Levothyroxine and Liothyronine - Uses, Mechanism of Action, Dosage, and Side Effects

Overview:

Levothyroxine and Liothyronine are drugs used to treat hypothyroidism (a condition where the body is unable to produce enough thyroid hormones due to an underlying pathological condition or removal of the thyroid gland). Levothyroxine treats primary, secondary, and tertiary hypothyroidism. Primary hypothyroidism is when the disorder is in the thyroid gland, secondary hypothyroidism is when it affects the pituitary gland, and there is decreased production of thyroid-stimulating hormone (TSH), and tertiary hypothyroidism is always sporadic. Liothyronine is a man-made form of thyroid hormone which is less in the body due to less production by the thyroid gland. Liothyronine is not only used to treat hypothyroidism but is also used in medical tests for thyroid disorders.

Levothyroxine:

Levothyroxine is an FDA (Food and Drug Administration) approved drug for the treatment of all three types of hypothyroidism. Primary hypothyroidism is attributed to thyroid gland disorders due to autoimmune diseases such as Hashimoto’s thyroiditis or iatrogenic hypothyroidism due to the removal of the thyroid gland (thyroidectomy). Secondary hypothyroidism is caused due to disorders of the pituitary gland and deficiency of thyroid-stimulating hormone (TSH). Tertiary hypothyroidism is a rare form that occurs due to problems in the hypothalamus leading to the impaired release of the thyroid-releasing hormone. Levothyroxine is also FDA-approved for suppression of pituitary thyrotropin before surgery or radioiodine therapy for the management of thyrotropin-dependent well-differentiated thyroid cancer. Injectable Levothyroxine has also been approved by the FDA for the treatment of severe hypothyroidism and myxedema coma (a life-threatening condition that occurs in cases of long untreated hypothyroidism).

How Does Levothyroxine Work?

Levothyroxine is a synthetic version of a natural hormone produced by the body known as thyroxine-4 (T4). In normal conditions of the body, the hypothalamus secretes thyrotropin-releasing hormone (TRH), which further stimulates the anterior pituitary to secrete thyroid-stimulating hormone (TSH), leading to the secretion of T4 (about 80 %) and triiodothyronine or T3 (about 20 %). As the amount of triiodothyronine is less, almost 50 % of the thyroxine (T4) is then converted into active metabolite L-triiodothyronine (T3). The thyroid hormones then bind to the thyroid receptor proteins, which are present in the cell nucleus. The thyroid hormone influences the DNA transcription in the nucleus, which further increases the body’s metabolism by stimulating gluconeogenesis, protein synthesis, and mobilization of glycogen stores in the body. Thus when the thyroxine secretion is altered in the body, Levothyroxine acts as a supplement to carry out all the functions.

What Are the Uses of Levothyroxine?

The primary function of the drug is the treatment of all three types of hypothyroidism, namely the primary, secondary, and tertiary types. Apart from these, it is also helpful in the treatment of thyrotropin-dependent well-differentiated thyroid cancer.

How to Take Different Forms of Levothyroxine?

Levothyroxine is available in different forms such as oral tablets, capsules, parenteral dosage forms, and solutions.

• The oral tablets of Levothyroxine are administered on an empty stomach as the acidity helps to increase its absorption.

• The capsules are consumed by swallowing them whole and not by crushing them.

• The tablet can be consumed after crushing them into about 10 ml of water.

• The solution can be administered directly in the mouth or can be diluted.

• The intravenous route is chosen when the patient is unable to take the drug through the mouth.

Warning:

Levothyroxine should not be administered within four hours of consumption of substances such as calcium or iron. It should also be avoided with proton pump inhibitors and antacids.

For Patients:

About the Disease:

What Is Hypothyroidism?

It is a condition in which the thyroid gland does not produce enough thyroid hormones such as thyroxine (T4), triiodothyronine (T3), and thyroid-stimulating hormone (TSH). The cause of deficiency can be an autoimmune disease such as Hashimoto’s thyroiditis, overresponse to the treatment of hyperthyroidism, or any thyroid surgery. Radiation therapy can also cause hypothyroidism when used to treat cancers of the neck region. Some medicines like Lithium (which is used to treat psychiatric disorders) also contribute to hypothyroidism.

The symptoms of hypothyroidism include:

• Fatigue and weight gain.

