Transcript Slide 1
Thyroid and antithyroid drugs (Abstract) Assoc. Prof. Iv. Lambev E-mail: [email protected] www.medpharm-sofia.eu THYROID DRUGS Thyroxine (T4) and tri-iodothyronine (T3) T3 and T4 are synthesized in the thyroid gland. Inorganic iodine is trapped with great avidity by the gland, oxidized and attached to tyrosine. Combination of mono- and/ordi-iodinated tyrosine forms T3 and T4. The thyroxine peroxidase is important both in the initial oxidation and the final combination steps. Tyrosine Inorganic iodine Thyroxine peroxidase Mono-iodotyrosine (MIT) Inorganic iodine Thyroxine peroxidase Di-iodtyrosine (DIT) MIT + DIT Thyreoglobulin T3 DIT + DIT Thyreoglobulin T4 NH2 CH2-CH HO COOH Tyrosine I NH2 CH2-CH HO COOH I Di-iodotyrosine I I CH2-CH O HO I NH2 I T4 = L-Thyroxine COOH Synthesis and release of T3 and T4 are controlled by the anterior pituitary hormone, thyrotrophin (TSH thyroid-stimulating hormone). Its secretion is controlled by the hypothalamic thyrotrophin-releasing hormone (TRH) and somatostatin. Circulating T3 and T4 exert a negative feedback on the TSH and TRH. Hypothalamus TRH Somatostatin (+) (-) Adenohypophysis TSH (+) (-) (-) Glandula Thyreoidea (+) T3 <I plasma (-) >I T4 Regulation of thyroid hormone synthesis Worldwide iodine nutrition 24 hrs: 80 mcg T4 40 mcg T3 200 mcg I 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% 99.91–99.97% Thyroxine-binding globulin AGENTS INLFUENCING PROTEINBINDING 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 t1/2 168 h. After entering into cells T4 converts into T3 which binds to receptor protein and interacts with DNA in the cell nucleus, causing the synthesis of new messenger 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. Hypothyroidism •Lack of energy •Weight gain •Feeling cold •Dry skin and hair •Constipation •Haevy menstrual periods Hyperthyroidism •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) ANTITHYROID DRUGS •Thioureas agents •Beta-blockers 131 •Radioactive iodine ( I) They are used to treat hyperthyroidism. 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 circulating concentrations to normal. •Carbimazole (prodrug) Thiamazole (Methimazole – USAN) •Propylthiouracil •Thiamazole – tabl. 5 mg Thioureas – adverse effects •Agranulocytosis •Nausea, taste disturbance •Placental transfer and secretion in breast milk can produce neonatal hypothyroidism (small doses are probably safe). Beta-blockers have immediate symptomatic effect on palpitation and tremor but do not alter the rate of T3 & T4 synthesis. 131I (t 8 days) is used to treat multinodular toxic goiters. It is taken up by the abnormal tissue. 1/2