Anti-Thyroid Drugs and Thyroid Hormone

OS 215 215:: Repr Repro o ucti uction on an Horm Hormon ona a Regu Regu atio atio LEC 06: ANTI-THYROID DRUGS AND THYROID HORMONE Exam 8 | Dr. Acampado| November 26, 2012 OUTLINE I. Therapeutic Overview II. Thyroid Physiology III. Thyroid Hormone Synthesis IV. Pharmacokinetics of Thyroid Hormone V. Effects of Drugs on Thyroid Hormone Production VI. Mechanisms for Thyroid Regulation VII. Thyroid Hormone Mechanism of Action VIII. Thyroid Hormone Effects IX. Thyroid preparations X. Hyperthyroidism XI. Anti-Thyroid Drugs and Radioactive Iodine Therapy XII. Summary

THERAPEUTIC THERAPEUT IC OVERVIEW 

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In terms of treatment, thyroid problems are easier to treat than diabetes. HYPOTHYROIDISM o Administer exogenous thyroxine (T4) or triidothyronine (T 3) HYPERTHYROIDISM o Surgery  –   –  typically reserved mostly for nodules that are suspicious for cancer. Note: Functioning nodules in a thyroid patient are usually NOT cancer. In these cases, use drugs, and if unresponsive, use radioactive iodine. long-term disease like Grave’s o Radioactive iodine - especially for long-term o Drugs: Thioureylenes, o Adjuncts: Beta- Adrenergic Receptor Blockers, Corticosteroids, Iodides

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the target of the action of many anti-thyroid drugs

THYROID HORMONE BIOSYNTHESIS

THYROID PHYSIOLOGY Thyroid gland maintains metabolic homeostasis by regulating: o growth and development,  Cretinism: stunted growth, physically and mentally o body temperature, and o energy levels Multiple functions are accomplished through two hormones, T3 and T4 Table 1. Comparison Between T3 and T4. Hormones Triiodothyronine Tetraiodothryonine Alias T3 T4 or thryoxine Molecular composition MIT + DIT DIT + DIT Iodine Content (%) 59 65 (larger content because it’s 4 molecules, not 3) Throid-hormone1 5 thyroglobulin ratio MIT = monoiodotyrosine, DIT = diiodotyrosine Thyroglobulin ratio – ratio – proteinatious  proteinatious ratio in the colloid. Number of thyroid hormones: more T4 in the thyroglobulin than T3. THYROID HORMONE SYNTHESIS

A. SIX MAJOR STEPS 1. Active Transport of Iodine across the basement membrane into the thyroid cell ( called iodide trapping). Remember that there is a symporter across the cell membrane that transports iodine intracellularly. 2. (Inside the cell): Oxidation of iodide & iodination of tyrosyl residues in thyroglobulin. Result: monoiodothyroxines. 3. Coupling of the monoiodotyrosine molecules within thyroglobulin to form T3 & T4 Tyrosine + I  MIT (monoiodothyroxine)  Tyrosine + I2  3, 5 DIT (diiodothyroxine)   MIT + DIT  3, 5, 3’ TIT (T3) 3, 3’, 5’ TIT (rT3 =inactive reverse T3)DIT + DIT  3, 5, 3’, 5’ (T4) Still attached to thyroglobulin. Must be released (see next step) 4. Proteolysis of thyroglobulin - release of free iodothyronines & iodotyrosines from colloid droplets (pinocytosis). They then find their way to the circulation. 

TRANSERS

Deiodination of iodotyrosines within the thyroid cells & recycling of iodine Intrathyroidal 5’-deiodination 5’-deiodination of T4 to T3  peripheral  *the peripheral  *the  conversion  conversion of T4  T3 T3 is an important step and is

T3 is the chemically active hormone Figure 1. Thyroid Hormone Hormone Biosynthesis. Refer to Figure 1: 1. Iodide (I ) absorbed in the GIT enters an extracellular pool from which the thyroid gland removes 75 mg daily. + 2. I  is taken up by thyroid follicular cells via a membrane Na /I transporter. 3. I  is then coupled to tyrosine residues on the thyroglobulin molecule (process is called organification) *therefore, basic substrate is iodine! 4. Formation of monoiodo-tyrosine (MIT) and diiodo-tyrosine (DIT) 5. Thyroid peroxidase (TPO) catalyzes the coupling of two molecules of DIT to form T4, and one molecule each of MIT and DIT to form T3 6. Thyroglobulin is stored as a colloid in the lumen 7. TSH signals (for secretion) to hydrolyze thyroglobulin to free MIT, DIT, T3 & T4 8. MIT and DIT are deiodinated for recycling while T3 & T4 are released by exocytosis Thyroid peroxidase is active in oxidation and coupling (steps 2 and 3) T4 will have peripheral conversion to t3 T3 active hormone, reverse t3-inactive hormone 

