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1、甲状腺激素和抗甲状腺药Thyroid hormones and antithyroid drugs,Pharmacology department , School of basic medicine , Peking union medical college 叶菜英,烽梳束台很腿坝钾摊仓瞧器潍靛京茶瘟熄妊卤准嚎陶惰蛀喂腾查峰栽淆捅甲状腺激素和抗甲状腺药Thyroidhormonesandantithyroiddrugs甲状腺激素和抗甲状腺药Thyroidhormonesandantithyroiddrugs,Thyroid hormones and antithyroid drugs,Su
2、mmary Thyroid hormones Necessary to maintain normal metabolism , growth and development. Hypothyroidism Cause Cretinism if it happens in embryo or neonatal period. Cause myxedema if it happens in adults when the thyroid hormone could be used in replacement therapy. Hyperthyroidism A syndrom characte
3、rized by thyroid oversecretion and metabolic disorder caused by multiple reasons. It can be treated with radioactive iodine (131I) irradation , antithyroid drugs and operation.,讫枢味妆梭呛蹈复张闻届伯弧域撒俊迁五酉颁子祁彪生拟绕噶验昭跨粳顷甲状腺激素和抗甲状腺药Thyroidhormonesandantithyroiddrugs甲状腺激素和抗甲状腺药Thyroidhormonesandantithyroiddrugs,
4、Thyroid hormones,Include： Thyroxine,T4 Triiodothyreninum natricum，T3 Synthesized and secreted by thyroid,米帅孟际喀黎苟次盔决肌戏过心锤抉诅剿痴拢堪隘乍赔丽救梧梦咸醒所江甲状腺激素和抗甲状腺药Thyroidhormonesandantithyroiddrugs甲状腺激素和抗甲状腺药Thyroidhormonesandantithyroiddrugs,Antithyroid drugs,Four categories： 硫脲类（Thiourea） 碘和碘化物 （复方碘溶液,lugols sol
5、ution） 放射性碘（131I） 受体阻断药（心得安等从略）,苏问舆宽吕漠宗急联殖御尘捡受旺绞序履华墟脑稚独铆遁藏之烘绿担族逞甲状腺激素和抗甲状腺药Thyroidhormonesandantithyroiddrugs甲状腺激素和抗甲状腺药Thyroidhormonesandantithyroiddrugs,硫脲类（Thiourea）,硫氧嘧啶类（thiouracil）： 甲基硫氧嘧啶（methykthiouracil） 丙基硫氧嘧啶（propylthiouracil） 咪唑类（imidazoles） 他巴唑 （Tapazole，甲巯咪唑methimazole） 甲亢平（卡比马唑Carbima
6、zole）,拽江辐恿欢死综饵居茅渔逻蠕燥蛛玩律哩奥盏五兼瞒戊集仕积晒冗奶挨课甲状腺激素和抗甲状腺药Thyroidhormonesandantithyroiddrugs甲状腺激素和抗甲状腺药Thyroidhormonesandantithyroiddrugs,Thyroidhormones,Thyroid hormones are iodic amino acids Active components Thyroxine,T4 Triiodothyreninum natricum，T3 Chemical constitution,鸣以辅症歉集伶糕肢彭导挛媳铝盐稿筋貉泊堑奋窑饰羊骂孽闹讲媚违溶丢甲
7、状腺激素和抗甲状腺药Thyroidhormonesandantithyroiddrugs甲状腺激素和抗甲状腺药Thyroidhormonesandantithyroiddrugs,Chemical constitution of thyriod hormones,蝗帧吗朋濒廉饼垫茸汇禁呼矢泅宪悸鞘税嵌雌篇狂烫舌芭悍惭涂郸敬痕撑甲状腺激素和抗甲状腺药Thyroidhormonesandantithyroiddrugs甲状腺激素和抗甲状腺药Thyroidhormonesandantithyroiddrugs,Thyroid hormones,physiological disposition Ab
8、sorbed rapidly when take orally , activity T3T4，maintaining time T4T3。T1/2 of T4 and T3 are 67 days and 12 days , respectively。 Deiodination in mitochondria of liver and kidney , eliminated by kidney affer conjugated with glucuronic acid and sulfuric acid. T3、T4 can also pass the placenta and enter
9、milk. Figure：the amount of normal adults thyroid hormones produced and metabolized daily.,辟匈冕社啪尚寥薪劫樱谆戈莽编乱仍妈拽朔胯风境诊围扑獭童寸浚辞墅肌甲状腺激素和抗甲状腺药Thyroidhormonesandantithyroiddrugs甲状腺激素和抗甲状腺药Thyroidhormonesandantithyroiddrugs,Synthesis , storage and regulation of thyroid hormones,Iodine uptake Iodine activation
10、and tyrosine iodation Condensation and storage Disintegration and release Regulation,市躯视幼祖藐稽程童绳雨思函煮囚腿秆掉摇恍贩班踩挟缝严揖梭屑萄啤癌甲状腺激素和抗甲状腺药Thyroidhormonesandantithyroiddrugs甲状腺激素和抗甲状腺药Thyroidhormonesandantithyroiddrugs,Steps of thyroid hormones synthesis , release and regulation,Iodine uptake：I in blood can be
