醫(yī)學(xué)專題甲狀腺激素和抗甲狀腺藥Thyroid

1、甲狀腺激素和抗甲狀腺藥Thyroid hormones and antithyroid drugs北京協(xié)和醫(yī)學(xué)院基礎(chǔ)醫(yī)學(xué)院藥理學(xué)系 葉菜英2021/7/19 星期一1SummaryThyroid 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 thyroi

2、d 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.2021/7/19 星期一2Thyroid hormonesThyroxine, T4T

3、riiodothyreninum natricum, T3Synthesized and secreted by thyroid2021/7/19 星期一3抗甲狀腺藥分為4類： 硫脲類 Thiourea碘和碘化物 （復(fù)方碘溶液， lugols solution） ）放射性碘（131I）受體阻斷藥（心得安等從略）2021/7/19 星期一4硫脲類硫氧嘧啶類（thiouracil）：甲基硫氧嘧啶（methykthiouracil）丙基硫氧嘧啶（propylthiouracil）咪唑類（imidazoles）他巴唑（Tapazole，甲巰咪唑methimazole）甲亢平（卡比馬唑Carbimazo

4、le）2021/7/19 星期一5Thyroid hormones are iodic amino acidsActive components Thyroxine, T4 Triiodothyreninum natricum, T3Chemical constitutionThyroid hormones2021/7/19 星期一6甲狀腺激素的化學(xué)結(jié)構(gòu)2021/7/19 星期一7Physiological disposition of thyroid hormonesAbsorbed rapidly when take orally , activity T3T4，maintaining t

5、ime 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 milk.Figure: the amount of normal adults thyroid hormones prod

6、uced and metabolized daily.2021/7/19 星期一8Synthesis, storage and regulation of thyroid hormonesIodine uptakeIodine activation and tyrosine iodationCondensation and storageDisintegration and releaseRegulation2021/7/19 星期一9Steps of thyroid hormones synthesis, release and regulation ()Iodine uptake: I i

7、n 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.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 for

8、ms monoiodotyrosine (MIT) and diiodotyrosine (DTT).2021/7/19 星期一10Condensation 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 int

9、o 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 a

10、nd thyroid synthesize T3 , T4.Steps of thyroid hormones synthesis, release and regulation ()2021/7/19 星期一11Synthesis, storage and release of thyroid hormone Gastrointestinal I-Blood I-I-PeroxidaseIoTGTyrIodationMITDITCon-den-sationMIT+DITDIT+DITT3T4TGAcinar luminaStorageSynthesisReleaseActivationPro

11、teaseT3T4MIT 一碘酪氨酸DIT 二碘酪氨酸TG 甲狀腺球蛋白blood2021/7/19 星期一12Thyroid hormonesMechanism of actionThe 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

12、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.2021/7/19 星期一13Mechanism of action（figure)It is believed now that the thermogenic action of T3 and T4 is due to the in

13、crease of sodium pumps activity on the cell membrane . Na+,K+ATPase activity ATP utilization ADP concentration mitochondria respiration oxide consumption and heat productionThyroid hormones2021/7/19 星期一14Physiological and pharmacological actions Keep normal growth and development Promote synthesis o

14、f 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. Promote metabolism and increase heat production Promote oxidation, increase oxygen consumption, basal metabolic rate and heat produ

15、ction. Elevate sensitivity of sympathetic - adrenal system Nervousness, trembling, heartbeat speed up, blood pressure increase2021/7/19 星期一15Thyroid clinical applicationReplacement therapy mainlyTherapy and diagnosis Application Cretinism Treating the infants and children as soon as possible could c

16、ure 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 is infusion of T3 （40-120g）intravenoiusly , reinjection 515g

17、 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 Pa

18、tients with iodine high uptake. 2021/7/19 星期一16Adverse effectsAdverse effectOverdoseCombinationContraindicationhyperthyreosisold people heart diseasebishydroxycoumarindantina or aspirindiabetes hypertensionCoronary heart diseasepyknocardiathyroid crisis: anxiety, fear, restlessness, high body temper

