Levothyroxine cause weight loss

Is Levothyroxine a Drug of Abuse?

What is Levothyroxine? It is a generic drug typically found as the brand name Synthroid. It is a synthetic hormone prescribed to treat hypothyroidism, which occurs when the thyroid does not produce enough hormone to maintain a normal body weight, height, and physical energy. The medication can also be found as the brand names Levothroid, Levo-T, Levoxyl, Tirosint, and Unithroid. The Food and Drug Administration (FDA) approved this medication officially in 2000, but the prescription has been used in the United States since the 1950s.

This synthetic thyroid hormone treats not just congenital hypothyroidism, but age-related hypothyroidism, which is most common in women over 60 years old. Levothyroxine can also help manage symptoms associated with thyroid cancer or an enlarged thyroid gland (goiter). Levothyroxine replaces thyroid hormone in the body when the thyroid cannot produce enough or when the thyroid has been removed via surgery

What Is Hypothyroidism?

Signs of hypothyroidism or another thyroid problem include:

  • Poor physical growth
  • Slow speech
  • Lack of energy
  • Excessive fatigue or tiredness
  • Weight gain
  • Constipation
  • Hair loss
  • Dry, thick skin
  • Joint and muscle pain
  • Increased temperature sensitivity, especially to cold
  • Depression

People who have normal thyroid function do not need synthetic hormones to manage thyroid issues, but in some cases, people have abused this drug as a performance-enhancer, a way to lose weight, or as a way to boost physical energy. Abusing this substance for nonmedical or self-medicating reasons can lead to severe, life-threatening side effects.

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Side Effects Associated with Levothyroxine

People who take levothyroxine are at a certain risk of experiencing side effects even if they take this medication as prescribed. However, side effects that are unmonitored or untreated are more likely to become serious. People who abuse levothyroxine are at a greater risk for developing uncomfortable side effects, which may become serious over time.

Common side effects associated with levothyroxine include:

  • Weight loss
  • Physical tremors
  • Nausea, vomiting, and stomach cramps
  • Diarrhea
  • Headache
  • Nervousness
  • Irritability
  • Excessive sweating
  • Increased appetite
  • Fever
  • Sensitivity to heat
  • Temporary hair loss
  • Insomnia

Severe side effects that can be life-threatening include:

  • Chest pain
  • Irregular pulse
  • Rapid heartbeat

Long-Term Physical Effects

Because women struggle with acquired hypothyroidism more often than men, women are prone to experiencing more serious side effects from taking this medication. When a woman is over 60 years old, she is more likely to develop osteoporosis in general, but taking levothyroxine appears to make the condition more likely to occur. This medication can decrease bone mineral density over time, and women are more susceptible to this effect than men. A study published in the Journal of Preventive Medicine & Public Health in 2014 found a correlation between older women taking levothyroxine and broken bones.

Cardiovascular damage may also be a side effect of levothyroxine. Signs of a heart attack like shortness of breath and chest pain, signs of heart failure like extreme tiredness and swelling in the legs, irregular heart rhythm, or a very fast heartbeat should all be taken seriously—get emergency medical treatment. While these symptoms may appear suddenly, the damage done to the heart may take time.

One unusual side effect called choreoathetosis is associated with abuse of levothyroxine or taking too much of this drug. This is a movement disorder in which the body involuntarily twitches or writhes, leading to impaired functioning in daily life. This condition prevents normal movement and walking, and in severe cases, it can lead to disability. A report published in 2009 found that thyrotoxicosis from abusing levothyroxine could trigger choreoathetosis; once the patient stopped taking levothyroxine, though, her symptoms cleared within one week.

Abuse of Levothyroxine to Lose Weight or Enhance Performance

Abusing levothyroxine to lose weight or increase physical energy is not a common practice, but it does occur, especially among athletes. This group is more likely to abuse drugs like this to fool drug tests while getting benefits similar to those of stimulants. A Daily Mail report from 2015 highlighted the story of a bronze medal-winning runner who had been pressured by her trainer to take levothyroxine to lose weight in order to compete again.

