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Therapeutics > Module 2 lecture 3 > Flashcards

Module 2 lecture 3 Flashcards

1
Q

Difference between osteoblasts and osteoclasts

A

Osteoblasts put calcium back into the bone
osteoclasts dig calcium out of bone

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2
Q

What does Osteocyte do

A

Decides whether osteoblasts are stimulated or osteoclasts

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3
Q

What percent of phosphate is in the bone

A

86%

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4
Q

The form of calcium that is in the bone is called______

It is composed of _______, ________ and ______-

A

hydroxyapatite
It is composed of calcium, PO4 and H20

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5
Q

T/F When we resorb calcium from bone via osteoclastic activity, we also bring phosphate out of the bone with calcium

A

True

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6
Q

Osteoclasts release

A

calcium and phosphate

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7
Q

how are osteocytes stimulated

A

Mechanical force detected by cell, which extends to canaliculli

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8
Q

Name two important factors that decrease BMD

A

Sclerostin and RANKL

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9
Q

Neutralizing what two factors is a strategy to combat post menopausal osteoporosis

A

sclerostin and RANKL

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10
Q

What is the main driver for elevating calcium levels if they get too low

A

PTH

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11
Q

Where is PTH secreted from

A

Parathyroid gland

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12
Q

How does PTH affect the extracellular Ca levels

A

Increases it

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13
Q

How does PTH increase the Ca levels

A

Stimulates osteoclastic activity

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14
Q

PTH effect on calcium reabsorption in kidneys

A

PTH stimulates calcium reabsorption from kidneys

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15
Q

How does PTH stimulate calcium reabsorption from kidneys

A

upregulates calcium channels ECac/ TrPV5

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16
Q

PTH effect on PO4 loss in urine

A

Increases PO4 loss in urine

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17
Q

PTH effect on vit D production in kidney

A

Increases vitamin D production in kidney

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18
Q

PTH secretion is triggered by

A

low serum Ca 2+ levels

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19
Q

What is CaSR

A

Gq linked GPCR that secretes PTH when not bound by Ca2+.

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20
Q

When Ca2+ is bound to CaSR it will stimulate

A

PLC

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21
Q

What kind of effect does PLC have on PTH secretion

A

Negative

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22
Q

One of the main activities of PTH is regulation of production of

A

1, 25 (OH)2-D3

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23
Q

first step of vitamin D synthesis

A

7- dehydrocholesterol–UV Irradiation——->cholecalciferol (vitamin D3)

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24
Q

Second step of vitamin D synthesis

A

Vitamin D3 (cholecalciferol) transported to liver via vitamin D binding protein and hydrolyzed to 25-hydroxy vitamin D3 by 25-hydroxylase

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25
Q

Third step of vitamin D synthesis

A

25 hydroxy vitamin D3 is transported to kidney and is catalyzed by 1-a-hydroxylase to form 1, 25 dihydroxy vitamin D3

(A more active form in terms of absorbing calcium from intestine)

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26
Q

Alternate third step for vitamin D synthesis

A

25- hydroxy vitamin D3 goes to the kidney and is catalyzed by 24-hydroxylase to form 24,25 dihydroxy vitamin D3 (less active interms of absorbing calcium)

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27
Q

______________ has activities in intestine in terms of calcium regulation

A

1,25 dihydroxy vitamin

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28
Q

Actions of vitamin D3 on Ca and PO4 absorption

A

Increases Ca and PO4 absorption

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29
Q

What is the rapid (direct) effect of vitamin D3

A

stimulates translocation of another calcium channel (TrPV6)

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30
Q

What happens to the TrPV6 channel in rapid (direct) effect of vitamin D3? How does this affect Ca.

A

Rapidly transported to luminal side of intestinal mucosal cells. This allows for the flow of Ca into mucosal cells

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31
Q

What does calbindin D9K do?

A

It acts as a transporter of Ca within the cell to pump out the calcium. Prevents calcium sequestration within enterocyte.

