B4 Pharm Exam 1 Answers Well Explained

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 HMG￾CoA 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 dose) - Pitavastatin (t1/2 = 12 hr) B4 Pharm Exam 1 Why does Pravastatin present with less AEs and DIs than other statins? - low prot binding & does NOT req CYP450 enz for metab --> low int w/ other drugs/body prots & excr largely unchanged from parent comp Beneficial CV Effects of Statins - - endoth func improv - incr athero plaque stab (ie. before surg) - anti-infl - lipoprot oxid inhib - anticoag by plt aggreg+plt thrombi inhib Statins w/ greatest effects on TGs (used for Mixed Hyperlipidemia) - - Atorvastatin - Rosuvastatin Use of Atorvastatin+Amlodipine (Caduet) - Amlodipine = Ca2+ chann blocker (vasodil) - combo for HTN/angina + hyperchol Statins for treatment of children w/ Heterozygous Familial Hypercholesterolemia (LDLR defect) - - Atorvastatin - Lovastatin - Simvastatin - Pravastatin Potential non-CV uses of statins - - Clin Trials = maybe prot ag osteop, cancer - recent findings that boost erec func AEs & CIs of Statins - - AEs = GI (cramps, constip, diarr, heartburn) most comm; liver tox; RHABDOMYOLYSIS = pot fat stat-ind myop by cell memb comp + elec props alterations --> discont statin if occurs - CIs = preg+nursing women b/c chol synth nec for fet growth DIs of Statins - - caution w/ fibric ac derivs b/c can also cause myops - Erythromycin & Itraconazole --> inhib statin metab --> incr AEs like myop - decr metab/incr levels of CYP450 substrates (Warfarin) Effects of Statin-Induced Rhabdomyolysis on Kidneys - statins alter musc cell memb comp --> weak myocytes --> musc prot leak --> decr elec props & lodging prots in kidney --> ac kidney fail Examples & MOA of Bile Acid Sequestrants (binding resins) for Hypercholesterolemia - incl Cholestyramine, Colestipol, Colesevelam - MOA = large mol wt polyms binding gut bile ac, excr in feces blocking enterohep bile ac cycling (BAS too large for liver absorp) --> more liv chol used for BA synth --> upreg liv LDLR --> decr LDL-C B4 Pharm Exam 1 Therapeutic Uses, AEs, DIs of Bile Acid Sequestrants - - Uses = mod effec hyperchol treatement (red LDL-C but may incr TG+VLDL), often combo w/ statins; treatment diarr+itching caused by excess BAs (BAs bind electros to absorb in intest+stool) - AEs = gen well-tol, mild GI sx, skin rash - DIs = bind digoxin, thyroxin, warfarin; Vit K malabs --> prolonged prothrombin time (decr clotting) MOA & PK of Ezetimibe - - MOA = chol absorp inhib by sel inhib NPC1L1 chol transp prot brush bord cells, decr chol transp from micelles into enteros by 50% w/o red TG/fatsol vit absorp - single daily dose --> decr LDL 15-20% + TG 8%, incr HDL 3% - esp effec in combo w/ statin - PK = rap absorb from intest after or admin, metab in intest+liver forming ezetimibeglucuronide conjug (highly water-sol by gluc ac, better excr); enterohep circ w/ t1/2 = 22 hrs Therapeutic Uses & AEs of Ezetimibe - - Uses = most comm nonstatin agent for lowering LDL; alone/combo w/ statins for hyperchol treatment - Ezetimibe+Simvastatin (Vytorin) = 60% LDL red for homoz fam hyperchol - AEs = gen well-tol but some impair liv func, dyspepsia, myalgia, rare myop, HA Use of Bile Acid Sequestrants if High TGs - BA seqs red LDL-C by 15-30% but not abs so no syst effects, but assoc w/ GI sx (constip) & can cause sev hyperTG if fasting TG 300+ Examples & Actions of Fibrates (fibric acid derivatives) - incl Gemfibrozil, Fenofibrate, Fenofibric Acid - decr TGs (40-50%), decr LDL-C (10%), incr HDL-C (10-20%) MOA of Fibrates for Lowering VLDL-TGs - bind+activ PPAR-alpha (peroxisome prolif activ rec alpha) --> incr LPL expr, decr ApoC-III (LPL inhib) expr --> incr hydr+rem VLDL TGs & chylomic TGs --> decr plasma TGs - also activ PPAR-alpha --> incr expr FA oxid enz --> decr TG synth MOA of Fibrates for Lowering LDL-C & Increasing HDL-C - activ PPAR-alpha --> incr liver LDLR expr --> incr LDL uptake by liver --> decr LDL-C - also activ PPAR-alpha --> incr FA oxid --> decr TG synth --> decr VLDL form --> decr LDL form (prod of VLDL by liver) - activ PPAR-alpha --> incr ApoA-I & ApoA-II synth (HDL comps) --> incr HDL form --> incr HDL-C Therapeutic Uses, AEs, DIs of Fibrates - - Uses = prim for hyperTG & HDL def; also for comb hyperchol & hyperTG - AEs = GI sx, myops (rhabdo), incr risk cholelithiasis - DIs = comb w/ statins (Rosuva, Prava) for comb hyperlip/decr HDL