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Thyroid Gland

Function: to secrete appropriate amount of thyroxine (T4) and triiodothyronine (T3, extra thyroidal deiodination of T4): 80 micrograms of T4/T3 per day.
T3 interacts with nuclear T3 receptors.
-Promote normal fetal/childhood growth and development.
-Regulates heart rate and myocardial contractility.
-Affects GI motility and renal water clearance.
-Modulates the body's energy expenditure, heat generation, and weight.
Structure of gland:
2 lobes connected by a band of tissue: isthmus.
Attached to the trachea.
Composed of spherical units called follicles.
-Follicular epithelium makes up the outside of the follicle.
-Follicle center is filled with proteinaceous colloid.
-Rich capillary network around follicle.
-Basement membrane separates follicular epithelium from the capillaries.
-20 to 40 follicles are separated into lobules and the connective tissue septa separates lobules.
1. Capture and transport sufficient iodide
2. Synthesize sufficient thyroglobulin.
3. Recapture thyroglobulin and the removal and secretion of thyroid hormones.


Thyroid Gland histology

Follicular epithelium (colloid, T3, T4)
-Many villi extend into the colloid
-Extensive ER
-Numerous lysosomes and mitochondria throughout cells.
Parafollicular cells (calcitonin)


Thyroid Hormones

-Thyroxine (T4): most abundant thyroid hormone in the circulation; can be considered as a prohormone
-Triiodothyronine (T3): most potent activator of the Thyroid Hormone Receptor.
-Reverse triiodithyronine (rT3): isomer of T3 that binds the Thyroid hormone receptor but does not activate it.


Iodine Requirements

Ingested iodine (or iodate)
-Converted to iodide
-Absorbed in the GI system.
Most iodide is excreted by the kidneys.
-Urinary iodide excretion is an index of dietary intake.
Dietary iodine deficiency


Iodine dietary deficiency

-Thyroid can thus not sustain adequate hormone production.
-Results in goiter and hypothyroidism.
Endemic dietary iodine defiiciency
-Neurologic and growth deficits in fetus and children.


Transport and concentration of iodide

-Sodium-iodide symporter (NIS)
-Energy from NA-K ATPase
-Maintain a concentration of free iodide 30-40X higher than that in plasma.
-Pool of iodine in the thyroid is very large; there is 8-10 mg stored in thyroid hormones and iodinated tyrosines.
-This buffers the variation in dietary intake.


Sodium-iodide symporter (NIS)

-iodide atom is moved against an electrochemical gradient
-expressed in the basolateral membrane of the thyroid cell.
-Also transports TcO4-, which is used as as a thyroid scanning tool when radioactive.
-ClO4- and SCN-
-KClO4- blocks iodide uptake in thyroid.
-Controlled by TSH (thyroid stimulating hormone): increased transcription of the NIS gene, prolongs NIS protein half-life, targets NIS to the cell membrane.
-This is stimulated pathophysiologically by TSH receptor stimulating antibody of GRAVES DISEASE.
-NIS is affected by large amounts of iodide (15-20 fold above normal): suppresses both NIS activity and NIS gene expression.
-It inhibits the organic binding of iodine within the thyroid.
-Autoregulatory phenomenon known as the Wolff-Chaikoff effect and causes temporary hypothyroidism.
-Effect lasts for a few days and is followed by the so called "escape" phenomenon.


Iodotyrosine dehalogenase (Dhal) enzymes

Dhal 1 transciption is stimulated by cyclicAMP.
It is a membrane protein concentrated at the apical cell surface.
-Catalyzes NADPH-dependent deiodonation of monoiodotyrosine and diiodotyrosine.
-The iodide released is reconjugated to newly synthesized thyroglobulin (protein that carries tyrosine necessary for iodide addition and thyroid hormone production).



Located on the apical membrane (opposite from NIS).
Transports iodide to the membrane-colloid interface.


Thyroglobulin synthesis

660 kD homodimer
134 tyrosyl residues
25-30 of these residues are iodinated.
Only residues 5, 1290, and 2553 form T4.
Only residue 2746 forms T3.
-Three to four T4 molecules in each molecule of Tg dimer under normal conditions.
-One in five molecules of human Tg contains T3 residue.


Iodide oxidation and organification

-oxidation of iodide
-incorporation of the intermediate into iodotyrosines MIT and DIT.
-MIT and DIT are hormonally inactive.
-Iodine bonds to C3 or C5 of tyrosine residues on Tg.
-Iodinations leading to formation of iodotyrosines (MIT or DIT) occur within thyroglobulin.
-This is mediated by the heme-containing protein thyroid peroxidase (TPO).


