Thyroid Pharmacology Lecture Notes PDF

Thyroid Pharmacology  Objectives  Introduce the physiology and the regulation of thyroid hormones.  Understand the pathways and mechanisms of feedback regulation of thyroid hormone synthesis and actions.  Explain the rational for effective drug treatment of thyroid dis...

Thyroid Pharmacology  Objectives  Introduce the physiology and the regulation of thyroid hormones.  Understand the pathways and mechanisms of feedback regulation of thyroid hormone synthesis and actions.  Explain the rational for effective drug treatment of thyroid diseases.  Major components of the neuroendocrine system HYPOTHALAMUS Neurohormones ADH (hypothalamic CRH GnRH TRH GHRH OT (VSP) releasing factors/hormones) POSTERIO ANTERIOR R PITUITARY PITUITARY OT ADH (VSP) Pituitary hormones ACTH LH/FSH TSH GH PRL ADRENAL GONADS THYROID LIVER BREAST CORTEX Target Sex organ Steroids T3 +T4 IGFs hormones hormones  Thyroid hormone axis Hypothalamus Stimulatory Hypothalamic GHRH GnRH TRH TRH? CRH Factors Anterior Pituitary Cells Somatotroph Lactotroph Gonadotroph Thyrotroph Corticotroph Pituitary Hormones LH and FSH TSH GH Prolactin ACTH Released Major Target Organ Liver Mammary gland Gonads Thyroid gland Adrenal cortex Thyroxine (T4) Estrogen, Cortisol, Insulin-like and Target Gland Hormones growth factor None progesterone triiodothyronine adrenal and testoterone androgens (T3)  Thyroid Gland  Follicular cells-secrete T4, T3 and rT3  Parafollicular C cells-secrete calcitonin (Bone metabolism)  T4-thyroxine  T3-triiodothyronine  rT3-reverse triiodothyronine  T4, T3 and rT3 hormones regulate growth, metabolism, and energy expenditure, from oxygen consumption to cardiac contractility Tyrosine  Hormonal control – feedback inhibition Systemic hormones produced by target organs negatively regulate the secretion of pituitary and hypothalamus, to maintain homeostasis. - Hypothalamus - Short-loop Releasing feedback hormone signal + (neurohormone) Long-loop Anterior - feedback signal pituitary Hormone + Target organ Hormone http://www.endocrineweb.com/conditions/thyroid-nodules/thyroid-gland-controls-bodys-metabolism- how-it-works-symptoms-hyperthyroi https://www.hopeforhh.org/what-is-hh/understanding-hh/the- hypothalamus/  Thyroid gland produces, stores and releases hormones  Thyroid uses iodine to synthesize two hormones  Triiodothyronine (T3) and Thyroxine (T4)  Hypothalamus and Pituitary communicate with thyroid gland to maintain normal levels of T3 and T4  Higher or lower levels of these hormones can be problematic  Thyroid gland regulation Speed with which the cellular metabolism works affecting:  Breathing  Heart rate  Central and peripheral nervous systems  Body weight  Muscle strength  Menstrual cycles  Body temperature  Cholesterol levels  Synthesis of thyroid hormones  Tyrosines are iodinated on position 3 to give monoiodotyrosine (MIT)  Some molecules are iodinated on position 5 also to give diodotyrosine (DIT)  In Thyroid gland, MIT and DIT are coupled as  MIT + DIT = T3  DIT + DIT = T4 This process is called “organification”  Metabolism of thyroid hormones Deiodination of T4  Generates of T3 and rT3 (T4-T3 conversion)  Mostly occurs in the liver  Agents increasing p450 activity also increase T4-T3 conversion - Catalyzed by 5′-deiodinases  Circulation - Thyroid Hormone  T4 – 90%  T3 - 9%  rT3 – 1%  Pathophysiology  Disturbance of Physiologic hypothalamic- pituitary-thyroid axis The major steps in the synthesis, storage, release, and interconversion of thyroid hormones  Uptake of iodide ion (I–) by the gland  Oxidation of iodide and the iodination of tyrosyl groups of thyroglobulin  Coupling of iodotyrosine residues by ether linkage to generate the iodothyronines  Resorption of the thyroglobulin colloid from the lumen into the cell  Proteolysis of thyroglobulin and the release of thyroxine and triiodothyronine into the blood  Recycling of the iodine within the thyroid cell via de-iodination of mono- and diiodotyrosines