Download Drugs used in the management of hyperlipidemia

Project Title
Guidelines for drugs used in Hyperlipidaemia
A research presented by
Student name:
Student No:
Asia Ibrahim Abdalla
9760093
Project supervisor Dr.Rafiq R. A. Abou-Shaaban
Jan.2001
Ajman University for Sciences and Technology
Abu Dhabi Branch
UAE
Research for this project was carried out by me during the period of Hospital
Pharmacy Training-1 no.700315(academic year 2000-2001)
Date Jan 10th 2000
Signed
1
ACKNOWLEDGMENTS
Sincere gratitude were extended
pharmaceutical
department, to
to Dr. Rafiq Abu Shaaban from
the
support, encouragement and
the
fruitful
accompaniment through out the training and presentation of this project.
The author is indebt to project supervisor Dr. Asim Ahmed, for the continuous
follow up, constructive criticism, and valuable comments.
The author wishes to express special gratitude and thanks to those contributing
in this revolutionary, distinctive and advanced Hospital Pharmacy training 1;
namely Dr.Danna Sallam and the staff of the New Medical Center Hospital.
Finally the author wishes to express heartfelt thanks to Dr. Abduelmula R.
Abduelkarem in charge of the central training committee for furnishing the
entire clinical pharmacy services.
2
INDEX
Description
Section l
Page no
Introduction
1.0 Definition of Hyperlipidaemia.
1.1Different types of lipoproteins
1.2 Lipid’s pathway (endogenous &exogenous)
1.3 Diagnostic and laboratory test
1.4Types of Hyperlipidaemia
1.5Inborn born errors of lipid metabolism.
1.6 Complications accompanied with hyperlipidemia
5
6
7
7-10
11
11,12
13
Section 11
2.0 Behavioral Oriented therapy.
2.0.1Dietry guidelines for patients with high cholesterol. 14-15
2.0.2Using exercise in the management of hyperlipedemia. 16,17
2.0.3 Stopping smoking.
18
2.1Natural products used in lowering the lipid levels
19,20
Section 111
Drugs used in the treatment of hyperlipidemia
This section will deal with:
21
3.0
The pharmacological mechanisms.
3.1
Anti hyperlipidaemic effect
23
3.2
Pharmacoeconomics
23
3
21,22
Section 1V
Closer look on hypolipidemics
4.0 Bile salt sequestering agents.
4.1 Fibrates.
4.1.1 Clofibrate
4.1.2 Gemfibrozil
4.1.3 Fenofibrate
4.2 Nicotinic acid (Niacin)
4.3 HMG CoA reductase.
24-26
27,28
29,30
30,31
32
33-36
Section V Summary
37-39
Section V1 Conclusion
40
References
41
4
Section l: Introduction
1.0
Definition of hyperlipidaemia
It’s a disorder characterized by the increase in circulating fatty acids, triglycerides
and cholesterol. It can be diagnosed performing a complete lipid profile. It can be
solely genetic in origin or secondary to a number of disease states such as diabetes,
hypothyroidism, liver or renal disease or some types of drug treatment but most
cases are attributable to diet. This increase in the circulating lipids is responsible for
other cardiovascular complications. These complications can be fetal with high
morbidity and mortality rate.
The risk profile for specific lipid concentration
Risk degree
Total lipid
LDL
HDL
Triglyceride
(mg/dl)
High
Above 245
Above 190
Below 35
1000
Moderate
221-244
160-189
36-44
500-999
Mild
201-220
130-159
45-54
250-499
Average
182-200
100-129
55-65
152-249
Low
Below 182
Below 100
Above 60
150
5
1.1
Types of lipoproteins:
It’s very important to understand what are lipoproteins, their different types and their specific
functions as the disease is nothing but a disturbance in their function or an abnormal count.
Also hyperlipidemia was classified according to the type of lipoprotein found in excess.
Lipoproteins are macromolecules found in the blood, their main function is to transport lipids
and overcome the hydrophilicity of blood. While the Apolipoproteins are recognition sites
found in the surface of lipoproteins facilitating their entry to the cell. Accordingly
Hyperlipoproteinemia can be considered as a result of abnormal increase in lipoproteins or
decrease in apolipoproteins.
They are five main types of lipoproteins:
1-chylomicrons: large triglyceride rich lipoproteins formed in the intestinal mucosa following
the digestion of dietary fat. They are released into the lymphatic system and then circulated
via the blood to body tissue where cells remove triglyceride for their energy needs.
2-VLDL: [very low-density lipoprotein] triglyceride rich structures formed in the liver from
chylomicron remnants and re-released into the circulation.
3-ILDL: [intermediate low-density lipoprotein] rare type of lipoprotein.
4-LDL: [low-density lipoprotein] derived from VLDL, these supply the tissue with
cholesterol for functions such as membrane and hormones synthesis. Most of the cholesterol
in the blood is carried on LDL and this fraction is associated with atherogensis. When the
LDL is found in large amounts the liver will stop its synthesis of cholesterol.
5-HDL: [high-density lipoprotein] it gathers up surplus cholesterol and transport it to the liver
for disposal. That is why a high level of it is protective. Their action can be summarized as

lowers the LDL

bind to free cholesterol and so prevent their disposition in muscles

transport cholesterol from the liver and GIT to peripheral tissue.

