Thyroid Hormones and Antithyroid Drugs Department of pharmacology Chapter 36 Thyroid Hormones and Antithyroid Drugs Department of pharmacology Liming zhou 2018.10

Contents Thyroid hormone Thioureas (硫脲类） Iodine and Iodide (碘及碘化物) Radioactive Iodine β adrenergic receptor antagonists

Thyroid hormone Thyroid follicular colloid Thyroglobulin T4 T3 hydrolysis T3 is more potent T4 is more than T3 but weak The thyroid gland is one of the largest endocrine organ and mainly consists of thyroid follicular , which is the main place to generate and secrete thyroid hormone.

Thyroid hormone —synthesis and secretion Follicle epithelial cell Thyroid follicle EC Space Follicle Lumen

Thyroid hormone—regulation anterior pituitary paraventricular nucleus Hypothalamus Anterior Pituitary Thyroid gland TRH + TSH Thyroid - T4, T3 SRIF

Thyroid hormone—intracorporal process Easy to absorb using Po and the oral absorption rate of T3 and T4 are 50% ~ 75% and 75% ~ 90% respectively. The rate of plasma protein combining is 99%, and the protein binding of T3 is less than the T4, the role of T3 is more potent than T4 with a half-life for 2 days, T4 is slow and weak with a half-life for 5 days.

Thyroid hormone—intracorporal process The liver is the major site of nondeiodinative degradation, T4 and T3 are conjugated with glucuronic and sulfuric acids and excreted in the renal As it can go through the placenta and breast milk, pregnancy and lactation women should be cautious.

Thyroid hormone—intracorporal process Tab 1 Summary of thyroid hormone kinetics kinetics T４ T3 daily production (µg) 70～90 15～30 fractional turnover per day (%) 10 60 metabolic clearance per day (L/d) 1.1 24 amount bound (％) 99.96 99.6 volume of distribution (Ｌ) 40 serum level(total) ( µg/dL) 4.5～11 60～180 serum level(free) (ng/dL) 0.7～1.86 0.2～0.52 half-life(biologic) (d) 7 1 biological potency 4 oral absorption (%) 80 95

Thyroid hormone—Pharmacological effects Growth and Development hypothyroidism ：child cretinism(呆小症) adult myxedema(黏液水肿) Calorigenic Effects : Increase the basal metabolic rate and excessive production of heat Improve the sensitivity of sympathetic—The susceptibility of adrenal system

Thyroid hormone—Pharmacological mechanism Mediated by activating its nuclear specificity T3 receptors. T4 translated into T3 by deiodination and combined with the specificity T3 receptors, and regulate gene transcription, protein synthesis and play functions Other factors lead to the decreasing in T3 receptors

Thyroid hormone—clinical application Cretinism　The hypofunction begin in fetus or infants, therapy is instituted within the first few weeks of life , normal physical and mental development is almost always achieved Myxedema Generally take thyroid tablet, from low does gradually increase to the full does.

Thyroid hormone—clinical application Simple goiter(单纯性甲状腺肿)　 Using table salt and food for prevention, thyroid tablets for a supplementary treatment. T3 suppression test As a differential diagnosis in patients with high ingestion rate of iodine.

Thyroid hormone—untoward effects Too much does of thyroid hormone can cause the clinical manifestations of  hyperthyroidism, angina and myocardial infarction may occur in cardiopath and old patients, using β adrenergic receptor antagonists to against the adverse effects and discontinuing thyroid hormone. Diabetes, coronary heart disease, rapid arrhythmia patients should not be used.

Antithyroid drugs Thiourea Iodine and iodide: Thiouracils 硫脲嘧啶: Propylthiouracil Thiourea Imidazole  咪唑: Methimazole Compound Iodine Oral Solution Iodine and iodide: Classify β adrenergic receptor antagonists: Atenolol Radioactive iodine 125I

incorporation of iodine Thiourea —【 Mechanism 】 Thiourea inhibit Iodine passed into the thyroid cells actively Peroxidase oxidation of iodide ion (I+) TSH Iodide in the blood incorporation of iodine into tyrosyl residues of thyroglobulin 2MIT MIT+DIT Peroxidase T4 T3

Thiourea—pharmacokinetics Propylthiouracil 丙基硫氧嘧啶: Absorption of propylthiouracil follows within 20 to 30 minutes of an oral dose and peak in 2 hours, plasma protein binding was 75%, concentrated in thyroid and could cross the placenta and also can be found in milk, with the half-life about 2 hours. Methimazole甲硫咪唑:The roles last for long time and and persistent with plasma t1/2 to 4 ~ 9 h ； methimazole, derived from the metabolism of carbimazole

