Medical University of Sofia, Faculty of MedicineDepartment of Pharmacology and Toxicology

Thyroid and antithyroid drugs

© Assoc. Prof. Iv. Lambev, PhDE-mail: itlambev@mail.bg

Thyroxine (T4) andtri-iodthyronine (T3)

THYROIDDRUGS

THYROIDDRUGS

T3 and T4 are synthesized in thethyroid gland. Inorganic iodine istrapped with great avidity by thegland, oxidized and attached to tyro-sine. Combination of mono- and/or-di-iodinated tyrosine forms T3 andT4. The thyroxine peroxidase is im-portant both in the initial oxidationand the final combination steps.

Mono-iodtyrosine (MIT)Mono-iodtyrosine (MIT)

TyrosineTyrosine

Di-iodtyrosine (DIT)Di-iodtyrosine (DIT)

Inorganic iodine Thyroxine peroxidase

Thyroxine peroxidaseInorganic iodine

MIT + DIT

DIT + DIT

T3

T4

Thyreoglobulin

Thyreoglobulin

Tyrosine

Di-iodtyrosine

CH2-CHHO

NH2I

I

COOH

CH2-CHHO

NH2

COOH

T4 = L-Thyroxine

CH2-CH

NH2I

I

O

I

I

HOCOOH

Synthesis and release of T3 and T4are controlled by the anterior pitu-itary hormone, thyrotrophin (TSH -thyroid-stimulating hormone). Itssecretion is controlled by the hypo-thalamic thyrotrophin-releasinghormone (TRH) and somatostatin.Circulating T3 and T4 exert a nega-tive feedback on the TSH and TRH.

AdenohypophysisAdenohypophysis

Glandula ThyreoideaGlandula Thyreoidea

TSH

HypothalamusTRH Somatostatin

(+)

(+)

(+)

p l a s m aT3 < I > I T4

Regulationof

thyroid hormonesynthesis

Worldwide iodine nutrition

80 mcg T440 mcg T3200 mcg I

24 hrs:24 hrs:

Circulating thyroid hormones arehighly protein-bound to TBG(thyroxine-binding globulin).

Less than 0.1% from T4 is free.Only the free fraction canbind to specific cell receptors.

PlasmaT4: 95% T3: 5%

Thyroxine-bindingglobulin

99.91–99.97%

AGENTS INLFUENCING PROTEIN-BOUND OF L-THYROXINE (T4)AGENTS INLFUENCING PROTEIN-BOUND OF L-THYROXINE (T4)

INCREASE•estrogens•methadone•heroin•clofibrate•tamoxifen

DECREASE•glucocorticoids•aspirin•phenytoin•carbamazepine•furosemide

T3 is much more biologically activethan T4. The plasma half-life of T3 is 36 h. T4 has t1/2 168 h.

After entering into cells T4 converts into T3 which binds to receptor protein and inte-racts with DNA in the cell nucleus,causing the synthesis of new messen-ger RNA and hence of new proteins.

The main effects of T3 and T4:•Stimulating of metabolism (which resulting in a raised basal meta- bolic rate).•Promotion of normal growth and maturation, particularly of the CNS and skeleton.•Sensitization to the effects of cate- cholamines (DA, NA, Adrenaline).

Intracellular (nuclear)steroid/thyroid receptors

EffectorCouplingTime scaleExamples

gene transcriptionvia DNAhourssteroid receptorsthyroid receptorsvitamin D receptors

T3&T4 – indications:•hypothyroidism•T3 is reserved for patients with myxoedemic coma.

Facial appearancein hypothyroidism

Jodthyrox (T4 + < I)Levothyroxine (T4) - tabl. 25 mcgLiothyronin (T3)Thyreoidea siccata

Thyrotrophin (TSH)

They are used to treathyperthyroidism.

•Thioureas agents•Beta-blockers•Radioactive iodnie (131I)

ANTITHYROIDDRUGS

ANTITHYROIDDRUGS

Thioureas agentsinhibit thyroxine peroxidase,and therefore synthesis of T3and T4. Because of long half-life of T4, changes in rate synthesistakes several weeks to low circu-lating concentrations to normal.

•Carbimazole (prodrug)

Thiamazole (Methimazole – USAN)

•Propylthiouracil•Thiamazole - tabl. 5 mg

Thioureas – adverse effects

•Nausea, taste disturbance•Agranulocytosis•Placental transfer and secretion in breast milk can produce neo- natal hypothyroidism (small doses are probably safe).

Beta-blockers have imme-diate symptomatic effect on palpitation and tremor but donot alter the rate of T3 & T4 synthesis.131I (t1/2 8 days) is used to treatmultinodular toxic goiters. It istaken up by the abnormal tissue.

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