HYPOLIPIDEMICS
Plasma Lipids
cholesterol and triglycerides
Essential fatty acid
linoleic acid and linolenic acid
Poly-unsaturated Fatty Acid
Lipids with special functions
1.Phospholipids-next largest lipid
component of the body after
triglycerides
lecithin, cephalins and glycolipids
2.Lipoproteins
trigycerides+phospholipids+
cholesterol with apoproteins
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
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
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.
APOLIPOPROTEINS
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
Cholesterol
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 metabolismLIVER and then intestines
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).
Predisposing Factors
in developing CAD
Age: Male > 45 years of age
Female > 55 years of age
NOTE: Premature CAD 1* male below 55
female below 65
Cigarette smoking
Hypertension ≥140/90
Low HDL <40 mg
Obesity
body mass index (BMI) >25 kg/m2
waist circumference male above 40 inches
female above 35 inches
Normal Values
Total Cholesterol
< 200 mg/dl DESIRABLE
200-239 mg/dl BORDERLINE to HIGH
≥240 mg/dl VERY HIGH
HDL
<40 mg/dl LOW
NOTE: <50 mg/dl as low for female
>60 mg/dl HIGH
LDL
<100 mg/dl OPTIMAL
100-129 mg/dl NEAR OPTIMAL
130-159 mg/dl BORDERLINE HIGH
160-189 mg/dl HIGH
>190 mg/dl VERY HIGH
TRIGLYCERIDES
<150 mg/dl NORMAL
150-199 mg/dl BORDERLINE HIGH
200-499 mg/dl HIGH
>500 mg/dl VERY HIGH
Lifestyle MODIFICATION
No CHD and 0-1 risk factor LDL >160
No CHD +2 risk factors LDL>130
With CHD or CHD equiv LDL>100
Primary
Hyperlipoproteinemias
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
D. Familial dysbetalipoproteinemia
↑ VLDL and chylomicron remnants
E. Familial hypercholesterolemia
Heterozygous or homozygous
↑LDL
F. Lp(a) hyperlipoproteinemia
↑ Lp(a)
SECONDARY CAUSES OF
HYPERLIPOPROTEINEMIA
A. Hypertriglyceridemia
DM, alcohol ingestion,
severe nephrosis, estrogens, uremia,
corticosteroid excess, hypothyrodism,
glycogen storage disease,
hypopituitarism, acromegaly,
Immunoglobulin-lipoprotein complex disease,
lipodystrophy, isotretinoin
B. Hypercholesterolemia
Hypothyrodism
Early nephrosis, resolving lipemia
Immunoglobulin-lipoprotein complex disorder,
anorexia nervosa, cholestasis,
hypopituitarism, corticosteroid excess
LIPID ALTERING DRUGS
A. VLDL SECRETION INHIBITORS
Niacin (Nicotinic Acid)
B. FIBRIC ACID DERIVATIVES
Clofibrate, Fenofibrate,
Bezafibrate, Gemfibrozil
C. BILE ACID BINDING RESINS
Cholestyramine, Colestipol
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
NICOTINIC ACID
Water soluble B-complex vitamin
Hypolipidemic 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.
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.
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.
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.
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.
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
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.
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.
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.
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.
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.
Gemfibrozil treatment of patients with mild
hypertriglyceridemia (e.g. triglycerides < 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%.
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.
Absorption, Fate and Excretion
All of the fibrate drugs are absorbed rapidly and
efficiently (>90%) 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.
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.
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.
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.
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.
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.
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.
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 LDLmediated 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.
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
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.
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.
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.
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
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.
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.
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.
Adverse Effects
Gastrointestinal symptoms (diarrhea,
flatulence, nausea), headache and
dizziness may occur in up 10% of patients.
Toxicity may include arrythmias.
Therapeutic Uses
Probucol is used primarily in subjects with
homozygous familial hypercholesterolemia
in whom it reduces tendon and planar
xanthomas.
Inhibitors of Intestinal
Sterol Absorption
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.