甲状腺激素和抗甲状腺药Thyroid

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SummaryThyroid 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 It can be treated with radioactive iodine(131I)irradation,antithyroid drugs and operation.Thyroid hormonesThyroxine,T4Triiodothyreninum natricum,T3Synthesized 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）Thyroid hormones are iodic amino acidsActive components Thyroxine,T4 Triiodothyreninum natricum,T3Chemical constitutionThyroid 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 hormonesFAbsorbed rapidly when take orally,activity T3T4，maintaining time T4T3.T1/2 of T4 and T3 are 67 days and 12 days,respectively.FDeiodination in mitochondria of liver and kidney,eliminated by kidney affer conjugated with glucuronic acid and sulfuric acid.FT3,T4 can also pass the placenta and enter milk.FFigure:the amount of normal adults thyroid hormones produced and metabolized daily.Synthesis,storage and regulation of thyroid hormonesIodine uptakeIodine activation and tyrosine iodationCondensation and storageDisintegration and releaseRegulationSteps of thyroid hormones synthesis,release and regulation()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.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 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 Steps of thyroid hormones synthesis,release and regulation()Synthesis,storage and release of thyroid hormone Gastrointestinal I-Blood I-I-PeroxidaseIoTGTyrIodationMITDITCon-den-sationMIT+DITDIT+DITT3T4TGAcinar luminaStorageSynthesisReleaseActivationProteaseT3T4MIT 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Thyroid 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 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.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 productionThyroid hormonesPhysiological and pharmacological actions Keep normal growth and developmentPromote 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.Promote oxidation,increase oxygen consumption,basal metabolic rate and heat production.Nervousness,trembling,heartbeat speed up,blood pressure increaseThyroid clinical applicationReplacement therapy mainlyTherapy 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 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 effectsAdverse effectOverdoseCombinationContraindicationhyperthyreosisold people heart diseasebishydroxycoumarindantina or aspirind i a b e t e s hypertensionCoronary heart diseasepyknocardiathyroid crisis:anxiety,fear,restlessness,high b o d y t e m p e r a t u r e,increase and irregular heart rate,increase pulse pressure,congestive heart f a i l u re w i t h v o m i t,diarrhea and dehydration which lead to coma and deathAngina or heart infarctionIncrease toxicity of thyroi d hormoneAntithyroid DrugsTherapies of hyperthyrosis include 131I radiotherapy,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.硫脲类硫脲类硫氧嘧啶类硫氧嘧啶类：甲基硫氧嘧啶丙基硫氧嘧啶咪唑类咪唑类他巴唑（又称甲巯咪唑）甲亢平（又称卡比马唑）ThioureaPhysiological 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.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 urine in a conjugative form.Carbimazole functions after turning into tapazole in vivo.Pharmacological 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 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 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).ThioureaPathogenesis of Exophthalmos hyperthyroidism and function 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 also LATS in patients,which is a kind of immuno inhibition.ThioureaClinical 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 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 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.Comparison among common thiourea homologues drugs drug potencytherapeutic dose maintenance adverse effects agranulemia (mg/d)dose incidence(%)incidence(%)mild moderate severe (mg/d)Methyl 1200-300400-60013.80.5thiouracil 300-40050-100Propyl0.753.30.4thiouracilTapazole 1020-3040-607.10.1Carbimazole1030-405-101.90.8ThioureaAdverse effects Although there are lots of adverse effects of thiourea homologues,incidences 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.The medication shoule be stopped if the symptoms as pharyngalgia,fever,cathaeresis occur.Thyroid cancer patients are forbidden to take.Iodine and iodideActions and applicationsLow 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 adjunctive 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.Iodine and iodide Adverse effects and application notes Acute effects:acute circumscribed edema，laryngeal edema and apnoea.Chronic toxicity: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.Allergic and active tuberculosis patients are forbidden to take.Radioactive 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 0.5mm 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 vitro.It is usually used in the examination of thyroid iodine uptaking function.Radioactive iodine（131I）Thyroid 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 HyperthyroidismwTrace amount could be used in diagnosis of thyroid functional status and thyroid adenoma.Radioactive iodine Adverse effects and application notesHypothyroidism is the predominant complication.The adverse effects can be reduced by strict dose control and resisted by thyrine.Patients with Total white blood cells less than 3000/mm3 are not suitable to take it.So are pragnant and lactant women,patients younger than 20 years old or with severe liver or kidney deseases.receptor blockersuValuable adjunctive therapy drugs for hyperthyroidism and thyroid crisis.They could improve symptoms caused by augmented sympathetic activity such as speed up heart rate and increase heart contraction force.They can also reduce the thyroid hormone secretion and T3 synthesis by inhibiting 5-deiodinase.uControl hyperthyroidism symptoms and can be used in preparation before operation.receptor blockersClinical applicationnAdjunctive therapy for hyperthyroidism and hyperthyroidism crisis.Mechanism of pharmacological actionsnExcited sympathetic-adrenergic system 1 receptor blockage heart rate drop Central receptor blockage to reduce anxiety 2 receptor on NA energinic peripheral nerve endings presynaptic membrane blockage reduces the release of NA.nAppropriately reduce T3,T4 secretion.Thanks!Thanks!。