Thyroid Replacement Medications

The thyroid gland Thyroid gland The thyroid gland is one of the largest endocrine glands in the human body. The thyroid gland is a highly vascular, brownish-red gland located in the visceral compartment of the anterior region of the neck. Thyroid Gland produces hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview called thyroxine (T4) and triiodothyronine (T3), which play important roles in processes such as metabolism, tissue growth, development, and in other regulatory pathways. When an individual’s thyroid does not produce enough hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview to maintain these processes, they are given synthetic or nonsynthetic forms of T3 and T4. These medications include levothyroxine, liothyronine, and desiccated thyroid extract. Correct dosing and intake of these hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview is important. Overdosing can cause symptoms of hyperthyroidism Hyperthyroidism Thyrotoxicosis refers to the classic physiologic manifestations of excess thyroid hormones and is not synonymous with hyperthyroidism, which is caused by sustained overproduction and release of T3 and/or T4. Graves' disease is the most common cause of primary hyperthyroidism, followed by toxic multinodular goiter and toxic adenoma. Thyrotoxicosis and Hyperthyroidism, and underdosing may not fully resolve the symptoms of hypothyroidism Hypothyroidism Hypothyroidism is a condition characterized by a deficiency of thyroid hormones. Iodine deficiency is the most common cause worldwide, but Hashimoto's disease (autoimmune thyroiditis) is the leading cause in non-iodine-deficient regions. Hypothyroidism. It is important to be aware of various drug and food interactions that can either decrease or increase the effect of these medications.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Overview

Pathophysiology of hypothyroidism Hypothyroidism Hypothyroidism is a condition characterized by a deficiency of thyroid hormones. Iodine deficiency is the most common cause worldwide, but Hashimoto's disease (autoimmune thyroiditis) is the leading cause in non-iodine-deficient regions. Hypothyroidism

  • Medical condition defined by deficiency of thyroid hormones Thyroid hormones The 2 primary thyroid hormones are triiodothyronine (T3) and thyroxine (T4). These hormones are synthesized and secreted by the thyroid, and they are responsible for stimulating metabolism in most cells of the body. Their secretion is regulated primarily by thyroid-stimulating hormone (TSH), which is produced by the pituitary gland. Thyroid Hormones
    • Thyroxine (T4)
    • Triiodothyronine (T3
  • These hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview play an integral role in various functions:
    • Metabolism
    • Growth and development 
    • Catecholamine function
    • Pituitary hormone synthesis regulation (feedback loop)
  • Clinically, a deficiency in these hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview can lead to abnormal changes in:
    • Energy levels
    • Weight
    • Thermoregulation
    • HR
    • Bowel movements
    • Mood

Thyroid replacement medications

The 3 drugs used for treatment of hypothyroidism Hypothyroidism Hypothyroidism is a condition characterized by a deficiency of thyroid hormones. Iodine deficiency is the most common cause worldwide, but Hashimoto's disease (autoimmune thyroiditis) is the leading cause in non-iodine-deficient regions. Hypothyroidism are:

  • Levothyroxine (L-T4)
  • Liothyronine (L-T3)
  • Desiccated thyroid extract

Levothyroxine

Pharmacodynamics Pharmacodynamics Pharmacodynamics is the science that studies the biochemical and physiologic effects of a drug and its organ-specific mechanism of action, including effects on the cellular level. Pharmacokinetics is "what the body does to the drug," whereas pharmacodynamics is "what the drug does to the body." Pharmacokinetics and Pharmacodynamics

  • Levothyroxine is a synthetic levo-isomer of T4
  • The prohormone T4 is converted to T3 (active) or reverse T3 (inactive) in the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver and other peripheral tissues via deiodination. 
  • ↑ T4 and T3 levels lead to:
    • Normalization of hormone effects on metabolic, growth, and development functions 
    • ↓ Pituitary overproduction of thyroid-stimulating hormone (TSH)

Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics

  • Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption
    • 40%‒80% absorbed from GI tract; can be erratic 
    • Food can ↓ absorption 
  • Distribution: Approximately 99% of T4 and T3 binds to plasma proteins (thyroxine-binding globulin ( TBG TBG A thyroid hormone transport protein found in serum. It binds about 75% of circulating thyroxine and 70% of circulating triiodothyronine. Thyroid Hormones)). 
  • Metabolism:
    • Deiodination in the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver and other peripheral tissues (including kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys) to the active form, T3
    • Renal and hepatic impairment can ↓ conversion to T3.
  • Excretion:
    • Urine (primarily)
    • Feces

Indications

  • Hypothyroidism (primary, secondary, and tertiary)
    • Levothyroxine is the drug of choice.
    • Goal is to mimic normal endogenous T4 production
    • Has a longer half-life than L-T3
    • Less chance of hypermetabolic side effects
  • Myxedema coma Coma Coma is defined as a deep state of unarousable unresponsiveness, characterized by a score of 3 points on the GCS. A comatose state can be caused by a multitude of conditions, making the precise epidemiology and prognosis of coma difficult to determine. Coma (in combination with L-T3)
  • TSH suppression in thyrotropin-dependent thyroid cancers (papillary and follicular)