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Figure 2. Steps in Thyroid Hormonogenesis. C oupling: thyroid peroxidase! (repeatedly mentioned, so don’t forget this enzyme)

PHARMACOKINETICS OF THYROID HORMONE  

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T3 & T4 are mostly bound to thyroxin binding globulin (TBG) Amounts of free or unbound hormones are minimal: 0.03% T4 and 0.3% T3 Only the unbound hormones have metabolic activity , used by peripheral tissue for the actions of thyroid hormone In peripheral tissues T4 is converted to T3 by iodothyronine 5’ deiodinase found mainly in liver, thyroid, and kidneys The active hormone in most target tissues is T3

EFFECTS OF DRUGS ON THYROID HORMONE PRODUCTION Table 3. Summary of Drugs that Act on Thyroid Hormone Synthesis. Metabolic Step Inhibitors -4 Iodide Transport Large Amounts of I , ClO , SCN , TcO4 (iodine and thiocyanates.) Iodide Oxidation Thionamide Drugs (PTU, MMI) Organification and Coupling Colloid Resorption and Iodine, Lithium Proteolysis If you take a lot of iodine: Wolff Chaikoff effect – high dose iodine impedes transport and release. Thiocyanates = root crops, deep green vegetables, cassava, broccoli Thionamides – inhibit organification and coupling by inhibiting thyroid peroxidase Lithium – treats manic depressive conditions but also inhibits thyroid hormone production! Half –life of T4 > than T3 MECHANISMS FOR THYROID REGULATION 1. Paraventricular nuclei in the hypothalamus secrete TRH 2. TRH stimulates the anterior pituitary to release TSH 3. TSH acts on the thyroid to release T3 and T4 4. T3 and T4 act by negative feedback to inhibit formation of TRH and TSHStress is a negative inhibitor. There is a decrease in thyroid hormone. Cold also sends signals to your hypothalamus, producing TRH Somatostatin, steroids, or dopamine can also inhibit TRH. Autoregulation within the thyroid modifies thyroid hormone synthesis through blood iodine levels: o High iodine levels inhibit iodide organification , leading to reduced T3 & T4 synthesis (hypothyroidism) 

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Figure 3. Peripheral Metabolism of Thyroxine. KINETICS: PERIPHERAL METABOLISM OF THYROXINE 

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Thyroid hormone released mostly as T4 because T4 to T3 ratio in thyroglobulin is 5:1 Peripheral metabolism of T4 is mainly by deiodination to form: [1] T3 which is 3-4 times more potent than T4,  or [2] reverse T3 which is metabolically inactive Total serum levels for T4 are higher because more of it is released and metabolic clearance of T3 is faster. With regards in secretion of the thyroid, it is more t4. Exogenous thyroid therapy is usually given as T4 to simulate normal physiologic processes. If you give T3 directly, patients will suffer from more adverse drug reactions (palpitations) Table 2. Summary of Thyroid Hormone Kinetics. Thyroid Hormones T3 T4 Daily Production (mg) 25 75 Daily Metabolic Clearance (L) 24 1.1 Total Serum Levels (nmol/L) 1.5-2.9 64-132 (more) Biologic Potency 3-4 1 (higher) Oral Absorption (%) 95 80 Half-life (days) 1 7 (longer) T3 is also the more potent of the two, as you can s ee above (more side effects) T4 lasts longer in circulation (see half life). However, both are only once a day dosing.

Figure 4. Hypothalamic-Pituitary Regulation THYROID HORMONE MECHANISM OF ACTION

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Figure 5. Mechanism of Action of Thyroid Hormone in Target Cell (PB, plasma binding protein; F, transcription factor; R, receptor; PP, proximal promoter proteins). Unique iodine-thyroxine association enables it to act on the nuclear receptor.

