B4 Pharm Exam 1

B4 Pharm Exam 1 How hyperlipidemia leads to heart failure - hyperlip --> athero --> CHD (ie. angina, MI) and/or HTN --> heart failure Classes of Antihyperlipidemic Drugs - - HMG-CoA reductase inhibs (statins) - Bile acid sequestrants - Chol absorp inhibs - Fibrates - Niacin - Others incl PCSK9 inhibs, HDL elevs, HoFH Lipoprotein - transp form of lipids made up of lipids+prots since lipids insol in plasma Chylomicrons - lipoprot synth in intest made of dietary (exog) TGs+chol; most imp apoprot = ApoB-48 VLDL - lipoprot synth in liver made up of endog/hep TGs; most imp apoprot = ApoB-100 IDL - lipoprot synth from VLDL catab made up of chol esters+endog TGs; most imp apoprot = ApoB-100 LDL - lipoprot synth from VLDL catab expr in liver+intest, made up of chol esters; most imp apoprot = ApoB-100 HDL - lipoprot synt in intest, liver, plasma made up of phospholips+chol esters; most imp apoprot = ApoA LDL structure - core of chol esters + outer layer of ApoB-100, phospholipids, free chol mols Relationship of Lipoprotein Size & Density - largest lipoprot (chylomicrons) has lowest density; highest dens = Lp(a) & HDL Exogenous Pathway of Lipid Metabolism - 1). Diet TGs+chol incorp into large chylomic lipoprots 2). Chylomics hydr by LPL on endoth surf adip+musc, cleaving FAs from TGs 3). Chylomic enters circ as predom chol (chylomic remnant) 4). Chylomic remnant into liver by rec-med endocyt Endogenous Pathway of Lipid Metabolism - 1). Liver secr TGs+chol in VLDL form, metab by LPL --> IDL 2). Chol dens in IDL incr until LDL form 3). LDL into liver/periph tiss by LDLR or accum in BVs (athero) 4). HDL prom chol rem from periph cells, tx to apoprot --> deliv back to liver for metab/excr B4 Pharm Exam 1 Pathogenesis of Atherosclerosis - LDL migr into BV intima, bind proteoglycans --> oxid/glycosylated --> aldehyde intermeds fragmenting ApoB-100 - endoth dam --> mac invasion --> endoth+mac GFs stim sm musc migr to tun int (sm musc hyperpl) --> oxLDL accum in macs (foam cells)+musc cells --> coll+el fibs into CT matrix forming subendoth fibr plaque Role of Hyperlipidemia in CVD - major CHD RF incl ac MI, ac+chron IHD, angina pectoris, athero CVD - gen+EVRal facs incr serum lipoprot lev - athero = predom MI cause by turb bl flow around cor art plaque prod occl thrombus Antihyperlipidemic Drugs for Treatment of Hypercholesterolemia - - HMG-CoA Reductase Inhibs = Atorvastatin, Lovastatin, Pravastatin, Simvastatin, Fluvastatin, Pitavastatin, Rosuvastatin - Bile Acid Sequestrants = Colestipol, Cholestyramine, Colesevelam - Chol Absorp Inhibs = Ezetimibe Antihyperlipidemic Drugs for Treatment of HyperTG - - Fibrates = Gemfibrozil, Fenofibrate, Fenofibric Acid - Niacin Statins in order from least LDL-lowering to greatest LDL-lowering - - Fluvastatin - Lovastatin - Pravastatin - Simvastatin - Pitavastatin - Atorvastatin - Rosuvastatin MOA & Pharm Consequences of HMG-CoA Reductase Inhibitors - - MOA = inhib HMGCoA reduc conv HMG-CoA to mevalonic ac in chol biosynth (rate-lim step) - inhib HMG-CoA red --> decr chol synth w/in cell --> upreg LDLR synth --> incr uptake LDL from bl, decr serum LDL, decr VLDL secr by liver by lack raw mats for VLDL synth Overall Pharmacological Effects of Statin Treatment on Lipids - - decr LDL-C - decr VLDL-C - incr HDL-C in some pts by incr ApoA-1 synth - decr serum TG by decr VLDL-C - Atorv, Lova, Prava, Simva --> decr fat+non-fat CHD ev, decr stroke, decr total mort Mode of excretion for most statins - biliary/fecal excr Examples of long-acting statins - - Atorvastatin (t1/2 = 14 hr --> once-daily dose) - Rosuvastatin (t1/2 = 19 hr --> once daily