HYPERLIPIDEMIASHYPERLIPIDEMIAS

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

HYPERLIPIDEMIASHYPERLIPIDEMIAS

Concern arises because an elevated Concern arises because an elevated concentration of lipoproteins can concentration of lipoproteins can accelerate the development of accelerate the development of atherosclerosis and its complications atherosclerosis and its complications (M.I., stroke, angina etc.).(M.I., stroke, angina etc.).

Studies have now shown that reducing Studies have now shown that reducing the lipoprotein levels diminishes the risk the lipoprotein levels diminishes the risk of M.I.of M.I.

LIPOPROTEINSLIPOPROTEINS

Lipids are insoluble in aqueous systems, Lipids are insoluble in aqueous systems, they must be solubilized by association they must be solubilized by association with proteins to be transported in blood. with proteins to be transported in blood.

Lipoproteins are spherical or ellipsoid Lipoproteins are spherical or ellipsoid particles composed of a core of nonpolar particles composed of a core of nonpolar lipid surrounded by protein and polar lipid surrounded by protein and polar lipids.lipids.

LIPOPROTEINSLIPOPROTEINS

Lipoproteins differ from one another in Lipoproteins differ from one another in size, shape and in the type and amount of size, shape and in the type and amount of protein and lipid that they contain.protein and lipid that they contain.

There are seven different classes.There are seven different classes.

LIPOPROTEINSLIPOPROTEINS

Each class has a specific tissue or tissues Each class has a specific tissue or tissues of origin and catabolism.of origin and catabolism.

Each plays a defined role in lipid Each plays a defined role in lipid transport.transport.

ATHEROGENIC ATHEROGENIC LIPOPROTEINSLIPOPROTEINS

Associated with an increased risk of Associated with an increased risk of atherosclerosis and coronary heart atherosclerosis and coronary heart disease.disease.

Atherogenic lipoproteins include LDL Atherogenic lipoproteins include LDL and IDL and IDL (VLDL).(VLDL).

Lp(a).Lp(a).

ANTIATHEROGENIC ANTIATHEROGENIC LIPOPROTEINSLIPOPROTEINS

HDL.HDL.

LIPOPROTEIN TRANSPORT LIPOPROTEIN TRANSPORT AND METABOLISMAND METABOLISM

Exogenous pathwayExogenous pathway

Endogenous pathway.Endogenous pathway.

EXOGENOUS PATHWAYEXOGENOUS PATHWAY

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

Liver

Exogenous PathwayDietary Fat

Lipoprotein Lipase

Bile Acids +CholesterolIntestine

FFA

Remnant receptor

Chylo.Rem.

CE >TG

E B-48

TG > CE“Chylomicron

B-48E C

Adipose Tissue and Muscle

Lipoprot.Lipase

LiverLiver Extrahepatic tissues

Endogenous Pathway

Plasma LCAT

LDL Receptor

LDL Receptors

FFAAdipose tissue and Muscle

A-1 A-2

HDLCholesterol

VLDLTG>CE

E C B-100

LDLCE

B-100

IDLCE

B-100E

> TG

Cholesterol uptake and Cholesterol uptake and internalizationinternalization

Rate limiting step for intracellular cholesterol production

HYPERLIPIDEMIASHYPERLIPIDEMIAS

Abnormally high concentrations of Abnormally high concentrations of lipoproteins in the plasma.lipoproteins in the plasma.

Six are recognized.Six are recognized.

Causes of the Causes of the HyperlipoproteinemiasHyperlipoproteinemias

Secondary- Associated with other Secondary- Associated with other diseases or metabolic disturbances or diseases or metabolic disturbances or drugs.drugs.

Immunosuppressives, isoretinoin, protease inhibitors

Primary Primary HyperlipoproteinemiasHyperlipoproteinemias

Genetically determined.Genetically determined.

Monogenic -single gene defect.Monogenic -single gene defect.

Multifactorial or polygenic -caused by a Multifactorial or polygenic -caused by a combination of multiple genetic factors.combination of multiple genetic factors.

THERAPEUTIC THERAPEUTIC STRATEGIESSTRATEGIES

DIETARY MANAGEMENTDIETARY MANAGEMENT

Decrease cholesterol and saturated fat Decrease cholesterol and saturated fat intake.intake.

