Radiation not only kills or slows the growth of cancer cells, it can also affect nearby healthy cells. Damage to healthy cells can cause side effects. Many people who get radiation therapy have fatigue. Fatigue is feeling exhausted and worn out. It can happen all at once or come on slowly. People feel fatigue in different ways and you may feel more or less fatigue than someone else who is getting the same amount of radiation therapy to the same part of the body. See Fatigue and Cancer Treatment to learn more. Other radiation therapy side effects you may have depend on the part of the body that is treated. To see which side effects you might expect, find the part of your body being treated in the following chart. Many of the side effects in the list link to more information in the Side Effects section. Discuss this chart with your doctor or nurse. Ask them about the side effects that you might expect. Treatment areas and possible side effectsHealthy cells that are damaged during radiation treatment usually recover within a few months after treatment is over. But sometimes people may have side effects that do not improve. Other side effects may show up months or years after radiation therapy is over. These are called late effects. Whether you might have late effects, and what they might be, depends on the part of your body that was treated, other cancer treatments you've had, genetics, and other factors, such as smoking. Ask your doctor or nurse which late effects you should watch for. See the section on Late Effects to learn more. Oral levothyroxine is primarily indicated for treating 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. 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. This activity covers important information about prescribing levothyroxine, including mechanism of action, pharmacology, adverse event profiles, eligible patient populations, and monitoring, and highlights the interprofessional team's role in managing various forms of hypothyroidism with levothyroxine. Objectives:
Oral levothyroxine is FDA approved for treating primary, secondary, and tertiary hypothyroidism.[1] Primary hypothyroidism is due to a 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 pituitary adenomas to post-surgical intervention), and there is a decrease in thyroid-stimulating hormone(TSH) production. Tertiary hypothyroidism is rare, and the problem is in the hypothalamus with decreased 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] Subclinical hypothyroidism with TSH >10 mIU/L and symptomatic patients should be treated with levothyroxine therapy.[7] 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). Fifty percent 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.[8] Once inside the nucleus, thyroid hormones directly influence DNA transcription to increase body metabolism by increasing gluconeogenesis, protein synthesis, the mobilization of glycogen stores, and other functions.[9] 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.[10] Pharmacokinetics Absorption: Orally administered levothyroxine is absorbed from the jejunum and upper ileum (40% to 80%). The relative bioavailability of levothyroxine tablets, compared to an equal dose of oral levothyroxine solution, is approximately 93%. Levothyroxine absorption is increased by fasting and is decreased in the presence of food and malabsorption syndromes. Dietary fiber reduces the bioavailability of T4. Distribution: Thyroid hormones are greater than 99% bound to plasma proteins, including thyroxine-binding globulin (TBG), thyroxine-binding prealbumin (TBPA), and albumin (TBA). T4 has a greater affinity for TBG and TBPA, leading to slower metabolic clearance and a longer half-life of T4 than T3. The free hormone is metabolically active. Many drugs and physiologic conditions alter the binding of thyroid hormones to serum proteins. Metabolism: Thyroid hormones are primarily metabolized by sequential deiodination. Approximately 80% of T3 derives from peripheral T4. The liver is the primary site of degradation for T4 and T3, with T4 deiodination also occurring at several additional sites, including the kidney. T4 is deiodinated to generate an equal quantity of T3 and reverse T3 (rT3). T3 and rT3 are then deiodinated to diiodothyronine. Thyroid hormones are also metabolized via conjugation and undergo enterohepatic recirculation. Excretion: The kidneys primarily excrete thyroid hormones. Approximately 20% of T4 is excreted in the stool. Urinary excretion of T4 decreases with age. Multiple dosage forms of levothyroxine are available, including oral tablets, capsules, solutions, and parenteral dosage forms. Specific instructions for the dosage forms are as below.
