Download Thyroid Medications

Pharmacology: Thyroid and Anti-Thyroid Agents (Davis)
THYROID GLAND
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Basics:
Sets the body’s basal metabolic rate though the secretion of thyroxine (T4) the triiodothyronine (T3)
T3 is the active hormone; T4 serves mainly as the prohormone (needs to be deiodinated to T3)
o T4 is major form synthesized and released into circulation
o T4 is more stable (ie. a storage form of the active hormone T3)
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Thyroid Hormone Actions:
Action:
o Both T3 and T4 act to INCREASE the basal metabolic rate
o Increases all of the following:
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Respiration (increased O2 utilization and CO2 production)
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Carbohydrate metabolism
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Fat metabolism
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Body temperature
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Heart rate
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Neuromuscular activity
o Function in development
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Cretinism: absence of thyroid hormone results in this form of mental retardation
Autoregulation of Production:
o Thyroid hormone feeds back to inhibit its own biosynthesis at the level of the anterior pituitary
o Depresses release of TSH, which normally stimulates thyroid hormone production
o The hypothalamus is the ultimate sensor and controller of the body’s basal metabolic rate
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Basal metabolism too low (TH needed)  Secretes TRH  Stimulates anterior pituitary to
release TSH (thyrotropin)
Thyroid Hormone Receptor:
o Steroid Receptor: localized in the nucleus and is a hormone-regulated transcription factor
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TH binds and activates the receptor, which then binds to promoter regions on DNA and
induces the transcription of specific hormone responsive genes (those downstream of the
DNA sequence elements bound by the activated receptor)
o Potency of T3 vs. T4:
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Receptor has a 10x higher affinity for T3 than T4
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Only T3 appears to activate the receptor
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Circulation and Metabolism of Thyroid Hormone:
General: effects of TH on metabolism are long-term (does not regulate metabolism on a minute to minute basis)
o THs have long half-lives
o Large steady-state pools of hormone available in the thyroid and in circulation
Thyroid Release of TH:
o Thyroglobulin: large quantities of TH are stored in the thyroid as this biosynthetic precursor
o Release of TH: 80% of the TH synthesized and released from the thyroid is T4 form
Half-Life: both are extremely long lived
o T3: 1 day
o T4: 7 days
Thyroxine-Binding Globulin (TBG):
o Bulk of circulating hormone is in this bound form (>99% of both T3 and T4)
o Accounts for long half lives (bound form not subject to metabolic degradation)
o T4 binds tighter to TBG than T3 (this is why its half life is longer)
Peripheral Conversion of T4 to T3:
o T4 converted to T3 using deiodinase enzymes in target tissues
o Equal amounts of T4 are also converted to inactive reverse T3 (dead-end reaction)
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Thyroid Hormone Biosynthesis:
General: this action is the main target of the major anti-thyroid pharmacologic agents
Iodide Trapping:
o Iodine: plays a key role in TH biosynthesis (main requirement for iodine in the body)
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Source: natural iodide found in salt-water seafood; table salt is now supplemented with
sodium iodide
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Iodide Deficiency: can be a cause of endemic hypothyroidism and goiter
 Goiter: enlargement of thyroid gland as it tries to scavenge more iodide
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Iodine Ions: absorbed from circulation by thyroid follicular cells (very efficient process that is energy
dependent)
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Blocking Uptake of Iodide Ions by Thyroid Follicular Cells:
 Thiocyanate (SCN-) and perchlorate (ClO4-) both inhibit the uptake of iodide
 Radioisotopes of iodine (ie. after nuclear explosions) are also efficiently taken up by
these cells
o Can be prevented by administering large quantities of sodium iodide,
which competes with the radioisotopes for uptake by the thyroid
Iodide Organification:
o Thyroperoxidase: enzyme required to further oxidize iodide and attach it to tyrosine
o Thyroglobulin: resident protein that provides tyrosine residues to be iodinated
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300kDal protein with ~100 tyrosine residues
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Some of these tyrosine residues serve as substrate for T4 synthesis (1-3 molecules T4
produced per molecule of thyroglobulin)
o Iodination of Tyrosine: two step reaction
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Iodine added at 3 position to give monoiodotyrosine (MIT)
