Thyroid and Anti-Thyroid Drugs (SY 2023-2024) - Lecture Notes PDF

THYROID AND ANTI- THYROID DRUGS DR DAN ESTANDARTE SY 2023-2024 REVIEW: THYROID HORMONES › The thyroid gland is the source of two fundamentally different types of hormones: – Iodothyronine hormones from the thyroid follicles › Thyroxine (T4) and › 3,5,3ʹ-triiodothyronine(T3) – Calci...

THYROID AND ANTI- THYROID DRUGS DR DAN ESTANDARTE SY 2023-2024 REVIEW: THYROID HORMONES › The thyroid gland is the source of two fundamentally different types of hormones: – Iodothyronine hormones from the thyroid follicles › Thyroxine (T4) and › 3,5,3ʹ-triiodothyronine(T3) – Calcitonin from parafollicular cells (C-cells) › The thyroid hormones are synthesized and stored as amino acid residues of thyroglobulin, a glycoprotein constituting the vast majority of the thyroid follicular colloid Major Steps In The Synthesis, Storage, Release, And Inter-conversion Of Thyroid Hormones 1. uptake of iodide ion (I–) by the gland 2. oxidation of iodide and the iodination of tyrosyl groups of thyroglobulin 3. coupling of iodotyrosine residues by ether linkage to generate the iodothyronines 4. resorption of the thyroglobulin colloid from the lumen into the cell 5. proteolysis of thyroglobulin and the release of thyroxine and triiodothyronine into the blood 6. recycling of the iodine within the thyroid cell via de- iodination of mono- and diiodotyrosines and reuse of the I– 7. conversion of thyroxine (T4) to triiodothyronine (T3) in peripheral tissues as well as in the thyroid (1) Uptake of Iodide › Dairy products and fish are relatively high in iodine › Iodine ingested in the diet reaches the circulation in the form of Iodide ion (I−) › Thyroid efficiently and actively transports the ion via a specific membrane-bound protein, termed the sodium iodide symporter (NIS) – The iodide transport mechanism is inhibited by a number of ions such as thiocyanate and perchlorate – Thyrotropin (thyroid-stimulating hormone [TSH]) stimulates NIS gene expression – Decreased stores of thyroid iodine enhance iodide uptake, and the administration of iodide decreases NIS protein expression (2) Oxidation and Iodination › The iodination of tyrosine residues requires the iodinating species to be in a higher state of oxidation – Oxidation of iodide to its active form is accomplished by thyroid peroxidase – Iodination leads to formation of monoiodotyrosyl and diiodotyrosyl residues in thyroglobulin – Storage in the lumen of the thyroid follicle (3) Formation of Thyroxine and Triiodothyronine from Iodotyrosines › Coupling of – two diiodotyrosyl residues to form thyroxine (T4) – monoiodotyrosyl and diiodotyrosyl residues to form triiodothyronine (T3) › Catalyzed by the same thyroid peroxidase › The relative rates of synthetic activity at the various sites depend on the – Concentration of TSH and the – Availability of iodide (4) Resorption; (5) Proteolysis of Colloid; and, (6) Secretion of Thyroid Hormones › Endocytosis of colloid from the follicular lumen › “ingested” thyroglobulin appears as intracellular colloid droplets, which apparently fuse with lysosomes containing the requisite proteolytic enzymes – TSH enhances the degradation of thyroglobulin by increasing the activity of several thiol endopeptidases of the lysosomes › Liberated hormones then exit the cell › When thyroglobulin is hydrolyzed, monoiodotyrosine and diiodotyrosine also are liberated but usually do not leave the thyroid; rather, they are selectively metabolized and the iodine, liberated as I−, is reincorporated into protein – Catalyzed by Iodotyrosine Deiodinase enzyme (7) Thyroid Hormone Metabolism and the Conversion of Thyroxine to Triiodothyronine in Peripheral Tissues › Normal daily production of – thyroxine is estimated to range between 80 and 100 µg – triiodothyronine is between 30 and 40 µg › Although triiodothyronine is secreted by the thyroid, deiodination of T4 in the peripheral tissues accounts for ~80% of circulating triiodothyronine – Catalyzed by Iodothyronine Deiodinases Transport of Thyroid Hormones in the Blood › The thyroid hormones are transported in the blood in strong but non-covalent association with certain plasma proteins – Thyroxine-binding globulin (TBG), a glycoprotein, is the major carrier of thyroid hormones – Thyroxine, but not triiodothyronine, also is bound by transthyretin (thyroxine-binding prealbumin) – Albumin also can bind thyroxine when the more avid carriers are saturated › Only the unbound hormone has metabolic activity Degradation and Excretion › The liver is the major site of non-deiodinative degradation of thyroid hormones – T4 and T3 are conjugated with glucuronic and sulfuric acids through the phenolic hydroxyl group and excreted in the bile Regulation of Thyroid Function › Thyrotropin-Releasing Hormone – Synthesized by the hypothalamus – TRH stimulates the release of preformed TSH – Also stimulates the subsequent synthesis of TSH › Thyrotropin or TSH – Synthesized by anterior pituitary gland – TSH secretion is precisely controlled by the › Hypothalamic peptide thyrotropin-releasing hormone (TRH) and by the › Concentration of free thyroid hormones in the circulation via feedback mechanism Actions of Thyroid-Stimulating Hormone on the Thyroid › All phases of hormone synthesis and release are stimulated: iodide uptake and organification, hormone synthesis, endocytosis, and proteolysis of colloid › Increased vascularity of the gland and › Hypertrophy and hyperplasia of thyroid cells › In response to Thyroid Stimulating Hormone (TSH) released by the pituitary gland, a normally functioning thyroid gland will produce and secrete T4, which is then converted through deiodination (by type I or type II 5ʹ-deiodinases) into its active metabolite T3. › While T4 is the major product secreted by the thyroid gland, T3 exerts the majority of the physiological effects of the thyroid hormones; T4 and T3 have a relative potency of ~1:4 (T4:T3). › T4 and T3 act on nearly every cell of the body but have a particularly strong effect on the cardiac system. As a result, many cardiac functions including heart rate, cardiac output, and systemic vascular resistance are closely linked to thyroid status. Thyroid Hormone Transport Into and Out of Cells › Thyroid hormone crosses the cell membrane primarily via specific transporter proteins – The only transporter of proven importance in humans is monocarboxylic acid transporter 8 (MCT8) Actions of Thyroid Hormones › The predominant actions of thyroid hormone are mediated through binding to nuclear thyroid hormone receptors (TRs) and modulating transcription of specific genes MAJOR CLINICAL EFFECTS OF THYROID HORMONES › Growth and Development – Brain development › Thermogenic Effects › Cardiovascular Effects – Positive chronotropic and inotropic effects – Cardiac hypertrophy – Decreased peripheral vascular resistance › Metabolic Effects – Increased rate of glucose absorption from the gut – Metabolism of cholesterol to bile acids – Insulin-resistant state LEVOTHYROXINE › Synthetic T4 hormone used to treat hypothyroidism that can be used along with surgery and radioiodine therapy to manage thyrotropin-dependent well-differentiated thyroid cancer. › Absorption of orally administered T4 from the gastrointestinal tract ranges from 40% to 80% with the majority of the levothyroxine dose absorbed from the jejunum and upper ileum. › T4 absorption is increased by fasting and decreased in malabsorption syndromes and by certain foods such as soybeans, milk, and dietary fiber. › Absorption may also decrease with age. › In addition, many drugs affect T4 absorption including bile acid sequestrants, sucralfate, proton pump inhibitors, and minerals such as calcium (including in yogurt and milk products), magnesium, iron, and aluminum supplements. › To prevent the formation of insoluble chelates, levothyroxine should generally be taken on an empty stomach at least 2 hours before a meal and separated by at least 4 hours from any interacting agents. › Liver is the major site of degradation for both T4 and T3, with T4 deiodination also occurring at a number of additional sites, including the kidney and other tissues. › Thyroid hormones are primarily eliminated by the kidneys. A portion of the conjugated hormone reaches the colon unchanged and is eliminated in the feces. Approximately 20% of T4 is eliminated in the stool. Urinary excretion of T4 decreases with age. › Toxicity – Hypermetabolic state indistinguishable from thyrotoxicosis of endogenous origin. – Symptoms of thyrotoxicosis include weight loss, increased appetite, palpitations, nervousness, diarrhea, abdominal cramps, sweating, tachycardia, increased pulse, and blood pressure, cardiac arrhythmias, tremors, insomnia, heat intolerance, fever, and menstrual irregularities. Therapeutic Uses of Thyroid Hormone › Hormone replacement therapy in patients with hypothyroidism – Thyroxine (levothyroxine