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20 Cards in this Set
- Front
- Back
List the lipid lowering drugs
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1. Statins
2. Ezetimibe 3. Resins 4. Niacin 5. Fibrates 6. Omega-3 FA |
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1. Statins - mechanism of action
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1. HMG CoA reductase inhibitors
(inhibit cholesterol synthesis from acetyl CoA) 2. less cholesterol biosyntheses -> hepatocyte cholesterol depletion 3. more LDL receptors via SREBP upregulation (sterol regulatory element binding protein) 4. Increased clearance of plasma LDL-C (also other atherogenic particles) 5. statins lower LDL-C, lower LDL-C = lower risk of coronary events |
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1. Statins - list, and special info
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Atorva, Rosuva, Fluva, Lova (not in Aus), Prava, Simva
Rosuvastatin and Pravistatin have low lipophilicity (less absorption into tissue, but less side effects) Atorvastatin and Simvastatin (and Lova) - CYP3A4 large ADRs Fluvastatin and Rosuvastatin - CYP2C9 Efficacy: R>A>S>P First dose is most cost effective (law of diminishing returns - double dose only incr efficacy by 7%) |
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1. Statins - side effects
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due to HMG-CoA reductase inhibition & more likely in lipophilic drugs
1) MUSCLE-RELATED (less cholestrol in muscle membrane, and less Coenzyme Q10 - electron transport chain and AOX) can be overcome by 1) switching to water soluble or 2) adding Coenzyme Q10 (insignificant): 2) Liver: increase in ALT+AST, hepatic necrosis rare 3) Kidneys: dose dependent incro. in protein in proximal tubule |
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Factors that increase the risk of Statin-induced myopathy
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Patient
age, female, kidney/liver/thyroid dysfunction, grapefruit, polypharmacy Statin high systemic exposure, lipophilicity, incr. bioavailability, protein binding, CYP3A4 |
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2. Ezetimibe
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Cholesterol Absorption Inhibitor
blocks NPC1L1 transporter on enterocyte brush border (blocks absorption of cholesterol in gut) reduces LDL-C by 18% in hypercholesterolaemics therefore, also reduces LDL in liver Enterohepatic circulation - taken once daily Ezetimibe & Statins (low dose) often used together - Dual Inhibition: cholesterol absorption AND syntheses |
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3. Bile Acid Resins - moa
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inhibit bile acid resorption by binding to it (since bile acid is made from cholesterol in the liver)
increased bile acid secretion less cholesterol in intracellular hepatocytes (incr. SREBP) incr. LDL receptors ~15-20% reduction in LDL-C |
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3. Bile Acid Resins - side effects & interactions
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headache
GIT: constipation, abdominal discomfort, intestinal gas, indigestion, diarrhea musculoskeletal pain impairment of fat soluble vitamins Can bind with other drugs (decreasing their absorption) - cholestipol and cholestyramine (should be given 1h before or 4h after) interaction risk less problematic with colesevelam |
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4. Niacin - basics: what does it do?
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Nicotinic Acid (in low doses it is Vit B3), in high doses - oldest known lipid lowering agent
1) decreases mobilization of FFA, leading to reduced production of VLDL 2) decreases hepatic output of ApoB, resulting in less VLDL 3) increases HDL-C levels due to a reduced clearance of HDL (not by increase production of HDL) |
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4. Niacin - moa on LDLs/VLDLs
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1. blocks 'hormone sensitive lipase' - so FFAs can't be hydrolysed from TGs in peripheral adipocytes
2. hence, less FFAs reaching hepatocytes 3. less FFAs means less TG re-synthesized in liver (2nd point of action - direct inhibitor of this step also by inhibiting DGAT2 in liver) 4. This decr VLDL production from liver -> lower serum VLDL 5. Since VLDL is the precursor of LDL, less LDL is produced (also TG poor VLDLs are less atherogenic and do not form reminants & small LDL) (by inhibiting fatty acid mobilization, you decrease the production of LDL - as compared to the first 3 drugs which increase catabolism) |
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4. Niacin - HDL
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Inhibits hepatic lipase
hepatic lipase takes up cholesterol from HDL returning to the liver, reducing lypolysis of large HDL (only drug which inhibits Lipoprotein (a) - atherogenic lipotprotein) |
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4. Niacin - adverse effects
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Flushing (as many as 88%)
nicotinic acid receptor also activated in dermal macrophages (releasing PGE2 - vasodilator) hence, combine with PGE2 inhibitor (Niacin + Laropriprant) others: hepatotoxicity, insulin resistance, blurry vision, gout |
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5. Fibrates
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PPAR-alpha Agonism (peroxisome proliferator-activated receptor a)
agonist for the PPAR-a receptor that increases lipid metabolism (by dimerising with RXR to form a TF) reduces TG & LDL and increases HDL |
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5. Fibrates - adverse efects
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Fenofibrate lowers fibrinogen whist Gemfibrozil increases fibrinogen
Often combine Fibrate with a Statin Gemfibrozil inhibits CYP2C8/9 therefore increases effects of all statins - ADRS :( Fenofibrate does not use any of these pathways and therefore less likely to cause any muscle side effects Typically well tolerated hepatic/renal dysfunction, pre-existing gallbladder disease ................................. |
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6. Essential Fatty Acids (Omega-3)
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EPA and DHA
needs to be in HIGH doses >1gm per day 1) inhibits TG synthesis 2) stimulates FA oxidation 3) stimulates VLDL clearance Omacor (AUS, UK) Lovaza (US) natural products, no ADRs includes other cardioprotective mechanisms |
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Look through table of lipid lowering drugs
1. LDL-C lowering 2. HDL-C raising 3. TG loweing |
Go through table.....
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Lowering LDL-C
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1) Use a Statin
2) Then combine with Bile Acid Sequestrant or Ezetimibe THE FIRST THREE IN SERNFO LOWER LDL-C |
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Lowering TG
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Fibrates, Omega-3, Niacin
THE LAST 3 IN SERNFO LOWER TGs |
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Raising HDL-C
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Niacin and Fibrates
(the same as the ones lowering TGs but without fish oil) |
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Which ones do not produce muscle side effects when coupled with statins
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the HDL-C raising ones (Niacin and Fibrates)
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