Activates lipoprotein lipase, which breaks down VLDL & Chylomicrons.
6
1.2
Lipids’ pathway:
1st) Exogenous pathway:
1. Chylomicrons formed from dietary cholesterol and triglycerides is metabolized in the
adipose tissue and muscle by the enzyme lipoprotein lipase which removes the
triglycerides leaving chylomicron remnants containing intact cholesterol esters.
2.When the chylomicron remnants reach the liver they are taken up by hepatocytes and then
cleaved releasing free cholesterol.
3.Cholesterol can be:
a) Stored in hepatocytes as cholesterol esters.
b) Released in bile as cholesterol or bile acids.
c) Used to form membranes or endogenous lipoprotein.
B) Endogenous Pathway:
1.VLDL is formed in the liver from triglycerides and cholesterol generally as a result of high
caloric intake.
2.VLDL is released in the plasma where lipoprotein lipase cleaves the triglycerides off.
3.The hydrolysis of VLDL produces IDL which:
One.
Can be taken up by the live via endocytosis and then cleave it to produce free
cholesterol via LDL receptors.
b. It can remain in circulation where triglycerides are removed so that IDL is metabolized to
LDL.
4.LDL is involved in the transport of endogenous cholesterol ester to the liver or to the
extrahepatic tissue. LDL is 60-70% of plasma cholesterol. Metabolic demand for cholesterol
(bile acids, steroids, and membranes) is met by increasing the synthesis of LDL receptors,
which promote endocytosis, and release of free cholesterol.
5. HDL: transports cholesterol from peripheral cells back to the liver. HDL absorbs free
cholesterol released during cell turnover.
This cholesterol is esterified by the enzyme lecithin: cholesterol acyltransferase and the
cholesterol esters are transferred to VLDL or LDL particles.
C) Non-Specific:
1.When lipoproteins increases macrophages take part in lipoprotein degradation.
2. This leads to cholesterol deposits in macrophages or arterial walls (atheromas) and tendons
and skin xanthomas.
Mainly this pathway will be responsible for the following complications
7
1.3
Diagnostic and laboratory test
The protein component of lipoproteins, which plays an important role in lipid transport, is
composed of several specific polypeptides called apolipoproteins. These are also involved in
the binding of lipoproteins to their receptors at the cell surface and so the lipid uptake.
There are two types:
1.
Apolipoprotein A (apoA): it is the major polypeptide component of HDL lipoprotein.
There are two types A-I that constitute 755 of the apoA and A-II, which constitute 20% of
the total HDL protein. When the apo A-I level increases it indicates an increase in the
HDL in the serum. That is why apo A is found in a higher concentration in women before
menopause. It was found that apoA gives a better index of atherogenic risk more than the
HDL assay.
2.
Apolipoprotein B (apo B) : it is the major polypeptide component of LDL lipoprotein.
At the same time it is 40% of protein portion of VLDL. It is found in two forms
apo B-100 & apoB-48. The latter transports ingested lipids through the intestine and into
the blood stream. While the former is mainly responsible for the disposition of cholesterol
and is the principal transport mechanism for endogenous cholesterol. That is why it is a
better indicator of atherosclerosis heart disease than LDL serum concentration.
3.
A new independent risk factor for atherosclerosis is lipoprotein (a) referred to as
“lipoprotein little a” which is made up of apoA and an LDL –like protein containing apoB
.

It was found that apoA is a deformed relative of plasminogen, the precursor of the
proteolytic enzyme plasmin, which is responsible for dissolving fiber clots. This strong
resemblance between an apolipoprotein and plasminogen may provide a link between
lipids the clotting mechanism and atherosclerosis. Microthrombi containing fibrin on the
vessel wall becomes incorporated into the atherosclerotic plaque. That is why it is
suggested that, the following endothelial damage, Lp (a) may institute itself into the
arterial wall inhibiting the cleavage of fibrin in microthrombi by computing with
plasminogen for access fibrin. And the so the atherogenic damage occur causing an
occlusive disease or damage.
8
 A group of factors was found to interfere with the apoA & apoB values and so these
factors can be classified as indications or risk factors for a patient with congestive heart
disease or atherosclerosis.
A] Factors interfering with the ApoA concentration:
1.
Physical exercise will increase apoA and especially the apo A-I which constitute 75%
of the apoA found in HDL.
2.
Smoking decreases the level that is why it is a risk factor for CHF.
3.
Some drugs increases apoA levels like carbamazepine, estrogen, ethanol (in low doses
because in high doses or chronic use it increases the apoB), lovastatin, niacin, oral
contraceptives, phenobarbital, pravastatin, and simvastatin.
4.
Some drugs decrease the apoA which include androgens (that is why men usually
have a lower HDL concentration and being a male is considered as one of the risk factors
for CHD), beta blockers, diuretics, and progestines.
B] Factors interfering with the ApoB concentration:
1.
Diets high in saturated fat and cholesterol may increase apoB.
2.
Drugs that increase apoB levels include androgens, beta blockers, diuretics and
progestins
3.
The drugs that decrease apoB are the statins, cholestyramine, estrogen, neomycin,
niacin and thyroxin.
C] Drugs that decrease lipoproteine (a) include estrogen, niacin, neomycin and stanzolol

Patients care:
1.
Before doing the test the procedure has to be explained to the patient and instruct him to
fast for 12 to 14 hours and smoking is prohibited.
2.
The test is done by collecting venous blood in a red-top tube. Any drugs taken which
may affect the test results has to be indicated.
3.
After the test apply pressure or pressure dressing on the venipuncture site and observe it.
9
Explanations of abnormal findings:
Apolipoprotein Increase
ApoA
Decrease
Pregnancy
Heart disease
Weight reduction
Familial hypoalphalipo-
Familial hyperalphalipo –
proteinamia
proteinaemia
Fish eye disease
Renal disease
Hemodialysis
ApoB
Hyperlipoprotenimia
Hyperthyroidism
Coronary artery disease
Malnutrition
Nephrotic syndrome
Weight reduction
Hypothyroidism
Chronic anemia
Anorexia nervosa
Reye’s syndrom
COPD
Inflammatory joint disease
Lp(a)
Chronic renal failure
Alcoholism
Estrogen depletion
Malnutrition
Sever hypothyroidism
Chronic liver hepatocellular
Premature coronary artery
disease
disease
Stenosis of cerebral arteries or
coronary arteries
Familial hypercholesterolaemia
10
1.4Classification of hyperlipidaemia:
Hyperlipidaema 1
11a
11b
111
1v
V
Lipid
Cholesterol
N+
+
+
N+
N-
N+
Triglyceride
+
N
+
N+
+
+
Chylomicron
+
N
N
N
N
+
VLDL
N-
N+
+
N-
+
+
Lipoprotein
ILDL
+
LDL
-
+
+
+
N-
-
HDL
-
N
N
N
N-
-
N= normal level
(+) = Increase
(-) =Decrease
N+ =slight increase
N- = slight decrease
1.5 Inborn errors of lipid metabolism:

Disorder of Sphingolipids
This disorder has a particular importance in nervous tissue, probably as vital components
of membranes. Disorders of their metabolism has sever consequences.

Gaucher’s disease
There are different forms with different ages of appearance of symptoms. In all
glucocerebroside accumulate because of deficiency of glucocerebrosiclase in the spleen,
liver, bone marrow, leukocytes, and sometimes in brain or lung. There is
hepatospleenomegaly, anemia, bone disorder & often cerebral degeneration.
11

Niemann-Pick disease
Sphingomyelin accumulation in spleen, bone marrow, liver & usually in brain and retina
with cerebral degeneration & early death.

Tay –Sachs disease
Famulal amaurotic idiocy. It is characterized by the accumulation of ganglioside in brain
resulting in progressive cerebral degeneration (with idiocy) and loss of vision
(amaurosis). The specific enzyme defect is not known, but the disease is due to
inheritance or a recessive gene. In the infantile form symptoms appear 4-6 months of age,
and the disease is lethal in early childhood.

Disorders of triglycerides metabolism:
1.
Hyperlipidaemia : It is due to high levels of triglycerides . Chylomicrons sometimes
occur in the plasma because of congenital absence of a specific lipase. The condition is
relatively benign. There may be xanthomata consisting of small lumps of fat under the
skin and enlargement of the liver and spleen.
2.
Acanthocytosis : It is the hereditary absence or deficiency of lipoprotein results in
a low level of plasma triglycerides. Cholesterol levels are also low. The red cells are
spherical & thorny but are restored to the normal shape by addition of a surfactant.
3.
Hypercholesterolaemia A : It is the hereditary tendency for high plasma level of
cholesterol to occur engenders an early occurrence of atherosclerotic disorder,
xanthomata are present in skin & tendon sheets
 Familial hyperlipidaemias:
Type
Hyper-
Elevated
Cholesterol
Triglyceride
lipoprotein
Level
Level
LDL
Very high
Normal
Cholesterolaemia
Cause
Impair removal
Of LDL
Combined
LDL &
Hyperlipidaemia
VLDL
Chylomicronaemia
Chylomicron
High
High
Increased in VLDL
and LDL
Normal
High
Enzyme deficiency
High
Increase VLDL
or slight rise
Hyper_
VLDL &
Triglyceridaemia
Chylomicron
Slight rise
&Triglycerides
12
1.6 Complications Accompanied with hyperlipedaemia:

Atheriosclerosis:
It’s a vascular disease characterized by patchy subintimal thickening of medium and large
arteries which can reduce or obstruct blood flow. The pathogenesis of atheriosclerosis is,
as yet, far from completely elucidated and, indeed, within the LDL particles themselves,
there is a structural heterogeneity. Approximately fifteen sub-fractions have been isolated
so far, presenting differing profiles in normal and hyperlipidaemic subjects. Some of these
subgroups seem to be linked with an atherogenic potential, this is the case for the smaller
and the denser of the particles. The particles must however undergo several in vivo and in
vitro transformations which modify their metabolism and are all the more important when
their half life is prolonged. These transformations, and in particular oxidation, lead, via the
macrophage pathway, to the accumulation of cholesterol, the production of foam cells, and
ultimately to the formation of the lipid streak. Antioxidants therefore open the way to new
therapeutic approaches. They can act synergistically with drugs that have a profound effect
on the quantity of circulating particle (mainly statins) or on the qualitative aspects (mainly
fibrates). Atherosclerosis is considered of one of the risk factors causing ischemic heart
diseases. This occurs when an atheroma (fatty tissue) is deposited in the wall of blood
vessels, and the coronary arteries seem particularly susceptible. Atherosclerosis develops
and is a complex mixture of fatty deposits, fibrous tissue, smooth muscle proliferation and
some blood constituents. Ischemic heart disease has to will managed by drugs because it
may lead to death. This is expected when a thrombus is formed in the coronary arteries
and so leading to a myocardial infarction or it might lead to heart failure. This occurs
when the heart fails to do its work of pumping the blood due to the lack of oxygen supply
and so in the heart ability to contract. The bright side is that the development of atheroma
occurs only when the lipids are found in excess amounts. This stimulates a new pathway
for the metabolism of lipids and will lead to the development of complications. Also
hyperlipidaemia along with smoking, hypertension and diabetes are one of the main causes
of peripheral vascular diseases.