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32
Q

What prevents calcium sequestration in enterocytes

A

Calbindin D9K

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33
Q

What prevents phosphate accumulation prevention

A

Fibroblast GF 23 (FGF23)

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34
Q

What is FGF 23 secreted by

A

Osteoblasts and osteocytes

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35
Q

FGF 23 is released in response to

A

elevated serum phosphate

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36
Q

FGF 23 effect on kidney

A

Stimulates phosphate secretion in kidney

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37
Q

How does FGF 23 stimulate phosphate excretion in kidney

A

by suppressing phosphate transporters that would reabsorb phosphate from renal filtrate

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38
Q

FGF 23 effect on PTH secretion

A

Inhibits PTH secretion

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39
Q

FGF 23 effect on vitamin D

A

inhibits synthesis

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40
Q

FGF 23 effect on bone mineralization

A

inhibits it

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41
Q

Does FGF 23 have autocrine or paracrine effects

A

Both autocrine and paracrine

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42
Q

what is the mutant version of FGF 23 called

A

protease resistant mutant of FGF 23

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43
Q

What does protease resistant mutant of FGF 23 cause

A

autosomal dominant hypophosphatemic rickets

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44
Q

What is autosomal dominant hypophosphatemic rickets

A

Lack of bone mineralization due to lack of phosphate

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45
Q

What are 3 factors that regulate PTH secretion from Parathyroid gland

A

CaSR
1, 25-(OH)2 vit D3
FGF 23

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46
Q

How does CaSR regulate PTH secretion

A

calcium increase inhibits PTH
calcium decrease stimulates PTH

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47
Q

How does 1, 25-(OH) vit D3 regulate PTH secretion

A

feedback inhibition of PTH secretion (PTH stimulates vit D3 production in the kidneys

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48
Q

How does FGF 23 affect PTH secretion

A

Inhibits PTH secretion

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49
Q

Calcitonin is secreted by

A

C cells in thyroid gland

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50
Q

How does calcitonin affect serum Ca2+

A

It is a negative regulator of serum

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51
Q

How does calcitonin affect osteoclastic activity

A

Inhibits osteoclastic bone resorption

52
Q

effect of calcitonin on calcium and PO4

A

Increase

53
Q

calcitonin is stimulated by

A

high serum calcium levels

54
Q

Calcitonin can be used to suppress

A

hypercalcemia

55
Q

What is pagets disease

A

It is characterized by uncontrolled osteoclastic bone resorption and secondary bone formation.

56
Q

Symptoms of pagets disease

A

bone pain
bone deformities
loss of hearing (hypercalcemia)
may be caused by virus

57
Q

postmenopausal osteoporosis causes

A

decrease in estrogen levels causes a decrease in bone mass
more osteoclasts. This causes shift towards bone remodeling towards resorption.

58
Q

Aging osteoporosis causes

A

age related dcerease in osteoblasts

59
Q

risk factors for osteoporosis

A

age, physical activity levels, low Ca2+ intake in early years, long term glucocorticoid therapy

60
Q

hypercalcemia is caused by

A

hyperthyroidism and malignant tumors

61
Q

how does hyperparathyroidism cause hypercalcemia

A

PTH causes increased bone resorption

62
Q

hypocalcemia is caused by

A

Hypoparathyroidism
Vitamin D deficiencies

63
Q

3 different vitamin 3 preparations

A

Cholecalciferol vit D3
Calcidiol
calcitrol

64
Q

people with compromised liver function will not be able to convert Vit D3 to

A

25-hydroxy

65
Q

People with compromised kidney function will not be able to convert ________to _______

A

25 hydroxy to 25 dihydroxy

66
Q

mechanism of action of vit D3

A

Increase calcium and PO4 absorption from gut and renal tubules

67
Q

vit D can be used for

A

Hypocalcemia, hypoparathyroidism

68
Q

First line of therapy for osteoporosis

A

Bissphosphonates

69
Q

What do bisphosphonates do?

