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Endocrine Pharmacology > Agents Affecting Bone Mineral Homeostasis > Flashcards

Agents Affecting Bone Mineral Homeostasis Flashcards

1
Q

Drug List for Calcium Regulating Hormones Categories?

A 
A. Parathyroid hormone
B. Calcitonin
C. Vitamin D agents
D. Bisphosphonates
E. Calcium Sensing Receptor Mimetics (calcimimetics)
F. Various forms of calcium supplements
G. Fluoride
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2
Q

Parathyroid hormone Drugs?

A
  1. teriparatide, hPTH(1-34)

2. full length hPTH(1-84)

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3
Q

Calcitonin Drugs?

A
  1. Synthetic human calcitonin hCT

2. Natural calcitonin from salmon

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4
Q

Vitamin D agents

A
  1. cholecalciferol = Vitamin D3 (fish liver oils)
  2. ergosterol
  3. ergocalciferol (after irradiation) = Vitamin D2
  4. 25-OH cholecalciferol
  5. calcipotriol
  6. dihydrotachysterol (reduced Vitamin D2 , DHT)
  7. paricalcitol
  8. 22-oxacalcitriol
  9. calcitriol
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5
Q

Bisphosphonates agents?

A 
First Generation
1. etidronate 
Second Generation
2. alendronate 
3. pamidronate 
4. ibandronate 
Third Generation
5. risedronate  
6. tiludronate 
7. zoledronate
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6
Q

Calcium Sensing Receptor Mimetics (calcimimetics)

A

cinacalcet

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7
Q

Regulation of Calcium Homeostasis is controlled by 3 calcitropic hormones?

A

– Parathyroid hormone, PTH
– Calcitonin
– Calcitriol, the active form of Vitamin D
– Coordination of these 3 hormones controls the
concentration of Ca2+ in blood.

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8
Q

Pools of Calcium in the Body

A

Intracellular calcium: 100 nM to greater than 1 μM.
Calcium in blood and extracellular fluid: 1 mM.
Bone calcium: Vast majority of body calcium.

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9
Q

Plasma calcium is tightly regulated at:

A

2.5 mM = 5 mEq/L = 10 mg/dl

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10
Q

Components of Plasma Calcium:

A

– 40 % protein-bound (albumin)
– 10 % complexed (citrate, phosphate)
– 50 % diffusable, ionic calcium or “free
calcium” (Ca2+ = 1 mM)

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11
Q

Three major sites of action for blood calcium

regulation:

A

– Bone.
– Gastrointestinal tract.
– Kidney.

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12
Q

Bone. Calcium and phosphate in the blood are in

equilibrium with the?

A

Hydroxyapatite of bone. This allows resorption of bone calcium into blood.

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13
Q

Gastrointestinal tract. Total dietary intake of

calcium is?

A

About 1,000 mg per day. Excretion in feces is 900 mg per day.

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14
Q

Kidney. Excretion of calcium by the kidney is?

.

A

About 100 mg per day

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15
Q

Parathyroid Hormone (PTH) Functions to?

A

Increase plasma Ca2+

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16
Q

Parathyroid Hormone (PTH) is synthesized by and acts on?

A 
Synthesized by parathyroid glands
3 major actions:
– Increases bone resorption  Ca2+
– Increases kidney reabsorption  Ca2+
– Increases active form of Vitamin D
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17
Q

Calcium-Sensing Receptor are?

A

(G protein-coupled receptor)

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18
Q

Activation of the calcium sensor has two major signal-transducing effects:

A
  1. Activation of phospholipase C, which leads to generation of the second messengers diacylglycerol and inositol trisphosphate.
  2. Inhibition of adenylate cyclase, which suppresses intracellular concentration of cyclic AMP.
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19
Q

What allows both PTH- and Calcitoninsecreting cells to respond to extracellular calcium, and where is it found?

A

Calcium-Sensing Receptor (G protein-coupled receptor)

In both parathyroid glands and parafollicular cells of thyroid.

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20
Q

The calcium sensor is also expressed in?

