Thyroid hormones and antithyroid drugs Shi-Hong Zhang ( 张世红 )

Front view Thyroid gland

Biosynthesis of thyroid hormones 1. Uptake of iodide 2. Oxidation of iodide (peroxidase) and iodination and coupling of tyrosine 3. Formation of thyroxine (T 4 ) and triiodothyronine (T 3 ) from iodotyrosine (peroxidase) 4. Secretion of thyroid hormones (proteolytic enzymes) 5. Regulation by thyroid stimulating hormone (TSH), T 4, T 3

三碘甲状腺原氨酸 四碘甲状腺原氨酸

甲状腺素的生理及药理作用 1 ．维持生长发育 2 ．促进代谢和产热 3 ．提高交感神经系统的敏感性

Hypothyroidism cretinism ( 呆小症 ) 瘿 simple goiter ( 单纯性甲状 腺肿 ) Hypothyroidism After treatment

Hyperthyroidism 颤抖 腱反射亢进 心慌，心脏肥大 甲状腺肿大，突眼，情绪激动 多食、腹泻、消瘦

Hypothyroidism: iodine and iodides ( small doses); thyroid hormone Therapeutic drugs on thyroid dysfunction 1 甲状腺功能低下：呆小病；黏液性水肿（甲状腺功能减退）； 不典型及亚临床型甲状腺功能减退；甲状腺切除术后 2 单纯性甲状腺肿 3 T 3 抑制试验（服用 T 3 后摄碘率下降 50% 者为单纯性甲状腺肿， <50% 者为甲亢） 甲状腺素的临床应用

Hypothyroidism: – thyroid hormones – iodine and iodides ( 小剂量 ) Hyperthyroidism: – antithyroid drugs: thiourea derivatives 硫脲类 iodine and iodides 碘和碘化物 （大剂量）  receptor antagonists Radioiodines 放射性碘 : 131 I Therapeutic drugs on thyroid dysfunction

( 硫代酰胺；硫脲类 )

丙硫氧嘧啶 PTU 卡比马唑，甲亢平 甲巯咪唑，他 巴唑 MMI Thiourea derivatives Antithyroid drugs 硫脲类

Thiourea derivatives 1. Pharmacological effects (1) Inhibit the formation of thyroid hormones by interfering with iodination: competing peroxidation, then the iodination and coupling Symptom relieving: 2-3 weeks Basic metabolic rate returning: 1-2 months (2) Inhibit peripheral deiodination of T 4 : T 4  T 3  (propylthiouracil 丙硫氧嘧啶 ), rapid remission of hyperthyroidism due to T3 upregulation. Antithyroid drugs

Thiourea derivatives 1. Pharmacological effects (3) Inhibit glucose metabolism by down- regulating β receptor (4) Immunosuppression: TSI↓ Antithyroid drugs

2. Clinical uses (1) Non-operative therapy of hyperthyroidism: long duration (1- 2y) (2) Preoperative therapy of hyperthyroidism: combined with large dose of iodide (3) Thyrotoxic crisis: propylthiouracil, combined with large dose of iodide, 3. Adverse effects (1)Hypersensitivity (2)Agranulocytosis (0.2% or more) (3) GI reactions (4) Goitrogenic action (goiter): TSH↑ Thiourea derivatives

Iodine and iodides 1. Pharmacological effects (1) Small doses: simple goiter (2) Large doses for short term use: inhibit the synthesis and release of thyroid hormone (proteolysis  ) by inhibiting peroxidase and GSH reductase. After iodide use, the thyroid vascularity is reduced, and the gland becomes much firmer, the cells become smaller. Antithyroid drugs

2. Clinical uses (1) Simple goiter (small doses) (2) Preoperative therapy of hyperthyroidism: combined with thiourea derivatives (3) Thyrotoxic crisis: combined with thiourea derivatives (propylthiouracil) Lugol’s solution 卢戈氏液 : 5% iodine and 10% potassium iodide Antithyroid drugs

3. Adverse effects (1) Acute effects: hypersensitivity, angioedema, swelling of the larynx (2) Chronic intoxication (iodism) (3) Thyroid dysfunction: exacerbation of hyperthyroidism, goiter Antithyroid drugs

21 Radioiodines 131 I, 125 I, 123 I Destroying thyroid tissue: βray Careful use for hyperthyroidism and differentiated thyroid carcinoma Radioactive iodine uptake test Antithyroid drugs

 receptor antagonists 1. Pharmacological effects (1) Heart:  1 block (2) CNS: relieving anxiety (3) Presynaptic  2 receptor: NE release  (4) Decrease T3: inhibit deiodination of T4 2. Clinical uses Adjuvant therapeutic drug Antithyroid drugs

Case report A 47-year-old woman consulted her physician because of heart palpitations, tremulousness, weight loss and heat tolerance. Examination: heart rate 110, BP 150/70, diffusely enlarged thyroid glands, wide-eyed stare, lid lag, FT4 40 pmol/L (normal: 10-31), FT pmol/L(normal: 4-10), TSH undetectable (2-10 mU/L), TSI ( 甲状 腺刺激性免疫球蛋白 )↑. The diagnosis was Graves’s disease.

Case report Continued She was started on treatment with propranolol, 40 mg tid, propylthiouracil ( 丙硫氧嘧啶 ) 200 mg bid. She became euthyroid ( 甲状腺功能正常 ) in 6 weeks, and the propranolol dose was gradually reduced and finally discontinued. She continued receiving a maintenance dose of propylthiouracil (50 mg bid) for 1 year, after which the drug was discontinued.

Case report Continued The symptoms of hyperthyroidism recurred 3 years later, and treatment with propranolol and propylthiouracil was reinitiated. However, she developed severe rash over her whole body. Therefore, the treatment was changed with oral Na 131 I for definitive control of her hyperthyroidism.

Case report Continued Three months later, the patient complained of lethargy, tiredness, a feeling of coldness at room temperature, puffiness ( 肿胀 ) around the eyes, and constipation. Laboratory testes showed lowered level of T4 and T3, but elevated level of TSH, confirming the diagnosis of hypothyroidism. She was started on levothyroxine 0.1 mg daily, and 6 weeks later, her complaints disappeared. She has remained well on this therapy.