Thiourea—pharmacological effects 1. Resistance to thyroid function Having no effects on the preformed hormone, the clinical effects become noticeable after 2-3 weeks, basal metabolic rate resumed normal after 1-3 months by inhibiting the peripheral deiodination脱碘 of T4 to T3 and controling the serum T3 level. As the feedback effects, which lead to  the increased secretion of TSH and the gland  hyperplasia 2. Immunosuppressive effects

Thiourea—clinical application Treatment of hyperthyroidism 　 Suitable for mild patients and who are unfavorable surgical or 131 I treatment, treatment last for 1 ~ 2 years. To control the disorder in preparation for surgical treatment Adjuvant therapy of the thyroid storm

Thiourea—adverse effects The incidence of side effects is relatively low 1. Frequent complications: pain and stiffnessn僵硬 in the joints, headache, nausea 2. Allergic reaction: purpuric, urticarial papular rash 3.Agranulocytosis. 粒性白血球缺乏症:the most serious reaction 4. Goiter and hypothyroidism 5Patients with thyroid cancer and nodular goiter is  forbidden

Iodine and iodide — pharmacological effects Low doses of iodine promote the synthesis of thyroid hormones High concentrations of iodide inhibit the release of thyroid hormone. This action is rapid and efficacious and discernible within 24 hours, with the maximal effect attained after 10 to 15 days

Iodine and iodide — clinical application Simple goiter : 1/105 ~ 1/104 potassium iodide or sodium iodide joined into the table salt can prevent this disease. Preparation for the hyperthyroidism preoperative: To facilitate operation and reduce bleeding Thyroid crisis: large doses of iodine can prevent thyroid hormone release and cooperate with thiourea. .

Iodine and iodide — adverse effects Allergic reaction: Acute reaction may occur immediately or several hours after administration, angioedema, laryngeal edema Chronic intoxication with iodide: unpleasant brassy taste and burning in the mouth and throat Thyroid dysfunction: Iodine can also enter into the milk and cross the placenta and cause neonatal goiter, pregnant women and lactating women should be used with caution.

Radioactive Iodine—pharmacological effects 131I is greatest used in clinical and half-life is 8 d 131I is rapidly and efficiently trapped by the thyroid , and the destructive β particles originate within the follicle and act exclusively upon the parenchymal cells of the thyroid, with little or no damage to surrounding tissue The γ radiation can be quantified by external detection, which can be used to measurement thyroid function

Radioactive Iodine—clinical application Treatment of hyperthyroidism :　131I is applied to the patients who can not be treatment with surgey, recurrence after surgery or thiourea treatment is invalid. Diagnosis of disorders of thyroid function: 　 Low does of 131I can be used to test the thyroid function

Radioactive Iodine—adverse effects High incidence of delayed hypothyroidism which can be treated with thyroid hormone 131 I is banned for pregnancy hyperthyroidism, children hyperthyroidism and patients with severe hyperthyroidism.

β Adrenergic antagonists Mechanism Mainly through blocking β receptor, and relieving the symptoms in patients with hyperthyroidism caused by adrenal system excitement. Further, it can inhibit thyroid hormone secretion and inhibit the peripheral deiodination of T4 to T3

β Adrenergic antagonists Application 1. Control the symptoms of hyperthyroidism 2. Preparation for the hyperthyroidism preoperative 3. Adjuvant therapy of thyroid crisis. The effect is much better shared with thiourea

Key Concepts Thioureas inhibit the synthesis of thyroid hormones. Propythiouracil can also block the conversion of T4 to T3 in peripheral tissues. High concentrations of iodide appear to influence almost all important aspects of iodide metabolism by the thyroid gland, especially including an inhibition of the release of thyroid hormones.

Key Concepts 131I exerts a destruction of thyroid gland by beta particles. The major indications for the therapeutic use of thyroid hormones are for hormone replacement therapy in patients with hypothyroidism or cretinism, and antithyroid drugs are for the treatment of hyperthyroid individual.

Key Concepts 131I exerts a destruction of thyroid gland by beta particles. The major indications for the therapeutic use of thyroid hormones are for hormone replacement therapy in patients with hypothyroidism or cretinism, and antithyroid drugs are for the treatment of hyperthyroid individual.

Review questions 1. Illustrate the influence of  drug dose on the drug effects, take the effects of  iodine on the thyroid function? 2. Try to explain the purpose of thiourea and iodine used on the hyperthyroidism preoperative?