sodium) is the hormone of choice for thyroid hormone replacement therapy due to its consistent potency and prolonged duration of action › Absorption is slightly increased when the hormone is taken on an empty stomach › Once-daily dosing › The average daily adult replacement dose of levothyroxine sodium is 1.7 µg/kg body weight › (12.5-50 µg per day) as initial dose. The dose can be increased at a rate of 25 µg per day every 6-8 weeks until the TSH is normalized – The dose of levothyroxine in the hypothyroid patient who becomes pregnant usually needs to be increased › Perhaps due to the increased serum concentration of TBG induced by estrogen › TSH suppression therapy in patients with thyroid nodules, thyroid cancer – Thyroid nodules › Only 22% of nodules decrease in volume by >50% with levothyroxine › Nodule will regrow if the levothyroxine is stopped › Use of levothyroxine to suppress TSH in euthyroid individuals with thyroid nodules cannot be recommended as a general practice. However, if the TSH is elevated, it is appropriate to administer levothyroxine to bring the TSH into the lower portion of the reference range – Thyroid Cancer › The rationale for TSH suppression is that TSH is a growth factor for these cancers ANTI-THYROID DRUGS AND OTHER THYROID INHIBITORS › The major inhibitors may be classified into four categories: – Anti-thyroid drugs, which interfere directly with the synthesis of thyroid hormones; – Ionic inhibitors, which block the iodide transport mechanism; – High concentrations of iodine, which decrease release of thyroid hormones from the gland and also may decrease hormone synthesis; – Radioactive iodine, which damages the thyroid gland with ionizing radiation › Adjuvant therapy with drugs that have no specific effects on thyroid hormone synthesis is useful in controlling the peripheral manifestations of thyrotoxicosis. These drugs include – Inhibitors of the peripheral deiodination of thyroxine to the active hormone, triiodothyronine › Dexamethasone – β adrenergic receptor antagonists, and › Propranolol, atenolol › Effective in antagonizing the sympathetic/adrenergic effects of thyrotoxicosis, thereby reducing the tachycardia, tremor, and stare, and relieving palpitations, anxiety, and tension – Ca2+ channel blockers › Diltiazem › Can be used to control tachycardia and decrease the incidence of supraventricular tachyarrhythmias in hyperthyroidism ANTI-THYROID DRUGS › Three General Categories – Thioureylenes, such as propylthiouracil (prototype), methimazole, carbimazole – Aniline derivatives, such as sulfonamides – Polyhydric phenols, such as resorcinol PROPYLTHIOURACIL › Thiourea antithyroid agent › Mechanism of Action – Binds to thyroid peroxidase and thereby inhibits the conversion of iodide to iodine – Interferes with the incorporation of iodine into tyrosyl residues of thyroglobulin – Inhibits the coupling of iodotyrosyl residues to form iodothyronines – In addition to blocking hormone synthesis, propylthiouracil partially inhibits the peripheral deiodination of T4 to T3 (not seen in methimazole) › Propylthiouracil is administered orally, initially as 300 mg/day in three divided doses every 8 hours (may reach up to 600 to 900 mg/day). › After the initial treatment, the general maintenance dose is 100 to 150 mg/day. The dose is adjusted to maintain normal TSH, T3, and T4 levels. › Absorption: 75% › Distribution: 80 to 85% of the drug is bound to plasma proteins (lipoproteins and albumin are the major binding proteins), Vd 0.4 L/kg. It concentrates in the thyroid gland. › Onset: 24 to 36 hours are necessary for a significant therapeutic effect. › Duration: 12 to 24 hours › Metabolism: PTU primarily undergoes metabolism in the liver to glucuronides or inorganic sulfates. › Elimination: 35% gets excreted as metabolites in the urine. › Adverse Effects – Acute liver injury: › There are cases reported in pregnancy, adults, and children. Hence, caution is necessary with its use, especially in the first six months of the start of therapy. › Educate the patient regarding the potential symptoms to come and visit the physician for anorexia, pruritis, right upper quadrant pain, nausea, vomiting, light-colored stool, and dark urine. › Stop the drug at the first appearance of these symptoms and perform laboratory tests: biochemical (bilirubin, alkaline phosphatase) and hepatocellular injury markers (AST, ALT). – Hypothyroidism: › PTU can lead to hypothyroidism- weight