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

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

Regulation of Thyroid Hormone Secretion Negative Feed Back

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

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)

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.

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:

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

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

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

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.

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

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

 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

Thioamides

 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

 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 – %)

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

Potassium Iodide

 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

 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

 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

Anion Inhibitor

 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

 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)

 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

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.

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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