarin) - increased effect
• Antidiabetic agents - possible alteration in blood glucose control
• Cholestyramine - may reduce levothyroxine absorption
• Calcium and iron supplements - may interfere with absorption
• Certain antidepressants (e.g., sertraline) - may require dose adjustment
• Estrogens - may increase levothyroxine requirements

Precautions

• Cardiac disease - need for careful dose adjustment
• Adrenal insufficiency - should be treated before starting levothyroxine
• Monitoring of thyroid levels is essential to avoid over-treatment
• Caution in patients with impaired hepatic or renal function

Pregnancy

Levothyroxine is considered safe during pregnancy, but dose adjustments may be required to maintain normal thyroid function.

Breast-feeding

Levothyroxine is excreted in breast milk in small amounts, but it is generally considered safe for use during breastfeeding.

Storage

Store in a cool, dry place away from light. Do not store above 25 degrees Celsius.

Formulations

• Tablets (various strengths)
• Oral solution

Mechanism of action

Levothyroxine is a synthetically prepared levo-isomer of the thyroid hormone thyroxine (T₄, a tetra-iodinated tyrosine derivative) that acts as a replacement in deficiency syndromes such as hypothyroidism. T₄ is the major hormone secreted from the thyroid gland and is chemically identical to the naturally secreted T₄: it increases metabolic rate, decreases thyroid-stimulating hormone (TSH) production from the anterior lobe of the pituitary gland, and, in peripheral tissues, is converted to T₃. Thyroxine is released from its precursor protein thyroglobulin through proteolysis and secreted into the blood where is it then peripherally deiodinated to form triiodothyronine (T₃) which exerts a broad spectrum of stimulatory effects on cell metabolism. T₄ and T₃ have a relative potency of ~1:4. Thyroid hormone increases the metabolic rate of cells of all tissues in the body. In the fetus and newborn, thyroid hormone is important for the growth and development of all tissues including bones and the brain. In adults, thyroid hormone helps to maintain brain function, food metabolism, and body temperature, among other effects. The symptoms of thyroid deficiency relieved by levothyroxine include slow speech, lack of energy, weight gain, hair loss, dry thick skin and unusual sensitivity to cold. The thyroid hormones have been shown to exert both genomic and non-genomic effects. They exert their genomic effects by diffusing into the cell nucleus and binding to thyroid hormone receptors in DNA regions called thyroid hormone response elements (TREs) near genes. This complex of T₄, T₃, DNA, and other coregulatory proteins causes a conformational change and a resulting shift in transcriptional regulation of nearby genes, synthesis of messenger RNA, and cytoplasmic protein production. For example, in cardiac tissues T₃ has been shown to regulate the genes for α- and β-myosin heavy chains, production of the sarcoplasmic reticulum proteins calcium-activated ATPase (Ca2+-ATPase) and phospholamban, β-adrenergic receptors, guanine-nucleotide regulatory proteins, and adenylyl cyclase types V and VI as well as several plasma-membrane ion transporters, such as Na+/K+–ATPase, Na+/Ca2+ exchanger, and voltage-gated potassium channels, including Kv1.5, Kv4.2, and Kv4.3. As a result, many cardiac functions including heart rate, cardiac output, and systemic vascular resistance are closely linked to thyroid status. The non-genomic actions of the thyroid hormones have been shown to occur through binding to a plasma membrane receptor integrin aVb3 at the Arg-Gly-Asp recognition site. From the cell-surface, T₄ binding to integrin results in down-stream effects including activation of mitogen-activated protein kinase (MAPK; ERK1/2) and causes subsequent effects on cellular/nuclear events including angiogenesis and tumor cell proliferation.

Pharmacodynamics

Oral levothyroxine is a synthetic hormone that exerts the same physiologic effect as endogenous T₄, thereby maintaining normal T₄ levels when a deficiency is present. Levothyroxine has a narrow therapeutic index and is titrated to maintain a euthyroid state with TSH (thyroid stimulating hormone) within a therapeutic range of 0.4–4.0 mIU/L. Over- or under-treatment with levothyroxine may have negative effects on growth and development, cardiovascular function, bone metabolism, reproductive function, cognitive function, emotional state, gastrointestinal function and glucose and lipid metabolism. The dose of levothyroxine should be titrated slowly and carefully and patients should be monitored for their response to titration to avoid these effects. TSH levels should be monitored at least yearly to avoid over-treating with levothyroxine which can result in hyperthyroidism (TSH <0.1mIU/L) and symptoms of increased heart rate, diarrhea, tremor, hypercalcemia, and weakness to name a few. As many cardiac functions including heart rate, cardiac output, and systemic vascular resistance are closely linked to thyroid status, over-treatment with levothyroxine may result in increases in heart rate, cardiac wall thickness, and cardiac contractility and may precipitate angina or arrhythmias, particularly in patients with cardiovascular disease and in elderly patients. In populations with any cardiac concerns, levothyroxine should be initiated at lower doses than those recommended in younger individuals or in patients without cardiac disease. Patients receiving concomitant levothyroxine and sympathomimetic agents should be monitored for signs and symptoms of coronary insufficiency. If cardiac symptoms develop or worsen, reduce the levothyroxine dose or withhold for one week and restart at a lower dose. Increased bone resorption and decreased bone mineral density may occur as a result of levothyroxine over-replacement, particularly in post-menopausal women. The increased bone resorption may be associated with increased serum levels and urinary excretion of calcium and phosphorous, elevations in bone alkaline phosphatase and suppressed serum parathyroid hormone levels. Administer the minimum dose of levothyroxine that achieves the desired clinical and biochemical response to mitigate this risk. Addition of levothyroxine therapy in patients with diabetes mellitus may worsen glycemic control and result in increased antidiabetic agent or insulin requirements. Carefully monitor glycemic control after starting, changing or discontinuing levothyroxine.