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Thyroid and Anti thyroid drugs

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1 Thyroid and Anti thyroid drugs

2 Role of the Thyroid gland
participates in normalizing growth and development and energy levels and the proper functioning and maintenance of tissues / organs critical for the nervous, skeletal and reproductive tissues it affects secretion and degradation rates of all hormones

3 Function of the Thyroid Gland
secretion of the following hormones: triiodothyronine (T3) ; 59% iodine tetraiodothyronine (T4; also known as thyroxine); 65% iodine calcitonin

4 THYROID PHYSIOLOGY Iodide Metabolism Biosynthesis of Thyroid Hormones
The recommended daily adult iodide (I-) intake is 150 mcg Biosynthesis of Thyroid Hormones Transport of Thyroid Hormones thyroxine-binding globulin (TBG) about 0.04% of total T4 and 0.4% of T3 exist in the free form.

5 Biosynthesis of thyroid hormones
Figure Biosynthesis of thyroid hormones. The sites of action of various drugs that interfere with thyroid hormone biosynthesis are shown.

6 Biosynthesis of thyroid hormones

7 Steps in Biosynthesis Iodide trapping Oxidation of iodide to iodine
Iodide Organification Formation of T4 and T3 Release of T4 and T3

8 Peripheral metabolism of thyroid hormones
The primary pathway for the peripheral metabolism of thyroxine (T4) is deiodination  deiodination of T4 may occur by monodeiodination of the outer ring, producing 3,5,3'-triiodothyronine (T3), which is three to four times more potent than T4


10 Basic pharmacology of thyroid & antithyroid drugs Thyroid hormones
A model of thyroid hormone action is depicted in Figure 38-4 T3 and T4 are triiodothyronine and thyroxine, respectively. PB, plasma binding protein; F, transcription factor; R, receptor; PP, proteins that bind at the proximal promoter. Figure Regulation of transcription by thyroid hormones

11 Hypothyroidism A syndrome resulting from a deficiency of thyroid hormones and is manifested largely by a reversible slowing down of all body functions. There is a striking retardation of growth and development. In children, manifested as dwarfism and severe MR.

12 Synthetic Thyroid Hormone
synthetic levothyroxine (synthetic T4) Brand names: Eltroxin , Euthyrox,Levoxyl, Levothroid, Synthroid for hormone replacement therapy in hypothyroidism DOSE Infants and Children require more T4/Kg body weight than adults Average dose for an infant micrograms/kg/d Average dose for an adult – 1.7micrograms/kg/d Once daily Pharmacokinetics should be taken 30min before or 1 hour after meals (delayed absorption for soy, other foods and drugs) takes 6-8 weeks to reach steady state levels Labs should be repeated after 2 months

13 Synthetic Thyroid Hormone
reasons for its use: stability content uniformity low cost lack of allergenic foreign protein easy laboratory measurements of serum levels long half-life (7days) once a day dosing

14 Synthetic Thyroid Hormone
Uses Hormone replacement therapy In young patients or those with mild disease- full replacement therapy started In older patients and in patients with cardiac disease -start treatment with reduced dosage Myxedema Coma – medical emergency Loading dose – of T4 – micrograms I/V initially f/by `50micrograms daily I/V T3 – more cardiotoxic and difficult to moniter Hypothyroidism and Pregnancy – daily dose –adequate

15 Synthetic Thyroid Hormone
synthetic liothyronine (synthetic T3) is 3-4x more potent (Cytomel,Triostat) not used alone for long term treatment secondary to short half life and large peaks in serum T3 levels increase risk for cardiac side effects secondary to hyperthyroid states during treatment

16 Hyperthyroidism A thyroid disorder caused by an antibody- mediated auto-immune reaction, but the trigger for this reaction is still unknown most common cause of hyperthyroidism

17 Anti-thyroid Drugs Thioamides Iodides radioactive iodine
Beta adrenoceptor blocking agents

18 Mechanism of action of anti thyroid drugs

19 Biosynthesis of thyroid hormones
Figure Biosynthesis of thyroid hormones. The sites of action of various drugs that interfere with thyroid hormone biosynthesis are shown.

