hyperlipidemia

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lipoproteins: Cholesterol & triglycerides (TG's) are bound to proteins in complex ways, to be carried in serum; there is a hydrophobic core (triglyceride and cholesterol) and a hydrophilic outer part (proteins and phospholipids)
chylomicrons: the largest and least dense as chylomicrons pass through serum, tissues remove TG's-gets smaller and denser
HDL: smallest and most dense
Physiology: 1. Insoluble hydrophobic lipids (C&TG) are transported in plasma via lipoprotiens (LP) 2. 5 classes, in decreasing order of size and increasing order of density-chylomicrons, VLDL, IDL, LDL, HDL 3. "simply stated": LDL ("bad cholesterol") takes C from liver to tissues HDL ("good cholesterol") takes C from tissues to liver
atherosclerosis: Lipoproteins are incorporated into arterial walls to conribute to atherosclerotic plaques. Plaques can slowly occlude vessels; however, especially in coronary arteries, the plaques rupture, causing platelet activation, leading to thrombi
atherosclerosis ctd: Treatment of hyperlipidemia can cause slow plaque regression. In addition, vigorous treatment after an MI can also lessen the inflammation of plaques, leading to rapid decrease in further events.
Primary dyslipidemias: genetic often the cause is not identified and plays little or no role in treatment Frederickson class
secondary hyperlipidemia: correction or modification should be sought before drug treatment -obesity: may produce lipoprotien alterations -TG's are related to the degree of control of DM -correction of hypothyroidism will improve lipids
Disease process: 1. HL, especially increased LDL is a major risk factor for CAD 2. Oxidation of LP's makes them more adherent to endothelium of blood vessels, causing atherosclerosis; high cholesterol itself also seems to increase oxidation 3. HDL is protective against CAD 5. Although less strong, increased TG is also CAD risk factor; major causes of increased TG are obesity, inactivity, tobacco, excess EtOH, high CHO intake, DM and some drugs
Assessment: 1. FLP (12 hours) in everyone q 5 yr. starting at age 20 2. assess C more often in pt w/ CAD risk 3. evaluate for secondary causes 4. lifestyle evaluation *** 5. LDL-C may be measured OR calculated 6. If elevated TG are > 500, use medication to prevent pancreatitis; for elvated TG < 500, follow LDL goals
HMG-CoA reductase inhibitors (statins): indications: hyperC (increased LDL) action: reversible competitive inhibitors of enzyme which is a rate-limiting process of C synthesis -complex actions-shlows C synthesis in liver, thus decreases LDL in serum; this decreases intracellular C, leading to increased LDL receptors in liver, leading to increased clearance of LDL from serum; also a modest increase HDL and decreased TG; may also decrease CRP, leading to decreased inflammation which leads to decreased atherosclerosis
contraindications/warnings of statins: c: active liver disease, unexplained elecations of LFTs, pregnancy, lactation W: liver dysfunction, myopathy Stop medication for marked elevation of LFt or CK Myalgias or GI symptoms should be evaluated Stop medication of LFT or CK goes to 3xnormal Usually these alterations are intermittent, benign Seriuos liver or muscle dysfunctions are very rare **Note: higher risk of myopathy at 80 mg simvastatin!!
