1. Drugs and the thyroid Dr Emma Baker Senior Lecturer in Clinical Pharmacology

2. Case 1. 60 year old woman Tired, loss of energy, feels the cold Constipated On examination –croaky voice, slow relaxing reflexes –Pulse 48bpm Question –What is your differential diagnosis?

3. Investigations TSH 10mU/L (0.5 - 4) Free T4 5pmol/L (12-25pmol/L) Cholesterol 8.5mmol/l(desirable <5.2) Question –How do you explain these results?

4. Thyroid hormones Tyrosine Monoiodotyrosine Diiodotyrosine Thyroxine (T4) 3,3,5 triiodothyronine rT3 3,3,5 triiodothyronine T3 Thyroid gland IODINE Thyroid binding globulin T4 Negative feedback Hypothalamus Pituitary TRH TSH Hypothyroid Stored as thyroglobulin in thyroid gland

5. How would you treat this condition? How quickly would you expect the treatment to work? What precautions would you take when starting treatment? Questions

6. Thyroid replacement Thyroxine (T4) or rarely Liothyronine (T3) Pharmacokinetics –well absorbed when given by mouth –T4 takes 10 days to reach max. effect and wears off after 2-3 weeks –T3 has max. effect 1 hour, wears off in 1 week Pharmacodynamics –Increases metabolic rate, oxygen consumption, sensitivity to catecholamines

7. Thyroid replacement - 2 Thyroxine can precipitate: –angina –atrial fibrillation –heart failure Start at low dose and increase slowly Monitor treatment with TSH - WHY?

8. Thyroid hormones Tyrosine Monoiodotyrosine Diiodotyrosine Thyroxine (T4) 3,3,5 triiodothyronine rT3 3,3,5 triiodothyronine T3 Thyroid gland IODINE Thyroid binding globulin T4 Negative feedback Hypothalamus Pituitary TRH TSH Thyroxine replacement

9. Case 2. 30 year old man Weight loss, diarrhoea, palpitations On examination –Hot and sweaty –Pulse 130bpm, BP 180/80mmHg Question –What is your differential diagnosis?

10. Investigations TSH <0.1mU/L (0.5 - 4) Free T4 40pmol/L (12 - 25) Do the investigations confirm your diagnosis?

11. Thyroid hormones Tyrosine Monoiodotyrosine Diiodotyrosine Thyroxine (T4) 3,3,5 triiodothyronine rT3 3,3,5 triiodothyronine T3 Thyroid gland IODINE Thyroid binding globulin T4 Negative feedback Hypothalamus Pituitary TRH TSH Hyperthyroid

12. Case 2 - continued How does your diagnosis explain his symptoms? –Weight loss, diarrhoea, tremor, palpitations How could you treat this patient? What is the quickest way to relieve his symptoms?

13. Treatment of hyperthyroidism Inhibit production of thyroid hormone by gland –Thionamines e.g. Carbimazole, propylthiouracil Removal of thyroid tissue –Surgery –Radioactive iodine Treat symptoms (thyroxine increases sensitivity to catecholamines) –Beta blockers

14. Drugs to treat hyperthyroidism Tyrosine Monoiodotyrosine Diiodotyrosine Thyroxine (T4) 3,3,5 triiodothyronine rT3 3,3,5 triiodothyronine T3 Thyroid gland IODINE Thyroid binding globulin T4 Negative feedback Hypothalamus Pituitary TRH TSH carbimazole propylthiouracil propylthiouracil Potassium iodide

15. Carbimazole and propylthiouracil Taken orally in once daily dose Inhibit production of T3/T4, therefore effect delayed until existing hormone stores depleted Clinical improvement: –starts in 1 week –euthyroid in 6 weeks, stop drug when euthyroid 4-6 months –50-70% relapse on stopping drug

16. Case 3. 48 year old woman Known thyrotoxicosis, on carbimazole Sore throat 24 hours On examination –Temp. 39oC, pulse 120bpm, inflamed ulcerated throat, skin rash Investigations –Hb 12g/dl (12-16), wcc 1 x 10 9 /L (4-11), platelets 180 x 10 9 /L (150 - 400) What is the diagnosis?

17. Adverse effects of thionamines Agranulocytosis –1 in 1000 treated patients –may be fatal - infection risk –reversible on stopping drug Rash GI upset Jaundice Alopecia

18. Recognition and treatment of agranulocytosis Recognition –can’t be predicted by monitoring –warn patient (verbal, leaflet) Treatment –stop drug –supportive therapy –treat hyperthyroidism by other means

19. Case 4. 28 year old woman Antenatal clinic appointment, 14 weeks pregnant. Anxious, palpitations On examination –thin –pulse 124bpm, BP 170/60mmHg Investigations –TSH < 0.1mU/L, Free T4 36pmol/l (12 - 25) What is the diagnosis What treatment would you recommend?

20. Case 4 - continued Started on carbimazole Asks you –“what is the risk to my baby if I take this treatment?” –“will I be able to breast feed” What would you tell her?

21. Hyperthyroidism in pregnancy MotherBaby TRH TSH T4 Thyroid TRH TSH T4 Thyroid Carbimazole Placenta Goitre

22. Case 5 - 29 year old woman Tired all the time On the pill, not pregnant On examination –pulse 96, hands cold and sweaty, slight tremor –small smooth palpable thyroid Total T4 180nmol/L (70 - 150) TSH 2.7mU/L (0.5 - 4) Is she thyrotoxic?

23. Thyroxine in the plasma Free thyroxine Thyroxine bound to thyroxine- binding globulin

24. Some drugs increase thyroxine-binding globulin and interfere with TFTs Free thyroxine unchanged Increased bound thyroxine (hence total T4 is increased) Oestrogens Clofibrate Neuroleptics

25. Free thyroxine unchanged Decreased bound thyroxine (hence total is decreased) Androgens Adrenocortical steroids Some drugs decrease thyroxine-binding globulin and interfere with TFTs

26. Case 5 - continued On the pill On examination –pulse 96, hands cold and sweaty, slight tremor –small smooth palpable thyroid Total T4 180nmol/L (70 - 150) TSH 2.7mU/L (0.5 - 4) If she is not thyrotoxic, how do you explain her findings?

27. Case 6. 58 year old man Chest pain, short of breath Thyrotoxic - treated with carbimazole for 8 months No treatment for 6 months On examination –pulse 112bpm, irregularly irregular –bibasal crepitations TSH <0.1mU/L (0.5-4), Free T4 36pmol/L (12- 25) What has happened?

28. Radioactive iodine 131 I, emits  and some  radiation which ablates gland Concentrated in thyroid gland - hence no ill effects on rest of body Taken orally, physical t1/2 8 days Beneficial effect in 1 month, action maximal after 3 months

29. Radioactive iodine continued Uses –hyperthyroidism (all ages) –Thyroid carcinoma or metastases if take up iodine selectively Adverse effects –Thyroid storm –Hypothyroidism (6-15% first year, 2-3%pa thereafter) –No evidence that it causes cancer - but avoid pregnancy for 6 months after dose

30. Finally.... Drugs causing unwanted hyperthyroidism –amiodarone –iodine-containing drugs if adenoma/hyperthyroid Drugs causing unwanted hypothyroidism –amiodarone –sulphonylureas –lithium –iodide - in large doses