HYPOLIPIDEMICS

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HYPOLIPIDEMICS
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Plasma Lipids cholesterol and
triglycerides Essential fatty acid
linoleic acid and linolenic acid
Poly-unsaturated Fatty Acid
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Lipids with special functions

• Phospholipids-next largest lipid component of the
  body after triglycerides
• lecithin, cephalins and glycolipids

2.Lipoproteinstrigyceridesphospholipidscholest
erol with apoproteins
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A. Chylomicrons
Triglyceride(mostly) phospholipids protein
Apoproteins-B-48, C, E, A-I, A-II
B. VLDL-principal carrier of triglycerides
Catabolism of VLDL results in the formation of
LDL. (Beta-shift)
Apoproteins-C species, B-100, E
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C. IDL- triglycerides cholesteryl esters
Apoproteins-B-100, E, C
D. LDL-cholesteryl esters (mostly)
Apoproteins-B-100
E. HDL Apoprotein phospholipids cholesterol
Apoproteins-A-I, A-II, C, E
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• HDL formed during the catabolism of chylomicrons.
  HDL2 is the major reason for the inverse
  correlation between HDL level and coronary risk.
  Low HDL---independent risk factor for coronary
  disease. Cigarette smoking is a major risk
  factor for coronary disease because it is
  associated with low level of HDL.

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• APOLIPOPROTEINS

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• Apo B-48 formed in the intestine, found in
  chylomicrons and their remnants
• Apo B-100 synthesized in the liver, found in
  VLDL,VLDL remnants (IDL), LDL and Lp(a)
  lipoproteins
• Apo A-I cofactor for lecithin
• Apo C-II required cofactor for lipoprotein
  lipase
• Apo E required for uptake of lipoprotein
  remnants by the liver

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• Cholesterol

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• Member of the large group of compound called
  STEROLS.
• Exogenous (present in food intake)
• Endogenous (synthesized in the cell)
• BILE ACIDS (80)-breakdown
• products.
• Main site of metabolism-
• LIVER and then intestines

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Foam Cells
Characteristic cellular components in
atherosclerotic plaques. They are transformed
macrophages and smooth muscle cells that are
filled with CHOLESTERYL ESTERS. They are the
result of endocytosis of chemically modified
lipoproteins via as many as 4 molecular species
of scavenger receptors (inability of these
receptors to be down regulated by high
intracellular levels of cholesterol).
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• Predisposing Factors
• in developing CAD
• Age Male gt 45 years of age
• Female gt 55 years
  of age
• NOTE Premature CAD 1 male below 55
• 
  female below 65
• Cigarette smoking
• Hypertension 140/90
• Low HDL lt40 mg
• Obesity
• body mass index (BMI) gt25 kg/m2
• waist circumference male above 40 inches
• female
  above 35 inches

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Normal Values

• Total Cholesterol
• lt 200 mg/dl DESIRABLE
• 200-239 mg/dl BORDERLINE to HIGH
• 240 mg/dl VERY HIGH HDL
• lt40 mg/dl LOW
• NOTE lt50 mg/dl as low for female
• gt60 mg/dl HIGH

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• LDL
• lt100 mg/dl OPTIMAL 100-129 mg/dl NEAR OPTIMAL
• 130-159 mg/dl BORDERLINE HIGH
• 160-189 mg/dl HIGH
• gt190 mg/dl VERY HIGH
• TRIGLYCERIDES
• lt150 mg/dl NORMAL
• 150-199 mg/dl BORDERLINE HIGH
• 200-499 mg/dl HIGH
• gt500 mg/dl VERY HIGH

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Lifestyle MODIFICATION

• No CHD and 0-1 risk factor LDL gt160
• No CHD 2 risk factors LDLgt130
• With CHD or CHD equiv LDLgt100

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• Primary Hyperlipoproteinemias

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• A. Primary chylomicronemia
• Familial lipoprotein lipase or cofactor
• deficiency Increased VLDL and chylomicrons

B. Familial hyperglyceridemia Severe--? VLDL,
chylomicrons Moderate- ? VLDL, may ?chylomicrons
C. Familial combined hyperlipoproteinemia
?VLDL, ?LDL, ?VLDL and LDL
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D. Familial dysbetalipoproteinemia ? VLDL
and chylomicron remnants
E. Familial hypercholesterolemia
Heterozygous or homozygous ?LDL
F. Lp(a) hyperlipoproteinemia ? Lp(a)
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• SECONDARY CAUSES OF HYPERLIPOPROTEINEMIA

