Thyroxinol

Uses

Hypothyroidism: As replacement or supplemental therapy in congenital or acquired hypothyroidism of any etiology, except transient hypothyroidism during the recovery phase of subacute-thyroiditis.

Specific indications: Primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) hypothyroidism and subclinical hypothyroidism.

Pituitary TSH Suppression: In the treatment or prevention of various types of euthyroid goiters, subacute or chronic lymphocytic thyroiditis (Hashimoto's thyroiditis), multinodular goiter and, as an adjunct to surgery and radioiodine therapy in the management of thyrotropin-dependent well-differentiated thyroid cancer.

Thyroxinol is also used to associated treatment for these conditions: Adiposity, Cellulite, Hypothyroidism, Myxedema coma, Euthyroid Goitre, Thyrotropin dependent Thyroid cancer

How Thyroxinol works

Thyroxinol 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.

Dosage

Thyroxinol dosage

In order to avoid irregular absorption, Thyroxinol should be taken preferably at a fixed time on an empty stomach. Concomitant intake of food may decrease the absorption of Thyroxinol. Dosing must be individualized and adjustments to be made based on periodic assessment of the patient's clinical response and laboratory parameters.

Adult Dosage:

Initial starting dose: 25-50 mcg/day, with gradual increments in dose at 6-8 week intervals, as needed. The Thyroxinol Sodium dose is generally adjusted in 12.5-25 mcg increments until the patient with primary hypothyroidism is clinically euthyroid and the serum TSH has normalized.

In patients with severe hypothyroidism: Initial dose is 12.5-25 mcg/day with increases of 25 mcg/day every 2-4 weeks, accompanied by clinical and laboratory assessment, until the TSH level is normalized.

In patients with secondary (pituitary) or tertiary (hypothalamic) hypothyroidism: Thyroxinol Sodium dose should be titrated until the patient is clinically euthyroid and the serum free - T 4 level is restored to the upper half of the normal range.For patients older than 50 years or for patients under 50 years of age with underlying cardiac disease: 1.7 mcg/kg/day.

TSH suppression: For thyrotropin-dependent well-differentiated thyroid cancer: Doses >2 mcg/kg/day may be given as a single dose to suppress TSH to <0.1 MIU/L. For benign nodules and nontoxic multinodular goitre: Target TSH is generally higher at 0.1-0.5 MIU/L for nodules and 0.5-1 MIU/L for multinodular goitre.

Pediatric Dosage:

Newborns: The recommended starting dose is 10-15 mcg/kg/day. A lower starting dose should be considered in infants at risk for cardiac failure, and the dose should be increased in 4-6 weeks as needed based on clinical and laboratory response to treatment. In infants with very low (< 5 mcg/dL) or undetectable serum T 4 concentrations, the recommended initial starting dose is 50 mcg/day of Thyroxinol Sodium.

Infants and Children: In children with chronic or severe hypothyroidism, initial dose of 25 mcg/day with increments of 25 mcg every 2-4 weeks until the desired effect is achieved. Hyperactivity in an older child can be minimized if the starting dose is one-fourth of the recommended full replacement dose, and the dose is then increased on a weekly basis by an amount equal to one-fourth the full-recommended replacement dose until the full recommended replacement dose is reached.

Daily dose per kg body weight:

• 0-3 months: 10-15 mcg/kg/day
• 3-6 months: 8-10 mcg/kg/day
• 6-12 months: 6-8 mcg/kg/day
• 1-5 years: 5-6 mcg/kg/day
• 6-12 years: 4-5 mcg/kg/day
• >12 years but growth and puberty incomplete: 2-3 mcg/ kg/ day
• Growth and puberty complete: 1.7 mcg/kg/day

The dose should be adjusted based on clinical response and laboratory parameters.