and reuse of the I–  Conversion of thyroxine (T4) to triiodothyronine (T3) in peripheral tissues as well as in the thyroid 1) Iodide uptake by Follicular Cells  Concentrate I- in Follicular Cells up to 500X  Energy-dependent process  Needs to Na+/I- symporter (NIS)  What is the action of TSH? 2) Oxidation of I- - Allows the I- to react with tyrosine residues of Thyroglobulin  Occurs at the apical membrane  Requires thyroperoxidase & H2O2 3) Iodination of tyrosine residues of Thyroglobulin  TG is synthesized at the apical surface  Process also called organification  In the absence of thyroid hormone, the thyroid hormone receptor (TR):retinoid X receptor (RXR) heterodimer associates with a corepressor complex, which binds to promoter regions of DNA and inhibits gene expression.  In the presence of thyroid hormone (T3), the corepressor complex dissociates from the TR:RXR heterodimer, coactivators are recruited, and gene transcription occurs.  Target Tissues  Affect virtually every cell in the body  Affect at the level of gene transcription and plasma membrane  Hormones, once inside the cell, bind Thyroid hormone Receptors (THR)  Two types of receptors-THRα and THRβ  THR binds Retinoid X Receptor (RXR)  Absence of hormone-corepressors are bound  Presence of hormone-coactivators are bound  Metabolism  Thyroid hormone circulates binding Thyroid Binding Globulin (TBG)  T4 is inactivated in liver  Deiodination is catalyzed by iodothyronine 5’- deiodinase  Three types of deiodinases => Type I, II and III  Most T4 to T3 conversion occurs in liver  Thyroid Diseases Anaplastic Thyroid Cancer Hypothyroidism De Quervain's Thyroiditis Medullary Thyroid Cancer Follicular Thyroid Cancer Papillary Thyroid Cancer Goiters Silent Thyroiditis Graves' Disease Thyroid Cancer Hashimoto's Thyroiditis Thyroid Nodules Hurthle Cell Thyroid Cancer Thyroiditis Hyperthyroidism  Thyroid problems  Goiter - enlargement of the thyroid gland  Hyperthyroidism - when your thyroid gland makes more thyroid hormones than your body needs, Graves’ Disease  Hypothyroidism - when your thyroid gland does not make enough thyroid hormones, Hashimoto’s Disease  Thyroid cancer  Thyroid nodules - lumps in the thyroid gland  Thyroiditis - swelling of the thyroid  Thyroid Diseases  Hypothyroid-Hashimoto’s Disease (Chronic lymphatic thyroiditis)- Autoimmune disease that slowly destroys the thyroid gland resulting in decreased production of hormones. Increased levels of TSH and low levels of T3 and T4 are detected.  Hyperthyroid-Graves’ Disease-Also an autoimmune disorder which results in increased levels of T4 and decreased TSH. Radioactive iodine uptake indicates increased uptake.  Thyroid Diseases  Goiter-Noncancerous enlargement of thyroid gland. Its most common cause is due to iodine deficiency. Radioactive iodine can shrink thyroid gland.  Tests for Thyroid gland Measurement of Serum Thyroid Hormones: T4 by RIA Measurement of Serum Thyroid Hormones: T3 by RIA Thyroid Binding Globulin Measurement of Pituitary Production of TSH TRH Test Iodine Uptake Scan Thyroid Scan Thyroid Ultrasound Thyroid Antibodies-Thyroid Peroxidase Antibody; Thyroglobulin Antibody; Thyroid Stimulating Hormone Receptor Antibody Thyroid Needle Biopsy  http://www.endocrineweb.com/conditions/thyroid/thyroid-gland-function  Test Results Test Abbreviation Typical Ranges Serum thyroxine T4 4.6-12 ug/dl Free thyroxine fraction FT4F 0.03-0.005% Free Thyroxine FT4 0.7-1.9 ng/dl Thyroid hormone THBR 0.9-1.1 binding ratio Free Thyroxine index FT4I 4-11 Serum T3 80-180 ng/dl Triiodothyronine Free Triiodothyronine l FT3 230-619 pg/d Free T3 Index FT3I 80-180 Radioactive iodine RAIU 10-30% uptake Serum thyrotropin TSH 0.5-6 uU/ml Thyroxine-binding 12-20 ug/dl T4 +1.8 TBG globulin ugm TRH stimulation test 9-30 uIU/ml at 20-30 TSH Peak min Serum thyroglobulin l Tg 0-30 ng/m Thyroid microsomal TMAb Varies with method antibody titer Thyroglobulin TgAb Varies with method antibody titer  Symptoms of too little T3 