gain, constipation, or drowsiness. › Hence, routine monitoring of TSH and T4 is necessary to maintain the euthyroid state. – Vasculitis: › Symptoms include- fever, weight loss, myalgia, arthralgia, and paresthesia. › Idiosyncratic reactions like this usually start within weeks of drug initiation but have been found to occur years later as well. › Most patients responded to drug withdrawal, immunosuppressants, and substitution with other thioamide drugs for hyperthyroid symptom control. › Complications included: leukoclastic vasculitis, glomerulonephritis (crescenteric or rapidly progressive), alveolar/pulmonary hemorrhage, cerebral angiitis, or ischemic colitis. – Hypersensitivity: › Reports of severe hypersensitivity reactions like Steven Johnson syndrome, toxic epidermal necrolysis, and urticaria have been described. – Agranulocytosis: › This is a potentially life-threatening occurrence with PTU in 0.2 to 0.5 % of patients. › The patients should receive instruction to report any symptoms suggestive of pancytopenia – fever, sore throat, interstitial pneumonitis. › The risk is at its highest in the first three months of treatment – Potential teratogenicity: PTU was a Category D drug for pregnancy › Therapeutic Uses – As definitive treatment, to control the disorder in anticipation of a spontaneous remission in Graves’ disease › Methimazole is the drug of choice for Graves’ disease; it is effective when given as a single daily dose, has improved adherence, and is less toxic than propylthiouracil › The thyrotoxic state usually improves within 3-6 weeks after the initiation of anti-thyroid drugs › When large doses are continued, and sometimes with the usual dose, hypothyroidism may develop as a result of overtreatment – After treatment is initiated, patients should be examined and thyroid function tests (serum FT4 and total or free triiodothyronine concentrations) measured every 2-4 months – Once euthyroidism is established, follow-up every 4-6 months is reasonable › During treatment, a positive sign that a remission may have taken place is reduced size of the goiter › Another favorable indication is continued freedom from all signs of hyperthyroidism when the maintenance dose is small › Prolonged drug therapy of Graves’ disease in anticipation of remission is most successful in patients with small goiters or mild hyperthyroidism › Those with large goiters or severe disease usually require definitive therapy with either surgery or radioactive iodine (131I). Radioactive iodine remains the treatment of choice for many endocrinologists. › Thyrotoxicosis in Pregnancy – PTU is the treatment of choice in 1st TM – Subtotal thyroidectomy if cannot tolerate or no response to anti-thyroids medications – Radioactive iodine is clearly contraindicated – In conjunction with radioactive iodine, to hasten recovery while awaiting the effects of radiation – To control the disorder in preparation for surgical treatment › To reduce operative morbidity and mortality, patients should be rendered euthyroid before subtotal thyroidectomy as definitive treatment for hyperthyroidism › Iodide is added to the regimen for 7-10 days before surgery to decrease the vascularity of the gland, making it less friable and decreasing the difficulties for the surgeon › Thyroid Storm – Life threatening complication of thyrotoxicosis – Cardinal features include fever (temperature usually >38.5°C) and tachycardia out of proportion to the fever. Nausea, vomiting, diarrhea, agitation, and confusion are frequent presentations. Coma and death may ensue in up to 20% of patients. – Treatment includes › Supportive measures such as intravenous fluids, antipyretics, cooling blankets, and sedation. › Anti-thyroid drugs are given in large doses – Propylthiouracil is preferred over methimazole because it also impairs peripheral conversion of T4→T3. – Propylthiouracil and methimazole can be administered by nasogastric tube or rectally if necessary › Oral iodides are used after the first dose of an anti-thyroid drug has been administered. › Hydrocortisone (100 mg intravenously every 8 hours) can be used in the setting of hypotension both as an inhibitor of conversion of thyroxine to triiodothyronine and as supportive therapy of possible relative adrenal insufficiency › Adjuvant treatment like propranolol – Plummer’s Disease (Toxic Nodular Goiter) › Medical therapy is not as helpful as with Graves' disease › RAI is also safe and effective, usually