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Second iodide added at 5 position to give diiodotyrosine (DIT)
 These steps are inhibited by main anti-thyroid drugs (thioureylenes)
o Formation of TH:
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Condensation of 2 DIT residues to form T4 (takes place when residues are still attached to
thyroglobulin backbone)
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Iodine-modified thyroglubulin then secreted out of follicular cells into the colloid
Thyroid Hormone Secretion:
o Storage in Colloid: newly formed T3 and T4 remain attached to thyroglobulin and are stored in the
extracellular colloid
o Release of TH:
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Uptake of iodinated thryoglobulin protein from colloid by phagocytosis
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Endocytosed to the lysosome where it is hydrolyzed to component amino acids
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Resident T3 and T4 molecules released and secreted into the blood
Role of TSH:
o Stimulates all aspects of the above described process:
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Iodide uptake and organification
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Lysosomal release of TH from thyroglobulin
o Also stimulates growth of the thyroid gland itself (contributes to goiter)
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Goiter: pathological enlargement of the thyroid gland that can accompany both hypo and
hyperthyroidism
THYROID FUNCTION TESTS:
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Free Thyroxine (FT4): level of free hormone (active and available for transport to tissue) is of greater interest than the
total levels of TH (TT4 or TT3)
Issue: no easy direct test for FT4
Free Thyroxine Index (FTI): indirect assessment of the FT4; calculated from the TT4 and from the fractional
bound state of circulating TBG
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TSH Level: excellent and sensitive measure of the current state of TH activity in the patient; best measure of thyroid
function*
Pros:
o Easily and accurately measured using ELISA and RIA
o Tightly and quantitatively related to FT4
o Powerful test because small changes in FT4 (feeds back to inhibit TSH release) are amplified into large
changes in TSH level

Use of TSH and FTI: together, provide a redundant assessment of thyroid function
Hyperthyroid: generally shows high FTI and low TSH
Hypothyroid: generally shows low FTI and high TSG
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Ant-Thyroid Antibodies: most common forms of hypo- and hyperthyroidism are due to autoimmune diseases
Immune response directed against thyroid Ags
If thyroid disease is suspected, serum tested for reactivity with different thyroid Ags
o Thyroperoxidase, thyroglobulin, TSH receptor
HYPOTHYROIDISM:
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General: deficient production of TH
Symptoms: broad and reflect underlying lowered basal metabolism
o Lack of facial affect
o Cold and dry skin
o Lowered cardiac output
o Husky, low-pitched speech
o Weakness
o Diminished appetite (but weight gain due to decreased metabolism)
Cretinism: hypothyroidism present from birth, resulting in dwarfism and mental retardation
o Most common cause is failure of development of thyroid gland
o Thyroid hormone actions on brain development are most significant in the weeks just prior to and
following birth (replacement therapy important at this time)
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Etiology of Hypothyroidism:
Hashimoto’s Thyroiditis: most common cause of hypothyroidism*
o Idiopathic autoimmune impairment of the thyroid
o Results in reduced T4/T3 synthesis and release
o More common in women
Dietary Deficiency of Iodide: often associated with enlargement of the thyroid (goiter)
Destruction of Thyroid:
o Surgery or trauma
o Radioactive iodine therapy
o Long-term progression of Grave’s Disease (a form of hyperthyroidism)
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Therapy:
Dietary Deficiency: supplementation with sodium iodide
Other Causes: generally requires thyroxine replacement
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Thyroid Hormone Replacement:
Agents: both absorbed orally through the GI tract
o Levothyroxin (Levothroid, Synthroid): synthetic T4

This is the agent that is typically used to manage hypothyroidism
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Cheaper, longer half life (once daily dosing) and peripheral iodination will yield active T3
o Liothronine Sodium: synthetic T3
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Used for the treatment of hypothyroidic coma (greater potency and faster acting)
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Generally not used for hypothyroidism because shorter half life makes it necessary to dose
multiple times per day
Use:
o Hypothyroidism: administration of T4 in a once daily pill very effective
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Steady state usually achieved in about 6 weeks (need to monitor thyroid function frequently
in the period leading up to this to optimize dose)
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Thyroid function should then be monitored at yearly check-ups or if patient complains of