20 Thioamides Methimazole Propylthiouracil (PTU) Carbimazole MOA:
inhibit synthesis by acting against iodide organification (both) coupling of iodotyrosines (both) Blocks peripheral conversion of T4 to T3 (PTU)

21 Thioamides Pharmacokinetics: almost completely absorbed in the GIT
serum half life: 90mins(PTU) ; 6 hours (methimazole) excretion: kidney – 24 hours (PTU) ; 48 hours (Methimazole) can cross placental barrier (lesser with PTU) Methimazole 10x more potent than PTU PTU more protein-bound

22 Thioamide uses Definitive therapy Preoperatively Along with RAI
Graves disease Toxic nodular goitre Preoperatively In thyrotoxic patients Along with RAI

23 Thioamides Adverse Effects: maculopapular rash
benign transient leukopenia agranulocytosis hepatitis (PTU) ; cholestatic jaundice (Methimazole) vasculitis lupus-like syndrome

24 Iodine131 preparations: sodium iodide 131
MOA: trapped within the gland and enter intracellularly and delivers strong beta radiations destroying follicular cells Penetration range µm Clinical uses: Grave’s, primary inoperable thyroid CA Contraindication: pregnancy

25 Iodine131 Advantages Easy administration Effectiveness Low expense
Absence of pain

26 Iodine131 Thioamides should be given initially and stop 5-7 days before radioactive iodine administration 131I dosage generally ranges between uCi/g of estimated thyroid wt. corrected for uptake. May be repeated after 6 months Adverse effects permanent hypothyroidism potential for genetic damage may precipitate thyroid crisis

27 Anion Inhibitors Monovalent anions such as perchlorates, pertechnetate and thiocyanate can block uptake of iodide by the gland by competitive inhibition can be overcome by large doses of iodides useful for iodide-induced hyperthyroidism (amiodarone-induced hyperthyroidism) rarely used due to its association with aplastic anemia

28 Biosynthesis of thyroid hormones
Figure Biosynthesis of thyroid hormones. The sites of action of various drugs that interfere with thyroid hormone biosynthesis are shown.

29 Inorganic Iodines major anti-thyroids before the introduction of thioamides (1950s) preparations: strong iodine solution (Lugol’s) potassium iodide iodone

30 Inorganic Iodines MOA: inhibit iodide organification Uses: Caution:
acutely blocks release of thyroid hormone from the gland by inhibiting thyroglobulin proteolysis inhibit iodide organification Uses: useful in thyroid storms: 2-7 days Preoperatively - iodides decrease vascularity, size and fragility of hyperplastic gland Caution: it may delay onset of thioamide effects; should be given after initiation of thioamides The gland will escape from inhibition after 2-8 weeks.

31 Iodinated Contrast Media
Ipodate (oral) Iopanoic acid (oral) Diatrizoate (intravenous) valuable in hyperthyroidism (but is not labeled for this indication) MOA: inhibits conversion of T4 to T3 in the liver, kidney, brain and pituitary Another MOA is due to inhibition of hormone release secondary to iodide levels in blood Useful in thyroid storms (adjunctive therapy)

32 Beta Blockers Drugs: Propranolol, Metoprolol, Atenolol MOA:
Membrane-stabilizing action: inhibits T4 to T3 Ameliorate many disturbing s/sxs of hyperthyroidism secondary to increased circulating catecholamines by blocking beta receptors Indications: Grave’s, Thyroid storm

33 Corticosteroids Prednisone is given for patients with Grave’s ophthalmopathy 1mg/kg/day (60mg/day 3 divided doses); if it should be given for more than 4 weeks, taper to decrease risk of adrenal crisis

34 Thyroid storm Sudden exacerbation of throtoxic symptoms
Life threatening condition Vigorous management Propanalol 1-2mg i/v or 40-80mg PO Q6h Diltiazem mg Po Q8-6 hrs or 5-10mgs intravenous infusion/hour

35 Thyroid storm Supportive therapy Plasmapheresis/peritoneal dialysis
Potassium iodide Propylthiouracil Hydrocortisone Supportive therapy Plasmapheresis/peritoneal dialysis

36 Hyperthyroidism and Pregnancy
Ideal situation- treat before pregnancy Pregnancy-Radioactive iodine CI Propylthiouracil Dose limitation≤ 300mgs/day Methimazole alternative- fetal scalp defects

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