• Recall the anatomy and physiology of thyroid glands

• Describe the effect of thyroid hormones on metabolism

• Compare the different mechanism of actions of thyroid and anti thyroid drugs

• List clinical uses and adverse effects of thyroid and anti thyroid drugs

• Explain the principles underling TSH therapy in diagnosis

• Describe the anti thyroid drugs - drug interaction

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Member of the Endocrine System• Secretes thyroid hormones, thyroxine and calcitonin,

which regulate metabolism and growth.• Located in neck adjacent to the 5th cervical vertebra (C5).• Composed of epithelial cells which specialize in the

absorption of iodine and, of course, secretion of thyroid hormones.

• Follicles surround a protein core, the colloid, where thyroglobulin, a substrate in thyroid hormone synthesis, and thyroid hormones are stored.

Thyroid hormones are synthesized by iodination of tyrosine residues on thyroglobulin within the lumen of the thyroid follicle.

The thyroglobulin is endocytosed and thyroxin (T4)

and triiodothyronine (T3) are secreted. Synthesis and secretion of T3 and T4 are regulated

by thyroid-stimulating hormone (TSH; thyrotrophin) and influenced by plasma iodide.

.

There is a large pool of T4 in the body; it has a low turnover rate and is found mainly in the circulation.

There is a small pool of T3 in the body; it has a fast turnover rate and is found mainly intracellular.

Detail of 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 a tyrosine residue of thyroglobulin to form monoiodothyronine MIT or diiodothyronine DIT

2-DIT condense together to form thyroxin, or T4, with four iodine substituent.

2-DIT condense with 1-MIT to form triiodothyronine, or T3, with three iodine substituent, accounts for about 10% of thyroid hormone production.

Stimulate metabolism generally causing - increased oxygen consumption -increased metabolic rate -Influence growth and development. Within cells, the T4 is converted to T3, which

interacts with a nuclear receptor; the receptor represses basal transcription when not bound to T3, and activates transcription when bound.

↓Metabolic rate Detected by hypothalamus Stimulates anterior pituitary Secretes TSH Blood stream target organ thyroid Stimulate Thyroid to secrete T3/T4 Blood stream target organs adrenal medulla

Secretes Epinephrine & Norepinephrine ↑Metabolic rate

Regulation:• The hypothalamus in the brain secretes thyroid

releasing hormone, TRH, that target the pituitary gland which, in turn, secretes thyroid stimulating hormone, TSH. The pituitary gland’s sensitivity toward TRH varies with the body’s need for thyroid hormones.

• Protirelin is a synthetic TRH causes increase secretion of TSH used for diagnostic purpose

TSH is absorbed into the thyroid, stimulating the thyroid to absorb iodine and synthesize hormones.Thyroid hormones provide negative feedback for TSH production via a “homeostatic feedback loop.”

Regulationof

thyroid hormonesynthesis

TSH acts on receptors on the membrane of thyroid follicle cells and its main second messenger is cAMP. It controls all aspects of thyroid hormone synthesis:

1-The uptake of iodide by follicle cells, by stimulating transcription of the Na+/I- transporter gene; this is the main mechanism by which it regulates thyroid function

2-The synthesis and secretion of thyroglobulin, 3-The generation of H2O2 and the iodination of

tyrosine 4- The endocytosis and proteolysis of

thyroglobulin 5- The secretion of T3 and T4 6-The blood flow through the gland. TSH also has a trophic action on the thyroid

cells; it stimulates the action of the genes for thyroglobulin, thyroperoxidase and the Na+/I- transporter

1. TH serves as a nuclear transcription factor, regulating gene expression in targeted cells to increase metabolism.1. Increase size and number of mitochondria in the cell.2. Synthesizes cytochromes which feed into the electron transfer

chain of cellular respiration, stimulating metabolism through increasing ATP production.

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

4. Increased K+ and Na+ concentrations in the cell.2. Increase the body’s basal metabolic rate, BMR, to maintain

electrochemical gradient in cell.3. Stimulate carbohydrate metabolism and lipolysis4. Affects protein synthesis.5. Increase the body’s sensitivity to catecholamine, i.e. adrenaline

Hyperthyroidism (thyrotoxicosis), either diffuse toxic goiter or toxic nodular goiter

Hypothyroidism; in adults this causes myxoedema, in infants, cretinism

Simple non-toxic goiter, caused by dietary iodine deficiency, usually with normal thyroid function

cretinism

simple goiter

Insufficient amount of thyroid hormone synthesized causing lethargy and weight gain, among other symptoms.

Primary hypothyroidism is typically caused by Hashimoto’s Disease, an auto-immune disorder in which 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.

Worldwide iodine nutrition

Enlarged thyroid, symptom of hypothyroidism.Goiters form for different reasons depending on the cause ofhypothyroidism

Hashimoto’s disease, also known as chronic lymphocyticthyroiditis, causes goiters due to the accumulation oflymphocytes.The decreased amount of thyroid hormones in the body,

due to Hashimoto’s or other thyroid disorders including infection, signals the increased production of TSH which accumulates in the thyroid causing a characteristic goiter.