requiring a single dose, but the results are delayed and it usually fails to resolve a goiter › Surgical treatment results in rapid, reliable resolution of hyperthyroidism and removal of the nodular goiter with low morbidity and no mortality  Pediatric population: PTU has been associated with liver injury in both adult and pediatric populations, whereas no case reports suggest liver injury with methimazole in the pediatric population. Hence, PTU is not for use in the pediatric population. Renal impairment: Dose adjustment is not required. Hepatobiliary disease: PTU causes liver injury; hence, it is not used in patients with liver impairment. Pregnant: PTU is a pregnancy category D drug. PTU can cross the placenta and can cause fetal cretinism and goiter. Methimazole causes fetal anatomical abnormalities; hence, if it is necessary to use antithyroid drugs in pregnancy, PTU is preferred in the first trimester with the lowest possible drug dose usage. Due to the increased reported risk of maternal hepatotoxicity from PTU, methimazole is the therapeutic choice in the second and third trimesters. Breastfeeding: PTU is excreted in breast milk in small amounts and delivered to infants. There are no clear-cut recommendations for its use in nursing. METHIMAZOLE › Thionamide antithyroid agent › Active metabolite of the pro-drug carbimazole › 10 times more potent than PTU › Inhibits the actions of thyroid peroxidase, leading to a reduction in thyroid hormone synthesis › Does not affect the existing thyroxine (T4) and triiodothyronine (T3) in the circulation › Absorption of methimazole after oral administration is rapid and extensive › Exhibits little-to-no protein binding, existing primarily as a free drug in the serum › Rapidly and extensively metabolized by the liver › Excreted mainly via urine; elimination via feces appears to be limited › Side effects of methimazole are mostly dose-related, like (most commonly) hives and itching, which improves with anti-histaminic medications or by discontinuing the drug. › Serious adverse effects: – Agranulocytosis › Propylthiouracil (PTU) and methimazole have cross-reactivity for agranulocytosis › Most frequently occurs in the first three months of starting therapy but can occur even after a year or more of exposure or during repeated exposures when treating a relapse › Fever and sore throat are the most common presenting features of agranulocytosis › Cut-off criterion for it is an absolute granulocyte count of less than 500 per mL › Stop methimazole if the count is less than 1000 per ml. Treat fever or any apparent infections with intravenous antibiotics.IV granulocyte colony-stimulating factor is known to reduce the length of hospitalization and recovery time. – Hepatotoxicity – Teratogenicity › Methimazole can cross the placental membrane readily due to its insignificant protein binding. › During the organogenesis phase, it causes immense fetal adverse effects, especially when administered in the first trimester. › Possible congenital disabilities seen in infants born to mothers who received methimazole during pregnancy include goiter, cretinism, aplasia cutis, umbilical abnormalities, facial dysmorphism, esophageal atresia, craniofacial defects, and choanal atresia › Propylthiouracil is the preferred antithyroid drug during pregnancy, especially for the first trimester, since the incidence of congenital anomalies is much less than methimazole – Hypothyroidism – Anti-vitamin-K activity of methimazole might increase the activity of oral anticoagulants Ionic Inhibitors › The term ionic inhibitors designates substances that interfere with the concentration of iodide by the thyroid gland – NIS inhibitors – Thiocyanate, Perchlorate, and Fluoroborate › Thiocyanate – Produced following the enzymatic hydrolysis of certain plant glycosides › e.g., cabbage and cigarette smoking › Result in an increased concentration of thiocyanate in the blood and urine – Administration of sodium nitroprusside › Perchlorate (ClO4–) – 10 times as active as thiocyanate – rapidly absorbed from the gastrointestinal (GI) tract – not reported to undergo metabolism – mainly excreted unchanged in the urine – doses of 400 mg/d for several weeks had adverse effects such as GI irritation, skin rash, and lymphadenopathy but cited no serious complications – 400 to 1,000 mg perchlorate daily, cases of agranulocytosis and fatal aplastic anemia have been reported – therapeutic use of potassium perchlorate