Pancreatitis:
This as an acute inflammation of the pancreas with a high mortality. The inflammation and
necrosis are caused by activation of destructive pancreatic enzymes. It is associated with
raised triglycerides
13
_______ ____________________
_Section11
2.0 Behavioral Oriented therapy
This method of therapy couples low fat vegetarian diet, exercise , and stopping smoking
along with stress reduction together to face cardiovascular complications such as
Hyperlipidaemia . It also emphasis involvement of the patient in the treatment program so as
to improve his well power and help him comply with medicine .The patient should know the
effectiveness of the early management, which can be summarized in three points:
1
Every 1% reduction will decrease the risk of further complications by 2%.
2
Each 1mg/dl increase of HDL will decrease the risk of cardiovascular
complications by 2-3%
3
A diet regimen that contains 30% of fat and 7% of the total diet is saturated fat will
lower LDL by 15%.
These results were very encouraging despite that several problems were encountered
1.It’s very hard for a patient to know the suitable diet and calculate the calorie intake daily.
2. The drug therapy shows fast and convincing results with least of effort.
3.Doctors prefer giving drugs because patient training to adapt a healthy life style will require
long counseling secessions.
4.The results obtained were variable.
2.0.1 Dietary guidelines for patient with high cholesterol:

Fruit and vegetable along with oats and pulses can lower the LDL and total cholesterol
when they are taken in large amounts in order to have significant results.

Dietary cholesterol has much less influence on blood cholesterol level than dietary fat.
This is because a large proportion of the body’s cholesterol is synthesized by the liver
rather than being obtained from diet. That is why within normal intake increased dietary
cholesterol will be counterbalanced by decreased cholesterol production by the liver.

Also he has to be aware of the type of fats found in his diet which can be classified
to:
1 Saturated fatty acid, these can rise the serum LDL and total cholesterol, they are
found in dairy & meat.
2
Monounsaturated fatty acids, they can lower LDL and total cholesterol and they
are found in olive oil.
14
3
Polyunsaturated fatty acids, they lower LDL and total cholesterol but in large
quantities they have the disadvantage of lowering HDL. This type is found in plant
oils.
4
Trans fatty acids, they are isomers of unsaturated fatty acids and they can rise LDL and
total cholesterol. They are artificially created when vegetable oils are hydrogenated .
Dietary recommendations as listed in Mayo clinic diet manual 7th edition,
chapter 7,P.141
Item
Avoid
Decrease
Use instead
Milk
Whole
or
2% milk ,ice cream cottage
Skim milk or 1% fat, non fat
yogurt from whole milk Ice-
cheese 4% ,low fat yogurt 1-
yogurt, fat free cheese, low fat
cream
2% skim milk cheese
cottage cheese, pot cheese.
Egg yolks, peanut butter
Lean meat, fish, water packed
marbled, cold cuts, bacon
Nuts, fish canned in oil
tuna or salmon, low fat cold
frankfurters, sausage fried
oysters, shrimp
cuts & frankfurters, egg white
milk,
cheese
or
nondietary
Substituents
Meat
Grain
Organ
meats
,heavily
meat, canned meat & meat
Poultry without skin, Dried
mixes
beans
Rich baked pies, cakes
Baking products made with
Whole
Cookies,donuts,sweet
unsaturated fat and less than
cereal, English muffins
Rolls, pastries & muffins
3g fat/serving
Bagels & bread sticks, rice,
,crackers & chips
grain
breads
and
pasta, macaroni, potatoes,plain
popcorn
Fig bar cookies
Fat
Saturated fat, butter, lard,
Mayonnaise,
creamy
salad
Oils:
corn,
sunflower,
bacon fat, gravy and cream,
dressing, reduced calorie sour
soybean, and sesame, cotton
sauce cream, cream cheese,
cream or cream cheese
seed, canola, peanut.
hydrogenated margarine &
Fat free:spreads, dressing
shortening coca butter &
Cream
cheese
&
sour
non dietary creamers
cream.Margarine
&
salad
dressing from un-saturated oil.
Fruit &
Coconut or servings with
Avocado & olives
cream, creamy sauce, butter
vegetable
Fresh, frozen, canned or dried
fruit and vegetable
& dips
Note:
15

In the previous table the term Low fat means less than 3g of fat/serving while fat free
means 0-0.5 of fat/serving
Patient advice:
There are certain hints, which can help the patient get restricted to his diet regimen they are:

Fat proof the house by throwing all the drugs which he has to avoid by this he can save
him self from getting back from his decision.

Set a rule that the only place for eating is the dinning table not the car or during work
because this will help him diet and to stick to his diet.

Find other interests and try to fill his time and revive old hobbies or start a new one
and get in touch with old friends and try to do all the things which will help you enjoy
your time then you can eat to live not live to eat.

Check the food labels to know the amount of fat found in them because it is a common
mistake to deprive ourselves from many things we like to eat and substitute them with
others which has a higher fat content.

Take it easy as the change in diet has to be done in steps and gradual until the person
change all his eating habits and change his overall lifestyle.
2.0.2 Using exercise in the management of hyperlipidemia
The National cholesterol education program (NCEP) Recommendations for the
management of high lipids level
Daily exercise is a healthy practice for all individuals of all age groups. Yet, in some cases
exercise becomes an essential daily practice and can also be considered as part of medication
and in case of dylipidaemia it is as important as diet . Individuals of high BMI more than 25
is of risk to cardiovascular complications especially when the BMI exceeds 35 then doing
exercises and especially walking (moderate speed for 20 min) will be of great benefit.
Also the regular exercise is of great use for the hyperlipidemic patient and this is because it
was found to be of use in elevation of HDL which protects from the cardiovascular
complications. On the other hand the weight reduction accompanied with the exercise will
decrease the risk of hyperlipidemia complications.
16
To obtain this benefit there is a specific program, which must be followed for one year to
obtain the wanted results. This program has to be supervised by professional trainers to help
the patient getting the most out of it.
Mainly the program is divided to three phases were the patient has to go through them in
sequence. The following table shows the different training phases.
Phase
Aerobics
Strength
Sets/Reps
Comments
Walking
General motion
2 set of 15 reps with
1-on 1 conditioning
10-15 min
of major
light weights
1
muscles
OR
Stationary
Light dumb
2 sets of 15 reps or 1-
Work on improving range of
cycling
Bells
2 sets of 5-10 reps
motion and techniques.
Light dumb
2-3 sets increase 8-10
5 lb. on upper body
Bells
reps/wk
10 lb. on lower body and
10-20 min
11
Work out
20
min
3-4
days/wk
111
Low
classes
improving self dependence
impact
Use
strength
machines
2-4 sets of
Must work in perfection of
10-8-6 reps
exercise strength and range of
motion.
Patient advice:
Every day researchers discover new health benefits that come from regular exercise. And to
do it regularly it has to part of the daily lifestyle and the patient has to enjoy it by:

Find an activity which you like then you will have a motive to go out for it every day.