A

Inhibit bone resorption

70
Q

What is it that allows bisphosphonates to accumulate in hydroxyapatite in bone

A

bisphosphonates are structural analogs of pyrophosphates.

71
Q

How do bisphosphonates treat osteoporosis (mechanism)

A

50% of absorbed dose goes to the bones and ends up bound in hydroxy apatite
It is taken up by osteoclasts
They have INHIBITORY effects on osteoclasts.

72
Q

Bisphosphonates get into bone and inhibit what enzyme

A

Farensyl PP synthase

73
Q

How does bisphosphonates affect osteoclasts

A

causes apoptosis

74
Q

Bisphosphonates effect on BMD and osteoclastic activity

A

increase BMD and decrease osteoclastic activity

75
Q

dosing precautions for bisphosphonates

A

Take before breakfast
stay upright for 30 mins

76
Q

Why do you want patient to be upright for 30 minutes after taking bisphosphonates

A

So it does not end up in esophagus and cause gastric irritation of esophagus

77
Q

all drug names for bisphosphonates end with

A

-Nate

78
Q

Which two bisphosphonate drugs are only approved for pagets and cancer and not osteoporosis

A

Pamidronate
etidronate

79
Q

What are isoprenoids

A

basic units used to build cholesterol

80
Q

FPP abbreviation

A

Farensyl pyrophosphate

81
Q

how is FPP formed

A

isopentene pyrophosphate (IPP) + dimethyl allopyrophosphate (DMAPP) = GPP

GPP+IPP gives FPP

82
Q

What can FPP be used for

A

To prenylate GTP binding proteins such as RAC and RAS

83
Q

Why do RAC and RAS need to be prenylated with FPP

A

farensyl groups are attached to the GTP binding proteins RAS and RAC, that is what inserts into membrane and localizes proteins to membrane

84
Q

What happens when Ras and Rac signaling is interrupted?

A

leads to a decrease in osteoclat survival and numbers

85
Q

How is Rac and Ras signalling interrupted?

A

By bisphosphonates when they inhibit production of farensyl pyrophosphate synthase

86
Q

What are 2 PTH drugs for osteoporosis

A

Teriparatide (forteo)
Abaloparatide (tymlos)

87
Q

How do the PTH drugs Forteo and tymlos work

A

they preferentially stimulate osteoblast activity

88
Q

How does teriparatide increase bone mass

A

preferentially stimulate osteoblast activity

89
Q

Explain the interaction of teriparatide with PTH 1 receptors

A

Continuous supply- leads to increase in osteoclast number and no change in osteoblast number.

If we give 1 h/day infusion, osteoblast numbers increase with no increase in osteoclasts.

90
Q

Why is there a dual effect seen during PTH exposure and osteoblasts

A

Osteoblasts have the ability to secrete factors that drive osteoclast differentiation (RANK L).

Continuous PTH exposure by osteoblasts, they secrete a high quantity RANK L. This activates the RANK receptor on surface of osteoclasts precursors, driving differentiation into osteoclasts.

91
Q

What does continuous RANK exposure do to osteoclast numbers

A

Increases it.

92
Q

What do osteoblasts secrete that neutralize RANKL

A

Osteoprotegorins

93
Q

How does continuous PTH (teriparatide) secretion affect osteoblast and osteoclasts

A

Increased RANKL
decreased OPG (osteoprotegorin)

Increased osteoclast differentiation

increased bone resorption
increased serum calcium

94
Q

How does intermittent PTH (Teriparatide) secretion affect osteoblasts and osteoclasts

A

Decreased osteoblast apoptosis
increased core binding factor (Cbfa1) (pre-osteoblasts)

Increased osteoblast number
increased bone mass and strength

95
Q

What do we use to rapidly increase BMD between bisphosphonates and teriparatide (PTH)

A

PTH rapidly increases BMD

96
Q

Comparison of teriparatide to bisphosphonates (pros)

A

May be more effective at preventing fractures than bisphosphonates. Builds bone mass at higher rate than bisphosphonates.

