HYPERLIPIDEMIAS

 Cholesterol is a necessary component of cell

membranes and is a precursor of steroid
hormones.

 Cholesterol is derived from both exogenous

(dietary) and endogenous
(synthesized in the liver) sources.
 Excessively high plasma levels of cholesterol
and related triglycerides constitute a major
risk factor for the development of
atherosclerosis and coronary artery disease.

 Cholesterol and the triglycerides are

transported in blood via large globular
particles called lipoproteins.
CLASSIFICATION OF PLASMA
LIPOPROTEINS
There are four types:
Chylomicrons:
 Formed in the intestine from food.
 They contain mainly triglycerides synthesized
from fatty acids with more than 12 carbons
and cholesterol.
 Once absorbed into lymph and
transported to plasma, chylomicrons are
acted upon by lipoprotein lipase to
release triglycerides which are
subsequently stored as fat or converted
to fatty acids.
VLDL
 Formed in the liver from free fatty acids
(FFA), cholesterol, and carbohydrate, VLDL
are subsequently stripped of some of their
triglycerides and converted to intermediate
density lipoproteins (IDL) or remnants.
LDL
 As IDL loses more triglycerides, it is
converted into LDL. LDL contains mainly
cholesterol.
HDL
 Produced by the liver and converted to
mature HDL in the circulation as a result
of acquiring cholesterol esters and apoproteins
from other lipoproteins.
HYPERLIPIDEMIAS
 Hyperlipidemia is a condition in which
the plasma concentration of cholesterol or
triglyceride exceeds the normal limit.
 Hyperlipidemias
Could be
1. Primary – familial history –genetically
determined

2. Secondary – due to diseases such as

diabetes, liver diseases, alcoholism,
nephrotic syndrome, hypothyroidism
Hyperlipidemias can be classified into
2. Hypercholesterolemia
3. Hypertriglyceridemia
4. Mixed (i.e. hypercholesterolemia and
hypertriglyceridemia).
THERAPEUTIC STRATEGIES
2. Dietary control
3. Eliminate predisposing or aggravating
factors – diabetes, alcoholism
hypothyroidism, smoking hypertension
3. Drug treatment.
DRUG TREATMENT OF HYPERLIPIDEMIAS
Administration of drugs that would lower
plasma concentration of lipoproteins either by
d. reducing the production of lipoproteins and/or
e. enhancing the efficiency of their removal
from the plasma.
 Anti-lipidemic drugs
HMG-CoA reductase inhibitors

Fibric acid derivatives

Bile acid sequestrants

Nicotinic acid

Probucol
Clofibrate
 Lower VLDL, Intermediate density
lipoproteins, and plasma triglyceride
Mechanism of Action:
 Increases breakdown of VLDL and
chylomicrons by increasing the activity of
lipoprotein lipase.
 interferes with hepatic synthesis and release
of VLDL.
 inhibits lipolysis in adipose tissues.
 reduces hepatic synthesis of cholesterol
probably as a result of altered VLDL
metabolism.
Uses
 Clofibrate is used to treat hyperlipidemias of
various etiologies in which there is an increase
in VLDL levels.
 It has mild antidiuretic action in individuals
with mild or moderate diabetes insipidus
Adverse effects
 Clofibrate is generally well tolerated.
 However, some side effects have been reported.
 These include weight gain, alopecia, nausea,
cholelithiasis and cholecystitis, leucopenia,
rash and drowsiness.
Gemifibrozil
 It is an analog of clofibrate.

Actions
 Decreases VLDL and increases HDL and
slightly reduces LDL
Mechanism of Action:
 It decreases lipolysis in adipose tissues thus
reducing the free fatty acid substrates for
hepatic synthesis of triglycerides.
 It also increases the clearance of VLDL from
the circulation.
Uses
 It is the drug of choice for patients with
hypertryglyceridemia with or without
hypercholesterolemia.

Adverse effects
 Incidence of adverse effects is low nausea,
vomiting, abdominal pain and epigastric pain
DRUGS AFFECTING PLASMA CHOLESTEROL
Cholestyramine & Colestipol
Mechanism of Action:
 Cholestyramine and colestipol are
non-absorbed resins that sequester bile acids
in the intestine, preventing their absorption.
 The decreased concentration of bile acids
returning to the liver increases the conversion
of cholesterol to bile acids, resulting in a
decrease in hepatic cholesterol.
Mechanism of Action (Cont’d):
 The liver responds to a lowering of its
cholesterol content by forming more
LDL receptors.
 As a result of the greater of LDL receptors on
hepatocyte plasma membranes, LDL
catabolism is increased.
Actions
 Reduce the concentration of cholesterol in
the plasma by lowering the levels of LDL.
 In most patients, the concentration of VLDL
is slightly increased during therapy.
 Treatment with these drugs is also associated
with an increase in the number of LDL
receptors.
 Effectiveness of these compounds depends
on the ability of hepatic cells to increase
LDL receptors.
 May also raise HDL levels slightly.
Uses
 Treatment of hyperlipidemias.
 Cholestyramine is the drug of choice for
hypercholesterolemia.

Adverse effects
 Abdominal pain, constipation, nausea.
Nicotinic Acid
 It lowers plasma levels of both
LDL-cholesterol and triglyceride.
 It increases the concentration of
HDL-cholesterol
 Decrease hepatic synthesis of VLDL.
Since LDL is derived from VLDL, a reduction
in the VLDL would also result in a decreased
plasma LDL.

 inhibits lipolysis

 increases activity of lipoprotein lipase

Uses
 Treatment of hyperlipoproteinemia

Adverse effects
 Intense cutaneous flush, nausea, abdominal
pain, hyperglycemia, jaundice and increase
in plasma concentration of uric acid.
HMG-CoA Reductase Inhibitors
Statins eg lovastatin, simvastatin,
atorvastatin
Dose-dependent decrease in LDL-cholesterol.
 Increased HDL levels
 Increase number of LDL-receptors
Mechanism of Action
♦ A potent inhibitor of HMG-COA reductase,
the rate-limiting step in the synthesis of
cholesterol.

♦ Increase the number of LDL receptor.

 Statins
----They are effective orally even though
Bioavailability could be affected by first pass
metabolism in the liver.

--- Lovastatin and Simvastatin are prodrugs-

They are converted in the GIT into active
compounds
Uses
 First-line drug for patients at high risk of
myocardial infarction due to
hypercholesterolemia.

 It is also effective in patients with

hypercholesterolemia associated with
diabetes mellitus or nephritic syndrome
Adverse effects
 Long treatment may cause a rise in serum
levels of the liver enzyme, transaminase.

 Other adverse effects include myopathy and

ocular damage (cataract).
Probucol
 Lowers serum cholesterol and decreases LDL
 Probucol treatment results in the production
of structurally altered LDL, which is more
rapidly removed from the circulation.
 Probucol also has antioxidant properties.
 This may reduce uptake of plasma lipids by
microphages thus reducing their
atherogenic nature.
Uses
 Treatment of primary hypercholesterolemia
associated with elevated LDL.

 Usually reserved for patients resistant or

hypersensitive to other cholesterol lowering
drugs.
Adverse effects
 Adverse effects are usually mild and of short
duration.

 They include nausea, diarrhea, flatulence,

abdominal pain, Nausea, Vomiting.