Find a partner to exercise with this will keep you company and keep you motivated .
when choosing the partner from the family or friends make sure that he is fit and of your
level because it can be discouraging when training with someone who is much better shape.

Join a local health club because the experts can answer your questions and set a program
for you which are challenging but yet manageable.

Start slowly until you can build your endurance then it will be easier for you to continue.

Don’t give up easily you may feel sore muscles. But remember, it took you your body
many years to become unhealthy so it will not magically change overnight. Just stick to it
17
and before you know it your muscles will stop aching , you’ll be able to work for longer
periods of time, and your weight will start to decrease .
2.0.3 Stopping smoking:
smoking is a bad habit and unfortunately many people are engaged to it despite of the
warning found in it which indicates that it is a direct cause for cancer, heart problems,
dyslipidaemia and atherosclerosis. That is why the patient has to be advised of the
importance of quitting smoking immediately and completely. It is not enough to decrease the
number of cigarettes or to switch to a filtered brand of cigarettes. Further smoking of any
kind increase the risk of having a heart attack. The good news is that it is easier to quit
smoking than ever before, thanks to nicotine replacement therapies and innovative support
programs. But yet it is the role of the patient to seek help after deciding to quit now and
forever. For some people it is hard to quit and for these they need to consult a professional
person to help him out. It is also important not to get discouraged if you failed or you didn’t
succeed right away, or you have a history of quitting and coming back. That is because the
benefit you are getting is worth trying on and on again.
Start now…
It is important for the patient to know that there is a lot to do which can save your heart and
your whole body. That’s why don’t waste another minute and know that the right time to
start is now. Toss out the bad habits and start living and make sure you know why are you
doing all this, because this will be your real motive to continue. Ask for a professional help
and consult him regularly to check that you progress toward a healthier heart and a better
future. Even if you failed, never mind as it’s the time to start again , learn from your
mistakes and then you may be a professional who can help others getting into the right tract
you are now in. A healthier life is worth going for and
18
2.1 Natural lipid lowering agents

Chromium:
It’s an element, which was first indicated for diabetic patients, as the chromium is a cofactor
for the insulin action. A similar action was found for the lipid metabolism. Yet it’s not so
effective as enough of it is already present in our diet and any excess will be excreted. That’s
why chromium supplement is only given to patients with deficiency.

Cod liver oil (anti- thrombogenic)
It’s common name is “oleum morrhuea” and it’s the partially destearinated fixed oil obtained
by aid of steam from fresh liver of the cod fish Gadus morrhua family Gadidae. The oil is
pale yellow liquid with slight fishy odour and taste. The oil consists of glycerides of
unsaturated acids 85% & glycerides of saturated acids in addition to VitA and the VitD. It
was found to increase the HDL and so it can protect from vascular complication like
atherosclerosis and ischemic heart disease. In commerce it is found in the form of capsules
and syrup known as Maxipam rich in omega-3-marine triglycerides. It is useful in the
treatment of hypertriglyceridemia however it can aggravate hypercholesterolemia.
Indications: to reduce plasma triglycerides especially after IHD or pancreatitis.
S/E: nausea and belching.
Capsules description:
1ml concentrated fish oil, Eicosapentaaenoic acid 18%, Docosahexaenoic acid 12%
Vit. A <100 unit/g, Vit. D < 10 units/g
Liquid description
Golden colored liquid with the same constituent.

Olive liver oil:
Its common name is “sweat oil” and its obtained from the expressed fixed oil from ripe fruits
of olea europaea family oleaceae. The olive oil is pale yellow or light greenish yellow oil
with characteristic odour and a bland faintly acrid taste. There are two varieties of olive
Turkish & Italian. Research has provided proof that a Mediterranean style diet, including
olive oil, is a healthy diet and that olive oil may reduce cholesterol levels.
19
The American Heart Association found that in researching the modern day diet that Greece
an especially the island of Crete had the lowest mortality rate due to cardio-vascular illness.
Finland and the United States had the highest mortality rate. The only notable difference
between the countries was the type of fat ingested. In countries with high incidents of
cardio-vascular disease, saturated fats were most often consumed. Saturated fats are high in
cholesterol. Monounsaturated, on the other hand, contain no cholesterol. Olive oil contains
unsaturated fatty acids and they are Oleic and linoleic acid. Olive oil is 80% oleic acid,
placing it at the top of the list of monounsaturated fats. Research has proved that using
olive oil significantly increases HDL levels and that olive oil is the main source of
monounsaturated fatty acids.

