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HYPERLIPIDEMIAS

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DRUG INTERACTIONS Bile acid sequestrants FISH OIL (OMEGA 3 FATTY ACID ETHYL ESTERS)--Omacor Combination of ethyl esters of eicosapentaenoic acid (EPA) ... – PowerPoint PPT presentation

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Title: HYPERLIPIDEMIAS


1
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.

4
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.

7
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).

11
ANTIATHEROGENIC LIPOPROTEINS
  • HDL.

12
LIPOPROTEIN TRANSPORT AND METABOLISM
  • Exogenous pathway
  • Endogenous pathway.

13
EXOGENOUS PATHWAY
  • The path fat takes from the food we eat to the
    liver.

14
Exogenous Pathway
Dietary Fat
Intestine
Bile Acids Cholesterol
Liver
Lipoprotein Lipase
FFA
Adipose Tissue and Muscle
15
Endogenous Pathway
LDL Receptor
Liver
Liver
Extrahepatic tissues
LDL Receptors
Plasma LCAT
B-100

Lipoprot.Lipase
Adipose tissue and Muscle
FFA
16
Cholesterol
LCAT
VLDL TGgtCE
HDL choles
LDL CE
CETP
REVERSE CHOLESTEROL TRANSPORT
17
Cholesterol uptake and internalization
18
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.

22
Causes of the Hyperlipoproteinemias
  • Secondary- Associated with other diseases or
    metabolic disturbances or drugs.

23
Immunosuppressives, isoretinoin, protease
inhibitors
24
Primary Hyperlipoproteinemias
  • Genetically determined.
  • Monogenic -single gene defect.
  • Multifactorial or polygenic -caused by a
    combination of multiple genetic factors.

25
THERAPEUTIC STRATEGIES
26
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.

33
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)

34
HMG COA REDUCTASE INHIBITORS
  • Very effective agents.
  • Generally well tolerated.
  • Primary mode of therapy for most patients with
    elevated LDL.

35
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 ).

38
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).

45
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.

47
Liver Enzymes
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STATINS
50
MYOPATHY
  • Enhanced by fibrates and niacin (rare).

51
CARCINOGENICITY??
52
DRUG INTERACTIONS
  • Lovastatin, simvastatin, cerivastatin,
    fluvastatin, and atorvastatin are substrates for
    the CYP3A4 and 2C8 isoenzymes.
  • Rosuvastatin is hydrophilic and undergoes limited
    metabolism.

53
CONTRAINDICATIONS
  • Pregnancy and lactation.
  • Liver disease.

54
FIBRIC ACID DERIVATIVES
  • Gemfibrozil
  • Fenofibrate
  • Clofibrate
  • Bezafibrate
  • Ciprofibrate

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CH3
CH3
(CH2)3
O
COOH
C
CH3
CH3
Gemfibrozil
57
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.

58
MECHANISM OF ACTION
  • Act primarily as ligands for the nuclear
    transcription receptor, peroxisome
    proliferator-activated receptor-alpha (PPAR-?).
  • Increase lipoprotein lipase activity.

59
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.

65
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).

67
Fibrates
68
CONTRAINDICATIONS AND PRECAUTIONS
  • Pregnancy and lactation.
  • Children.
  • Renal and hepatic failure.

69
DRUG INTERACTIONS
  • Concurrent use with the statins may result in an
    increased risk of myopathy and rhabdomyolysis.
  • Warfarin.

70
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).

73
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.

81
DRUG INTERACTIONS
  • They can bind other drugs given concurrently.
  • Give other drugs 1 hr before or 3-4 hrs. after.

82
COLESEVELAM
  • Fewer GI adverse effects and less interference
    with intestinal absorption of vitamins and some
    drugs.

83
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).

85
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.

88
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.

103
CONTRAINDICATIONS
  • Pregnancy
  • Hepatic Disease
  • Peptic Ulcer
  • Gouty arthritis

104
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.

108
THERAPEUTIC USES
  • Primarily as adjunctive agents with statins.

109
ADVERSE EFFECTS
  • Diarrhea.

110
DRUG INTERACTIONS
  • Bile acid sequestrants

111
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

112
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)

113
INHIBITORS OF CETP
  • Levels of HDL are increased by 45-106

114
OTHER COMPOUNDS ALTERING LIPOPROTEIN LEVELS.
  • Probucol
  • Estrogens
  • Vitamin E

115
COMBINATION THERAPY
  • When tolerable doses of one drug does not lower
    blood lipids sufficiently then 2 or 3 drugs can
    be used together.

116
COMBINATION THERAPY
  • Hypercholesterolemia-A statin plus a bile acid
    binding resin (or ezetimibe).
  • Hypercholesterolemia plus hypertriglyceridemia- A
    statin plus niacin or gemfibrozil.

117
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.

121
MECHANISM OF ACTION
  • Acts primarily as an antioxidant.

122
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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