Although levothyroxine may be misused or abused by some athletes to lose weight for competitions, the World Anti-Doping Agency (WADA) has not yet listed this medication on their list of forbidden substances. Despite its dangers, athletes are currently free to take this drug even if they have normal thyroid function.

Athletes may abuse levothyroxine as a performance-enhancer, but sometimes, others abuse it to lose weight. Stimulants like Adderall and cocaine have been abused for this reason, and they are more commonly found as drugs of abuse among people who have eating disorders. However, levothyroxine has sometimes been found as a drug of abuse in these cases.

Withdrawal and Overdose from Levothyroxine

Withdrawing from levothyroxine is not dangerous. In fact, if the drug is abused, quitting is safer than continuing, but it may include a resurgence of symptoms associated with the underlying thyroid problem. Symptoms include rapid weight gain, depression, low energy, and dry skin. People who abuse levothyroxine may develop insulin resistance during withdrawal, which can trigger diabetes.

When taken as prescribed, levothyroxine is a safe medication to treat thyroid-related disorders. However, when this drug is abused, or mixed with substances that increase the drug’s potency, there is a risk of overdose. Call 911 immediately if someone displays the following signs of a levothyroxine overdose:

  • Intense headache
  • Leg cramps
  • Physical tremors that are not controllable
  • Extreme nervousness
  • Irritability
  • Chest pain
  • Rapid, pounding heartbeat
  • Shortness of breath
  • Very high fever, leading to hyperthermia

Other signs that too much levothyroxine has been taken include warm or feverish skin due to blood flow changes and increased metabolism; gastrointestinal discomfort; anxiety or restlessness; trouble concentrating; and memory loss.

Dangers of Mixing Levothyroxine With Other Prescription or Illicit Medications

Since levothyroxine is a hormonal supplement, this medication will interact with many different prescriptions. It is important to be clear with the prescribing physician about any substances that are taken, including illicit drug abuse, potential alcohol abuse, and other prescription medications. It is also important to notify the doctor of any history of drug or alcohol abuse.

Substances that may interfere or interact negatively with levothyroxine include:

  • Amphetamines, including Adderall or illicit amphetamine drugs
  • Aspirin
  • Blood thinners line warfarin
  • Antidepressants or anti-anxiety medications
  • Heart disease medications
  • Antiseizure drugs
  • Oral contraceptives
  • Insulin and other diabetes medications
  • Ketamine

Professional Help to End Levothyroxine Abuse and Prevent Relapse

Abusing drugs or alcohol requires evidence-based treatment that starts with detox, follows through a rehabilitation program, and continues with ongoing support from loved ones, peer support groups, and potentially an individual therapist, counselor, life coach, or spiritual or religious leader. Once rehabilitation is complete, it is important to keep focused on recovery and sobriety with help from a community that has been through similar struggles. Support groups are great for this form of emotional help.

A good starting place for all kinds of support, including mutual support groups or different approaches to rehabilitation, can be found through the Substance Abuse and Mental Health Services Administration’s online treatment finder.

Support groups for prescription drug abuse include SMART Recovery and Pills Anonymous (PA). Additionally, if a prescription drug like levothyroxine was abused as part of an eating disorder problem, treatment for this co-occurring disorder is important. Help can be found through the National Eating Disorders Association (NEDA), both through their helpline and through their online support group finder.

Evidence-based detox and rehabilitation are the most effective ways to overcome substance abuse, including abuse of prescription drugs like levothyroxine. However, between 40% and 60% of people who struggle with addiction will experience relapse. The National Institute on Drug Abuse (NIDA) states that relapse is part of the chronic disease of addiction. A focus on aftercare when rehabilitation has been completed can help to reduce the risk of relapse and get one back into treatment faster when relapse does occur. This is crucial as addiction can still be effectively managed after relapse.

Facing hypothyroidism: Elisa’s story

ELISA:

When I was growing up, I didn’t realize I had a problem. I just knew that there was an issue there. So when I was diagnosed and was reading about each of the symptoms, that’s when I really connected—the symptoms I had in high school and middle school were in fact symptoms and not the normalcy of most day-to-day people.