Increase the amounts of soluble fiber Increase the amounts of soluble fiber (e.g.pectins)-hypochlolesterolemic effect.(e.g.pectins)-hypochlolesterolemic effect.

DIETARY MANAGEMENTDIETARY MANAGEMENT

Fish oil supplementsFish oil supplements

THERAPEUTIC THERAPEUTIC STRATEGIESSTRATEGIES

Elimination of aggravating factors(life Elimination of aggravating factors(life style changes).style changes).

DRUG THERAPYDRUG THERAPY

Based on the specific physiological defect.Based on the specific physiological defect.

Use drugs plus diet.Use drugs plus diet.

Continuous and lifelong.Continuous and lifelong.

No single drug is consistently effective in No single drug is consistently effective in all types of lipoprotein disorders.all types of lipoprotein disorders.

HYPOLIPOPROTEINEMIC HYPOLIPOPROTEINEMIC DRUGSDRUGS

HMG COA REDUCTASE INHIBITORS (Statins)HMG COA REDUCTASE INHIBITORS (Statins)

FIBRIC ACID COMPOUNDS (Fibrates)FIBRIC ACID COMPOUNDS (Fibrates)

BILE ACID BINDING RESINSBILE ACID BINDING RESINS

NICOTINIC ACID (Niacin)NICOTINIC ACID (Niacin)

EZETIMIBE (Zetia)EZETIMIBE (Zetia)

OMEGA-3 FATTY ACIDS (Omacor)OMEGA-3 FATTY ACIDS (Omacor)

HMG COA REDUCTASE HMG COA REDUCTASE INHIBITORSINHIBITORS

Very effective agents.Very effective agents.

Generally well tolerated.Generally well tolerated.

Primary mode of therapy for most Primary mode of therapy for most patients with elevated LDL.patients with elevated LDL.

HMG COA REDUCTASE HMG COA REDUCTASE INHIBITORSINHIBITORS

Lovastatin (Mevavor)Lovastatin (Mevavor) Pravastatin (Pravachol)Pravastatin (Pravachol) Fluvastatin (Lescol)Fluvastatin (Lescol) Simvastatin (Zocor)Simvastatin (Zocor) Atorvastatin (Lipitor)Atorvastatin (Lipitor) Rosuvastatin (Crestor)Rosuvastatin (Crestor)

EFFECTS ON PLASMA EFFECTS ON PLASMA LIPIDS AND LIPOPROTEINSLIPIDS AND LIPOPROTEINS

They lower LDL cholesterol (20-55%).They lower LDL cholesterol (20-55%).

Triglyceride concentrations are Triglyceride concentrations are decreased (about 20%).decreased (about 20%).

HDL cholesterol concentrations increase HDL cholesterol concentrations increase (around 10 %). (around 10 %).

CARDIOPROTECTIVE CARDIOPROTECTIVE EFFECTSEFFECTS

Enhances endothelial cell NO synthesis Enhances endothelial cell NO synthesis ( vasodilation).( vasodilation).

Stabilizes plaques.Stabilizes plaques.

They may help decrease inflammation at site of They may help decrease inflammation at site of plaque and decrease risk of thrombosis, help plaque and decrease risk of thrombosis, help normalize endothelial function.normalize endothelial function.

Decrease CRP.Decrease CRP.

CARDIOPROTECTIVE CARDIOPROTECTIVE EFFECTSEFFECTS

Antioxidants Antioxidants

Reduces platelet aggregation Reduces platelet aggregation

MECHANISM OF ACTIONMECHANISM OF ACTION

Enhance clearance of LDL precursors.Enhance clearance of LDL precursors.

May decrease VLDL production.May decrease VLDL production.

PHARMACOKINETICSPHARMACOKINETICS

They are given orally.They are given orally.

Usually given at night. Usually given at night.

Metabolized in the liver and excreted in Metabolized in the liver and excreted in the bile (glucuronides).the bile (glucuronides).

Atorvastatin and rosuvastatin have Atorvastatin and rosuvastatin have prolonged half-lives (20 h).prolonged half-lives (20 h).

