Mechanism Of Action
Thyroid hormones exert their physiologic actions through
control of DNA transcription and protein synthesis. Triiodothyronine (T3)
and levothyroxine (T4) diffuse into the cell nucleus and bind to thyroid
receptor proteins attached to DNA. This hormone nuclear receptor complex
activates gene transcription and synthesis of messenger RNA and cytoplasmic
The physiological actions of thyroid hormones are
produced predominantly by T , the majority of which (approximately 80%) is
derived from T by deiodination in peripheral tissues.
Thyroid hormone synthesis and secretion is regulated by
the hypothalamic pituitary-thyroid axis. Thyrotropin releasing hormone (TRH)
released from the hypothalamus stimulates secretion of thyrotropin stimulating
hormone (TSH) from the anterior pituitary. TSH, in turn, is the physiologic stimulus
for the synthesis and secretion of thyroid hormones, T4 and T3,
by the thyroid gland. Circulating serum T3 and T4 levels
exert a feedback effect on both TRH and TSH secretion. When serum T3
and T4 levels increase, TRH and TSH secretion decrease. When thyroid
hormone levels decrease, TRH and TSH secretion increases. TSH is used for the
diagnosis of hypothyroidism and evaluation of levothyroxine therapy adequacy
with other laboratory and clinical data [see Dosage].
There are drugs known to affect thyroid hormones and TSH
by various mechanisms and those examples are diazepam, ethioamide, lovastatin,
metoclopramide, 6-mercaptopurine, nitroprusside, perphenazine, and thiazide
diuretics. Some drugs may cause a transient decrease in TSH secretion without
hypothyroidism and those drugs (dose) are dopamine (greater than 1 mcg per kg
per min), glucocorticoids (hydrocortisone greater than 100 mg per day or
equivalent) and octreotide (greater than 100 mcg per day).
Thyroid hormones regulate multiple metabolic processes
and play an essential role in normal growth and development, and normal
maturation of the central nervous system and bone. The metabolic actions of
thyroid hormones include augmentation of cellular respiration and thermogenesis,
as well as metabolism of proteins, carbohydrates and lipids. The protein
anabolic effects of thyroid hormones are essential to normal growth and
Levothyroxine Sodium for Injection is administered via the
intravenous route. Following administration, the synthetic levothyroxine cannot
be distinguished from the natural hormone that is secreted endogenously.
Circulating thyroid hormones are greater than 99% bound
to plasma proteins, including thyroxine binding globulin (TBG), thyroxine
binding prealbumin (TBPA), and albumin (TBA), whose capacities and affinities
vary for each hormone. The higher affinity of both TBG and TBPA for T4
partially explains the higher serum levels, slower metabolic clearance, and
longer half life of T4 compared to T3. Protein bound
thyroid hormones exist in reverse equilibrium with small amounts of free
hormone. Only unbound hormone is metabolically active. Many drugs and
physiologic conditions affect the binding of thyroid hormones to serum proteins
[see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS].
Thyroid hormones do not readily cross the placental barrier [see WARNINGS
AND PRECAUTIONS and Use in Specific Populations].
T4 is slowly eliminated. The major pathway of
thyroid hormone metabolism is through sequential deiodination. Approximately eighty percent of
circulating T3 is derived from peripheral T4 by
monodeiodination. The liver is the major site of degradation for both T4
and T3, with T4 deiodination also occurring at a number
of additional sites, including the kidney and other tissues. Approximately 80%
of the daily dose of T4 is deiodinated to yield equal amounts of T3
and reverse T4 (r T3). T3 and r T3
are further deiodinated to diiodothyronine. Thyroid hormones are also
metabolized via conjugation with glucuronides and sulfates and excreted
directly into the bile and gut where they undergo enterohepatic recirculation.
Thyroid hormones are primarily eliminated by the kidneys.
A portion of the conjugated hormone reaches the colon unchanged, where it is
hydrolyzed and eliminated in feces as the free hormones. Urinary excretion of T4
decreases with age.
Table 1: Pharmacokinetic Parameters of Thyroid
Hormones in Euthyroid Patients
||Ratio in Thyroglobulin
||Protein Binding (%)2
||10 to 20
||6 to 81
|| < 2
|T4 : Levothyroxine
13 to 4 days in hyperthyroidism, 9 to 10 days in hypothyroidism.
2Includes TBG, TBPA, and TBA.
A listing of drug interaction with T4 is provided
in the following tables, although it may not be comprehensive due to the
introduction of new drugs that interact with the thyroidal axis or the discovery
of previously unknown interactions. The prescriber should be aware of this fact
and should consult appropriate reference sources (e.g., package inserts of
newly approved drugs, medical literature) for additional information if a
drug-drug interaction with levothyroxine is suspected.
Table 2: Drugs That May Alter T4 and T3
Serum Transport Without Affecting free T4 Concentration (Euthyroidism)
|Drugs That May Increase Serum TBG Concentration
||Drugs That May Decrease Serum TBG Concentration
|Clofibrate Estrogen-containing oral contraceptives
Slow-Release Nicotinic Acid
|Drugs That May Cause Protein-Binding Site Displacement
Potential impact: Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid.
|Salicylates ( > 2 g/day)
||Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%.
Furosemide ( > 80 mg IV)
Non-Steroidal Anti-inflammatory Drugs
Table 3: Drugs That May Alter Hepatic Metabolism of T4
Potential impact: Stimulation of hepatic microsomal drug-metabolizing enzyme
activity may cause increased hepatic degradation of levothyroxine, resulting in
increased levothyroxine requirements.
|Drug or Drug Class
|Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Table 4: Drugs That May Decrease Conversion of T4
Potential impact: Administration of these enzyme inhibitors decreases the
peripheral conversion of T4 to T3, leading to decreased T3
levels. However, serum T4 levels are usually normal but may occasionally
be slightly increased.
|Drug or Drug Class
|Beta-adrenergic antagonists (e.g.Propranolol > 160 mg/day)
||In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state.
|Glucocorticoids (e.g. Dexamethasone ≥ 4 mg/day)
||Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above).
|Other drug: Amiodarone
Animal Toxicology And Pharmacology
No animal toxicology studies have been conducted with
Levothyroxine Sodium for Injection.
No clinical studies have been conducted with
Levothyroxine Sodium for Injection in patients with myxedema coma. However,
data from published literature support the intravenous use of levothyroxine sodium
for the treatment of myxedema coma.