Study Guide - Drugs for Osteoporosis

Study Guide - Drugs for Osteoporosis + Describe the mechanism of action of Estrogen and its analogs in treating osteoporosis Skip beenevesorption 2. Describe the mechanism of action of Tamoxifen and Raloxifene Estrogen analogs/agonist in Bone Act as estrogen analogs in osteoclast and osteoblast receptor in bone. Stimulate bone formation and reduce bone resorption. Selective estrogen receptor modulators 3. Differentiate between the actions Tamoxifen and Raloxifene at receptors on osteoblasts and osteoclasts and those in breast and uterine tissue. Agonists at osteoblast and osteoclast estrogen receptors bones Antagonists at breast and uterine estrogen receptors 4. Describe the pharmacokinetic characteristics of Raloxifene. Given monthly and has month half-life. Undergoes Enterohepatic cycling. Excreted in bile. 5. Recognize the structure of Bisphosphonates. Θ R1 P R2 Θ (hydroxy ) RI R P P 11 Bisphosphonate R ₁ = hydroxy 1 R₂ = varies Know this structure for exam. 6. Describe the important structural difference between pyrophosphate and the Bisphosphonates. Pyrophosphate oxygen linkage between the phosphate Bisphosphonates carbon linkage between the phosphate Ante resorptive 7. Describe the mechanisms of action of the Bisphosphonates. They both are antimetabolites and mess up the metabolic process of the cell Nonnitrogen bisphosphonates: Most closely mimic pyrophosphate and get incorporated into nonhydrolyzable ATP analogs (cell wants to use ATP but it can't because it can't be hydrolyzed and ATP utilization involves hydrolysis, prevents energy production 1. They go into osteoclasts, which are cells that break down bone. ii. Inside the osteoclasts, they disrupt normal cell function. iii. They stick to the bone and get taken up by the osteoclasts. iv. Once inside, they turn into non-functional substances that mess up the osteoclasts' metabolism. v. This interference leads to the death of the osteoclasts. Nitrogen-containing bisphosphonates: inhibits prenylation of proteins. 1. These bisphosphonates interfere with a pathway involved in making cholesterol. mevalonate pathway ii. They also mess with a process called prenylation in osteoclasts. iii. Prenylation is a process that adds small lipid molecules called isoprenoids to certain proteins. iv. This process is important for osteoclasts to function and survive. v. By blocking the mevalonate pathway and interfering with prenylation, these bisphosphonates disrupt the osteoclasts' normal function. vi. As a result, the osteoclasts end up dying. (apoptosis) 8. Describe the pharmacokinetics of Bisphosphonates Poorly absorbed but whatever it absorbed goes to bone, and they have long half-life in the tissue up to 10 years. 9. Explain why calcitonin-salmon is preferred therapeutically over calcitonin-human. calcitonin-salmon has greater receptor affinity (potency) and longer half-life than human hormone that's why its preferred over human calcitonin. 10.Describe the structural differences between calcitonin-salmon and calcitonin-human.. Both are 32 amino acids. Both are same length. But they differ in 1 6 of the 32 of amino acids. Describe the important therapeutic effects of calcitonin-salmon. Skip 12. Describe how Teriparatide is structurally related to PTH. (Not on exam) Teriparatide is the recombinant human parathyroid hormone for amino acid 1 -34 a. So parathyroid is 84 amino acids. 13.Describe the three main steps in the biosynthesis of PTH. (Not on exam) Starts 1 1 5 amino acids. Cleaves off 25 and yields 90 amino acids Pro-PTH Removal of an additional 6 amino acids from the amino terminus the active 84 amino acid hormone PTH 14.Identify the two types of PTH receptors and their locations in the body. Two types of PTH receptors . PTH-1 receptors are a found in bone and kidney. b. PTH-2 receptors are other tissues. 1 5. Describe the Teriparatide effects bone differently depending on whether it is dosed intermittently or continuously. ostogast Agonist at PTH-1 type receptor. Once Daily or Intermittent Exposure: a. enhances osteoblastic function bone formation. Continuous Exposure a. it enhances osteoclastic function, which means it promotes bone resorption. b. This results in the breakdown of bone tissue. 16. Explain how Abaloparatide differs structurally from Teriparatide. Abaloparatide analog to parathyroid hormone related protein 7. Describe the mechanism of action of Abaloparatide. Skip 18. Describe the general pharmacokinetic behavior of Teriparatide and Abaloparatide. Both are short haif-lives. 19. Describe the mechanism of action of Denosumab Denosumab is a fully human IgG2 monoclonal antibody to RANKL, and functions as a RANKL inhibitor. Same function as osteoprotegrin 20. Describe the pharmacokinetics of Denosumab. Once a month dosing 21 Describe the biological function of Sclerostin. Glycopeptide Secreted by osteocytes. Binds to receptors that modulate WNT and inhibits that pathway inhibitors osteoblast genesis and stimulates osteoclastogenesis. Stimulates bone breakdown.. Molecule that inhibits bone formation Stimulates bone resorption. 22. Explain the mechanism of action of Romosozumab Binds to Sclerostin and inhibits the action of sclerostin so that it does not inhibit bone formation and does not stimulate bone resorption 23. Explain the origin of the abbreviation WNT, as used in the WNT signaling pathway. skip