CLINICAL USESCLINICAL USES

Drugs of choice for hypercholesterolemia Drugs of choice for hypercholesterolemia due to elevated LDL. due to elevated LDL.

Additive with the bile acid binding resins Additive with the bile acid binding resins (20-30 % greater reduction in LDL).(20-30 % greater reduction in LDL).

ADVERSE EFFECTSADVERSE EFFECTS

GI disturbances, headache and rash are GI disturbances, headache and rash are common.common.

Liver Enzymes

STATINS

MYOPATHYMYOPATHY

Enhanced by fibrates and niacin (rare).Enhanced by fibrates and niacin (rare).

CARCINOGENICITY??CARCINOGENICITY??

DRUG INTERACTIONSDRUG INTERACTIONS

Lovastatin, simvastatin, cerivastatin, Lovastatin, simvastatin, cerivastatin, fluvastatin, and atorvastatin are fluvastatin, and atorvastatin are substrates for the CYP3A4 and 2C8 substrates for the CYP3A4 and 2C8 isoenzymes.isoenzymes.

Rosuvastatin is hydrophilic and Rosuvastatin is hydrophilic and undergoes limited metabolism.undergoes limited metabolism.

CONTRAINDICATIONSCONTRAINDICATIONS

Pregnancy and lactation. Pregnancy and lactation.

Liver disease. Liver disease.

FIBRIC ACID DERIVATIVESFIBRIC ACID DERIVATIVES

GemfibrozilGemfibrozil FenofibrateFenofibrate ClofibrateClofibrate BezafibrateBezafibrate CiprofibrateCiprofibrate

EFFECTS ON PLASMA EFFECTS ON PLASMA LIPIDS AND LIPOPROTEINSLIPIDS AND LIPOPROTEINS

Lower VLDL concentrations and thus Lower VLDL concentrations and thus lower triglyceride concentrations (40-lower triglyceride concentrations (40-55%).55%).

Increase plasma HDL levels (10-25%).Increase plasma HDL levels (10-25%).

Variable effects on LDL levels.Variable effects on LDL levels.

FIBRATES

MECHANISM OF ACTIONMECHANISM OF ACTION

Reduced expression of apoC-III Reduced expression of apoC-III (an (an inhibitor of lipolytic processing and inhibitor of lipolytic processing and clearance)clearance) enhancing VLDL clearance enhancing VLDL clearance from the circulation. from the circulation.

Increases in HDL are due to PPAR-Increases in HDL are due to PPAR- stimulation of apoA-I and II levels which stimulation of apoA-I and II levels which increase HDL levels.increase HDL levels.

MECHANISM OF ACTIONMECHANISM OF ACTION

Potential antiatherothrombotic effects, Potential antiatherothrombotic effects, including inhibition of coagulation and including inhibition of coagulation and enhancement of fibrinolysis.enhancement of fibrinolysis.

PHARMACOKINETICSPHARMACOKINETICS

Very well absorbed when orally Very well absorbed when orally administered.administered.

T T ½½’s differ significantly.’s differ significantly.

Excreted primarily as glucuronides.Excreted primarily as glucuronides.

Excretion impaired in renal failure.Excretion impaired in renal failure.

CLINICAL USESCLINICAL USES

Type III hyperlipoproteinemia (high Type III hyperlipoproteinemia (high TG’s (VLDL))TG’s (VLDL))

Patients with severe Patients with severe hypertriglyceridemia who are at risk for hypertriglyceridemia who are at risk for pancreatitis. pancreatitis.

Hypertriglyceridemia assoc’d with PI’s.Hypertriglyceridemia assoc’d with PI’s.

ADVERSE EFFECTSADVERSE EFFECTS

GI Disturbances (nausea, abdominal GI Disturbances (nausea, abdominal pain, diarrhea) are frequent.pain, diarrhea) are frequent.

Skin rash, myalgias, headache, urticaria, Skin rash, myalgias, headache, urticaria, fatigue.fatigue.

Myositis- flu-like syndrome (especially Myositis- flu-like syndrome (especially when combined with statins).when combined with statins).

Fibrates

CONTRAINDICATIONS AND CONTRAINDICATIONS AND PRECAUTIONSPRECAUTIONS

Pregnancy and lactation.Pregnancy and lactation.

