1. Thyroid and Antithyroid Drugs Peng Qing

2. Objectives You should: You should: - be able to describe the physiology of thyroid. - be able to describe the drugs used in the treatment of thyroid disorder including the mechanisms of action, clinical uses and adverse reactions.

3. Thyroid physiology Thyroid physiology Thyroid hormones includes tetraiodothyronine (T 4 ) and triiodothyronine(T 3 ). Thyroid hormones includes tetraiodothyronine (T 4 ) and triiodothyronine(T 3 ). Normalize growth and development, body temperature, and energy levels. These hormones contain 65% and 59% (respectively) of iodine as an essential part of the molecule. Normalize growth and development, body temperature, and energy levels. These hormones contain 65% and 59% (respectively) of iodine as an essential part of the molecule.

4. Thyroid physiology Calcitonin, the second type of thyroid hormone, is important in the regulation of calcium metabolism Calcitonin, the second type of thyroid hormone, is important in the regulation of calcium metabolism

5. Iodide Metabolism Iodide Metabolism Iodide (I - ) intake is via the gastrointestinal tract from food, water, or medication. Iodide (I - ) intake is via the gastrointestinal tract from food, water, or medication. The recommended daily adult intake is 150μg (200μg during pregnancy). The recommended daily adult intake is 150μg (200μg during pregnancy). The thyroid gland takes up about 75μg a day for hormone secretion. The thyroid gland takes up about 75μg a day for hormone secretion.

6. Thyroid physiology

7. Biosynthesis of Thyroid Hormone Biosynthesis of Thyroid Hormone 1. Iodide trapping( 摄取 ): iodine pump, 2. Iodide organification (Iodide activation and Tyrosine iodized): iodide is oxidized by thyroidal peroxidase( 过氧 化酶 ) to iodine, in which form it iodinates tyrosine residues ( 酪氨酸残基 ) within the thyroglobulin molecule to form monoiodotyrosine (MIT) and diiodotyrosine (DIT). 3. Combine: DIT+DIT→T 4, DIT+MIT →T 3. 4. Release: proteolysis and exocytosis. T 4 ＞ 90%.  The process of proteolysis is also blocked by high levels of intrathyroidal iodide.

8. Control of Thyroid Function Control of Thyroid Function 1. Hypothalamic(TRH)- Pituitary (TSH)- Thyroid (T 4 and T 3 ). 2. Autoregulation of the thyroid gland: related to the level of iodine in the blood.

9. Peripheral Metabolism of Thyroid Hormones

10. BASIC PHARMACOLOGY OF THYROID & ANTITHYROID DRUGS

11. Thyroid hormones Chemistry The synthetic dextro (D) isomer of thyroxine, dextrothyroxine, has approximately 4% of the biologic activity of the L isomer as evidenced by its lesser ability to suppress TSH secretion and correct hypothyroidism. Chemistry The synthetic dextro (D) isomer of thyroxine, dextrothyroxine, has approximately 4% of the biologic activity of the L isomer as evidenced by its lesser ability to suppress TSH secretion and correct hypothyroidism.

12. Physiological and Pharmacological Effects 1. Maintain normal growth and development: critical for nervous, skeletal, reproductive tissues. Depend upon protein synthesis.  Child —— cretinism( 呆小病, 克汀病 ): irreversible mental retardation( 智力低下 ) and dwarfism( 矮小 )  Adult —— myxedema( 粘液性水肿 ): 2. Promote energy metabolism and calorigenesis: basal metabolic rate (BMR) ↑ 3. Sympathetic nervous system overactivity: increase numbers of β- receptor or enhanced amplification of the β receptor signal

13. Pharmacokinetics Rapidly absorbed when taken orally, but the absorption rate of T 4 was affected by intestinal contents. Rapidly absorbed when taken orally, but the absorption rate of T 4 was affected by intestinal contents. Oral bioavailability of current preparations of L- thyroxine averages 80%. In contrast, T3 is almost completely absorbed (95%) Oral bioavailability of current preparations of L- thyroxine averages 80%. In contrast, T3 is almost completely absorbed (95%) T3 is not recommended for routine replacement therapy because of its shorter half-life. T3 is not recommended for routine replacement therapy because of its shorter half-life. Malabsorption when taken orally in severe myxedema( 粘液水肿 ). Malabsorption when taken orally in severe myxedema( 粘液水肿 ).

