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10/28/2014 PHARMACOLOGICAL TREATMENT OF THYROID DISEASES 1. 2. 3. 4. Synthesis, chemistry and physiology of thyroid hormones Regulation and disorders of hormone synthesis Therapy of hypothyroidism: Hormone replacement Therapy of hyperthyroidism : Anti-thyroid drugs –T3: triiodothyronine (lyothyronine) -T4: thyroxine • • • • 1915: isolation (Kendall) 1926: discovery of the chemical structure 1927: synthesis (Harington és Barger) 1952: synthetic production of T3 1.1. Synthesis of thyroid hormones I. -Iodine uptake: TSH-dependent 20-50 times higher iodine concentration in the thyroid gland than in the plasma (100 times in stimulated conditions!) -Iodine incorporation: TSHdependent (increased production of H2O2) Hormones are produced during the synthesis of a special glycoprotein, thyroglobulin. Elementary iodine is oxydased (due to thyroperoxidase) and binds to the thyrosyl side chanes of TG⇒ mono- and diiodotyrosine (MIT and DIT)⇒ T3 and T4 (normally 1:4, but in iodine deficiency might be more T3) 1 10/28/2014 1.1. Synthesis of thyroid hormones II. Endocytosis: TSHdependent (increases lysosomal endopeptidase activity); TG is degradaded in the lysosomes of the follicular cells ⇒ T3 and T4 outflow into the bloodstream - Peripheral metabolism: T4→ T3 metabolism by the 5’deiodinase enzyme (in the peripheral tissues in 30-35%) 1.2. Chemistry of the thyroid hormones - Dehalogenation at the C3 and C5 positions is essential for the biological effects (eg. rT3 is inactive) -T3 is 4-times more effective than T4 - Only the L-stereoisomeric form is biologically active 2 10/28/2014 1.3. Physiological effects of T3/ T4 - Growth, development (neural systems, skeletal - - muscle, reproductive tissues)⇒ thyreoid gland: kretenism (mental and growth retardation) Increased basal metabolism, oxydative processes, regulation of the body temperature Increased cholesterol→ bile acid transformation Increased lipolytic/ glycolytic effects of catecholamines, increased glucose absorption ⇒ increased blood glucose and fatty acid levels Increased catehcolamine-sensitivity of the heart⇒ tachycardia Mechanism: high affinity T3 receptor is present in the nucleus and the cytoplasm (α and β forms, quantity is tissuespecific)⇒ the HR complex binds to specific regions of the DNS (THRE)⇒ regulation of DNA transcription and protein synthesis (derepression or activation of gene transcription) There is a binding site in the mitochondrial memrane too. 3 10/28/2014 2.1. Regulation of hormone synthesis -Daily production: 70-90µg T4 and 15-30 µg T3 get into the circulation Synthesis is increased by - HTH: TRH - Pituitary: TSH 2.2. Kinetics of T3/T4 -Transport in the circulation: T3 and bind to thyroxinebinding globulin (TBG; higher affinity to T4), T4 also binds to thyroxine-binding prealbumine -Free fraction: T4 0.03-0.04%, T3 0.2-0.5% -T1/2: 6-7 days - Amount and hormone-binding of TBG increases in eg. pregnancy, decreases in eg. liver diseases - Metabolism: deiodination⇒ glucuronidation, sulphatation (conjugation), enterohepatic recirculation 4 10/28/2014 2.3. Disorders of the thyroid function Normal serum hormone levels free T3: 2.5-6 pmol/l free T4: 9-24 pmol/l TSH: 0.5-4.5 mU/l Hypothyreoidism Hyperthyreoidism Symptoms: Symptoms: -Weight loss despite good appetite -Increased body weight - Diarrhea -Constipation - Nervousness, excitedness -Slow thinking, decreased physical-Tremor, sleeping disorders, activity, sleepiness, tiredness anxiety - Mixoedema - Increased sweating - Laboratory parameters: -Atrial arrhytmias increased serum cholesterol - Laboratory parameters: decreased Congenital: kretenism serum cholesterol Special type: Graves-Basedow disease 3. Pharmacological therapy of hypothyroidism 3.1. HORMONE-SUBSTITUTION TH. (Long ago: dried thyroid gland powder) Synthetic L-thyroxine (levothyroxine) or Ltriiodothyronine/ (liothyronine; levotriiodothyronine) L-thyroxine: more balanced effect, longer action, safer administration Clinical use: - Kretenism - Mixoedema - Hypothyroid condition after thyroid gland operation - Usually long-lasting therapy is needed -Well-balanced dosing might be neccessary to be altered due to drug interactions - TSH control is needed every 6 months 5 10/28/2014 Kinetics: -Good oral absorption from the small intestine, but influenced by lots of alimentary factors and drugs (iron, Al, calcium) and the normal bacterial flora, motility -Oral bioavailability: 75-95% -Strong plasma protein binding -T4⇒ T3 metabolism in the periphery -Levothyroxine t1/2: 7 days; liothyronine t1/2: 1 day -Small ratio is excreted into the milk