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• A. Hypertriglyceridemia
• DM, alcohol ingestion,
• severe nephrosis, estrogens, uremia,
  corticosteroid excess, hypothyrodism, glycogen
  storage disease, hypopituitarism, acromegaly,
  Immunoglobulin-lipoprotein complex disease,
  lipodystrophy, isotretinoin

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• B. Hypercholesterolemia
• Hypothyrodism
• Early nephrosis, resolving lipemia
  Immunoglobulin-lipoprotein complex disorder,
  anorexia nervosa, cholestasis, hypopituitarism,
  corticosteroid excess

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• LIPID ALTERING DRUGS

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• A. VLDL SECRETION INHIBITORS
• Niacin (Nicotinic Acid)

B. FIBRIC ACID DERIVATIVES Clofibrate,
Fenofibrate, Bezafibrate, Gemfibrozil
C. BILE ACID BINDING RESINS Cholestyramine,
Colestipol
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• D. HMG ( 3 hydroxy-3 methyl glutaryl )-CoA
  REDUCTASE INHIBITORS
• Simvastatin, Lovastatin,
• Pravastatin, Fluvastatin
• Rosuvastatin, Atorvastatin

E. PROBUCOL
F. INHIBITORS OF INTESTINAL STEROL ABSORPTION
Ezetimibe
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• NICOTINIC ACID

Water soluble B-complex vitaminHypolipidemic
properties of nicotonic acid are unrelated to its
role as vitamin. Nicotinamide does not have
hypolipidemic properties.Nicotinic acid is used
most frequently in an attempt to raise low HDL
levels and to lower VLDL and LDL levels. When
tolerated, it is effective as either primary
therapy or, commonly, as adjunctive therapy.
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• Mechanism of Action

decreased production of VLDL, which may be due,
at least in part, to a transient inhibitory
effect of nicotinic acid on lipolysis, a
decreased delivery of free fatty acids to the
liver, and a decrease in triglycerides synthesis
and VLDL-triglyceride transport. Enhanced
clearance of VLDL also may occur, possibly owing
to enhanced activity of lipoprotein lipase.
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• The decrease in LDL levels could be due to
• decreased VLDL production and enhanced
• hepatic clearance of LDL precursor.
• Nicotinic acid also raises HDL cholesterol
• levels via mechanism not yet understood,
• but a decrease in the clearance rate of
• apo A-I.
• Nicotinic acid does not alter the rates of
• cholesterol synthesis or bile acid excretion.

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• Absorption,Fate and Excretion

Nicotinic acid is absorbed readily Half-life is
short. The short half-life necessitates frequent
dosing. High doses of nicotinic acid are
eliminated primarily by renal clearance of
uncharged drug. At lower doses, the major
excretion products are metabolites, principally
products of catabolism of the pyridine
dinucleotides.
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• Adverse Effects

Intense flushing and associated pruritus
(cutaneous vasodilatation) and warm
sensation(prostaglandin mediated) that usually
involves the face and upper part of the body.
Flushing may be more tolerable if a patient
begins with low dose and gradually increase the
dose over a period of weeks. May be avoided by
taking aspirin before NIACIN is given.
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• Dry skin is another common side effect of
• prolonged nicotinic treatment. Others include
• rashes, acanthosis nigricans, nausea and
• abdominal discomfort.
• ?transaminases and alkaline phosphatase but not
• associated with serious liver toxicity.
• Rarely, severe acute hepatic necrosis may occur
• ?in blood sugar may aggravate diabetes
• ? uric acid may aggravate gout
• Arrhythmia and toxic amblyopia

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• Therapeutic Uses

The usual therapeutic dose is 2 to 6 g/day
divided into 3 doses taken with meals. Because of
its many side effects, nicotinic acid is most
frequently used as adjunctive therapy to lower
LDL levels in patients with familial
hypercholesterolemia already on bile acid
sequestrant and/or a statin.
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• Second major use is in patients with low HDL
  levels and elevated triglyceride levels, such as
  those with familial combined hyperlipoproteinemia.
  Mixed hyperlipidemia, cholesterol and
  triglyceride levels, is another clinical
  indication for treatment with nicotinic acid.