Thyroid peroxidase (TPO)

-TPO located in the apical membrane of the thyroid cell.
-Requires hydrogen peroxide generated by the Ca dependent Duox1 and 2 enzymes (THOX1 AND THOX2).
-Duox1 and Duox2 are glycoflavoproteins expressed at the apical membrane.
-These agents can cause intrathyroidal iodine deficiency in patients receiving these agents.
-Iodide excess inhibits DUOX2 glycosylation (inhibiting indirectly Tg iodination and therefore T4/T3 synthesis): Wolff-Chaikoff.
-The rate of organic iodinations is dependent on the degree of thyroid stimulation by TSH.


Iodothyronine synthesis (coupling reactions)-MIT and DIT

MIT and DIT are precursors of the hormonally active iodothyronines T4 and T3.
-Synthesis of T4 from DIT requires the TPO-catalyzed fusion of two DIT molecules.
-Synthesis of T3 from DIT and MIT requires the TPO-catalyzed fusion of a DIT and a MIT molecule.


Storage of thyroid hormone

-Iodinated tyrosines on thyroglobulin are stored as colloid in the follicular lumen.
-Thyroglobulin contains MIT, DIT, T3 and T4.
-Unique in that it has a large store of hormone (5000 micrograms of T4 in a 20g gland).
-This is sufficient to maintain a euthyroid state for at least 50 days.
-Low rate of hormone turnover (1% per day).


Thyroid Hormone Release

-Endocytosis of colloid from the follicular lumen by two processes:
1. Macropinocytosis by pseudopods formed at the apical membrane.
2. Micropinocytosis by small coated vesicles that form at the apical surface (DOMINANT PROCESS).
-Both processes stimulated by TSH.
-Endocytotic vesicles fuse with lysosomes
-Proteolysis is catalyzed by cathepsin D and D-like thiol proteases.
-Iodotyrosines are released from thyroglobulin and rapidly deiodianted by a NADPH-dependent iodotyrosine deiodinasae (Dhal 1) and recycled.
-Thyroid hormones are released from thyroglobulin.
-MCT8 (thyroid hormone transporter) moves T4 and T3 to the cytosol.
-T4 is accessible to the thyroidal type 1 and type 2 deiodinases (D1 and D2).
-Basal and TSH-stimulated conversion of T4 to T3.
-MOST T3 is produced by peripheral 5'-deiodination of T4.
-This conversion is inhibited by propylthiouracil (PTU) (thiourea drug).


Thyroid hormone release and drugs

-T4 and T3 are released from the thyroid cells by transporters.
-This is inhibited by several agents (MOST IMPORTANT IS IODIDE).
-Responsible for the rapid improvement that iodide causes in hyperthyroid patients.
-Lithium inhibits thyroid hormone release.
-Iodide inhibits the stimulation of thyroid adenylate cyclase by TSH and by the stimulatory immunoglobulins of Graves' disease.


Thyroid hormone transport (circulation)

-Normal individual: 90% T4, 9% Ts, 1% rT3.
Most is bound to plasma proteins; 0.04% of T4 and 0.4% of T3 are unbound and free in the blood.
-Three major thyroid hormone transport proteins:
1. Thyroxine-binding globulin (TBG)
2. Transthyretin, formerly called TBPA.
3. Albumin
-Large circulating thyroid hormone pool: stable 7-day plasma half life.


Thyroxine-binding globulin (TBG)

-There are drugs that can decrease the plasma TBG concentrations:
Androgenic steroids
-There are drugs that can increase the plasma TBG concentrations:
-There are drugs that cab displace T4 and T3 binding to TBG:
high-dose phenytoin
IV furosemide
-Heparin stimulation of lipoprotein lipase:
Releases FA that displace thyroid hormones from TBG.
-Altered TBG levels and/or displacement of thyroid hormones from TBG initiates feedback loops due to high free hormone levels.
-Hypothalamic-pituitary-thyroid axis preserves normal free hormone concentrations by lowering serum total thyroid hormone levels.
-Other rare conditions affecting serum binding proteins elicit a similar feedback response.


Metabolism of thyroid hormones: secretion and interconversion

-Most of the plasma pool of T3 is from monodeiodination of T4 in peripheral tissues.


