Pharmacotherapy of Thyroid/Antithyroid Drugs Flashcards
Hypothyroidism
- hypofunction
- In primary hypothyroidism the key biochemical problem is failure to produce sufficient levothyroxine and liothyronine (T4/T3).
-T4 is not the active hormone and is converted intracellularly to T3 that is active.
•Signs and symptoms may be subtle and insidious, but can progress to a severe form referred to as myxedema.
Causes of Hypothyroidism
- Autoimmune thyroiditis – Hashimoto’s Disease (most common)
- Iatrogenic (surgery and radiation)
- Iodine deficiency (<100 mcg/day) and excess. -Rare in North America.
- Antibodies against Peroxidase
- TSH receptor blocking antibodies
- Drugs (some common ones are lithium, amiodarone, and interferon-alfa.
-Less common are amioglutethimide, thalidomide, radiocontrast agents, Kelp tablets, SSKI – saturation solution of potassium iodide).
***OF NOTE, amiodarone and SSKI can also cause HYPERthyroidism.***
•In hypothyroidism the thyroid gland can be goitrous (enlarged because of hypertrophy/hyperplasia); OR nongoitrous (atrophy of gland)
Serum Chemistry of Hypothyroidism
- In primary hypothyroidism TSH (reference range 0.5 – 4.5 micro units/ml) is increased and the T4 (free T4 reference range 0.7 – 1.9 ng/dL) is decreased.
- The current TSH assays are sensitive to 0.01 mU/ml and can be used as a single screen test.
Therapy for Hypothyroidism
- Treating SUBCLINICAL disease (TSH >4.5-9.9 microunits/ml) is not needed. Repeating TSH measurement in 1-3 months is reasonable to validate subclinical disease.
- Unsure iodine intake is sufficient (an uncommon issue in North America)
- Institute hormone replacement with levothyroxine only if symptoms/signs presents
- There is no need to use desiccated thyroid ever.
- This product can cause allergic reactions (source is pigs).
- It has variable amounts of levothyroxine and triiodothyronine (T3) that makes dosing much harder.
•About 100 mcg of levothyroxine is about 65 mg of desiccated thyroid.
-Conversion to levothyroxine is reasonable.
Levothyroxine (T4)
- Levothyroxine (T4) is used most often (only drug to use unless very specific cases).
- It is sold as Synthroid, Levoxyl, Levothyroid, and several generics that are approved as interchangeable by the FDA (Mylan, Sandoz, or Lannett).
-The American Association of Endocrinologists, The Endocrine Society, and the American Thyroid Association published a position statement disagreeing with the FDA.
•There is no evidence that one T4 product is better than another. It is best to use ONE form.
-he professional organizations agree that if switching from one product to another, it is reasonable to recheck labs if a change in product is done after 6-8 weeks.
•A large number of tablet strengths are available ranging from 25 to 300 mcg. This large number of dosage forms allow for accurate titration of therapy.
Key Points About T4
- Incompletely absorbed (~50%) when taken orally and recommended to take on an empty stomach (this is important for the RARE patient treated for hypothyroidism that ends up hospitalized and needs parenteral therapy. This SHOULD BE given IV at about ½ the total oral dose given one time a week).
- A prodrug (prohormone) – converted to triiodothyronine (T3), the active form, in the liver and other tissues by deiodinases
- Circulating hormone is highly protein bound (99%) to TBG (thyroxine-binding globulin) and transthyretin. T3 is also highly bound to serum proteins.
- Long elimination half-life (~7 days). Possible to take all the dose ONE day each week.
- Alterations in binding can influence “free T4” level
- Pregnancy and estrogen treatment increase TBG binding and decrease free hormone
- Certain drugs increase binding and decrease free hormone
- T4 and T3 metabolized by glucuronosyltransferases and sulfotransferases.
- This promotes their biliary excretion.
- Enzyme inducers can lower T4 plasma levels.
•Goals of therapy are to administer T4 at doses that will relieve symptoms and achieve stable biochemical euthyroid state.
Pediatric Patients and T4
•Pediatric patients need a higher dose per body weight.
Dosing of T4 for patients <50 years old
•For healthy patients, less than 50 years old, the full replacement dose can be prescribed.
-That dose is in the range of 1.6-1.8 mcg/kg/day (100-125 mcg/day for 60-80 kg adult).
- A repeat of the TSH is done after 6-8 weeks (earlier may be misleading given the long half-life of T4) to provide information about the adequacy of replacement.
