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Class thyroid and antithyroid drugs

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Class thyroid and antithyroid drugs

  1. 1. Dr. RAGHU PRASADA M S MBBS,MD ASSISTANT PROFESSOR DEPT. OF PHARMACOLOGY SSIMS & RC. 1
  2. 2. Thyroid gland secretes 2 hormones : Thyroxine (tetraiodothyronine or T4) Triiodothyronine (T3) Secretion ratio T4 to T3 is 15:1 Iodine is attached to tyrosine amino acid residues of thyroglobulin in the gland (organification) Coupling of these residues then produces T4 & T3 Thyroid Physiology
  3. 3. Thyroid Physiology T4 & T3 released by the gland are bound & transported by serum proteins : Thyroxine-Binding Globulin (TBG) : 75 % Thyroxine-Binding Prealbumin (TBPA) Albumin The free (or unbound) hormone levels are the levels which are maintained constant by feedback & regulate thyroid function Total measured serum T4 includes bound & unbound
  4. 4. Thyroxine Binding Proteins Causes of increased TBG levels : Pregnancy, estrogens, cirrhosis, hepatitis, porphyrias Causes of decreased TBG levels : Protein malnutrition, nephrotic syndrome, hepatic failure, androgenic steroids, high dose glucocorticoids Free T4 (FT4) usually constant in the above conditions
  5. 5. Thyroid Hormone T4 deiodonated in periphery to T3 This is 80 % of T3 produced Other metabolite of T4 is reverse T3 (rT3) which is metabolically inactive T3 enters cells & binds to group of nuclear receptors, then affects wide range of cellular metabolic functions Thyroid hormone required for normal cell metabolism
  6. 6. Step 1-Iodide trapping Step 2-Oxidation of iodide to iodine Step -3 Iodide Organification Step -4 Formation of T4 and T3 Step -5 Release of T4 and T3
  7. 7. Peripheral metabolism of thyroid hormones The primary pathway for the peripheral metabolism of thyroxine (T4) is deiodination  deiodination of T4 may occur by monodeiodination of the outer ring, producing 3,5,3'-triiodothyronine (T3), which is three to four times more potent than T4
  8. 8.  Free form of T3 and T4 enter cell by diffusion /active transport . T4 is converted to T3 and enters nucleus and binds to T3 receptors, this leads to increased formation of mRNA and subsequent protein synthesis. 9
  9. 9. T4, best absorbed in duodenum and ileum, this can be altered by food and drugs, such as calcium preparations and antacids containing aluminum, intestinal flora . Absorption of T4 is 80% and of T3 is 95%. Absorption is not affected by mild hypothyroidism but impaired in myxedema with illeus, in this condition parental route is preferred. 10
  10. 10. T4 production is more than T3 T4 is converted to T3 in periphery T3 is more potent than T4 T3 acts faster thanT4 T3 enters cell easily than T4 T3 binds to receptors in nucleus. 11
  11. 11. Regulation of Thyroid Hormone Normal regulation requires intact hypothalamic- pituitary system Hypothalamus secretes Thyrotropin-Releasing Hormone (TRH) TRH then stimulates synthesis & release of thyrotropin (Thyroid Stimulating Hormone or TSH) by the anterior pituitary TSH then stimulates the thyroid gland to uptake iodine, synthesize & release T4 & T3 T4 & T3 levels feedback to both hypothalamus & pituitary affecting TRH & TSH release
  12. 12. Regulation of Thyroid Hormone Normal regulation requires intact hypothalamic- pituitary system Hypothalamus secretes Thyrotropin-Releasing Hormone (TRH) TRH then stimulates synthesis & release of thyrotropin (Thyroid Stimulating Hormone or TSH) by the anterior pituitary TSH then stimulates the thyroid gland to uptake iodine, synthesize & release T4 & T3 T4 & T3 levels feedback to both hypothalamus & pituitary affecting TRH & TSH release
  13. 13. 14 Hypothalamic –pitutary – thyroid axix Thyroid regulation
  14. 14. Hypothyroidism Cold intolerance Dyspnea Anorexia Constipation Menorrhagia or amenorrhea Arthralgias, myalgias Fatigue Depression Irritability Decreased attention & memory Paresthesias
  15. 15. 16
  16. 16. Hypothyroidism Signs Dry, yellow (carotenemic ) skin Weight gain (41 % of cases) Thinning, coarse hair Myxedema signs (mucopolysaccharide deposition in tissues) : Puffy eyelids Hoarse voice Dependent edema Carpal tunnel syndrome Anemia