ON SCREEN:

FACING HYPOTHYROIDISM: ELISA’S STORY

ELISA:

I was technically diagnosed in 2009 by a doctor that I went in just for a physical, and she had felt my neck and pulled back and was like, “Ma’am, your thyroid is swollen.” So although I was diagnosed then,

ON SCREEN:

Elisa

Living with hypothyroidism

ELISA:

and I went and I had just got blood work done, and they called me the next day and told me, I didn’t do anything about it until 2010.

ON SCREEN:

If you are experiencing symptoms, talk to your doctor. Your doctor may decide to have your thyroid levels tested.

ELISA:

Part of the reason that I waited was lack of education. I took anatomy in high school and college, and I knew where the thyroid was, and I knew how to spell it. But beyond that, I knew nothing about its function.

I didn’t really understand that it was going to be a lifelong disease. I didn’t…it was so much to take on, that I had to take time to educate myself before I was willing to go back through the door at the doctor’s office and say, “You know, I’m ready to get on medication the rest of my life.”

It was hard to accept, is the bottom line.

ON SCREEN:

UNDERSTANDING HYPOTHYROIDISM

ELISA:

The first doctor I saw did not explain to me what hypothyroidism is. She did tell me that I have hypothyroidism and that my thyroid was swollen. But she didn’t really go beyond that.

But the doctor that I did see a year later, he was extremely informative. He detailed extensively, what it meant, where the thyroid was. He even pulled out charts and showed me my blood work and showed, you know, “Here’s your range that you’re supposed to be in and here’s where you’re at.”

ON SCREEN:

A TSH test can help determine if your thyroid levels are in range.

ELISA:

Once I learned what the disease was and what it entailed I didn’t feel as crazy as I had felt for so many years.

ON SCREEN:

GETTING YOUR THYROID LEVELS IN BALANCE

ELISA:

He did explain each of the options for treatment. He went through and explained, branded versus generic. He explained how important it was to get on a regimen. He did recommend Synthroid. When I started Synthroid it was not a quick fix. That’s the best way to put it.

ON SCREEN:

SYNTHROID is not for everyone. Talk to your doctor to determine which medication is right for you.

ELISA:

The doctor also explained that it’s going to take time to get your level, you know, within that range that it needs to be. It took me some time to get that level straightened out. And really finding out, you know, what’s going to work for me.

ON SCREEN:

Your doctor will carefully monitor your thyroid levels regularly.

And once I got in range, I don’t want to say, like, everything’s perfect. But it was finally like that glaze came off and a light bulb came on and I felt for the first time in control.

ON SCREEN:

When starting SYNTHROID, it may take time for you and your doctor to find the dose that works for you.

ELISA:

I would tell someone that’s just starting on Synthroid that once they’ve made that commitment to stick with it. And be willing to allow yourself to not be perfect. But remember that each day is a new day, and you need to make that commitment, and you have to be willing to do it.

ON SCREEN:

Take SYNTHROID as your doctor prescribed.

Molecular Testing in Thyroid Practice

Role of the Thyroid Hormones

Role of the Thyroid Hormones
Thyroid hormones play a vital role in the human body and, as such, the absence of such hormones requires treatment. Generally, levothyroxine is used to treat thyroid hormone deficiency, and after a brief review of thyroid hormone physiology, this article will highlight what is known about the pharmacokinetics (PKs) of levothyroxine, as well as describe factors that can influence its PKs. The thyroid gland is responsible for the synthesis, storage and release of metabolic hormones including iodinecontaining thyroxine (T4) and triiodothyroxine (T3). These hormones are crucial in the regulation of many metabolic processes and are vital for normal growth and development.1 They are also involved in calorigenic, cardiovascular and metabolic effects. The hormones exert their effects presumably by activating gene transcription of messenger RNA and proteins. To do so, they enter the cell nucleus and bind to DNA-bound thyroid receptors, which regulate gene transcription.1,2