Type 1 5'-deiodonase

-Activity is increased in hyperthyroidism
-Activity is decreased in hypothyroidism
-Inhibited by thioamide antithyroid drug proplthiouracil (PTU).
-Inhibited by amiodarone and iodinated radio contrast dyes such as sodium ipodate (these do not treat thyroid conditions, they are responsible for the side effects when these are administered for other reasons).
-Dietary selenium deficiency can also impair T4 to T3 conversion.
-Substrates rT3>T4>T3
-Tissue Distribution: Liver, kidney, skeletal muscle, thyroid.
-Function: plasma T3 production.
-Decreased in hypothyroidism and increased in hyperthyroidism.


Type 2 5'-deiodinase

-Predominantly expressed in the brain and pituitary gland.
-Maintains a constant level of intracellular T3 in the CNS.
-Very sensitive to circulating T4.
-Lower circulating T4 rapidly increases enzyme concentration, which maintains the level in intracellular T3.
-Substrates: T4>rT3
-Function: local T3 production in the CNS.
-Increased in hypothyroidism and decreased in hyperthyroidism (counteracts these diseases).


Type 3, 5-deiodinase

-Found in placental chorionic membranes and glial cells in the CNS.
-Inactivates T4 by converting it to rT3.
-Inactivates T3 by converting it to 3,3'-diiodothyronine.
-May protect the fetus in the brain from T4 excess or deficiency.
-Increased in hyperthyroidism and decreased in hypothyroidism (need all T3 you can get so it will not be degraded by this D3).


Conditions that Inhibit Type 1 5-Deiodinase Activity

-Beta-adrenergic receptor antagonists (high doses of propranolol)
-Amiodarone (not for treatment, just has side effects that effect the thyroid).
-Propylthiouracil (PTU)
-Selenium deficiency


Physiological important of deiodinases

1. Permit local tissue and cellular modulation of thyroid hormone actions.
2. Help the organism adapt to changing states like iodine deficiency or chronic illness.
3. Regulate thyroid hormone actions in early development of many vertebrates.


Other forms of T4 metabolism...

80% of T4 is metabolized by deiodination.
The remainder is inactivated by glucorindation in the liver and biliary secretion.
Lesser extent sulfation, deamination or decarboxylation.
10% of the extra thyroidal T4 pool is cleared each day.
-T4 plasma half life is 7 days (used as drug in hormone replacement therapy)
-T3 plasma half life is 1 day (lower binding affinity for plasma proteins).
-rT3 plasma half-life is 0.2 day.


Thyroid hormone receptors

-Present in most cells of the body
-Contain thyroid hormone binding, DNA binding, and dimerization domains.
-Nuclear transcription factors.
-Two classes:
-Both can be expressed as multiple isoforms.
-TR monomers can interact in a dimerization reaction to form homodimers.
-Can also interact with retinoid X receptor (RXR) to form heterodimers.
-They are activated by the binding of thyroid hormone.
-Multiple different combinations of TRs and tissue distributions create tissue specificity.


Acton of hormones on thyroid hormone receptors

-Thyroid hormone receptor dimers associate with corepressor molecules.
-Bind to and inactivate thyroid hormone-stimulated genes.
-Promotes dissociation of the co repressors.
-Recruits coactivators to the DNA and activates gene transcription!


Effects of thyroid Hormone on Target Tissues

-Thyroid hormone is able to down-regulat TSH (positive signal to make and secrete thyroid hormone) gene expression.
-Causes negative feedback of thyroid hormone on the hypothalamic-pituitary-thyroid axis.
-Nongenomic effects on mitochondrial metabolism.
-Plasma membrane receptors that stimulate intracellular signal transduction.


General physiologic effects of thyroid hormones

-Important for growth and development of the nervous system.
-Congenital deficiency of thyroid hormone results in cretinism (severely stunted physical and mental growth); this is due to genetics or the mother has iodine deficiency).


General physiologic functions of thyroid hormones

-Regulates general body metabolism and energy expenditure.
-Regulates Na/K ATPase and many of the enzymes of intermediary metabolism.
High levels of thyroid hormone...
-Can result in futile cycling (same basic biochemical process that goes in both directions, produces heat but do not gain anything out if it) and increasing body temperature.
Increased cardiac contractility and heart rate, excitability, nervousness, sweating.
Low levels of thyroid hormone...
Myxedema, Lethargy, dry skin, coarse voice, cold intolerance.


