PA2107 Lecture 1 Thyroid and Antithyroid Drugs
PA2107 Lecture 1 Thyroid and Antithyroid Drugs PA2107
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Date Created: 08/12/15
PA2107 Lecture 1 Thvroid and Antithvroid Drug These notes are largely extracted from Chapter 38 Basic and Clinical Pharmacology 11th Edition Hormones secreted by the thyroid gland Triiodothyronine T3 Tetra39 d thy39f quot39quote T439 Calcitonin thyroxme Normalise growth and development body temperature and Important in regulation of energy levels calcium metabolism Action of thyroid hormones 1 Thyroid hormone is critical for the development and functioning of nervous skeletal and reproductive tissues Its effects depend on protein synthesis as well as potentiation of the secretion and action of growth hormone Thyroid deprivation early in life results in irreversible mental retardation 4x lower IQ and dwarfism 2 Thyroid hyperactivity may cause effects similar to sympathetic nervous system overactivity esp in the cardiovascular system Increased number of B receptors or enhanced amplification of 3 receptor signal may cause these effects In order to produce T3 and T4 the body requires iodine The daily recommended iodide intake by adults is 150 mcg and 200 mcg for pregnant women The body obtains iodide through food water or medication Iodide is rapidly absorbed the thyroid gland removes about 75 mcg a day from the pool of iodide in order to synthesise T3 and T4 The balance is excreted in the urine If iodide intake is increased the fraction of iodine uptake by the thyroid is decreased in normal physiological function Biosynthesis of thyroid hormones 1 Uptake of At the cell basement membrane iodide is transported into the thyroid gland iodine by a protein known as the sodiumiodide symporter NIS This can be inhibited by anions such as thiocyanate SCN39 pertechnetate TcO439 and perchlorate CIO439 At the apical cell membrane a second iodide transport enzyme called pendrin controls the flow of iodide across the membrane 2 Oxidation of At the apical cell membrane iodide is oxidized by thyroidal peroxidase to iodide to iodine iodine Thyroidal peroxidase is transiently blocked by high levels of intrathyroidal iodide and blocked more persistently by thioamide drugs 3 lodination of tyrosine lodination of tyrosine in thyroglobulin organification Iodine rapidly iodinates tyrosine residues within the thyroglobulin molecule to form monoiodotyrosine MIT and diiodotyrosine DIT This process is known as iodide organification 4 Coup ng Coupling of iodotyrosines to form iodothyronines DIT DITT4 I MIT DITT3 DIT MIT reverse T3 biologically inactive 5 Release of T3 and T4 T3 T4 MIT and DIT are released from thyroglobulin by exocytosis and proteoloysis of thyroglobulin at the apical colloid border MIT and DIT are deiodinated within the gland and the iodine is reutilized The process of proteolysis is blocked by high levels of intrathyroidal iodide 6 Transport of hormones T3 and T4 in the plasma are reversibly bound to proteins primarily the thyroxinebinding globulin TBG 996 and 9996 of T3 and T4 respectively are protein bound 7 Peripheral metabolism ofthyroid hormones T3 is 434 mere pe ten t than T3 l Jl gtIgl ll39ll iIIII lull l 7 as amlcdarone lodinated Tyroxlilmefml May be caused by drugs such contrast media B blockers and certicc ste reids and severe Illness er starvation these i n h ilbit 5 xdeicd i nase necessary fer ccnversion cf T4 in T3 Comparison of T3 and T4 Variable T3 T4 Iodine content 59 65 Daily production 25 mcg 75 mcg Binding to plasma 996 9996 protein Oral bioavailability 95 80 Biologic halflife 1 day better for emergency tx because it is easier to control levels 7 days better for replacement therapy longer tlz because needs to be changed to T3 first for effects to be seen Serum level 100 ml 95160 ng 511 mcg Biological potency 4 four times stronger effect com pa red to T4 therefore better for emergency tx 1 Diseases resulting from thyroid gland dysfunction Hyperthyroidism Hypothyroidism Thyrotoxicosis Graves Disease Graves Disease lymphocytes secrete a TSH receptor stimulating antibody This immunoglobulin binds to the TSH receptor and stimulates the gland much longer duration TSH receptors are also found in orbital Hashimoto s hypothyroidism immunologic disorder myxedema severe form of hypothyroidism possibly resulting in myxedema coma a medical emergency in the same fashion as TSH itself but with a fibrocytes hence the symptoms of the eyes Jitteriness