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Thyroid and anti thyroid drugs

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Summary of thyroid and antithyroid drugs
-Introduction
-Synthesis
-Pharmacological Action
-Mechanism of action
-Drugs in Hypothyroidism
-Thyroid Inhibitors
-Drugs in Hyperthyroidism

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Thyroid and anti thyroid drugs

  1. 1. THYROID AND ANTI-THYROID DRUGS Prepared By- Shadab Khan Guided By- Dr. Dharmesh Sisodiya
  2. 2. THYROID GLAND  It is an Endocrine Gland, found at the front of Neck below Adam’s Apple.  Produces three Hormones:-  Thyroxine T4  Triidothyronine T3  Calcitonin  T4 and T3 have same Biological activity and termed as “Thyroid Gland” secreted by Folliclular cell.  Calcitonin is produced by C Cells which regulate Ca2+ metabolism.
  3. 3. CHEMISTRY AND SYNTHESIS  T4 and T3 are iodine containing thyronine derivatives:- 2tyrosineThyronine + 3I-  3,5,3’triiodothyronine (T3) + 4 I- 3,5,3’,5’tetraiodothyronine (T4)  Iodide Uptake  Oxidation and Iodination  Coupling  Storage and Release  Peripheral Conversion of T4 to T3
  4. 4. FOLLICLE CELL NIS PDS P P PLASMA FOLLICLE LUMEN TSH Stimulates gene transcription for this carrier I-I- IODIDE UPTAKE Iodine obtain from food and water Body Contains 30-50 mg out of which 1/5th in Thyroid Actively transported by Na+: Iodide Symporter (NIS) from blood to follicle TSH stimulate uptake by 100 folds
  5. 5. FOLLICLE CELL NIS PDS P P PLASMA FOLLICLE LUMEN TSH Stimulates gene transcription for this carrier I-I-
  6. 6. FOLLICLE CELL NIS PDS P P PLASMA FOLLICLE LUMEN I-I- Thyroperoxidase TG T DIT MITMIT T T T DIT TG T T T T T Protein Synthesis OXIDATION AND IODINATION Follicle iodide carried across apical membrane by Pendrin(PDS) Iodide oxidized by Thyroid Peroxidase which easily binds to tyrosil to form MIT and DIT which are attached to Thyroglobulin
  7. 7. FOLLICLE CELL NIS PDS P P PLASMA FOLLICLE LUMEN I-I- Thyroperoxidase TG T DIT MITMIT T T T DIT TG T T T T T Protein Synthesis
  8. 8. FOLLICLE CELL NIS PDS P P PLASMA FOLLICLE LUMEN I-I- Thyroperoxidase TG T DIT MITMIT T T T DIT TG T T T T T Protein Synthesis COLLOID MIT+DIT =Triidothyronine T3 DIT+DIT =Thyroxine T4 COUPLING AND STORAGE Tyrosil Residue Couple to Form T4 and T3 TSH stimulate both Coupling and Oxidation Thyroglobulin transported to Colloid present interior of follicle
  9. 9. FOLLICLE CELL NIS PDS P P PLASMA FOLLICLE LUMEN I-I- Thyroperoxidase TG T DIT MITMIT T T T DIT TG T T T T T Protein Synthesis COLLOID MIT+DIT =Triidothyronine T3 DIT+DIT =Thyroxine T4
  10. 10. FOLLICLE CELL NIS PDS P P PLASMA FOLLICLE LUMEN I-I- Thyroperoxidase TG T DIT MITMIT T T T DIT TG T T T T T Protein Synthesis COLLOID MIT+DIT =Triidothyronine T3 DIT+DIT =Thyroxine T4 T G TG L T4 T3 T4 T3 MIT DIT I- deiodination RELEASE AND CONVERSION  Thyroid Colloid is taken by endocytosis Broken by Lysosymal Protease T4 and T3 are released while MIT and DIT are re-utilized Normal Human Secretes 60-90μg of T4 and 10-30μg of T3 Peripheral tissue, Liver, Kidney convert about 1/3rd T4 to T3 by Iodothyronine deiodinase Target tissue take up T3 for metabolic need
  11. 11. FOLLICLE CELL NIS PDS P P PLASMA FOLLICLE LUMEN I-I- Thyroperoxidase TG T DIT MITMIT T T T DIT TG T T T T T Protein Synthesis COLLOID MIT+DIT =Triidothyronine T3 DIT+DIT =Thyroxine T4 T G TG L T4 T3 T4 T3 MIT DIT I- deiodination
  12. 12. REGULATION OF SECRETION