A

Several cell types in the kidney, osteoblasts, a variety of hematopoietic cells in bone marrow, and in the
gastrointestinal mucosa.

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21
Q

Where is Calcitonin synthesized and what is its function and major actions?

A

Synthesized by parafolicular cells of thyroid and
Functions to decrease plasma Ca2+.
3 major actions:
– Decreases bone resorption
– Decreases kidney reabsorption
– Decreases active form of Vitamin D
In general, calcitonin opposes PTH actions.

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22
Q

Calcitonin also synthesized in other tissues?

A

Including the lung and intestinal tract.

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23
Q

Where is Calcitriol synthesized and what is its function?

A

The active form of Vitamin D and Functions to increase plasma Ca2+. Synthesized in skin and blood

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24
Q

Calcitriol most important physiological action?

A

Increases calcium uptake from GI

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25
Q

Calcitriol additional pharmacological actions include?

A

Increases kidney reabsorption (pharmacologic dose)
Increases bone resorption (pharmacologic dose)
This is paradoxical, but true, and increasing doses
promote even more resorption. Calcium can
reverse this effect.

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26
Q

Things that can cause a loss of Calcium Homeostasis?

A 
Estrogen deficiency (postmenopausal osteoporosis)
Glucocorticoid excess
Growth hormone deficiency
Insulin deficiency
Primary hypoparathyroidism
Cancer
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27
Q

Low Calcium is detected by?

A

Detected by parathyroid, causing increased

PTH synthesis.

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28
Q

Increased PTH then causes?

A

Increased absorption of calcium by kidney
Increased synthesis of Calcitriol
Increased resorption of bone
More calcitriol results in increased GI absorption of calcium

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29
Q

High Calcium detected by?

A

Detected by parafolicular cells of the thyroid, causing increased Calcitonin synthesis.

30
Q

Increased Calcitonin then causes?

A

Decreased synthesis and secretion of PTH
Decreased resorption of bone (opposing PTH)
Shift to inactive form of Vitamin D
Decreased PTH causes increased excretion of calcium

31
Q

Hypoparathyroidism diseases?

A

Autoimmune disease rare, more common from thyroid surgery or parathyroid cancer. Very serious but treatable

32
Q

Bioengineered hPTH now available for treatment of?

A

Hypoparathyroidism

short half-life (peptide).

33
Q

Hypoparathyroidism most common treaatment?

A

More commonly treated with Vitamin D, with or without dietary supplements of calcium.

34
Q

What is Teriparatide and what is its mechanism?

A

hrPTH 1-34 directly stimulates bone formation
Excess endogenous PTH causes bone resorption
Exogenous PTH in low doses increases bone formation without stimulating resorption.

35
Q

Teriparatide can be used for?

A

Important for women with osteoporosis after bisphosphonate therapy

36
Q

The function of Fibroblast Growth Factor 23 (FGF23) and it is produced by?

A

FGF23 inhibits production of 1, 25-(OH)2D3.
Thus opposes PTH in kidney
Produced by osteoclasts and osteoblasts

37
Q

Calcitonin Mechanism of Action

A

Binds to plasma membrane receptor
Decreases ruffled border surface area on osteoclasts
Not a global inhibitor of PTH
Has direct renal effects

38
Q

Main Therapeutic uses of Calcitonin?

A

Hypercalcemia (as from Hyperparathyroidism)
Paget’s disease (bone remodeling disorder)
Now used in treatment of osteoporosis

39
Q

Calcitonin very effective for?

A
  • Short term treatment Hypercalcemia (as from Hyperparathyroidism). Prednisone can be used (takes 1 to 2 weeks)
  • Paget’s disease (bone remodeling disorder)
  • Now used as injection and nasal spray treatment for osteoporosis
40
Q

With long-term use of Calcitonin?

A

Antibody development occurs (even with hCT)

41
Q

Calcitriol is synthesised by and is the most important?

