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Part 6

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waveurflag's version from 2018-03-29 03:12

Section

Question Answer
• PTH snow plow, breaks bone down
• Calcitonin builds up bone
• Parathyroid secretes PTH
• Thyroid secretes calcitonin
LOW CALCIUM IN BLOODo PTH activates to resorb the bone and release it into the blood stream o This gives away its calcium thus creating bone resorbtion
HIGH CALCIUM IN BLOODo Calcitonin activates to have calcium absorb into the bone to build it up and remove calcium from the system o Creating calcium bone build up
• What senses the levels of calcium in the blood?• Ca receptor is a GPCR in the parathyroid gland
Low concentration of calciumhigh PTH, • Kidney stops excreting Ca in urine • Kidney produces vitamin D to stimulate enhanced absorption of Ca in intestine • Bone releases calcium from store, making bones weak
Vitamin D production• Vitamin D production in kidney • Vitamin converted by liver and then will find kidney to produce calcitrol
Skin7-dehydrocholestrol
Livervitamin D3
Kidney25(OH) vitamin D3
• CABP28K (calcium binding protein 28k) protein that is created o Linked where site that vitamin D will bind
Instead of excreting calcium, how is calcium kept and not excreted?• Vitamin D is a “sticky factor” to keep Ca from being excreted • Usually Ca goes through kidney to be excreted • Vitamin D makes more CaBP28k  binds to calcium to prevent its excretion
Parathyroid Hormone • Stimulates production of the biologically-active form of vitamin D within the kidney. • Facilitates mobilization of calcium and phosphate from bone. • Maximizes tubular reabsorption of calcium through the calcium binding protein induced by vitamin D
• Calcitonin is a hormone (secreted by thyroid) that functions to reduce blood calcium levels. It is secreted in response to hypercalcemia and has at least two effects: o 1) Suppression of renal tubular reabsorption of calcium. In other words, calcitonin enhances excretion of calcium into urine. o 2) Inhibition of bone resorption, which would minimize fluxes of calcium from bone into blood.
Effects of PTH on Bone: Bone Resorbing• Inhibits osteoblasts • Stimulates osteoclasts • Bone is broken down, releasing calcium ions into bloodstream
• HOW DOES PTH STIMULATE OSTEOCLASTS?PTH Stimulation of Osteoclasts through Osteoblasts • OsteoBLAST has PTH receptor • RANK ligand – expressed by osteoblast in response to PTH when it activates PTHR • Osteoclast “baby” has RANK receptor • Osteoclast will be differentiated into a fully functioning osteoclast • Osteoprotegerin – acts as shield for rank ligand o OPG is good! Protects bone from resorption • Estrogen activates OPG o Menopause – estrogen is not present, menopausal women lose the OPG shield and their osteoclasts are more active
• Bisphosphonates Osteoclast inhibitor, a class of drugs that prevent the loss of bone mass, used to treat osteoporosis
Bisphosphonate MOA"stick" to calcium and bind to it. The largest store of calcium in the human body is in bones, so bisphosphonates accumulate to a high concentration only in bones. • Bisphosphonates, when attached to bone tissue, are "ingested" by osteoclasts, the bone cells that break down bone tissue.
Non-Nitrogenous Bisphosphonates he non-nitrogenous are metabolised in the cell to compounds that replace the terminal pyrophosphate moiety of ATP, forming a nonfunctional molecule that competes with adenosine triphosphate (ATP) in the cellular energy metabolism. • The osteoclast initiates apoptosis and dies, leading to an overall decrease in the breakdown of bone. • Non-nitrogeonous bisphosphonate disguises itself as ATP. Osteoclast thinks it needs it and takes it up. Bisphosphoate kills osteoclast
Nitrogenous Bisphosphonates• Affects Prenylation of proteins • Prenylation – anchors an important signaling molecule to the membrane • Prenylation of RAS – helps make sure RAS gets to membrane o RAS induces creation of osteoclasts • Want to inhibit prenylation of RAS to prevent it from activating and creating new osteoclasts • Figure of RAS being anchored to membrane
Side Effects and Indications of Bisphosphonates •BONE FRACTURE. Because food and liquids can reduce the absorption of bisphosphonates, they should be given with a glass of plain water 30 minutes before the first meal or beverage of the day. • Patients should not lie down for at least 30 minutes to lessen the chance of esophageal irritation
• Zoledronic acid or pamidronate is indicated for the treatment of patients with known bone metastates (bone cancer) due to any type of malignancy
DENOSUMABmimics OPG, an endogenous RANKL inhibitor, that presents with decreasing concentrations (and perhaps decreased avidity) in patients who are suffering from osteoporosis
Denosumab Side Effectssevere allergic rxns, endocarditis, and suppression of immune system
Calcium Mimetic MOAwill trick parathyroid into thinking there is a high level of calcium. This will inhibit PTH
Cinacalcet (Sensipar)binds to the CaR and increases its sensitivity to extracellular calcium • When calcium binds to the CaR, the receptor is activated • PTH release is inhibited
Calcitriola synthetic vitamin D analog which is active in the regulation of the absorption of calcium from the gastrointestinal tract and its utilization in the body. • Vitamin D induces synthesis of a calcium-binding protein in intestinal epithelial cells that facilitates efficient absorption of calcium into blood. • Viramin D increases CaBP28k to keep ca in kidneys from being excreted
Thiazolidinedione PPAR γ AGONISTS• Insulin sensitizers • ROSIGLITAZONE • PIOGLITAZONE
Thiazolidinedione PPAR γ AGONISTS Side Effects• Fluid retention, weight gain, and congestive heart failure. • Rosiglitazone linked to heart attacks, but most patients will not die from the heart attack TZDS AND BONE LOSS • Rosiglitasone inhibits osteoplasts and activates osteoclasts • Can cause weak bones, watch for fracture!
Rosiglitazone linked to heart attacks
• Effects of prednisone on bone fractures are due to:o 1-Increased production of RANKL o 2-suppression of osteoprotegerin expression by osteoblasts. • Both of these actions would lead to continued stimulation of osteoclasts.
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