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Oral levothyroxine is primarily indicated for the treatment of primary, secondary, and tertiary hypothyroidism. Primary hypothyroidism is when the problem occurs in the thyroid gland. Secondary hypothyroidism is when the problem is in the pituitary gland, and there is a decrease in the production of thyroid-stimulating hormone (TSH). Tertiary hypothyroidism is sporadic. This activity covers levothyroxine, including mechanism of action, pharmacology, adverse event profiles, eligible patient populations, monitoring, and highlights the role of the interprofessional team in the management of various forms of hypothyroidism with levothyroxine.
Objectives:
Explain the mechanism of action of levothyroxine.
Describe the pathophysiology of the three primary forms of hypothyroidism.
Outline the contraindications to initiating therapy with levothyroxine.
Summarize interprofessional team strategies for improving care coordination and communication to advance levothyroxine and improve outcomes.
Oral levothyroxine is FDA approved for the treatment of primary, secondary, and tertiary hypothyroidism.[1] Primary hypothyroidism is due to the problem in the thyroid gland, with the most common cause being an autoimmune condition (Hashimoto thyroiditis) and iatrogenic hypothyroidism (after thyroidectomy). Secondary hypothyroidism is when the problem is in the pituitary gland (from adenomas to post-surgical intervention), and there is a decrease in the production of thyroid-stimulating hormone(TSH). Tertiary hypothyroidism is rare, and the problem is in the hypothalamus with decrease production of a thyroid-releasing hormone(TRH).[2]
Additionally, levothyroxine has FDA approval for pituitary thyrotropin suppression as an adjunct to surgery and radioiodine therapy to manage thyrotropin-dependent well-differentiated thyroid cancer.[3] Injectable levothyroxine is FDA approved for the treatment of myxedema coma or severe hypothyroidism.[4]
Off-label usage of levothyroxine includes cadaveric organ recovery and subclinical hypothyroidism.[5][6]
Levothyroxine(T4) is a synthetic version of the body’s natural thyroid hormone: thyroxine(T4). Normally, the hypothalamus secretes thyrotropin-releasing hormone(TRH), which then stimulates the anterior pituitary to secrete thyroid-stimulating hormone(TSH), which subsequently stimulates the thyroid to secrete 80% thyroxine (T4) and 20% L-triiodothyronine(T3). 50% of thyroxine (T4) then gets converted to its active metabolite L-triiodothyronine (T3). The thyroid hormones then work by binding to thyroid receptor proteins contained within the cell nucleus.[7]
Once inside the nucleus, thyroid hormones work by directly influencing DNA transcription to increase body metabolism by increasing gluconeogenesis, protein synthesis, the mobilization of glycogen stores, and other functions.[8] In scenarios where this process is interrupted (as seen in primary, secondary, or tertiary hypothyroidism), levothyroxine(LT4) can mimic the body’s endogenous T4 production by the thyroid.[9]
Multiple dosage forms of levothyroxine are available, including oral tablets, capsules, solution, and parenteral dosage forms. Specific instructions for the dosage forms are as below.
Oral: Administer levothyroxine on an empty stomach (acidity increases absorption), at least 30 to 60 minutes before breakfast or 3 to 4 hours after dinner. Do not administer levothyroxine within 4 hours of administration of products that may contain iron or calcium. Do not administer levothyroxine in conjunction with antacids or proton pump inhibitors.[10]
Capsule: Swallow whole; Do not crush or cut.
Tablet: May crush into 5 to 10 mL of water and drank immediately. If swallowing the tablet whole, administer with a full glass of water to prevent dysphagia.
Solution: Give either undiluted (directly squeeze contents into the mouth) or diluted in water only (squeeze contents into water, stir, and drink immediately).
Intravenous levothyroxine is exclusively for use in the hospital setting in which vital signs can undergo close monitoring.
