drugs in management of musculoskeletal conditions Flashcards
what is pharmacokinetics
process by which drug is absorbed, distributed, metabolised and eliminated by the body
ADME
What is bioavailability
Degree to which a drug or other substance becomes available to the target tissue after administration
Which bones more susceptible to breakage
Hip
Wrist
Spine
Although certain groups of people are more likely to break bones such as older people and women this doesn’t mean that their…
Ability to repair bone is reduced
Men are less likely to develop osteoporosis than women but what are they at greater risk of
Mortality after a hip fracture
What form osteoclasts and where do they reside
Fusion of many circulating monocytes - because many cells fuse together to form osteoclasts means that this cells are multinucleated histologically
Howship lacunae
What gives rise to osteoblasts
Arise from differentiation of osteogenic cells in the periosteum. This process requires blood supply otherwise chondroblasts are formed which eventually become chrondrocytes (mature cartilage cells)
Chondroblasts become surrounded by matrix and become osteocytes
How do osteoclasts resorb bone
Attaches to bone via its integrins which are linked to the actin cytoskeleton. Alters the environment through:
- proton pump on osteoclasts which increases acidity within the sealing zone —> acidic environment = degradation
- osteoclasts pump in Cathepsins, metalloproteinases and lysosomal enzymes causing breakdown.
Causes release of calcium which is uptaken by osteoclast and then transported out via blood supply
How do osteoblasts communicate and control balance of osteoclasts
Osteoblasts produces RANKL which upon binding to RANK on osteoclast which will cause maturation
Osteoblast can also produce OPG which will bind to RANKL thus preventing it from binding to RANK preventing maturation of osteoclast
Why are women more likely to be affected by osteoporosis
Bone density increases until 25
Bone density is maintained between 25-35
After that both males and females lose bone density but this is much larger in females as they have less initially and loss is further exacerbated by hormonal changes during the menopause
How can MSK disorders be managed
Appropriate diet and exercise
Drugs
Replacement of joints
What are bisphsophonates
Enzymes resistant analogues of pyrophosphate.
What does pyrophosphate do
Inhibits mineralisation in the bone
What property allows bisphosphonates to be specific to the bones
Two phosphonat groups are able to bind to calcium and therefore can accumulate readily in bone
BP will also sit in bone until is released by action of osteoclast
What is the R1 position of the BP associated with
Mode of action of the drug
What is the R2 position of the BP associated with
The pharmacokinetics of the drug
What are the two classes of BP’s
Nitrogen containing Bps in the variable R group
Non nitrogen containing BPS in the variable R group
How do the two classes of BPs differ
Drugs have different potency and different mode of action
Example of nitrogen containing BP
Alendronate (contains amine group in R1 region)
Example of non nitrogen containing BP
Etidronate (contains methyl group in R1 position)
What is the mechanism of action of NNBPs
Metabolically incorporated into analogues of ATP that may then inhibit ATP-dependent intracellular enzymes
What is the mechanism of action of NBPs
Upto a 1000x more potent
Inhibits enzyme that produces molecules needed for post translational modification of GTP binding proteins such as Rab, Rho and Rac.
Above proteins required for actin cytoskeleton and cell motility
In osteoclast action prevents formation of sealing zone thus impairing ability to degrade bone
What is the major side effect of BPS
Osteonecrosis of the jaw (not that common but is more common in those with bone cancer)
However is still used to treat metastatic bone cancer
What are the 3 types of HRT
- oestrogen only
- mix of progesterone and oestrogen
- SERMs such as raloxifene
