2Role of the Thyroid gland participates in normalizing growth and development and energy levels and the proper functioning and maintenance of tissues / organscritical for the nervous, skeletal and reproductive tissuesit affects secretion and degradation rates of all hormones
3Function of the Thyroid Gland secretion of the following hormones:triiodothyronine (T3) ; 59% iodinetetraiodothyronine (T4; also known as thyroxine); 65% iodinecalcitonin
4THYROID PHYSIOLOGY Iodide Metabolism Biosynthesis of Thyroid Hormones The recommended daily adult iodide (I-) intake is 150 mcgBiosynthesis of Thyroid HormonesTransport of Thyroid Hormonesthyroxine-binding globulin (TBG)about 0.04% of total T4 and 0.4% of T3 exist in the free form.
5Biosynthesis of thyroid hormones Figure Biosynthesis of thyroid hormones. The sites of action of various drugs that interfere with thyroid hormone biosynthesis are shown.
7Steps in Biosynthesis Iodide trapping Oxidation of iodide to iodine Iodide OrganificationFormation of T4 and T3Release of T4 and T3
8Peripheral 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
10Basic pharmacology of thyroid & antithyroid drugs Thyroid hormones A model of thyroid hormone action is depicted in Figure 38-4T3 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
11HypothyroidismA 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.
12Synthetic Thyroid Hormone synthetic levothyroxine (synthetic T4)Brand names: Eltroxin , Euthyrox,Levoxyl, Levothroid, Synthroidfor hormone replacement therapy in hypothyroidismDOSEInfants and Children require more T4/Kg body weight than adultsAverage dose for an infant micrograms/kg/dAverage dose for an adult – 1.7micrograms/kg/dOnce dailyPharmacokineticsshould 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 levelsLabs should be repeated after 2 months
13Synthetic Thyroid Hormone reasons for its use:stabilitycontent uniformitylow costlack of allergenic foreign proteineasy laboratory measurements of serum levelslong half-life (7days)once a day dosing
14Synthetic Thyroid Hormone UsesHormone replacement therapyIn young patients or those with mild disease- full replacement therapy startedIn older patients and in patients with cardiac disease -start treatment with reduced dosageMyxedema Coma – medical emergencyLoading dose – of T4 – micrograms I/V initially f/by `50micrograms dailyI/V T3 – more cardiotoxic and difficult to moniterHypothyroidism and Pregnancy – daily dose –adequate
15Synthetic 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 levelsincrease risk for cardiac side effects secondary to hyperthyroid states during treatment
16HyperthyroidismA thyroid disorder caused by an antibody- mediated auto-immune reaction, but the trigger for this reaction is still unknownmost common cause of hyperthyroidism
19Biosynthesis of thyroid hormones Figure Biosynthesis of thyroid hormones. The sites of action of various drugs that interfere with thyroid hormone biosynthesis are shown.
20Thioamides 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)
21Thioamides 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 PTUPTU more protein-bound
22Thioamide uses Definitive therapy Preoperatively Along with RAI Graves diseaseToxic nodular goitrePreoperativelyIn thyrotoxic patientsAlong with RAI
24Iodine131 preparations: sodium iodide 131 MOA: trapped within the gland and enter intracellularly and delivers strong beta radiations destroying follicular cellsPenetration range µmClinical uses: Grave’s, primary inoperable thyroid CAContraindication: pregnancy
25Iodine131 Advantages Easy administration Effectiveness Low expense Absence of pain
26Iodine131Thioamides should be given initially and stop 5-7 days before radioactive iodine administration131I dosage generally ranges between uCi/g of estimated thyroid wt. corrected for uptake. May be repeated after 6 monthsAdverse effectspermanent hypothyroidismpotential for genetic damagemay precipitate thyroid crisis
27Anion InhibitorsMonovalent anions such as perchlorates, pertechnetate and thiocyanate can block uptake of iodide by the gland by competitive inhibitioncan be overcome by large doses of iodidesuseful for iodide-induced hyperthyroidism (amiodarone-induced hyperthyroidism)rarely used due to its association with aplastic anemia
28Biosynthesis of thyroid hormones Figure Biosynthesis of thyroid hormones. The sites of action of various drugs that interfere with thyroid hormone biosynthesis are shown.
29Inorganic Iodinesmajor anti-thyroids before the introduction of thioamides (1950s)preparations:strong iodine solution (Lugol’s)potassium iodideiodone
30Inorganic Iodines MOA: inhibit iodide organification Uses: Caution: acutely blocks release of thyroid hormone from the gland by inhibiting thyroglobulin proteolysisinhibit iodide organificationUses:useful in thyroid storms: 2-7 daysPreoperatively - iodides decrease vascularity, size and fragility of hyperplastic glandCaution:it may delay onset of thioamide effects; should be given after initiation of thioamidesThe gland will escape from inhibition after 2-8 weeks.
31Iodinated 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 pituitaryAnother MOA is due to inhibition of hormone release secondary to iodide levels in bloodUseful in thyroid storms (adjunctive therapy)
32Beta Blockers Drugs: Propranolol, Metoprolol, Atenolol MOA: Membrane-stabilizing action: inhibits T4 to T3Ameliorate many disturbing s/sxs of hyperthyroidism secondary to increased circulating catecholamines by blocking beta receptorsIndications: Grave’s, Thyroid storm
33CorticosteroidsPrednisone is given for patients with Grave’s ophthalmopathy1mg/kg/day (60mg/day 3 divided doses); if it should be given for more than 4 weeks, taper to decrease risk of adrenal crisis
34Thyroid storm Sudden exacerbation of throtoxic symptoms Life threatening conditionVigorous managementPropanalol 1-2mg i/v or 40-80mg PO Q6hDiltiazem mg Po Q8-6 hrs or 5-10mgs intravenous infusion/hour