T4 and T3 Production and Feedback Loop Mechanism
Normally, the hormones secreted by the thyroid are regulated by the hypothalamic–pituitary–thyroid (HPT) axis through a negative feedback system. Low levels of circulating T4 and T3 initiate the release of thyrotropin-releasing hormone (TRH) from the hypothalamus and thyroidstimulating hormones (TSH) from the pituitary. On interaction with its specific receptor, TSH stimulates the thyroid follicular cells to synthesise T4 and T3 and release them into the bloodstream. When circulating levels of T4 and T3 increase, they inhibit the release of TRH and TSH (i.e. negative feedback mechanism) thereby decreasing their own production.1–4 The predominant hormone produced by the thyroid gland is T4, with approximately 70–90 mcg of T4 and 15–30 mcg of T3 produced daily.1,5 The production of the T3 hormone by the thyroid gland is insufficient to meet the daily requirements of the organs in the body. Therefore, approximately 80 % of the body’s required T3 comes from peripheral conversion of T4 to T3.4,6 Although both T4 and T3 are active, T3 is more active as thyroid receptors within the cell nucleus have a 10-fold greater affinity for T3.2,4

Indication and Dosage
Levothyroxine is a synthetic T4 hormone that is biochemically and physiologically indistinguishable from the natural one, and it is administered when the body is deficient in the natural hormone.7 Oral administration of levothyroxine is thus indicated for acquired primary (thyroidal), secondary (pituitary) and tertiary (hypothalamic) hypothyroidism.8 It is also used to treat euthyroid goiters including thyroid nodules, subacute or chronic lymphocytic thyroiditis, multinodular goiter or for thyroid cancer patients who have undergone thyroidectomy, and as an adjunct to surgery and radioiodine therapy.1

For an average adult under the age of 50, the typical levothyroxine sodium dose is approximately 1.7 mcg/kg/day, which is equivalent to approximately 100–125 mcg/day. Older patients or patients with cardiac disease may require less levothyroxine and doses should be titrated at intervals of 4–6 weeks. Newborns, infants and adolescents require doses greater than 1.7 mcg/kg/day.The guidelines that were recently released by the American Association of Clinical Endocrinologists and American Thyroid Association task force on hypothyroidism in adults, in addition to diagnosis, include suggestions of therapy.9

Literature Search Method
A literature review was conducted in PubMed, Embase (1974 to week 47 of 2012) and Medline (1946 to third week of November 2012) using the terms ‘levothyroxine’ and ‘pharmacokinetics’. The searches in Pubmed and Embase/Medline returned 1217 and 147 publications, respectively.
Pharmacokinetic Properties
Major characteristics of levothyroxine PKs are summarised in Table 1 and are described in more detail below.

Absorption and Bioavailability
Levothyroxine is mainly absorbed in the small intestine, more specifically through the duodenum, jejunum and ileum.10,11 Very little is absorbed in the stomach. Consequently, patients with shorter small intestines (bowel resection) have reduced absorption and require higher levothyroxine doses.12 The time to maximum concentration (Tmax) occurs at approximately 2 hours in euthyroid volunteers while it is delayed to approximately 3 hours in hypothyroid patients.13 Food also delays Tmax.13,14

The bioavailability of levothyroxine is approximately 60–80 % in euthyroid volunteers.14–16 It may be slightly higher in hypothyroid and hyperthyroid patients,15,16 and is decreased in the presence of food from 79 % under fasted conditions to 64 % under fed conditions for a 100 mcg dose.14

The absorption of levothyroxine appears to be influenced by gastric pH.17,18 Centanni et al. demonstrated that in euthyroid patients suffering from nontoxic multinodular goiter, impaired gastric acid secretion or the use of omeprazole was associated with increased dosing requirements in order to adequately suppress TSH.17 Similarly, Sachmechi and colleagues showed that chronic lansoprazole use in hypothyroid patients also resulted in increased levothyroxine dose requirements to maintain targeted TSH levels.18

Volume of Distribution
Levothyroxine has a limited volume of distribution, which has been reported to be 11.6 litres (L) in euthyroid volunteers and 14.7 L in primary hypothyroid subjects.19 This is approximately equivalent to the extracellular fluid volume of the body.