and T4 in your body (hypothyroidism):  Trouble sleeping  Tiredness and fatigue  Difficulty concentrating  Dry skin and hair  Depression  Sensitivity to cold temperature  Frequent, heavy periods  Joint and muscle pain  Hypothyroidism Treatment Replacement of thyroid hormone  Exogenous and endogenous thyroid hormone is structurally similar  Replaces endogenous thyroid hormone  T4 is chemically synthesized  T3 vs. T4  In blood, T4 (90%)is more than T3 (9%)  T4 is the pro-drug  Blood is a reservoir  Adding to reservoir will help maintain normal metabolic rates in different conditions  T3 vs. T4 Half Life-  T3 - 1 day  T4 - 6 days  Overall long term therapy for Hypothyroidism is safe and effective  Metabolism of thyroid hormones T4 T3 Consequences Plasma 1/2-life (days) 6-7 1 Changes by (strong binding to (faster metabolic pharmacologic TGB) clearance) intervention are observed only 1-2 weeks later. Biologic potency 1 4-10 Concentration ~ 10-7 mol/l ~ 2x10-9 mol/l T4 is the predominant thyroid hormone in blood % in plasma 90% 9% The T4 large pool in (75% of which from the plasma provides a peripheral conversion of reserve of prohormone T4 in liver & kidneys) available for T3 synthesis Inactivation deamination, decarboxylation, deodination or conjugation and excretion by the liver Regulation of T3/T4 secretion (I) 1) Positive regulators: - TRH, TSH - Low T3/T4 - Low I- 2) Negative regulators: - Somatostatin, Dopamine - High T3/T4 - High I- - Glucocorticoids NIS (Na/I Symporter) - Increase I- uptake - Expression inversely regulated by I- - Selectively expressed in the thyroid => Radioactive iodine scanning (selective therapy)  Regulation of T3/T4 secretion (II): Specific regulatory effects Wolff-Chaikoff Effect: - Excess I- => transiently decreases NIS - Reduction in T3/T4 synthesis - Normal thyroid: Quick recovery - Abnormal thyroid - Hypothyroidism: Persistent suppression - Hyperthyroidism: Transient suppression Jod-Basedow Phenomenon: - Excess I- => Thyrotoxicosis - Occurs in thyroid cancer  Levothyroxine (T4)  Identical to Thyroxine  L-thyroxine  For treatment of Hypothyroidism  WHO lists as essential medicine  Lifelong therapy for hypothyroidism-not cure  Given once daily  Half life is 6-7 days  Levothyroxine sodium tablets, USP, for oral administration, are available containing 25 mcg, 50 mcg, 75 mcg, 88 mcg, 100 mcg, 112 mcg, 125 mcg, 137 mcg, 150 mcg, 175 mcg, 200 mcg or 300 mcg of Levothyroxine sodium, USP.  Levothyroxine (T4)  Levothroid, Levoxyl, Synthroid, and Unithroid  Thyroid hormone replacement therapy Assessment  TSH test generally recommended at 6 to 8 week intervals until normalization  After normalization TSH test every 6 months to a year depending on the clinical situation  Physical exam and TSH levels monitored annually  Range varies with patient characteristics Reference range (TSH mIU/L*)  0.4-5.0 (EUTHYROID)  5.0 (HYPOTHYROID)  *mIU/L = milli-international units per liter  High TSH levels indicates - not replacing enough Noncompliance Decreased absorption -Celiac disease, Crohn’s disease -Resins such as sodium polystyrene sulfonate (Kayexelate®), and cholestyramine, Iron, calcium supplements, aluminum hydroxide, sucralfate Decreased bioavailability-Increased Thyroxine-binding globulin During pregnancy, hepatitis or estrogen treatment Increased metabolism-Increased P450 enzymes and increased hepatic secretion (Rifampin, phenytoin, carbamazepine)  Low TSH levels indicates – Too much  Self-administration of excess T4  High dose glucocorticoids  Decreased Thyroid-Binding Globulin: Androgens, nephrotic syndrome, chronic liver disease, severe systemic illness  Patients with hypothyroidism and hypertension or cardiovascular problems should begin levothyroxine therapy with a low dosage  Patients with hypothyroidism and hypertension or cardiovascular problems should begin levothyroxine therapy with a low dosage  Liothyronine (T3)  Identical to T3  Half Life – 1-2 days  More Potent – active form of thyroid hormone  