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T3 receptors belong to a superfamily of nuclear receptors (c-erb includes receptors for steroid hormones and vitamins A and D) Many T3 receptors are found in responsive tissues like pituitary, liver, kidney, heart (tachycardia), skeletal muscle, lung, and intestine (hyperdefecation) *hence, hyperthyroidism is a multi-system disease T3 & T4 are dissociated from thyroid-binding proteins   enter target cells by diffusion or active transport  in the cytoplasm 5’deiodinase converts T4 to T3  T3 enters the nucleus to bind to T3 receptors  more RNA are formed  increased protein synthesis * Hormone binding dissociates the co-repressors and allows the recruitment of coactivators that enhance transcription. Interaction with coexpressors explains the fact that TR silences gene expression in the absence of hormone binding.

High-output heart failure (heart very active but because of decrease in diastolic function, heart is unable to relax to perfuse the coronaries) o Arrhythmia o Angina – if with coronary artery disease 4. Metabolic effects: o Decreased cholesterol and triglycerides o Increased basal metabolic rate o Hyperglycemia o Appetite THYROID PREPARATIONS Major clinical use of T3 & T4 is f or hormone replacement therapy in hypothyroidism or cretinism Involves replacement of thyroid hormone adequate to meet the patient’s needs 100 mcg in a ~65 kg person Dose for replacement: 1.6-1.7 mcg/kg *drugs given in multiples of 25 (25, 50, 100, 150) o

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Figure 6. Role of T3 in RNA Synthesis. T3 acts on Intracellular thyroid hormone receptors (TRs) located in all cells of the body TR monomers interact with retinoic acid X receptor (RXR) to form heterodimers In the absence of T3 , the TR:RXR heterodimer associates with a corepressor complex that binds to DNA to inhibit gene expression In the presence of T3 , the co-repressor complex dissociates, coactivators form to stimulate gene expression Binding to TR dimmers, thus, serves as a molecular switch from inhibition to activation of gene expression THYROID HORMONE EFFECTS

Generally responsible for optimal growth, development, function, and energy levels in all tissues hyperthyroidism (thyrotoxicosis) –the more o Excess encompassing term. Any elevation of thyroid hormone, regardless of cause. On the other hand, hyperthyroidism merely refers to problems in the thyroid gland. hypothyroidism (myxedema) o Inadequacy 1. Nervous, musculoskeletal, and reproductive tissues: o Nervousness o Restlessness o Emotional lability o Muscle weakness and fatigue o Osteoporosis o Menstrual irregularities o Hyper: irregular o Hypo: metromenorrhagia 2. Calorigenic effect: o Increased oxygen consumption o Sweating 3. Sympathetic hyperactivity due to increased b- adrenergic sensitivity leads to dramatic cardiovascular effects including o Tachycardia o Increased stroke volume and cardiac output

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INDICATIONS Post-procedural hypothyroidism – post surgery. Most common cause of deficiency in the Philippines!  Lack of iodine is second most common. Endemic goiter Congenital hypothyroidism: cretinism- thyroid hormone should be replaced to prevent metnal retardation, it is good that we have newborn screening now to pick up earlier this disease. Any cause of hypothyroidism, i.e. thyroiditis Suppression of growth of nodules, thyroid CA o Dose for suppression: 2.2-3.0 mcg/kg o A higher dose is necessary than that of the dose for replacement Monitor effectiveness of therapy by measuring TSH levels Treatment is therefore based on the weight of the patient, and range of the patient’s response to the medications. Dose may be adjusted accordingly. For hypothyroidism, no matter what the cause, the ONLY treatment is THYROID HORMONE (particularly T4) Surgery and radiation in thyroid cancer- lower the tsh values to decrease the growth of the tumor. THYROID HORMONE REPLACEMENTS IN THE MARKET SYNTHETIC LEVOTHYROXINE (T4)

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Van, Gellai, Charles

For the elderly, or with CAD or arrhythmia, implement SLOW replacement (titrate the dose). If you replace too fast, erratic levels of thyroid hormones. You can develop vasospasm of coronary arteries, arrhythmias, etc. So, keep it slow! For younger patients, you can give full replacement right away.