Metabolism
Although T4 is subject to multiple metabolic reactions,20–22 the main metabolic route for T4 involves deiodination reactions (removal of iodine) by deiodinase enzymes.23–25 Removal of iodine from the carbon 5 of the outer ring transforms T4 to T3, thus T4 can be regarded somewhat as a pro-hormone for T3. Deiodination of the inner ring of T4 can also occur, leading to the formation of inactive reverse T3(rT3). Approximately half of deiodinised T4 is metabolised to rT3 and half to T3.25,26 Both T3 and rT3 are further metabolised to diiodothyronine (T2), iodothyronamine (T1) and reverse T2 and T1.25,26

Elimination
The daily turnover rate for T4 is approximately 10 % while it is approximately 50–70 % for T3, with a slightly faster turnover rate in normal volunteers compared with patients with primary hypothyroidism.1,2 This equates to a half-life for T4 of 7.5 days in hypothyroid patients and 6.2 days in euthyroid individuals, while the T3 half-life is approximately 1.4 and 1.0 days for hypothyroid and euthyroid volunteers, respectively.19 Clearance for T4 was similar with 0.056 and 0.054 L/h in hypothyroid and euthyroid subjects, respectively.19 These values are similar to other values reported in hypothyroid patients (0.0385 L/h/70 kg)27 and in normal control subjects (0.053 to 0.064 L/h).28,29

Protein Binding
Both T4 and T3 are highly bound to plasma proteins at greater than 99.8 % (i.e. unbound T4 = 0.02–0.03 %; unbound T3 = 0.2 %) in both euthyroid and primary hypothyroid volunteers.1,19,30,31 Both T4 and T3 bind predominantly (>80 %) to thyroxine-binding globulin (TBG), and to a lesser extent to thyroxine-binding prealbumin and albumin.1,30 Benvenga and Robbins have also demonstrated binding to lipoproteins such as high-density lipoprotein.32,33 The T3 affinity for binding to these proteins is approximately one-thirtieth that of T4,34 which explains the higher turnover rate of T3 compared with T4.

Transporters/Cytochrome Enzymes
Active transport of thyroxine into cells has been recognised for some time.35,36 In vitro studies have shown that organic anion transporting polypeptides (OATP) (such as OATP1A2, OATP1B1, OATP1C1, etc.), monocarboxylate transporter and sodium-taurocholate cotransporting polypeptide are involved at different levels.37–41

However, few articles have been published on the in vivo significance of these transporters on the PK of levothyroxine. Lilja et al. demonstrated the effects of the influx intestinal OATP transporter inhibition by grapefruit juice consumption on levothyroxine absorption.42 They concluded that grapefruit juice had only a minor effect if any on levothyroxine absorption (AUC0-6 dropped by 9 % and Tmax was slightly delayed).42

A transporter that may be induced by levothyroxine is PgP (ABCB1 gene). Jin et al. published results that showed that cyclosporine A trough concentrations were lower in patients taking levothyroxine. In addition, the expression of this transporter was increased and oral cyclosporine A concentrations and bioavailability were lower in rats treated with levothyroxine.43
PK Properties in Special Populations
Table 2 summarises the effects of different conditions on the PK of levothyroxine and additional details are presented below.

Renally Impaired Patients
The kidney plays a significant role in the peripheral metabolism of T4 to T3.1 Therefore, this metabolic route is significantly reduced in renally impaired patients, partially due to accumulated uremic toxins.44,45 In patients with renal disease, there is a reduction in total and free T3 while T4 is less affected;46,47 however, some patients with end-stage renal disease are also diagnosed with hypothyroidism.48 It has also been reported that other metabolic routes may be enhanced, resulting in higher T3 sulphate concentrations.49 The proteinuria associated with the nephrotic syndrome may cause urinary loss of the thyroid hormones bound to the thyroid hormone transport proteins.50,51

The volume of distribution of thyroxine is also increased in patients with renal failure, which is probably due to the decreased protein binding of thyroxine.52 Haemodialysis does not have an impact on levothyroxine requirements in this patient population.47,48 However, kidney transplantation has been shown to affect the levels of thyroid hormones.47 Some authors report that levels of T3 increase with time after transplantation and doses of levothyroxine can consequently be reduced,45,47 while others report the contrary.53 The increased levothyroxine dose could also be due to drug–drug interactions with the medications patients are required to take after kidney transplantation.47