hypothyroidism and myxedema coma  Liothyronine (T3)  Liothyronine, Triostat, Cytomel  Side Effects Due to inappropriate dosing  Severe: Hyperthyroidism, Risk of cardiac Dysrhythmias, Cardiac failure  Less severe: Bone resorption => osteoporosis  T4 = INACTIVE hormone and must be converted to T3 to become active  T3 = ​ACTIVE thyroid hormone, does NOT need to be converted  ​With T4, patient relies upon your body to convert to T3  Symptoms of too much T3 and T4 in your body (hyperthyroidism):  Anxiety  Irritability or moodiness  Nervousness, hyperactivity  Sweating or sensitivity to high temperatures  Hand trembling (shaking)  Hair loss  Missed or light menstrual periods  Treatment of Hyperthyroidism  Surgery  Inhibitors of Iodide uptake  Inhibitors of organification and hormone release  Inhibitors of Peripheral Thyroid hormone metabolism  Agents affecting thyroid hormone homeostasis  Antagonism of excessive thyroid hormone I- Surgery: II- Pharmacological inhibition of hormone synthesis: 1- Inhibitors of Iodide Uptake 2- Inhibitors of Organification and Hormone Release: a- Iodides i) Inorganic ii) Radioactive b- Thioamines 3- Inhibitors of Peripheral Thyroid Hormone Metabolism a- Ipodate b- β-Adrenergic Blockers  Antagonism of excessive thyroid hormone I- Surgery: II- Pharmacological inhibition of hormone synthesis: 1- Inhibitors of Iodide Uptake 2- Inhibitors of Organification and Hormone Release: a- Iodides i) Inorganic ii) Radioactive b- Thioamines 3- Inhibitors of Peripheral Thyroid Hormone Metabolism a- Ipodate b- β-Adrenergic Blockers Antagonism of excessive thyroid hormone: 1- Inhibitor of Iodide uptake Analogs: Perchlorate, Thiocyanate, Pertechnetate MOA: - Anions with a molecular radius equal to that of I- => Compete with I- for uptake by the NIS Limitations: Delayed effect. Side effects: Aplastic anemia (uncommon) Applications: Radiopaque contrast material.  Antagonism of excessive thyroid hormone I- Surgery: II- Pharmacological inhibition of hormone synthesis: 1- Inhibitors of Iodide Uptake 2- Inhibitors of Organification and Hormone Release: a- Iodides i) Inorganic ii) Radioactive b- Thioamines 3- Inhibitors of Peripheral Thyroid Hormone Metabolism a- Ipodate b- β-Adrenergic Blockers Antagonism of excessive thyroid hormone: 2- Inhibitors of Organification and Hormone Release: a- Iodide: i) Inorganic iodide Analog: Potassium iodide MOA: - Wolff–Chaikoff effect - Reduces the transcription of thyroid peroxidase => reduces H2O2 generation => reduces iodination of TG Limitations: - Transient effect Indications: - Thyroid surgical resection (reduce size and vascularity of thyroid) - Preventive effects (suppresses thyroid function temporarily and prevent the uptake of 131I-)  Antagonism of excessive thyroid hormone I- Surgery: II- Pharmacological inhibition of hormone synthesis: 1- Inhibitors of Iodide Uptake 2- Inhibitors of Organification and Hormone Release: a- Iodides i) Inorganic ii) Radioactive b- Thioamines 3- Inhibitors of Peripheral Thyroid Hormone Metabolism a- Ipodate b- β-Adrenergic Blockers Antagonism of excessive thyroid hormone: 2- Inhibitors of Organification and Hormone Release: a- Iodide: ii) Radioactive iodide: 131I- Indications: - Low dose: Test of thyroid function (tracer) - High dose: First-line therapy for hyperthyroidism (alternative to surgery) MOA: - 131I- incorporated into TG => selective destruction of thyroid; - Cytotoxic effect after 1-2 months with a maximum after 3-4 months; - Stop anti-thyroid drugs 2-5 days prior Side effects: - Overdose kills FC => disappearance of colloid => risk of hypothyroidism (easy to manage) Limitations: - Avoid in children, breast-feeding or pregnant women  Antagonism of excessive thyroid hormone I- Surgery: II- Pharmacological inhibition of hormone synthesis: 1- Inhibitors of Iodide Uptake 2- Inhibitors of Organification and Hormone Release: a- Iodides i) Inorganic ii) Radioactive b- Thioamines 3- Inhibitors of Peripheral Thyroid Hormone Metabolism