• Increased sensitivity to cold.

• Stiffness, pain, and swelling in the joint.

• Pain in muscles with tenderness.

• Depression, slow heart rate, and impaired memory.

• Dry skin and puffy face.

Before Starting the Drug:

When and Why to Start Levothyroxine?

When the person feels symptoms such as excessive weight gain, fatigue, and pain in muscles or joints, it is important to consult a doctor and get thyroid function tests done. If the concentration of thyroxine (T4) is less than the normal concentration, the patient is advised by the healthcare professional to start the drug. The dosage of the drug depends on age, body weight, and deficiency of the hormone in the body.

How Does Levothyroxine Work for Disease?

Levothyroxine acts as synthetic thyroxine (T4) in the body and helps in the production of triiodothyronine (T3). It further helps to carry out transcription in the nuclei of cells which helps to increase the body’s metabolism by stimulating the process of gluconeogenesis.

Gluconeogenesis is the formation of glucose from the non-carbohydrate carbon substances present in the body.

How Long Does Levothyroxine Take To Work?

It is advisable to take the drug Levothyroxine almost 30 to 60 minutes before breakfast as the absorption of the drug is better in the acidic environment of the stomach. 40 to 80 % of Levothyroxine absorption takes place from the duodenum or ileum.

What Information Should Be Given to the Doctor Before Taking Levothyroxine?

Before starting Levothyroxine, it is important to inform the doctor of the following conditions:

• If the person is suffering from thyrotoxicosis (toxicity due to thyroid hormones).

• Presence of untreated or uncontrolled adrenal gland disorders in the body.

• If the patient has a feeling of a heart attack, such as severe chest pain which spreads to the shoulder, feeling of nausea, and sweating.

• If there is any kidney disease or anemia in the patient.

• Presence of any clotting disorder in the body or any drug allergies.

Starting the Drug:

How to Take Levothyroxine?

The drug should be taken as advised by the doctor, and all the directions mentioned on the prescription should be followed. Levothyroxine may be taken in different ways:

• Oral Tablets: They are advised approximately 60 minutes before breakfast every day. It is ideal if the time of administration of the drug is the same every day.

• Injection: The injection of Levothyroxine should be infused in a vein. This form of drug administration is advised only when the patient is unable to take the drug orally.

• Capsule: The consumption of a capsule or tablet should be done with a full glass of water. The drug has the capability to dissolve quickly and can swell in the throat if less water is consumed.

• Liquid Solution: This form of Levothyroxine should be consumed properly by measuring through a dosing syringe or a medicine dose-measuring device.

What to Do if the Dose Is Missed?

If a dose of Levothyroxine is missed, it is better to take the dose as soon as possible. However, if it is already time for the next dose, only that does need to be taken, as a double dose of the drug is not recommended.

What Are the Common Side Effects of Levothyroxine?

Some of the side effects of Levothyroxine that should not be ignored are:

• Chest pain that spreads to the jaw and shoulders.

• Fast or irregular heartbeats with shortness of breath.

• Sweating followed by hot flashes and fever.

• Difficulties in sleeping lead to tiredness and weakness.

• Development of depression.

• Muscle pain, headaches, and leg cramps.

• Dryness of skin and hair leads to hair loss.

• Change in weight and appetite.

Staying on the Drug:

While staying on the drugs, it is important to take care of the following points:

• There should be at least a four-hour gap between Levothyroxine dose and consumption of substances such as calcium or iron.

• Food items such as grapefruit juice, soybean flour, infant soy formula, walnuts, or high-fiber foods should be avoided as they lead to less absorption of Levothyroxine.

For Doctors:

Indication:

Levothyroxine is indicated in cases of primary, secondary, and tertiary hypothyroidism, which can be congenital or acquired in nature. It can also be used in cases of surgery or radioiodine therapy which are used for the management of thyrotropin-dependent well-differentiated thyroid cancer.

