THYROID AND ANTI-THYROID DRUGS

Mr. D.Raju, M.pharm,Lecturer

ANATOMY AND PHYSIOLOGY OF THE THYROID GLAND

Member of the Endocrine SystemSecretes 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.

SYNTHESIS OF THYROID HORMONES

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.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.”

●Regulation of thyroid function

TRH: thyrotropin-releasing hormoneTSH: thyroid-stimulating hormone

●Synthesis of thyroid hormones

Thyroid hormones

triiodothyronine (T3)

tetraiodothyronine (T4, thyroxine)

Materials

iodine & tyrosine

Steps

1. Iodide is trapped by sodium-iodide symporter

2. Iodide is oxidized by thyroidal peroxidase to iodine

3. Tyrosine in thyroglobulin is iodinated and forms MIT & DIT

4. Iodotyrosines condensation

MIT+DIT→T3; DIT+DIT→T4

MIT: monoiodotyrosineDIT: diiodotyrosine

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 a tyrosine residue of thyroglobulin.Two iodinated thyrosine rings condense to form thyroxine, or T4, with four iodine substituents.Triiodothyronine, or T3, with three iodine substituents, accounts for about 10% of thyroid hormone production.

●MECHANISM OF ACTIONSOF THYROID HORMONES

• Some of T4 are converted to T3 in kidney and liver

• The actions of T3 on several organ systems are shown

• BMR: basal metabolic rate; CNS: central nervous system

T3, via its nuclear receptor, induces new proteins generation which produce effects

CONDITIONS THAT IMPAIR THYROID FUNCTION: HYPOTHYROIDISM

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.

SYMPTOMS OF THYROID DYSFUNCTION: GOITER

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

Hashimoto’s disease, also known as chronic lymphocytic thyroiditis, causes goiters due to the accumulation of lymphocytes.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.

TREATMENT FOR HYPOTHYROIDISM

Hormone replacement therapyAdministered orally with a bioavailability ranging from 48%-80%.

Levothyroxine—Synthetic T4Liothyronine—Synthetic T3Liotrix—Combination of synthetic T4 and T3Natural Thyroid Hormones—Thyroid hormones derived from pigs, contains T4 and T3

Armour ThyroidDosage specific to individual and is determined by their TSH 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.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.

CONDITIONS THAT IMPAIR THYROID FUNCTION: HYPERTHYROIDISM

The over production of thyroid hormones.Symptoms include fatigue, weight lose, rapid heart beat, anxiety, swollen eyes, and sensitivity to hot temperatures.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 FOR HYPERTHYROIDISM

Anti-thyroid drugs—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.

PropylthiouracilMethimazoleCarbamizole─Degraded to methimazole in the body.

Radioactive IodineThyroidectomyβ-Blockers used in the treatment of thyroiditis to treat symptoms.

●Pharmacological effectsee physiological effect

● Clinical use1.Hypothyroidism: cretinism & myxedema;2.simple goiter: for pathogeny remaining unclear

(endemic goiter directly supply iodine)3. Others: ● Adverse reactions

Overmuch leads to thyrotoxicosis;Angina or myocardial infarction usually appears in

ageds

Class Representative

Thioamides

propylthiouracil

methylthiouracil

methimazole

carbimazole

Iodides KI, NaIRadioactive iodine β-adrenoceptor blockers

131Ipropranolol

Antithyroid drugs● Drugs

The thiocarbamide group is essential for antithyroid activity

І. Thioamides

◆Structure

Pharmacological action

Inhibition of the synthesis of T3 & T4

MechanismAll thioamides inhibit peroxidase-catalyzing reactions

Iodine organificationIodotyrosines condensation

Propylthiouracil also inhibit T4 converting to T3

Characteristics① Result appears slowly: in 3-4 w hyperthyroid ameliorated, and in 2-3 months BMR normalized;② Long-term use leads to thyroid hyperplasia③ Methimazole is 10 times as potent as propylthiouracil

First choice for thyroid crisis

Clinical usetreatment of hyperthyroid

1. Mild hyperthyroid and those surgery & 131I not permitted;

2. Operation preparation;3. Thyroid crisis (comprehensive therapy).

Adverse reactions1. Long-term use leads to thyroid hyperplasia;2. Pruritic maculopapular rash is the most common

adverse raaction3. The severe adverse reaction is agranulocytosis

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Iodides (NaI, KI)Pharmacological action

Inhibition of T3 & T4 release and synthesisDecrease of size & vascularity of the hyperplastic gland

Clinical useMinistrant treatment of hyperthyroid

1. Operation preparation; 2. Thyroid crisis.

Adverse reactions1. Acneiform rash (similar to that of bromism);2. Swollen salivary glands, mucous membrane ulcerations, and etc.

RADIOACTIVE IODINE (131I)

131I is the only isotope for treatment of thyrotoxicosis.

Its therapeutic effect depends on emission of β rays with an effective half-life of 5 days & a penetration range of 0.4-2 mm.

Woman in pregnancy or lactation is forbidden!

β-adrenoceptor blockers

βblockers are effective in treatment of thyrotoxicosis.

Propranolol is the most widely studied and used.

THYROID TREATMENT: POTENTIAL DRUG INTERACTIONS

Drugs that reduce thyroid hormone productionLithium 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 thyroxineRifampin (Rifadin) Phenobarbital Carbamazepine (Tegretol) Warfarin (Coumadin) Oral hypoglycemic agents

Drugs that displace thyroid hormone from protein bindingFurosemide (Lasix) Mefenamic acid (Ponstel) Salicylates

TSH REPLACEMENT DRUGS

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.