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

Thyroxine is the standard replacement therapy for hypothyroidism. Thyroxine has all the actions of endogenous thyroxine; it is given orally.

Liothyronine (T3) is the treatment of choice for myxoedema coma. Liothyronine has all the actions of endogenous triiodothyronine; it is given intravenously

1. Hormone replacement therapy2. Administered orally with a bioavailability ranging

from 48%-80%.1. Levothyroxine—Synthetic T42. Liothyronine—Synthetic T33. Liotrix—Combination of synthetic T4 and T34. Natural Thyroid Hormones—Thyroid hormones

derived from pigs, contains T4 and T31. Armour Thyroid

Dosage specific to individual and is determined by theirTSH serum levels. Typically 1.5μg 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 of their age. Synthetic T3 is reserved for younger patients, who do not have a history of heart problems and individuals non-responsive to T4 treatment.

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

The over production of thyroid hormones.Symptoms include fatigue, weight lose, rapid heartbeat, anxiety, swollen eyes, and sensitivity to hottemperatures.

Causes:Grave’s disease, and autoimmune disorder in which

antibodies serve as agonists to the THS receptors on the thyroid’s surface, causing thyroid growth and activation of hormone synthesis and secretion.

Thyroid tumors which cause the uncontrolled synthesis and secretion of thyroid hormones.

Thyroiditis, inflammation of the thyroid typically caused by infection.

Treatment of Hyperthyroidism

•Drugs•thioureylenes•iodides•radioactive iodine•beta adrenoceptor blocking agents•'Lugol's iodine

Surgical Subtotal

Thyroidectomy

1-Anti-thyroid drugs—Thioureylenes

Inhibits thyroid hormone synthesis by irreversibly binding to TPO inhibiting its ability to break down iodine (I2→I-) and covalently attach it to the tyrosine residue of thyroglobulin.

Three thioureylenes available:PropylthiouracilMethimazoleCarbamizole─Degraded to methimazole in the body.Best indicated for children ,adolescents ,young adults

and pregnant women.

Methimazole 5mg; Propylthiouracil (PTU) 50mg; Carbimazole 5mg, 20mg

MOA: • contain a sulfhydryl group and a

thiourea moiety within a heterocyclic structure

• inhibit synthesis by acting against iodide organification (both)

• coupling of iodotyrosines (both)• blocks conversion of T4 to T3 (PTU)

A- Carbimazole (or propylthiouracil)1-Hyperthyroidism (diffuse toxic goitre), at least 1

year of treatment being necessary; recurrence occurs eventually in over half the patients but can be managed by a repeat course of treatment.

2-Propylthiouracil can be used in patients who suffer sensitivity reactions to carbimazole.

3-Preliminary to surgery for toxic goitre. 4-Part of the treatment of thyroid storm (very severe

hyperthyroidism); propylthiouracil is preferred because of its action in decreasing the conversion of T4 to T3 in the tissues

Effective in the long-term treatment of hyperthyroidism.6-8 weeks before maximum effect of the drug achieved. Drug

inhibits hormone synthesis, so hormones synthesized prior to drug use will continue to cause hyperthyroid condition.

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

Serious liver damage, decreased red and white blood cell synthesis, as well as decreased platelet production have been reported in a few cases. The drug’s interaction with other enzymes responsible for clotting factor synthesis accounts for some of these serious side effects.

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

β-blockers are effective in treatment of

thyrotoxicosis to treat symptoms Propranolol is the most widely studied and used.

As first-line treatment for hyperthyroidism; recurrence is rare provided the dose is adequate.

For treatment of relapse of hyperthyroidism after carbimazole therapy or surgery.

Radioiodine, given orally, is selectively taken up by

thyroid and damages cells; it emits short-range β

radiation, which affects only thyroid follicle cells of..

Hypothyroidism will eventually occur. Woman in

pregnancy or lactation is forbidden

131I cytotoxic action is restricted to the cells of the thyroid follicles, resulting in significant destruction of the tissue. 131I has a half-life of 8 days, so by 2 months its radioactivity has effectively disappeared. It is given as one single dose, but its cytotoxic effect on the gland is delayed for 1-2 months and does not reach its maximum for a further 2 months.

Iodine dissolved in aqueous potassium iodide ('Lugol's iodine') is used short-term to control thyrotoxicosis preoperatively. It reduces the vascularity of the gland.

Iodine, given orally in high doses, transiently reduces thyroid hormone secretion and decreases vascularity of the gland.

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

Thyrotropin alpha—A synthetic form of TSH. Administered intravenously.

Used in thyroid cancer treatment.Tumors of the hypothalamus or pituitary gland can cause the

uncontrolled release of TSH, which accumulates in the thyroid and can cause subsequent follicular or papillary cancer of the thyroid. Partial or total thyroidectomy typical.

Following thyroidectomy, the individual is dependent on exogenous thyroid hormones to regulate metabolism, but thyrotropin alpha is also used to suppress the release of endogenous TSH, which could trigger cancerous growth again.

Used as a diagnostic tool to determine the reoccurrence of cancer.