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Continuing Education Activity

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 very rare. 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.


  • Explain the mechanism of action of levothyroxine.
  • Describe the pathophysiology of the three primary forms of hypothyroidism.
  • Outline the adverse event profile and contraindications to initiating therapy with levothyroxine.
  • Summarize interprofessional team strategies for improving care coordination and communication to advance levothyroxine and improve outcomes.
Earn continuing education credits (CME/CE) on this topic.


Oral levothyroxine is primarily indicated for the treatment of primary, secondary, and tertiary hypothyroidism.[1] Primary hypothyroidism is when the problem occurs in the thyroid gland, with the most common cause being an autoimmune condition (Hashimoto thyroiditis) follow up by 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 very rare, and the problem is in the hypothalamus with decrease production of thyroid releasing hormone (TRH).

Injectable levothyroxine is for the treatment of myxedema coma or severe hypothyroidism.[2]

Off-label usage includes cadaveric organ recovery.[3]

Mechanism of Action

Levothyroxine (T4) is a synthetic version of one of the body’s natural thyroid hormones: 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.

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 more functions.

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.[4]


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.

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.[5][6] 

In cases where the patient can not tolerate anything by mouth due to an underlying problem, the levothyroxine capsules are usable as a suppository and are well absorbed. 

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.[5][6] 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.[5][6][7]

To treat myxedema coma (IV) or severe hypothyroidism: 200 to 400 mcg initial IV loading dose 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.[6] The equivalence between intravenous to oral is 0.75 to 1 (for example, 200 mcg IV of levothyroxine is equal to 266 mcg of oral levothyroxine )

For organ recovery from a cadaver (IV):20 mcg IV bolus to the donor, followed by 10 mcg/hour continuous infusion. Given with methylprednisolone, dextrose, and insulin.[8]

Adverse Effects

Generally, adverse events result from incorrect dosing (excessive dosing) often forms a hyperthyroid-like picture or due to an allergic reaction to the excipient of the levothyroxine tablets. Levothyroxine 50 mcg tablets are white and don't contain any die, so there is a decreased risk for an allergic response.

Adverse effects (frequency undefined) include: angina pectoris, tachycardia, palpitations, arrhythmias, myocardial infarction, dyspnea, anxiety, fatigue, headache, heat intolerance, insomnia, irritability, diaphoresis, skin rash, alopecia, goiter, weight loss, menstrual irregularities, abdominal cramps, diarrhea, emesis, reduced fertility, and decreased bone mineral density (a result of TSH suppression).[5][6]


Levothyroxine is contraindicated in individuals with uncorrected adrenal insufficiency, individuals with acute myocardial infarction, acute myocarditis, pancarditis, active heart arrhythmias, and persons with thyrotoxicosis or hyperthyroidism.[5][6]


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 4 to 6 months after, and then every 12 months after that.  Patients should receive education about the symptoms of hyperthyroidism,  and to contact their clinician for medication dose decrease if those symptoms were to appear.[5][6] Important to mention that patients with secondary or tertiary hypothyroidism, the TSH is not reliable (will remain low), and the best indicator to adjust dosing will be the free or total T4.


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. 

The onset of signs and symptoms may delay from 3 to 10 days, and as such, close monitoring should continue in such patients. 

There is no antidote for the treatment of levothyroxine overdose. Treatment options include gastric lavage, activated charcoal, cholestyramine, glucocorticoids, beta-blockers, propylthiouracil, and supportive measures.[9]

Enhancing Healthcare Team Outcomes

An interprofessional team of healthcare professionals is necessary for the management of levothyroxine overdose. This team would include a nurse, laboratory technician, pharmacist, and clinicians (both primary care and endocrinologist).  

Upon first prescribing levothyroxine, adjustment of the medication should take place 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 or nurse should then order TSH and free T4 levels immediately. If the free T4 comes back elevated, the clinician should decrease the dose of the levothyroxine to prevent cardiac complications and other symptoms of hyperthyroidism.

Continuing Education / Review Questions


Cooper DS, Halpern R, Wood LC, Levin AA, Ridgway EC. L-Thyroxine therapy in subclinical hypothyroidism. A double-blind, placebo-controlled trial. Ann Intern Med. 1984 Jul;101(1):18-24. [PubMed: 6428290]
Ono Y, Ono S, Yasunaga H, Matsui H, Fushimi K, Tanaka Y. Clinical characteristics and outcomes of myxedema coma: Analysis of a national inpatient database in Japan. J Epidemiol. 2017 Mar;27(3):117-122. [PMC free article: PMC5350620] [PubMed: 28142035]
Salim A, Vassiliu P, Velmahos GC, Sava J, Murray JA, Belzberg H, Asensio JA, Demetriades D. The role of thyroid hormone administration in potential organ donors. Arch Surg. 2001 Dec;136(12):1377-80. [PubMed: 11735863]
Fish LH, Schwartz HL, Cavanaugh J, Steffes MW, Bantle JP, Oppenheimer JH. Replacement dose, metabolism, and bioavailability of levothyroxine in the treatment of hypothyroidism. Role of triiodothyronine in pituitary feedback in humans. N Engl J Med. 1987 Mar 26;316(13):764-70. [PubMed: 3821822]
Garber JR, Cobin RH, Gharib H, Hennessey JV, Klein I, Mechanick JI, Pessah-Pollack R, Singer PA, Woeber KA., American Association of Clinical Endocrinologists and American Thyroid Association Taskforce on Hypothyroidism in Adults. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Endocr Pract. 2012 Nov-Dec;18(6):988-1028. [PubMed: 23246686]
Jonklaas J, Bianco AC, Bauer AJ, Burman KD, Cappola AR, Celi FS, Cooper DS, Kim BW, Peeters RP, Rosenthal MS, Sawka AM., American Thyroid Association Task Force on Thyroid Hormone Replacement. Guidelines for the treatment of hypothyroidism: prepared by the american thyroid association task force on thyroid hormone replacement. Thyroid. 2014 Dec;24(12):1670-751. [PMC free article: PMC4267409] [PubMed: 25266247]
Alexander EK, Marqusee E, Lawrence J, Jarolim P, Fischer GA, Larsen PR. Timing and magnitude of increases in levothyroxine requirements during pregnancy in women with hypothyroidism. N Engl J Med. 2004 Jul 15;351(3):241-9. [PubMed: 15254282]
Nath DS, Ilias Basha H, Liu MH, Moazami N, Ewald GA. Increased recovery of thoracic organs after hormonal resuscitation therapy. J Heart Lung Transplant. 2010 May;29(5):594-6. [PubMed: 20207554]
Medeiros-Neto G. Thyroxine Poisoning. In: Feingold KR, Anawalt B, Boyce A, Chrousos G, de Herder WW, Dungan K, Grossman A, Hershman JM, Hofland J, Kaltsas G, Koch C, Kopp P, Korbonits M, McLachlan R, Morley JE, New M, Purnell J, Singer F, Stratakis CA, Trence DL, Wilson DP, editors. Endotext [Internet]., Inc.; South Dartmouth (MA): Jul 17, 2018. [PubMed: 25905265]
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