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Preparation of choice for replacement & suppression therapy because of its: o Stability o uniform content o low cost o long half-life (7 days) o conversion to produce both T3 & T4 DESICCATED THYROID In the past, desiccated animal thyroid preparations were used as treatment. But this is not used anymore. If you are fond of eating burgers, bopis, etc., beware! You may develop thyrotoxicosis if the animal’s thyroid is mixed in with the meat. Though inexpensive, it is not recommended for replacement therapy because of its antigenicity, instability, and variable hormone content. LIOTHYRONINE (T3)

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3-4 times more active than levothyroxine [T4 is still preferred over T3 despite the latter being stronger] Not recommended for routine replacement therapy o higher cost (than the two previous thyroid preparations) o short half-life (24 hours)

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greater potential for cardiotoxicity due to its potency and large peaks (unpredictability)  –  greater induction of myocardial ishcemia

not inhibit the release of already preformed hormones; for RAPID action, the last steps of the process should be targeted

These drugs are preferentially iodinated, depriving thyroglobulin of iodide and shutting down the synthesis of thyroid hormones Accumulate readily in the thyroid gland for treatment of thyrotoxicosis Effects are not immediate. This mainly prevents f urther thyroid hormone production. Plasma half lives: 6hr for MMI and 1.5 hrs for PTU Methimazole (5 mg; more expensive, can be given once a day) is 10x more active than PTU (50 mg) Additional MOA: PTU, but not methimazole, affects by inhibiting the processing of T4 to T3 in the peripheral tissues [PTU is therefore the preferred drug in thyroid storm treatment] 

LIOTRIX

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4:1 combination of synthetic T4 and T3 also expensive with the same disadvantages as liothyronine * currently we still use the pure levothyroxine or pure t3

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THYROTOXICOSIS Consequence of excessive thyroid hormone action due to Causes: o Diffuse toxic goiter (Graves’ disease) [Grave’s disease is the most common cause , accounting for 60-

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80% of thyrotoxicosis]

Toxic adenoma o Toxic multinodular goiter (Plummer’s) o Painful subacute thyroiditis o Silent thyroiditis; e.g. lymphocytic and postpartum variations o Iodine-induced hyperthyroidism o Excessive pituitary TSH or trophoblastic disease o Excessive ingestion of thyroid hormones Clinical features o Signs & symptoms are due to the effects of excess thyroid hormone in the circulation o Severity of signs & symptoms may be related to the duration of the illness, magnitude of hormone excess & the age of the patient

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Since T3 is 10x as active as T4 this conversion step is important

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METHIMAZOLE VS. PROPYLTHIOURACIL (PTU) Slow onset of action requiring 3 -4 weeks to deplete T4 stores Methimazole is 10x more potent than PTU! In PTU you need to give more tablets, more often. PTU is cheaper Methimazole is the antithyroid drug of choice Avoid PTU, due also to excessive hepatic risks. Multiple mechanisms of action including: o Major action: prevent hormone synthesis by inhibiting thyroid peroxidase reactions to block iodine organification and iodotyrosine coupling (both Methimazole and PTU) o Inhibit peripheral deiodination of T3 & T4 (only PTU) Adverse reactions occur in 3-12% of treated patients (in the Philippines, almost 20%, but effects are transient): Most common: maculopapular pruritic rash Rarely: urticarial rash, vasculitis, arthralgia, lupus-like reaction,  jaundice, hepatitis hypothrombinemia Most dangerous: agranulocytosis (rapid fall in WBC coun t, manifests with fever, soar throat, cough – stop the drug then have the CBC done. If not discontinued, later: GI complications, diarrhea, sepsis; usually with high doses) Angioedema (severe allergy): therefore if symptoms above are seen, just discontinue drug then have CBC done. SIDE EFFECTS OF THIOUREYLENES Rash, urticaria – in as much as 20% of users; usually transient even w/o treatment Auto-immune (lupus-like) nephritis, PAN Granulocytopenia,a granulocytosis: RARE but potentially fatal Watch out sore throat for, fever, diarrhea * If minor side effects result , patient may either continue therapy but  

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Pwedeng mauna ung opthalmopathy but it very rare. If they have opthalmopathy, they have already hyperthyroidism. Table 4. Signs and Symptoms of Hyperthyroidism. Signs Symptoms Weakness and Fatigue Goiter/Thyroid Bruit Heat Intolerance Hyperkinesis Nervousness Ophthalmopathy Increased Sweating Lid retractions/stare Tremor Lid lag Palpitations Tremor Increased Appetite Warm, moist skin Weight Loss Muscle weakness Dyspnea Hyperreflexia Menstrual Amenorrhea Tachycardia/arrhythmia – most common is sinus tachycardia followed by atrial fibrillation Hyperdefecation Widened Pulse Pressure ANTI-THYROID DRUGS AND RADIOACTIVE IODINE THERAPY 1. Thioamides: methimazole propylthiouracil

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with antihistamine, lower the dose of the medication, or shift to another drug. * If life-threatening side effects result , NEVER reintroduce the precipitating agent .