If the patient can not tolerate anything by mouth, the levothyroxine capsules are used as a suppository and are well absorbed.[11]
Adult Dosing
For the treatment of hypothyroidism (oral): Adults who are healthy and diagnosed with hypothyroidism for a few months should receive an initial dose of 1.6 mcg/kg/day with a 12.5 to 25 mcg/day dose adjustment every 6 to 8 weeks as needed.
Adults with cardiac disease or elderly over 65 years old and hypothyroidism should receive an initial dose of 25 mcg/day with a dose adjustment of 12.5 to 25 mcg every 4 to 6 weeks as needed.[12]
Pregnant patients with newly diagnosed hypothyroidism should receive initial treatment at 1.8 mcg/kg/day. Adjust dose every four weeks as needed. If a patient has a diagnosis of hypothyroidism before pregnancy, adjust the dose of levothyroxine as needed. After pregnancy, the dose of levothyroxine should decrease to 1.6 mcg/kg/day.[13]
Infant and Pediatric Dosing
Levothyroxine replacement 10–15 μg/kg/d should be initiated once newborn screening is positive. Higher doses may be required for infants with severe congenital hypothyroidism. According to product labeling by the FDA following dose of levothyroxine is recommended. The levothyroxine dose is adjusted based on clinical response and laboratory parameters.[14]
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
Greater than 12 years but growth and puberty incomplete: 2-3 mcg/kg/day
Growth and puberty completeL1.6 mcg/kg/day
1-year-old children 4–6 μg/kg/d, adolescents 2–4 μg/kg/d, transition to the average adult dose of 1.6 μg/kg/d once endocrine maturation is complete.
Newborns (0-3 months) at risk for cardiac failure: Consider a lower starting dose in newborns at risk for cardiac failure. Increase the dose every 4 to 6 weeks as needed based on clinical and laboratory response.
Myxedema Coma (IV) or Severe Hypothyroidism
200 to 400 mcg initial IV loading dose is followed by a daily dose of 1.2 mcg/kg/day with consideration to use lower doses in patients with a history of cardiac disease, arrhythmia, or older patients. Switch to oral therapy (8 mcg/kg/day) when symptoms resolve. The equivalence between intravenous to oral levothyroxine is 0.75 to 1 (for example, 200 mcg IV of levothyroxine is equal to 266 mcg of oral levothyroxine).[15]
Organ Recovery from a Cadaver
20 mcg IV bolus to the donor, followed by 10 mcg/hour continuous infusion. Given with methylprednisolone, dextrose, and insulin.[16]
Generally, adverse events resulting from incorrect dosing (excessive dosing) often form a hyperthyroid-like picture or an allergic reaction to the excipient of the levothyroxine tablets. Levothyroxine 50 mcg tablets don't contain allergic excipients, so there is a decreased risk for immune reactions.[17]
Adverse Drug Reactions According to System Organ Classification(SOC) [18]
Cardiovascular Adverse Drug Reactions
Angina pectoris
Tachycardia
Palpitations
Arrhythmia
Myocardial infarction[19]
Atrial fibrillation
Neuropsychiatric Adverse Drug Reactions
Anxiety
Insomnia(advise the patient to take levothyroxine in the morning)
Gastrointestinal Adverse Drug Reactions
Weight loss
Fatigue
Diarrhea
Emesis
Dermatological Adverse Drug Reactions
Skin rash
Alopecia
Diaphoresis
Endocrine Adverse Drug Reactions
Goiter
Menstrual irregularities
Heat intolerance
Decreased bone mineral density (a result of TSH suppression).[12][15]
Hepatic Adverse Drug Reactions
Increased liver enzymes(hepatocellular or mixed pattern)
Immunoallergic hepatitis(with eosinophilia)[20]
Among older persons treated with levothyroxine, levothyroxine at doses more than 75 mcg per day is associated with an increased risk of atrial fibrillation.[21]
Contraindications
Acute myocardial infarction
Uncorrected adrenal insufficiency
Acute myocarditis, pancarditis
Active cardiac arrhythmias
