Thyroid hormones and

antithyroid drugs

normal amount of thyroid hormones are essential for normal growth and development by maintaining the level of energy metabolism in the tissue.

Either too little or too much thyroid hormones will bring disorders to the body.

Part 1 Thyroid hormones

Two major thyroid hormones are: triiodothyronine （ T3, the most active form ） thyroxin （ T4 ） The characteristic of their chemical structure is that they all contain iodine as an essential part of the molecule.

Structure

inadequate secretion of thyroid hormone (hypothyroidism) can bring many disorders to the body (eg. bradycardia, poor resistance to cold, both mental and physical slowing.)

[Synthesis, storage and release of thyroid

hormones]

Synthesis

Iodine is the raw material of the thyroid biosynthesis. Once taken up by the thyroid gland, iodine undergoes a series of enzymatic reactions before it converts into active thyroid hormones.

Synthesis; four steps1. iodine trapping :uptake of iodine by the thyroid

gland2. oxidation of iodine: (to its active form) thyroid peroxidase (key enzyme of the synthesis) 3. iodide organification :the iodination of tyrosyl gr

oups of thyroglobulin productions: MIT and DIT4. formation of T4 and T3 from MIT and DIT : thyroid peroxidase

storage store in the colloid droplets of thyroglobulin

release The hormones are released by proteolysis of thyroglobulin . Enzyme: thyroglobulin hydrolase The ratio of T4 to T3 within thyroglobulin is about 5:1

Differences between T3 and T4

the effect of T3 is much faster, stronger and shorter than that of T4.

conversion T4 can converse to T3 through deniodonite in peripheral tissues as well as in the thyroid. (catalyzed by deiodinase)

Regulation:

TRHTSH

T3,T4

Hypothalamuspituitary

thyroid

Controled by HPT(hypothalamic-pituitary-thyroid) axis

Regulation

TRH (thyrotropin releasing hormone) TSH (thyroid stimulating hormone or thyrotropin)

[Pharmacokinetics]

Pharmacological actions

Effects on growth and development Calorigenic effects : Hypersensitivity to catecholamine :

Pharmacological actions

1.Effects on growth and development : responsible for normal growth and maturation of human being , especially for nervous and skeletal tissues. so the absence of thyroid hormones before birth leads to both mental and physical retardation （ cretinism ）

Pharmacological actions

2.Calorigenic effects: T3 /T4 can increase oxygen consumption, promote metabolism and BMR（ basal metabolic rate ） ,↓utility. So hyperthyroidism will result in excess heat production and body wasting.

Pharmacological actions 3. hypersensitivity to

catecholamine Cardiovascular effects: Tachycardia, hypertension nervous Effects: anxiety, nervous.

mechanism TR CBP NUCLEAR R

Clinical uses the major indications for the

therapeutic use of thyroid hormones are for hormone replacement therapy in patients with hypothyroidism .

Clinical uses1.Cretinism :congenital hypothyroidism often happens in newborn babies, mainly caused

by iodine deficiency before birth . Success in the treatment of cretinism depends

on the age at which therapy is started. The earlier, the better.

Symptoms: 1.Physical slow: dwarf, with short extremities ,2.mentally retarded: inactive, uncomplaining

and listless. incidence :about 1 per 400 birthsPrevention and therapy: Prevention: Iodine replacement is the best

method prior to pregnancy. Therapy: thyroid hormones replacement(T4 is

more often used than T3)

Cretinism

Clinical uses

2.Myxedema: adult hypothyroidism

Happens after individual development

Slow in mentality With special edema Mortality :60%

Clinical uses 3.Simple goiter: A kind of prevalent disease caused by insufficient dietary iodine TSH can promote hyperplasy and hypertrophy of thyroid gland. 4. Differential diagnosis of simple goiter and hyperthyroidism

Simple goiter

adverse reactions hyperthyroidism

Part 2 Antithyroid drugs

Grave’s syndrome

Treatment of hyperthyroidismThe goal of therapy is to decrease

the additional hormone and attend to normal levels.