Hepatically Impaired Patients
The liver is a major site for T4 deiodination to T3.1,2 In addition, T3 and T4 are conjugated with glucuronic and sulphuric acids and then excreted in the bile.6 Approximately 20 % of T4 is eliminated in faeces.1 Therefore, it is expected that patients with hepatic impairment would have different levels of circulating T4 and T3 compared with patients with normal hepatic activity. Indeed, several studies have reported similar or higher levels of total and free T4,54,55 decreased levels of total and free T3 and elevated concentrations of rT356–59 in patients with severe cirrhosis compared with normal patients. Other authors have not shown significant reduction in T3 concentrations in patients with different degrees of liver impairment except when patients had severe cirrhosis.60

The clinical impact of severe cirrhosis on thyroid hormone levels is also influenced by other factors, such as lower levels of thyroxine binding proteins such as albumin. Overall, this possibly leads to an increase in free T4 concentrations or the ratio of free T3 to bound T3, meaning that despite overall lower levels of T3, more free T4 and T3 is available. Thus, because levothyroxine is a low-extraction drug, changes in protein binding will affect total levels but not free levels of hormone. Furthermore, increasing the dose of levothyroxine may not compensate for the lack of liver metabolism of T4 to T3.

Obesity
TSH values are increased in obese patients, which could be attributed to leptin, a hormone produced by adipose tissue that may increase TSH secretion.61,62 Therefore, in such patients, increased levels of TSH do not necessarily indicate hypothyroidism, and TSH should not be the only criteria used to adjust doses.

Some authors have reported higher circulating concentrations of T4 and T3 in obese patients while others have reported lower levels.63,64 Santini et al. reported the lack of a correlation between serum leptin concentrations and the total dose of levothyroxine administered and that adipose tissue had a minor impact on levothyroxine requirements.65 The authors also indicated that lean body mass was superior to actual weight as a predictor of dosage, which is in line with levothyroxine’s small volume of distribution. Greater dose requirements in obese patients are probably attributed to a slightly higher volume of distribution (i.e. higher lean body mass and peripheral mass) compared to non-obese patients rather than to a greater overall weight (fat weight). If weight is used to determine a starting dose in obese patients, total weight may lead to supra-therapeutic doses, therefore using lean body mass might be a better alternative.65

Pregnancy
Following conception in euthyroid women, TBG increases quickly with a rise in total T4 concentrations, and decreases in free T4 and TSH in the first trimester.66 T4 production increases 20–40 % in the early part of the first trimester and this continues throughout the pregnancy.67 In hypothyroid women who become pregnant, T4 requirements are also similarly increased, often necessitating an increase in levothyroxine dosage.68 It should be noted that as TSH values are normally lower in the first trimester, increased T4 requirements may not be recognised if TSH is the only marker used to adjust levothyroxine administration doses. Soldin et al. reported that levothyroxine clearance was faster in nonpregnant women at 7.0 L/h versus 4.5 L/h in pregnant women, despite similarities in Tmax and Cmax.67 In addition, PK parameters in pregnant women appeared to be more variable.67
Children
Heskel et al. reported a shorter half-life for T4 in euthyroid children compared with adults (4.95 days for children and almost 7 days in adults).69 They concluded that when considering weight, there was a decreased pool of T4 and an increased elimination rate of thyroxine. Furthermore, Mainwaring et al. reported a shorter half-life for T3 in children undergoing cardiopulmonary bypass compared with adults having the same procedure (seven hours versus close to one day).70 According to the American Thyroid Association71 and the levothyroxine product monograph,72 infants and children require higher doses per weight or per body surface area compared with adults.73 The typical dose can be as high as 10–15 mcg/kg/day for infants from 0–3 months old and it decreases towards adulthood where the typical dose is 1.7 mcg/kg/day.

Elderly
In healthy elderly individuals, secretion of T4 and T3 and metabolism of T4 to T3 are reduced while rT3 levels appear to increase.74,75 Accordingly, the elimination half-life for T4 is longer and reported to be 9.3 days in patients older than 80 years old.76 Absorption of T4 is also slightly lower for patients above 70.77 Although T4 concentrations do not appear to be decreased in older euthyroid patients, total and free T3 concentrations are reportedly lower in individuals 61–90 years old compared with younger individuals74 , which is expected due to their decreased metabolism. Therefore, measurements of only T4 may be insufficient to explain changes in elderly patients’ thyroid function.