  17. 17. Primary Hypothyroidism Autoimmune : most common Some have lymphocytic infiltration variant Post surgical thyroidectomy External radiation Iodine 131 Rx for hyperthyroidism Severe prolonged iodine deficiency Antithyroid medications (such as lithium) Inherited enzymatic defects True idiopathic
  18. 18. Hypothyroidism and Myxedema Coma Hypotension Bradycardia Pericardial effusion Low voltage EKG Prolonged QT interval Inverted / flattened T waves
  19. 19. Thyroid Function Tests Free T4 Index (FT4I) Correlates with level of Free T4 T3 radioimmunoassay (less useful) Normal 75 to 195 ng / dl Serum TSH Normal is 0.3 to 5.0 mcU / ml TRH Stimulation Test Measures TSH response to TRH IV injection Normal is increase in TSH to 30 mcU / ml
  20. 20. LEVOTHYROXINE:(T4) This is the preparation of choice for thyroid replacement and suppression therapy, because it is stable and has a long (7 days) half life, to be administered once daily. Oral preparations available are from 0.025 to 0.3 mg tablets For parentral use 200-500µg (100µg/ml when reconstituted) for injection. 21
  21. 21. LIOTHYRONINE(T3): This is more potent (3-4 times) and rapid acting than levothyroxine but has a short half life (24 hours) compared to levo, is not recommended for routine replacement therapy, it requires multiple dosing in a day. It should be avoided in cardiac patients. Oral preparation available are 5-50µg tablets For parentral use 10µg/ml 22 Thyroid hormone preparations
  22. 22. Treatment of Myxedema Coma O2 +/- intubation / ventilation if resp. failure Rapid blood glucose check +/- IV D50 +/- Hydrocortisone 100 to 250 mg IV Cautious slow rewarming (warm O2, scalp, groin, & axilla warm packs, +/- NG lavage) Thyroxine (T4) 500 mcg IV, then 50 mcg IV q day Add 25 mcg T3 PO or by NG q 12 h (if T4 to T3 peripheral conversion possibly impaired) Careful IV fluid rehydration (watch for CHF)
  23. 23. Disorders of Thyroid Hormone Excess "Thyrotoxicosis" is the term for all disorders with increased levels of circulating thyroid hormones "Hyperthyroidism" refers to disorders in which the thyroid gland secretes too much hormone Radioactive iodine uptake test (RAUI) distinguishes hyperthyroidism from other forms of thyrotoxicosis
  24. 24. Thyrotoxicosis with Elevated RAUI Graves' Disease Pituitary tumor secreting excess TSH Pituitary insensitivity to feedback Hydatidiform mole Choriocarcinoma Testis embryonal carcinoma Toxic multinodular goiter Toxic uninodular goiter Drugs inducing hyperthyroidism Iodine Amiodarone Lithium
  25. 25. Features of Graves' Disease (Toxic Diffuse Goiter) Most common cause of hyperthyroidism (70 to 85 % of all cases) Caused by thyroid stimulating immunoglobulins Mainly in young adults ages 20 to 50 5 times more frequent in women Half of cases have infiltrative ophthalmopathy with exopthalmos (not seen with other causes of hyperthyroidism) 5 % have pretibial myxedema Toxic multinodular goiter-Second most common cause of hyperthyroidism Most cases in women in 5th to 7th decades Often have long standing goiter Symptoms usually develop slowly
  26. 26. Symptoms of Thyrotoxicosis Nervousness, restlessness, shortened attention span, emotional liability, difficulty sleeping Increased appetite Weight loss Heat intolerance, fever Diaphoresis, Weakness Menstrual irregularities
  27. 27. Signs of Thyrotoxicosis Sinus tachycardia, Atrial fibrillation Tremor, hyper-reflexia, muscle wasting Warm, erythematous, moist skin Alopecia, nail friability & separation from bed Hyperventilation Eyelid retraction, lid lag, persistent stare Hyperactive bowel sounds With Graves' : may have exopthalmos, tender enlarged thyroid, & pretibial myxedema
  28. 28. Thioamides METHIMAZOLE CARBIMAZOLE PROPYLTHIOURACIL Radioactive iodine 131IODINE Iodides aqueous potassium iodide solution- LUGOL’S IODINE Iodinated contrast media ORAL IPODATE AND IPANOIC ACID-DIATRIAZOATE Mechanism Agents which interfere production of thyroid hormone Agents which modify tissue response to thyroid hormones Glandular destruction with radiation or surgery. 29
  29. 29. 30 Methimazole, Carbimazole, Propylthiouracil Methimazole is 10 times more active than Propyl thiouracil. They act by: Inhibiting thyroid peroxidase –catalysed reaction to block iodine organification. They block coupling of iodotyrosine They inhibit peripheral Deiodination of T4 to T3. Onset of drug is slow requiring 3-4 weeks before stores of T4 are depleted.