B. OTHER ANTI-THYROID DRUGS: ADJUNCTIVE TREATMENT

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2. Iodides: potassium iodide solution 3. Radioactive Iodine (RAI) 4. Other Drugs: anion inhibitors b-adrenergic blockers THIOUREYLENE OR THIOAMIDES: Methimazole and Propylthiouracil MAIN anti-thyroid drugs Propylthiouracil, Methimazole/Thiamazole, Carbimazole (will be converted to methimazole) *in US, only PTU and Methimazole are available MOA: inhibit thyroid peroxidase-mediated iodination & coupling steps (steps 2 and 3) *because action is on the early steps, there is SLOW onset of action 

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since it merely prevents the formation of new hormones but does

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MONOVALENT CATIONS Block thyroid hormone synthesis by competitively inhibiting the active transport of iodide into the thyroid o Pertechnetate, Perchlorate: little clinical use o High dose iodides: Potassium Iodide, SSKI, Lugol’s solution, Intravenous Contrast Agents (recall Wolff Chaikoff effect) o Watch out for angioedema with iodides ANION INHIBITORS AND B-ADRENERGIC BLOCKERS Monocovalent ions such as perchlorate (ClO4-), pertechnetate (TcO4-), and thiocyanate (SCN-): block iodide uptake through competitive inhibition of the iodide transport mechanism, but their effectiveness is unpredictable. This time, they prevent the transpot of iodine to the gland.  Thus these are not commonly used. Potassium perchlorate is no longer used clinically because it causes aplastic anemia Iodinated contrast media (iopdate and iopanoic acid by mouth, or

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diatrizoate IV) though not FDA approved, act by inhibiting conversion of T4 to T3 in liver, kidney, pituitary, and brain Since many symptoms of thyrotoxicosis result from sympathetic hyperactivity, guanethidine or b-adrenergic blockers have also been used for treatment IODIDES: POTASSIUM IODIDE SOLUTION Used in the past to decrease size and vascularity of hyperplastic thyroid gland in Graves Disease, but no longer done because it is dangerous. Instead, make the patient euthyroid (normalized hormones) before sending them off to surgery. Why dangerous? Patients tended to lower the dose or discontinue meds after surgery, then develop hypothyroidism. Many thyroid actions including: of hormone release by reducing thyroglobulin o Inhibition proteolysis o Decrease in size and vascularity of the hyperplastic gland Given in HIGH doses (gram doses) to inhibit iodide transport; if given in small (microgram doses), iodine actually enhances synthesis * Wolff-Chaikoff effect is the phenomenon wherein excess

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Figure 7. Summary of thyroid treatment and steps affected

iodide actually blocks organification and prevents further synthesis of new hormones in the thyroid gland. 

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Thyrotoxic symptoms improve within 2-7 days, but should not be used alone because the gland “escapes’ from iodide block after 2-8 weeks and withdrawal may result in severe thyrotoxicosis Avoid chronic use in pregnancy as iodides cross the placenta and can cause fetal goiter. Advantages: o Simplicity o Inexpensive o Relatively nontoxic o Absence of glandular destruction Adverse reactions (MANY): o Acneiform rash (most common form) o Swollen salivary glands o Mucous membrane ulceration o Conjunctivitis o Rhinorrhea o Metallic taste o Drug fever o Bleeding disorders o Anaphylaxis Disadvantages o “Escape”- after around a week, escape from Wolff Chaikoff, and becomes incorporated into thyroid hormones and become hyperthyroid again. o Aggravation of thyrotoxicosis o Allergic reactions intraglandular iodine which can delay onset of o Increased thioamide therapy or prevent use of radioactive iodine therapy for several weeks o If done with radioactive scan, Iodide should be washed off first so that the radioactive scan will be more accurate. BETA-ADRENERGIC RECEPTOR BLOCKING DRUGS Examples: Propanolol, Atenolol * Better to select the non-cardiac selective b eta-adrenergic receptor

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Act peripherally rather than at the thyroid gland (prevent T4 to T3 conversion) When to use: tachycardic, tremors, sweatiness; many drugs already being used and yet persistently elevated T3 MOA: uncertain but may relate to inhibition of deiodination  no peripheral conversion of T4 to T3 (ex. Propanolol) Also blocks the sympathetic (adrenergic) effects of hyperthyroidism esp. on the heart * Helpful in the control of adrenergic symptoms, especially in the

