ANTIHYPERLIPIDEMIC

S
Prof. Dr. Shah Murad
shahmurad655@yahoo.com

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 As if we didn't have enough cholesterol
in our diet, our liver actually makes the
stuff!

 Our body uses cholesterol for building

cellular structures and making steroid 2
>>>>>>> But, with high fat diets, we get
way more than we need.

The extra cholesterol gets stuck to the

walls of our blood vessels and clogs them
with disastrous effects to the heart and
brain (heart attack and stroke).

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 Ifyou can't bring down your
cholesterol with diet and exercise,
you may need a prescription for one
of the HYPOLIPIDEMIC DRUG

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 The most frequently prescribed drugs
are generically called "statins",
because their chemical names all
end with…..statin! They reduce the
manufacture of cholesterol in our
liver.

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 Thereare also other drugs used to lower
cholesterol that work by different
mechanisms.

 Niacinworks indirectly to reduce total

cholesterol by reducing the production of
building blocks for low density
lipoprotein, "bad" cholesterol, and
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 Hyperlipidemia
    
More than 650,000 people die
every year of coronary heart disease
(CHD) in the US alone.

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 In1984 it was demonstrated for the first
time that there exists a link between
serum cholesterol levels and risk to CHD.

A 1% drop in serum cholesterol reduces

the risk for CHD by 2%.

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Positive risk factors for CHD
include:
 Age (men>45 yrs, women>55 yrs);
 family history of premature CHD;
 smoking;
 hypertension (>140/90 mm Hg);
 low HDL cholesterol (<35 mg/dl);
 obesity (>30% overweight);
 diabetes; and
 high LDL (>160 mg/dl).
 Negative risk factors include high
HDL levels (>60 mg/dl).
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    The structure of Ch suggests a highly
non-polar nature indicating that it should
be reasonably insoluble in aqueous
solution.

Thus we expect it to be not soluble in

plasma.

Yet we see values as high as 250 mg per

deciliter which gives an amount of 2.5 g /
L in plasma. How does this occur?  11
    
This comes about because cholesterol
does not occur alone in plasma.

 It is always associated with lipoproteins.

 Lipoproteins are proteins carrying lipids.

 Cholesterol is one of the lipids. 12

 Long chain fatty acids are also carried by
these lipoproteins in the form of
triglycerides (TG).

 Lipoproteins are actually aggregrates.

 There are several forms of lipoproteins,

very low density lipoproteins (VLDL),
intermediate density lipoproteins (IDL),
low density lipoproteins (LDL), and high
density lipoproteins (HDL), depending on
the density of their packing or
alternatively their size 13
 Theterm hyperlipidemia refers to the
excessive lipid content in the blood
plasma.

A lipid profile of patient's blood plasma is

the distribution in concentration of
various forms of lipoproteins

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 (5) Types of
hyperlipidemia

I (familial hypertriglyceridemia)
 IIa (familial hyperlipidemia)
 IIb (familial dysbetalipoproteinemia)
 III (familial
hypoalphalipoproteinemia)
 IV (familal hypercholesterolemia)

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 Lipoprotein Particles
                 triglycerides
                 phospholipids
                 cholesterol
                 cholesterol esters

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 Chylomicrons (TG >> C, CE )
 VLDL (TG > CE )
 IDL (CE > TG )
 LDL (CE >> TG )
 HDL (CE > TG )

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 Mechanism of Lipid
Transport
 Dietary fat including cholesterol and
triglycerides are absorbed in the intestine and
released in the blood stream as chylomicrons.

 These are least dense particles having very

high proportion of triacylglycerides.

 Lipoprotein lipase acts on these particles to

release some free fatty acids that deposit in
adipose tissues 18
 Theremnants of chylomicrons are picked
up by the liver which has a receptor
specific to chylomicron remnants.

 Afterfurther clean up liver releases

particles called the very low density
lipoproteins in the blood.

 Thesehave lower triacyl glycerides than

chylomicrons.

 Once again LPL works on these VLDL

particles releasing more free fatty acids
and changing the content of the particles
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 There are LDL receptors on the cell
membranes of the extrahepatic cells
which can pick up the LDL particles.
 This is how cholesterol reaches the
interior of normal cells.
 Within cells, LDL particles are
repackaged.

 Excess cholesterol is esterified and

stored.

 Excess cholesterol suppresses the

biosynthesis of LDL-receptors so that
intake of cholesterol decreases. It also 20
 Repackaged LDL particles called HDL
particles are then released into the blood
stream.

