Antihyperlipidemic

Agents
Antihyperlipidemic agents are a
diverse group of pharmaceuticals
that are used in the treatment of
hyperlipidemias.
What’s Hyperlipidemia?
Hyperlipidemia is the condition
of abnormally elevated levels of
any or all lipids and/or
lipoproteins in the blood (serum)
Normal Lipid profile(in mg/dl):

Cholesterol < 200

Triglycerides < 150

HDL (High-Density Lipoprotein) > 60

LDL (Low-Density Lipoprotein) < 130

Cholesterol to HDL Ratio < 3.4 (no unit)

There are five types of
Hyperlipidemia(hyperlipoproteine
mia), each with a different profile
of blood fat and a different set of
associated risks of heart disease.
 V IV III IIb IIa I Type
Familial Familial Familial Familial Familial Familial Scientific
mixed hypertriglyc dysbetalipop mixed hypercholest Hyperchylo Name
hypertriglyc eridemia roteinemia hyperlipide erolemia micronemia
eridemia mia
,VLDL VLDL IDL VLDL,LDL LDL Chylomicron Increased
Chylomiron Lipoprotein
Class
Increased Overproduc Overproduc Overproduc Defect in Deficiency of Cause
production of tion or tion or tion of VLDL synthesis or lipoprotein
decreased decreased underutiliza by liver processing lipase or
clearance of
VLDL and
removal of tion of IDL of LDL apolipoprot
Chylomicrons VLDL TG in receptors ein CII
serum

Nacin, ,Niacin Nacin, Bile acid- Bile acid- Low fat diet Treatment
fibrate,statin fibrate fibrate,statin sequestrant sequestrant intake
and niacin and niacin
or statin or statin
 V IV III IIb IIa I Type
Familial Familial Familial Familial Familial Familial Scientific
mixed hypertriglyc dysbetalipop mixed hypercholest Hyperchylo Name
hypertriglyc eridemia roteinemia hyperlipide erolemia micronemia
eridemia mia
,VLDL VLDL IDL VLDL,LDL LDL Chylomicron Increased
Chylomiron Lipoprotein
Class
Increased Overproduc Overproduc Overproduc Defect in Deficiency of Cause
production of tion or tion or tion of VLDL synthesis or lipoprotein
decreased decreased underutiliza by liver processing lipase or
clearance of
VLDL and
removal of tion of IDL of LDL apolipoprot
Chylomicrons VLDL TG in receptors ein CII
serum

Nacin, ,Niacin Nacin, Bile acid- Bile acid- Low fat diet Treatment
fibrate,statin fibrate fibrate,statin sequestrant sequestrant intake
and niacin and niacin
or statin or statin

All types require low fat diet intake

Antihyperlipidemic drugs include:

• Statins
• Fibrates
• Bile Acid Sequestrants
• Nicotinic Acid
• Ezetimibe
 Diet Biosynthesis

Serum Cholesterol Cellular

Cholesterol
Bile Acids
Re-absorption
Intestine
Lipoprotein
Feces
catabolism
 Diet Biosynthesis
STATINS

Serum Cholesterol Cellular

Cholesterol
Bile Acids
Re-absorption
Intestine
Lipoprotein
Feces
catabolism
 Diet Biosynthesis
Ezetimibe

Serum Cholesterol Cellular

Cholesterol
Bile Acids
Re-absorption
Intestine
Lipoprotein
Feces
catabolism
 Diet Biosynthesis

Serum Cholesterol Cellular

Cholesterol
Bile Acids
Re-absorption FIBRATES
Intestine
Lipoprotein
Feces
catabolism
 Diet Biosynthesis

Serum Cholesterol Cellular

Cholesterol
Bile Acids
Re-absorption
Intestine
Lipoprotein
BILE ACID catabolism
Feces
SEQUESTRANTS
 Nicotinic
Acid
Diet Biosynthesis

Serum Cholesterol Cellular

Cholesterol
Bile Acids
Re-absorption
Intestine
Lipoprotein
Feces
catabolism
 Nicotinic
Acid
Diet Biosynthesis
Ezetimibe STATINS