Adverse effects

  • Hypermetabolic state:
    • Can occur with:
      • Overtreatment 
      • Elderly individuals
      • Initiation of therapy
    • Signs and symptoms:
      • Palpitations
      • Tachycardia (including atrial fibrillation Atrial fibrillation Atrial fibrillation (AF or Afib) is a supraventricular tachyarrhythmia and the most common kind of arrhythmia. It is caused by rapid, uncontrolled atrial contractions and uncoordinated ventricular responses. Atrial Fibrillation)
      • Widened pulse pressure
      • Sweating
      • Weight loss
      • Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea 
      • Agitation and restlessness
  • Allergy to the dye or filler:
    • Swelling
    • Dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea
  • Untreated adrenal insufficiency Adrenal Insufficiency Adrenal insufficiency (AI) is the inadequate production of adrenocortical hormones: glucocorticoids, mineralocorticoids, and adrenal androgens. Primary AI, also called Addison’s disease, is caused by autoimmune disease, infections, and malignancy, among others. Adrenal insufficiency can also occur because of decreased production of adrenocorticotropic hormone (ACTH) from disease in the pituitary gland (secondary) or hypothalamic disorders and prolonged glucocorticoid therapy (tertiary). Adrenal Insufficiency and Addison’s Disease: Levothyroxine can precipitate acute adrenal crisis.

Precautions

  • Pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-HCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care
    • Associated with ↑ metabolic needs.
    • Normal physiologic ↑ in TBG TBG A thyroid hormone transport protein found in serum. It binds about 75% of circulating thyroxine and 70% of circulating triiodothyronine. Thyroid Hormones and TSH → ↑ thyroid hormones Thyroid hormones The 2 primary thyroid hormones are triiodothyronine (T3) and thyroxine (T4). These hormones are synthesized and secreted by the thyroid, and they are responsible for stimulating metabolism in most cells of the body. Their secretion is regulated primarily by thyroid-stimulating hormone (TSH), which is produced by the pituitary gland. Thyroid Hormones
    • Pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-HCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care: Mothers require ↑ in L-T4 dosage.
    • Remember to change back to prepregnancy dose postpartum.
  • Elderly individuals or those with cardiovascular disease:
    • Thyroid hormone therapy has inotropic and chronotropic effects on the heart, which can result in angina.
    • Older individuals (> 60 years) and those with cardiovascular disease should be started on a lower dose.
    • This low dose can be slowly titrated upward (“start low, go slow”)
  • Individuals with diabetes mellitus Diabetes mellitus Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus may need to have the dosage of their antidiabetes medication adjusted with administration of L-T4.

Drug and food interactions

  • Foods that interfere with absorption (medication should be taken on empty stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach):
    • High-fiber foods
    • Calcium-containing foods
    • Grapefruit
    • Coffee
  • Drugs that interfere with absorption:
    • Calcium carbonate
    • Iron supplements
    • Bile acid sequestrants 
    • Aluminum-containing antacids
  • Severe drug interactions:
    • Ketamine: hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension and tachycardia
    • Tricyclic antidepressants Tricyclic antidepressants Tricyclic antidepressants (TCAs) are a class of medications used in the management of mood disorders, primarily depression. These agents, named after their 3-ring chemical structure, act via reuptake inhibition of neurotransmitters (particularly norepinephrine and serotonin) in the brain. Tricyclic Antidepressants (TCAs): ↑ arrhythmogenic effect

Drugs that may alter levothyroxine efficacy

Table: Drugs that may alter levothyroxine efficacy
Mechanism Drugs Levothyroxine adjustment
Drugs that ↑ hepatic conversion of T4 to T3
  • Phenobarbital
  • Phenytoin
  • Carbamazepine
  • Rifampin
  • Sertraline
  • Imatinib
↑ Dosage may be necessary
Drugs that ↑ serum TBG TBG A thyroid hormone transport protein found in serum. It binds about 75% of circulating thyroxine and 70% of circulating triiodothyronine. Thyroid Hormones concentration
  • Estrogen Estrogen Compounds that interact with estrogen receptors in target tissues to bring about the effects similar to those of estradiol. Estrogens stimulate the female reproductive organs, and the development of secondary female sex characteristics. Estrogenic chemicals include natural, synthetic, steroidal, or non-steroidal compounds. Ovaries
  • Tamoxifen
  • Raloxifene
  • Clofibrate
  • Opioids Opioids Opiates are drugs that are derived from the sap of the opium poppy. Opiates have been used since antiquity for the relief of acute severe pain. Opioids are synthetic opiates with properties that are substantially similar to those of opiates. Opioid Analgesics
  • Fluorouracil
  • Capecitabine
↑ Dosage may be necessary
Drugs that ↓ serum TBG TBG A thyroid hormone transport protein found in serum. It binds about 75% of circulating thyroxine and 70% of circulating triiodothyronine. Thyroid Hormones concentration
  • Glucocorticoids
  • Androgens
↓ Dosage may be necessary

