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63 Cards in this Set
- Front
- Back
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**What drug is approved for the treatment of osteoporosis and is particularly useful for women who cannot tolerate estrogen?**
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Alendronate (Fosamax)
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**What is Risedronate approved for?**
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osteoperosis
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**MOA: Raloxifene?**
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Specific Estrogen Receptor Modulator (SERM) - it is the 1st approved in this class
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Signs of hypocalcemia?
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neuromuscular tetany
muscle cramps convulsions laryngospasm |
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What is rickets?
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inadequate bone mineralization during development
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What is osteomalacia?
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inadequate bone mineralization in adult
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5 causes of osteomalacia?
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1. inadequate dietary Ca++ and/or vitamin D
2. malabsorption due to defect in vit D activation 3. malabsorption due to end-organ resistance to vitamin D 4. hypoparathyroidism 5. renal failure |
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**Signs/symptoms of hypercalcemia?** (4)
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1. cardiac arrhythmias
2. renal damage (stones) 3. soft tissue calcification 4. CNS abnormalities |
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Etiologies of hypercalcemia?
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hyperparathyroidism
hypervitaminosis D sarcoidosis neoplasia hyperthyroidism |
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General treatment options for hypercalcemia?
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treatment depends on cause of disease:
fluids low Ca++ diets loop diuretics glucocorticoids sulfate calcitonin anti-inflamm agents anticancer drugs |
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Explain vitamin D:
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-considered a hormone
-synthesized in skin (not required in diet) -transported by blood to tissues where it is activated and binds |
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How is vitamin D produced:
in yeast and fungi? in animals and higher plants? |
yeast and fungi (vit D2) - U.V. irradiation-elicited activation of ergosterol
animal and higher plants (vit D3) |
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Explain the activation of vitamin D:
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D2 and D3 are not biologically active but are both good prohormones*
initial activation occurs in liver --> 25-hydroxy-vitD (calcifediol) --> PTH and low phosphate stimulate final hydroxylation in kidney --> 1,25-dihydroxy vit D (calcitrol, i.e. the most potent form of vit D) |
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What is calcifediol?
What is calcitriol? |
calcifediol = 25-hydroxy-vit D
calcitriol = 1,25-dihydroxy vit D |
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see slides...
How can 1,25-dihydroxy vitamin D be inhibited? |
High Ca2+ directly inhibits 25 hydoxylase and indirectly decreases PTH secretion - same for 1,25-di(OH) D (transcription of PTH).
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**Potency of the vitamin D forms:**
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vitamin D3 < 25-hydroxy D < 1,25 di-hydroxy D
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Effects of vit D:
How does vit D cause increased Ca++ absorption?** |
vit D binds to receptors --> alters transcriptional regulation of genes --> increases calbindins* (Ca++ absorption)
active vit D (25-hydroxy and 1,25-dihydroxy) increase serum Ca++ by increasing absorption of Ca++ and phosphate from intestine increases calbindins! |
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When will vitamin D stimulate Ca++ mobilization from bone?
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only when Ca++ from diet is inadequate
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**How does vitamin D mobilize Ca++ from bone?**
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stimulates osteoblasts* of the bone which then activates osteoclasts to cause bone resorption --> inc phosphate and calcium
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Therapeutic uses of vitamin D?
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1. prophylaxis and cure of nutritional rickets (inadequate sunlight or diet)
2. treatment of metabolic rickets and osteomalacia 3. treatment of hypoparathyroidism |
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MOA of PTH?
(see p.4 figure) |
1. acts directly on kidneys to stimulate renal tubular reabsorption of Ca++ and increases formation of 1.25-dihydroxy vit D
2. decreases phosphate reabsorption from kidney 3. stimulates Ca++ resorption from bone 4. indirectly enhance dietary Ca++ absorption by increasing the formation of 1,25-dihydroxy-vitD |
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Why can cancers cause hypercalcemia?**
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PTH-related protein is produced by several types of tumor cells**
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How is PTH used clinically?
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diagnostically to examine cAMP production by the kidneys to detect pseudohypoparathyroidism
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why does PTH have little* therapeutic use?
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very short half-life
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What are 2 therapeutic uses for PTH?**
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1. short intermittent increase in PTH increases calcium deposition
2. recombinant 1-34-PTH (teriparatide) approved for osteoperosis** |
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How is hypoparathyroidism best treated?
