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Hyperthyroid Disorders

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  • 1. Endocrinology 3a – Hyperthyroid Disorders 2 Anil Chopra 1. List the different possible causes of hyperthyroidism. 2. Describe the clinical features of hyperthyroidism, Graves’ disease and thyroid storm. 3. List and explain the different treatments available for hyperthyroidism and thyroid cancer. The following specific questions highlight some important pharmacological considerations:- 4. Drugs and Hyperthyroid Conditions. i) To which class of drugs does carbimazole belong? ii) Name another drug of the same class used to treat hyperthyroidism. iii) Using a labelled diagram of the steps in the synthesis of thyroid hormones (see diagram in handout) explain the mechanisms of action of the thiourylenes. iv) Using carbimazole as an example, explain the term 'pro-drug'. v) Describe the signs and symptoms which will disappear after treatment with thiourylenes. vi) Describe two situations in which hyperthyroid patients may be given large doses of potassium iodide. vii) Why is radioactive iodine an effective therapy for hyperthyroidism? viii) Name two drugs used in thyroid function tests. Hyperthyroidism Graves Disease  Autoimmune (IgG)  Antibodies bind to stimulate to the TSH receptor in the thyroid.  Causes smooth goitre Plummer’s Disease Different from Grave’s disease in that:  There is a toxic nodular goitre  It is NOT autoimmune  There is a benign adenoma that is overactive and makes thyroxine  No pretibial myxoedema present.  No exophthalmos seen.  There will be low TSH Thyroid Storm – a medical emergency. Any 2 of the following results in thyroid storm - 50% death if untreated.  Heart rhythm becomes irregular  Hyperpyrexia (body temperature above 41oC)  Accelerated tachycardia  Arrhythmia  Cardiac failure  Delirium/frank psychosis  Hepatocellular dysfunction; jaundice
  • 2. Symptoms:  Antibodies also bind to the muscles behind the eyes  causes exophthalmos (forward protrusion of eyeballs).  Pretibial myxoedema – thickening of skin on anterior lower leg.  Thyroid is larger – can cause goitre (smooth in Grave’s disease).  Palpitations  Sweating  Diarrhoea  Weight loss despite increased appetite.  Muscle wasting.  Breathlessness  Tachycardia  Heat intolerance due to increased temperature.  Lid lag – (Von Graefe's sign) lagging of upper eyelid in downward movement of eye  Tremor  Oligomenorrhoea / amenorrhoea in women.  Gynaecomastia in men.  Emotional liability  Feeling of fatigue  Hair loss
  • 3. Effects of Thyroxine:  Increases basal metabolic rate.  Weight loss despite increased appetite  Increase in temperature  Sensitises beta adrenoceptors to ambient levels of adrenaline and noradrenaline.  Thus there is apparent sympathetic activation  Tachycardia, palpitations, tremor in hands, lid lag e.t.c. Treatment Options - Surgery (thyroidectomy) o Removal of thyroid gland o Risk of loss of parathyroids causing hypocalcaemia o Have to take calcium every day o Damage to recurrent laryngeal nerve - Radioiodine (capsule of radioactive iodine) o Irradiates thyroid gland. - Drugs o Propanolol (β-blocker) o Carbimazole, Propylthiouracil (anti-thyroid drugs) - Some people have relapsing hyperthyroidism o Lifelong antithyroid drugs forever o Surgery o Radioiodine Viral (de Quervain’s) Thyroiditis A virus attacks the thyroid gland resulting in:  Painful dysphagia  Tenderness  Hyperthyroidism – the thyroid stops making thyroxine and makes virus instead  Pyrexia  Raised ESR The thyroid gland is no longer visible on a thyroid scan because of the lack of thyroxine being produced. There is no iodine uptake and so no thyroxine is going to be synthesised. After around 4 weeks, patients have hypothyroidism. After a month, when the virus is resolved, patients return back to normal thyroid function. Normal  1 month hyperthyroidism  1 month hypothyroidism  normal Thyroid Cancers ♦ Papillary (takes up radioiodine) ♦ Follicular (takes up radioiodine) ♦ Anaplastic (bad news) ♦ Medullary (rare) Both papillary and follicular cancers can be encouraged to grow by TSH. In this case a total thyroidectomy is needed with a large dose of radioiodine. Large amounts of thyroxine should also be given to stop the TSH production.
  • 4. Pharmacology Thiourylenes Names carbimazole & propylthiouracil Usage These are use to treat hyperthyroidism conditions such as diffuse toxic goitre/Graves disease/exophthalmic goitre. They are also used in treatment before surgery or during thyroid irradiation with radioiodine. Mode of Action Their mechanism of action is not clearly understood but it is thought that they work by inhibiting thyroperoxidase, inhibiting the action and production of antibodies in Grave’s disease and reducing conversion of T4 to T3 in peripheral tissues. Their clinical effects may take weeks because of hormone store in colloid.
  • 5. Side Effects • agranulocytosis/ granulocytopenia (reduction or absence of granular leukocytes) - rare and reversible on withdrawal of drug. • rashes (relatively common) • headaches • Tachycardia and tremor • nausea • jaundice • joint pain • Can be give with a β-blocker to stop the tachycardia and tremor Pharmacokinetics • Administered orally • Carbimazole is a pro-drug which first has to be converted to methimazole • Half life of 6-15 hours • Crosses placenta and is secreted in milk • Metabolised in liver and secreted in urine Name – Iodide Usage These are used mainly in thyrotoxicosis, thyroid storm and in preparation before surgery. Mode of Action Iodide is given in large doses (30 times that normally taken) and can inhibit the production of thyroid hormones. Inhibits the secretion of thyroid hormones in thyrotoxic patients. Inhibition of iodination of thyroglobulin by swamping with iodine. Also inhibits H2O2 generation.
  • 6. Side effects • Allergic reaction e.g. rashes, fever, angio-oedema Pharmacokinetics • Given orally, maximum effects after 10 days’ continuous administration Radioiodine Name - Radioiodine – 131I: Usage Used in hyperthyroidism to kill tumours. It is also used in very small doses to assess thyroid function. It works in that it imitates the action of iodine, but the radioisotope is selectively cytotoxic for thyroid cells. Mode of Action  Body processes isotope as for stable iodide; isotope concentrates in thyroid gland and becomes incorporated into thyroglobulin  Cytotoxic, almost selectively on thyroid follicular cells by virtue of irradiating β- particles which have a very short rage (γ- particles have a long range and pass straight through the tissue)  Negligible cytotoxicity when used as tracer doses for thyroid function tests Pharmacokinetics Give as a single dose (orally in Grave’s, orally or IV in tracer tests) Half life = 8 days Radioactivity negligible by 2 months Maximum effect after 2-3 months Side Effects Hypothyroidism Avoid in children and pregnant patients
  • 7. 50% of patients presenting with hyperthyroid Grave’s disease will go into remission after 18 months of treatment with drugs. In the 50% that do not go into remission there are 3 choices: Life long anti-thyroid drugs Radioiodine therapy Surgery – subtotal thyroidectomy. Risk of loss if parathyroids and associated hypocalcaemia and risk of damage to recurrent laryngeal nerve and voice damage