Thyroid and Parathyroid Pharmacology

1
Thyroid and Parathyroid Pharmacology
2
Thyroid Hormones

• Thyroxine (T4, tetraiodothyronine)
• Liothyronine (T3, triiodothyronine)
• Iodinated diphenyl ether structure
• Built and stored on thyroglobulin
• gt99 protein bound in plasma
• Only free form has physiologic effects
• T3 more potent T4 longer lasting
• Peripheral deiodination

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

4
Thyroid Anatomy
5
Thyroid Structure
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
9
Thyroid Gland Regulation


Hypothalamus
Anterior Pituitary
Thyroid Gland
TRH
TSH
Adenylyl Cyclase
TSH Receptor
cAMP
-
-
T3/T4
10
Hyperthyroidism

• Causes
• Graves 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
  Graves disease

12
Hyperthyroidism

• Pharmacologic Treatments
• Thionamides (thiourelynes)

13
Hyperthyroidism

• Methimazole (Tapazole)
• Typical dose 15 30 mg QD
• Rapidly absorbed (Cmax lt 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 -gt 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 -gt T3 conversion
• Control HR and palpitations, sweats
• Rapid action
• Corticosteriods
• Reduce T4 -gt T3 conversion
• May reduce TSHR antibody effect in Graves

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/Cd
• 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 Lugols solution)
• Beta blockers
• Corticosteriods

20
New Antithyroid Drug?
21
Graves Disease
Compound 1
TSHRab
X


Hypothalamus
Anterior Pituitary
Thyroid Gland
TRH
TSH
X
Adenylyl Cyclase
TSH Receptor
cAMP
-
-
T3/T4
22
New Antithyroid Drug?
23
Hypothyroidism

• Causes
• Primary
• 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 (gt90)
• Half-life 1 2 days
• Synthetic T4T3 (Liotrix 41 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
• Bone
• Kidney
• Intestine
• 3 Hormones
• PTH
• Calcitonin
• Activated Vitamin D3 (1,25OH2-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
• 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
• 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
• 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
• 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