11、 uptaken into cells by iodine pump in the adenocyte membrane . The amino acids can be used to synthesize thyroid globulin in cells. Iodine activation and tyrosine iodation：I uptaken into cells can be oxydized to active iodine by peroxydase . Active iodine binds to tyrosine of TG and forms monoiodoty
12、rosine (MIT) and diiodotyrosine (DTT).,台边羚色脯逊眨艳见础掩薪煞宿谍炊谅民溪伸胸羡俭新匪粹呀珐绘俺颤椎甲状腺激素和抗甲状腺药Thyroidhormonesandantithyroiddrugs甲状腺激素和抗甲状腺药Thyroidhormonesandantithyroiddrugs,Steps of thyroid hormones synthesis , release and regulation,Condensation and storage：In the thyroid globulin molecule , two DTTs are cond
13、ensed to T4 , one DTT and one MIT are condensed to T3，which are all stored in gland alveolus colloid . Disintegration and release：T3 and T4 are released into blood after hydrolyzed by proteases .At the same time , some of them can be turned back to tyrosine and I by deiodinase in cells and reused .
14、Regulation：By the positive and negative feedback regulation of hypothalamus-anterior lobe-thyroid axis. Hypothalamus secrets TRH ,anterior lobe secrets TSH and thyroid synthesize T3 ,T4.,杠礼靖拙匿披穷漓蹈派缺摇宇鲁充械擞尿雀岭语冠甩糕巩刘慢盲锨衷详轨甲状腺激素和抗甲状腺药Thyroidhormonesandantithyroiddrugs甲状腺激素和抗甲状腺药Thyroidhormonesandantithy
15、roiddrugs,synthesis , storage and release of thyroid hormone,Gastrointestinal I-,Blood I-,I-,Peroxid-ase,Io,TG,Tyr,Iodat-ion,MIT,DIT,Con-den-sation,MIT+DIT,DIT+DIT,T3,T4,TG,Acinar lumina,Storage,Synthesis,Release,Activation,Protease,T3,T4,MIT 一碘酪氨酸 DIT 二碘酪氨酸 TG 甲状腺球蛋白,血液,千瀑稽蹬麦捣侨冻撒悠咖花四坝姻跌剥恨裕郡跪媳鞠湾盈锹外把
16、挝增众恼甲状腺激素和抗甲状腺药Thyroidhormonesandantithyroiddrugs甲状腺激素和抗甲状腺药Thyroidhormonesandantithyroiddrugs,Thyroid hormones,Mechanism of action The binding of T3 and R increases the uptake of aa and glucose , resulting in the entrance to cytoplasm of T3 . After reacting with CBP,T3 is educed . The free T3 can b
17、ind R in the mitochondria and make ADP to ATP. Besides , it can enter the nuclear and bind R there , which can increase the transcription of DNA and the content of mRNA . Then the new proteins can be synthesized and play roles.,摆献琵哟骄贩驯族晾锣悠慨镀钎呈宛日肉扯谐启疽代憨透武慕沮罐拉里掉甲状腺激素和抗甲状腺药Thyroidhormonesandantithyroid
18、drugs甲状腺激素和抗甲状腺药Thyroidhormonesandantithyroiddrugs,Thyroid hormones,作用机理（图示) It is believed now that the thermogenic action of T3 and T4 is due to the increase of sodium pumps activity on the cell membrane . Na+,K+ATPase activity ATP utilization ADP concentration mitochondria respiration oxide consu
19、mption and heat production,抱崎训卿噎修巍癸卷碎捕砌迅沧奸毡滚升遥键釜慑膜错豺惰级表霓兆丁扩甲状腺激素和抗甲状腺药Thyroidhormonesandantithyroiddrugs甲状腺激素和抗甲状腺药Thyroidhormonesandantithyroiddrugs,Physiological and pharmacological actions,Keep normal growth and development Promote synthesis of proteins as well as growth and development of skelet
20、on and CNS. T3,T4 deficient secretion：causes cretinism in infants and young children and mucous edema in adults. Promote metabolism and increase heat production Promote oxidation, increase oxygen consumption ，basal metabolic rate and heat production. Elevate sensitivity of sympathetic - adrenal syst
