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Chapter 33 Thyroid & Antithyroid Drugs

Fig 1 Fig 2

＊ Thyroid follicles are the structural & functional units of the thyroid gland. ＊ Each follicle is surround mainly by simple cuboidal epithelium and is filled with a colloid which mainly composed by thyroglobulin. ＊ Thyroid hormones are mainly synthesized in colloid while the simple cuboidal epithelium undertaking thyroglobulin production, iodide intake & thyroid hormones release.

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●●Synthesis of thyroid hormonesSynthesis 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 thyroidalthyroidal peroxidase peroxidase to iodine

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

4. Iodotyrosines condensation

MIT+DIT→T3; DIT+DIT→T4

Thioamide drugs

MIT: monoiodotyrosine

DIT: diiodotyrosine

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Intra-thyroidal synthesis and processing of thyroidal hormones

1. Iodide is taken up at the basolateral cell membrane and transported to the apical membrane

2. Polypeptide chains of Tg (thyroglobulin) are synthesized in the rough endoplasmic reticulum, and posttranslational modifications take place in the Golgi

3. Newly formed Tg is transported to the cell surface in small apical vesicles (AV)

4. Within the follicular lumen, iodide is activated and iodinates tyrosyl residues on Tg, producing fully iodinated Tg containing MIT, DIT, T4 and a small amount of T3 (organification and coupling), which is stored as colloid in the follicular lumen

5. Upon TSH stimulation, villi at the apical membrane engulf the colloid and endocytose the iodinated Tg as either colloid droplets (CD) or small vesicles (MPV)

6. Lysosomal proteolysis of the droplets or vesicles hydrolyzes Tg to release its iodinated amino acids and carbohydrates

7. T4 and T3 are released into the circulation

8. DIT and MIT are deiodinated, and the iodide and tyrosine are recycled

thyroidalthyroidal peroxidase peroxidase

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●Regulation of thyroid function

TRH: thyrotropin-releasing hormoneTSH: thyroid-stimulating hormone

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●●PPhysiological actions of thyroid hormoneshysiological actions of thyroid hormones

To normalize growth and development, body

temperature, and energy levels

▲Insufficiency→ cretinism (infant & child), and myxede

ma (adult);

▲Excess→hyperthyroid

To enhance CNS excitability & sensitivity of CVS to NA

＃ T3 is 3 to 4 times more potent than T4 in heat production;

＃ T4 in colloid is about 4 times more numerous than T3 ;

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cretinism

myxedema

hyperthyroid

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Stems from both the hyperthyroid and hypothyroid conditions,

results from the accumulation of increased amounts of

hyaluronic acid and chondroitin sulfate in the dermis in both

lesional and normal skin.

The mechanism that causes myxedema is still not yet

understood. Sympotoms include:

●Skin thickening ●Coarse skin ●Change in facial appearance

●Thickening nose ●Swollen lips ●Puffiness around the eyes

●Jelly-like infiltrations in subcutaneous tissues ●Slow speech

●Mental dullness ●Lethargy ●Mental problems

●Dry skin ●Yellow skin ●Swollen subcutaneous tissue

●Weight gain ●Constipation ●Thinning hair

● Brittle hair ●Bald patches ●Muscle pains

Myxedema

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• 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

●Mechanism of actions of thyroid hormones

T3, via its nuclear

receptor, induces

new proteins

generation which

produce effects

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● ● RepresentativeRepresentative drugs drugs

levothyroxine (L-T4, levoxyl, synthroid)

liothyronine (T3, cytomel, triostat)

liotrix (T4 plus T3) (euthyroid, thyrolar)

Thyroid drugs

●● PharmacokineticsPharmacokinetics

po easily absorbed; the bioavailablity of T4 is 80%, and T3 is 9

5%.

Drugs that induce hepatic microsomal enzymes (e.g., rifampin,

phenbarbital, phenytoin, and etc) improve their metabolism.

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●Pharmacological effect see physiological effect

● Clinical use

1.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

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Class Representative

Thioamides

propylthiouracil

methylthiouracil

methimazole

carbimazole

Iodides KI, NaI

Radioactive iodine β-adrenoceptor blockers

131I

propranolol

Antithyroid drugs

● Drugs

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The thiocarbamide gr

oup is essential for a

ntithyroid activity

І . Thioamides

◆Structure

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Pharmacological action

Inhibition of the synthesis of T3T3 && T4T4

MechanismMechanism

All thioamides inhibit peroxidase-catalyzing reactions

Iodine organification

Iodotyrosines condensation

Propylthiouracil also inhibit T4 converting to T3

CharacteristicsCharacteristics

① Result appears slowly: in 3-4 w hyperthyroid ameliorate

d, and in 2-3 months BMR normalized;

② Long-term use leads to thyroid hyperplasia

③ Methimazole is 10 times as potent as propylthiouracil

First choice for thyroid crisis

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Clinical use

treatment of hyperthyroid

1. Mild hyperthyroid and those surgery & 131I no

t permitted;

2. Operation preparation;

3. Thyroid crisis (comprehensive therapy).

Adverse reactions

1. Long-term use leads to thyroid hyperplasia;

2. Pruritic maculopapular rash is the most common

adverse raaction

3. The severe adverse reaction is agranulocytosis

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Iodides (NaI, KI)

Pharmacological action

Inhibition of T3 & T4 release and synthesisT3 & T4 release and synthesis

Decrease of size & vascularity of the hyperplastic glandDecrease of size & vascularity of the hyperplastic gland

Clinical use

Ministrant treatment of hyperthyroid

1. Operation preparation;

2. Thyroid crisis.

Adverse reactions

1. Acneiform rash (similar to that of bromism);

2. Swollen salivary glands, mucous membrane ulcerations, and etc.

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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.