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.

Dietary Fat

Exogenous Pathway
Bile Acids +Cholesterol

Intestine

Liver

Chylomicron

E B-48
Chylo.Rem.

Remnant receptor

TG > CE E C B-48

CE >TG

Lipoprotein Lipase

Adipose Tissue and Muscle

FFA

Endogenous Pathway Liver Liver

LDL
CE
LDL Receptors

LDL Receptor

B-100

Extrahepatic tissues

VLDL
TG>CE

IDL E B-100
CE > TG
Plasma LCAT

Cholesterol

HDL

EC

B-100

A-1

A-2

Lipoprot.Lipase

Adipose tissue and Muscle

FFA

Cholesterol uptake and internalization

Rate limiting step for intracellular cholesterol production

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

EFFECTS ON PLASMA LIPIDS AND LIPOPROTEINS

Lower VLDL concentrations and thus lower triglyceride concentrations (4055%). Increase plasma HDL levels (10-25%). Variable effects on LDL levels.

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 s differ significantly. Excreted primarily as glucuronides. Excretion impaired in renal failure.

CLINICAL USES

Type III hyperlipoproteinemia (high TGs (VLDL)) Patients with severe hypertriglyceridemia who are at risk for pancreatitis. Hypertriglyceridemia assocd with PIs.

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

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.

O C 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 TGs 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 FAs. 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 TGs and mixed disorders). Most hyperlipidemias can be effectively controlled by drugs with fewer side effects. Often used in combination.

ADVERSE REACTIONS

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.

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)

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.