Presentation on theme: "Thyroid Hormones Eric Lazartigues, Ph.D. Department of Pharmacology (504) 568-3210."— Presentation transcript:
Thyroid Hormones Eric Lazartigues, Ph.D. Department of Pharmacology (504)
O I I I I HO I 2 + Tyrosine C C COOH HH HNH 2 90 % Thyroxine (T4) deiodinase Bound to plasma proteins: TBG C C COOH HH HNH 2 HO MIT C C COOH HH HNH 2 HO DIT I I I C C COOH HH HNH 2 I I O HO I C C COOH HH HNH 2 T 3 (active) Reverse T 3 (inactive) O I I I HO C C COOH HH HNH 2
Blood Biosynthesis of Thyroid Hormones: Steps 1 and Follicular cell Step 1: Iodide uptake: Na/I Pump (symporter)- ATP dependent. Inhibited by ClO 4 - and SCN - Activated by TSH (↓stores iodine→↑ uptake) Step 2: Oxidation of iodide and iodination of thyroglobulin Thyroid peroxidase (TPO) (apical surface) Fomation of MIT and DIT Storage in the lumen of thyroid follicle Inhibited by PTU and MMI
Biosynthesis of Thyroid Hormones: Steps 3 and 4 Blood 1 2 Follicular cell 3 4 Step 3: Coupling of iodotyrosine residues to generate iodothyronines. Thyroid peroxidase. Formation T4 (DIT+DIT) and T3 (MIT+DIT) Activity: [TSH] and iodide availability Inhibition: PTU, MMI Step 4: resorption of the TRG colloid into cell Endocytosis of TRG via receptor: megalin Inhibition: Colchicine, Li 2+, I -, cytochalasine B
Biosynthesis of Thyroid Hormones: Steps 5 to 7 Blood Step 5: Proteolysis of TRG. Colloid droplets fuse with lysosomes Enhanced by TSH Endopeptidases: TRG→intermediates Exopeptidates: intermediates→MIT+DIT 90% T4 and 10% T3 Step 6: Recycling of Iodine I - →TRG Step 7: conversion T4→T3 5’deiodinase
G s AC cAMP Protein Kinase A (+) TSH Increased DNA RNA Protein Cell size Cell number Follicle formation Trapping of I Iodination Endocytosis of colloid Thyroglobulin degradation Glucose oxidation NADPH generation GrowthHormone Synthesis Figure 4 : Effects of TSH on thyroid gland TSH
TRH Hypothalamus TRH release synthesis TSH T4,T3 T4 Somatostatin Dopamine TSH Long Loop Thermal Caloric Signals T3 T 4 Figure 5. Axis for Thyroid Control Thyroid Tissue
Conditions and Factors That Inhibit Type I 5'-Deiodinase Activity Acute and chronic illness Caloric deprivation (especially carbohydrate) and Malnutrition Glucocorticoids Adrenergic receptor antagonists (e.g., propranolol in high doses) Oral cholecystographic agents (e.g., iopanoic acid, sodium ipodate) Propylthiouracil
T 4 T 3 T 3 TR mRNA Proteins for growth and maturation Na +, K + - ATPase Mitochondria Respiratory enzymes O 2 ConsumptionMetabolic rate CO 2 Urea Ventilation Renal Function Muscle Mass Adipose Tissue Thermogenesis Sweating Insensible water loss Substrates O 2 Cardiac Output Ventilation Food Intake Mobilization of stored fat, carbohydrates and Proteins Other enzymes, proteins Nucleus Cytoplasm Whole Body Effects (permissive) Tissue deiodinase Intracellular Effects ATP use
Nervous System: 1. T 3 is absolutely required for perinatal brain development. i). Growth of cerebral and cerebellar cortex. ii). Axon proliferation iii). Synaptogenesis. 2. In Adults, enhances: i). Wakefulness and responsiveness ii). Emotional tone iii). memory Sympathetic Nervous System. 1. Synergizes with sympathetic nervous system. i). Promotes increases in -adrenergic receptor and Gs proteins. ii). Important for metabolic and cardiac effects of thyroid hormone. Effects of Thyroid Hormone
Primary Hyperthyroidism: T4 and T3, TSH 1. Autoimmune thyroiditis: Grave’s disease - Autoantibodies bind and activate TSH receptors - Other: Tumor of thyroid gland. 2. Symptoms: - Large increases in BMR Leads to weight loss despite increased food intake. - Heat production: heat intolerance and excessive sweating. - SNS activity Tachycardia, tremor, nervousness, wide-eyed stare - Enlarged thyroid gland –Goiter - Exophthalmos: Protrusion of eyeballs.
