甲状腺激素和抗甲状腺药Thyroid
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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 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 adults when the thyroid hormone could be used in replacement therapy.
Steps of thyroid hormones synthesis, release and regulation (Ⅰ) Ⅰ
Iodine uptake: I－ in blood can be uptaken into
cells by iodine pump in the adenocyte membrane . The amino acids can be used to synthesize thyroid globulin in cells.
Mucous edema
Simple goiter
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 children and mucous edema in adults.
Synthesis, storage and regulation of thyroid hormones Iodine uptake Iodine activation and tyrosine iodation Condensation and storage Disintegration and release Regulation
Nervousness, trembling, heartbeat speed up, blood pressure increase
Thyroid clinical application
Replacement therapy mainly
Therapy and diagnosis Application
Hyperthyroidism
A syndrom characterized by thyroid oversecretion and metabolic disorder caused by multiple reasons. reasons. It can be treated with radioactive iodine (131I) irradation, antithyroid drugs and operation.
Thyroid hormones
Thyroxine, T4 Triiodothyreninum natricum, T3
Synthesized and secreted by thyroid
抗甲状腺药
分为4类 分为 类： 硫脲类 Thiourea 碘和碘化物 （复方碘溶液， lugol’s solution） ） 放射性碘（131I） β受体阻断药（心得安等从略）
Thyroid hormones
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 mitochondria respiration oxide consumption and heat production
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. Increase the dosage of thyroid pallet gradually . Too large dosage may aggravate heart diseases . Patients in coma should be given a fist aid, which is infusion of T3 （40-120µg）intravenoiusly , ） reinjection 5－15µg every 6h and oral administration － when awake. Hypopituitarism patients should be given cortical hormone first and followed by thyroid hormone. Replacement therapy can inhibit TSH oversecretion and contract the glandular organ, 3-6 months. Differential diagnosis for Patients with iodine high uptake.
Thyroid hormones
Thyroid hormones are iodic amino acids Active components Thyroxine, T4 Triiodothyreninum natricum, T3 Chemical constitution
甲状腺激素的化学结构
Synthesis, storage and release of thyroid hormone
Gastrointestinal IMIT+DIT
Peroxidase Iodation
MLeabharlann BaiduT Con-
T3
Acinar lumina
T3
Blood I-
I-
Io
Tyr TG
denDIT sation
Protease
TG
DIT+DIT
T4
T4
blood
MIT 一碘酪氨酸 DIT 二碘酪氨酸 TG 甲状腺球蛋白
Activation
Synthesis
Storage Release
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 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 and the content of mRNA. Then the new proteins can be synthesized and play roles.
Physiological disposition of thyroid hormones
Absorbed rapidly when take orally , activity T3>T4， ， maintaining time T4>T3. T1/2 of T4 and T3 are 6－7 days and 1－2 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.
Promote metabolism and increase heat production
Promote oxidation, increase oxygen consumption, basal metabolic rate and heat production.
Elevate sensitivity of sympathetic - adrenal system
Steps of thyroid hormones synthesis, release and regulation (Ⅱ) Ⅱ
Condensation and storage: 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 tyrosine 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.
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）
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).
Thyroid hormones and antithyroid drugs
北京协和医学院基础医学院药理学系 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 adults when the thyroid hormone could be used in replacement therapy.
Steps of thyroid hormones synthesis, release and regulation (Ⅰ) Ⅰ
Iodine uptake: I－ in blood can be uptaken into
cells by iodine pump in the adenocyte membrane . The amino acids can be used to synthesize thyroid globulin in cells.
Mucous edema
Simple goiter
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 children and mucous edema in adults.
Synthesis, storage and regulation of thyroid hormones Iodine uptake Iodine activation and tyrosine iodation Condensation and storage Disintegration and release Regulation
Nervousness, trembling, heartbeat speed up, blood pressure increase
Thyroid clinical application
Replacement therapy mainly
Therapy and diagnosis Application
Hyperthyroidism
A syndrom characterized by thyroid oversecretion and metabolic disorder caused by multiple reasons. reasons. It can be treated with radioactive iodine (131I) irradation, antithyroid drugs and operation.
Thyroid hormones
Thyroxine, T4 Triiodothyreninum natricum, T3
Synthesized and secreted by thyroid
抗甲状腺药
分为4类 分为 类： 硫脲类 Thiourea 碘和碘化物 （复方碘溶液， lugol’s solution） ） 放射性碘（131I） β受体阻断药（心得安等从略）
Thyroid hormones
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 mitochondria respiration oxide consumption and heat production
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. Increase the dosage of thyroid pallet gradually . Too large dosage may aggravate heart diseases . Patients in coma should be given a fist aid, which is infusion of T3 （40-120µg）intravenoiusly , ） reinjection 5－15µg every 6h and oral administration － when awake. Hypopituitarism patients should be given cortical hormone first and followed by thyroid hormone. Replacement therapy can inhibit TSH oversecretion and contract the glandular organ, 3-6 months. Differential diagnosis for Patients with iodine high uptake.
Thyroid hormones
Thyroid hormones are iodic amino acids Active components Thyroxine, T4 Triiodothyreninum natricum, T3 Chemical constitution
甲状腺激素的化学结构
Synthesis, storage and release of thyroid hormone
Gastrointestinal IMIT+DIT
Peroxidase Iodation
MLeabharlann BaiduT Con-
T3
Acinar lumina
T3
Blood I-
I-
Io
Tyr TG
denDIT sation
Protease
TG
DIT+DIT
T4
T4
blood
MIT 一碘酪氨酸 DIT 二碘酪氨酸 TG 甲状腺球蛋白
Activation
Synthesis
Storage Release
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 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 and the content of mRNA. Then the new proteins can be synthesized and play roles.
Physiological disposition of thyroid hormones
Absorbed rapidly when take orally , activity T3>T4， ， maintaining time T4>T3. T1/2 of T4 and T3 are 6－7 days and 1－2 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.
Promote metabolism and increase heat production
Promote oxidation, increase oxygen consumption, basal metabolic rate and heat production.
Elevate sensitivity of sympathetic - adrenal system
Steps of thyroid hormones synthesis, release and regulation (Ⅱ) Ⅱ
Condensation and storage: 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 tyrosine 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.
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）
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).