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• Fibric Acid Derivatives

Clofibrate was the most widely prescribed
hypolipidemic drug a number of years. Its usage
declined dramatically, however, following
results, the obvious potential of this drug to
increase gallstone formation and its relative
inefficiency in reducing LDL levels has led to
its virtual abandonment.
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• Mechanism of Action

?VLDL, modestly raise HDL levels and have
variables effects on LDL levels. The effects on
VLDL levels probably result primarily from an
increase in lipoprotein lipase activity,
especially in muscle. This would lead to enhanced
hydrolysis of VLDL triglyceride content and an
enhance VLDL catabolism.
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• Effects on Lipoprotein Levels

The effects of the fibric acid agents on
lipoprotein levels differ widely depending on the
starting lipoprotein profile, the presence or
absence of a genetic hyperlipoprotein-emia, the
associated environmental influences, and the drug
used. Elevated triglyceride and cholesterol
levels may be dramatically lowered, and
tuboeruptive and palmar xanthomas may regress
completely.
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Gemfibrozil treatment of patients with mild
hypertriglyceridemia (e.g. triglycerides lt 400
mg/dl) usually produces a decrease in
triglyceride levels of 50 or more, an increase
in HDL cholesterol concentrations of 15 to 25
and either no change or an increase in LDL
cholesterol levels, particularly in subjects with
familial combined hyperlipidemia. The second
generation agents, such as fenofibrate,bezafibrate
, and ciprofibrate, lower VLDL levels to a degree
similar to that produced by gemfibrozil, but they
also decrease LDL levels by 15 to 20.
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In patients with more marked hypertriglyceridemia,
(triglyceride levels of 400 to 1000 mg/dl), a
similar fall in triglycerides occurs, but
increases in LDL of 10 to 30 frequently are
seen. In contrast, treatment of patients with
heterozygous familial hypercholesterolemia
usually produces a decrease in LDL levels of 10
with gemfibrozil, and of 20 to 30 with other
agents.
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• Absorption, Fate and Excretion

All of the fibrate drugs are absorbed rapidly and
efficiently (gt90) when given with a meal but
less efficiently when taken on an empty stomach.
More than 95 of these drugs in plasma are
protein-bound, nearly exclusively to albumin.
Half-lives differ significantly within this
group. Gemfibrozil has a half-life of 1.1 hours
fenofibrate has a half life of 20 hours. The
drugs are widely distributed and concentrations
in liver, kidney and intestine exceed the plasma
level.
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Gemfibrozil is transferred across the placenta.
The fibrate drugs are excreted predominantly as
glucuronide conjugates 60 to 90 of an oral
dose is excreted in the urine, with smaller
amounts appearing in the feces. Excretion of
these drugs is impaired in renal failure, though
excretion of gemfibrozil was reported to be less
severely compromised in renal insufficiency than
excretion of other fibrates.
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• Adverse Effects and Drug Interactions