Rx For Hyperthyroidism - 1 capcap I-I- I-I- I-I- Na 1 Block Active Transport of iodide Complex anions: monovalent, hydrated ions similar in size to Iodide. Thiocyanate: found in certain foods and in cigarette smoke (in large doses, thiocyanate can also inhibit organification) Problems- The Jim Jones effect Perchlorate (ClO 4 - ) – 10x more active as thiocyanate. Low doses (750 mg per day) have been used in the treatment of Grave’s disease. Excessive doses (2-3 g per day ) causes increased incidence of fatal aplastic anemia.
Treatments I-I- 3 IoIo IoIo MIT DIT T3T3 T4T4 TPX MIT DIT T3T3 T4T4 MIT DIT T3T3 T4T4 MIT 4 Other: Side effects headaches drowsiness or dizziness. immunosupression Iodination of Thyroglobulin and Coupling Reaction (thyroperoxidase) Thionamides or thioureylenes : propylthiouracil, methamizole, carbimazole Drug-drug interactions: especially: warfarin, digoxin, beta-blockers Rx For Hyperthyroidism - 2 Methimazole
Treatments I-I- 3 IoIo IoIo MIT DIT T3T3 T4T4 TPX MIT DIT T3T3 T4T4 MIT DIT T3T3 T4T4 MIT 4 Rx For Hyperthyroidism - 3 Iodide: High doses cause paradoxical decrease in thyroxin biosynthesis, at the organification step Striking and rapid (changes in basal metabolic rate within hours) Radioactive Iodide ( 131 I), (IODOTOPE THERAPEUTIC) - 80 to 150 µCi/gram (lower doses may limit rebound hypothyroidism). This leads to partial destruction of the gland. - Used when prolonged treatment with anti-thyroid drugs or surgery has not led to remission. More commonly used in older patients- Major disadvantage is long period of time required before hyperthyroidism is controlled. Drugs that block Type I deiodinases: propylthiouracil Drugs that block both Type 1 and Type II deiodinases: sodium ipodate, iopanoic acid. In addition, metabolism of these drugs lead to the release of mgs of iodide, which can further inhibit T4/T3 secretion. These drugs are commonly used as radiology contrast dyes.
THYROID STORM 1. Thyroid storm is a crisis or life-threatening condition characterized by an exaggeration of the usual physiologic response seen in hyperthyroidism * High fever * Tachycardia * Nausea/vomiting * Irregular heart beat * Acute heart failure * Confusion/disorientation 2. Usually precipitated by concurrent medical problems (infections, stress, surgery, trauma, heart disease, diabetic ketoacidosis) 3. Treatment: - antipyretics, - large dose ( mg) propylthiouracil because of additional action of blocking peripheral T4 conversion - -blockers (propranalol) to counteract effects on SNS and heart
Primary Hypothyroidism T 4 and T 3 TSH 1. Autoimmune disease of thyroid: Hashimoto’s disease -Blocks hormone synthesis and glandular growth 2. Other Causes: i). Genetic defect in or autoantibodies vs. enzymes necessary for thyroid hormone synthesis or the conversion of T 4 to T 3. Severe iodide deficiency Lithium 3. Symptoms: - Myxedema: Accumulation of mucopolysaccharides with resultant fluid accumulation. - Decreased thermogenesis: cold intolerance - Lethargy, sleepiness, decreased mentation - Bradycardia. - Lowering of upper eyelid(ptosis) - In utero or infancy and childhood: Marked retardation in growth. Severe mental retardation due to poorly developed nervous system. Known as "cretins".
Iodide replacement in small quantities ( µg/day) if iodide deficiency is suspected. Hormone Replacement with T4 or T3 All can be given orally Synthetic Thyroxins: Levothyroxine sodium (SYNTHROID,) Synthetic T3: Lyothyronine sodium (L-T3) - 80% absorption in the small intestine that is partially blocked by Ca 2+ and iron supplements Efficacy is monitored by serum TSH levels Adverse Effects: Rare and most often associated with excessive doses Looks like hyperthyroidism: heat intolerance, irritability, insomnia, nausea/vomiting, nervousness or anxiety, tremor, and weight loss. In patients with underlying cardiac problems: angina, atrial fibrillation, heart failure, palpitations, peripheral edema.
CONTRAINDICATIONS: Patients with heart disease, diabetes, adrenal insufficiency and treatment for obesity DRUG INTERACTIONS Estrogen: Thyroxine-binding globulin (TBg) thereby free T4/T3 Barbiturates: hepatic metabolism of both Levothyroxine ( SYNTHROID) and Lyothyronine T4/T3 Enhances the response to: anticoagulant therapy, Tricyclic antidepressants ( receptor responsiveness), vasopresors and symapthomimetics ( receptor expression) Metabolism of Corticosteroids