Mechanism of Action:

Levothyroxine is a synthetic form of thyroxine (T4) that is capable of exerting the same physiological effects as human-secreted thyroxine (T4). It helps to maintain a level of thyroxine in the body when there is a deficiency. Levothyroxine has a very narrow therapeutic index of 0.4 to 4.0 mIU/L. If it is under treatment with Levothyroxine, there can be negative effects on the growth of the body, which will affect bone metabolism, cardiovascular function, reproductive function, gastrointestinal function, and glucose and lipid metabolism. Levothyroxine increases the metabolic rate and decreases the production of thyroid-stimulating hormone (TSH) from the anterior pituitary gland. It is then converted into triiodothyronine (T3) in the peripheral cells of the tissues. The mechanism of action of Levothyroxine is the same as natural thyroid hormone as it helps in the growth and development of the body in children and helps to maintain body functions in adults.

Absorption:

The absorption of orally administered thyroxine (T4) from the gastrointestinal tract takes place primarily in the duodenum and the upper ileum (about 40 to 80 %). The absorption of Levothyroxine is accelerated on an empty stomach and reduced in cases of malabsorption or impaired absorption in the digestive tract. There are some food items that should be avoided as they delay absorption. These include soybean milk, soy, and dietary fibers. Absorption also decreases with age. There are several drugs that also affect the absorption of Levothyroxine, such as Proton-pump inhibitors, Bile acid sequestrants, and minerals such as calcium, magnesium, iron, and aluminum.

Metabolism:

It is observed that almost 70 % of the T4 (thyroxine) is converted to equal concentrations of T3 (triiodothyronine) and reverse triiodothyronine (rT3) which is an inactive form of T4. The elimination of thyroxine occurs quite slowly through its metabolic pathway by being converted into triiodothyronine. The liver is the main site for the breaking down of both thyroxine (T4) and triiodothyronine (T3), whereas the conversion of thyroxine (deiodination) can take place in some other sites such as the kidney also.

Route of Elimination:

The primary route of elimination of thyroid hormones is in the kidneys through urine. But as the age increases, the elimination through urine gradually decreases. The other way of elimination of both thyroxine and triiodothyronine takes place by hepatic conjugation to glucuronic acid and sulfuric acids. As conjugates, the hormone undergoes enterohepatic circulation, gets hydrolyzed in the intestine, and then gets absorbed. However, some amount of conjugated hormones that reach the colon is hydrolyzed and then eliminated through the feces.

Precautions:

Overconsumption of the drug may lead to thyrotoxicosis. The symptoms of thyrotoxicosis include weight loss, increase in appetite, nervousness, sweating, diarrhea, abdominal cramps, tachycardia, increased pulse rate and blood pressure, heat intolerance, fever, and menstrual irregularities in females. Thus it is important to regulate the doses of Levothyroxine periodically by taking hormone level tests and consulting the doctor.

Drug Forms and Strengths:

The doses of Levothyroxine vary for adults and children. It also varies among adults for otherwise healthy patients, patients suffering from cardiac disease, and pregnant women. The doses for different groups of people are:

• Healthy adults diagnosed with hypothyroidism should be given the first dose of 1.6 mcg/Kg/day, which should be adjusted every six to eight weeks to 12.5 to 25 mcg/day dose as per the need.

• Adults who suffer from cardiac diseases or who are over 65 years of age should be given an initial dose of 25 mcg/day and then an adjustment dose to 12.5 to 25 mcg/ day every four to six weeks as per their needs.

• In cases of pregnant women diagnosed with hypothyroidism, the initial dose of the drug should be 1.8 mcg/Kg/day. This dose should be adjusted every four weeks, and the dose of Levothyroxine should be reduced to 1.6 mcg/kg/day after pregnancy.

• In cases of newborn babies diagnosed with hypothyroidism, the initial dose is 10-15 mcg/kg/day, which can be altered later according to age. In cases of congenital hypothyroidism, higher doses of Levothyroxine may be required. The doses for children according to FDA labeling are:

1. 0 to 3 Months: 10 to 15 mcg/kg/day.
2. 3 to 6 Months: 8 to 10 mcg/kg/day.
3. 6 to 12 Months: 6 to 8 mcg/kg/day.
4. 1 to 5 Years: 5 to 6 mcg/kg/day.
5. 6 to 12 Years: 4 to 5 mcg/kg/day.
6. Greater Than 12 Years of Age (When Puberty Is Incomplete): 2 to 3 mcg/kg/day.
7. After Completion of Puberty: 1.6 mcg/kg/day.

• If newborns (0 to 3 months) are at risk of cardiac failure, the initial dose of Levothyroxine is low and is then adjusted every four to six weeks.

