Drugs In The Management Of Musculoskeletal Conditions Flashcards
(42 cards)
What is an osteoclast?
Multinucleated cell for bone dissolution and absorption contained within Howship lacunae in bone
What is an osteoblasts?
Important for bone cell synthesis, derived from mesenchymal stem cell progenitors in the periosteum which require a blood supply to undergo differentiation.
What happens when there is insufficient blood supply in osteoblasts synthesis?
Mesenchymal stem cell progenitor will differentiate into —> chondroblast which will form cartilage rather than bone.
How do osteoclasts resorp bone?
Osteoclasts have an outer membrane called the ruffled border, lined with integrin receptors for binding to bone and create a sealing space. Osteoclasts first pump acidic H+ ions into the sealing space, disintegrating hydroxyapatite crystals and its contents are taken up by osteoclasts for distribution to capillaries. They also pump metalloproteases for cartilage degradation, collagenase, cathespin K protein and lysosomal enzymes. Osteoclasts use GTP proteins for vesicular trafficking of breakdown products.
How is osteogenesis regulated?
Osteoblasts will release RANK-L ligand to bind to osteoclasts and induce maturation. When bone density is low, osteoblasts produce OPG ligand to bind to RANKL and prevent binding for osteoclast activation.
How can MSK disorders be treated?
Diet and exercise: —> for nutrition and the exercise of stress for maintenance of bone density
Drugs:
Replacement of joints
Which factors increase osteoclast activity?
Hypoxia
Smoking
Alcohol intake
High cortisol levels
Low BMI
Hyperactive adrenal gland
Immobilisation
What are bisphosphates?
Analogue of pyrophosphate which binds to calcium ions in hydroxyapatite crystals which act on osteoclasts when they resorp bones to induce apoptosis. It contains 2 phosphate groups which increase its specificity for calcium to bind to bones and increase duration of action.
What are the side effects of bisphosphate?
May result in osteonecrosis of the jaw, hypocalcaemia and hypophosphataemia. In the long term, results in atypical femoral fracture.
What is pyrophosphate?
An acid which prevents calcium mineralisation and increases calcium accumulation for regulation of osteogenesis.
Why are bisphosphates given?
For post-menopausal women
Glucocorticoid-induced osteoporosis.
What are the classes of bisphosphates?
Nitrogen containing bisphosphates
Non-nitrogen containing bisphosphates
How do Non-nitrogen containing bisphosphates work?
They contain a nitrogen R group which is methyl compound and acts to inhibit osteoclast apoptosis and prevent osteoclast development.
When broken down, bisphosphate forms a non-hydrolysable ATP analogue which is non functional and competes with ATP for cellular metabolism, interfering with ATP dependent processes
What are isoprenoids?
Naturally occurring chemical compounds which contain isoprene. Examples of these include vitamin A and Vitamin E. They are important in post-transcriptional modification of small GTP binding proteins such as Rab, Rho and RAC.
What are GTP binding proteins?
AKA G proteins which are secondary messenger molecules
How do nitrogen containing bisphosphates work?
They contain an amine R group and important for osteoclast apoptosis to increase osteoblasts formation. It acts by inhibiting Farnesyl pyrophosphate synthase for biosynthesis of isoprenoid compounds. This inhibits post-transcriptional modification of GTP proteins for activity in the sealing space by osteoclasts.
What is the osteonecrosis of jaw?
Death of the mandible cells caused by use of bisphosphates. The risk factors include poor dental hygeine, prolonged exposure to high dose bisphosphates and invasive dental procedures.
How can HRT be used to treat osteoporosis?
Supplementation of oestrogen and/or progesterone prevents bone resorption
Use of selective oestrogen receptor modulators which bind to oestrogen receptors with both agonist and antagonistic effects depending on target tissue. It avoids the adverse off target side effects.
How does calcitonin work?
Released when calcium levels are high in the blood by C cells of the parathyroid gland to increase osteoblast activity and reduce Ca2+ re absorption.
What is the hormonal control of Ca2+ levels?
Thyroid gland c cells produce calcitonin when Ca2+ levels are high to decreases osteoclast activity, reducing bone resorption.
Parathyroid gland produces PTH hormone when Ca2+ levels are low to increase osteoclast activity and increase bone resorption.
What is the treatment for rheumatoid arthritis?
NSAIDS
Disease modifying Antigens
Steroids
Biological therapies
How do NSAIDS work?
Inhibit COX enzymes for the conversion of arachidionic acid -> prostaglandins/thromboxane/prostacyclin in inflammation. For rheumatoid arthritis, ideally the main NSAID should be COX-2 specific such as coxibs for inhibition of prostaglandin formation associated with pain.
** Used to treat the inflammatory manifestations of the disease.**
What is the difference between COX-1 and COX-2?
COX-1: Arachidonic acid -> prostacyclin, thromboxane and prostaglandins which maintain stomach and intestine lining. COX-1 is found in most tissues
COX-2: Arachidionic acid -> prostaglandins associated with pain and inflammation. COX-2 is expressed only in inflammation
What are DMARDS?
Disease modifying anti-rheumatic drugs which are used as a treatment for the underlying inflammation in rheumatoid arthritis, typically alongside NSAIDs. There are two types of DMARDS which are small molecule DMARDS and biologic DMARDS. These can be used to achieve RA remission.