Garlic was worshipped by the ancient Egyptians, chewed by Greek Olympian atheletes
and thought to be essential for keeping vampires at bay! But it is also good for zapping
bacteria, keeping your heart healthy, warding off coughs and colds .There are now over
12 well designed studies published around the world that confirm that garlic in several
forms can reduce cholesterol. Most recently researchers in Oxford and America have
published some summaries of all the good data on garlic. Garlic as lipid lowering agent a meta analysis The Journal of the Royal College of Physicians. The authors state that
garlic supplements have an important part to play in the treatment of high cholesterol and
that this paper reviews all the published and unpublished data from around the world.
Overall a 12% reduction in total cholesterol was shown over a placebo and that this
reduction was normally evident after only 4 weeks treatment and that this was likely to
persist for as long as the study was in progress. The largest study so far was conducted in
Germany where 261 patients from 30 general practices were given either garlic powder
tablets or a placebo. After a 12 week treatment period mean serum cholesterol levels
dropped by 12% in the garlic treated group and triglycerides dropped by 17% compared
to the placebo group

Diet rich in fiber is also useful in people suffer from high lipid levels because it will
decrease the appetite and so help the patient decrease the weight to the normal BMI
which is 20-25.It also decreases the lipid absorption from the GIT.
20
Section 111
3.0 Drugs used in the management of hyperlipidemia:
The use of drug for the management of hyperlipidaemia is not the first line of treatment. As
before prescribing any medication the physician first has to:
1.
Define the type of hyperlipoproteinemia and establish the baseline serum cholesterol
and triglyceride levels.
2.
Institute a trial of diet, weight reduction and physical activity and make sure that the
patient adhere to the diet regimen,
3.
If the dietary program failed to reduce the lipids level then therapy has to initiate.
4.
Monitor serum cholesterol and triglyceride during therapy.
5.
If the prescribed medicine failed to reduce the cholesterol and triglycerides within
three to four month then this medication has to be discontinued and start a new drug or
use combination therapy.
Hypolipidemics is a classification for a group of drugs, which has the ability to lower the
serum cholesterol or triglycerides. Their correction of blood lipid abnormalities offers scope
for a major impact on cardiovascular disease. They are classified into four main groups
according to their mechanism of action
1) Anion exchange resins [bile salt sequestrates]
2) Fibric acid derivatives
3) Nicotinic acid and derivatives
4) Stations [HMG COA reductase inhibitor]
3.1

pharmacology of lipid lowering agents:
Anion exchange resins
They act by binding to bile acids in the intestine and so they are lost in the feces and so the
depletion of the bile acid pool stimulates conversion of cholesterol to bile acid in the liver.
This will lower LDL by 20-25%. That’s why they are first line treatment in
hypercholesteraemia but it can aggravate hypertriglyceridaemia
It’s suitable for type 11a, 11b hyperlipidaemia.
21
 Fibric acid derivatives
These drugs inhibit hepatic lipid synthesis. This will cause a drop in plasma cholesterol by
10-15% and triglycerides by 20-30%. This effect is associated rise in the protective HDL
that’s why it was found that the use of this group of drugs will decrease the danger of
myocardial infarction in patients with history of ischemic heart disease. Suitable for type
11b,111,1V & V of hyperlipdaemia

Nicotinic acid and it’s derivatives
They exert their action by reducing the supply of non-esterified free fatty acids and hence the
availability of substrate for hepatic triglyceride synthesis. Another mechanism of action is
that it increases lipoprotein lipase activity. That’s why its beneficial in lowering both
cholesterol (VLDL & LDL) and triglycerides . It also increases HDL cholesterol. It is suitable
for 11a, 11b, 111, 1V And type V of hyperlipidaemia.

Statins
They inhibit the rate-limiting enzyme in endogenous cholesterol synthesis, hydroxyl-methylglutaryl coenzyme A reductase. This result in increased synthesis of LDL receptors (up
regulation) in the liver and clearing of LDL from the circulation; plasma total Cholesterol and
LDL cholesterol undergo a dose-related reduction. LDL cholesterol falls by about 30% at a
dose of 20 mg/dl. Statins are the drugs of choice for type 11a with severs intractable
hypercholesterolaemia especially those with established vascular disease.

Others
1. Probucol: this drug increases the excretion of bile acids and reduces cholesterol
biosynthesis; the resulting fall in plasma lipid concentration affects both LDL and the
protective HDL. It’s useful For type 11a & type 11b hyperlipidemia. It is useful in
atherosclerosis and its also thought to be carditoxic.
2. Dextrothyroxine sodium: this drug stimulates the liver to increase catabolism and
excretion of cholesterol and it’s degradation products via the biliary route into the feces.
In this mechanism cholesterol synthesis is not inhibited and it is normally metabolized so
no accumulation occur in the blood. This drug was also used for obese patients as it has a
significant effect in weight reduction but on the other hand it was found that large doses
could produce toxic life threatening side effect.
22
This effect was more encouraged by along term study that stated that the subjects taking
dextrothyroxine had a higher mortality than placebo subjects. That is why dextrothyroxine
is considerably no more used.
3.2
Antihyperlipidaemic effects
Drugs
Lipid
Lipoprotein
Cholesterol
Triglyceride
VLDL
LDL
HDL
Cholestyramine
D
-I
-I
D
-I
Clofibrate
D
D
D
+D
-I
Gemfibrozil
D
D
D
+D
I
Fenofibrate
D
D
D
I
I
Nicotinic acid
D
D
D
D
I
Statins
D
D
D
D
I
Dextrothyroxine
D
+-
+-
D
+-
NOTE:
D = Decrease, I = Increase , -I = Increase or unchanged, +D= Decrease or unchanged,
+- = unchanged
3.3
Pharmacoeconomics
The price of the drug is one of the considerations, which has to be
taken into consideration when prescribing a drug. Generally all lipid-lowering
agents are expensive so the physician has to consider the economical status of
the patient so that to obtain the optimum compliance.
Trade name
Drug
Produced by
Price Dhs
Lopid 600 mg
Gemfibrozil
Parke- Davis
151.5 Dhs
Lipitor 20/10mg
Atrovastatin
Parke-Davis
256.5 Dhs
Lipostat 20/10 mg
Provastatin
B.M.S
146.5 Dhs
Zocor 20 mg
Semvastatin
MSD
225.5 Dhs
Lescol 40 mg
Fluvastatin
Novartis
116.5 Dhs
Lipobay 0.3/0.2 mg Cerivastatin
Roche
145 Dhs
Xenical 120 mg
Fournier
361 Dhs
Lipase inhibitor
23
Lipanthyl
Fenofibrate
Bayer
20.5 Dhs
Section 1V
Closer look on Hypolipidemics
4.0 Bile salt sequestrants (BAS)
Namely Cholestyramine & Colestipol
Indications:
1.
Hyperlipoproteinemia which doesn’t respond to diet
2.
Cholestyramine is used for biliary obstruction.
3.
It can be used for pesticide poisoning by binding to chlordecone (kepone)
4.
Antidote for digitalis toxicity as it decreases its absorption from the GIT.
5.
Cholestyramine is given for thyroid hormone overdose.
Pharmacokinatices
Reduction in cholesterol begins in the first month. Its not absorbed from the GIT tract.
Resin and its complexes are excreted in the feces.
Dosage form:

Cholestyramine:
It is found in the form of powder 4g resin/9g drug packet or scoop. Or in the form of
powder 4g resin/5g packet or scoop.

Colestipol :
Granules 5g resin/7.5g packet or scoop Or in the form of 1g tablet not to be broken.
Doses :

Cholestyramine:
Initial dose 4g daily bid
Maintenance dose 8-16 g/day in 1-6 doses, to maximum of 24g/day.

Colestipol :
Initial dose 5g daily bid
Maintenance dose 15-30g/day in 1-4 doses.
Note :
24
The increase in the dose was not always accompanied with decrease in the lipid levels that’s
why the drug is best given at its low doses. Also because at low doses the side effects are less
and are well tolerated
Warning:
1.
Not to be given in powder form and accidental inhalation has to be avoided
2.
Calcified material was observed during the treatment with BAS but it is not certain that
this material is due to the treatment as it can be due to a pre-existing liver disease
3.
Carcinogensis: Alimentary system cancer was noticed during the treatment with
cholestyramine but in a study done on mice it was found that fatal and non-fatal neoplasm
was similar in both treated and controlled.
Precautions:
1.
The serum cholesterol has to closely monitored for the first few month. Then periodical
check for serum cholesterol and triglycerides has to be carried out.
2.
Malabsorption: It interferes with normal fat absorption and digestion and so causes
deficiency in vit A,D,E,K & folic acid .That is why supplements of these vitamins should
be given with the treatment.
3.
Hyperchloremic acidosis : this is common in young patients and those using high doses
4.
Constipation :this is due to the accumulation of feces and its impaction which might
aggravate hemorrhoids. This side effect is dangerous in patients with symptomatic
coronary artery disease. When constipation is so sever decreasing the dose or even
discontinuation of the treatment is advisable. Also laxatives or stool softeners can be
given.
Drug interactions:

Cholestyramine interactions:
1.
Decrease anticoagulants effect so increase their dose, this interaction is most possible in
pateint with high lipid levels using BAS and is taking aspirin prophylactically after a
history of MI.
2.
Decrease the AUC of Mycophenolate by 40%. This indicates a change in drug
clearance which is possibly an increase, that is why a recalculation of the dose will be
important.
3.
Increase piroxicam elimination. That makes other NSAIDs more suitable.
25
4.
Causes loss thyroid hormone efficiency and so aggravates hypothyrodism.

