HYPERLIPIDEMIAS  Conditions in which the concentrations of cholesterol or triglyceride carrying lipoproteins exceed arbitrary normal limits.

HYPERLIPIDEMIAS  Concern arises because an elevated concentration of lipoproteins can accelerate the development of atherosclerosis and its complications (M.I., stroke, angina etc.).  Studies have now shown that reducing the lipoprotein levels diminishes the risk of M.I.

LIPOPROTEINS  Lipids are insoluble in aqueous systems, they must be solubilized by association with proteins to be transported in blood.  Lipoproteins are spherical or ellipsoid particles composed of a core of nonpolar lipid surrounded by protein and polar lipids.

LIPOPROTEINS  Lipoproteins differ from one another in size, shape and in the type and amount of protein and lipid that they contain.  There are seven different classes.

LIPOPROTEINS  Each class has a specific tissue or tissues of origin and catabolism.  Each plays a defined role in lipid transport.

ATHEROGENIC LIPOPROTEINS  Associated with an increased risk of atherosclerosis and coronary heart disease.  Atherogenic lipoproteins include LDL and IDL (VLDL).  Lp(a).

ANTIATHEROGENIC LIPOPROTEINS  HDL.

LIPOPROTEIN TRANSPORT AND METABOLISM  Exogenous pathway  Endogenous pathway.

EXOGENOUS PATHWAY  The path fat takes from the food we eat to the liver.

Liver Exogenous Pathway Dietary Fat Lipoprotein Lipase Bile Acids +Cholesterol Intestine FFA Remnant receptor Chylo.Rem. CE >TG EB-48 TG > CE “Chylomicron B-48 E C Adipose Tissue and Muscle

Lipoprot.Lipase Liver Extrahepatic tissues Endogenous Pathway Plasma LCAT LDL Receptor LDL Receptors FFA Adipose tissue and Muscle A-1 A-2 HDL Cholesterol VLDL TG>CE E C B-100 LDL CE B-100 IDL CE B-100 E > TG

HDL choles VLDL TG>CE CETP REVERSE CHOLESTEROL TRANSPORT Cholesterol LCAT LDL CE

Cholesterol uptake and internalization Rate limiting step for intracellular cholesterol production

Reverse cholesterol transport LIVER “New” HDL Biconcave disc HDL3 HDL2 ApoA HDL receptor LCAT Cholesterol Tissues CETP VLDL/chylo Chol ApoA, C, E, TG Chol

HYPERLIPIDEMIAS  Abnormally high concentrations of lipoproteins in the plasma.  Six are recognized.

Causes of the Hyperlipoproteinemias  Secondary- Associated with other diseases or metabolic disturbances or drugs.

Immunosuppressives, isoretinoin, protease inhibitors

Primary Hyperlipoproteinemias  Genetically determined.  Monogenic -single gene defect.  Multifactorial or polygenic -caused by a combination of multiple genetic factors.

THERAPEUTIC STRATEGIES

DIETARY MANAGEMENT  Decrease cholesterol and saturated fat intake.  Increase the amounts of soluble fiber (e.g.pectins)-hypochlolesterolemic effect.

DIETARY MANAGEMENT  Fish oil supplements

THERAPEUTIC STRATEGIES  Elimination of aggravating factors(life style changes).

DRUG THERAPY  Based on the specific physiological defect.  Use drugs plus diet.  Continuous and lifelong.  No single drug is consistently effective in all types of lipoprotein disorders.

HYPOLIPOPROTEINEMIC DRUGS  HMG COA REDUCTASE INHIBITORS (Statins)  FIBRIC ACID COMPOUNDS (Fibrates)  BILE ACID BINDING RESINS  NICOTINIC ACID (Niacin)  EZETIMIBE (Zetia)  OMEGA-3 FATTY ACIDS (Omacor)

HMG COA REDUCTASE INHIBITORS  Very effective agents.  Generally well tolerated.  Primary mode of therapy for most patients with elevated LDL.

HMG COA REDUCTASE INHIBITORS  Lovastatin (Mevavor)  Pravastatin (Pravachol)  Fluvastatin (Lescol)  Simvastatin (Zocor)  Atorvastatin (Lipitor)  Rosuvastatin (Crestor)

EFFECTS ON PLASMA LIPIDS AND LIPOPROTEINS  They lower LDL cholesterol (20-55%).  Triglyceride concentrations are decreased (about 20%).  HDL cholesterol concentrations increase (around 10 %).

