Medical University of Sofia Faculty of Me Department

Medical University of Sofia, Faculty of Me Department of Pharmacology and Toxi Thyroid antithyroid dru © Assoc. Prof. Iv. Lambev, Ph. D E-mail: itlambev@mail. bg

THYROID DRUGS Thyroxine (T 4) and tri-iodthyronine (T 3)

T 3 and T 4 are synthesized in the thyroid gland. Inorganic iodine is trapped with great avidity by the gland, oxidized and attached to t sine. Combination of mono- and/ di-iodinated tyrosine forms T 3 an T 4. The thyroxine peroxidase is i portant both in the initial oxidatio and the final combination steps.

Tyrosine Inorganic iodine Thyroxine peroxidase Mono-iodtyrosine (MIT) Inorganic iodine Thyroxine peroxidase Di-iodtyrosine (DIT)

MIT + DIT Thyreoglobulin T 3 DIT + DIT Thyreoglobulin T 4

Tyrosine Di-iodtyrosine

T 4 = L-Thyroxine

Synthesis and release of T 3 and are controlled by the anterior pit itary hormone, thyrotrophin (TSH thyroid-stimulating hormone). Its secretion is controlled by the hy thalamic thyrotrophin-releasing hormone (TRH) and somatostati Circulating T 3 and T 4 exert a neg tive feedback on the TSH and TR

Hypothalamus TRH Somatostatin (+) (-) Adenohypophysis TSH (+) (-) Glandula Thyreoidea (+) T 3 <I plasma (-) >I T 4

Regulation of thyroid hormone synthesis

Worldwide iodine nutrition

24 hrs: 80 mcg T 4 40 mcg T 3 200 mcg I

Circulating thyroid hormone highly protein-bound to TBG (thyroxine-binding globulin). Less than 0. 1% from T 4 is fre Only the free fraction can bind to specific cell receptor

Plasma T 4: 95% T 3: 5% 99. 91– 99. 97% Thyroxine-binding globulin

AGENTS INLFUENCING PROTE BOUND OF L-THYROXINE (T 4) INCREASE • estrogens • methadone • heroin • clofibrate • tamoxifen DECREASE • glucocorticoids • aspirin • phenytoin • carbamazepine • furosemide

T 3 is much more biologically act than T 4. The plasma half-life of T 3 is 36 h. T 4 has t 1/2 168 h. After entering into cells T 4 converts into T 3 whi binds to receptor protein and inte racts with DNA in the cell nucleus causing the synthesis of new mes ger RNA and hence of new protei

The main effects of T 3 and T • Stimulating of metabolism (whi resulting in a raised basal meta bolic rate). • Promotion of normal growth an maturation, particularly of the CNS and skeleton. • Sensitization to the effects of ca cholamines (DA, NA, Adrenaline

Intracellular (nuclear) steroid/thyroid receptors Effector Coupling Time scale Examples gene transcription via DNA hours steroid receptors thyroid receptors vitamin D receptors

T 3&T 4 – indication • hypothyroidism • T 3 is reserved for patients with myxoedemic coma

Facial appearance in hypothyroidism

Jodthyrox (T 4 + < I) Levothyroxine (T 4) - tabl. 25 mcg Liothyronin (T 3) Thyreoidea siccata Thyrotrophin (TSH)

ANTITHYROID DRUGS • Thioureas agents • Beta-blockers 131 • Radioactive iodnie ( I) They are used to treat hyperthyroidism.

Thioureas agent inhibit thyroxine peroxidase, and therefore synthesis of T 3 and T 4. Because of long halfof T 4, changes in rate synthes takes several weeks to low ci lating concentrations to norm

• Carbimazole (prodrug) Thiamazole (Methimazole – USAN) • Propylthiourac • Thiamazole - tabl. 5 mg

Thioureas – adverse effec • Nausea, taste disturbance • Agranulocytosis • Placental transfer and secretion in breast milk can produce neonatal hypothyroidism (small doses are probably safe).

Beta-blockers have imm diate symptomatic effect on palpitation and tremor but do not alter the rate of T 3 & T 4 synthesis. 131 I (t 8 days) is used to tre 1/2 multinodular toxic goiters. It i taken up by the abnormal tiss

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