19、ature, increase and irregular heart rate, increase pulse pressure, congestive heart failure with vomit, diarrhea and dehydration which lead to coma and deathAngina or heart infarctionIncrease toxicity of thyroid hormone2021/7/19 星期一17Antithyroid DrugsTherapies of hyperthyrosis include 131I radiother

20、apy, 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.2021/7/19 星期一18硫脲類硫氧嘧啶類：甲基硫氧嘧啶丙基硫氧嘧啶咪唑類他巴唑（又稱甲巰咪唑）甲亢平（又稱卡比馬唑）2

21、021/7/19 星期一19ThioureaPhysiological processAbsorption: 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 effective with T1/2 of 2h. Imidazol

22、e 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 urine in a conjugative form. Ca

23、rbimazole functions after turning into tapazole in vivo. 2021/7/19 星期一20Pharmacological actionsInhibit peroxydase in adenocytes , which results in the 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

24、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 T4, which feedback increases the secretion of TSH and makes thyroid hyperplasy and hyperemic compensatorily.Propylthiouracil can inhibit T4 turning to T3

25、 and control T3 level in blood . So it is the first choice in hyperthyroidism crisis, severe hyperthyroidism and pregnant hyperthyroidism.Inhibit immuno-system (as hyperthyroidism is related with abnormal immunoreactions).Thiourea2021/7/19 星期一21Pathogenesis of Exophthalmos hyperthyroidism and functi

26、on link of thiourea homologuesThis 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

27、also LATS in patients, which is a kind of immuno inhibition.2021/7/19 星期一22ThioureaClinical applicationHyperthyroidism For who has mild symptoms and is not suitable to have operations and 131I radiotherapy. Give Larger dose at the beginning. After 13 months, symtoms decreased and basal metabolic rat

28、e 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 decrease bleeding in operation and prevent thyroid crisis after operation.Adjunctive med

29、ication of thyroid crisis Besides integrate measures, large dose of Thiourea homologues can be used as adjunctive therapy, So is Propranolol.2021/7/19 星期一23Comparison among common thiourea homologues drugs drug potencytherapeutic dose maintenance adverse effects agranulemia (mg/d)dose incidence(%) i

30、ncidence(%)mild moderate severe (mg/d)Methyl 1200-300400-60013.80.5thiouracil 300-40050-100Propyl0.753.30.4thiouracilTapazole 1020-3040-607.10.1Carbimazole1030-405-101.90.82021/7/19 星期一24ThioureaAdverse effects Although there are lots of adverse effects of thiourea homologues, incidences of propylth

31、iouracil 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. The medication shoule be stopp

32、ed if the symptoms as pharyngalgia, fever, cathaeresis occur. Thyroid cancer patients are forbidden to take.2021/7/19 星期一25Iodine and iodideActions and applicationsLow dose of iodine (physiological dose) could prevent and cure simple (endemicity) goiter. Add 1/100001/100000 potassium iodide or sodiu

33、m 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 adjunctive therapy for hyperthyroidism: preparation before operation: administration of aqueous iodine solution two weeks before operation degenerate

34、s the glandular tissue, decreases vessels and bleeding; adjunctive therapy for thyroid crisis: could be used combined with thiourea homologues.2021/7/19 星期一26Iodine and iodide Adverse effects and application notes Acute effects: acute circumscribed edema，laryngeal edema and apnoea.Chronic toxicity:

35、mouth and throat burning sensation, increase 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.Alle

36、rgic and active tuberculosis patients are forbidden to take. 2021/7/19 星期一27Radioactive iodine（131I）T1/2 is 8.04 daysActions 131I could be uptaken by throid , participate in the synthesis of T3, T4 and is stored in follecular colloid.131I mainly generatesray （99）with average and maximum path of 0.5m

37、m 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 vitro. It is usually used in the examination of thyroid iodine uptaking function

38、.2021/7/19 星期一28Radioactive iodine（131I）Clinical applicationThyroid iodine uptake function examination: iodine uptake rate high when hyperthyroid, time of iodine uptake peak antelocation iodine uptake rate low when hypothyroid , time of iodine uptake peak retroposition HyperthyroidismTrace amount could be used in diagnosis of thyroid functional status and thyroid adenoma .20