Thyroid and Parathyroid Pharmacology Thyroid Hormones Thyroxine T4 tetraiodothyronine Liothyronine T3 triiodothyronine Iodinated diphenyl ether structure Built and stored on thyroglobulin 99 protein bound in plasma Only free form has physiologic effects T3 more potent T4 longer lasting Peripheral deiodination Physiological Effects Increases transcription nuclear Increases mitochondrial metabolism Net effects are target dependent Oxygen consumption Heat production Metabolism growth differentiation Promotes effects of hormones Steroids catecholamines Thyroid Anatomy Thyroid Structure Hypothyroid Euthyroid Hyperthyroid Thyroid Biosynthesis Thyroid Biosynthesis Iodide Trapping Thyroglobulin Synthesis Iodination Coupling Proteolysis to release T3 T4 Deiodination and recycling Thyroid Biosynthesis Thyroid Gland Regulation Hypothalamus TRH Anterior Pituitary TSH Thyroid Gland TSH Receptor Adenylyl Cyclase cAMP T3 T4 Hyperthyroidism Causes Grave s disease TSHR autoantibodies 0 1 to 1 prevalence higher in women Thyroiditis Toxic adenoma Non pharmacologic treatments Subtotal thyroidectomy Radioiodine Arterial embolization 2005 Case Report 47 yo woman reports palpitations tremulousness weight loss heat intolerance of 6 weeks duration PE reveals HR 110 bpm BP 150 70 a diffusely enlarged thyroid gland fine tremor of outstretched hands and a wide eyed stare Lab reports free T4 40 pmol L free T3 10 6 pmol L with undetectable TSH and elevated thyroid stimulating globulins confirming a Dx of Grave s disease Hyperthyroidism Pharmacologic Treatments Thionamides thiourelynes Hyperthyroidism Methimazole Tapazole Typical dose 15 30 mg QD Rapidly absorbed Cmax 2 hours Half life 13 18 hours Propylthiouracil PTU Typical dose 50 600 mg BID Good bioavailability Half life 2 4 hours Blocks peripheral T4 T3 conversion Thionamide MOA Coupling is also highly sensitive to drug Thionamide Side Effects Rash itch Fever Rarely Liver dysfunction Leucocytopenia Other Antithyroid Options Iodide loading High doses can inhibit iodide formation Effect transient May be useful prior to RAI or surgery Debulk and devascularize gland Side effects Rash hypersalivation oral ulcers CI in pregnancy may cause fetal goiter Other Antithyroid Options Beta Blockers Adjunctive treatment May reduce T4 T3 conversion Control HR and palpitations sweats Rapid action Corticosteriods Reduce T4 T3 conversion May reduce TSHR antibody effect in Grave s Case Report Patient started on PTU 200 mg BIDand propranolol 40 mg TID becoming euthyroid in 6 weeks whereupon the propranolol was tapered and D C d Remained on maintenance PTU for one year 50 mg bid then discontinued and remained well for 3 yrs Symptoms recurred and PTU propranolol was reinstituted for symptomatic relief After 7 weeks she developed a whole body red itchy rash She received Na131I in a dose of 10 mCi by mouth for definitive control of her hyperthyroidism Thyroid Storm Potentially life threatening Combined treatment strategy High dose PTU Give 1st iodide will reduce drug uptake in gland Iodide loading IV Lugol s solution Beta blockers Corticosteriods New Antithyroid Drug Grave s Disease TSHRab X Hypothalamus TRH Anterior Pituitary X TSH Compound 1 Thyroid Gland TSH Receptor Adenylyl Cyclase cAMP T3 T4 New Antithyroid Drug Hypothyroidism Causes Primary Idiopathic Autoimmune Traumatic Iatrogenic Secondary Pituitary dysfunction Increased protein binding estrogen HIV liver dysfunction heroin Hypothyroidism Treatment Hormone Replacement Synthetic T4 synthroid Absorption fair 65 Half life 5 7 days Synthetic T3 liothyronine Absorption good 90 Half life 1 2 days Synthetic T4 T3 Liotrix 4 1 ratio Case Report 3 months later she returned with lethargy fatigue coldness at room temperature puffiness around the eyes and constipation Labs showed free T4 8 pmol L free T3 2 pmol L and TSH 8 mU mL confirming hypothyroidism Levothyroxine 0 1mg daily was instituted and after 6 weeks blood tests showed a TSH level of 3 2 mU mL and all symptoms had resolved She has remained well on this regimen for 2 years Parathyroid Basics Parathyroid Basics Parathyroid Hormone Small molecule 34 amino acids Activity based on amino terminal No disulfide linkages Encoded on chromosome 11 Half life only 2 4 minutes Secreted by chief cells Calcium Homeostasis 3 Tissues 3 Hormones Bone Kidney Intestine PTH Calcitonin Activated Vitamin D3 1 25 OH 2 D3 3 Cells Osteoblasts Osteocytes Osteoclasts Hypoparathyroidism Decreased bone resorption osteocytic activity Hypocalcemia Increased neuromuscular excitability Tetanic muscle contractions spasms Seizure Prolonged QT interval Cataract Trousseau Sign Chvostek Sign Low or absent iPTH Hypoparathyroidism Causes Surgical most common Idiopathic Genetic familial forms Circulating receptor antibodies Functional Due to hypomagnesemia Mg2 necessary for PTH release Psuedohypoparathyroidism Target organs resistant to PTH Congential defect of PTHR1 Plasma Ca2 low Plasma phosphate high Renal phosphatase activity high Hypoparathyroidism Maintenance Treatment Combined oral calcium Vitamin D Phosphate restriction may be used Acute Treatment Tetany or Hungry Bone Syndrome Parenteral calcium followed by vitamin D supp oral calcium Hyperparathyroidism Primary Excess PTH high calcium low phosphate Tumor adenoma hyperplasia More common in women Marrow fibrosis Osteitis fibrosa cystica Metabolic acidosis Increased Alk Phos bone Kidney stones Hyperparathyroidism Primary Diagnosis Multiple elevated Ca2 serum tests Elevated iPTH Alk Phos typically low Corticosteroid suppression test Prednisolone reduces serum Ca2 Indicates non parathyroid origin Sarcoid vitamin D intoxication etc Hyperparathyroidism Treatment Acute Severe forms Adequate hydration forced diuresis Other Agents Corticosteroids Blood malignancies Mythramycin Toxic antibiotic used to inhibit bone resorption hematologic and solid neoplasms Hyperparathyroidism Treatment Other Agents Calcitonin Inhibits osteoclast activity and bone resorption Biphosphonates Given IV or orally to reduce bone resorption Estrogen Can be given to postmenopausal women with 1 hyperparathyroidism as medical therapy Hyperparathyroidism Treatment Surgery Definitive treatment 2 Hyperparathyroidism Adaptive unrelated to intrinsic disease of glands Due to chronic stimulation of glands by low serum Ca2 levels 2 Hyperparathyroidism Causes Dietary deficiency of vitamin D or Ca2 Decreased intestinal absorption of vitamin D or Ca2 Drugs such as phenytoin phenobarbital Renal
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