Thyroid and Parathyroid PharmacologyThyroid HormonesPhysiological EffectsThyroid AnatomyThyroid StructureThyroid BiosynthesisSlide 7Slide 8Thyroid Gland RegulationHyperthyroidismCase ReportSlide 12Slide 13Thionamide MOAThionamide Side EffectsOther Antithyroid OptionsSlide 17Slide 18Thyroid StormNew Antithyroid Drug?Grave’s DiseasePowerPoint PresentationHypothyroidismSlide 24Slide 25Parathyroid BasicsSlide 27Calcium HomeostasisHypoparathyroidismSlide 30PsuedohypoparathyroidismSlide 32HyperparathyroidismHyperparathyroidismSlide 35Slide 36Slide 372° HyperparathyroidismSlide 39Thyroid and Parathyroid PharmacologyThyroid HormonesThyroxine (T4, tetraiodothyronine)Liothyronine (T3, triiodothyronine)•Iodinated diphenyl ether structure•Built and stored on thyroglobulin•>99% protein bound in plasma•Only free form has physiologic effectsT3 more potent; T4 longer lasting•Peripheral deiodinationPhysiological EffectsIncreases transcription (nuclear)Increases mitochondrial metabolismNet effects are target dependent•Oxygen consumption•Heat production•Metabolism, growth, differentiation•Promotes effects of hormones•Steroids, catecholaminesThyroid AnatomyThyroid StructureHypothyroid Euthyroid HyperthyroidThyroid BiosynthesisThyroid BiosynthesisIodide TrappingThyroglobulin SynthesisIodinationCouplingProteolysis to release T3/T4Deiodination and recyclingThyroid BiosynthesisThyroid Gland RegulationHypothalamusAnterior PituitaryThyroid GlandTRHT3/T4TSH++- -TSH ReceptorAdenylyl CyclasecAMPHyperthyroidismCauses•Grave’s disease (TSHR autoantibodies)•0.1% to 1% prevalence, higher in women•Thyroiditis•Toxic adenomaNon-pharmacologic treatments•Subtotal thyroidectomy•Radioiodine•Arterial embolization (2005)Case Report47 yo woman reports palpitations, tremulousness, weight loss, heat intolerance of 6 weeks durationPE reveals HR = 110 bpm, BP = 150/70 a diffusely enlarged thyroid gland, fine tremor of outstretched hands and a wide-eyed stareLab 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 diseaseHyperthyroidismPharmacologic Treatments•Thionamides (thiourelynes)HyperthyroidismMethimazole (Tapazole)•Typical dose 15 – 30 mg QD•Rapidly absorbed (Cmax < 2 hours)•Half-life 13 – 18 hoursPropylthiouracil (PTU)•Typical dose 50– 600 mg BID•Good bioavailability•Half-life 2 – 4 hours•Blocks peripheral T4 -> T3 conversionThionamide MOACoupling is also highly sensitive to drugThionamide Side EffectsRash/itchFeverRarely:•Liver dysfunction•LeucocytopeniaOther Antithyroid OptionsIodide 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 OptionsBeta Blockers•Adjunctive treatment•May reduce T4 -> T3 conversion•Control HR and palpitations, sweats•Rapid actionCorticosteriods•Reduce T4 -> T3 conversion•May reduce TSHR antibody effect in Grave’sCase ReportPatient started on PTU 200 mg BIDand propranolol 40 mg TID, becoming euthyroid in 6 weeks whereupon the propranolol was tapered and D/C’dRemained on maintenance PTU for one year (50 mg bid) then discontinued and remained well for 3 yrsSymptoms recurred and PTU + propranolol was re-instituted for symptomatic relief. After 7 weeks, she developed a whole body red itchy rashShe received Na131I in a dose of 10 mCi by mouth for definitive control of her hyperthyroidismThyroid StormPotentially life threateningCombined treatment strategy•High dose PTU•Give 1st; iodide will reduce drug uptake in gland•Iodide loading (IV Lugol’s solution)•Beta blockers•CorticosteriodsNew Antithyroid Drug?Grave’s DiseaseHypothalamusAnterior PituitaryThyroid GlandTRHT3/T4TSH++- -TSH ReceptorAdenylyl CyclasecAMPXTSHRabXCompound “1”New Antithyroid Drug?HypothyroidismCauses•Primary•Idiopathic•Autoimmune•Traumatic•Iatrogenic•Secondary•Pituitary dysfunction•Increased protein binding•estrogen; HIV; liver dysfunction; heroinHypothyroidismTreatment = 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 Report3 months later, she returned with lethargy, fatigue, coldness at room temperature, puffiness around the eyes and constipationLabs showed free T4 = 8 pmol/L, free T3 = 2 pmol/L and TSH = 8 mU/mL confirming hypothyroidismLevothyroxine 0.1mg daily was instituted and after 6 weeks, blood tests showed a TSH level of 3.2 mU/mL and all symptoms had resolvedShe has remained well on this regimen for 2 yearsParathyroid BasicsParathyroid BasicsParathyroid 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 cellsCalcium Homeostasis3 Tissues•Bone•Kidney•Intestine3 Hormones•PTH•Calcitonin•Activated Vitamin D3 (1,25[OH]2-D3)3 Cells•Osteoblasts•Osteocytes•OsteoclastsHypoparathyroidismDecreased bone resorption & osteocytic activityHypocalcemia•Increased neuromuscular excitability•Tetanic muscle contractions/spasms•Seizure•Prolonged QT interval•Cataract•Trousseau Sign•Chvostek SignLow or absent iPTHHypoparathyroidismCauses•Surgical (most common)•Idiopathic•Genetic familial forms•Circulating receptor antibodies•Functional•Due to hypomagnesemia•Mg2+ necessary for PTH releasePsuedohypoparathyroidismTarget organs resistant to PTH•Congential defect of PTHR1Plasma Ca2+ lowPlasma phosphate highRenal phosphatase activity highHypoparathyroidismMaintenance Treatment•Combined oral calcium + Vitamin D•Phosphate restriction may be usedAcute Treatment•Tetany or Hungry Bone Syndrome•Parenteral calcium followed by vitamin D supp + oral calciumHyperparathyroidismPrimary•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 stonesHyperparathyroidismPrimary – Diagnosis•Multiple
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