symptoms of hypo- or hypterhyroidism
o Congenital Thyroid Deficiency: prevent development of cretinism
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Some physicians recommend monitoring of maternal thyroid function before/throughout
pregnancy due to concerns about fetal neural development
Adverse Effects: main concern is overdosing with T4  hyperthyroid symptomology
HYPERTHYROIDISM:

General: excess secretion of thyroid hormone
Symptoms: due to elevated basal metabolism (thyrotoxicosis)
o Exophthalamus (protrusion of eyeballs)
o Goiter
o Warm, flushed and moist skin
o Muscle tremor
o Insomnia, anxiety and apprehension
Episodes of Thyroid Storm: sudden acute exacerbation of above symptoms may occur (life-threatening; may
include severe tachycardia with atrial fibrillation and eventual heart failure)
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Etiology:
Graves’ Disease: autoimmune disease in which Abs to TSH receptor mimic the action of TSH
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o Constant stimulation of thyroid gland increases production and release of THs
o Thyroid itself also grows, causing goiter
o Most common in young or middle-aged women
Other Causes:
o Toxic Adenoma: pituitary tumor of TSH-secreting cells
o Toxic Multinodular Goiter
Treatment of Graves’ Disease: overall goal is to reduce circulating levels of thyroid hormone
Three Diverse Treatments:
o Anti-thyroid drugs: block thyroid hormone biosynthesis
o Ablation of thyroid gland: with radioactive iodide
o Surgical resection of thyroid gland
Issues: reduction in thyroid hormone synthesis to appropriate levels is difficult, and can often result in
hypothyroid state (unclear if this is due to over treatment or natural progression of Graves’ disease)
o Hypothyroid state can be easily treated with thyroxine (T4)
Anti-Thyroid Drugs (Thioureylenes/Thionamides):
Agents:
o Methimazole: more commonly used (once daily dosing due to long duration of action)
o Propylthiouracil: not as commonly used due to issues with hepatotoxicity
MOA: decrease synthesis of thyroid hormones through competitive inhibition of tyrosyl iodination (drug acts as a
substrate for iodination by thyroid peroxidase)
o Propylthiouracil: has added activity of inhibition peripheral deiodination of T4 to T3
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Additional Use: sometimes used in treatment of acute thyroid storm (b/c of additional MOA)
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Approved Use: long-term stabilization of hyperthyroidism (but limited due to hepatotoxicity)
Therapeutic Use:
o Administration: oral
o Action: depression of new hormone synthesis occurs within 12 hours of administration, but relief of
symptoms may not occur for up to 2-4 months
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Reasons for Slow Action:
 Slow turnover of pre-existing circulating TH
 Large thyroid stores of pre-existing TH
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Once Symptom Relief Occurs: need to decrease dosage to avoid hypothyroidism
o Use in Graves’ Disease: generally used to control symptoms until remission occurs (remissions often
not permanent and further therapy may be required)
o More intense therapy often required: surgical resection or ablation
Partial Surgical Removal of Thyroid:
Overall Effect: stops excess thyroid hormone production
Issue: result is hypothyroidism (little or no hormone produced) and must take thyroxine replacement for life
Partial Destruction of Thyroid with Radioactive Iodine:
Current Use: preferred and most common treatment for Graves’ Disease* (safe and painless and provides
definitive long-term cure)
MOA:
o 131I emits both β-particles and γ-rays (radioactive half-life of 8 days)
o Patient ingests a single dose of sodium iodide containing this radioisotope (capsule or liquid), and it is
taken up into the thyroid where it causes tissue destruction (action localized specifically to thyroid)
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β particles induce a slow inflammatory response (destroys thyroid over weeks to months)
Contraindications:
o No use of thionamide anti-thyroid drugs prior to or during treatment with radioactive iodine (inhibit
incorporation of iodine into thyroglobulin, as well as the tissue destruction by 131I)
o Pregnancy (uptake of 131I b the fetus)
o Should be avoided in young men and women (concerns remain regarding fertility and cancer)
Adverse Effects:
o Hypothyroidism may occur depending on the degree of tissue destruction (requires T4 replacement)
Iodide:
Paradoxical Effect: high doses of iodide can be used to treat hyperthyroidism
Action: results in rapid inhibition of TH release (compared to thionamides); only short term treatment (transient)
o Symptoms of hyperthyroidism subside in 1-2 days
o Reduction in vascularity of thyroid gland and decreased sized seen in 10-14 days
o May be combined with thionamides to inhibit increased TH synthesis
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Propanolol (Beta-Blockers):
Symptomatic Relief: of tachycardia, arrhythmias, tremors and general agitation
Use:
o During prolonged lag period following initiation of thioureylene therapy
o Immediate control of hyperthyroid symptoms during thyroid storm