1、甲状腺激素和抗甲状腺药甲状腺激素和抗甲状腺药Thyroid hormones and antithyroid drugs 北京协和医学院基础医学院药理学系北京协和医学院基础医学院药理学系 叶菜英叶菜英 Summary 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 adult
2、s when the thyroid hormone could be used in replacement therapy.Hyperthyroidism A syndrom characterized by thyroid oversecretion and metabolic disorder caused by multiple reasons.It can be treated with radioactive iodine(131I)irradation,antithyroid drugs and operation.Thyroid hormones Thyroxine,T4 T
3、riiodothyreninum natricum,T3 Synthesized and secreted by thyroid 抗甲状腺药抗甲状腺药 分为分为4类类：硫脲类 Thiourea 碘和碘化物 （复方碘溶液，lugols solution）放射性碘（131I）受体阻断药（心得安等从略）硫脲类硫脲类 硫氧嘧啶类硫氧嘧啶类（thiouracil）：甲基硫氧嘧啶（methykthiouracil）丙基硫氧嘧啶（propylthiouracil）咪唑类咪唑类（imidazoles）他 巴 唑（Tapazole，甲 巯 咪 唑methimazole）甲亢平（卡比马唑Carbimazole）T
4、hyroid hormones are iodic amino acids Active components Thyroxine,T4 Triiodothyreninum natricum,T3 Chemical constitution Thyroid hormones 甲状腺激素的化学结构甲状腺激素的化学结构 Physiological disposition of thyroid hormones Absorbed rapidly when take orally,activity T3T4，maintaining time T4T3.T1/2 of T4 and T3 are 67
5、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 milk.Figure:the amount of normal adults thyroid hormones produced and metabolized daily.Synthesis,sto
6、rage and regulation of thyroid hormones Iodine uptake Iodine activation and tyrosine iodation Condensation and storage Disintegration and release Regulation Steps of thyroid hormones synthesis,release and regulation()Iodine uptake:I in blood can be uptaken into cells by iodine pump in the adenocyte
7、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 monoiodotyrosine(MIT)and diiodotyrosine(DTT).Condensation and stora
8、ge:In the thyroid globulin molecule,two DTTs are condensed 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 tyros
9、ine and I by deiodinase in cells and reused.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.Steps of thyroid hormones synthesis,release and regulation()Synthesis,sto
10、rage and release of thyroid hormone Gastrointestinal I-Blood I-I-Peroxidase Io TG Tyr Iodation MIT DIT Con-den-sation MIT+DIT DIT+DIT T3 T4 TG Acinar lumina Storage Synthesis Release Activation Protease T3 T4 MIT 一碘酪氨酸一碘酪氨酸 DIT 二碘酪氨酸二碘酪氨酸 TG 甲状腺球蛋白甲状腺球蛋白 blood Thyroid hormones Mechanism of action Th
11、e 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 bind 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
12、and the content of mRNA.Then the new proteins can be synthesized and play roles.Mechanism of action（figure)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 mitochon
13、dria respiration oxide consumption and heat production Thyroid hormones Physiological and pharmacological actions Keep normal growth and development Promote synthesis of proteins as well as growth and development of skeleton and CNS.T3,T4 deficient secretion:causes cretinism in infants and young chi
14、ldren 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 system Nervousness,trembling,heartbeat speed up,blood pressure increase Thyroid clinical
15、application Replacement therapy mainly Therapy and diagnosis Application Cretinism Treating 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
16、 aggravate heart diseases.Patients in coma should be given a fist aid,which is 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,3-6 months.T3 inhibition test Differential diagnosis for Patients with iodine high uptake.Adverse effects Adverse effect Overdose