RADIOACTIVE IODINE THERAPY Used for definitive therapy or ablation The only isotopes used for treatment of thyrotoxicosis Uses the following radioisotopes: I123 or I131 Basically we are using the I131 Side-effects are minimal: avoid in children (may inhibit bone growth, but unsure if it were the treatment or the previous hyperthyroidism) and pregnant women or those intending pregnancy Contraceptives are encouraged among those who are sexually active But we do not give RIT to a pregnant woman. Make sure do a pregnancy test before giving the drug, RADIOACTIVE IODINE (RAI)

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blocking drugs 

Inhibit peripheral conversion of T4 to T3 (like B-adrenergic Receptor Blocking Drugs) Can suppress thyroid-stimulating antibodies (Graves) Antipyretic May be used to treat adrenal insufficiency in patients with thyroid storm Graves’ disease is an autoimmune disorder which can manifest with thyroid storm because of increase stress.

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Given as oral solution, I131 is rapidly absorbed and concentrated in the thyroid gland Iodine 123 or Iodine 131 are the radioisotopes used Used for definitive therapy or ablation Radioiodine causes progressive destruction of thyroid cells o Thyroid parenchymal destruction becomes evident within weeks in the form of epithelial swelling, necrosis, follicular disruption, edema, and leukocyte infiltration Therapeutic effect depends on emission of beta rays with: (1)Penetration range of 400-2000 mm,(2) Effective half-life of 5 days Advantages: easy administration, effectiveness, low expense (3-5k if charity ward), & absence of pain Major disadvantage is induction of hypothyroidism. 90% develop this in the next few years. You need lifelong l evothyroxine treatment. But side effects are minimal. Side effect will have hypothyroidism. However it is easier to manage the hypothyroidism. You should have only to f ind the replacement dose for the patient. But the patient ’ s condition is stable. Avoid in children (inhibit bone growth) and pregnant women or those intending pregnancy. RAI crosses the placenta and is excreted in breast milk. Misconception: “causes sterility” – no, it does not. Preferred treatment over surgery/thyroidectomy in Grave’s disease. Advice patient to dispose of their body wastes properly (because it’s radioactive) SUMMARY

early stages before anti-thyroid drugs take effect.  

Avoid in patient with asthma Calcium channel blockers can also be used. CORTICOSTEROIDS

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THYROID HORMONES AND ANTI-THYROID DRUGS b. ½ of 150 mcg tablet OD c. 100 mcg OD d. 50 mcg BID Your friend from surgery referred a patient with hypo thyroidism to you for management prior to planned cholecystectomy for gall bladde r stones. On the average, how soon can you render this patient euthyroid if you w ill give the patient methimazole? a. Two weeks b. Eight weeks c. Four weeks d. Six months Proper course of action in a patient w ho developed agranulocytosis secondary to methimazole: a. Shift methimazole to PTU b. Continue methimazole but decrease the dose to less than 40 mcg/day c. Administer RAI upon admission for ablation of go iter d. Discontinue thionamides permanently

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Figure 7. Drugs Affecting T3 and T4 Synthesis Anions (perchlorate, pertechnetate, & thiocyanate) compete with I- uptake. RAI causes selective thyroid destruction Iodide (high levels) reduce T3-T4 release by inhibiting thyroglobulin proteolysis. Thioamides inhibit peroxidase to block organification Some Scenarios: (not mentioned in lecture) 1. For young patients with small goiter and mild hyperthyroidism, give antithyroid drugs for a few months. To induce remission, give a large dose then taper it off – (only 30% success rate. 2. For patients with large goiters and nodules, give drugs for 2-3 months then subsequently send for surgery. 3. Give antithyroid drugs till normothyroid, then give another definitive form of treatment: radioactive iodine. END OF TRANSCRIPTION

Van: Merry Christmas!  Gellai: Hi 2016! Last week of plenary sessions and then back to block a and block b na.  buuuuuuut we’ll be spending more time together because it’sssssssssss TRP! Wee! Hi to all TRP dancers ! :D galingan pa rin natin ung tipong pang opening pa rin.  Join Handog Committee!  Hi PHIphi! Marky Ray and Jow! Thanks to all who came to OBP next year ulit!  To the Maramba babies. Eto naaaaa eto naaaaaa eto naaaaaa.  good luck to our mice. :p Hi PHIerless!