use of statins: expensive, effective, well tolerated maximum effect in 4-6 weeks Usually want at least 30% reduction of LDL discontinue temporarily in major illness/trauma c
Statins: Lovastatin Fluvastatin Simvastatin Pravastatin Atorvastatin (lipitor) Rosuvastatin Pitavastatin
interactions of statins: Lova, simva, atorva: metabolized by CYP450 3A4 substrate in liver-can interact with macrolides, antifungals, HIV meds, nefazodone, fibrates, phenytoin, barbiturates, thiazolidinediones (glitazones) grapefruit juice*** Fluva, rosu, and pita: metabolized by CYP2C9 sinstrate; thus can interact w/ antifungals, metronidazole, amiodarone, cimetidine, erythromycin Pravastatin: metabolized by CYP450 also, but not by either of above substrates Simvastatin: with calcium channel blockers; increased myopathy or liver injury risk; avoid adding one to the other-however many patients are already stable on this combo
Fibric acid derivatives (fibrates) indications: Reducing risk of CAD in patients w/o CAD, w/ low HDL and high TG; also reduce risk of pancreatitis in patient with markedly increased G; thus mainly for increased TG, decreased HDL; minimal effect of lowering LDL
mech of action (fibrates): upregulation of LPL --> increased catabolism of VLDL and increased oxidation of FFA's by liver and muscle; may also decrease G synthesis in adipose tissue; this also raises HDL
Contraindications (fibrates): hepatic dysfunction, severe renal, dysfunction, gallbladder disease
toxicity (fibrates): occasional liver dysfunction and gallstones **Statins and fibrates together have increased risk of myopathy (esp gemfibrozil) May lower uric acid; fenofibrate may be safer, especially with statins
note (fibrates): gemfibrozil + statins can lead to increased risk of myopathy (monitor CK and monitor LFTs more often) Maximum effect in 4 weeks Both statins and fibrates lower diabetic peripheral neuropathy No cardiovascular benefit with fibrates, and a trend toward increased noncardiovascular deaths; perhaps their only benefit is in patients with high TGs
Bile acid sequestrants (resins): indicated with primary hyper C Action: work in gut, not absorbed, so SAFEST CLASS! bile binds bile acids in gut, leading to large diversion of C into bile synthesis, leading to decreased intracellular C, leading to increased LDL catabolism by liver`
contraindications/precautions (resins): CI: biliary or bowel obstruction Precautions: may interfere with absorption of fat-soluble vitamins (A, D, E, K); may see constipation, hemorrhoids
statins: monitor: CBC, LFT q 3 months X 1 year, then annually; watch for decreased effect of drugs that can be blocked, especially digoxin, warfarin, thyroid diuretics Expect LDL decreaes of about 20%-max effect in 4 weeks ***Must be taken with meals to be effecting (otherwise nothing to bind to) Binds many drugs in GI tract; don't give with any meds except niacin; other meds should be given 1 hr before or 4 hours after resin
Niacin (Nicotinic acid or vitamin B3): indicated for all forms of increased C or TG mechanism: may act on lipase to decrease lipolysis in adipose cells, leading to decreased FFA to liver > decreased VLDL secretion > leading to decreased LDL production > also increased VLDL clearance leading to decreased TG also decreases HDL catabolism; the most effective agent to raise HDL
Niacin (warnings): watch LFTs more oftne, and watch CK, if using with other meds; will increase glucose by 16%
niacin side effects: Flushing: can be minimized by gradually increasing dose over 2-4 months, and taking ASA 30 min before dose; also tachyphylaxis will occur to the flushing dyspepsia, mildly increased LFT, possible insulin resistance, increased uric acid
Omega-3 polyunsaturated fatty acids (O-3's): indicated for very high TGs Action: reduction of liver TG production leads to decrease VLDL production; HDL unaffected and LDL may increase
O-3s: CI: none; caution if fish allergy monitor LFTs; may prolong bleeding time One rx med: Lovaza, not omacor; a mixture of esters of 2O-3 FA's, total 1gm per cap has been shown to decrease mortality after recent MI; role in chronic CAD is unclear; no evidence for use in general population
Elevated LDL-C: can start with statins, resins, or niacin "statins are preferred initial treatment"
Elevated TG: most effective drugs are niacin, fibrates, fish oils
Low HDL-C: most effectiv eis niacin If elevatedTG > 500, use medication to prevent pancreatitis If elevated TG <500, follow LDL goals
Use combination tx to reach all goals: if statin can't get to goal and TG okay, consider resin If HDL still low on statin, consider niacin Adding niacin or fibrate to statin should reduce TG 3 way treatment;may be very efficacious with less toxicity
How to monitor: All meds: simplified FLP, AST or ALT-baseline, 12 weeks then annually Statins: same as ^; stop med if ALT > 3x normal Resins: CBC, LFT q 3 months for 1 year, then annually; watch for decreased effect of drugs that can be bocked esp. digoxin, warfarin, thyroid, diuretics Niacin: only need to monitor FLP If using statin _ fibrate, watch LFT and CK more Elderly: no data on age > 75, but established CAD should be treated the same

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