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Thyroid and Antithyroid Drugs Thyroid Gland Secretes: Tetraiodothyronine (T4) [Thyroxine] Triiodothyronine (T3) o T3 and T4 normalise growth development, body temperature and energy levels Calcitonin o Regulation of calcium metabolism Biosynthesis of Thyroid Hormone 1. Transportation of iodide into thyroid gland by the sodium/iodide symporter (NIS) 2. Iodide is oxidised to iodine by thyroidal peroxidase. Iodine rapidly iodinates tyrosine residues to form monoiodotyrosine (MIT) and diiodotyrosine (DIT) 3. Two DIT combine to form T4 (L-Thyroxine); 1 MIT plus one DIT combine to form T3 4. Secretion of thyroid hormone Metabolism The primary pathway for peripheral metabolism of T4 is deiodination Monodeiodination of the outer ring produces 3,5,3-triiodothyronine (T3), which is 3 to 4 times more potent than T4 Deiodination in the inner ring produces 3,3,5-triiodothyronine (rT3), which is metabolically inactive Ipodate, -blockers, corticosteroids, severe illness or starvation inhibit 5-deiodinase (necessary for the conversion of T4 to T3) resulting in low T3 and high rT3 Pharmacokinetics Given orally T4 best absorbed in the duodenum and ileum Oral bioavailability: T4 (80%), T3 (95%) Can also be administered intravenously Metabolism of both T4 and T3 is increased by drugs that induce hepatic microsomal enzymes (eg, rifampicin, phenobarbital, carbamazepine, phenytoin) Mechanism of Action Free forms of T4 and T3 enter the cell by diffusion or active transport T4 is converted to T3 by 5-deiodinase T3 enters the nucleus and binds to specific T3 receptor protein Lead to increased formation of RNA and subsequent protein synthesis Effects of Thyroid Hormones Responsible for optimal growth, development, function and maintenance of all body tissues Critical for nervous, skeletal and reproductive tissues Thyroid deprivation in early life results in irreversible mental retardation and dwarfism Have a great influence on the metabolism of drugs, carbohydrates, fats, proteins and vitamins Influence the secretion and degradation of almost all other hormones Hypothyroidism Decreased basal metabolic rate Slow speech Deep hoarse voice Lethargy Bradycardia Mental impairment Causes of Hypothyroidism Iodine deficiency Autoimmune disease Drugs (lithium) Post irradiation Management of hypothyroidism Drug-induced hypothyroidism is treated by removing the depressant agent All other forms are managed by replacement therapy Most satisfactory preparation is thyroxine (T4) Adult, initially 50-100mcg (od) before breakfast for 4 weeks, then increase by 25-50mcg every 4 weeks until euthyroid Hyperthyroidism

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Increased basal metabolic rate Heat intolerance Exophthalmos Increased inotropic and chronotropic effects Arrythmias Causes of Hyperthyroidism Autoimmune disease Tumours/Nodular growth TSH secreting tumours Drugs (amiodarone) Thyroditis (viral) Management of Hyperthyroidism Radioactive iodine: Iodine isotope 131I Given orally rapidly absorbed taken up by the gland Emits and rays ( rays cytotoxic; T1/2 = 5 days; penetration range = 400-2000 m) Beneficial effects take 1-2 months Advantages: easy administration, effectiveness, low cost, absence of pain Side effects: Hypothyroidism; not recommended in children and pregnant women

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Thioureylenes - Thioamides Carbimazole, methimazole, propylthiouracil Methimazole is 10 times more potent than propylthiouracil Carbimazole is converted to methimazole in vivo Inhibit thyroid peroxidase catalysed reaction and block iodine organification Inhibit peripheral deiodination of T4 to T3 Delayed response due to large hormone stores Given orally Thioureylenes - Thioamides T1/2: propylthiouracil = 1,5 hrs; methimazole = 6 hrs T1/2 has little effect on duration of antithyroid action since they accumulate in the gland Cross placenta/ appear in breast milk Propylthiouracil is preferable in pregnancy Excreted in urine Side effects: rashes, headaches, nausea, jaundice, agranulocytosis Iodine/iodide Lugols iodine (Potassium iodide) Given orally Inhibit organification and hormone release Rapid improvement: 2-7 days Decrease the vascularity of the hyperplastic gland in 10-15 days (useful in preparation for surgery) Iodine/iodide Useful in thyroid storm Good for adjunct therapy Side effects: Allergies Cross placenta thus chronic use in pregnancy should be avoided Other Drugs Beta Blockers - Propranolol Decrease signs and symptoms Useful in preparation for surgery Treatment of thyroid storm 20-40 mg orally 6-8 hourly Diltiazem 90-120 mg tds or qid where propranolol is contraindicated Other Drugs

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Guanethidine N.A. blocker eye drops to decrease exophthalmos Barbiturates Accelerate T4 breakdown Adequate nutrition and vitamin supplements