Children.Children.

Renal and hepatic failure.Renal and hepatic failure.

DRUG INTERACTIONSDRUG INTERACTIONS

Concurrent use with the Concurrent use with the statinsstatins may may result in an increased risk of myopathy result in an increased risk of myopathy and rhabdomyolysis.and rhabdomyolysis.

Warfarin.Warfarin.

BILE ACID BILE ACID BINDING RESINSBINDING RESINS

CHOLESTYRAMINE (QUESTRAN)CHOLESTYRAMINE (QUESTRAN)

COLESTIPOL (COLESTID)COLESTIPOL (COLESTID)

COLESEVELAM (WELCHOL)COLESEVELAM (WELCHOL)

EFFECTS ON PLASMA EFFECTS ON PLASMA LIPIDSLIPIDS

Lower LDL levels (10-20%).Lower LDL levels (10-20%).

No net effect on VLDL levels. No net effect on VLDL levels.

Small rise in HDL levels (5%).Small rise in HDL levels (5%).

MECHANISM OF ACTIONMECHANISM OF ACTION

LDL receptors. LDL receptors.

HMG COA reductase.HMG COA reductase.

PHARMACOKINETICSPHARMACOKINETICS

They are not absorbed after oral They are not absorbed after oral administration.administration.

CLINICAL USESCLINICAL USES

Best used in conjunction with the statins.Best used in conjunction with the statins.

Type IIA hypercholesterolemia.Type IIA hypercholesterolemia.

ADVERSE EFFECTSADVERSE EFFECTS

Bloating, dyspepsia and constipation. Bloating, dyspepsia and constipation.

Mild steatorrhea can develop as a result Mild steatorrhea can develop as a result of increased fecal excretion of long-chain of increased fecal excretion of long-chain fatty acids.fatty acids.

DRUG INTERACTIONSDRUG INTERACTIONS

They can bind other drugs given They can bind other drugs given concurrently.concurrently.

Give other drugs 1 hr before or 3-4 hrs. Give other drugs 1 hr before or 3-4 hrs. after.after.

N

C

O

OH

NICOTINIC ACID (NIACIN)

EFFECT ON PLASMA EFFECT ON PLASMA LIPIDS AND LIPOPROTEINSLIPIDS AND LIPOPROTEINS Rapidly lowers TG levels by lowering Rapidly lowers TG levels by lowering

VLDL levels (35-50%).VLDL levels (35-50%).

Lowers LDL levels more slowly ( 25%).Lowers LDL levels more slowly ( 25%).

Increases in HDL levels (15-30%).Increases in HDL levels (15-30%).

MECHANISM OF ACTIONMECHANISM OF ACTION

Multiple effects on LP metabolism.Multiple effects on LP metabolism.

In adipose tissue it inhibits the lipolysis of In adipose tissue it inhibits the lipolysis of TG’s which reduces transport of FFAs TG’s which reduces transport of FFAs to the liver and decreases hepatic TG to the liver and decreases hepatic TG synthesis.synthesis.

MECHANISM OF ACTIONMECHANISM OF ACTION

In the liver it reduces TG synthesis by In the liver it reduces TG synthesis by inhibiting both the synthesis and esterification inhibiting both the synthesis and esterification of FA’s.of FA’s.

Lowers VLDL through several diverse Lowers VLDL through several diverse mechanisms including inhibition of lipolysis in mechanisms including inhibition of lipolysis in adipose tissue, decreased esterification of liver adipose tissue, decreased esterification of liver triglycerides in the liver and increased activity triglycerides in the liver and increased activity of lipoprotein lipase.of lipoprotein lipase.

MECHANISM OF ACTIONMECHANISM OF ACTION

Raises HDL (by decreasing clearance of Raises HDL (by decreasing clearance of HDL-apoA-I).HDL-apoA-I).

PHARMACOKINETICSPHARMACOKINETICS

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

CLINICAL USESCLINICAL USES

All types of lipoprotein disorders All types of lipoprotein disorders (especially in those with elevated TG’s (especially in those with elevated TG’s and mixed disorders).and mixed disorders).