Serum Cholesterol Cellular

Cholesterol
Bile Acids
Re-absorption FIBRATES
Intestine
Lipoprotein
BILE ACID catabolism
Feces
SEQUESTRANTS
 STATINS
(ex:Atorvastatin,Cerivastatin,Fluvastatin,Lovasta
tin,Pravastatin,Simvastatin,
Mevastatin…etc)
Statins are used to treat
Type II,III and V of
hyperlipidemia.
How do they work?
1. Inhibiting cholesterol synthesis by
inhibiting HMG-CoA
reductase,which plays a central role
in the production of cholesterol in
the liver, statins block the pathway
for synthesizing cholesterol in the
liver.
This is significant because most
circulating cholesterol comes from
internal manufacture rather than the
diet. When the liver can no longer
produce cholesterol, levels of
cholesterol in the blood will fall.
2.Increasing LDL uptake
Liver cells sense the reduced levels of
liver cholesterol since the intracellular
synthesis of cholesterol is inhibited and
cells are therefore dependent on
extracellular sources of cholesterol and
seek to compensate by synthesizing LDL
receptors to draw cholesterol out of the
circulation.
LDL and VLDL are drawn out of
circulation into the liver where
the cholesterol is reprocessed
into bile salts.
Adverse effect:

• Liver: Changes in liver function

occur in a small fraction of
people,withdraw of the drug The
liver is expected to return to
normal function.
• Muscle:“Myopathy" involving actual
damage to muscle tissue, can be very
serious, if myopathy occurs and the
drugs are not stopped a condition,
called “rhabdomyolysis”(is the rapid
breakdown (lysis) of skeletal
muscle)can be fetal.
Myopathy and rhabdomyolysis are
more common if people are on
other cholesterol lowering drugs,
particularly niacin or fibrates as
well as a statin.
Drug interaction:

• They increase effect of Warfarin.

• Grapefruit juice increases

simvastatin levels, so should be
avoided.
• Patients started on some macrolide
antibiotics, such as erythromycin, or
azole antifungals should stop the
statin for the duration of the course
or should have an alternative
antibiotic prescribed.
 FIBRATES
(ex:Bezafibrate,Ciprofibrate,
Clofibrate,Gemfibrozil,Fenofibrate…etc)
Fibrates are used to treat
Type III,IV and V of
hyperlipidemia.
How do they work?
Fibrates are agonists of the
PPAR-α receptor in muscle,
liver, and other tissues.
Activation of PPAR-α signaling
results in:

•Increased β-oxidation in the liver

•Decreased hepatic triglyceride

secretion
•Increased lipoprotein lipase activity,
and thus increased VLDL clearance

•Increased HDL

•Increased clearance of remnant

particles
Adverse effect:

• Most fibrates can cause mild stomach

upset and myopathy (muscle pain with
CPK” creatine phosphokinase”
elevations).
• Since fibrates increase the
cholesterol content of bile, they
increase the risk for gallstones.
Drug interaction:

• They compete with coumarin

anticoagulant and some acidic drugs
such as phenytoin and tolbutamide for
binding with albumin and therefore
increase their effect.
•In combination with statin drugs,
fibrates cause an increased risk of
rhabdomyolysis, idiosyncratic
destruction of muscle tissue, leading
to renal failure

•They also may increase the risk of

cancer
 Bile Acid
Sequestrants
(ex: Cholestyramine,Colesevelam,
Colestipol)
Bile acid sequestrants are
used to treat Type IIa and
IIb of hyperlipidemia.
How do they work?
  
Bile acid sequestrants serve as
ion exchange resins. They
exchange anions such as chloride
ions for bile acids. By doing so,
they bind bile acids and sequester
them from enterohepatic
circulation.
 
• bile acid sequestrants, along
with any bile acids bound to
the drug, are excreted via the
feces after passage through the
gastrointestinal tract
• Since bile acids are biosynthesized
from cholesterol, the disruption of
bile acid reabsorption will decrease
cholesterol levels, in particular LDL
Adverse effect:

constipation, diarrhea, and

flatulence. Some patients complain
of the bad taste.
Drug interaction:

• Interfere with intestinal absorption

of some drugs such as
(tetracycline,phenobarbital,digoxin,
warfarin,statin,aspirin,thiazide
diuretics)
•They may also bind fat-soluble
vitamins, such as vitamin A, vitamin D,
vitamin E, and vitamin K. This effect
may result in a vitamin deficiency.
Hence, vitamin supplementation may
be warranted.
Nicotinic acid
(also known as vitamin B3, niacin.Ex: :
Nicolar and Niaspan…etc)
Nicotinic acids are used to
treat Type II,III,IV and V of
hyperlipidemia.
How do they work?
Niacin blocks the
breakdown of fats in
adipose tissue. These fats
are used to build VLDL in the
liver, which are precursors
of LDL or "bad" cholesterol.
Because niacin blocks the
breakdown of fats, it causes a
decrease in free fatty acids in
the blood and, as a
consequence, decreases the
secretion of VLDL and
cholesterol by the liver.
By lowering VLDL levels, niacin
also increases the level of high-
density lipoprotein (HDL) or
"good" cholesterol in blood, and
therefore it is sometimes
prescribed for patients with low
HDL, who are also at high risk of a
heart attack.
Adverse effect:

• dermatological conditions such as

skin flushing and itching, dry skin,
and skin rashes.
• Gastrointestinal complaints, such as
dyspepsia (indigestion), nausea and
liver toxicity.
• High-dose niacin may also
elevate blood sugar, thereby
worsening diabetes mellitus.

• Hyperuricemia is another side

effect of taking high-dose
niacin, and may exacerbate
gout.
• Extremely high doses of niacin can
also cause niacin maculopathy, a
thickening of the macula and retina,
which leads to blurred vision and
blindness. This maculopathy is
reversible after stopping niacin
intake.
• Side effects of hyperglycemia,
cardiac arrhythmias and "birth
defects in experimental
animals" have also been
reported.
Drug interaction:

• Alcohol (Ethanol) and Hot drinks

Consuming alcohol or hot drinks
along with niacin might make the
flushing and itching worse. And also
alcohol might increase the chance of
having liver damage.
• Bile acid sequestrants
bile acid sequestrants can decrease how
much niacin the body absorbs. This
might reduce the effectiveness of
niacin.Take niacin and the bile acid
sequestrants at least 4-6 hours apart.
•Statins
Niacin can adversely affect the
muscles.statins can also affect the
muscles. Taking niacin along with these
medications might increase the risk of
muscle problems.
 Ezetimibe
(cholesterol absorption inhibitor,it is
marketed as Zetia or Ezetrol)
Ezetimibe is used to treat
Type II,III,IV and V of
hyperlipidemia.
How do they work?
Ezetimibe localises at the brush
border of the small intestine, where
it inhibits the absorption of
cholesterol from the intestine.
Specifically, it appears to bind to a
critical mediator of cholesterol
absorption, the Niemann-Pick C1-
Like 1 (NPC1L1) protein on the
gastrointestinal tract epithelial cells
as well as in hepatocytes.
In addition to this direct effect,
decreased cholesterol absorption
leads to an upregulation of LDL-
receptors on the surface of cells and
an increased LDL-cholesterol uptake
into cells, thus decreasing levels of
LDL in the blood plasma which
contribute to atherosclerosis and
cardiovascular events.
Adverse effect:

• Headache and diarrhea.

• Infrequent adverse effects

include: myalgia and raised liver
function test (ALT/AST) results.
•Rarely hypersensitivity reactions
(rash, angioedema) or myopathy
may occur.

•Myalgia, rhabdomyolysis,
hepatitis, pancreatitis, and
thrombocytopenia were also
noted.
Drug interaction:

• Fenofibrate
fenofibrate and ezetimibe together may
increase the levels of ezetimibe in the
blood and also cause problems in people
with gallbladder disease.
• Cyclosporine
cyclosporine together with ezetimibe may
increasing the risk of developing myopathy.
• Warfarin
longer clotting times if the patient is currently
on warfarin while on the cholesterol-lowering
medication.

• Cholestyramine,Colestipol and Colesevelam

These drugs bind to ezetimibe and reduce its
absorption from the intestine by about 50%.
References:

• Lippincott’s Illustrated
Reviews
• Goodman and Gilman’s
Pharmacological Basis of
Therapeutics
• Some websites
Prepared By:

• Brwa Dilshad
• Hasan Mohammad
• Sana Kawa
• Nashmeel Dler