97
Q

Comparison of teriparatides to bisphosphonates (CONS)

A

injected daily
not recommended beyond 2 yrs
black box warning for risk of bone cancer

98
Q

What is prolia (denosumab) binding to?

A

Binds to RANKL

99
Q

What does denosumab binding to RANKL do?

A

prevents activation of RANK on osteoclast precursors, preventing differentiation of osteoclasts

100
Q

What is a step that needs to be taken before administering denosumab

A

get hypercalcemia under controlM

101
Q

Difference between romosozumab and denosumab

A

Denosumab targets RANKL, romosozumab targets sclerostin

102
Q

How and when is sclerostin secreted

A

sclerostin is secreted from osteocytes in absence of load.

103
Q

What does sclerostin do

A

Increases osteoclasts and decreases osteoblasts (decreases BMD)

104
Q

Contraindication of romosozumab

A

Not used in patients with MI or stroke

105
Q

Romosozumab mechanism

A

Binds sclerostin and neutralizes it. This prevents it from decreasing osteoblasts and increasing osteoclasts

106
Q

how does sclerostin interact with LRP 5/6 and WNT

A

Sclerostin binds LRP 5/6 and inhibits WnT signalling

107
Q

What is more effective at preventing fractures between raloxifene and estradiol

A

Estradiol is more effective

108
Q

What is the advantage that raloxifene has over estradiol

A

It is selective for bones, does not increase risk for breast cancer or uterine cancer.

109
Q

Mechanism of calcitonin

A

Decreases osteoclast activity and blocks renal absorption of PO4 and Ca2+

110
Q

Calcitonin is most commonly used to treat

A

Hypercalcemia

111
Q

what does cinacalcet treat

A

Hyperparathyroidism

112
Q

What happens to Ca sensing receptor in CKD patients

A

It can become less responsive to Ca2+

113
Q

Why does hyperparathyroidism happen in patients with CKD

A

Kidneys do not make 1,25 (OH) vit D in response to PTH (1,25 vit D is an important feedback inhibitor for PTH secretion.

114
Q

How does cinacalcet enhance the response of the CaR to elevated Ca levels

A

Binds CaR and inhibits the release of PTH

115
Q

How does cinacalcet affect PTH and calcium levels

A

decreases both PTH and calcium levels

116
Q

cinacalcet is a PAM of CaR T/F

A

True

117
Q

etelcalcetide effects on PTH and serum Ca

A

decreases both PTH and Ca2+

118
Q

mechanism of etelcalcetide

A

Similar to cinacalcet (given after dialysis to activate the CaR by acting as a PAM. Makes calcium more effective at that receptor.

119
Q

Name two analogs of vitamin D

A

Zempar and Hectorol

120
Q

Which one is the prodrug hectorol or zemplar

A

Hectorol

121
Q

Mechanism of zemplar and hectorol? how do they differ from cinacalcite and etelcalcetide

A

Zemplar and hectorol bind to the Parathyroid gland and inhibit PTH production. Cinacalcite and etelcalcitide bind to CaR to reduce PTH secretion

122
Q

CKD patients lose their ability to excrete phosphate in response to

A

PTH and FGF 23

123
Q

How can hyperphosphatemia be dangerous

A

can block blood flow in small blood vessels

124
Q

Name two phosphate binders

A

Fosenrol (lanthanum carbonate)
Renagel (sevelamer)

125
Q

mechanism of fosenrol

A

forms insoluble lanthanum salts in GI tract, these salts are not absorbed into the blood stream

126
Q

fosenrol effects on serum PO4 and Ca 2+ levels

A

Decreases

127
Q

Renagel mechanism of action

A

Amine containing polymer that binds PO4 in the GI tract

Therapeutics (46 decks)

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