  30. 30. 31 Propylthiouracil Methimazole Absorption Rapid but incomplete At variable rates but complete Vol.of Dist. Approximates body waters Similar Protein binding more less accumulation In thyroid Similar Excretion Kidneys as inactive Glucuronide in 24 hrs Excretion slow,60-70% of drug is recovered in urine in 48 hrs
  31. 31. 32 Propylthiouracil Methimazole Half life 1.5 hrs 6 hrs Administration Every 6-8 hrs As a single dose in 24 hrs Duration of activity 100 mg inhibits iodine organification for 7 hrs 30 mg exerts Antithyroid effect for longer than 24 hrs Pregnancy Preferred, though cross placenta and is conc .in fetal thyroid but is highly protein bound ,cross placenta less readily Cross placenta and concentrated by fetal thyroid Nursing mothers Less secreted in breast milk secreted
  32. 32. 33 It occurs in 3-12 % of treated patients Maculopapular rash and fever are earlier effects. Urticarial rash, vasculitis, arthralgia, cholestatic jaundice, lymphadenopathy, and hypoprothrombinemia. Most dangerous complication is agranulocytosis this is infrequent but may be fatal.
  33. 33. 34 Well and rapidly absorbed from intestines Rapidly taken by thyroid gland and concentrated there Moderate increase leads to hormone secretion but substantial excess inhibits hormone release and promotes its storage, making the organ less vascular and firmer. Iodides stores in thyroid delays response to thioamides They inhibit organification and hormone release. With a dose of > 6 mg /day. They should be initiated after onset of thioamides therapy. It also decreases the vascularity of hyperplastic gland Improvement is rapid within 2-7 days (valuable in thyroid storm)
  34. 34. 35 Should not be used as a single therapy Should not be used in pregnancy May produce iodism causing acneform rash, swelling of salivary glands, mucous membrane ulceration, metallic taste bleeding disorders and rarely anaphylaxis.
  35. 35. 36 131 I isotope, administered orally It is rapidly absorbed, concentrated in thyroid gland and stored in follicles. It has a half life of 8 days and emits gamma rays and beta particles. The beta particles get accumulated in gland and destroy parenchyma. It is easy to administer, effective, painless and less expensive It causes destruction of parenchyma, necrosis and follicular disruption Therapeutic effect is due to emission of β-rays. Patients with age above 40 years only can be treated with this It crosses placenta and excreted in breast milk It may cause genetic damage and leukemia and neoplasia, it may be carcinogenic
  36. 36. Iodinated constrast medias Oral ipodate and ipanoic acid and IV diastrizoate These are richly iodinated compounds which inhibit 5- deiodinase enzymes and prevent conversion of t4 to t3 in liver, kidney, pituitary gland and brain
  37. 37. Drugs causing Euthyroid Hyperthyroxinemia Oral contraceptives Narcotics (methadone, heroin) Perphenazine Clofibrate 5-flurouracil Heparin Amiodarone Iodine contrast agents
  38. 38. Thyroid Storm (hyperthyroidism crisis) "Exaggerated or florid state of thyrotoxicosis" "Life threatening, sudden onset of thyroid hyperactivity" May represent end stage of a continuum : Thyroid hyperactivity to thyrotoxicosis to thyrotoxic crisis to thyroid storm "Probably reflects the addition of adrenergic hyperactivity, induced by a nonspecific stress, into the setting of untreated or undertreated hyperthyroidism"
  39. 39. Thyroid Storm Most cases secondary to Graves' disease Some due to toxic multinodular goiter Rare causes : Acute thyroiditis Factitious Malignancies (most do not efficiently produce thyroid hormones)
  40. 40. Thyroid Storm Important features : High fever (usually over 40 degrees C) Significantly abnormal mental status Agitation, confusion, psychosis, coma Marked tachycardia Vomiting, diarrhea Jaundice (in 20 %) Associated signs of Graves' disease
  41. 41. Thyroid Storm treatment High flow O2 Rapid cooling if markedly hyperthermic Ice packs, cooling blanket, mist / fans, nasogastric tube lavage, acetominophen (Salicylates contraindicated because cause peripheral deiodination to T3) IV fluid bolus if dehydrated May need inotropes instead if in CHF Propranolol 1 mg doses or labetolol 10 to 20 mg doses IV & repeat doses as needed
  42. 42. IV diltiazem +/- digoxin for rate control for atrial fib IV diuretics if in CHF IV hydrocortisone (or equivalent) 100 mg Propylthiouracil (PTU) 600 to 1200 mg PO or by NG Sodium iodide 1 gram IV one hour after the PTU Find and treat the precipitating cause Thyroid Storm treatment
  43. 43. THANKYOU Download slides from Authorstream-raghuprasada Slideshare-raghuprasada Youtube-raghuprasada

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