- For a severely hypothyroid patient, increasing the dose can be done every 2-4 weeks until symptoms improve.
- A dose of >200 mcg/day should make one consider non-adherence, malabsorption, or drug-interaction that inhibits absorption (e.g., Aluminum & Magnesium Hydroxides Antacids, Simethicone, Bile Acid Sequestrants [Cholestyramine, Colestipol] Calcium carbonate, Ferrous sulfate, Orlistat, Cation Exchange Resin [Kayexalate], Sucralfate; doses can be separated by 2-4 hours if potential absorption issue) or increased metabolism (e.g., rifampin, phenytoin, phenobarbital, carbamazepine).
- The dose is taken once daily (preferably in the morning on an empty stomach, but can be taken at bedtime). Taking levothyroxine with food reduces absorption – being CONSISTENT in when taking doses may be more important to avoid large fluctuations in serum concentrations.
- Reevaluate with measuring TSH in 6-8 weeks (4 weeks if severally hypothyroid and then every 6-8 weeks).
- Once euthyroid, change to measuring TSH every 6-12 months.
- If not adherent to daily therapy, it is possible to give one dose of levothyroxine every 7 days due to the long half-life.
-This can be done under observation to ensure the drug is taken (e.g., 700 mcg every Saturday instead of 100 mcg daily).
Dosing for patients >50 years old
- For older patients (>50 years old) the initial dosage should be reduced to 25-50 mcg/day; for those with pre-existing cardiac decrease the dose to 12.5 - 25 mcg /day.
- The evidence for this is very weak, but it is what is recommended.
Dose Adjusment for T4
- Dose adjustment can be achieved by a change in dosage form or by a change in dosing frequency at intervals that are most often every 6-8 weeks.
- For a severally hypothyroid patient, the dose can be increased at 2-4 weeks.
-The dose can be changed 12.5-25 mcg/day to achieve a normal TSH.
•If the TSH is not decreasing, it is important to check if getting prescription filled and it is taken.
Pregnancy and Thyroid Hormone
- The hypothyroid patient should be monitored (i.e. serum TSH in each trimester) because pregnancy often requires an increase in the dose of T4, perhaps as a result of increased serum TBG and thus, a reduction in the “free T4”.
- Overt hypothyroidism is associated with fetal distress, so the issue is to protect the mother and the fetus.
- T4 doses are normally higher during pregnancy (~30-50% more).
- The dose needs to be returned to pre-pregnancy amounts postpartum (and check TSH in 6-8 weeks).
- Thyroid hormones are poorly secreted into breast milk.
- However, monitoring the new born for signs/symptoms of hyperthyroidism is reasonable.
- Lactation may stop if hypothyroidism recurs postpartum.
Myxedema and Thyroid Hormone
- Now rare, but is profound hypothyroidism that can negatively impact most (maybe all) organ function.
- It should be considered in any patient with stupor or coma who is also hypothermic, hyponatremic, and/or hypocapneic.
- Intravenous levothyroxine is given in a dose of 100-500 mcg (lower dose in older patients or those with cardiovascular disease) that is followed by 100 mcg daily until able to take oral meds is one approach.
- Some would give T3 with T4 starting at 5 mcg/day.
-There is no evidence this improves the outcome.
•Patients with myxedema should also be evaluated for adrenal insufficiency and they should be treated with hydrocortisone 100 mg IV every 8 hours until that diagnosis is excluded.
Cretinism and Thyroid Hormone
- T4 therapy in first few weeks of life, critical stages of CNS development. Doses: 10-15 mcg/Kg per day.
- Adjust at 4-6 week intervals during first 6 months
TSH Suppression Therapy and Thyroid Hormone
•T4 is used to suppress release of TSH in nodular thyroid disease, following thyroid surgery for thyroid cancer and as a preventive therapy in individuals exposed to radiation (which may result in increased nodular development).
Liothyronine
- T3 (Cytomel) is 3-4 times more potent than T4.
- T3 is not used long term because of a shorter t½ (1 day) than T4 and has more variable blood levels.
- However, its faster onset of action can be advantageous, as noted before, in myxedema coma.
- Daily maintenance dose 50-75 mcg. Initial dose 25 mcg with gradual increases.
- Use: initial therapy in myxedema coma (5-20 mcg and then 2.5-10 mcg every 6-8 hours).
- Once the patient is stable, T3 can be stopped and treated with T4 alone.