Specific physiologic effects of thyroid hormones

Calorigenic action (one of the main effects of excess thyroid hormone)
-T4 and T3 increase the oxygen consumption of almost all metabolically active tissues.
-Some exceptions: T4 depresses the oxygen consumption of the anterior pituitary and inhibits TSH secretion.
-A single dose of T4 has measurable effects after several hours and lasts 6 day or more (half life is 7 days).
-Some of the calorigenic effect of due to metabolism of the FA.
-Increase in the activity of the membrane-bound Na-K ATPase in many tissues.


Effects Secondary to calorigenesis

-Nitrogen secretion is increased
-If food intake is not increased, endogenous protein and fat stores are catabolized.
-Weight lost
-If there is too much thyroid hormone, the need for all vitamins is increased.
-Vitamin deficiency syndromes may be precipitated by excess thyroid hormone.
-Thyroid hormones are necessary for hepatic conversion of carotene to vitamin A.
-Carotene accumulation in the blood (carotenemia) gives a yellowish tint to the skin (absence of thyroid hormone).
-Thyroid hormones maintain normal skin, which contains proteins combined with polysaccharides, hyaluronic acid, chondroitin sulfate=part of extracellular matrix.
-In hypothyroidism, ECM complexes accumulate because there is not proper turnover of ECM components: promotes water retention and causes puffiness of the skin (myxedema).
-Milk secretion is decreased in hypothyroidism.
-Thyroid hormones are essential for normal menstrual cycles and fertility.


Effects secondary to calorigenesis

-In hypothyroid children...
Small doses of thyroid hormones cause a positive nitrogen balance due to growth.
Large doses cause protein catabolism similar to that produced when there is excess thyroid hormone in the adult (loss of muscle and fat).
Potassium liberated during protein catabolism appears in the urine.
There is an increase in urinary hexosamine and uric acid excretion (if thee is too much).


Effects on the cardiovascular system

-Large doses of thyroid hormone cause enough heat production to raise body temperature.
-This activates heat-dissipating mechanisms (sweating, vasodilation).
-Peripheral resistance decreases due to cutaneous vasodilation
-Increased levels of sodium and water absorption, expanding blood volume.
-Cardiac output is increased by direct action of thyroid hormones and catecholamines on the heart; thyroid hormones increase sensitivity to catecholamines.
-Pulse pressure and cardiac rate are increased.


Effects on the myocytes

-Increased thyroid hormone enhances expression of alpha myosin heavy chain, sarcoplasmic reticulum Ca ATPase, beta-adrenergic receptors, G proteins, NA-K ATPase, and certain K channels.
-Inhibtis expression of beta-myosin heavy chain, phospholamban, two types of adneylyl cyclase, T3 nuclear receptors, and the Na-Ca exchanger.
-The NET RESULT is increased heart rate and force of contraction.


Effects on the nervous system

-In hypothyroidism, mentation is slow and the CSF protein levels are elevated.
-Large doses of thyroid hormone cause rapid mentation, irritability ,and restlessness.
-Thyroid hormones enter the brain in adults: direct action in CNS.
-Astrocytes in the brain convert T4 to T3.
-There is a sharp increase in brain D2 activity after thyroidectomy (no more thyroid hormone being produced, so D2 that acts in the brain and pituitary takes any T4 it can find and makes active T3).
-Some effects of thyroid hormones are secondary to increased responsiveness to catecholamines.
-Increased activation of the reticular activating system,.
-Thyroid hormones have marked effects on brain development.
-The cerebral cortex and the basal ganglia are the most effected in the CNS; in hypothyroid children.
-Cochlea also affected.
-Thyroid hormone deficiency during development causes mental retardation, motor rigidity, and deal-mutism.
-Also effects reaction time of stretch reflexes ( they are shortened in hyperthyroidism and prolonged in hypothyroidism).


Thyroid hormone relation to catecholamines

Epinephrine effects:
-Increases the metabolic rate, stimulates the nervous system, produces CV effects.
Norepinephrine effects:
-Similar but briefer effects.
-These are enhanced when there is excess thyroid hormone levels.
-CV effects, tremulousness, sweating produced by thyroid hormones can be reduced or abolished by sympathectomy.
-Can also be reduced by drugs such as propranolol that BLOCK BETA ADRENERGIC RECEPTORS.
-Beta blockers used extensively in treatment of thyrotoxicosis and thyroid storms: they have little effect on the other actions of thyroid hormones (these don't directly address the disease itself, but block the symptoms).