shaking nervousness Sleepy fatigue due to lack of energy increased irritability Weight gain Tachycardia or palpitations Feeling cold Feeling hot Dry skin and hair Weight loss Slowed thinking Fatigue due to high activity Treatment options for hypothyroidism coma Levothyroxine replacement therapy for hypothyroidism Liothyroxine not commonly used for replacement therapy reserved for tx of myxedema Toxicity of thyroid hormones Adults overdosing brings about symptoms of hyperthyroidism Children overdosing causes insomnia restlessness accelerated growth and bone maturation Treatment options for hyperthyroidism Surgery thyroidectomy Only considered when the thyroid gland is too big and compresses the airway Otherwise antithyroid drugs are the firstline treatment Patients are treated with antithyroid drugs for about 6 weeks For 1014 days prior to the surgery they receive saturated solutions of KI 5 drops twice a day to diminish vascularity of the gland and simplify surgery About 8090 of patients will require thyroid supplementation following neartotal thyroidectomy Radioiodine 131 is the preferred tx for patients gt21 yo 131I emits Bparticles which have strong cytotoxic action thus destroying follicles that produce thyroid hormones Because Bparticles have a short emission distance they have no effect on other cells of the body No radiationinduced genetic damage leukemia or neoplasma have been reported The benefits of radioiodine easy administration effective not expensive and no pain 131I also emits longerdistance yrays that are able to pass through tissues This can be used as a diagnostic tool wrt how much iodidetrapping occurs in the thyroid glands The more 131 is trapped in the thyroid gland the higher the signal of the yrays Radioiodine tx will cause hypothyroidism in about 80 of patients upon which they should undergo oral replacement with levothyroxine 50150 mcg daily Also contraindicated in pregnant and breastfeeding women Thioamides or thioureylenes Thioamides carbimazole methimazole active metabolite of carbimazole Thioureylenes propylthiouracil 10x less potent than methimazole Carbimazole methimazole and propylthiouracil are absorbed and accumulated in the thyroid gland where they exert their effects Their major action is to prevent hormone synthesis by inhibiting the thyroid peroxidasecatalysed reactions and blocking iodine organification They also block the coupling of iodotyrosines Propylthiouracil inhibits the peripheral deiodination of T3 and T4 Since the synthesis rather than the release of hormones is affected the onset of the effects is slow requiring 34 weeks before stores of T4 are depleted Hence Bblockers should be given concurrently to reduce symptoms while waiting for onset of thioamides Propylthiouracil is rapidly absorbed and has a halflife of 15h hence it should be dosed about 100 mg q 68h Carbimzaole is partially metabolized in the liver to methimazole and the rest is excreted in the urine It has a halflife of 36h Methimazole is rapidly absorbed and has a longer halflife of 615h Hence it can be dosed 30 mg OM Adverse reactions to thioamides such as nausea and GI distress occur in 312 of patients Patients may also experience an altered sense of taste or smell with methimazole The most common adverse effect is a maculopapular pruritic rash 46 at times accompanied by fever The most dangerous complication is agranulocytosis granulocyte count lt 500 cellsmm3 occurring in 0105 of patients Older patients and those receiving higherdose methimazole therapy are at higher risk of agranulocytosis Because thioamides cross the placental barrier and can cause hypothyroidism in the baby they are contraindicated in pregnancy but ok for nursing infants Propylthiouracil may be considered for pregnant women due to their higher plasma protein binding levels Anion inhibitors Monovalent anions such as thiocyanate SCN39 pertechnetate TcO439 and perchlorate CIO439 can block uptake of iodide by the gland through competitive inhibition of NIS Their effects can be overcome by large doses of iodides so their effectiveness is somewhat unpredictable Furthermore potassium perchlorate is rarely used clinically due to association with aplastic anemia Adrenoceptor blocking agents Eg propranolol Bring about clinical improvement of hyperthyroid symptoms but do not alter thyroid hormone levels Propranolol of doses greater than 160 mgdose may also reduce T3 levels approximately by 20 by inhibiting the peripheral conversion of T4 to T3