Side Effects

Adverse reactions associated with Thyroxinol therapy are primarily those of hyperthyroidism due to therapeutic overdose. They include the following:

• General: Fatigue, increased appetite, weight loss, heat intolerance, fever, excessive sweating
• Central nervous system: headache, hyperactivity, nervousness, anxiety, irritability, emotional lability, insomnia
• Musculoskeletal: Tremors, muscle weakness
• Cardiovascular: Palpitations, tachycardia, arrhythmias, increased pulse and blood pressure
• Respiratory: Dyspnea
• Gastrointestinal: Diarrhea, vomiting, abdominal cramps
• Dermatologic: Hair loss, flushing

Toxicity

LD₅₀=20 mg/kg (orally in rat). Hypermetabolic state indistinguishable from thyrotoxicosis of endogenous origin. Symptoms of thyrotoxicosis include weight loss, increased appetite, palpitations, nervousness, diarrhea, abdominal cramps, sweating, tachycardia, increased pulse and blood pressure, cardiac arrhythmias, tremors, insomnia, heat intolerance, fever, and menstrual irregularities.

Precaution

Thyroxinol has a narrow therapeutic index. So, careful dosage titration is necessary to avoid the consequences of over- or under-treatment. Caution is needed when administering Thyroxinol to patients with cardiovascular disorders, to the elderly in whom there is an increased risk of occult cardiac disease & for patients with nontoxic diffuse goiter or nodular thyroid disease in order to prevent precipitation of thyrotoxicosis

Interaction

Concurrent use of tri/tetracyclic antidepressants and Thyroxinol may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on Thyroxinol may result in increased Thyroxinol requirements. Addition of Thyroxinol to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.

Food Interaction

• Avoid calcium supplements/calcium rich foods. Calcium may interfere with the absorption of this drug by forming an insoluble complex. Separate medication administration by at least 4 hours.
• Avoid grapefruit products. Grapefruit may delay the absorption of this medication.
• Avoid iron supplements. Iron may interfere with the absorption of this drug by forming an insoluble complex. Separate medication administration by at least 4 hours.
• Avoid multivalent ions. Examples include iron, magnesium, and calcium. These are often found in antacids, vitamins, and supplements - separate medication administration by at least 4 hours.
• Do not take with bran and high fiber foods. Dietary fiber, soybean flour, cottonseed meal, and walnuts may reduce the absorption of levothyroxine.
• Take on an empty stomach. Thyroxinol should be taken on an empty stomach 30-60 minutes prior to the first meal of the day.

[Moderate] ADJUST DOSING INTERVAL: Consumption of certain foods as well as the timing of meals relative to dosing may affect the absorption of T4 thyroid hormone (i.e., levothyroxine).

T4 absorption is increased by fasting and decreased by foods such as soybean flour (e.g., infant formula), cotton seed meal, walnuts, dietary fiber, calcium, and calcium fortified juices.

MANAGEMENT: Preparations containing T4 thyroid hormone should be administered on a consistent schedule with regard to time of day and relation to meals so as to avoid large fluctuations in serum levels.

Foods that may affect T4 absorption should be avoided within several hours of dosing if possible.

When administered to patients receiving continuous enteral nutrition for more than 7 days, some experts recommend that the tube feeding should be interrupted for at least 1 hour before and 1 hour after the dose of levothyroxine is given and to monitor patients' thyroid function.

Thyroxinol Hypertension interaction

[Major] Thyroid hormones cause increases in myocardial contractility and heart rate as a result of increased metabolic demands and oxygen consumption.

Therapy with thyroid hormones should be administered cautiously and initiated at reduced dosages in patients with cardiovascular disorders such as angina, coronary artery disease, and hypertension.

Clinical monitoring of cardiovascular function is recommended.

If chest pain or exacerbation of cardiovascular disease occurs, the dosage of thyroid hormone should be reduced, even at the expense of achieving euthyroid state.

Thyroid hormones should not be administered to patients with an acute myocardial infarction that is not complicated by hypothyroidism.

Thyroxinol multivitamins interaction

[Moderate] ADJUST DOSING INTERVAL: Concurrent administration of calcium-containing products may decrease the oral bioavailability of levothyroxine by one-third in some patients.