Effects on skeletal muscle

-Muscle weakness occurs in most patients with hyperthyroidism (thyrotoxic myopathy); may be due in part to increased protein catabolism.
-Hypothyroidism is also associated with muscle weakness, cramps, and stiffness (muscle requires an ideal amount of thyroid hormone, if you have too little, you will get weakness).


Effects on carbohydrate metabolism

-Excess thyroid hormone increases the rate of absorption of carbohydrate from the GI tract.
-This is independent of the calorigenic action that consumes carbs.
-Plasma glucose levels rise rapidly after a CHO meal.


Effects on cholesterol metabolism

-Thyroid hormones lower circulating cholesterol levels.
-Plasma cholesterol levels drop before the metabolic rate rises (increased heat).
-Action independent of the stimulation of oxygen consumption.
-Due instead to increased formation of LDL receptors in the liver.


Effects on growth

-Thyroid hormones are essential for normal growth and skeletal maturation.
-Hypothyroid children...
Bone growth is slowed and epiphyseal closure is delayed.
Growth hormone secretion is also depressed.
Thyroid hormones potentiate the effect of growth hormone on the tissues.


Regulating thyroid hormone secretion: Hypothalamic-Pituitary-Thyroid axis

-Hypothalamus releases thyrotropin-releasing hormone (TRH)
Travels via the portal circulation to the anterior pituitary gland thyrotrophs.
Binds to plasma membrane G protein-coupled receptor.
-Pituitary: TRH promotes synthesis and release of thyroid-stimulating hormone (TSH).
-Thyroid gland: TSH stimulates every aspect of thyroid hormone production
iodide uptake, organification and coupling, thyroglobulin internalization, secretion of thyroid hormone.
-TSH promotes increased vascularization and growth of the thyroid gland (GOITERS CAN DEVELOP).
-Pathologic conditions occur where TSH or TSH mimic is secreted at high levels: thyroid gland can enlarge to several times its normal size (goiter).
-Negative feedback to the hypothalamus/pituitary: thyroid hormone effects both and inhibits TRH and TSH transcription.


Graves' Disease

Hormone excess-hyperthyroidism
IgG autoantibody specific for TSH receptor: thyroid-stimulating immunoglobulin (Tslg).
-Antibody activates the TSH receptor.
-Stimulates the synthesis and release of thyroid hormone.
-Tslg is NOT subject to negative feedback.
Clinical symptoms
Laboratory values:
High plasma thyroid hormone levels
Low or undetectable TSH levels
High Tslg levels


Hasimoto's thyroiditis

Antibodies (autoimmune) specific for many thyroid gland proteins found in patients (thyroglobulin and thyroid peroxidase).
Antibodies selectively destroy thyroid function.
Clinical course:
Gradual inflammatory destruction of the thyroid gland.
-Early there may be transient increases in thyroid hormone levels (because of stores of thyroid hormone in colloid, unregulated release when gland is destroyed).
-Eventually, the gland is almost completely destroyed.
-Lethargy and decreased metabolic rate.
-Therapy: pharmacological replacement with oral synthetic thyroid hormone.


Other causes of hypothyroidism and hyperthyroidism

1. Developmental anomalies
2. Subacute thyroiditis
3. Thyroid adenomas and carcinomas
4. Use of some drugs


Drug Effects and Thyroid Function

1. Inhibition of TRH or TSH secretion without induction of hypo or hyper thyroids: corticosteroids and metformin.
2. Inhibition of thyroid hormone synthesis or release with the induction of hypothyroidism (occasionally hyperthyroidism): iodides (can block release of thyroid hormone and uptake of iodide into gland, Wolff-Chaikoff effect, a lot of drugs with iodide in their structure) (including amiodarone), lithium, thioamides.
3. Increased TBG (T4 carrier protein): Estrogens
4. Decreased TBG: Androgens, glucocorticoids
5. Displacement of T3 and T4 from TBG with transient hyperthyroxinemia: Salicylates.
THE LAST THREE: can impact total serum thyroid hormone levels, but don't effect free levels; people are euthyroid.


Effect of thyroid function on drug effects

1. Anticoagulation: Lower doses of warfarin required in hyperthyroidism, higher doses in hypo.
2. Glucose control: Increased hepatic glucose production and glucose intolerance in hyper; impaired insulin action and glucose disposal in hypo.
3. Cardiac drugs: Higher doses of digoxin required in hyper; lower doses in hypo.
4. Sedatives; analgesics: Increased sedative and respiratory depressant effects from sedatives and opioids in hypothyroidism; converse in hyper.