How do you treat hyperparathyroidism? |
hypo: vitamin D and dietary Ca++
hyper: surgical resection of the gland (if can't do surgery, then give low Ca+ and lots of fluids) |
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Actions of calcitonin? How is it regulated?
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Calcitonin actions are generally opposite those of PTH
Regulated by plasma calcium levels Actions: 1. decreases absorption of calcium from intestine (opposes vitamin D) 2. increased secretion of Ca2+, Na+, Mg2+, Cl-, and PO3+ 3. inhibits osteoclast activity --> decreased bone resorption and thus increased deposition --> decreased plasma Ca++ concentration |
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see slides: sites of actions of calcemic hormones on bone
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Hormone-osteoblast complex activates osteoclast. Receptors on osteoblasts stimulate the activity of osteoclasts, releasing Ca++ from bone. Calcitonin inhibits the activity of osteoclasts.
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Therapeutic uses of calcitonin?
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1. Paget's disease - abnormal bone turnover
2. hypercalcemia associated w/ malignancy (osteolytic bone metastasis) - not a common use 3. osteoperosis - decreases bone resorption and diminishes chances of fractures 4. vit D intoxication |
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What are the adverse effects of calcitonin?
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1. hypersensitivity reactions, nausea
2. calcitonin "escape" phenomena - loss of effectiveness especially of actions at the bone tissue |
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What is Gallium Nitrate approved for?
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hypercalcemia of malignancy: decreases bone resorption
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Adverse effects of Gallium Nitrate?
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nephrotoxic
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How are glucocorticoids useful for glucocorticoids?
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Antagonizes the actions of vitamin D to increase absorption of Ca2+ from GI tract. Therefore, used in treatment of hypercalcemia associated with sarcoidosis or Vit. D intoxication. Not particularly effective in PTH induced hypercalcemia – so differentiate cause.
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Adverse effects of glucocorticoids?
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Should be used for intermediate treatment since long term treatment can result in osteoperosis.
Also the suppression of the hypothalamic-adrenal axis. |
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What are thiazide diuretics used for? How do they work?
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renal hypercalciuria
Site of action: early segment of distal convoluted tubules in the kidneys - Inhibits renal stone formation by increasing renal reabsorption of calcium from the lumen of the tubules. |
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Etidronate:
Pharmacokinetics? Approved for osteoperosis? C/Is? |
• Pharmacokinetics
-poorly absorbed (decreased with food) -distributes readily and concentrates in bone -excreted by kidneys; not metabolized -plasma elimination half-life -6 hr-retention half-life in bone - 3-6 months Not approved for osteoperosis •Contraindications/precautions -children, pregnancy, breast-feeding colitis - renal impairment |
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What are bisphosphonates used for?
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treatment of bone diseases involving excessive bone destruction or resorption:
1. Paget's dz 2. tumor-associated osteolysis 3. post-menopausal osteoporosis |
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How do bisphosphonates work?
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Act by adsorbing to bone crystals making bone resistant to enzymatic hydrolysis. Inhibits activity of osteoclasts that manage to ingest bisphosphonate-containing bone.
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Etidronate:
Drug interactions? Adverse effects? |
• Interactions-aluminum hydroxide
-antacids-calcium salts, magnesium salts -iron salts •Adverse effects -bone pain -adverse GI effects -dysphagia, pain, etc. -hypocalcemia, osteomalacia -metallic taste |
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Slides: main pts of bisphosphonates
Pharmacokinetics of bisphosphonates? |
stx similar to pyrophosphate*
low absorption (decreased further by food - give on empty stomach!) short half-life in plasma, but very long half-life in bone |
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Contraindications of bisphosphonates?
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children
pregnancy breast feeding GI ulcers decreased renal function |
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Drugs interactions of bisphosphonates:
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1. aluminum hydroxide antacids
2. Ca, Mg, Fe salts 3. NSAIDS |
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Pamidronate:
Pharmacokinetcis? Admin? C/Is? |
• Pharmacokinetics
-poorly absorbed or tolerated orally -concentrates in bone -biphasic disposition -half-life: 2.1 hr; ß-half-life: 28 hr -excreted by kidneys; not metabolized -plasma elimination half-life -6 hr • Administration: i.v. •Contraindications/precautions -children, pregnancy, breast-feeding -renal impairment |
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What bisphosphonate does not have drug interactions?
