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PHA 332 > OSTEOPOROSIS DRUGS STEVE DARBY > Flashcards

OSTEOPOROSIS DRUGS STEVE DARBY Flashcards

1
Q

what is osteoporosis?

A

loss of bone mass due to reduced organic bone matrix and mineral content

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2
Q

what are the causes of osteoprosis?

A

–Increased bone resorption (osteoclasts)
–Decreased bone formation (osteoblasts)
–Both

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3
Q

how do you classify osteoporosis?

A

primary:
menopause- typically inc bone resportion
age- dec bone function

secondary:
malnutrition
endocrine disorders
cancer
drug use
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4
Q

what are the hormones that regulate calcium?

A

–Calcitonin
–Parathyroid hormone
–Vitamin D

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5
Q

what influences osteoporosis?

A

calcium, mg, phosphate
osteoclast/blast levels and activity
multiple signalling pathways implicated

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6
Q

what is RANK responsible for?

A

= Receptor Activated NFκB >Osetoclast activator

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7
Q

what is RANKL ?

A

Receptor Activated NFκB LIGAND

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8
Q

what is OPG?

A

Oseteoprotegerin = inhibits bone resporption

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9
Q

what is oestrogens role in bone formation?

A

stimulate pre-osteoblasts
blick HSC and T cell activation
cause osteocyte formation

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10
Q

what are simple preventive measures for osteoporosis?

A

•Oral calcium supplements increase bone mineral density in the spine in postmenopausal women
•The addition of vitamin D confers greater benefit
•HRT
smoking cessation
inc exercise

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11
Q

how do anti-resorptive therapies work?

A

Decrease markers of bone formation and bone resorption. •Bisphosphonates, •Raloxifene, Oestrogen •Denosumab

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12
Q

how do bone forming therapies work?

A

Increase markers of bone formation overbone resorption.
•Calcitonin
•Teriparatide

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13
Q

why do you give it as a bisphosphonate rather than a pyrophosphonate?

A

due to hydrolysis in the GI tract

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14
Q

what is the mechanism of bisphosphonates?

A
  • Inhibit osteoclast proliferation
  • Inhibit osteoclast activity
  • Inhibit the malaveonate pathway in osteoclasts

reduce bone turnover
allow osteoblasts to function

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15
Q

what is the mevalonate pathway?

A

bisphosphonates block the conversion of geranyl pyrophosphate to GGPP
these are requred for the post translation modification of small GTPases which are required for osteoclast function

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16
Q

how are bisphosphonates excreted?

A

via kidneys

17
Q

what is the serum and tissue half life for bisphosphonates?

A
  • Serum half life = 4-6hours
  • Tissue half life = >10 YEARS
  • ONE dose of zoledronic acid lasts one year…
18
Q

what is a first generation oral bisphosphonate?

A

etidronate disodium
Effective in Pagetsdisease BUT produced poorly mineralised bone…….Not approved or clinically used for osteoporosis treatment

19
Q

what are second generation oral bisphosphonates?

A 
nitrogen containing compoinds
alendronic acid
more potent
produces well mineralised bone
take one per week
20
Q

what is a third generation bisphosphonate?

A

nitrogen containing
risedronate sodium
produces well mineralised bone
once per week

21
Q

what IV bisphosphonates are availible?

A

zoledronic acid
IV annually
caution of osteonecrosis of the jaw

22
Q

when do we consider renal function?

A

eGFR<35ml/min/1.73m2 Alendronic acid •eGFR<30ml/min/1.73m2 Risedronate
•Hypocalcaemia •Dysphagia

23
Q

why are bisphosphonates taken once a week?

A

poorly absorbed from the gut, and oral formulations are best taken once weekly with the stomach empty to avoid binding by Ca2+in food.

24
Q

how long does it take to remove bisphosphonates from the body?

A

Removal of most bisphosphonates from blood via the kidney is rapid, but their effect is prolonged since a fraction remains tightly bound to Ca2+in bone for years

25
Q

what is the s/e from bisphosphonates?

A

•Gastrointestinal disturbance, particularly nausea, abdominal pain, diarrhoea or constipation with the oral treatments. •Alendronicacid and risedronatesodium can cause severe oesophagitis and oesophageal strictures. •
Headache, dizziness, vertigo, musculoskeletal pain.
•Transient pyrexia and influenza-like symptoms after intravenous infusion.
•Osteonecrosis of the jaw, especially after intravenous use in the treatment of cancer.

26
Q

how does Denosumab work by RANKL inhibition?

A
  • Mimicking nature is a GOOD idea
  • Simply copying what OPG is doing
  • Bind to RANKL to prevent osteoclast activation
  • Use a monoclonal antibody specific to RANKL
27
Q

what are some osteoporosis therapies using ER agonists?

A
  • Oestrogen replacement
  • Hormone replacement Therapy (HRT)
  • Preventative measure
28
Q

how does ER receptor activation occur?

A
  • HRT causes Helix H12 to fold over the E2binding site
  • This conformational change then enables ER to bind to transcriptional cofactors and DNA •Initiates ER target gene transcription
  • Promotes cellular growth and bone formation
29
Q

how is serms used i?

A

In a previous session (ER lecture) discussed raloxifeneas an ER antagonistin breast tissue
•However, in osteoclasts it is and ER Agonist..!!•Stimulates ER, reduces osteoclast activity

30
Q

what is ralocifenes therapeutic action?

A

clinically shown to decrease fracture risk and promotes bone formation

31
Q

what is a second generation SERM and how is it used?

A

Lasofoxifene

Prevents bone loss

32
Q

what causes the SERM effects?

A

ERE– EstrogenResponse Element Breast Tissue

RRE– Raloxifene Response ElementBone

33
Q

how does PTH work?

A

Indirectlystimulates intestinal absorption of calcium and promotes bone resorption.
•PTH stimulates bone resorption by several mechanisms: •(1) osteoprogenitor cells become osteoclasts presence of PTH•(2) PTH promotes the deep osteocytes to mobilize calcium•(3) surface osteocytes are stimulated by PTH to increase the flow of calcium out of the bone.

34
Q

what is the MOA of pth?

A
  • Binds PTH1R Receptor

* Promotes bone resorption

35
Q

what is the dual effects of PTH?

A
  • Stimulates bone resorption: Increases osteoclastic activity through up regulation ofRANKL and downregulation of OPG secretion by osteoblasts.
  • Increases bone formation:Bone formation increased indirectly via autocrine and paracrine pathways through release of IGF-1, FGF-2 and amphiregulin from osteoblasts.
36
Q

what is teripartide?

A

Anabolic treatment – bone forming NOT anti-resorptive
•Recombinant portion of parathyroid hormone (PTH)
•Activates Parathyroid Hormone Receptor
•Favours Activation of osteoblasts
Decreases osteoclasts

37
Q

when is teripartide used?

A

most severe cases

38
Q

how does teripartide work?

A

Activates osteoblasts more than osteoclasts. Stimulating new bone formation leading to increased bone mineral density

PHA 332 (42 decks)

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