Hypothyroidism-General treatment strategy

Replace with regularly administered exogenous thyroid hormone.
-Generally T4, produced by chemical synthesis.
-T3 is more metabolically active
-Reasons T4 is used (levothyroxine)
Most thyroid hormone in the blood is in the form of T4.
Reserves of "prodrug" T4 may be an effective buffer.
Normalizes metabolic rates over a wide range of conditions.
The half life is 7 days compared to 1 day for T3; allows a patient to take just one thyroid hormone replacement pill per day.
-Exception: myxedema coma
-Liothyronine is the synthetic therapeutic form of T3; after onset of action enhances recovery from life-threatening hypothyroidism.


Treatment Efficacy Monitoring

Patient stabilized on levothyroxine
Plasma TSH and thyroid hormone levels are measured.
-TSH is very sensitive to feedback control by thyroid hormone.
-Monitor TSH levels every 6 months-1 year.



Serious Adverse Effects:
Pseudotumor cerebri
Myocardial infarction
-Expect TSH to decrease with this treatment.


Hyperthyroidism Treatment Strategy

-Radioactive iodide
-Drugs that work for prolonged treatment
-Drugs for acute use and/or treating symptoms (but not addressing underlying disease).



3 distinct types of iodide are used in practice:
1. Radioactive iodide (I131)
2. Inorganic iodide (I127, not radioactive).
3. I123 is also a low radiation isotope used for thyroid imagining, but not for treatment.


Radioactive iodide (I131)

-Ablation without the complications of surgery.
-Strongly emits beta-particles toxic to cells.
-NIS cannot distinguish I131 from normal stable iodide I127.
-I131 because sequestered within the thyroid gland.
-Makes radioactive I131 a specific and effective therapy for HYPERTHYROIDISM.
-Results in SELECTIVE LOCAL DESTRUCTION of the thyroid gland.
-Used to treat thyrotoxicosis.
-Alternative to surgery in the treatment of hyperthyroidism.
-Pretreatment with antithyroid drugs before radioactive I131 treatment.
-The rationale is to decrease a post-RAI increase in thyroid hormone release.
-This is especially dangerous in older age groups with ischemic heart disease.
-May also prevent the post-RAI increase in thyroid autoantibodies that may affect ophthalmopathy (due to cross reaction with antigens in the eye).
-Therapeutic concerns:
Too much of the thyroid may be destroyed, causing hypothyroidism.
-The goals is to administer enough I131 to result in a euthyroid state.
-Hypothyroidism is easier to manage clinically than hyperthyroidism.
-It is unlikely that therapeutic doses of I131 cause cancers: no thyroid carcinoma, leukemia, or an increase in thyroid cell mutation rates.
-Age limit for the use of radio iodine has been lowered progressively; initial lower limit of 40, now 10 years of age or younger.
-Recurrence is rare with ablative therapy-surgery or radio iodine.


Inorganic iodide (I127)

-High levels of iodide inhibit thyroid hormone synthesis and release.
-negative feedback effect is reversible and transient.
-Thyroid hormone synthesis and release returns to normal a few days.
-Inorganic iodide is NOT A USEFUL LONG-TERM THERAPY for hyperthyroidism.
-High iodide dosing reduces the size and vascularity of the thyroid gland; often administered before thyroid gland surgery, which results in technically easier excision of the gland.
-The major action of iodide is to inhibit hormone release.
-Iodine acutely retards the rate of secretion of T4.
-Effect is rapidly lost when iodine is withdrawn (also lose effects with continue use)
-Iodine is rarely used as a sole therapy; used to prep for thyroid surgery.
-Patients with actual or impending thyrotoxic crisis, severe thyrocardiac disease or acute surgical emergencies.
-Rapid slowing of hormone release for prompt relief of thyrotoxicosis.
-More effective than thioamide drugs (long acting, delayed onset of action).
-iodide is very effective after a therapeutic dose of I131 for thyrotoxicosis.
-Dosing forms: Saturated solution of potassium iodide (SSKI) or Lugol's solution.
-Adverse effects and other problems:
Enrichment of glandular organic iodine stores may retard response to thioamides.
-Decrease radioiodine uptake preventing treatment for several weeks (inorganic iodide prevents the NIS to take up iodide in the thyroid gland).
-Iodine withdrawal after increasing the hormone pool may exacerbate hyperthyroidism.