Liothyronine

Pharmacodynamics Pharmacodynamics Pharmacodynamics is the science that studies the biochemical and physiologic effects of a drug and its organ-specific mechanism of action, including effects on the cellular level. Pharmacokinetics is "what the body does to the drug," whereas pharmacodynamics is "what the drug does to the body." Pharmacokinetics and Pharmacodynamics

  • Liothyronine is the synthetic form of active T3
  • Effects are stronger and faster than those of L-T4.

Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics

  • Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption
    • Rapid 
    • Well absorbed (approximately 95%)
  • Distribution: approximately 99% bound to proteins, such as TBG TBG A thyroid hormone transport protein found in serum. It binds about 75% of circulating thyroxine and 70% of circulating triiodothyronine. Thyroid Hormones
  • Excretion:
    • Urine (primarily)
    • Feces

Indications

  • Hypothyroidism
    • Not typically used alone owing to short half-life
    • Used in individuals who continue to have symptoms despite L-T4 therapy
  • Myxedema coma Coma Coma is defined as a deep state of unarousable unresponsiveness, characterized by a score of 3 points on the GCS. A comatose state can be caused by a multitude of conditions, making the precise epidemiology and prognosis of coma difficult to determine. Coma (in conjunction with L-T4)
  • Nontoxic goiter Goiter A goiter is a chronic enlargement of the thyroid gland due to nonneoplastic growth occurring in the setting of hypothyroidism, hyperthyroidism, or euthyroidism. Morphologically, thyroid enlargement can be diffuse (smooth consistency) or nodular (uninodular or multinodular). Goiter

Adverse effects, precautions, and drug interactions

Adverse effects, precautions, and drug interactions are similar to those for L-T4.

Desiccated Thyroid

Pharmacodynamics Pharmacodynamics Pharmacodynamics is the science that studies the biochemical and physiologic effects of a drug and its organ-specific mechanism of action, including effects on the cellular level. Pharmacokinetics is "what the body does to the drug," whereas pharmacodynamics is "what the drug does to the body." Pharmacokinetics and Pharmacodynamics

  • Nonsynthetic thyroid hormone extracted from the thyroid of domesticated animals (e.g., pigs, sheep, cows) 
  • Contains both T3 and T4 in a ratio that does not naturally occur in human beings

Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics

  • Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption: 40%–80% 
  • Distribution: protein-bound (similar to L-T3 and L-T4)
  • Metabolism: T4 component is converted to T3
  • Excretion:
    • Urine (primarily)
    • Feces

Indications

Desiccated thyroid is a rarely used treatment for hypothyroidism Hypothyroidism Hypothyroidism is a condition characterized by a deficiency of thyroid hormones. Iodine deficiency is the most common cause worldwide, but Hashimoto's disease (autoimmune thyroiditis) is the leading cause in non-iodine-deficient regions. Hypothyroidism.

  • May be considered for individuals who want a natural treatment
  • Not FDA-approved

Adverse effects

  • Side effects are similar to those for the synthetic thyroid medications
  • Manufacturing and quality control issues are common because of variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables hormone concentrations.

References

  1. T.A. (2013). A review of the pharmacokinetics of levothyroxine for the treatment of hypothyroidism. Touch Endocrinol. https://www.touchendocrinology.com/thyroid/journal-articles/a-review-of-the-pharmacokinetics-of-levothyroxine-for-the-treatment-of-hypothyroidism/
  2. Synthroid, Levoxyl (levothyroxine) dosing, indications, interactions, adverse effects, and more. (2021). MedScape. Retrieved August 3, 2021, from https://reference.medscape.com/drug/synthroid-levoxyl-levothyroxine-342732#11
  3. DrugBank Online. (2021). Levothyroxine: uses, interactions, mechanism of action. https://go.drugbank.com/drugs/DB00451
  4. American Thyroid Association. (2020). Thyroid hormone treatment. http://www.thyroid.org/thyroid-hormone-treatment/
  5. Ross, D.S. (2021). Treatment of primary hypothyroidism in adults. UpToDate. Retrieved July 31, 2021, from https://www.uptodate.com/contents/treatment-of-primary-hypothyroidism-in-adults
  6. Dong, B.J., Greenspan, F.S. (2012). Thyroid & antithyroid drugs. In: Katzung, B.G., Masters, S.B., Trevor, A.J. (Eds.), Basic & Clinical Pharmacology, 12th ed. McGraw-Hill Lange, pp. 681–696. https://pharmacomedicale.org/images/cnpm/CNPM_2016/katzung-pharmacology.pdf

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