Dosing: Oral (except mixoedema coma when i.v.) Should be taken before meals (better and safer absorption), The daily required amount should be divided into 3 doses! Small starting dose and gradual increase to 0.05-0.15 mg/day Drug interactions: - Increased effect with tricyclic antidepressants - Increased oral antidiabetic drug and insuline requirements - Cholestyramine decrease the absorption - Enzyme inducers (e.g. phenitoin, carbamazepine, ethanol) increase the metabolism - Protein binding Increase Oestrogens, tamoxifen, methadone, clofibrate, 5-FU, heroine Decrease GCC, salycilates, androgens, antiepileptic drugs, furosemide Liver diseases, acute infections 6 10/28/2014 Side effects: - Cardiovascular complaints (tachycardia, atrial arrhytmia/fibrillation, angina) - Sweating, weight loss, anxiety - Osteoporosis (especially in elderly women) 3.2. Iodine supplementation Iodine deficiency might be the reason of insufficient thyroid gland function. Daily requirement: 0.1 mg (food, drinking water, salt) For profilaxis or for the therapy of thyroid nodules with hypo- or normofunction: 0.05-0.15 mg iodine/day p.o. Good absorption, good distribution, concentration in the thyroid gland, elimination through the kidneys 4. Therapy of hyperthyroidism 4.1. INHIBITION OF HORMONE SYNTHESIS 4.1.1. EXCESSIVE IODINE INTAKE Effect: - High amount of iodine decreases all steps of T3/T4 synthesis (but particularly proteolysis) - Decreased thyroid gland size, vascularization and the symptoms of hyperthyroidism - Effect can be observed within maximum 10-15 days - Contraindicated in pregnancy! (can cause nodules in the foetus) 7 10/28/2014 Clinical application: daily D 300-600 mg -Thyrotoxic crisis: daily 1-2 g isopropanol-diiodate - Preoperative treatment before thyroid gland operations for the prevention of thyrotoxic crisis: Lugol solution (5% elementary iodine + 10% potassium iodine) Side effects: - acute allergic reactions -„iodism”: fever, skin raches, swollen salivary glands, mucosal irritations Iodine-containing contrast materials (ipodate, iopanoate): decrease hormone synthesis and also peripheral T4→T3 metabolism (daily 1g) 3.1.2. THIOAMIDES (metimazol) Chemistry: - Common structural feature is the thiocarbamide group, which is essential for the anti-thyroid activity 8 10/28/2014 Mechanism of action: - Decrease the incorporation of the uptaken iodine into the tyrosil side-chaine of TG by inhibiting the peroxydase enzyme - The peripheral hormone levels decrease after 3-4 weeks (there is a stored TG pool) -Propylthiouracil also inhibits peripheral T4⇒T3 metabolism and enhances T4⇒ rT3 metabolism (might be more effective acutely) - Exert immunosupressive effect: in Basedow disease decrease the level of the stimulating antibody and the lymphocyte number - increase the thyroid gland size by increasing TSH production (compensatory) Kinetics: -Oral bioavailability: -metimazole: 100% propylthiouracil: 50-70% (partial absorption, first pass effect) - Plasma protein binding: metimazole: negligible propylthiouracil: 75% -Plasma t1/2: metimazole: 4-6 h propylthiouracil: 75 min -Elimination: As inactive glucuronide through the kidneys Propylthiouracil less penetrates through the placenta (it should be chosen in pragnancy) 9 10/28/2014 Clinical use: - Oral administration, exc. thyrotoxic crisis when i.v. - Higher initial D, then gradual decrease - First usually metimazole, then in case of side effects or ineffectivity propylthiouracil Side effects: - Increased thyroid gland size (even nodules) due to the compensatory TSH production increase - Allergic symptoms (predominantly skin) - Bone marrow damage (leukopenia, thrombocytopenia, agranulocytosis, aplastic anaemia) - Headache, painful swelling of the salivary gland, paresthesia, hear loss, liver toxicity 3.1.3. LITHIUM-CARBONATE - Decreases the outflow of thyroid hormones - Decreases peripheral T4→T3 metabolism - Rarely given before operations or 131J-treatment 3.1.4. PERCHLORATE -Inhibits the Na+/J- symporter, and therefore decreases iodine uptake by the thyroid gland - Very rarely used due to the rare side effect of agranulocytosis 10 10/28/2014 3.2. RADIODESTRUCTION OF THE THYROID GLAND: 131I Mechanism of action: - It is taken up and accumulated in the thyroid gland, produces β irradiation, which is very short penetrating(0.5 mm), so only destroys tissues locally - Usually p.o. 4-10 mCi - Premedication: propylthiouracil to achieve euthyroid condition - Effect starts after 1-2 weeks and reaches its maximum 3 months later Clinical use: Basedow disease, thyroid nodules, inoperable cancers or metastatic cancers in the thyroid gland 11