Can be accomplished by removing part of the gland Inhibiting synthesis Blocking releasing

four categories of anti-thyroid drugs

Ⅰ Thioureas : ( 硫脲类 ) interfere directly with the synthesis of thyroid hor

mones Ⅱ High concentrations of iodine : decrease the release of thyroid hormones Ⅲ Radioactive iodine : damage the gland with ionizing radiation Ⅳ β- receptor antagonists: control the manifestations

Ⅰ Thioureas( 硫脲类 )

Thiouracils: methythiouracil , propylthiouracil Imidazoles: methimazole , carbimazole.

Ⅰ Thioureas Pharmacological action : Decrease the level of thyroid hormonesMechanism 1.inhibit the thyroid peroxidase : (key enzyme of synthesis) interfere the oxidation of iodine and the coupling of MIT and DIT to form T3/T4

2. inhibit conversion from T4 to T3 3.immunosupressive effect: TSI

Pharmacokinetics: Absorption Distribution Excretion Pass through placenta, milk

Therapeutic uses 1.As definitive treatment to control hyperthyroi

dism 2.Preoperative preparations for subtotal thyroi

dectomy: to control the disorder in preparation for surgical treatment.

(thioureas plus large dose of iodine) 3. Thyroid crisis Propylthiouracil is the first ch

oice.

Adverse reactions 1.allergic response 2.GI reaction3.granulocytopenia (0.3%-0.6%)

4.Longterm use: goiter and hypothyroidism

Drug interactions ↑ Li ， sulfasulfonamide ， PAS ， para

minan （对氨苯甲酸）， phenylbutazone ， barbital ， phentolamine ， sulfonyl urea ， vitB12

↓ iodine

Ⅱ Iodine and iodide Oldest agent have completely different

effects due to different doses

Pharmacological effects

in small dose: ↑ synthesis of thyroid hormones in large dose : antithyroid 1) ↓the release of thyroid hormones into the cir

culation: strong Mechanism: Inhibit thyroglobulin hydrolase 2)↓synthesis of thyroid hormones: weakMechanism: Inhibit thyroid peroxidase

Therapeutic uses1.Simple goiter : in small dose2.In preparation for thyroidectomy : used after the hyperthyroidism has been controlle

d by thioureas, given for 7 to 10 days immediately preceding the operation. (The changes after a fairly long term of administration include: the vascularity of the thyroid gland is reduced, the gland becomes much firmer and smaller.)

3.Thryotoxic crisis

Adverse reactions1. Chronic iodism2.Acute allergic action :angioneurotic edema and larynx edema 3. Thyroid dysfunction

Ⅲ Radioactive iodine 131I : most often used isotope

of iodine γ rays （ 1% ） : β particles （ 99%):

destructive

Effects on the thyroid gland 131I is rapidly and efficiently trapped by the thyr

oid gland and slowly emitsβparticles and γrays.

The destructive βparticles can destroy the thyroid cells with little damage to surrounding tissues (the penetration range is only 0.4-2.0mm).

Theγrays can pass through the tissue and be quantified by external detection

Clinical uses

1.hyperthyroidism: administrated orally and the effective dose differs for individual patients.

2.diagnosis of thyroid functions

Adverse reactions: hypothyroidism contraindications pregnancy and milk mothers

IV β-adrenergic receptor antagonists

------ adjuvant therapy many of the symptoms of hyperthyroidism are associated with sympathetic stimulation, so β-R blockers are effective in antagonizing the catecholaminegic symptoms such as tachycardia, palpitations ,anxiety and tension.

Action: (1)block 1-R of heart (2)block -R of CNS (3) block -R of presynaptic membrane of peripheral nerve. (4) Inhibit T4 converted into T3

Uses: 1.Control the symptoms of hyperthyroidism before confirmed diagnosis 2.Thyroid crisis 3.Preoperation of hyperthyroidism 4.Hyperthyroidism

Section 3 TSH and TRH

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