Pharmacologic effects of levothyroxine may be reduced.

The exact mechanism of interaction is unknown but may involve nonspecific adsorption of levothyroxine to calcium at acidic pH levels, resulting in an insoluble complex that is poorly absorbed from the gastrointestinal tract.

In one study, 20 patients with hypothyroidism who were taking a stable long-term regimen of levothyroxine demonstrated modest but significant decreases in mean free and total thyroxine (T4) levels as well as a corresponding increase in mean thyrotropin (thyroid-stimulating hormone, or TSH) level following the addition of calcium carbonate (1200 mg

Four patients had serum TSH levels that were higher than the normal range.

Both T4 and TSH levels returned to near-baseline 2 months after discontinuation of calcium, which further supported the likelihood of an interaction.

In addition, there have been case reports suggesting decreased efficacy of levothyroxine during calcium coadministration.

It is not known whether this interaction occurs with other thyroid hormone preparations.

Some experts recommend separating the times of administration of levothyroxine and calcium-containing preparations by at least 4 hours.

Monitoring of serum TSH levels is recommended.

Patients with gastrointestinal or malabsorption disorders may be at a greater risk of developing clinical or subclinical hypothyroidism due to this interaction.

Thyroxinol Drug Interaction

Minor: metoprolol, metoprololUnknown: aspirin, aspirin, duloxetine, duloxetine, omega-3 polyunsaturated fatty acids, omega-3 polyunsaturated fatty acids, pregabalin, pregabalin, acetaminophen, acetaminophen, cyanocobalamin, cyanocobalamin, ascorbic acid, ascorbic acid, cholecalciferol, cholecalciferol, cetirizine, cetirizine

Thyroxinol Disease Interaction

Major: adrenal insufficiency, cardiovascular disease, thyrotoxicosisModerate: diabetes, seizures

Elimination Route

Absorption of orally administered T4 from the gastrointestinal tract ranges from 40% to 80% with the majority of the levothyroxine dose absorbed from the jejunum and upper ileum. T4 absorption is increased by fasting, and decreased in malabsorption syndromes and by certain foods such as soybeans, milk, and dietary fiber. Absorption may also decrease with age. In addition, many drugs affect T4 absorption including bile acide sequestrants, sucralfate, proton pump inhibitors, and minerals such as calcium (including in yogurt and milk products), magnesium, iron, and aluminum supplements. To prevent the formation of insoluble chelates, levothyroxine should generally be taken on an empty stomach at least 2 hours before a meal and separated by at least 4 hours from any interacting agents.

Half Life

T₄ half-life is 6 to 7 days. T₃ half-life is 1 to 2 days.

Elimination Route

Thyroid hormones are primarily eliminated by the kidneys. A portion of the conjugated hormone reaches the colon unchanged and is eliminated in the feces. Approximately 20% of T₄ is eliminated in the stool. Urinary excretion of T₄ decreases with age.

Pregnancy & Breastfeeding use

Pregnancy Category A. Pregnancy may increase Thyroxinol requirements. Although thyroid hormones are excreted only minimally in human milk, caution should be exercised when it is administered to a nursing woman. However, adequate replacement doses of Thyroxinol are generally needed to maintain normal lactation.

Contraindication

Untreated subclinical or overt thyrotoxicosis of any etiology and acute myocardial infarction.

Acute Overdose

The signs and symptoms of overdose are those of hyperthyroidism – agitation, confusion, irritability, hyperactivity, headache, sweating, mydriasis, tachycardia, arrhythmias, tachypnoea, pyrexia, increased bowel movements and convulsions. Cerebral embolism, shock, coma, and death have been reported. Symptoms may not necessarily be evident or may not appear until several days after ingestion of Thyroxinol Sodium.

Treatment of Overdose: Thyroxinol Sodium should be reduced in dose or temporarily discontinued if signs or symptoms of overdosage occur. Treatment is symptomatic.

Storage Condition

Store in a cool place, protect from light & moisture.

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