A

(1,25-Dihydroxy-D3)
Synthesized by the skin & Transported in the blood.
Most important calcium-regulating hormone and most important for therapeutics

42
Q

Calcitriol Mechanism of Action

A

Stimulates Ca2+ and phosphate absorption in the small intestine
Induces synthesis of calbindin (family of Ca2+
binding proteins)
Binds to transcription factor to increase mRNA, protein synthesis
Has additional effects to increase uptake of Ca2+ from intestine.

43
Q

Major Uses of Calcitriol in Therapeutics

A

Prophylaxis and cure of nutritional rickets
Treatment of metabolic rickets and osteomalacia
Treatment of hypoparathyroidism
Prevention and treatment of osteoporosis

44
Q

What is Cholecalciferol and what is it found in?

A

= Vitamin D3
Found in fish liver oils. Takes effect in 12 to 24 hours.
Remains in lipid stores for months.

45
Q

Ergosterol is similar to?

A

cholesterol

46
Q

Ergocalciferol is?

A

(after irradiation) = Vitamin D2

47
Q

25-OH Cholecalciferol is

A

Vitamin D2

48
Q

What is Calcipotriol & what is it more effective than?

A

Analog of Calcitriol used in treatment of Psoriasis topical. More effective than glucocorticoids.

49
Q

What is Dihydrotachysterol & how effective is it?

A

Reduced Vitamin D2 , (DHT). It is 0.002 times as active as calcitriol, but more effective in high doses.

50
Q

Dihydrotachysterol (DHT) now used in treatment of?

A

OSTEOPOROSIS either by Injection and nasal spray

51
Q

Paricalcitol reduces?

A

PTH secretion

52
Q

22-Oxacalcitriol supresses?

A

PTH gene expression.

53
Q

Bisphosphonates are?

A

Nonhydrolyzable analogs of inorganic pyrophosphate

54
Q

Bisphosphonates work by & are used to treat?

A

Inhibitors of bone resorption
First used in Paget’s disease
Effective in treatment of osteoporosis

55
Q

Two Bisphosphonates that are not effective orally?

A

The drugs etidronate and pamidronate are not effective in management of hypercalcemia but a 4 to 24 hr infusion is effective in lowering calcium for several weeks.

56
Q

Etidronate, alendronate, & risedronate used in?

A

Paget’s disease

57
Q

Alendronate used for?

A

Osteoporosis

58
Q

Etidronate, alendronate, & risedronate are absorbed and taken with?

A

All are absorbed very poorly in the intestine & must be taken after an overnight fast with a full glass of water. No food for 30 minutes. Now have weekly dosage form.

59
Q

Alendronate Potency?

A

10-100X

60
Q

Risedronate Potency?

A

1,000-10,000

61
Q

Serious complication of bisphosphonates therapy?

A

Osteonecrosis of the Jaw
80% of cases follow dental extraction.
Many cases are complicated by infection.
Mainly in patients with cancer after prolonged therapy.
Much more common with 3rd generation drugs.

62
Q

Glucocorticoids are a common cause of?

A

Osteoporosis in adults by antagonize Ca uptake in intestine. Useful in reversing lymphoma-induced hypercalcemia

63
Q

Estrogens are good for (blank), but increase the risk of (blank)?

A

Effective in preventing osteoporosis, but replacement therapy trials have shown increased risk of thrombosis.

64
Q

Bisphosphonates have been demonstrated to prevent?

A

Cancer treatment induced bone loss.

65
Q

Calcimimetics function?

A

Calcium Sensor Receptor Mimetics bind to the Calcium Sensor Receptor (CaSR)

66
Q

Cinacalcet mechanism?

A

Binds allosterically to CaSR and allows PTH suppression at lower [Ca2+]. Effectively lowers circulating PTH.

67
Q

Cinacalcet approved for?

A

Hyperparathyroidism in patients with parathyroid carcinoma.

68
Q

Fluoride Potential agent in preventing?

A

Osteoporosis

69
Q

Fluoride uses?

A

Long used for dental caries prevention

F – binds Calcium. Can be used to prevent blood clotting.

70
Q

Fluoride Toxicity:

A

Osteosclerosis (hydroxyapatite replaced by fluoroapatite), mottled enamel (fluorosis).

Endocrine Pharmacology (5 decks)

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