Pharmacology of the Parathyroids and Bone Flashcards
What effect does PTH have on kidney?
decreased phosphate reabsorption
activation of VD3 via upregulation of 1-alpha-hydroxylase
Increased calcium reabsorption
What is the effect of PTH on the intestines?
Secondary to activation of D3
Increased calcium and phosphate reabsorption
What is the effect of PTH on the bones?
increased calcium and phosphate reabsorption
What stimulates PTH secretion?
o Decreased serum ionized calcium
o Mild decrease in magnesium
o Increased serum phosphate (indirect effect through PO4-Ca complexing)
What inhibits PTH secretion?
o High ionized serum calcium
o High serum magnesium (causes reversible
hypoparathyroid symptoms and hypocalcemia)
o Vitamin D3 (1,25 dihydroxy)
What condition causes these symptoms?
carpo-pedal muscular spasms, cramping, muscle spasms (tetany), generalized seizures, circumoral numbness and tingling
Hypocalcemia
Diarrhea, aminoglycosides, loop diuretics and alcohol abuse can trigger what change in PTH secretion?
Decreased PTH secretion
all are major causes of magnesium loss
Phosphate excretion is increased by
PTH, PTHrP, hypercalcemia, hypokalemia, hypomagnesemia calcitonin, glucocorticoids diuretics
Proximal tubular reabsorption is increased by phosphate depletion, hypoparathyroidism, and hypocalcemia
What drugs inhibit magnesium reabsorption?
furosemide and cisplatin
When is surgery indicated for primary hyperparathyroidism?
serum calcium of >1mg/dL
BMD T-score mg/day (with stones or risk of stones)
In someone under 50
What drug is indicated for pts with
secondary hyperparathyroidism with renal disease,
parathyroid carcinoma,
or primary hyperparathyroidism that don’t have surgery?
cinacalcet
What is the MOA of cinacalcet? What indications is it used for?
calcimimetic - reduces PTH and serum calcium levels
secondary hyperparathyroidism with renal failure
parathyroid carcinoma
primary hyperparathyroidism not treated by surgery
What drug can be given to patients with his risk osteoporosis that have failed other treatments?
Teriperatide
what is the MOA of Teriperatide?
PTH analougue - bolus SQ injections given to stimulate bone resorption and formation (activates RANKL on osteoblasts, inhibits OPG)
terrible because requires multiple SQ injections and contraindicated in pts with increased risk of osteosarcoma (paget’s, radiation treatment)
What drug/hormone can be given to rapidly improve hypercalcemia (e.g. in patients with paget’s disease)?
Side effect is rhinitis - nasal spray increases risk of cancer - can only be used effectively for 2-3 days due to rapid diminishing effectiveness
calcitonin
What is Raloxifene?
selective estrogen receptor modulator - activates some receptors blocks others - only given to women - used for osteoporosis (INCREASED RISK OF HOT FLASHES AND DVT!)
What is Zoledronic acid? what is it used for? Side effects?
I.V. bisphosphonate (only one that doesnt end in “dronate”) - used to treat:
hypercalcemia of malignancy
paget’s disease of the bone
prevention of fractures in osteogenesis imperfecta
Flue like symptoms
What is the mechanism of action of bisphosphonates?
reduce osteoclast reabsorption of bone
Which bisphosphonate can be used to treat hypercalcemia, osteoporosis, pagets disease of the bone, and prevention of bone fractures in osteogenesis imperfecta?
Residronate - must take sitting up on empty stomach - major side effect is esophogeal iritation
What is a possible paraneoplastic side effect of multiple meyloma?
hypercalcemia of malignancy - due to release of local osteolytic factors
What is Familial hypercalcemic hypocalciuria?
calcium sensing receptors detect low calcium when there is normal – stimulates inappropriate PTH release – kidneys also have calcium sensing receptors – respond by increasing cacium reabsorption – high blood calcium low urine calcium
What is Denosumab?
monoclonal antibody that binds RANKL – inhibits activation of osteoclasts
Hypercalcemia of malignancy
oversecretion of PTH related peptide (FROM TUMOR –squamous cell carcinoma of the lung - SMOKER)
Same features as primary hyperparathyroidism except low PTH (low phosphate, high calcium, high VD3)
What type of diuretic causes hypercalcemia which type treats it?
thiazide diuretics can cause excessive calcium reabsorption (hypercalcemia) and can be used to treat kidney stones
Loop diuretics (furosumide, bumetinide, torsemide, ethacrynic acid) inhibit Ca2+ reabsorption and can be used to treat hypercalcemia
Corticosteroids - decrease production of vitamin D
When can they be useful for treating hypercalcemia?
vitamin D intoxification
granulomatous diseases and hematologic malignancies
What are the major types of treatments for hypercalcemia?
Fluids, diuretics (Loop, not thiazide), bisphosphonates, calcitonin, corticosteroids, dialysis (if others fail)
What is tertiary hyperparathyroidism?
parathyroid glands exhibit autonomous secretion of PTH
How is QT interval affected by calcium levels?
Hypocalcemia = prolonged QT; heart block; CHF Hypercalcemia = shortened QT; hypertension, bradycardi
What is the role of FGF23 in secondary hyperparathyroidism due to chronic kidney disease?
Supresses alpha-1 hydroxilase expression and decreases production of 1,25 dihydroxy vitaminD3
- contributes to increase in PTH levels (high D3
How is vitamin D linked to ADH (aka AVP)?
normally calcium is regulated. CaSn cells in PH detect low Ca2+ levels and release PTH => PTH inhibts OPG and stimulates RANKL, also increases Ca2+ reabsorption at distal tubule and increases alpha-1 hydroxylase to increase active D3. Active D3 stimulates Ca/PO4 absorption from the kidneys and reabsorption from bone ==> leads to elevated levels of phosphate and calcium and inhibition of PTH release. D3 feedback inhibits its own production wherease Calcitonin is released when Ca2+ levels are too high which counteracts PTH effect on kidney and bone ==> leads to increased renal Ca2+ excretion and absorption by bone.
Level of ionized calcium in primary hyperparathyroidism leads to hyperosmotic diuresis is elevated which triggers hypothalamous to detect hyperosmolar serum. AVP release is inhibited.
What is used to treat secondary hyperparathyroidism?
Active vitamin D (calcitriol) or Vitamin D analogues (paracalcitol or doxercalciferol)
phosphate binders (calcium carbonate, calcium acetate, or sevelamer )
and cacimimetics to decrease PTH secretion (Cinacalcet)
What is sevelamer ?
phosphate binder - used for secondary HPTism
what are the main side effects of denosumab?
skin infections, hypocalcemia (particularly in those with a lower GFR). (RANKL monoclonal antibody)