14. Mechanism of Action Gene effects: Gene effects: T 3 nuclear receptor → mRNA → protein synthesis (eg, Na + /K + ATPase) T 3 nuclear receptor → mRNA → protein synthesis (eg, Na + /K + ATPase) Non-gene effects: Non-gene effects: Receptors in cell membrane, mitochondrion( 线粒 体 ), ribosome( 核蛋白体 ) → influencing post- transcriptional process, energy metabolism, transportation of membrane. Receptors in cell membrane, mitochondrion( 线粒 体 ), ribosome( 核蛋白体 ) → influencing post- transcriptional process, energy metabolism, transportation of membrane.

15. The affinity for T 4 is about ten times lower than that for T 3. The affinity for T 4 is about ten times lower than that for T 3. The number of nuclear receptors may be altered to preserve body homeostasis( 内环境 稳定 ). eg, starvation, malnutrition, obesity→ R↓ The number of nuclear receptors may be altered to preserve body homeostasis( 内环境 稳定 ). eg, starvation, malnutrition, obesity→ R↓

16. Clinical Uses 1. Cretinism( 呆小病, 克汀病 ) 2. Myxedema( 粘液性水肿 ) 3. Simple goiter( 单纯性甲状腺肿 ), Suppression of TSH

17. Thyroid Preparations Synthetic or of animal origin. Synthetic or of animal origin. Synthetic levothyroxine is the preparation of choice for thyroid replacement and suppression therapy because of its stability, content uniformity, low cost, lack of allergenic foreign protein, easy laboratory measurement of serum levels, and long half-life (7 days). Synthetic levothyroxine is the preparation of choice for thyroid replacement and suppression therapy because of its stability, content uniformity, low cost, lack of allergenic foreign protein, easy laboratory measurement of serum levels, and long half-life (7 days).

18. Adverse Reactions Palpitation( 心悸 ), hand tremor, sweating, lose weight, insomnia( 失眠 ). Palpitation( 心悸 ), hand tremor, sweating, lose weight, insomnia( 失眠 ). Diarrhea, vomiting, fever, angina pectoris( 心绞 痛 ) —— β-blocker Diarrhea, vomiting, fever, angina pectoris( 心绞 痛 ) —— β-blocker

19. Antithyroid agents Thioureas (thioamides) Thioureas (thioamides) Iodine / iodide Iodine / iodide Iodine-131 ( 131 I) Iodine-131 ( 131 I) β-adrenoceptor antagonists β-adrenoceptor antagonists

20. Thioureas Classification: 1. Thiouracils: methlthyiouracil (MTU), propylthiouracil (PTU) 2. Imidazoles: methimazole (tapazole), carbimazole

21. Pharmacokinetics PTU is rapidly absorbed, reaching peak serum levels after 1 hour. The bioavailability of 50- 80%. PTU is rapidly absorbed, reaching peak serum levels after 1 hour. The bioavailability of 50- 80%. Methimazole is completely absorbed. It is readily accumulated by the thyroid gland and has a volume of distribution similar to that of PTU. Methimazole is completely absorbed. It is readily accumulated by the thyroid gland and has a volume of distribution similar to that of PTU. Cross the placental barrier and are concentrated by the fetal thyroid. Cross the placental barrier and are concentrated by the fetal thyroid.

22. Mechanism of action Prevent hormone synthesis by inhibiting the thyroid peroxidase-catalyzed reactions and blocking iodine organification. In addition, they block coupling of the iodotyrosines. Prevent hormone synthesis by inhibiting the thyroid peroxidase-catalyzed reactions and blocking iodine organification. In addition, they block coupling of the iodotyrosines. Inhibit the peripheral conversion of T4 to T3. Inhibit the peripheral conversion of T4 to T3. Since the synthesis rather than the release of hormones is affected, the onset of these agents is slow, often requiring 3-4 weeks before stores of T4 are depleted. Since the synthesis rather than the release of hormones is affected, the onset of these agents is slow, often requiring 3-4 weeks before stores of T4 are depleted.

23. Clinical Uses 1. therapy of hyperthyroidism( 甲亢 ): 1~2 year of treatment course. 2. preoperative preparation of thyroidectomy: adding iodine / iodide. 3. therapy of thyroid crisis: large dose iodine / iodide + PTU

24. Toxicity Allergic reaction: maculopapular ( 斑丘疹的 ) pruritic ( 搔痒 ) rash (4-6%), accompanied by fever. Allergic reaction: maculopapular ( 斑丘疹的 ) pruritic ( 搔痒 ) rash (4-6%), accompanied by fever. Nausea and gastrointestinal distress. Nausea and gastrointestinal distress. Agranulocytosis( 0.1-0.5%) Agranulocytosis( 0.1-0.5%) Goiter ( 甲状腺肿 ) and hypothyroidism: Goiter ( 甲状腺肿 ) and hypothyroidism:

25. Iodine / iodide Liguor iodine Co (Lugol ’ s solution): Liguor iodine Co (Lugol ’ s solution): 5% iodine + 10% KI 5% iodine + 10% KI KI or NaI KI or NaI

26. Pharmacological Effect Pharmacological Effect Small dose: prevent simple goiter. iodised salts 20mg/kg-30mg/kg Small dose: prevent simple goiter. iodised salts 20mg/kg-30mg/kg Large dose(>6mg/d): Large dose(>6mg/d): 1. Inhibit thyroid hormone release: inhibit glutathione reductase ( 谷胱甘肽还原酶 ) → GSH↓ 2. Inhibit thyroid hormone synthesis: inhibit thyroidal peroxidase → tyrosine iodized and combining ↓ 3. Decrease the size and vascularity of the hyperplastic( 增生的 ) gland: anti-TSH

27. Clinical Uses Clinical Uses 1. preoperative preparation of hyperthyroidism 2. therapy of thyroid crisis: large dose iodine / iodide + PTU 3. radiation emergencies

28. Adverse Reactions: Adverse Reactions: 1. Common response: metallic taste, rhinorrhea ( 鼻溢液 ), conjunctivitis ( 结膜炎 ), swollen salivary glands, mucous membrane ulcerations, bleeding disorders. 2. Inducing thyroid function disturbance:  hyperthyroidism or hypothyroidism  crossing the placenta and entering milk → influencing newborn or infant thyroid function.

29. Radioiodine 131 I, t 1/2 =8d. 131 I, t 1/2 =8d. Administered orally in solution as sodium 131 I. Rapidlly absorbed. Concentrated by the thyroid. Administered orally in solution as sodium 131 I. Rapidlly absorbed. Concentrated by the thyroid.

30. Pharmacologic Effects Pharmacologic Effects β rays (99%), penetration range of 2mm, destruction of the thyroid parenchyma ( 实质 ). β rays (99%), penetration range of 2mm, destruction of the thyroid parenchyma ( 实质 ). γrays (1%), can be monitored out of the body — — thyroid iodine uptake. γrays (1%), can be monitored out of the body — — thyroid iodine uptake.

31. Clinical uses Clinical uses 1. Determination of thyroid iodine uptake: 2. therapy of hyperthyroidism: Advantages of radioiodine include easy administration, effectiveness, low expense, and absence of pain. Advantages of radioiodine include easy administration, effectiveness, low expense, and absence of pain.

32. Fears of radiation-induced genetic damage, leukemia, and neoplasia. Fears of radiation-induced genetic damage, leukemia, and neoplasia. large dose → hypothyroidism large dose → hypothyroidism Not for patient less than 20y, pregnant women or nursing mothers, and renal malfunction; thyroid crisis, severe infiltrative exophthalmos( 突眼 ), and thyroid iodine non-uptake. Not for patient less than 20y, pregnant women or nursing mothers, and renal malfunction; thyroid crisis, severe infiltrative exophthalmos( 突眼 ), and thyroid iodine non-uptake.

33. β- adrenoceptor antagonists Beta blockers cause clinical improvement of hyperthyroid symptoms but do not typically alter thyroid hormone levels. Beta blockers cause clinical improvement of hyperthyroid symptoms but do not typically alter thyroid hormone levels. β- adrenoceptor antagonists without intrinsic sympathomimetic ( 拟交感 ) are the agents of choice. β- adrenoceptor antagonists without intrinsic sympathomimetic ( 拟交感 ) are the agents of choice. Propranolol at doses greater than 160 mg/d may also reduce T3 levels approximately 20% by inhibiting the peripheral conversion of T4 to T3. Propranolol at doses greater than 160 mg/d may also reduce T3 levels approximately 20% by inhibiting the peripheral conversion of T4 to T3.

34. Advantages: Advantages: 1. Influence to thyroid function tests is low. 2. No interference to the effect of thioureas on thyroid. 3. Not increase the size and fragility of the gland Clinical Uses 1. Hyperthyroidism: 2. thyroid crisis: i.v. 3. preoperative preparation: β- adrenoceptor antagonist + PTU + large dose iodine / iodide

35. Summary Thyroid hormone Thyroid hormone Antithyroid drugs Antithyroid drugs Thioureas (thioamides) Thioureas (thioamides) Iodine / iodide Iodine / iodide Iodine-131 ( 131 I) Iodine-131 ( 131 I) β-adrenoceptor antagonists β-adrenoceptor antagonists