-These drugs compete with thyroglobulin for oxidized iodide.
-The process is catalyzed by the enzyme thyroid peroxidase(TPO).
-Causes a selective decrease i thyroid hormone production.
-Iodinated thiamin's may also be able to bind to thyroglobulin to further antagonize any coupling reactions.
-The effects of thiamines are not seen for several weeks (still have thyroid hormone stores available for use).
-Thioamines are generally effective at controlling hyperthyroidism.
-Large percentage of patients go into remission over the course of 6 months to a year (become hyperthyroid again).
-May maintain a euthyroid state after discontinuation of these medications.
-Some develop persistent hyperthyroidism needing radioactive iodide or surgery.
-Propylthiouracil (PTU) and methimazole are generally well tolerated.
-Most frequent adverse effects:
Pruritic rash early which may remit spontaneously (urge to scratch), arthralgia (joint pain) are a common reason for stopping these agents.
-Rare but serious side effects: agranulocytosis (increased vulnerability to infection), hepatotoxicity, vasculitis.
-Often results in goiter formation.
-Methimazole and propylthiouracil both cross the placenta, but have been used in pregnancy.
-They can cause hypothyroidism if given in excessive amounts over long periods: patients often complain of gain in weight, sluggishness and fatigue.



Inhibits peripheral T4 to T3 conversion.
-PTU-sensitive iodinase D1 is the major source of peripheral T3 production.
PTU has a half-life of 1.5 hours, which necessitate dosing three times a day.



-Can be administered ONCE DAILY.
-It has a plasma half life of 6 hours.
-It is PREFERRED TO PROPYLTHIOURACIL for must uses due to its fewer adverse effects (especially liver toxicity).



-Beta adrenergic blocker
-Amerliorate some of the manifestations of thyrotoxicosis.
Tremulousness, palpitations, sweating, eyelid retraction, and hear rate decrease.
-Mediated through the increased sensitivity of the sympathetic nervous system induced by excess thyroid hormone.
-Propanolol (BUT NOT OTHER BETA-ADRENERGIC DRUGS) block the conversion of T4 to T3.
-Often used as adjuncts (supplement) in management.
-Used in the interval before the response to thioamide or radio iodine therapy occurs.
-Useful in patients with thyrotoxic symptoms.
-Useful in patients with impending or actual thyrotoxic crisis (thyroid storm).
-Useful when tachycardia is contributing to cardiac insufficiency.
-Useful in controlling signs and symptoms during preparation for surgery.
Adverse effects:
Relatively free of adverse effects!
-May be contraindicated with asthma or COPD because it aggravates bronchospasms and reduces lung function.
-Also contraindicated in patients with heart block and in patients with congestive heart failure.
-Myocardial depressent action.



-Beta adrenergic blocker
-Rapid onset of action and short elimination half life (9 minutes).
-Can be a useful beta-adrenergic antagonist for treatment of thyroid storm symptoms during acute care (because of rapid onset).
-Not for long term treatment.


Inhibitors of iodide uptake

Perchlorate, thoicyanate, pertechnetate
-Structure: approximate atomic radius of iodide.
-Mechanism: complete with iodide transport via follicular cell NIS.
These drugs decrease the amount of iodide available for thyroid hormone synthesis.
-The effects of anion uptake inhibitors is usually NOT IMMEDIATELY APPARENT due to the large stores of iodide, T3, and T4 in the colloid.
-Perchlorate, thiocyanate, and pertechnetate use is historically important, but now is uncommon.
-They have a potential for causing aplastic anemia.
-Thioamines are more effective.
-These anions are often used in radiopaque contrast materials.
-Adverse effects and contraindications:
Patient can show hypothyroidism after extensive radiographic studies.
Perchlorate and thiocyanate may cause aplastic anemia.
Pertechnetate used in radio contract agents may cause GI irritation.
No major contraindications for any of these agents.
-Imaging agents, not used for long term treatments.



-Structurally resembles thyroid hormone and contains a large concentration of iodine.
-The metabolism of amiodarone release iodine as iodide; results in increased plasma concentrations of iodide.
Results in hypothyroidism by the Wolff-Chaikoff effect.
-Amiodarone can also cause hyperthyroidism: excess iodide load can lead increased thyroid hormone synthesis and release.
-Can induce an autoimmune thyroiditis that leads to release of excess thyroid hormone.
-Amiodarone may also act as a homologue (similar) of thyroid hormone at the level of the receptor.
-Amiodarone competitively inhibits type 1 5'-deiodinase, which results in decreased T4/T3 conversion and increased plasma concentrations of rT3.


