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Pharmacology 200 > 3 - osteoperosis > Flashcards

3 - osteoperosis Flashcards

1
Q

what is osteoporosis

A

skeletal disorder in which deterioration of bone density and bone quality increases the risk of fracture

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2
Q

how does oseoperosis effect more (men or women)

A

women (4:1)

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3
Q

what is the role of hydroxyapatite

A

calcium and phosphate in a 3d matrix, provides compression and resistance and hardness
it is 65% of bone mass

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4
Q

what does hydroxyapatite associate with

A

collagen fibre

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5
Q

what is the role of osteoclasts

A

bone reabsorption (break down)

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6
Q

what is the role of osteoblasts

A

bone deposition (both collagen and hydroxyapatite)

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7
Q

what happens when osteoclasts do their thing

A

they break down bone, releasing growth factors and acid and collegenase

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8
Q

what do the growth factors released from osteoclasts cause

A

stimulate osteoblast formation from progenitor cells

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9
Q

what is collagenase

A

enzyme that degrades collagen

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10
Q

what are biphosphonates structure

A

two phosphate groups attached to a central carbon

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11
Q

what do the phosphonate groups do in biphosphonates

A

act as anchors to bone and are essential for both binding to hydroxyapatite and for biochemical actions

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12
Q

what happens when R1=OH in biphosphates

A

there is an improved binding to bone via interaction with calcium

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13
Q

what does the R2 group in biphosphonates determine

A

antiresorptive potency and affects binding to hydroxyapatite

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14
Q

when do biphosphonates have the highest affinity for bone

A

bone undergoing remodeling (this happens more in osteoperosis)

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15
Q

are biphosphonates natural in the body or drugs

A

drugs

they mimic the pyrophosphate that circulates in the blood

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16
Q

what are the names for 1st gen BPs

A

non-nitrogen BPs

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17
Q

what is an example of first gen BPs

A

medronate

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18
Q

what is the R groups of medronate

A

H

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19
Q

what are the R groups in first gen

A

they are minimally modifies, no nitrogen or OH

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20
Q

what is an example of 2nd gen

A

alendronate

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21
Q

what are the R groups in alendronate

A

R1=OH

R2=nitrogen after a carbon chain

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22
Q

how much more potent is gen 2 than gen 1

A

10-100X

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23
Q

why are gen 2 more potent than gen 1

A

more affinity to bone

24
Q

what are the general structure of 2nd gen

A

nitrogen containing with alkyl-amino structure

25
Q

what are the general structure of 3rd gen

A

nitrogen containing BP with heterocyclic structure

26
Q

what is an example of 3rd gen

A

zoledronate

27
Q

what is the R in zoledronate

A

R1=OH

R2=nitrogen incorporated in rigid ring structure

28
Q

how much are gen 3 more potent than gen 1

A

10 000X

29
Q

where do biphosphonates bind

A

hydroxyapatite

30
Q

what causes differences in potency

A

different abilities of binding to hydroxyapatite

31
Q

what is the main role of OH in the biphosphonates

A

initial binding to the bone

32
Q

what happens to osteoclasts when people are on biphosphonates

A

the osteoclasts taken up the biphosphonates

along with the calcium phosphate and collagen

33
Q

how do non nitrogen biphosphonates interfere with osteoclasts (2)

A

they interfere with ATP production, making non-hydrolysable ATP analogues

also the ATP analogues inhibit the mitochondrial ADP/ATP translocase protein which exports ATP and imports ADP

34
Q

what is the net effect of non nitrogen biphosphonates in osteoclasts

A

they are starved of energy cause they have no ATP causing apoptosis

35
Q

what is the mechanism of action of nitrogen containing biphosphonates

A

they inhibit the mevalonate pathway which is involved in cholesterol synthesis
(and other sterols)

36
Q

what is the major target of nitrogen containing biphosphonates

A

FPPS enzyme in osteoclasts

37
Q

what does FPPS do

A

produce essential lipids that are linked to proteins in prenylation

38
Q

what does prenylation allow

A

proteins to associate with membranes

39
Q

what is prenylation

A

when you add fatty acid tail to protein

40
Q

what are 4 roles of Ras protein

A

cytoskeletal arrangement, membrane ruffling, trafficking of vesicles, apoptosis

41
Q

what are Ras proteins known as / referred to as

A

“molecular switches”

42
Q

what is Ras protein (what kind of protein)

A

GTPase protein

43
Q

what happens if Ras is not prenylated

A

they are not able to go to the membrane, they become dysfunctional and kills the osteoclasts

44
Q

how does it prevent prenylation at FPPS (mechanism of action at FPPS)

A

phosphate groups bind to two magnesium atoms

45
Q

what causes high affinity binding to FPPS

A

interaction with nitrogen on R2 with lysine and threonine in the binding site

46
Q

what must the distance between nitrogen and oxygen be for optimal binding

A

3 angstroms

47
Q

are the actions at FPPS competitive or non competitive

A

mix of both

48
Q

what is common between biphosphonates and statins

A

they both inhibit the mevalonate pathway

49
Q

where do statins inhibit in the mevalonate pathway

A

HMG-CoA reductase

50
Q

are statins of biphosphonates more potent in inhibiting osteoclasts and bone resoption in cultures

A

statins

51
Q 
do statins work in vivo on bones
and why (2 things)
A

no
they are transported into liver tissue via specific transporters not present in bone
no affinity for hydroxyapatite

52
Q

do statins affect liver cholesterol production and why

A

no because they are not transported into the liver

53
Q

which biphosphonates can cause flu symptoms and why

A

nitrogen biphosphonates because inhibition of FPPS results in accumulation of precursors (IPP)

54
Q

which precursor is accumulated that causes the flu like symptoms

A

IPP which is immediately upstream from FPPS

55
Q

what happens with extra IPP

A

agonist at receptors on circulating immune cells

56
Q

what does activation of immune cell receptors cause (from IPP)

A

release of tumor necrosis factor alpha

TNF_alpha) which is a signalling molecule which initiates inflammation (acute phase reaction

Pharmacology 200 (29 decks)

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