HYPERLIPIDEMIAS

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HYPERLIPIDEMIAS

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

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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.

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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.

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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.

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LIPOPROTEINS

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

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ATHEROGENIC LIPOPROTEINS

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

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ANTIATHEROGENIC LIPOPROTEINS

• HDL.

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LIPOPROTEIN TRANSPORT AND METABOLISM

• Exogenous pathway
• Endogenous pathway.

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EXOGENOUS PATHWAY

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

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Exogenous Pathway
Dietary Fat
Intestine
Bile Acids Cholesterol
Liver
Lipoprotein Lipase
FFA
Adipose Tissue and Muscle
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Endogenous Pathway
LDL Receptor
Liver
Liver
Extrahepatic tissues
LDL Receptors
Plasma LCAT
B-100

Lipoprot.Lipase
Adipose tissue and Muscle
FFA
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Cholesterol
LCAT
VLDL TGgtCE
HDL choles
LDL CE
CETP
REVERSE CHOLESTEROL TRANSPORT
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Cholesterol uptake and internalization
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Reverse cholesterol transport
New HDL Biconcave disc
ApoA
LIVER
Cholesterol
Chol
LCAT
Tissues
HDL receptor
HDL3
ApoA, C, E, TG
Chol
VLDL/chylo
HDL2
CETP
Chol
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HYPERLIPIDEMIAS

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

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Causes of the Hyperlipoproteinemias

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

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Immunosuppressives, isoretinoin, protease
inhibitors
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Primary Hyperlipoproteinemias

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

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THERAPEUTIC STRATEGIES
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DIETARY MANAGEMENT

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

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DIETARY MANAGEMENT

• Fish oil supplements

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THERAPEUTIC STRATEGIES

• Elimination of aggravating factors(life style
  changes).

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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.

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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)

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HMG COA REDUCTASE INHIBITORS

• Very effective agents.
• Generally well tolerated.
• Primary mode of therapy for most patients with
  elevated LDL.

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HMG COA REDUCTASE INHIBITORS

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

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EFFECTS ON PLASMA LIPIDS AND LIPOPROTEINS

• They lower LDL cholesterol (20-55).
• Triglyceride concentrations are decreased (about
  20).
• HDL cholesterol concentrations increase (around
  10 ).

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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.

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CARDIOPROTECTIVE EFFECTS

• Antioxidants
• Reduces platelet aggregation

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MECHANISM OF ACTION

• Enhance clearance of LDL precursors.
• May decrease VLDL production.

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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).

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CLINICAL USES

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

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ADVERSE EFFECTS

• GI disturbances, headache and rash are common.

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Liver Enzymes
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STATINS
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MYOPATHY

• Enhanced by fibrates and niacin (rare).

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CARCINOGENICITY??
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DRUG INTERACTIONS

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

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CONTRAINDICATIONS

• Pregnancy and lactation.
• Liver disease.

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FIBRIC ACID DERIVATIVES

• Gemfibrozil
• Fenofibrate
• Clofibrate
• Bezafibrate
• Ciprofibrate

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CH3
CH3
(CH2)3
O
COOH
C
CH3
CH3
Gemfibrozil
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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.

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MECHANISM OF ACTION

• Act primarily as ligands for the nuclear
  transcription receptor, peroxisome
  proliferator-activated receptor-alpha (PPAR-?).
• Increase lipoprotein lipase activity.

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FIBRATES
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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.

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MECHANISM OF ACTION

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

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PHARMACOKINETICS

• Very well absorbed when orally administered.
• T ½s differ significantly.
• Excreted primarily as glucuronides.
• Excretion impaired in renal failure.

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CLINICAL USES

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

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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).

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Fibrates
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CONTRAINDICATIONS AND PRECAUTIONS

• Pregnancy and lactation.
• Children.
• Renal and hepatic failure.

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DRUG INTERACTIONS

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

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BILE ACID BINDING RESINS

• CHOLESTYRAMINE (QUESTRAN)
• COLESTIPOL (COLESTID)
• COLESEVELAM (WELCHOL)

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EFFECTS ON PLASMA LIPIDS

• Lower LDL levels (10-20).
• No net effect on VLDL levels.
• Small rise in HDL levels (5).

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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.

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MECHANISM OF ACTION

• LDL receptors.
• HMG COA reductase.

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PHARMACOKINETICS

• They are not absorbed after oral administration.

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CLINICAL USES

• Best used in conjunction with the statins.
• Type IIA hypercholesterolemia.

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ADVERSE EFFECTS

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

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DRUG INTERACTIONS

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

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COLESEVELAM

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

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O
C
N
NICOTINIC ACID
(NIACIN)
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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).

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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.

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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.

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MECHANISM OF ACTION

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

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PHARMACOKINETICS

• Readily absorbed from all parts of the intestinal
  tract.

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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.

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ADVERSE REACTIONS
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ADVERSE REACTIONS

• Gastrointestinal disturbances are common.

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ADVERSE REACTIONS

• Hepatotoxicity.
• Peptic ulcer activation.
• Hyperglycemia and decreased glucose tolerance.
• Hyperuricemia.

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CONTRAINDICATIONS

• Pregnancy
• Hepatic Disease
• Peptic Ulcer
• Gouty arthritis

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DRUG INTERACTIONS

• Myopathy with concomitant statin administration.

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EZETIMIBE
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EZETIMIBE (ZETIA)

• Primary effect is a reduction in LDL levels.

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THERAPEUTIC USES

• Primarily as adjunctive agents with statins.

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ADVERSE EFFECTS

• Diarrhea.

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DRUG INTERACTIONS

• Bile acid sequestrants

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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 A1,2-diacylglycerol
  acyltransferase

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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)

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INHIBITORS OF CETP

• Levels of HDL are increased by 45-106

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OTHER COMPOUNDS ALTERING LIPOPROTEIN LEVELS.

• Probucol
• Estrogens
• Vitamin E

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COMBINATION THERAPY

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

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COMBINATION THERAPY

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

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COMBINATION THERAPY

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

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EFFECTS ON PLASMA LIPIDS AND LIPOPROTEINS

• Decrease in LDL cholesterol.
• Decrease in HDL.
• Decreases number of xanthomas and atheromas.

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MECHANISM OF ACTION

• Acts primarily as an antioxidant.

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THERAPEUTIC USES

• Best used in combination with other
  antihyperlipidemic agents.

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ADVERSE EFFECTS

• Mild GI effects are common.
• Cardiotoxicity.

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