Thyroid And Anti Thyroid Drugs

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The two metabolic iodinated amino acid hormones produced by the thyroid are

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L-triiodothyronine T3

L-thyroxine T4

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Signs of hyperthyroidsm

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Tachycardia, cardiac arythmia,body wasting, nervousness, tremor, excess heat production

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Signs of hypothyroidism

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Bradycardia, poor resistance to cold, mental and physical slowing (MR and dwarfism in children)

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Calcitonin

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Involved in control of plasma Ca2+

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The only known iodine containing compounds with metabolic activity. The major metabolic hormones.

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Triiodothyronine

Thyroxine

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Ion channels that are targets for thyroid hormone action.

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Ryanodine channel

L and T type calcium channel

Sodium calcium exchanger protein

IF channel

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Thyroid follicles or acini

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Functional units of the thyroid gland.

Produces colloid

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Colloid

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Thick proteinaceous fluid that fills the lumen. It is composed primarily of thyroglobulin.

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Thyroglobulin

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A high molecular weight glycoprotein that contains about 115 tyrosine residues.

It is synthesized, glycosylated and secreted by the follicle.

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Function of thyroglobulin

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It provides the matrix for thyroid hormone synthesis.

It stores a large supply of iodine and thyroid hormones for secretion at a steady rate or on demand.

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Where thyroid hormone is assembled

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Thyroid follicular lumen

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Process of assembly

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Iodine binds to tyrosyl residues in Tg to form MIT and DIT at apical surface of follicular cells.

MIT and DIT join to form T3 and T4.

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Summary of thyroid hormone synthesis

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Uptake of iodide ion (I-1)

Synthesis of Tg

Iodination

Condensation

Proteolytic release of hormones

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Peroxidase

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Converts I-1 to I2

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Inhibitors of Iodination

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Propylthiouracil

Methimazole

Elevated iodide (I-)

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Inhibitors of condensation

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Propylthiouracil

Methimazole

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Goitrogens

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Flavonoids (inhibit TPO)

Catechin in tea

Infants fed with soy formula

Excess iodine intake in fetus and neonate may lead to hyper or hypothyroidism

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Uptake of iodide is mediated by

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Iodide active transport by:

NIS in basolateral surface of thyrocytes

PDS (pendrin): an I-/Cl- porter in apical membrane

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Mutations in NIS and PDS genes contribute to

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Thyroid diseases in some patients

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What stimulates iodide transport process?

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TSH

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What blocks iodide uptake

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Lack of O2, Metabolic inhibitors, cardiac glycosides

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Structurally related things that are competitive inhibitors of iodine transport

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Perchlorate

Pertechnate

Permanganate

Bromine

Fluorine

Calcium

Lithium

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Lithium also works by

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Inhibiting thyroid adenylate cyclase

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How thiocyanate works to prevent iodine transport

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It is not taken up itself. It works by:

Displacing iodine from the pump

Increasing permeability of follicles to lose I-

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What is TPO

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A haem containing peroxidase

Requires H2O2 to generate hypoiodate (OI-), the iodinating species.

Catalysis the oxidation of I- to I2

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How do thioureas inhibit Iodination?

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Sulphenyl iodide is a reactive intermediate.

Thioureas block it by reacting with lactoglobulin Sulphenyl iodide

Thus liberating iodide and forming an inactive mixed disulphide.

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If dietary I2 is normal

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MIT- 20-30

DIT- 30-46

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If I2 is deficient

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An increase in MIT to DIT ratio occurs hence T3 is more.

This is beneficial in iodine depleted areas cos T3 is more potent

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A high degree of Iodination is required for

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coupling MIT and DIT to form T3 and T4

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When do thioureas inhibit the formation of T4

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When the thioureas are at a concentration lower than that needed for inhibiting Iodination

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How is extrathyroidal T3 formed

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T4 deiodination

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Blocks the release of preformed thyroid hormones

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Iodide

Lithium

MOA is poorly understood.

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Functions of TPO

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Iodination

Condensation

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Summary of role of thioureas

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Displaces iodide from pumps

Makes follicles lose iodide

Reacts with sulphonyl iodide to block Iodination

Inhibits T4 production when it's concentration is too low to inhibit Iodination.

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Other organs that can actively transport iodide

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Salivary gland

GIT

But they can't incorporate iodide into proteins.

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When tyrosine molecules are iodinated on proteins other than Tg

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They lack the proper tertiary structure needed to allow the formation of active thyroid hormones.

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TPO uses H2O2 as oxidant to activate

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I2 to OI- the iodinating species

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Pharmacokinetics of T3 compared to T4

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Greater volume of distribution, fractional turnover per day, Metabolic clearance per day, total serum levels but serum concentration is less because of greater volume of distribution. Also greater potency and oral absorption.

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Pharmacokinetics of T4 compared to T3

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Greater extrathyroidal pool, daily production, T1/2, concentration of free.

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Amount bound- T3 and T4

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The same- 99.96%

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These increase T4 binding globulin

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Estrogens, pregnancy

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These decrease T4 binding globulin

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Gc

Androgens

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These displace T4 and T3 and may affect test results

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Dicoumarol

clofibrate

Phenytoin

Salicylates

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Inducers of P450

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Phenytoin

Rifampin

Phenobarbital.

These accelerate the metabolism of the hormones

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How many different 5-monodeiodinase enzymes are in the body

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3

Type 1 (peripheral tissues)

Type 2 (CNS, pituitary, thyroid)

Type 3 (placenta, skin, developing brain)

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Function of the 5- monodeiodinase enzyme

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Inactivates T3 and T4

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Drug interactions of thyroid hormones

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T4 potentiates antidepressant actions of TCA

Potentiate the effects of anticoagulants of coumarine and indanedione types by increasing receptor affinity or decreasing vitK

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Primary pathway of peripheral metabolism of thyroxine -T4

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Deiodination (can be monodeiodination producing 3, 5, 3-triiodithyronine (T3) )

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Other pathways for inactivation of thyroxine

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Deamination

Decarboxylation

Conjugation (glucuronide and sulfate)

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Physiologic role of type 1 deiodinase

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Extracellular T3 production in peripheral tissue