in hyperthyroidism has been ceased due to a high risk for developing aplastic anemia and nephrotic syndrome Iodide › Mechanism of Action – High concentrations of iodide › Limit iodide transport › Acute inhibition of the synthesis of iodotyrosines and iodothyronines – Wolff-Chaikoff effect › An important clinical effect of high [I–]plasma is inhibition of the release of thyroid hormone – This action is rapid and efficacious in severe thyrotoxicosis › In the thyroid gland, vascularity is reduced, the gland becomes much firmer, the cells become smaller › Unfortunately, iodide therapy usually does not completely control the manifestations of hyperthyroidism, and after a variable period of time, the beneficial effect disappears. With continued treatment, the hyperthyroidism may return in its initial intensity or may become even more severe than it was at first. › Therapeutic Uses – Preoperative period in preparation for thyroidectomy › Before surgery, iodide is sometimes employed alone, but more frequently it is used after the hyperthyroidism has been controlled by an anti-thyroid drug. It is then given for 7-10 days immediately preceding the operation – In conjunction with antithyroid drugs and propranolol, in the treatment of thyrotoxic crisis – Another use of iodide is to protect the thyroid from radioactive iodine fallout following a nuclear accident, military exposure, or large scale radioiodination procedures in laboratories. Because the uptake of radioactive iodine is inversely proportional to the serum concentration of stable iodine, the administration of 30-100 mg of iodide daily will markedly decrease the thyroid uptake of radioisotopes of iodine › Untoward Reactions – Angioedema – Multiple cutaneous hemorrhages may be present – Serum-sickness type of hypersensitivity—such as fever, arthralgia, lymph node enlargement, and eosinophilia—may appear – Thrombotic thrombocytopenic purpura and fatal periarteritis nodosa attributed to hypersensitivity to iodide also have been described – Chronic intoxication with iodide (iodism) › Related to the dose › Symptoms – Start with an unpleasant brassy taste and burning in the mouth and throat as well as soreness of the teeth and gums – Increased salivation is noted – Coryza, sneezing, and irritation of the eyes with swelling of the eyelids are commonly observed › Symptoms of iodism disappear spontaneously within a few days after stopping the administration of iodide Radioactive Iodine › Iodine has several radioactive isotopes, although the primary ones used for the diagnosis and treatment of thyroid disease are 123I and 131I – 123I, is primarily a γ-emitter with a t1/2 of only 13 hours and is used in diagnostic studies to measure 24-hour iodine uptake and for thyroid imaging – 131I has a t1/2of 8 days and emits both γrays and βparticles. More than 99% of its radiation is expended within 56 days. It is used therapeutically for thyroid destruction of an overactive or enlarged thyroid and in thyroid cancer for thyroid ablation and treatment of metastatic disease › 131I – Deposited in the colloid of the follicles, from which it is slowly liberated – Destructive βparticles originate within the follicle and act almost exclusively on the parenchymal cells of the thyroid, with little or no damage to surrounding tissue – The γ radiation passes through the tissue and can be quantified by external detection – Pyknosis and necrosis of the follicular cells are followed by disappearance of colloid and fibrosis of the gland. With properly selected doses of 131I, it is possible to destroy the thyroid gland completely without detectable injury to adjacent tissues. › Therapeutic Uses – Diagnosis of disorders of thyroid function – Treatment of hyperthyroidism › Β Adrenergic antagonists, anti-thyroid drugs, or both, or stable iodide, can be used to hasten the control of hyperthyroidism while awaiting the full effects of the radioactive iodine – Treatment of thyroid cancer › Disadvantages – Hypothyroidism – Radioactive iodine treatment can induce a radiation thyroiditis, with release of preformed thyroxine and triiodothyronine into the circulation. In most patients, this is asymptomatic, but in some there can be worsening of symptoms of hyperthyroidism – Salivary gland dysfunction may be seen. Salivary gland damage is most strongly linked to the cumulative dose of radioiodine › Contraindications – Main contraindication for the use of 131I therapy is pregnancy END