Most hyperlipidemias can be effectively Most hyperlipidemias can be effectively controlled by drugs with fewer side controlled by drugs with fewer side effects.effects.

Often used in combination.Often used in combination.

ADVERSE REACTIONSADVERSE REACTIONS

ADVERSE REACTIONSADVERSE REACTIONS

Gastrointestinal disturbances are Gastrointestinal disturbances are common.common.

ADVERSE REACTIONSADVERSE REACTIONS

Hepatotoxicity.Hepatotoxicity. Peptic ulcer activation.Peptic ulcer activation. Hyperglycemia and decreased glucose Hyperglycemia and decreased glucose

tolerance.tolerance. Hyperuricemia.Hyperuricemia.

CONTRAINDICATIONSCONTRAINDICATIONS

PregnancyPregnancy

Hepatic DiseaseHepatic Disease

Peptic UlcerPeptic Ulcer

Gouty arthritisGouty arthritis

DRUG INTERACTIONSDRUG INTERACTIONS

Myopathy with concomitant statin Myopathy with concomitant statin administration.administration.

EZETIMIBE

EZETIMIBE (ZETIA)EZETIMIBE (ZETIA)

Primary effect is a reduction in LDL Primary effect is a reduction in LDL levels.levels.

THERAPEUTIC USESTHERAPEUTIC USES

Primarily as adjunctive agents with Primarily as adjunctive agents with statins.statins.

ADVERSE EFFECTSADVERSE EFFECTS

Diarrhea. Diarrhea.

FISH OIL (OMEGA 3 FATTY FISH OIL (OMEGA 3 FATTY ACID ETHYL ESTERS)--OmacorACID ETHYL ESTERS)--Omacor

Combination of ethyl esters of eicosapentaenoic acid Combination of ethyl esters of eicosapentaenoic acid (EPA) and docosahexaenoic (DCA)(EPA) and docosahexaenoic (DCA)

Mechanism of actionMechanism of action

– Reduction in hepatic production of triglycerides (and small Reduction in hepatic production of triglycerides (and small decreases in VLDL).decreases in VLDL).

– Inhibition of acyl coenzyme A:1,2-diacylglycerol acyltransferaseInhibition of acyl coenzyme A:1,2-diacylglycerol acyltransferase

FISH OIL (OMEGA 3 FATTY FISH OIL (OMEGA 3 FATTY ACID ETHYL ESTERS)ACID ETHYL ESTERS)

Therapeutic usesTherapeutic uses– Adjunct in the treatment of severe Adjunct in the treatment of severe

hypertriglyceridemia.hypertriglyceridemia.– Associated with decreased incidence of Associated with decreased incidence of

coronary heart disease and mortality. coronary heart disease and mortality.

Adverse effects-GI (dyspepsia, taste, belching)Adverse effects-GI (dyspepsia, taste, belching)

COMBINATION THERAPYCOMBINATION THERAPY

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

COMBINATION THERAPYCOMBINATION THERAPY

Hypercholesterolemia-Hypercholesterolemia-A statin plus a bile A statin plus a bile acid binding resin (or ezetimibe).acid binding resin (or ezetimibe).

Hypercholesterolemia plus Hypercholesterolemia plus hypertriglyceridemia- hypertriglyceridemia- A statin plus A statin plus niacin or gemfibrozil. niacin or gemfibrozil.

COMBINATION THERAPYCOMBINATION THERAPY

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

EFFECTS ON PLASMA EFFECTS ON PLASMA LIPIDS AND LIPOPROTEINSLIPIDS AND LIPOPROTEINS

Decrease in LDL cholesterol.Decrease in LDL cholesterol.

Decrease in HDL.Decrease in HDL.

Decreases number of xanthomas and Decreases number of xanthomas and atheromas.atheromas.

MECHANISM OF ACTIONMECHANISM OF ACTION

Acts primarily as an antioxidant.Acts primarily as an antioxidant.

THERAPEUTIC USESTHERAPEUTIC USES

Best used in combination with other Best used in combination with other antihyperlipidemic agents.antihyperlipidemic agents.

ADVERSE EFFECTSADVERSE EFFECTS

Mild GI effects are common.Mild GI effects are common.

Cardiotoxicity.Cardiotoxicity.