CARDIOPROTECTIVE EFFECTS  Enhances endothelial cell NO synthesis ( vasodilation).  Stabilizes plaques.  They may help decrease inflammation at site of plaque and decrease risk of thrombosis, help normalize endothelial function.  Decrease CRP.

CARDIOPROTECTIVE EFFECTS  Antioxidants  Reduces platelet aggregation

MECHANISM OF ACTION  Enhance clearance of LDL precursors.  May decrease VLDL production.

PHARMACOKINETICS  They are given orally.  Usually given at night.  Metabolized in the liver and excreted in the bile (glucuronides).  Atorvastatin and rosuvastatin have prolonged half-lives (20 h).

CLINICAL USES  Drugs of choice for hypercholesterolemia due to elevated LDL.  Additive with the bile acid binding resins (20-30 % greater reduction in LDL).

ADVERSE EFFECTS  GI disturbances, headache and rash are common.

Liver Enzymes

STATINS

MYOPATHY  Enhanced by fibrates and niacin (rare).

CARCINOGENICITY??

DRUG INTERACTIONS  Lovastatin, simvastatin, cerivastatin, fluvastatin, and atorvastatin are substrates for the CYP3A4 and 2C8 isoenzymes.  Rosuvastatin is hydrophilic and undergoes limited metabolism.

CONTRAINDICATIONS  Pregnancy and lactation.  Liver disease.

FIBRIC ACID DERIVATIVES  Gemfibrozil  Fenofibrate  Clofibrate  Bezafibrate  Ciprofibrate

CH 3 (CH 2 ) 3 COOH O C Gemfibrozil

EFFECTS ON PLASMA LIPIDS AND LIPOPROTEINS  Lower VLDL concentrations and thus lower triglyceride concentrations (40- 55%).  Increase plasma HDL levels (10-25%).  Variable effects on LDL levels.

MECHANISM OF ACTION  Act primarily as ligands for the nuclear transcription receptor, peroxisome proliferator-activated receptor-alpha (PPAR-  ).  Increase lipoprotein lipase activity.

FIBRATES

MECHANISM OF ACTION  Reduced expression of apoC-III (an inhibitor of lipolytic processing and clearance) enhancing VLDL clearance from the circulation.  Increases in HDL are due to PPAR-  stimulation of apoA-I and II levels which increase HDL levels.

MECHANISM OF ACTION  Potential antiatherothrombotic effects, including inhibition of coagulation and enhancement of fibrinolysis.

PHARMACOKINETICS  Very well absorbed when orally administered.  T ½ ’s differ significantly.  Excreted primarily as glucuronides.  Excretion impaired in renal failure.

CLINICAL USES  Type III hyperlipoproteinemia (high TG’s (VLDL))  Patients with severe hypertriglyceridemia who are at risk for pancreatitis.  Hypertriglyceridemia assoc’d with PI’s.

ADVERSE EFFECTS  GI Disturbances (nausea, abdominal pain, diarrhea) are frequent.  Skin rash, myalgias, headache, urticaria, fatigue.  Myositis- flu-like syndrome (especially when combined with statins).

Fibrates

CONTRAINDICATIONS AND PRECAUTIONS  Pregnancy and lactation.  Children.  Renal and hepatic failure.

DRUG INTERACTIONS  Concurrent use with the statins may result in an increased risk of myopathy and rhabdomyolysis.  Warfarin.

BILE ACID BINDING RESINS  CHOLESTYRAMINE (QUESTRAN)  COLESTIPOL (COLESTID)  COLESEVELAM (WELCHOL)

EFFECTS ON PLASMA LIPIDS  Lower LDL levels (10-20%).  No net effect on VLDL levels.  Small rise in HDL levels (5%).

MECHANISM OF ACTION  Bind bile acids in the intestine and prevent their reabsorption.  Decreases feedback inhibition of the enzyme converting cholesterol to bile acids.  Increased breakdown of hepatic cholesterol.

MECHANISM OF ACTION  LDL receptors.  HMG COA reductase.

PHARMACOKINETICS  They are not absorbed after oral administration.