 Theseparticles are sensed by the liver

through the HDL-receptors. Thus the liver
gets constant information as to how
much LDL and HDL are present in the
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 Statins
 Statins inhibit the rate-limiting step in the
biosynthesis of cholesterol - HMG -CoA
reductase.
 Decreased cholesterol biosynthesis steps up the
levels of the LDL-receptor resulting in the
positive cycle for lowered cholesterol levels in
serum.
 For patients who have familial
hypercholesterolemia due to defective
LDL-receptor genes these drugs are not
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 Statins
are most effective cholesterol
lowering drugs.

 Statinslower total cholesterol and LDL

particles.

 These are competitive inhibitors.

 The HMG-CoA has a conformation similar

to the lactone moiety of statins resulting
in binding at the same site without any 25
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 All
statins are highly protein bound (95-
98%) except for pravastatin (50%, due to
carboxylate moiety).

 Moststatins have a short half-life of

about 1-3 hr except for atorvastatin
which has a t1/2 of about 14 h.

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A 15-30 point drop in LDL could be
reasonably expected with most
statins after a therapy of about 1
month.

A combination therapy (with bile acid

sequestering agents) is helpful for
particularly difficult cases.
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 Fibrates
 Gemfibrozil was introduced in 1981 and
remains the second most useful
antilipidemic agent.

 It primarily decreases serum

triglycerides.

 Newer drugs including beclofibrates,

ciprofibrates, fenofibrates,  are more 29
 However,the fibrates are almost
never used alone.

 They are mostly used in combination

with bile acid sequestering agents. 

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31
 The antitriglycedemic effect of clofibrate
in human is related to the increased
catabolism of serum TG-rich proteins
(VLDL and VLDL remnants), but not to
any effect on hepatic TG or VLDL
synthesis and release from liver.

 The action of clofibrate is related to an

increase in adipose tissue or muscle LPL
activity which accelerates the rate of
intravascular catabolism of VLDL to IDL 32
 Clofibrateis metabolized to
chlorophenoxyisobutyric acid (CPIB)
which is the active form of the drug.

 The drug is high protein bound with a

half-life of around 15 hrs. 

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 Bile Acid Sequestering
(BAS) Agents
 Colestipol
and cholestyramine are anion
exchange resins that are approved in
1970s for the reduction of elevated
serum cholesterol in patients with
hypercholesterolemia.

 These resins are water insoluble, inert to

digestive enzymes in the intestinal tract
and are not absorbed.
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 Both resins are quaternized at stomach
pH and exchange anions for bile acids
dramatically reducing the reabsorption of
bile acids.

 Theliver senses that bile acid

concentrations have gone down and
hence turns on cholesterol metabolism.

 Serum HDL and TG levels remain 35

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 The fall in LDL concentration is apparent in 4 to
7 days.

 The decline in serum cholesterol is usually

evident by 1 month.

 When the resins are discontinued, the serum

cholesterol usually returns to baseline within a
month.

 When bile acid secretion is partially blocked,

serum bile acid concentration rises.

 For these patients, cholestyramine reduces bile

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 One of greatest advantage of these
polymeric agents is that they can be
safely used for pregnant women.

 However, exercise caution for nursing

women because presence of these
cationic polymeric agents in the GI tract
might lower the absorption of vitamin D.

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 BASagents may also lower the
amount of anticoagulants (warfarin,
coumadin) absorbed due to
sequestration

So >>>>> drug-drug interactions

may be watched and controlled

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 Nicotinic Acid (Vitamin
    Pharmacologic B-3)
doses of nicotinic acid
reduce serum cholesterol and TG levels in
types II, III, IV, and V
hyperlipoproteinemias.

 TG and VLDL are reduced by 20 to 40% in

1 to 4 days, LDL reduction may be seen in
5-7 days.
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 Thedecrease in LDL is usually greater if
niacin is used with a BAS resin.

 HDL is increased by 20%.

 MOA>>>>> It is known that niacin
decreases lipolysis in adipose tissue,
decreases TG esterification in the liver
and increase LPL activity. 

 Niacin is rapidly absorbed 41

Nicotinic Acid (Niacin)

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n Administered in large doses (0.5
to 6 grams daily)

 RDA (45-60 mg)/day

JUST IMAGINE RELATION
BETWEEN RDA and
HYPOLIPIDEMIC effects of this
VITAMIN
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 SEs
 Flushingon dependant parts o body
due to synthesis of PG-D3

 Titer the dose to avoid flushing

 LFT must be routinely checked

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 Abdominal cramps when taken in empty
stomach

 Diarrhea

 Nausea

 TSH may be altered

 Hypervitaminosis

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Very new Anti-hyperlipidemic Drug – Ezetimibe
• Approved in October 2002
• Reduces serum LDL, TC, and TG and increases HDL
• Prevents the absorption of cholesterol from diet
• Useful in Type IIa, IIb, III, IV and V hyperlipidemias

OH
OH

N
F O

F 46