Thyroid and Antithyroid Drugs By Sadeghi E Ph

Thyroid and Antithyroid Drugs By: Sadeghi. E, Ph. D School of Medicine, Medical Sciences

Thyroid & Antithyroid drugs Dr. Aali, Ph. D Department of Pharmacology Faculty of Medicine

Thyroid Gland Hormones n n n Thyrotropin (TSH) produced in anterior Pituitary gland. TSH secretion regulated by TRH. T 4 & T 3 regulation by TRH & TSH balance.

Synthesis and Transport of Thyroid Hormones n n n n Thyroid secretes 2 iodine-containing hormones: v Triiodothyronine (T 3). v Thyroxine (Tetraiodothyronine, T 4) The iodine comes from food or iodide supplements. Iodide ion is actively taken up by and concentrated in thyroid gland. Iodine organification by thyroidal Peroxidase. Thyroglobulin serves as a scaffold for thyroid hormone synthesis. Tyrosine residues in thyroglobulin are iodinated to form monoiodotyrosine (MIT). Diiodotyrosine (DIT) 1 molecule each of MIT and DIT combine to form T 3. 2 molecules of DIT combine to form T 4.

Biosynthesis of thyroid hormones

THYROID PHYSIOLOGY n Iodide Metabolism n n The recommended daily adult iodide (I-) intake is 150 mcg Transport of Thyroid Hormones n Thyroxine-binding globulin (TBG)

Thyroid Hormones Triiodothyronine (T 3) Thyroxine (T 4): Tetraiodothyronine Role: v v Increase basal metabolic rate. Normal growth and developme of nervous, skeletal, reproductive systems Normal body temperature Control of metabolism of fats, carbohydrates, proteins, and vitamins.

Hypothalamic-pituitary-thyroid axis

Hyperthyroidism n Hyperthyroidism(Thyrotoxicosis) : v v v Graves' disease (autoimmune disorder, antibody activates TSH receptor ) Thyroid adenoma Pituitary adenoma Medicine : Amiodarone (iodine-rich compound) ……

Hypothyroidism cause: v Iodine deficiency (endemic goiter ) v Autoimmune chronic thyroiditis: Hashimoto's thyroiditis v Postpartum thyroiditis v Medical treatments (Surgery, radioactive iodine ) v …. n Myxedema coma (Elderly) n Cretinism (Children)

Key features of thyrotoxicosis and hypothyroidism

BASIC PHARMACOLOGY

THYROID HORMONES n Chemistry n n n Levo (L) Dextro (D), dextrothyroxine, has approximately 4% of biologic activity of the L isomer T 3 is about 10 times more potent than T 4.

Thyroid hormone kinetics Variable T 4 T 3 Volume of distribution 10 L 40 L Daily production 75 mcg 25 mcg Half-life (biologic) 7 days 1 day Amount bound 99. 96% 99. 6% Biologic potency 1 4 Oral absorption 80% 95%

Mechanisms of Action of T 4 and T 3 v The free forms of T 4 and T 3 transport to peripheral tissue. v T 4 is converted to T 3 by deiodinase. v T 3 enters the nucleus. v T 3 binds to a specific T 3 receptor protein.

Thyroid hormones v v v T 3 bound to receptors, change conformation of receptor. Activate transcription. Lead to increased formation of RNA and subsequent protein synthesis.

Model of interaction of T 3 with T 3 receptor TR-LBD, : T 3 receptor ligand-binding domain

Thyroid hormones n n Thyroid hormones control expression of genes responsible for many metabolic processes. Most proteins including: § Na+/K+-ATPase § Contractile proteins in smooth muscle and heart § Enzymes involved in metabolism

Thyroid Preparations n Animal origin n n Desiccated thyroid Synthetic: n levothyroxine, liothyronine, liotrix n levothyroxine (L-T 4, levoxyl, synthroid) liothyronine (T 3, cytomel, triostat) liotrix (T 4 plus T 3) (euthyroid, thyrolar)

Levothyroxine n n n Synthetic levo isomer of T 4. PO available. Preferred drug for hypothyroidism. Better standardization and stability. Facilitates maintenance of a steady physiologic replacement. Long duration.

Liothyronine n n n n Synthetic L-T 3. PO available. More difficult to monitor than T 4. More expensive. Faster actin Shorter duration of action. Treatment of choice for Mixedema coma.

Clinical use 1. Hypothyroidism: Cretinism & Myxedema 1. Simple goiter 23

Adverse effects q Cardiac effects are the most important, specially in old patients: § Angina pectoris, palpitation, cardiac dysrhythmias or heart failure. § Palpitation can be treated with BB

ANTITHYROID AGENTS

ANTITHYROID AGENTS n n n Thioamides Anion Inhibitors Iodides Radioactive Iodine Adrenoceptor-Blocking Agents

Biosynthesis of thyroid hormones

Thioamides Structure of thioamides

Thioamides n Pharmacokinetics n Propylthiouracil (PTU) is rapidly absorbed and the bioavailability is 50 -80% n Methimazole is completely absorbed n Both thioamides cross the placental barrier n PTU is safer to use in pregnancy since it is not teratogenic.

Thioamides; Pharmacodynamics q q Act by multiple mechanisms n Prevent hormone synthesis by inhibiting thyroid peroxidase (organification). n Inhibiting peripheral deiodination of T 4 and T 3 The onset of these agents is slow, often requiring 3 -4 weeks

Thioamides: Toxicity: n Occur in 3 -12% of treated patients n The most common adverse effect is a rash (4 -6%) n Rare adverse effects include: n n an urticarial rash, vasculitis, a lupus-like reaction, lymphadenopathy, hypoprothrombinemia, acute arthralgia. Hepatitis can be fatal n Nausea and GI distress n The most dangerous complication is agranulocytosis

Anion Inhibitors n Perchlorate (Cl. O 4 -) n Thiocyanate (SCN-) n They cause aplastic anemia, so rarely used clinically.

Iodides (Iodine+ Potassium iodide) Lugol’s solution (solution of iodine and potassium iodide in water) n Inhibit organification n Inhibit Hormone release n Onset of action: 2 -7 days n Decrease the size and vascularity of hyperplastic gland n Iodide should not be used alone, because: v Gland will escape from the iodide block in 2– 8 weeks v its withdrawal may produce severe exacerbation of thyrotoxicosis in an iodine-enriched gland. n

Clinical Use Thyroid storm Prepare patients for surgical resection of a hyperactive thyroid. n n § Given prior to surgery, facilitate thyroidectomy.

Radioactive Iodine n n n 131 I is the only isotope used for treatment of thyrotoxicosis. Therapeutic effect depends on emission of rays A dose large severely destroy the gland

Adrenoceptor-Blocking Agents n n n Metoprolol Propranolol Atenolol Useful in controlling tachycardia and other cardiac abnormalities of thyrotoxicosis. Propranolol also inhibits the peripheral conversion of T 4 to T 3.

Summary