  13. 13. ACTION  T4 and T3 have same quantitatively action  Growth and Development:-  Essential for normal growth  Control protein synthesis  Hypothyrodism suffer nervous system mostly  Cause impaired intelligence and slow movement  Intermediary Metabolism:-  Lipid:  Indirectly enhance lypolysis  Results in increase plasma free fatty acid  Hyperthyroidism cause hypocholesterolemia  Carbohydrates:  Metabolism Stimulated  Increase utilization of sugar  Absorption from intestine is faster causes hyperglycaemia
  14. 14.  Protein:  Regulate Protein Synthesis, mainly catabolise  Weight Loss in Hyperthyroidism  Calorigenesis:-  Increase BMR by stimulating cellular metabolism and resets energy state  CVS:-  Increase peripheral demand  Increase cardiac actions:- HR, FOC and output  Myocardial O2 consumption is decreased in hypothyroidism  Nervous System:-  Hypothyroidism: mental retardation (cretinism), sluggishness (myxoedema)  Hyperthyroidism: anxiousness, nervousness, excitable, Tremor and weakness  GIT:-  Propulsive activity of gut is increased-  Diarrhea: hyperthyroidism  Constipation: Hypothyroidism
  15. 15. MECHANISM OF ACTION  T4 and T3 penetrate cell by active transport and produces action by combining with nuclear Thyroid Hormone Receptor (TR) bound to TRE in enhancer region of target gene along with co- repressor causes gene transcription suppression  When T3 bind to ligand binding domain of TR, TR heterodimerizes and undergoes conformational change  This causes corepressor release and coactivator binding these induces gene expression Gene transcrtiption  Production of mRNA  Protein Synthesis  various metabolic and anabolic effect  Repression by T3: The unliganded TR allow gene transcription while binding of T3 to TR halt process  Tachycardia, high BP, tremor, hyperglycemia are mediated by sensitization of adrenergic receptors to catecholamines
  16. 16. Mechanism of action of thyroid hormone on nuclear thyroid hormone receptor (TR). T3—Triiodothyronine; T4—Thyroxine; TRE—Thyroid hormone response element; RXR— Retinoid Xreceptor; mRNA—Messenger ribonucleic acid; 5’DI—5’Deiodinase
  17. 17. DRUG IN HYPOTHYROIDISM  Clinically, 1-thyroxine is preferred because of more sustained and uniform action as well as lower risk of cardiac arrthymias  Pharmacokinetic: ~ 75% oral bioavailability  Uses:  Cretinism: Failure or defect in thyroid development, usually in infants, treatment should be fast (8-12 μg/kg daily)  Adult Hypothyroidism (Myxoedema): Disorder caused by autoimmmune thyroiditis or thyroidectomy, Simple Goiter in iodine deficiency, Antibodies against thyroid H2O2 / Thyroglobulin, Drugs such as 131I iodide, Li also causes (start low dose 50μg daily& increased every 2-3 week to 100-200μg)  Myxoema Coma: Emergency caused by progressive mental deterioration, Rapid thyroid replacement (200-500μg i.v. followed by 100μg OD till oral therapy instituted)  Nontoxic Goitre, Thyroid Nodule, Empirical Use: Mental depression, Obstimate Constipation  Marketed Preparation: Eltroxin 25μg, 50μg, 100μg tab; Thyronorm tab
  18. 18. THYROID INHIBITORS  These drugs lower the functional capacity of the hyperactive thyroid gland (treat hyperthyroidism)  Thyrotoxicosis is due to excessive secreation of thyroid hormone two main causes:-  Grave’s Disease: Autoimmune disease, IgG antibodies to TSH receptor bind and show TSH like effect, feedback mechanism is inhibited because TSH levels are low  Toxic Nodular Goiter: Produces thyroid hormone independent of TSH  CLASSIFICATION:-  Inhibit Hormone Synthesis (Anti thyroid Drugs):-  Propylthiouracil, Methimazole, Carbimazole  Inhibit Iodide Trapping (Ionic Inhibitors):-  Thiocynates (-SCN), Perchlorates (-ClO4), Nitrates(-NO3)  Inhibit Hormone Release:-  Iodine, Iodides of Na and K, Organic Iodide  Destroy Thyroid Tissue:-  Radioactive Iodine (131I, 125I, 123I)