Adult Dosing
Infant and Pediatric Dosing
Myxedema Coma (IV) or Severe Hypothyroidism
Organ Recovery from a Cadaver
Patients with Hepatic Impairment: There is no information regarding dosage adjustment of levothyroxine in patients with hepatic impairment in the manufacturer's product labeling. Patients with Renal Impairment: There is no information regarding dosage adjustment of levothyroxine in patients with renal impairment in the manufacturer's product labeling. Pregnancy Considerations: Pregnancy may increase levothyroxine requirements. Therefore, clinicians should monitor serum TSH levels and adjust levothyroxine dosage during pregnancy. Pregnant patients with newly diagnosed hypothyroidism should receive initial treatment at 1.8 mcg/kg/day. Adjust the dose every four weeks as needed. If a patient is diagnosed with hypothyroidism before pregnancy, adjust the dose of levothyroxine as needed. After pregnancy, levothyroxine should decrease to 1.6 mcg/kg/day.[17] The American Thyroid Association (ATA) recommends levothyroxine as the treatment of choice for maternal hypothyroidism. Other thyroid preparations, such as T3 or desiccated preparations, should not be used in pregnancy.[18] Breastfeeding Considerations: Levothyroxine (T4) is a component of human milk. Adequate levothyroxine during lactation may normalize milk production in hypothyroid lactating mothers. The health benefits of breastfeeding should be evaluated, along with the mother's clinical requirement for levothyroxine and possible adverse effects on the breastfed infant from levothyroxine. Exogenous replacement of levothyroxine during breastfeeding has no adverse effects in infants. The American Thyroid Association(ATA) suggests hypothyroidism should be treated with levothyroxine in lactating women. After delivery, levothyroxine should be reduced to the patient's preconception dose. Further thyroid function testing should be performed at approximately six weeks postpartum.[19] 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.[20] Allergy to the excipients such as dye(tartrazine yellow), lactose, acacia, or even gluten in the levothyroxine tablet may infrequently occur. Hence, allergy or intolerance to levothyroxine can be managed by changing the product, including consideration of gel capsules.[15]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] Adverse Drug Reactions (According to System Organ Classification)[22] Cardiovascular Adverse Drug Reactions
Neuropsychiatric Adverse Drug Reactions
Gastrointestinal Adverse Drug Reactions
Dermatological Adverse Drug Reactions
Endocrine Adverse Drug Reactions
Hepatic Adverse Drug Reactions
Drug Interactions
Boxed Warning: Levothyroxine or other thyroid hormones, alone or with other therapeutic drugs, should not be used to treat obesity or promote weight loss. In euthyroid patients, levothyroxine dose in the range of daily hormonal requirements is ineffective for weight loss. In addition, larger doses of levothyroxine may lead to serious and life-threatening manifestations, especially when combined with sympathomimetic amines like phentermine used for anorectic effects. 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 appear.[13][15] It is important to consider that 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.[27] The clinician should counsel the patient to use the same levothyroxine brand because of the narrow therapeutic index.[28] Oral semaglutide (GLP-1 analog) increases total T4 exposure when given levothyroxine. In addition, levothyroxine pharmacokinetics is influenced by co-administration with oral semaglutide. Therefore, thyroid function tests should be monitored, and the clinician should adjust the levothyroxine dose.[29] 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 storms, acute psychosis, arrhythmias, and acute myocardial infarction may occur. Laboratory workup usually reveals elevated serum total T4 and T3, suppressed serum TSH, and elevated Free T4 and Free T3. Employ the following treatment approach in acute levothyroxine overdose.
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.[33] Upon first prescribing levothyroxine, medication adjustment should occur every 6 to 8 weeks until the patient reaches a steady state. Clinicians should also evaluate the response to levothyroxine by using a validated questionnaire, such as thyroid-related quality of life (ThyPRO) and the underactive thyroid treatment satisfaction questionnaire (ThySRQ).[34][35] 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. Finally, clinicians should refer the patient to an endocrinologist if hypothyroidism is due to central causes. In all the scenarios mentioned above, pharmacists should ensure proper dosing and report to the clinician if there is any potential drug-drug interaction or if supplies may dictate a change to a different formulation. In an 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 essential role in managing thyroid storms. In the case of extreme overdose where hemoperfusion or hemodialysis is planned, a nephrologist referral is required.[31] In such cases, nursing will play a crucial role in monitoring the patient, administering medication, and reporting any patient status changes to the clinician. 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 Questions1. 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] 2.Chaker L, Bianco AC, Jonklaas J, Peeters RP. Hypothyroidism. Lancet. 2017 Sep 23;390(10101):1550-1562. 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