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Thyroid and Anti-Thyroid Drugs

An overview of the thyroid, thyroid

drugs, and the mechanisms throughwhich they affect thyroid function.

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Anatomy and Physiologyof the Thyroid Gland Member of the Endocrine System

Secretes thyroid hormones, thyroxine andcalcitonin, which regulate metabolism and growth.

Located in neck adjacent to the 5th cervical vertebra(C5).

Composed of epithelial cells which specialize in theabsorption of iodine and, of course, secretion of

thyroid hormones. Follicles surround a protein core, the colloid, where

thyroglobulin, a substrate in thyroid hormonesynthesis, and thyroid hormones are stored.

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Synthesis of ThyroidHormones Regulation:

The hypothalamus in the brain secretes thyroid releasing hormone, TRH, thattarget the pituitary gland which, in turn, secretes thyroid stimulating hormone,TSH. The pituitary glands sensitivity toward TRH varies with the bodys needfor thyroid hormones.

TSH is absorbed into the thyroid, stimulating the thyroid to absorb iodine andsynthesize hormones.

Thyroid hormones provide negative feedback for TSH production via ahomeostatic feedback loop.

TH Synthesis: Thyroid peroxidase (TPO) catalyzes the conversion of iodide (I2) to iodine (I

-)using H2O2 as a cofactor.

TPO then catalyzes the addition of iodine to the C-3 and C-5 position of atyrosine residue of thyroglobulin.

Two iodinated thyrosine rings condense to form thyroxine, or T4, with fouriodine substituents.

Triiodothyronine, or T3, with three iodine substituents, accounts for about 10%of thyroid hormone production.

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Mechanism of THActivation in Body Hydrophobic molecule transported in the bloodstream with a

requisite carrier protein, TBG. Albumin also serves as a THcarrier protein.

Transported across the cell membrane using a transporter

complex. TH enters nucleus. The iodine at position 5 on the outer ring serves to sterically hinder

the thyroid hormone binding enzyme. T4 is converted to T3, theactive form.

Deiodinase, specifically IDI or IDII, cleaves the iodine at position 5to yield triiodithronine, T3.

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TH Effects on Metabolism TH serves as a nuclear transcription factor, regulating gene

expression in targeted cells to increase metabolism. Increase size and number of mitochondria in the cell.

Synthesizes cytochromes which feed into the electron transfer chainof cellular respiration, stimulating metabolism through increasing ATPproduction.

Increase ATPase concentration, the enzyme which cleaves aphosphate group from ATP forming ADP and inorganic phosphate.

Increased K+ and Na+ concentrations in the cell.

Increase the bodys basal metabolic rate, BMR, to maintainelectrochemical gradient in cell.

Stimulate carbohydrate metabolism and lipolysis, or the breakdown of fats.

Affects protein synthesis.

Increase the bodys sensitivity to cathecholamines, i.e. adrenaline,which is also a derivative of TH.

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Conditions that ImpairThyroid Function:Hypothyroidism

Insufficient amount of thyroid hormone synthesizedcausing lethargy and weight gain, among othersymptoms.

Primary hypothyroidism is typically caused byHashimotos Disease, an auto-immune disorder inwhich the thyroid is destroyed by antibodies.

Impaired hypothalamus and pituitary function,typically due to a tumor, can inhibit the secretion of

THS, causing secondary hypothyroidism. A diet insufficient in iodine causes hypothyroidism

as well.

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Symptoms of ThyroidDisfunction: Goiter Enlarged thyroid, symptom of hypothyroidism.

Goiters form for different reasons depending on thecause of hypothyroidism

Hashimotos disease, also known as chronic lymphocyticthyroiditis, causes goiters due to the accumulation oflymphocytes.

The decreased amount of thyroid hormones in the body, due toHashimotos or other thyroid disorders including infection,signals the increased production of TSH which accumulates inthe thyroid causing a characteristic goiter.

Goiters form due to an insufficient amount of ingested iodineand serve to increase the surface area of the thyroid and aid inits absorption of iodine.

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Treatment forHypothyroidism Hormone replacement therapy

Administered orally with a bioavailability ranging from 48%-80%. LevothyroxineSynthetic T4

LiothyronineSynthetic T3

LiotrixCombination of synthetic T4 and T3

Natural Thyroid HormonesThyroid hormones derived from pigs, contains T4 and T3 Armour Thyroid

Dosage specific to individual and is determined by their TSH serum levels.Typically 1.5g T4 per kg body weight. Because thyroid hormones serve to increase heart rate, T4, the inactive form, is typically

administered to older patients who have an increased risk for heart attack on account oftheir age. Synthetic T3 is reserved for younger patients, who do not have a history ofheart problems and individuals non-responsive to T4 treatment.