Gastrointestinal Disorders
Certain gastrointestinal disorders, including celiac disease78 and Helicobacter pylori infection17 , can impede the absorption of levothyroxine. As levothyroxine is mainly absorbed through the small intestine, its absorption is compromised in patients with coeliac disease.78 Higher levothyroxine doses were reportedly required in patients with coeliac disease and when patients followed a gluten-free diet, levothyroxine dose requirement was reduced.78,79 H. pylori infection causes chronic gastritis and affects gastric acid secretion in the stomach.17 Levothyroxine doses have been reported to be higher in hypothyroid patients with this disease.17,80 However, following resolution of the infection, Bugdaci et al. recommend that doses be lowered.80 Other gastrointestinal disorders such as inflammatory bowel disease, lactose intolerance and atrophic gastritis have also been demonstrated to affect levothyroxine absorption.

Drug and Food Interactions
Many substances are known to influence T4 or T3 levels and the impact appears to be more significant in hypothyroid patients being treated with exogenous supplementation compared with patients without thyroid pathology, probably due to their intact feedback mechanisms. In addition, interactions with levothyroxine can also occur indirectly via modulation of the HPT axis. All these will be described below and are summarised in Table 3.

Food
The oral absorption of levothyroxine can be impaired by various substances, such as food13,81–83 , soy bean,84–91 papaya92 and grapefruit.42 Benvenga and colleagues have demonstrated that coffee can also impair the absorption of certain levothyroxine formulations.93,94

Drugs Drugs
can alter the PKs of thyroid hormones in various ways.95 Drugs that decrease TSH secretion (dopamine,96–100 glucocorticoids,101,102 octreotide103,104 and rexinoids105,106 ) lead to decreased thyroid hormone concentrations, while thyroid hormone synthesis is interfered with by other drugs,107 such as lithium, iodine108 , tolbutamide, sulphonamides and amiodarone.109,110

Proton-pump inhibitors, such as omeprazole17 and lansoprazole,18 have also been shown to influence the absorption of levothyroxine, as assessed by TSH levels in patients, since normal gastric acid secretion plays a major role in the absorption of thyroxine. Interestingly, others found that in healthy volunteers, famotidine and esomeprazole had no such effect.111 Aluminium hydroxide112–114 , dietary fibre115 , calcium carbonate,116–119 calcium citrate,120 calcium acetate, ferrous sulphate,121–123 cholestyramine124 and colsevelam125,126 decrease levothyroxine absorption by binding to it and forming complexes that are not absorbed. Sucralphate127 may decrease levothyroxine absorption by interfering with its intra-luminal transport or by binding to it.82 .Other products such as phosphate binders,126,128,129 orlistat130 and cimetidine131 also appear to decrease the absorption of levothyroxine, although the interaction mechanism/s is/are not as clearly defined.

Drug interactions can also influence other PK processes. For instance, the administration of beta blockers such as acebutolol, oxprenolol and timolol appear to modify the extracellular distribution of T3, thereby decreasing T3 levels.132 Changes in protein binding can also influence the PK of levothyroxine, as decreased protein binding is associated with greater levels of free levothyroxine, which is then more readily eliminated from the systemic circulation. Drugs that decrease levothyroxine protein binding include carbamazepine,133 androgens, anabolic steroids,134,135 and nicotinic acid.136,137 Certain drugs are associated with transient increases in free T4 levels due to inhibition of protein binding,107 including high-dose furosemide,138 salicylates139–141 and heparin.140,142 Conversely, drugs that increase protein binding are associated with a reduced clearance of levothyroxine. Such drugs include ethinyl oestradiol,143–145 tamoxifen,146 heroin, methadone,147–150 mitotane and fluorouracil.151,152