In adults, monitor TSH levels approximately 6 to 8 weeks after initiating treatment with levothyroxine. Upon achieving the correct dosing of levothyroxine, monitor TSH levels after 4 to 6 months and then every 12 months. Patients should receive education about the symptoms of hyperthyroidism and contact their clinician for medication dose decrease if those symptoms were to appear.[12][15] It is important to consider that the TSH is unreliable in patients with secondary or tertiary hypothyroidism, and the best indicator to adjust dosing will be the free T4 or total T4.[22]
The clinician should counsel the patient to use the same levothyroxine brand because of the narrow therapeutic index.[23]
Levothyroxine toxicity is rare; however, it is most likely to occur in the setting of accidental ingestion by children or older adults. Thyroxine (T4) and triiodothyronine (T3) levels rise within 1 to 2 hours of ingestion. In the initial stage of overdose (6 to 12 hours post-ingestion), the common signs of toxicity would be tremulousness, tachycardia, hypertension, anxiety, and diarrhea. Rarely, convulsions, thyroid storm, acute psychosis, arrhythmias, and acute myocardial infarction may occur. Laboratory workup usually reveals elevated serum total T4 and T3, suppressed serum TSH, elevated Free T4, and Free T3.
Employ following treatment approach in acute levothyroxine overdose.
Administer activated charcoal to prevent the absorption of levothyroxine.
Cholestyramine binds thyroxine and enhances its elimination. The dose used is 4 grams orally every 8 hours.[24]
Beta-blockers are beneficial to alleviate the metabolic effects of thyroid hormone, mainly on the cardiac system (controlling tachycardia, preventing arrhythmias). Propranolol also blocks the peripheral conversion of T4 to T3.
Glucocorticoids such as (Dexamethasone 4 mg orally) can reduce the conversion of LT4 to T3, the active hormone.
Propylthiouracil can be used to prevent the conversion of T4 to T3.
Hemodialysis is utilized in severe cases, but it is of limited benefit since T3 and T4 are primarily protein-bound.
Hemoperfusion utilizing activated charcoal is a complex but efficient procedure for reducing thyroxine levels. Therefore, reserve it for adult patients with severe intoxication.[25]
The severe cases of intoxication leading to a thyroid storm require treatment in an ICU.[26]
In summary, it is essential to note that there is no antidote to treat levothyroxine overdose. Treatment options include gastric lavage, activated charcoal, cholestyramine, glucocorticoids, beta-blockers, propylthiouracil, and supportive measures.[27]
Upon first prescribing levothyroxine, medication adjustment should occur every 6 to 8 weeks until the patient reaches a steady state. If the patient has symptoms of hyperthyroidism, advise the patient to contact the clinician to determine if these are side effects of the medication. A clinician should then order TSH and free T4 levels immediately. If the free T4 comes back elevated, the clinician should decrease the dose of levothyroxine to prevent cardiac complications and other symptoms of hyperthyroidism. Clinicians should refer the patient to an endocrinologist if hypothyroidism is due to central causes. In all the above-mentioned scenarios, pharmacists should ensure proper dosing and report back to the clinician if there is any potential drug-drug interaction.
In acute overdose of levothyroxine, emergency department physician and triage nurses stabilize the patient, focusing on maintaining a patent airway, breathing, and circulation. Critical care physicians play an important role in managing thyroid storms. In the case of extreme overdose where hemoperfusion or hemodialysis is planned, a nephrologist referral is required.[25] As described above, multiple healthcare professionals take care of the patient prescribed levothyroxine for various indications. An interprofessional team-based approach involving clinicians(MDs, DOs, NPs, PAs), specialists, nurses, pharmacists, and other healthcare providers achieves maximum efficacy. It minimizes the adverse drug reactions associated with levothyroxine therapy which translates to improved patient outcomes. [level 5]
Review Questions
1.
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