Some men are inefficient in the conversion of T4 to T3, making combination drugs like

Litrix and Armour Thyroid ideal treatment options. Dosage for individuals suffering from secondary hypothyroidism determined by the

amount of free T4 and T3 circulating in their system.

Administering too high of a dosage leads to hyperthyroid symptoms.

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Conditions that ImpairThyroid Function:Hyperthyroidism

The over production of thyroid hormones.

Symptoms include fatigue, weight lose, rapid heartbeat, anxiety, swollen eyes, and sensitivity to hottemperatures.

Causes: Graves disease, and autoimmune disorder in which antibodies

serve as agonists to the THS receptors on the thyroidssurface, causing thyroid growth and activation of hormonesynthesis and secretion.

Thyroid tumors which cause the uncontrolled synthesis andsecretion of thyroid hormones.

Thyroiditis, inflammation of the thyroid typically caused byinfection.

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Treatment forHyperthyroidism Anti-thyroid drugsInhibits thyroid hormone synthesis

by irreversibly binding to TPO inhibiting its ability tobreak down iodine (I2I

-) and covalently attach it to the

tyrosine residue of thyroglobulin. Propylthiouracil

Methimazole

CarbamizoleDegraded to methimazole in the body.

Radioactive Iodine

Thyroidectomy -Blockers used in the treatment of thyroiditis to treat

symptoms.

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Anti-Thyroid Drugs Effective in the long-term treatment of hyperthyroidism.

6-8 weeks before maximum effect of the drug achieved. Druginhibits hormone synthesis, so hormones synthesized prior to druguse will continue to cause hyperthyroid condition.

Typical side effects include headache, nausea, vomiting, itchy skinand rash, and muscle aches and pains.

Serious liver damage, decreased red and white blood cellsynthesis, as well as decreased platelet production have beenreported in a few cases. The drugs interaction with otherenzymes responsible for clotting factor synthesis accounts forsome of these serious side effects.

Administering too high a dosage of anti-thyroid drugs can causehypothyroidism.

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Thyroid Treatment: PotentialDrug Interactions Drugs that reduce thyroid hormone production

Lithium

Iodine-containing medications

Amiodarone (Cordarone)

Drugs that reduce thyroid hormone absorption

Sucralfate (Carafate)

Ferrous sulfate (Slow Fe)

Cholestyramine (Questran)

Colestipol (Colestid)

Aluminum-containing antacids

Calcium products

Drugs that increase metabolism of thyroxine

Rifampin (Rifadin)

Phenobarbital

Carbamazepine (Tegretol)

Warfarin (Coumadin)

Oral hypoglycemic agents

Drugs that displace thyroid hormone from protein binding

Furosemide (Lasix)

Mefenamic acid (Ponstel)

Salicylates

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TSH Replacement Drugs Thyrotropin alphaA synthetic form of TSH.

Administered intravenously.

Used in thyroid cancer treatment.

Tumors of the hypothalamus or pituitary gland can cause theuncontrolled release of TSH, which accumulates in the thyroidand can cause subsequent follicular or papillary cancer of thethyroid. Partial or total thyroidectomy typical.

Following thyroidectomy, the individual is dependent onexogenous thyroid hormones to regulate metabolism, but

thyrotropin alpha is also used to suppress the release ofendogenous TSH, which could trigger cancerous growth again.

Used as a diagnostic tool to determine the reoccurrence ofcancer.

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References http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=endocrin.section.28

0

http://www.rxlist.com/cgi/generic2/thyrotropin_cp.htm

http://www.thyroid-info.com/drugs/armour.htm

http://thyroid.about.com/cs/drugdatabase/f/thyrogen.htm http://www.parathyroid.com/hypoparathyroidism.htm

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2482800&dopt=Abstract

http://www.5mcc.com/Assets/SUMMARY/TP0466.html

http://www.dundee.ac.uk/medther/tayendoweb/images/carbimazole.htm

http://www.home.duq.edu/~harrold/Chem3D/thyroid_SAR_page_5.html

http://www.aafp.org/afp/20011115/1717.html

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