a- Ipodate b- β-Adrenergic Blockers Antagonism of excessive thyroid hormone: 2- Inhibitors of Organification and Hormone Release: b- Thioamines: Analogs: Methimazole, Propylthiouracil (PTU) MOA: - Compete with TG for oxidized I- - Iodinated thioamines bind TG - PTU also inhibits T4-T3 conversion Limitations: - Delayed effects (weeks) - Affects synthesis but NOT secretion - If hyperthyroidism persists: radioactive I-, surgery Side effects: Goitrogens effects, Pruritic rash, Arthralgias Rare complications: - Agranulocytosis (fever, sore throat) => Baseline measurement of white blood cell count is recommended; Angioedema  Some terms  Goitrogens effects- Agents that disrupt the production of thyroid hormones by interfering with iodine uptake in the thyroid gland. This triggers the pituitary to release TSH, which then promotes the growth of thyroid tissue, eventually leading to goiter.  Pruritic rash-Itching Rash  Arthralgia-Joint pain  Agranulocytosis-An acute condition involving a severe and dangerous leukopenia  Propylthiouracil (protein-bound) Methimazole Actions Inhibits thyroid peroxidase & Inhibits thyroid peroxidase peripheral T4 to T3 conversion only Half-life and administration Short 1/2life (1h); 3 times a day Once a day (4-6h) Last longer Effect on the basal metabolic rate 2-4 weeks 2-4 weeks Tolerability Well tolerated Well tolerated Side effects (1): Bleeding Deplete levels of prothrombin >>> Less frequent hypoprothrombinemia & increased bleeding tendency Side effects (2): Allergic hepatitis More frequent Less frequent Indication (1): Most cases Not recommended Recommended (especially Graves‘ disease) Indication (2): Acute management Recommended (additional ability to Not recommended of severe hyperthyroidism block T4-T3 conversion) (thyroid storm) Indication (3): Pregnancy & Recommended (extensive safety Not recommended lactation record) (development of aplasia cutis)  Propylthiouracil (protein-bound) Methimazole Actions Inhibits thyroid peroxidase & Inhibits thyroid peroxidase peripheral T4 to T3 conversion only Half-life and administration Short 1/2life (1h); 3 times a day Once a day (4-6h) Last longer Effect on the basal metabolic rate 2-4 weeks 2-4 weeks Tolerability Use methimazole Well tolerated in all Well tolerated Side effects (1): Bleeding Graves’ Disease Deplete levels patients of prothrombin >>> Less frequent hypoprothrombinemia & increased EXCEPT: bleeding tendency Side effects (2): Allergic hepatitis Pregnancy More frequent Less frequent Indication (1): Most cases Not recommended Recommended (especially Graves‘ disease) Lactation Indication (2): Acute management of severe hyperthyroidism Thyroid block storm Recommended (additional ability to T4-T3 conversion) Not recommended (thyroid storm) Indication (3): Pregnancy & Recommended (extensive safety Not recommended lactation record) (development of aplasia cutis)  Antagonism of excessive thyroid hormone I- Surgery: II- Pharmacological inhibition of hormone synthesis: 1- Inhibitors of Iodide Uptake 2- Inhibitors of Organification and Hormone Release: a- Iodides i) Inorganic ii) Radioactive b- Thioamines 3- Inhibitors of Peripheral Thyroid Hormone Metabolism a- Ipodate b- β-Adrenergic Blockers Antagonism of excessive thyroid hormone: 3- Inhibitors of Peripheral Thyroid Hormone Metabolism: a- Ipodate (not FDA approved): radiopaque contrast media used for X-rays b- β-Adrenergic Blockers β-Adrenergic Blockers MOA: - Reduces T4/T3 conversion - Reduces beta-adrenergic like symptoms (sweating, tremor, tachycardia) Analogs: - Esmolol: - Treatment of thyroid storm (rapid onset of action) - Propranol: - Preparation of patient for surgery - Initial treatment while radioiodine take effects - Acute hyperthyroid crisis  Objectives  Introduce the physiology and the regulation of thyroid hormones.  Understand the pathways and mechanisms of feedback regulation of thyroid hormone synthesis and actions.  Explain the rational for effective drug treatment of thyroid diseases.