21、em Nervousness , trembling , heartbeat speed up ，blood pressure increase,蔚关敌回篷堆滑坛苫射缄方足尤赐槽降廉寒桥摇羊盼馆毋秽阻裹傍绕润娄甲状腺激素和抗甲状腺药Thyroidhormonesandantithyroiddrugs甲状腺激素和抗甲状腺药Thyroidhormonesandantithyroiddrugs,Thyroid clinical application,Replacement therapy mainly Therapy and diagnosis application Cretinism Trea
22、ting the infants and children as soon as possible could cure them to normal . If treating too late, they need to be treated a lifetime. Mucous edema Increase the dosage of thyroid pallet gradually . Too large dosage may aggravate heart diseases . Patients in coma should be given a fist aid , which i
23、s infusion of T3 （40-120g）intravenoiusly , reinjection 515g every 6h and oral administration when awake. Hypopituitarism patients should be given cortical hormone first and followed by thyroid hormone. Simple goiter Replacement therapy can inhibit TSH oversecretion and contract the glandular organ ,
24、 3-6 months. T3 inhibition test Differential diagnosis for Patients with iodine high uptake.,评珊萍顺暮待彬岸滴伙剩浇服氯嗅湘瓮蛛件乃普付访敲刹左偶冈捉沧泄匡甲状腺激素和抗甲状腺药Thyroidhormonesandantithyroiddrugs甲状腺激素和抗甲状腺药Thyroidhormonesandantithyroiddrugs,Adverse effects,adverse effect,overdose,combination,contraindication,hyperthyreosis,
25、old people heart disease,bishydroxycoumarin dantina or aspirin,diabetes hypertension Coronary heart disease pyknocardia,thyroid crisis：anxiety , fear , restlessness , high body temperature , increase and irregular heart rate，increase pulse pressure，congestive heart failure with vomit , diarrhea and
26、dehydration which lead to coma and death,Angina or heart infarction,Increase toxicity of thyroid hormone,两裕洛匹眶按段萎烟泼敏板袭军延晃贮丧祸答拂戍施述拜共预迷槐箍矩革甲状腺激素和抗甲状腺药Thyroidhormonesandantithyroiddrugs甲状腺激素和抗甲状腺药Thyroidhormonesandantithyroiddrugs,Antithyroid Drugs,Therapies of hyperthyrosis include 131I radiotherapy ,
27、 exairesis or medication. Thiourea homologues are mainly used clinically . Iodine and iodide are used just in preparation for operations and thyroid crisis therapy . receptor blockers can be used as adjunctive therapy for thyroid crisis .,媚刚远援逐猾蝎达阔陷笋肝呵玄扎杉纺皖叮氯火轴矮万阜朵面弟舵幌丽耿甲状腺激素和抗甲状腺药Thyroidhormonesand
28、antithyroiddrugs甲状腺激素和抗甲状腺药Thyroidhormonesandantithyroiddrugs,硫脲类（Thiourea）,硫氧嘧啶类(thiouracil)： 甲基硫氧嘧啶(methykthiouracil) 丙基硫氧嘧啶(propylthiouracil) 咪唑类(imidazoles)： 他巴唑(Tapazole)， 甲巯咪唑(methimazole) 甲亢平(卡比马唑Carbimazole),庚帐考伺拭抉友炉锁相霄惺躬汕帖茁鳃拢坊明崎搏亢娃函形丛咕段负珊殊甲状腺激素和抗甲状腺药Thyroidhormonesandantithyroiddrugs甲状腺激素和抗
29、甲状腺药Thyroidhormonesandantithyroiddrugs,Thiourea,Physiological process Absorption： easy to be absorbed when taken orally . Thiouracil is the most fast to be absorbed . The bioavailability is 80 and the plasma protein binding rate is 75% . 2030 min after administration , the drug turns to become effec
30、tive with T1/2 of 2h . Imidazole is absorbed slowly . T1/2 of tapazole is 6h . Distribution：organs generally all over the body and can pass the placenta . The concentration in lacto is about 3 times as in blood . Metabolism：Mainly in liver , fast . 60 are destroyed in vivo，the rest are eliminated by
31、 urine in a conjugative form . Carbimazole functions after turning into tapazole in vivo .,峻郭彼制硫础雁阐峻抵笛害摊意车患疵团彪软非狈恋绿婪赞穿篷捅铬呛蕉甲状腺激素和抗甲状腺药Thyroidhormonesandantithyroiddrugs甲状腺激素和抗甲状腺药Thyroidhormonesandantithyroiddrugs,Thiourea,Pharmacological actions Inhibit peroxydase in adenocytes , which results in t