Gastrointestinal side effects like nausea and
abdominal discomfort are most common Other side
effects are reported infrequently and include
rash, urticaria, hair loss, myalgias, fatigue,
headache, impotence, breast tenderness in men,
anemia and renal dysfunction. Minor increases in
liver transaminases and decreases in alkaline
phosphatase have been reported.
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Reported cases also like GIT and hepatobiliary
CA. Enhances hypoglycemic effect of
sulfonylureas. Potentiates anti-coagulant effect
on coumarin by decreasing platelet activity. A
myositis-flulike syndrome occasionally occurs in
subjects on gemifibrozil and may occur in up to
5 of patients treated with a combination of an
HMG CoA reductase inhibitor and gemfibrozil,
particularly when higher doses of the reductase
inhibitors are used. Clofibrate, and indeed all
the fibrates, increase the lithogenicity of the
bile.
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BILE ACID-BINDING RESINS
Lower LDL cholesterol in hypercholesterolemic
subjects. Because they are non-systemic agent,
they are in principle the safest agents
available. They may be particularly appropriate
for use in young patients, such as young adults
with familial hypercholesterolemia.
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They also are frequently used as adjunctive
therapy with other agents, such as statins or
nicotinic acid. While safety and absence of
serious side effects in their major attraction,
annoying gastrointestinal side effects limit
their widespread use.
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Mechanism of Action
Normally, up to 97 of bile acids are reabsorbed
into the entero-hepatic circulation via the
jejunum, and only a few are excreted in the
feces. The anion exchange resins are not
absorbed, the net effect is to promote bile acid
excretion.
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Inhibition of the return of bile acids to the
liver results in an increase in conversion of
cholesterol to bile acids. The loss of bile
acids, as well as neutral steroids, leads to a
compensatory increase in the number of hepatic
LDL receptors and to induction of HMG CoA
reductase activity. Thus, hepatocyte cholesterol
content is restored both by enhanced uptake of
plasma LDL-mediated by increased LDL receptor
expression and by enhanced endogenous cholesterol
biosynthesis. These results both in decreased
plasma LDL levels and in restoration of bile acid
production.
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Adverse Effects
The side effects that limit their usage most
often are the associated bloating, abdominal
discomfort, constipation, heartburn, steatorrhea
and malabsorption of Vit. K and folic acid.
Usually the first two symptoms gradually
disappear with continued use, but for some
subjects the constipation persists. Fecal
impaction has been reported. May even increase
VLDL and triglycerides. May even impaired
absorption of some drugs like digitalis,
vancomycin, thiazide, warfarin, iron,
tetracycline, folic acid, phenylbutazone and
aspirin
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HMG CoA REDUCTASE INHIBITORS
Mechanism of Action
Inhibitors of HMG CoA reductase block synthesis
of cholesterol in the liver by competitively
inhibiting HMG CoA reductase activity thus ?LDL
and TAG and ? HDL cholesterol.
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Therapeutic Uses
The initial choice of which statin to use depends
on the degree of cholesterol lowering
desired. Useful alone or in combination with bile
acid binding resins or niacin.
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For greater lowering of LDL, particularly in
subjects with familial hypercholesterolemia,
higher doses of lovastatin or simvastatin usually
are required. A baseline determination of CPK
activity and a panel of liver function tests
should be obtained before beginning therapy, and
analysis of liver transaminases should be
repeated at 2 to 3 month intervals after that.
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Adverse Effects
The most important adverse effects are increases
in hepatic transaminases in serum and myopathy.
Increase creatinine kinase activity. Myopathy
may be worsen if used with clofibrate, niacin,
cyclosporine and erythromycin. May also cause
lens opacity, lupus-like hypersensitivity and
rhabdomyolysis
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These compounds may cause fetal harm if given to
pregnant women. They should be given to women
childbearing potential only if they are unlikely
to become pregnant and only in situations of
extreme hypercholesterolemia not responsive to
other agents. Contraindication also in lactating
women and children.
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Probucol
Marketed for several years for its hypolipidemic
properties, but because of its erratic ability to
lower LDL levels and its potent and persistent
ability to lower HDL cholesterol levels, it is
now considered a second or third line therapeutic
agent. However, probucol is the only
hypolipidemic drug that lowers cholesterol and
causes regression of xanthomas in patients with
homozygous familial hypercholesterolemia by
reducing atherogenesis due to inhibition of foam
cell formation.
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The ability of probucol to inhibit
atherosclerosis has been attributed to its
antioxidant properties. Mechanism of action is
unclear. Inhibits sterol biosynthesis. Improves
transport of cholesterol from periphery to the
liver. May even ? HDL substantially and ? LDL
only marginally.
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Adverse Effects
Gastrointestinal symptoms (diarrhea, flatulence,
nausea), headache and dizziness may occur in up
10 of patients. Toxicity may include arrythmias.
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Therapeutic Uses
Probucol is used primarily in subjects with
homozygous familial hypercholesterolemia in whom
it reduces tendon and planar xanthomas.
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Inhibitors of Intestinal Sterol Absorption
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EZETIMIBE
First member Inhibits phytosterol and cholesterol
intestinal absorption. Readily absorbed and
conjugated in the intestine through
entero-hepatic circulation. Half life is 22
hours. Excreted in the feces by 50. Undergoes
glucorunidation in the intestine and the absorbed
glucuronide is excreted into the bile by the
liver. Used in primary hypercholesterolemia.
Liver function test is requested initially and at
2-4 months.