1. THYROID & ANTITHYROID DRUGS Dr. Nur Azlina Mohd Fahami Dept. of Pharmacology 2005

2. The Thyroid Gland Located at anterior part of neck on either side of trachea Comprised to 2 lobes; 20 g wt Rich in blood supply from autonomic system Function: Facilitate normal growth & maturation. Maintaining metabolism in tissue optimal for normal function

3. Regulation of Thyroid Hormone Secretion Negative Feed Back

4. I. Dietary iodine is absorbed in the blood as iodide (I - ).  Iodide is then actively taken up by the thyroid gland (“iodide trapping”)  Within the thyroid via thyroidal peroxidase: a. Oxidation: oxidizes iodide to a more reactive form of iodide (iodine). b. Iodination: to form mono (MIT) & diiodinated tyrosine (DIT) c. Coupling : to form the iodothyronine residues T3 (Triiodothyronine) & T4 (Thyroxine) BIOSYNTHESIS, STORAGE AND RELEASE OF T3 AND T4

5. O CH 3 CHCOOH NH 2 I 3 5 I HO I I 3’ 5’ DIT + DIT O CH 3 CHCOOH NH 2 I 3 5 I HO I 3’ 5’ DIT + MIT 3,5,3’,5’-Tetraiodothyronine (thyroxine, or T4) 3,5,3’-Triiodothyronine (T3)

6. 4. Storage: T3 and T4 are stored in the thyroid follicles as part of the thyroglobulin.  Release: Thyroglobulin is taken up by endocytosis, T3 and T4 are extensively bound to thyroxin-binding globulin (TBG). Release is stimulated by TSH.  T3 (active form), T4 (less-active) converted to T3 in the peripheral tissue by enzyme deiodinase.

8. Hypothyroidism – a decrease in the amount of thyroid hormones manufactured and secreted. –Eg. Hashimoto disease Hyperthyroidism – an increase in the amount of thyroid hormones manufactured and secreted. –Eg: Graves’ disease Two diseases are related to the hormone producing activity of the thyroid gland:

9. TREATMENT AIMS  Thyroid hormones Levothyroxine (T4) Liothyronine (T3) Liotrix (T3 and T4)  Thyroid hormones Thioamides (methimazole & propylthiouracil) Iodide salts Radioactive iodine HYPOTHYROIDISM HYPERTHYROIDISM Beta-Adrenergic receptor antagonists

10. Replacement therapy is used to treat hypothyroidism. Synthetic preparations the T3 and T4 are used. 1. Levothyroxine (L-T 4 )  drug of choice  oral or i.v.  Absorbed well – duodenum & ileum (80%) - cases of myxedema coma (give IV)  T1/2= 7 days, give once/day.  Stable, uniform content, low cost   allergy Treatment of Hypothyroidism

11. 2. Liothyronine (L-T 3 ) more potent that levothyroxine but is not used much due to shorter half life (multiple daily doses needed) greater cardiotoxicity ( T 3 should be avoided in patients with cardiac disease.)  cost. 3. Liotrix (T 3 and T 4; 1:4 ratio)  no advantage over above preparations.  >>>expensive Treatment of Hypothyroidism

12. TOXIC EFFECT ADULT Similar to hyperthyroidism symptoms  Sympathetic Nervous System activity Tacchycardia,  CO, hypertension, arrhythmias, tremors, muscle weakness,  BW etc. CHILDREN Anxiety, insomnia, increase in bone growth,  growth.

13. Radioactive Iodine TREATMENT OF HYPERTHYROIDISM Antithyroid Drugs Thyroid Surgery (thyroidectomy)

14. TREATMENT OF HYPERTHYROIDISM ANTITHYROID AGENTS  In thyroid activity & hormones can be achieved by: Agents that interfere with the production of thyroid hormones Agents that interfere with the release of thyroid hormones Glandular destruction with radiation or surgery

15.  Methimazole & Propylthiouracil (PTU)  Methimazole is about 10 x more active than PTU.  MOA:  inhibit thyroid peroxidase, ionization of thyroxine residue (formation of MIT & DIT)  block coupling of iodothyrosine and  inhibit peripheral deiodination of T4 to T3 (> PTU). THIOAMIDES