CLINICAL USES  Best used in conjunction with the statins.  Type IIA hypercholesterolemia.

ADVERSE EFFECTS  Bloating, dyspepsia and constipation.  Mild steatorrhea can develop as a result of increased fecal excretion of long-chain fatty acids.

DRUG INTERACTIONS  They can bind other drugs given concurrently.  Give other drugs 1 hr before or 3-4 hrs. after.

COLESEVELAM  Fewer GI adverse effects and less interference with intestinal absorption of vitamins and some drugs.

N C O OH NICOTINIC ACID(NIACIN)

EFFECT ON PLASMA LIPIDS AND LIPOPROTEINS  Rapidly lowers TG levels by lowering VLDL levels (35-50%).  Lowers LDL levels more slowly ( 25%).  Increases in HDL levels (15-30%).

MECHANISM OF ACTION  Multiple effects on LP metabolism.  In adipose tissue it inhibits the lipolysis of TG’s which reduces transport of FFAs to the liver and decreases hepatic TG synthesis.

MECHANISM OF ACTION  In the liver it reduces TG synthesis by inhibiting both the synthesis and esterification of FA’s.  Lowers VLDL through several diverse mechanisms including inhibition of lipolysis in adipose tissue, decreased esterification of liver triglycerides in the liver and increased activity of lipoprotein lipase.

MECHANISM OF ACTION  Raises HDL (by decreasing clearance of HDL-apoA-I).

PHARMACOKINETICS  Readily absorbed from all parts of the intestinal tract.

CLINICAL USES  All types of lipoprotein disorders (especially in those with elevated TG’s and mixed disorders).  Most hyperlipidemias can be effectively controlled by drugs with fewer side effects.  Often used in combination.

ADVERSE REACTIONS

 Gastrointestinal disturbances are common.

ADVERSE REACTIONS  Hepatotoxicity.  Peptic ulcer activation.  Hyperglycemia and decreased glucose tolerance.  Hyperuricemia.

CONTRAINDICATIONS  Pregnancy  Hepatic Disease  Peptic Ulcer  Gouty arthritis

DRUG INTERACTIONS  Myopathy with concomitant statin administration.

EZETIMIBE

EZETIMIBE (ZETIA)  Primary effect is a reduction in LDL levels.

THERAPEUTIC USES  Primarily as adjunctive agents with statins.

ADVERSE EFFECTS  Diarrhea.

DRUG INTERACTIONS  Bile acid sequestrants

FISH OIL (OMEGA 3 FATTY ACID ETHYL ESTERS)--Omacor  Combination of ethyl esters of eicosapentaenoic acid (EPA) and docosahexaenoic (DCA)  Mechanism of action –Reduction in hepatic production of triglycerides (and small decreases in VLDL). –Inhibition of acyl coenzyme A:1,2-diacylglycerol acyltransferase

FISH OIL (OMEGA 3 FATTY ACID ETHYL ESTERS)  Therapeutic uses –Adjunct in the treatment of severe hypertriglyceridemia. –Associated with decreased incidence of coronary heart disease and mortality. Adverse effects-GI (dyspepsia, taste, belching)

INHIBITORS OF CETP  Levels of HDL are increased by %

OTHER COMPOUNDS ALTERING LIPOPROTEIN LEVELS.  Probucol  Estrogens  Vitamin E

COMBINATION THERAPY  When tolerable doses of one drug does not lower blood lipids sufficiently then 2 or 3 drugs can be used together.

COMBINATION THERAPY  Hypercholesterolemia-A statin plus a bile acid binding resin (or ezetimibe).  Hypercholesterolemia plus hypertriglyceridemia- A statin plus niacin or gemfibrozil.

COMBINATION THERAPY  In severe hypertriglyceridemia not controlled by diet or one drug use niacin plus gemfibrozil. This may substantially lower triglyceride levels.

EFFECTS ON PLASMA LIPIDS AND LIPOPROTEINS  Decrease in LDL cholesterol.  Decrease in HDL.  Decreases number of xanthomas and atheromas.

MECHANISM OF ACTION  Acts primarily as an antioxidant.

THERAPEUTIC USES  Best used in combination with other antihyperlipidemic agents.

ADVERSE EFFECTS  Mild GI effects are common.  Cardiotoxicity.