hyperlipidemias conditions in which the concentrations of cholesterol or triglyceride carrying...
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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.