  19. 19. ANTITHYROID DRUGS (THIOAMIDES)  Propylthiouracil  Methimazole  Carbimazole  Mode of Action:-  Bind to Thyroidperoxidase and prevent oxidation of iodide residue, thereby:-  Inhibition of iodination of tyrosine residues in thyroglobulin  Inhibition of coupling of iodotyrosine residue  They do not interfere with trapping of iodide and do not modify T3 and T4 action  They do not affect release of T3 and T4 and show no effect till thyroid is depleted  Propylthiouracil inhibit T4 to T3 conversion while Methimazole and Carbimazole cannot while they antagonizes former  Pharmacokinetic: All drugs are quickly absorbed orally and widely distributed in body
  20. 20. FOLLICLE CELL NIS PDS P P PLASMA FOLLICLE LUMEN I-I- Thyroperoxidase TG T DIT MITMIT T T T DIT TG T T T T T Protein Synthesis COLLOID MIT+DIT =Triidothyronine T3 DIT+DIT =Thyroxine T4 T G TG L T4 T3 T4 T3 MIT DIT I- deiodination Thioamides and Excess I- Propylthiouracil Methimazole Carbimazole
  21. 21.  Adverse Effect:-  Hypothyroidism and goiter can occur due to overtreatment of drug but reversible on stopping treatment  GI intolerance, Skin Rashes and Joint Pain  USES:-  Controls thyrotoxicosis in both Grave’s disease and toxic nodule goiter  Clinical improvements starts after 1-2 weeks or more  Advantage:- No surgical risk, reversible hypothyroidism, use for children  Disadvantage:- Prolonged treatment, Drug toxicity  Marketed Preparation:-  Propylthiouracil: 50-150 mg TDS followed by 25-50 mg BD-TDS for maintenance PTU 50 mg  Methimazole: 5-10 mg TDS initially, maintenance dose 5-10 mg OD-BD  Carbimazole: 5-15 mg TDS initially, maintenance dose 2.5-10 mg OD-BD Neo Mercazole, Thy rozole, Antithyrox
  22. 22. IODINE AND IODIDES  Constituent of thyroid hormone and potentiate thyrotoxicosis but excess causes inhibition of hormone release “Thyroid Constipation”  Endocytosis of colloid and proteolysis of thyroglobulin comes to a halt  USE:-  Preoperative preparation for thyoidectomy in Grave’s disease  Thyroid storm  Prophylaxis of endemic goiter  Antiseptic  Adverse effect:-  Acute: Swelling of lips, eyelids, fever joint pain  Chronic: Inflammation of mucous membrane, salivation, headache,rashes  Marketed Preparations:-  Lugol’ Solution (5% iodine in 10% KI solution) Lugol’s Solution; Colloid Iodine 10% Collosol 5 mg
  23. 23. REGULATION OF SECRETION
  24. 24. RADIOACTIVE IODINE  Stable isotope 131I is medicinal important (half life 8 days)  Both diagnostic and therapeutic use:-  Diagnostic: γ-rays are useful in tracer studies 25-100 μCurie is given, counting or scanning is done at intervals, No damage to thyroid at this dose  Thrapeutic: β-particles are used for their destructive effectb on thyroid cells 131I concentrated in thyroid colloid and emit radiation from within and penetrates only 0.5-2 mm Average 3-6 mCurie is used on the basis of thyroid size. The response is slow and starts after 2 weeks  Advantage:-  Simple an inexpensive  No surgical Risk, Scar or Injury  Cure is permanent after control  Disadvantage:-  Hypothyroidism  Long latent response period  Not suitable for young patients
  25. 25. THANK YOU
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Summary of thyroid and antithyroid drugs -Introduction -Synthesis -Pharmacological Action -Mechanism of action -Drugs in Hypothyroidism -Thyroid Inhibitors -Drugs in Hyperthyroidism

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