Finally, some drug interactions with levothyroxine can be explained by an effect on its metabolism, such as the extrathyroidal conversion rate of T4 to T3. Certain drugs, such as propranolol28,29,153,154 and amiodarone,107 reduce this metabolism. Conversely, carbamazepine,133,155–158 phenobarbital,159,160 rifampin107 and phenytoin155,161 induce liver microsomal enzymes and increase this peripheral metabolism.
Available Formulations
Commercial levothyroxine oral formulations available in North America and Europe include powders for intravenous solutions, tablets (e.g. Synthroid®, Levo-T™, Levothroid®, Levoxyl®, Unithroid®, Eltroxin®, Elthyrone®, Euthyrox®, Eferox®, Berlthyrox®, Letrox®, Tirosint®), soft gel capsules (Tirosint®) and oral solutions (Eltroxin®, Tirosint®oral drops and Tirosint®oral solution in unit-dose ampules).

There are advantages and disadvantages that are unique to the formulation type and not to levothyroxine per se. For instance, while tablets and capsules offer the advantage of precise dosing, solutions and liquids can be easier to swallow for children or the elderly. Formulation differences that are specific to levothyroxine also exist. The influence of pH on dissolution profiles of tablets and soft gel capsules is dissimilar,162 as well as the negative impact of coffee intake on levothyroxine absorption.93,94

Bioequivalence
The existence of multiple levothyroxine formulations is also the result of the availability of many generic versions of these compounds. Many studies have been published describing comparisons of the PK properties of various levothyroxine formulations163–181 and various approaches have been employed since bioequivalence assessments of levothyroxine are complicated by baseline levels, feedback mechanisms and by the fact that levothyroxine is considered by some to be a ‘narrow therapeutic index’ (NTI) drug, which some believe merit more stringent criteria (confidence intervals of 90–111 % rather than the standard 80–125 %, or stability throughout the shelf-life of +/-5 % instead of +/-10 %). For this reason, specific guidelines pertaining to assessing the bioequivalence of levothyroxine formulations have been published, in particular by the US Food and Drug Administration (FDA).

Current regulatory guidelines published by the FDA recommend that bioequivalence of levothyroxine formulations be assessed by comparing PK measures of T4.182 The underlying assumption regarding the use of T4 rather than TSH or T3 is that systemic T4 levels reflect the levels at the site of action, and that a relationship exists between the efficacy and safety of the product and its systemic levels. Despite TSH sensitivity to changes in thyroid hormone level, TSH is not used to assess bioequivalence of thyroid formulations because it is a secondary response to levothyroxine and there is a significant time delay between the administration of exogenous levothyroxine and the changes noted in TSH levels. In addition, it is simply not a direct measure of levothyroxine- administered product, as are baseline-adjusted T4 concentrations.

Because levothyroxine is an endogenous compound, it is important to take baseline levels into consideration when performing bioequivalence assessments to avoid biasing comparisons which can lead to failure in distinguishing true differences between formulations.183 Current FDA bioequivalence guidelines require that supra-therapeutic doses of levothyroxine (600 mcg) be administered and that levothyroxine PK parameters be corrected for individual baseline values. This minimises the effect of endogenous concentrations on bioequivalence assessments182,184 by ensuring a high signal (concentrations related to exogenous levothyroxine) to noise (endogenous levels) ratio.

In addition to some of the recommendations described above, the FDA also stipulates that a levothyroxine product must have a 95–105 % potency specification over its entire shelf-life instead of previously accepted potency limits of 90–110 %.185 This was established to ensure greater consistency in levothyroxine administered to patients and to reduce possibly large fluctuations in drug concentrations.

Thus, recommendations from current regulatory guidelines regarding study design and baseline adjustment of PK parameters ensure that a conservative approach to bioequivalence of levothyroxine formulations is adopted.

Summary
Although levothyroxine has long been a mainstay in the treatment of hypothyroidism, its optimal use often remains elusive. Not only are thyroid hormones levels governed by sensitive and complicated feedback mechanisms, but they are also subject to the influence of disease, the intake of food and the use of concomitant medication. While these competing factors can pose a challenge for clinicians, a thorough comprehension of these elements as well as other PK considerations will ultimately be beneficial for the patient.

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Levothyroxine – not all tablets are the same.

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