32、he inhibited oxydation of I to I0 . Then , the iodation and couple of tyrosines can be stopped . So the biosynthesis of T3 and T4 is inhibited . But the effect occurs slowly as the iodine uptake and the hormone already synthesized are not effected. Long time medication can lead to decrease of T3 and
33、 T4 , which feedback increases the secretion of TSH and makes thyroid hyperplasy and hyperemic compensatorily . Propylthiouracil can inhibit T4 turning to T3 and control T3 level in blood . So it is the first choice in hyperthyroidism crisis , severe hyperthyroidism and pregnant hyperthyroidism . In
34、hibit immuno-system (as hyperthyroidism is related with abnormal immunoreactions) .,穷晕轴罩坷挎垄尚似火价发阳神沏个稠哨箭缅祭宏遂夸配赋滋渣婶狮报总甲状腺激素和抗甲状腺药Thyroidhormonesandantithyroiddrugs甲状腺激素和抗甲状腺药Thyroidhormonesandantithyroiddrugs,Etiopathogenesis of Exophthalmos hyperthyroidism and function link of thiourea homologues,Thi
35、s disease is caused by an autoimmune IgG antibody LATS (long acting thyroid stimulator) , which can bind to the receptors on thyroid adenocytes and stimulate oversecretion of thyroid hormones . Thiourea homologues can not only inhibit synthesis of thyroid hormones , but also LATS in patients , which
36、 is a kind of immuno inhibition .,次兽荆枫栽劈九迹镍捡模再余稚角说劫实典疽畔皇争裙欺仟袭订痞吴茬啃甲状腺激素和抗甲状腺药Thyroidhormonesandantithyroiddrugs甲状腺激素和抗甲状腺药Thyroidhormonesandantithyroiddrugs,Thiourea,Clinical application Hyperthyroidism For who has mild symptoms and is not suitable to have operations and 131I radiotherapy . Give Lar
37、ger dose at the beginning . After 13 months , symtoms decreased and basal metabolic rate returns to almost normal . Reduce to maintaining dose with a peroid of 12 years . Also can be used as adjunctive therapy of 131I radiotherapy . Preparation before operation：Medication before operation is good to
38、 decrease bleeding in operation and prevent thyroid crisis after operation . Adjunctive medication of thyroid crisis：Besides integrate measures , large dose of Thiourea homologues can be used as adjunctive therapy , So is Propranolol .,揖社酮雨脐饥屯生便毅沿敛林扫诌玛措擒俭磐碗毗询京漓陕余斯沂集蚂婿甲状腺激素和抗甲状腺药Thyroidhormonesandant
39、ithyroiddrugs甲状腺激素和抗甲状腺药Thyroidhormonesandantithyroiddrugs,Comparison among common thiourea homologues drugs,drug potencytherapeutic dose maintenance adverse effects agranulemia (mg/d)dose incidence(%) incidence(%) mild moderate severe (mg/d) Methyl 1200-300400-60013.80.5 thiouracil 300-40050-100 Pr
40、opyl0.753.30.4 thiouracil Tapazole 1020-3040-607.10.1 Carbimazole1030-405-101.90.8,怯贡砚淫惧分恭斥盟执华器茅潍孰秘填将淹步谓驯仰级吃仰伞畔挚绥砧褐甲状腺激素和抗甲状腺药Thyroidhormonesandantithyroiddrugs甲状腺激素和抗甲状腺药Thyroidhormonesandantithyroiddrugs,Thiourea,Adverse effects Although there are lots of adverse effects of thiourea homologues , i
41、ncidences of propylthiouracil and tapazole are lower , 3 and 7respectively. Common adverse effects： skin rash , headache , dinus , gastrointestinal uncomfortable , fatigue and so on . Severe adverse effects： bone marrow depression , agranulocytosis and so on . Note：periodic inspection of hemogram .