16. Thioamides

17.  Oral, well absorbed, actively concentrated in the thyroid,  short T1/2 (Methimazole = 6hrs, PTU = 1.5hrs), metabolized liver, excreted via kidney.  Dose: Methimazole: 1x/day, PTU: 3/4x/day  Takes 3-4 weeks for onset of therapeutic effect.  Cross placenta (Use with caution in pregnancy).  PTU safer – bound to PP X cross placenta readily.  PTU not secreted sufficiently in milk. PHARMACOKINETICS

18.  Mild & Moderate hyperthyroidism  Graves disease to induce remission or  before surgery or radiation to control symptoms. CLINICAL USES ADVERSE EFFECTS  Maculopapular skin rash (3-12%)  Arthralgia, fever, hepatitis, lupus-like syndrome  Most dangerous: severe agranulocytosis (esp. in older pts – 0.3-0.6%)

19. MOA: inhibit the release of thyroid hormones from thyroid gland & reduce size and vascularization of the hyperplastic gland. IODIDE SALTS (POTASSIUM IODIDE)  Oral, duration 4 hrs, metabolized.  Rapid improvement of thyrotoxicosis symptom within 2- 7 days.  Cross placenta.  iodine escape  occurs within 2 – 8 weeks and its withdrawal may produce severe thyrotoxicosis. PHARMACOKINETICS

20. Potassium Iodide

21.  Initiation therapy (onset of Thioamides therapy)  thyroid storm (thyrotoxicosis) or in patients awaiting surgery. CLINICAL USES ADVERSE EFFECTS  sore mouth and throat, swollen salivary glands  metallic taste, mucous membrane ulceration  Goiter (fetus).  skin rashes (acneiform), drug fever

22.  Iodinated contrast agents (x-ray film)  Valuable for treatment of hyperthyroidism  MOA: rapidly inhibit the conversion of T4 to T3 in liver, kidney, pituitary gland and brain  Use: adjunct therapy of thyroid storm (alternative to Potassium iodide/Thioamides)  Side Effects: relatively non-toxic, patients may experience similar adverse effects as Iodide (with chronic use). SODIUM IPODATE

23.  Perchlorate (Clo 4 - ), thiocyanate (SCN - )  MOA: block uptake of iodide by gland through competitive inhibition of iodide transport mechanism.  Use: Percholorate, block thyroidal reuptake of iodide in patients with iodide-induced hyperthyroidism (amiodarone induced hyperthyroidism)  Side Effects: toxic, aplastic anemia (rarely used) ANION INHIBITORS

24. Anion Inhibitor

25.  131 I, the only isotope used for treatment of hyperthyroidism. Sodium 131 I orally.  MOA: concentrated uptake by thyroid, beta particle emission destroys thyroid tissue.  Pharmacokinetics:  Oral solution, rapidly absorbed,  cross placenta, excreted in milk,  isotope T1/2 = 5 days. RADIOACTIVE IODINE (RAI) 131 IODIDE

26.  Destruction of thyroid tissue in thyrotoxicosis  Absolutely contraindicated in pregnancy or nursing  Advantage: easy to administered, effective, cheap and absence of pain. CLINICAL USES ADVERSE EFFECTS  Hypothyroidism – require life long treatment with thyroid drugs  Radiation induced genetic damage, gonad damage, leukemia (extremely rare)

27.  Adjunct therapy  MOA: blockade of  -adrenergic receptors to decrease the tachycardia, palpitations and arrhythmias caused by elevated levels of thyroid hormones. Propranolol used.  Pharmacokinetics: Oral, duration 4 hrs, metabolized.  Use: thyroid storm or in patients awaiting surgery or response to radiation treatment. BETA-ADRENERGIC RECEPTOR ANTAGONISTS

28. Thyrotoxicosis in Pregnancy Ideally treatment with 131 I or subtotal thyroidectomy prior to pregnancy Safest: Propylthiouracil (PTU) throughout pregnancy or First trimester – PTU, followed by subtotal thyroidectomy mid trimester. Methimazole as alternative but possible risk of fetal scalp defect.

29. THYROID STORM Sudden acute exacerbation of all symptoms of thyrotoxicosis (life threatening syndrome) Propanolol – IV Reduce severe CVS manifestation Potassium Iodide (10 drops orally) –Reduce release of thyroid hormone PTU –Reduces hormone synthesis –inhibit peripheral deiodination of T4 toT3 Steroid (hydrocortisone) Protect patient against shock

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