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63 Cards in this Set

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**What drug is approved for the treatment of osteoporosis and is particularly useful for women who cannot tolerate estrogen?**
Alendronate (Fosamax)
**What is Risedronate approved for?**
osteoperosis
**MOA: Raloxifene?**
Specific Estrogen Receptor Modulator (SERM) - it is the 1st approved in this class
Signs of hypocalcemia?
neuromuscular tetany
muscle cramps
convulsions
laryngospasm
What is rickets?
inadequate bone mineralization during development
What is osteomalacia?
inadequate bone mineralization in adult
5 causes of osteomalacia?
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
**Signs/symptoms of hypercalcemia?** (4)
1. cardiac arrhythmias
2. renal damage (stones)
3. soft tissue calcification
4. CNS abnormalities
Etiologies of hypercalcemia?
hyperparathyroidism
hypervitaminosis D
sarcoidosis
neoplasia
hyperthyroidism
General treatment options for hypercalcemia?
treatment depends on cause of disease:

fluids
low Ca++ diets
loop diuretics
glucocorticoids
sulfate
calcitonin
anti-inflamm agents
anticancer drugs
Explain vitamin D:
-considered a hormone
-synthesized in skin (not required in diet)
-transported by blood to tissues where it is activated and binds
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)
Explain the activation of vitamin D:
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)
What is calcifediol?

What is calcitriol?
calcifediol = 25-hydroxy-vit D

calcitriol = 1,25-dihydroxy vit D
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).
**Potency of the vitamin D forms:**
vitamin D3 < 25-hydroxy D < 1,25 di-hydroxy D
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!
When will vitamin D stimulate Ca++ mobilization from bone?
only when Ca++ from diet is inadequate
**How does vitamin D mobilize Ca++ from bone?**
stimulates osteoblasts* of the bone which then activates osteoclasts to cause bone resorption --> inc phosphate and calcium
Therapeutic uses of vitamin D?
1. prophylaxis and cure of nutritional rickets (inadequate sunlight or diet)
2. treatment of metabolic rickets and osteomalacia
3. treatment of hypoparathyroidism
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
Why can cancers cause hypercalcemia?**
PTH-related protein is produced by several types of tumor cells**
How is PTH used clinically?
diagnostically to examine cAMP production by the kidneys to detect pseudohypoparathyroidism
why does PTH have little* therapeutic use?
very short half-life
What are 2 therapeutic uses for PTH?**
1. short intermittent increase in PTH increases calcium deposition
2. recombinant 1-34-PTH (teriparatide) approved for osteoperosis**
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)
Actions of calcitonin? How is it regulated?
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
see slides: sites of actions of calcemic hormones on bone
Hormone-osteoblast complex activates osteoclast. Receptors on osteoblasts stimulate the activity of osteoclasts, releasing Ca++ from bone. Calcitonin inhibits the activity of osteoclasts.
Therapeutic uses of calcitonin?
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
What are the adverse effects of calcitonin?
1. hypersensitivity reactions, nausea
2. calcitonin "escape" phenomena - loss of effectiveness especially of actions at the bone tissue
What is Gallium Nitrate approved for?
hypercalcemia of malignancy: decreases bone resorption
Adverse effects of Gallium Nitrate?
nephrotoxic
How are glucocorticoids useful for glucocorticoids?
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.
Adverse effects of glucocorticoids?
Should be used for intermediate treatment since long term treatment can result in osteoperosis.

Also the suppression of the hypothalamic-adrenal axis.
What are thiazide diuretics used for? How do they work?
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.
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
What are bisphosphonates used for?
treatment of bone diseases involving excessive bone destruction or resorption:
1. Paget's dz
2. tumor-associated osteolysis
3. post-menopausal osteoporosis
How do bisphosphonates work?
Act by adsorbing to bone crystals making bone resistant to enzymatic hydrolysis. Inhibits activity of osteoclasts that manage to ingest bisphosphonate-containing bone.
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
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
Contraindications of bisphosphonates?
children
pregnancy
breast feeding
GI ulcers
decreased renal function
Drugs interactions of bisphosphonates:
1. aluminum hydroxide antacids
2. Ca, Mg, Fe salts
3. NSAIDS
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
What bisphosphonate does not have drug interactions?
Palmidronate (given IV)
Pamidronate:

Interactions?

Adverse effects?
• Interactions
-no drug interactions

• Adverse effects
-bone pain, abdominal pain
-anorexia
-dyspepsia
-fever
-hypocalcemia, hypokalemia
Adverse effects of bisphosphonates?
bone pain
GI issues: dyspepsia...
What 3 bisphosphonates have been approved for osteoperosis?**
1. Alendronate
2. Risedronate
3. Ibandronate
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.
MOA of Fluoride?
mitogen for osteoblasts to stimulate bone formation
Pharmacokinetics of Fluoride?
absorption form GI tract is rapid and complete
stored in bones and teeth
active form is the ion
renal excretion: 90% by kidney...
Contraindications of Fluoride?
arthralgia
pregnancy, breast-feeding, children
dental fluorosis: mottled enamel, stains on teeth (if given in excess)
Alendronate:

C/Is?
•Contraindications/precautions
-children, pregnancy, breast-feeding
-dysphagia
-GI disease, esophagitis, gastritis
-hypocalcemia
-renal impairment
-vitamin D deficiency
Adverse effects of fluorides?
dermatitis
fluorosis
GI bleeding
nausea/vomiting
stomatits
urticaria
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
What is estrogen used for?
to prevent osteoperosis in post-menopausal women
What does estrogen increase risk for?
endometrial carcinoma

(combined w/ progestins decreases risk, but the combo may cause menstruation again)
MOA of estrogen?
- 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.
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.
Why were SERMs developed?
estrogen agonist in bone, but estrogen antagonist in breast and uterine tissues (also in brain - causes hot flashes)
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
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?
Adverse effects of Teriparatide?
osteosarcoma: don't use in pts at risk for osteosarcoma or in Paget's dz; not approved for kids
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