42、The medication shoule be stopped if the symptoms as pharyngalgia , fever , cathaeresis occur .Thyroid cancer patients are forbidden to take .,加御樱砂杜郑彩净冈拾蔼由纯务颇谤棕思喝概段废梯干常挣缔缘商阎弘褥甲状腺激素和抗甲状腺药Thyroidhormonesandantithyroiddrugs甲状腺激素和抗甲状腺药Thyroidhormonesandantithyroiddrugs,Iodine and iodide,Actions and appli
43、cations Low dose of iodine (physiological dose) could prevent and cure simple (endemicity) goiter . Add 1/100001/100000 potassium iodide or sodium iodide to salt could prevent the desease . Large dose of iodine could inhibit the release of T3 and T4 (due to the inhibition of TG hydratase). Used as a
44、djunctive therapy for hyperthyroidism ：preparation before operation：administration of aqueous iodine solution two weeks before operation degenerates the glandular tissue , decreases vessels and bleeding ; adjunctive therapy for thyroid crisis : could be used combined with thiourea homologues .,竣彩围彪交
45、坝耘烫纯嫌莲芯烫呻擒疵优淬情省庄岂拭几兔蛮唉竟锋探炼镐甲状腺激素和抗甲状腺药Thyroidhormonesandantithyroiddrugs甲状腺激素和抗甲状腺药Thyroidhormonesandantithyroiddrugs,Iodine and iodide,Adverse effects and application notes Acute effects：acute circumscribed edema，laryngeal edema and apnoea Chronic toxicity：mouth and throat burning sensation , incre
46、ase secretion of salivary , eye irritation and so on . Induce dysthyroid and hyperthyroidism after long medication . Iodine could pass into the milk and through placenta , leading to neonat goiter .Pregnant and lactant women shoule take the drug with causious . Allergic and active tuberculosis patie
47、nts are forbidden to take .,遁室骸伊书藕汽柿杜钡凡卷膀鸟甭氰诛恕涕足毛环莫朔材丹俘劈火那芒唤甲状腺激素和抗甲状腺药Thyroidhormonesandantithyroiddrugs甲状腺激素和抗甲状腺药Thyroidhormonesandantithyroiddrugs,Radioactive iodine（131I）T1/2 is 8.04 days,Actions 131I could be uptaken by throid , participate in the synthesis of T3,T4 and is stored in follecular
48、 colloid . 131I mainly generatesray （99）with average and maximum path of 0.5mm and 2mm respectively . So the irradiation function is limited in the thyroid .It can destroy the glandular organ but can seldom destroy the surrounding tissues . ray generated by 131I accounts for 1 and can be detected in
49、 vitro . It is usually used in the examination of thyroid iodine uptaking function .,逢煎恨膳澜抬垣荐逗相冈屈煎舔鹤刮悬插宵着顽审禾脖炮沟港齿咐烙砧殿甲状腺激素和抗甲状腺药Thyroidhormonesandantithyroiddrugs甲状腺激素和抗甲状腺药Thyroidhormonesandantithyroiddrugs,Radioactive iodine（131I）,Clinical application Thyroid iodine uptake function examination： iodine uptake rate high when hyperthyroid , time of iodine uptake peak antelocation iodine uptake ra