Drug Interactions:

The interaction of Levothyroxine with some of the other drugs are:

• Abemaciclib: Abemaciclib is used to treat metastatic cases of breast cancer. Levothyroxine decreases the serum concentration of Abemaciclib when combined together.

• Acebutolol: It is a beta-blocker used to treat hypertension and arrhythmias. It decreases the efficacy of Levothyroxine when used in combination.

• Betamethasone: It is a steroid drug that is used to treat a number of diseases, including rheumatoid arthritis. It decreases the therapeutic efficacy of Levothyroxine when used in combination.

• Caffeine: Levothyroxine increases the elimination rate of caffeine which may result in a lower serum level in the body leading to a reduction in its efficacy.

• Diazepam: It is used to treat conditions such as anxiety, seizures, and alcohol withdrawal. It reduces the therapeutic efficacy of Levothyroxine when used in combination.

Clinical Trials:

• Thyroid Hormone Replacement for Subclinical Hypothyroidism: Subclinical hypothyroidism is a common condition that affects men and women above the age of 65. This is a possible contributor to many diseases in the older age of an individual. This clinical study is about the replacement of thyroid hormone with Levothyroxine.

  • Type of Study: Interventional

  • Number of Patients Enrolled: 737

  • Type of Allocation: Randomized.

The oral dose of Levothyroxine was administered starting from 25 to 50 mcg and to a maximum of 150 mcg daily. In cases of patients suffering from cardiac problems, the doses are kept less.

Results: No results were posted about this study.

• Levothyroxine and Cardiovascular Outcomes in Older Patients With Subclinical Hypothyroidism:

  • The Objective of Clinical Trials: To evaluate the effect of Levothyroxine on cardiovascular outcomes in older patients suffering from subclinical hypothyroidism.

  • Methods: A combined data of two trials which are randomized, double-blinded, and placebo-controlled. In cases of participants aged 65 years and above, TRUST (thyroid hormone replacement for untreated older adults with subclinical hypothyroidism) was performed, whereas in cases of participants aged 80 years and above, IEMO80+ (the institute for evidence-based medicine in old age 80 plus thyroid trial) was performed.

  • Results: Treatment with Levothyroxine does not change the outcome of cardiovascular diseases in individuals above the age of 65 years, irrespective of their history of any cardiovascular disease.

Levothyroxine and Pregnancy:

Women who are suffering from hypothyroidism and get pregnant should not stop the medicine without their doctor’s advice because low concentrations of thyroid hormone can affect the growth of the fetus. It is important to inform the doctor, who may alter the doses as required.

Levothyroxine and Breastfeeding:

There is no specific effect of Levothyroxine on breastfeeding mothers and children. However, the dose should be regularly adjusted by the doctor depending on the thyroid hormone level.

Levothyroxine and Geriatric Patients: Older patients suffering from hypothyroidism can be advised Levothyroxine, but their other diseases such as cardiovascular dysfunctions should be evaluated properly.

Liothyronine:

It is a man-made form of thyroid hormone which is prescribed when the thyroid gland is unable to produce enough thyroid hormones for the proper functioning of the body. It can also be used as a part of medical tests to evaluate thyroid disorders. It can also be used with radioactive iodine therapy and surgery in cases of thyroid cancer.

Warnings:

• Liothyronine should not be used to treat conditions of obesity or weight gain problems.

• It should also be avoided in cases of thyroid toxicity leading to symptoms such as pounding heartbeats, chest pain, a feeling of nervousness, and sweating.

• Liothyronine should be avoided in cases of adrenal gland disorders.

Dosage:

The doses of Liothyronine depend on the weight of the individuals and may vary if the weight varies. Administration of other thyroid medicines is generally stopped once Liothyronine is started.

For Patients:

Before Taking Liothyronine:

Points to Be Mentioned to the Doctor:

Before starting the drug Liothyronine, it is important to mention the following conditions to the healthcare professionals or the doctors:

• Disorders related to the adrenal and pituitary glands.

• Bleeding disorder or anticoagulant disorder.

• Low bone mineral density or osteoporosis.

• Diabetes or increased blood glucose levels.

• Heart problems such as angina.

• Pregnancy.

How to Take Liothyronine?

• All the instructions mentioned on the prescription should be followed properly, including the advised dose of medicine, time of taking the medicines, and others.