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Palmidronate (given IV)
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Pamidronate:
Interactions? Adverse effects? |
• Interactions
-no drug interactions • Adverse effects -bone pain, abdominal pain -anorexia -dyspepsia -fever -hypocalcemia, hypokalemia |
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Adverse effects of bisphosphonates?
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bone pain
GI issues: dyspepsia... |
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What 3 bisphosphonates have been approved for osteoperosis?**
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1. Alendronate
2. Risedronate 3. Ibandronate |
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Alendronate (Fosamax):
Pharmacokinetics? Approved for?** Admin? |
• Pharmacokinetics
-poor oral absorption -transient distribution to soft tissue, with rapid redistribution to bone -78% protein bound -excreted unchanged in urine -half-life in bone: 10 years **Approved for treatment of osteoperosis – particularly useful in women who cannot tolerate estrogen** • Administration: oral or i.v. |
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MOA of Fluoride?
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mitogen for osteoblasts to stimulate bone formation
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Pharmacokinetics of Fluoride?
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absorption form GI tract is rapid and complete
stored in bones and teeth active form is the ion renal excretion: 90% by kidney... |
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Contraindications of Fluoride?
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arthralgia
pregnancy, breast-feeding, children dental fluorosis: mottled enamel, stains on teeth (if given in excess) |
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Alendronate:
C/Is? |
•Contraindications/precautions
-children, pregnancy, breast-feeding -dysphagia -GI disease, esophagitis, gastritis -hypocalcemia -renal impairment -vitamin D deficiency |
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Adverse effects of fluorides?
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dermatitis
fluorosis GI bleeding nausea/vomiting stomatits urticaria |
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Alendronate:
Drug interactions? Adverse effects? |
Interactions:
-aluminum hydroxide -antacids -calcium salts, iron salts, magnesium salts -NSAIDs, ranitidine, salicylates - ulcerations** Adverse effects: -abdominal pain, constipation, -diarrhea, bone pain, dysphagia -esophageal ulceration, esophagitis, gastritis -headache -hypocalcemia,hypophosphatemia |
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What is estrogen used for?
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to prevent osteoperosis in post-menopausal women
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What does estrogen increase risk for?
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endometrial carcinoma
(combined w/ progestins decreases risk, but the combo may cause menstruation again) |
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MOA of estrogen?
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- probably works by decreasing the actions of PTH to increase bone resorption
- also increases 1,25-di-OH vit D probably by decreasing serum phosphate - may also have direct actions on bone remodeling. |
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Main characterisitics of Bisphosphonates:
Pharmacokinetics? C/I? Drug interactions? Adverse effects? Indications? Other effects? |
1)Pharmacokinetics: Low absorption when orally administered
-decreased further by food! -short plasma half-life, but half-life after deposition in bone long - 3/6 mths etidronate -> 10 yrs alendronate 2) Contraindication: Children, pregnancy, breast feeding, GI ulcers, decreased renal function. 3) Drug Interactions: Al(OH)3, Antacids, Ca, Mg, Fe salts, NSAIDs - None with Palmidronate (i.v.) 4) Adverse Effects: Bone pain, GI -dyspepsia,anorexia, esophageal ulcerations, hypocalcemia, hypophosphatemia 5) Indications: Paget’s disease, Osteoperosis -alendronate,risendronate, ibandronate 6) Other effects: decreased production of 1, 25 di(OH) D decreased intestinal transport of Ca. |
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Why were SERMs developed?
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estrogen agonist in bone, but estrogen antagonist in breast and uterine tissues (also in brain - causes hot flashes)
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What is Raloxifene (Evista) approved for?
How does it affect ovulation? Raloxifene increases risk for what? |
1st SERM approved for preventing spinal fractures*
does not effect ovulation and may be option for women at risk for osteoporosis who are still menstruating, but should not be used in pregnant or breast-feeding women increases risk of DVT |
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What is Terparatide?
How is it delivered? What drugs may be used in combo against osteoperosis? |
use: osteoperosis (increases bone formation)
available only in injectable form combo w/ alendronate may increase efficacy? |
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Adverse effects of Teriparatide?
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osteosarcoma: don't use in pts at risk for osteosarcoma or in Paget's dz; not approved for kids
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What drug is a Calcimimetic?**
What is its MOA?** Indications for Cinacalcet? |
**Cinacalcet: activates the Ca+ sensing receptor (CaR) which has greatest conc in parathyroid gland; CaR activation inhibits PTH release**
Indications: secondary hyperparathyroidism parathyroid carcinoma chronic kidney dz |
