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Thyroid and Parathyroid Pharmacology

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Presentation on theme: "Thyroid and Parathyroid Pharmacology"— Presentation transcript:

1 Thyroid and Parathyroid Pharmacology

2 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 Noncovalent protein binding.

3 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 No effects on brain, spleen, testes

4 Thyroid Anatomy Healthy thyroid not palpable. Extends from C5 – T1.
“Thyroid” from the Greek, meaning “shield”.

5 Thyroid Structure Hypothyroid Euthyroid Hyperthyroid
Unique endocrine organ, in having large extracellular storage space. Hypothyroid Euthyroid Hyperthyroid

6 Thyroid Biosynthesis

7 Thyroid Biosynthesis Iodide Trapping Thyroglobulin Synthesis
Iodination Coupling Proteolysis to release T3/T4 Deiodination and recycling

8 Thyroid Biosynthesis Dietary iodine (I2) converted to iodide (I-) for absorption. Active transport to achieve 30X in lumen vs plasma Thyroglobulin synthesis in ER -> golgi -> exocytosis into lumen I- oxidized into I2 by TPO. MIT and DIT (TPO dep). Coupling occurs on apical microvilli. Endocytosis into vesicles -> proteolysis (cathepsins) to cleave T3/T4

9 Thyroid Gland Regulation
Hypothalamus TRH + Anterior Pituitary TSH + Thyroid Gland Adenylyl Cyclase TSH Receptor cAMP - - T3/T4

10 Hyperthyroidism Causes Non-pharmacologic treatments
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)

11 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 Normal freee T4 = 9 – 30 pmol/L Normal free T3 = 2.8 – 6.5 pmol/L Normal TSH = 0.3 – 5 mU/L

12 Hyperthyroidism Pharmacologic Treatments Thionamides (thiourelynes)

13 Hyperthyroidism Methimazole (Tapazole) Propylthiouracil (PTU)
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

14 Thionamide MOA Coupling is also highly sensitive to drug

15 Thionamide Side Effects
Rash/itch Fever Rarely: Liver dysfunction Leucocytopenia

16 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)

17 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 Contraindicated in asthma or reactive airways disease.

18 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 re-instituted 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

19 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

20 New Antithyroid Drug?

21 Grave’s Disease X TSHRab Hypothalamus TRH + Anterior Pituitary TSH +
Compound “1” TSHRab X Hypothalamus TRH + Anterior Pituitary TSH + Thyroid Gland X Adenylyl Cyclase TSH Receptor cAMP - - T3/T4

22 New Antithyroid Drug?

23 Hypothyroidism Causes Primary Secondary Idiopathic Autoimmune
Traumatic Iatrogenic Secondary Pituitary dysfunction Increased protein binding estrogen; HIV; liver dysfunction; heroin

24 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)

25 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

26 Parathyroid Basics

27 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

28 Calcium Homeostasis 3 Tissues 3 Hormones 3 Cells Bone Kidney Intestine
PTH Calcitonin Activated Vitamin D3 (1,25[OH]2-D3) 3 Cells Osteoblasts Osteocytes Osteoclasts

29 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

30 Hypoparathyroidism Causes Surgical (most common) Idiopathic Functional
Genetic familial forms Circulating receptor antibodies Functional Due to hypomagnesemia Mg2+ necessary for PTH release

31 Psuedohypoparathyroidism
Target organs resistant to PTH Congential defect of PTHR1 Plasma Ca2+ low Plasma phosphate high Renal phosphatase activity high

32 Hypoparathyroidism Maintenance Treatment Acute 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

33 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

34 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.

35 Hyperparathyroidism Treatment Acute Severe forms Other Agents
Adequate hydration, forced diuresis Other Agents Corticosteroids – Blood malignancies Mythramycin Toxic antibiotic used to inhibit bone resorption – hematologic and solid neoplasms

36 Hyperparathyroidism Treatment Other Agents Calcitonin Biphosphonates
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

37 Hyperparathyroidism Treatment Surgery Definitive treatment

38 2° Hyperparathyroidism
Adaptive & unrelated to intrinsic disease of glands Due to chronic stimulation of glands by low serum Ca2+ levels

39 2° Hyperparathyroidism
Causes Dietary deficiency of vitamin D or Ca2+ Decreased intestinal absorption of vitamin D or Ca2+ Drugs such as phenytoin, phenobarbital Renal Failure Decreased activation of vitamin D3 Hypomagnesemia


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