Thyroid and antithyroid drugs (Abstract) (Abstract) Assoc. Prof. Iv. Lambev

Thyroxine (T4) and tri-iodothyronine (T3) THYROID DRUGS THYROID DRUGS

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

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

MIT + DIT DIT + DIT T3 T4 Thyreoglobulin

Tyrosine Di-iodotyrosine

T4 = L-Thyroxine

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

Adenohypophysis Glandula Thyreoidea TSH Hypothalamus TRHSomatostatin (+)  (+)  p l a s m a T3< I> IT4

Regulation of thyroid hormone synthesis

Worldwide iodine nutrition

80 mcg T4 40 mcg T3 200 mcg I 24 hrs:

Circulating thyroid hormones are highly protein-bound to TBG (thyroxine-binding globulin). Less than 0.1% from T4 is free. Only the free fraction can bind to specific cell receptors.

Plasma T4: 95%T3: 5% Thyroxine-binding globulin 99.91–99.97%

AGENTS INLFUENCING PROTEIN- BINDING OF L-THYROXINE (T4) AGENTS INLFUENCING PROTEIN- BINDING OF L-THYROXINE (T4) INCREASE estrogens methadone heroin clofibrate tamoxifen DECREASE glucocorticoids aspirin phenytoin carbamazepine furosemide

T3 is much more biologically active than T4. The plasma half-life of T3 is 36 h. T4 has t 1/2 168 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 results in a raised basal metabolic rate). Promotion of normal growth and maturation, particularly of the CNS, and skeleton. Sensitization to the effects of catecholamines (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

Directly at nuclear receptors: Thyroid hormones (T3, T4) T3 or T4 penetrates the nucleus Combines with their receptors Alters DNA-RNA mediated protein synthesis

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

Lack of energy Weight gain Feeling cold Dry skin and hair Constipation Haevy menstrual periods HypothyroidismHyperthyroidism Fatigue, weight loss Feeling hot Palpitations, irritability More bowel movements Schorter or lighter menstrual periods

Facial appearance in hypothyroidism

Jodthyrox  (T4 + < I) Levothyroxine  (T4) - tabl. 25 mcg Liothyronin  (T3) Thyreoidea siccata  Thyrotrophin (TSH)

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

Thiourea agents inhibit thyroxine peroxidase, and therefore the synthesis of T3 and T4. Because of the long half-life of T4, changes in the rate synthesis takes several weeks to lower circu- lating concentrations to normal.

Propylthiouracil Thiamazole – tabl. 5 mg Carbimazole (prodrug) Thiamazole (Methimazole – USAN)

Thioureas – adverse effects Agranulocytosis Nausea, taste disturbance 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 do not alter the rate of T3 & T4 synthesis. 131 I (t 1/2 8 days) is used to treat multinodular toxic goiters. It is taken up by the abnormal tissue.