Corticosteroids (dexamethasone)

-Inhibits the glandular secretion of hormone.
-Inhibtis the peripheral conversation of T4 to T3.
-It is additive to propylthiouracil, suggesting that there is another different mechanism of action.
-It has immunosuppressive effects.
-Used as a combination therapy with propylthiouracil, SSKI (inorganic iodide), and dexamethasone.
-For patients with severe accelerating thyrotoxicosis (thyroid storm).
-Causes a rapid reduction in serum T3 concentration within the normal range in 24-48 hours.
-glucocorticoids for exophthalmos.



-This drug can causes hypothyroidism.
-Lithium is actively concentrated in the thyroid gland.
-High levels of lithium inhibit thyroid hormone release from thyroid follicular cells.
-It also may inhibit thyroid hormone synthesis.
-Unlike iodine, it does NOT interfere with the accumulation of radiodine (does not block radioiodine entry into the thyroid like iodide does).


Lithium carbonate

-This drug is employed only to provide temporary control of thyrotoxicosis.
-For patients who are allergic to both thioamide and iodide.
-The blocking effect is often lost with time.
-Also used short term as an adjunct to radio iodine.
-Lithium carbonate slows the release of iodine from the thyroid.


Thyroid Storm (Accelerated Hyperthyroidism)

-Accentuation of thyrotoxicosis
-The mechanism is a release of large amounts of thyroid hormone over a short period of time and excessive activation of thyroid hormone receptors.
-Thyroid Storm usually occurs IN ASSOCIATION WITH GRAVES' DISEASE.
-Presentation: these are patients with thyrotoxicosis that were treated incompletely or not at all.
-Occurs abruptly
-Precipitated y infection, trauma, surgical emergencies, or operations.
-May be related to cytokine release and cute immunologic disturbance.
-Fever is invariable and may be severe.
-Profuse sweating
-Marked tachycardia of sinus or ectopic origin and arrhythmias.
-May be accompanied by pulmonary edema or congestive heart failure.
-Tremulousness and restlessness are present.
-Delerium or frånk psychosis may supervene.
-Nausea, vomiting, abdominal pain may occur early in the course.
-As thyroid storm progresses, apathy (lack of enthusiasm or concern), stupor (near unconsciousness), and coma may supervene.
-Hypotension can develop.


Treatment of thyroid storm

-Large doses of propylthiouracil are give first; PTU is preferred to methimazole because it inhibits peripheral T4 to T3 conversion immediately, that is an additional mechanism of PTU).
-Iodine is administered in Lugol's solution of SSKI.
-This acutely retards the release of hormone from the thyroid gland.
-Large doses of dexamethasone are given, this supports the response to stress.
-Dexamethasone also inhibits the release of hormone from the gland (synergistic with iodide).
-In the absence of cardiac insufficiency or asthma, beta-adrengergi blocking agent is given to ameliorate the hyperadrenergic state.


Graves' Disease and PREGNANCY

-Antithyroid drug treatment poses no greater risk than does surgery.
-Women get a usual improvement of the disease from pregnancy alone; the dosage of antithyroid drug required in the latter phases of pregnancy is much less.
-Overtreatment of hyperthyroid pregnant women remains a common clinical problem.


Graves' Disease and Pregnancy: PTU and methimazole (thioamines)

-Both drugs readily and easily cross the placenta.
-They concentrate in the fetal thyroid.
-Excess quantity can cause goitrous hypothyroidism in the fetus.
-PTU is generally preferred over methimazole in this treatment.
-There are claims for more fetal side effects with methimazole.
-Both drugs have proven safe in millions of pregnancies.


Graves' Disease and Pregnancy: Iodide

-Radioiodide is contraindicated in pregnancy; although, no harm has been shown in diagnostic doses.
-Iodide itself should bot be used as therapy for any length of time in the pregnant woman.
-Iodide readily crosses the placenta and can induce in the fetus and EXTREMELY LARGE GOITER.


Graves' Disease and Pregnancy: beta-blockers

-Propanolol and other beta-blockers use in pregnancy has been a matter of debate.
-There is associated possible intrauterine growth retardation, delayed lung development, and neonatal hypoglycemia or depression.
-Large studies suggest it can be safely used for short periods or at very low doses.