• Older adults are generally more sensitive to Liothyronine compared to any other thyroid medication, so the doses should be lower for this age group.

• It is important to stop other thyroid medicine while starting Liothyronine.

• When Liothyronine is given as a part of the thyroid suppression test, it is prescribed for several days to prepare the individual for the test.

• In cases of surgery, it is important to tell the doctor as he may stop the doses for a few days.

What if a Dose of Liothyronine Is Missed?

It is advisable to take the missed dose as soon as possible, but if it is almost time for the next dose, then it is better to take only the next dose. Taking two doses at a time is not advisable.

What if There Is an Overdose of Liothyronine?

Overdose of the drug Liothyronine may result in symptoms such as irregular menstrual cycles, diarrhea, sweating, faster heart rate, and swelling in the hands or feet. It is very important to evaluate the doses at regular intervals.

For Doctors:

Indications:

Liothyronine is used as a replacement for T3 plasma levels and restores insufficient thyroid hormone production in the body. It is also officially approved for the following conditions:

• Adjunct therapy to radioiodine or surgical management of thyroid cancer.

• As a diagnostic agent in suppression tests done for mild hypothyroidism or in cases of thyroid gland autonomy.

• Replacement of thyroid hormones in primary, secondary, or tertiary cases of hypothyroidism.

Pharmacodynamics:

Liothyronine is considered to present more potent and faster actions compared to Levothyroxine, but the duration is comparatively shorter. The effect of the drug is noted a few hours after the administration, and the maximum effect of the drug is seen after two to three days. Liothyronine produces normal plasma levels of triiodothyronine (T3) but has no effects on thyroxine (T4) plasma levels.

Mechanism of Action:

Liothyronine is known to replace the deficiency of thyroid hormone and exert physiologic effects by controlling DNA transcription and protein synthesis. These effects are carried out by the binding of Liothyronine to the thyroid receptors present in the DNA. Liothyronine performs all the functions of triiodothyronine (T3), which include increased energy expenditure, maturation and metabolism of body tissues, myelination of nerves, and acceleration of the rate of cellular oxidation stimulating growth. It also enhances carbohydrates and protein metabolism.

Absorption:

Liothyronine is completely absorbed orally like other thyroid medicines but is not affected by any food items like Levothyroxine in the process of absorption.

Protein Binding:

Liothyronine shows a very large binding to plasma proteins. Almost 99.7 % of the dose administered is bound. The proteins it binds to are albumin, thyroxine-binding prealbumin, and thyroxine-binding globulin.

Metabolism:

Liothyronine is generally metabolized in the liver, where it gets deiodinated to diiodothyronine and monoiodothyronine and then conjugates with sulfates and glucuronides. The iodine released during the metabolism of Liothyronine is later taken by the thyroid cells.

Routes of Elimination:

The main organ for eliminating the thyroid hormones is the kidney. Gradually with age, this route of elimination gets reduced in action. Some amount of Liothyronine is also excreted out through the gut and bile.

Drug Interactions:

• Aceclofenac: It is used to cure pain, and it decreases the excretion rate of Liothyronine, which results in higher serum levels.

• Acetaminophen: Liothyronine decreases the excretion rate of Acetaminophen, which leads to higher serum levels.

• Desmopressin: It is man-made vasopressin, which may decrease the excretion rate of Liothyronine, and thus there are higher serum levels.

• Diflucortolone: It decreases the therapeutic efficacy of Liothyronine.

Clinical Trials:

A study of sustained release of Liothyronine sodium (T3) in healthy subjects:

• Study Type: Interventional.

• Number of Enrollments: 12.

• Ages Eligible: 18 years or older.

• Inclusion Criteria: Healthy adults who are capable enough to swallow the tablets.

• Exclusion Criteria: Patients of hypothyroidism or pregnant women.

• Results: No results were posted for the clinical trial.

Liothyronine and Pregnancy:

There is no evidence of thyroid hormones crossing the placenta and causing any adverse effects on the development of the fetus. Thus Liothyronine can be used in pregnant women, but under the doctor’s supervision as alterations in thyroid levels can affect fetus growth.

Liothyronine and Breastfeeding:

Studies have shown that Liothyronine is found in human milk, so it is important to regulate the doses to prevent toxicity in infants.