1、Chapter 36 Thyroid Hormones and Antithyroid DrugsDepartment of pharmacologyLiming zhou2015.10ContentsThyroid hormone Thioureas(硫脲类）硫脲类）Iodine and Iodide(碘及碘化物碘及碘化物)Radioactive Iodine adrenergic receptor antagonistsThyroid hormoneThe thyroid gland is one of the largest endocrine organ and mainly cons
2、ists of thyroid follicular,which is the main place to generate and secrete thyroid hormone.Thyroid follicular colloidThyroglobulinT4T3hydrolysisT3 is more potentT4 is more than T3but weakFollicle epithelial cellThyroid follicleThyroid follicleThyroid follicleanterior pituitaryparaventricular nucleus
3、HypothalamusAnterior PituitaryThyroid glandTRH+TSHThyroid-T4,T3-SRIFThyroid hormoneintracorporal 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,th
4、e 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 hormoneintracorporal process The liver is the major site of nondeiodinative degradation,T4 and T3 are conjugated with glucuronic and sulfuric acids and excreted in the renalAs it c
5、an go through the placenta and breast milk,pregnancy and lactation women should be cautious.kinetics TT3daily production(g)70901530fractional turnover per day(%)1060metabolic clearance per day(L/d)1.124amount bound()99.9699.6volume of distribution()1040serum level(total)(g/dL)4.51160180serum level(f
6、ree)(ng/dL)0.71.860.20.52half-life(biologic)(d)71biological potency14oral absorption(%)8095 Tab 1 Summary of thyroid hormone kineticsTab 1 Summary of thyroid hormone kineticsThyroid hormonePharmacological effects Growth and Development hypothyroidism：child cretinism(呆小症)adult myxedema(黏液水肿)Calorigen
7、ic Effects:Increase the basal metabolic rate and excessive production of heat Improve the sensitivity of sympatheticThe susceptibility of adrenal system Thyroid hormonePharmacological mechanismMediated by activating its nuclear specificity T3 receptors.T4 translated into T3 by deiodination and combi
8、ned with the specificity T3 receptors,and regulate gene transcription,protein synthesis and play functions Other factors lead to the decreasing in T3 receptorsThyroid hormoneclinical applicationCretinismThe hypofunction begin in fetus or infants,therapy is instituted within the first few weeks of li
9、fe,normal physical and mental development is almost always achievedMyxedema Generally take thyroid tablet,from low does gradually increase to the full does.Thyroid hormoneclinical applicationSimple goiter(单纯性甲状腺肿单纯性甲状腺肿)Using table salt and food for prevention,thyroid tablets for a supplementary tre
10、atment.T3 suppression test As a differential diagnosis in patients with high ingestion rate of iodine.Thyroid hormoneuntoward effectsq Too much does of thyroid hormone can cause the clinical manifestations of hyperthyroidism,angina and myocardial infarction may occur in cardiopath and old patients,u
11、sing adrenergic receptor antagonists to against the adverse effects and discontinuing thyroid hormone.qDiabetes,coronary heart disease,rapid arrhythmia patients should not be used.ClassifyThioureaIodine and iodide:adrenergic receptor antagonists:Thiouracils 硫脲嘧啶:PropylthiouracilImidazole 咪唑:Methimaz
12、ole Antithyroid drugsCompound Iodine Oral SolutionAtenololRadioactive iodine 125125I IThiourea【Mechanism】Iodide in the bloodIodine passed into the thyroid cells activelyincorporation of iodine into tyrosyl residues of thyroglobulinTSHPeroxidase2DITMIT+DIToxidation of iodide ion(I+)PeroxidaseT4 T3Thi
13、ourea inhibitPropylthiouracil 丙基硫氧嘧啶丙基硫氧嘧啶: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
14、甲硫咪唑甲硫咪唑:The roles last for long time and and persistent with plasma t1/2 to 4 9 h；methimazole,derived from the metabolism of carbimazole,and not used in Thyroid StormThioureapharmacokinetics1.1.Resistance to thyroid functionHaving no effects on the preformed hormone,the clinicaleffects become notic
15、eable 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 hyperplasia2.ImmunosuppressiveeffectsThioureapharmac
16、ological effectsThioureaclinical 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 thyroidstormThioureaadverse effe
17、ctsThe incidence of side effects is relatively low1.Frequent complications:pain and stiffnessn僵硬僵硬 in the joints,headache,nausea2.Allergic reaction:purpuric,urticarial papular rash3.Agranulocytosis.粒性白血球缺乏症粒性白血球缺乏症:the most serious reaction4.Goiter and hypothyroidism5.Patients with thyroid cancer an
18、d nodular goiter is forbiddenIodine 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 attai
19、ned after 10 to 15 daysIodine 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 bleedingThyroid crisis:large doses of iod
20、ine can prevent thyroid hormone release and cooperate with thiourea.Iodine and iodide adverse effectsAllergic reaction:Acute reaction may occur immediately or several hours after administration,angioedema(血管性水肿),laryngeal edema(喉水肿)Chronic intoxication with iodide:unpleasant brassy taste and burning
21、 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 Iodinepharmacological effects 131I is greatest used in clinical and half-life is 8 d 131I is ra
22、pidly and efficiently trapped by the thyroid,and the destructive particles originate within the follicle and act exclusively upon the parenchymal cells of the thyroid,with little or no damage to surrounding tissue The radiation can be quantified by external detection,which can be used to measurement
23、 thyroid function 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 functionRadioactive Iodineclinical
24、 applicationHigh incidence of delayed hypothyroidism which can be treated with thyroid hormone131 I is banned for pregnancy hyperthyroidism,children hyperthyroidism and patients with severe hyperthyroidism.Radioactive Iodineadverse effects Mechanism Mainly through blocking receptor,and relieving the
25、 symptoms in patients with hyperthyroidism caused by adrenal system excitement.it can inhibit thyroid hormone secretion and inhibit the peripheral deiodination of T4 to T3 Adrenergic antagonistsApplication1.Control the symptoms of hyperthyroidism2.Preparation for the hyperthyroidism preoperative 3.A
26、djuvant therapy of thyroid crisis.The effect is much better shared with thiourea Adrenergic antagonistsqThioureas inhibit the synthesis of thyroid hormones.Propythiouracil can also block the conversion of T4 to T3 in peripheral tissues.Key ConceptsqHigh concentrations of iodide appear to influence a
27、lmost all important aspects of iodide metabolism by the thyroid gland,especially including an inhibition of the release of thyroid hormones.q131I exerts a destruction of thyroid gland by beta particles.qThe major indications for the therapeutic use of thyroid hormones are for hormone replacement the
28、rapy in patients with hypothyroidism or cretinism,and antithyroid drugs are for the treatment of hyperthyroid individual.Key Conceptsq131I exerts a destruction of thyroid gland by beta particles.qThe major indications for the therapeutic use of thyroid hormones are for hormone replacement therapy in
29、 patients with hypothyroidism or cretinism,and antithyroid drugs are for the treatment of hyperthyroid individual.Key Concepts1.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?Review questions