Colestipol decreases the bioavailability of gemfibrozil

BAS (colestipol & cholestyramine) causes:
1.
Decrease the AUC and Cmax of Diclofenac. It can be subistituted with another NSAID.
2.
Decrease the absorption of Ursodiol.
3.
Decreases the GIT absorption of many drugs like:
Aspirin, Clindamycin, Clofibrate, Digitalis, Furosemide, Glipizide, Hydrocortisone,
Imipramin, Methyl dopa, Nicotinic acid, Penicillin
Phenytoin, Phosphate supplement, Propranalol, Tetracyclines, Thiazide diuretics &
Tolbutamide
Adverse reactions:
1.
The most common adverse reaction is constipation.
2.
In the CNS it has a vasoconstriction effect that’s why headache, syncope, dizziness,
drowsiness are common. Also the use of the drug might be accompanied with insomnia,
fatigue & vertigo.
3.
Hemolytic problems will lead to anemia & echymosis.
4.
Hypersensitivity in the skin or respiratory system.
5.
In the renal it might induce dysuria, hematouria or diuresis.
6.
Others: edema, weakness and loss of weight can a result of hemolytic problems or
malabsorption which will also lead to Vit A, K, D deficiency and if supplement were not
given then other complications might arise like rash, osteoporosis & bleeding
abnormalities.
Patient advice:
1.
The drug is taken before meals.
2.
The drug is not taken in a dry form but it has to taken with fluids.
3.
Other medications should not be taken 1hr before or 4 to 6hrs after.
4.
GIT disturbances can disappear upon repeated administration of the drug. And
constipation can be decreased by laxatives.
26
5.
Regular counseling with the doctor to perform the laboratory investigations for the LDL
level, liver function tests & hemoglobin.
6.
If the patient cannot tolerate the side effects he has to be aware of measuring the risk to
benefit ratio and these facts has to clearly explained to him.
4.1Fibric Acid derivatives:
Namely they are: Clofibrate, Gemfibrozil & Fenofibrate .
They all share the major pharmacological action of all fibric acid derivatives but they are
different in other aspects like the indications, contraindications, doses and patient advice
when being on any of them.
4.1.1 Clofibrate:
Indications:
1.Dysbetalipoproteinemia: this is type 111 hyperlipidaemia which is not responding to diet
therapy.
2.hyperlipidaemia for type 1v & v hyperlipidaemia.
Pharmacokinatices:
It is a prodrug as it is hydrolysed in the body to the active form of the drug which is CPIB.
The plasma peak levels occur within 3 to 6hrs. The drug has a 97% plasma protein binding
which decreases with the increase of plasma concentration. 40-70% of the drug was found in
the urine in the form of glucuronide ester derivative of CPIB. The plasma elimination half life
is about 15%hrs which increases in case of renal impairment.
Administration & Dosage:
The adult dose is 2g daily in divided doses.
Contraindications & warning :
1.The use of clofibrate was found to be related with a high incidence of liver tumorigenicity
as well as malignancy and choletethiasis.
2.It is not used in the management of fatal myocardial infarctions as it was found to be
accompanied with increase in cardiac arrythmias, definite or suspected thromboemoblic
events and angina.
Pregnancy & lactation:
27
The drug is not indicated for pregnant or lactating women as it was found that it can cross the
placenta and is excreted in the milk.
Drug interactions:
1.It decreases the effectiveness of anticoagulants so the dose has to be increased when given
with clofibrate.
2.reduction of the plasma protein binding of dantrolene so its dose has to be decreased in
order to avoid the toxicity which can occur when the two drugs are given together.
3.an exaggerated diuretic effect was experienced with furosemide when taken with clofibrate
so dose reduction has to be done and take care of the dehydration or hypotension which can
be one of the complications of this therapy.
4.When given with ursodiol its effectiveness especially when gallstones are produced.
5.Oral contraceptives increase the elimination of clofibrate and so its dose has to be
increased.
6.Probenecid increase the effectiveness and toxicity of the drug by decreasing its renal
clearence so lowering the dose is necessary.
Major side effects:
1.Was found to induce ischemic heart diseases and arrythmia, this side effect is significant if
we put in mind that most hyperlipidaemic patients is suffering from cardiovascular
complications.
2.Induces allergy in the skin and kidney causing hematuria, dysuria and in some cases
proteinuria. Another side effect is loss of lipido and impotence.
3.commenly is flu-like side effects
4.GIT disorders nausea is most common & inflammation or gall stone
Patient advice:
1.Monitor the lipid level as in some cases it was found that clofibrate was not effective in
lowering the lipid levels.
2.Perform complete blood count regularly as the use of the drug was found to be associated
with anemia and leuckopneia.
28
3.Perform frequent liver function tests to indicate any liver dysfunction at its early stages.
4.Any contributing factor should be pointed out and treated like alcohol, obesity,
hypothyroidism and diabetes mellitus.
5.Adhere to the prescribed diet after the start of therapy.
6.If any GIT upset was noticed then the patient should be advised to take the drug after food.
4.1.2 Gemfibrozil
Indications:
1.Hyperlipidemias of type 1V and V with very high serum triglycerides
2.Patients at risk of pancreatitis and not responding to diet.
3.Patients with low HDL levels and are not responding to weight loss, diet or exercise and
other drugs like BAS or niacin.
3.For type 11b patients but they do not have a CHD history.
Pharmacokinatices:
It is well absorbed from the GIT. The maximum action is obtained after 4-12 weeks and the
lipid return to the pretreatment level after drug discontinuation. They are rapidly and
completely absorbed after oral administration Mean peak serum concentration of 15-25 mg/L
occur within 1-2 hr. Metabolism is done by oxidation. Serum concentrations are directly
proportional to dose. The drug is 97-98.6% bound to plasma albumin. Clearance appear to be
independent of renal function, but in this case further study and dose adjustment has to
done.70% of the dose is excreted in the urine primarily as glucuronide conjugates. 2% is
excreted unchanged. The t.5 is 1.5 –2 hr. but it may be longer allowing complete distribution.
Dosage form:
A 600 mg tablets are present.
Doses:
Adult dose is 1200mg/daily in divided doses.
Contraindications and warnings:
1.
Cholelithiasis and liver carcinoma was noticed that’s why the drug has to be
discontinued when gall stones appear.
2.
Rhabdomyolysis, myositis and elevation in creatinine level noticed
3.
Not given to patient with renal insufficiency as it may cause myoglobinuria leading to
acute renal faliure.
29
4.
When giving high doses fertility impairment were noticed which was reversed upon
discontinuation of therapy.
5.
It was found to be safe during pregnancy but not given during lactation.
Drug interactions:
1. HMG CoA reductase inhibitors when used in combination with gemfibrozil this therapy
was found to increase the incidence of rhabdomyolysis.
2. Gemfibrozil enhances the effect of oral anticoagulants.
Common side effects:
GIT disturbances are most common like dyspepsia, abdominal pain
&Diarrhea others are: inflammation of muscles, gall stones and elevated liver function tests.
Patient Advice:
1.the drug is taken 30 minutes before morning and evening doses
2.Dizziness or blurred vision was noticed after the treatment with gemfibrozil so caution has
to be done when doing physical or driving.
3.If GIT disturbances were pronounced consult the physician
4.Periodic liver function test has to be performed.
6.Moderate hyperglycemia effect was noticed so contraindicated in diabetic patient and
glucose monitoring is essential.
4.1.3 Fenofibrate
Indication:
1.For type 1V & V hyperlipidemia.
2.Reduces platelets aggregation and decrease serum uric acid .
Pharmacokinatices:
It is a prodrug as after it’s absorption they are hydrolyzed to the active drug. They are highly
bound to plasma proteins.
They are predominantly excreted unchanged in the urine with half-life of 20hrs; this duration
is prolonged in case of kidney dysfunction.
30
Dosage Form:
Capsules of 67 mg.
Adult dose:
Initial dose is 67mg/ day which can be increased within 4-8 weeks to a maximum dose of 201
mg/day.
Side effects:
1.GIT disturbances as well as allergic reaction and pain.
2.Cholelithiasis was reported but not frequent.
Patient advice:
1.Drug should be taken with a meal
2.In case of a history of liver, gall bladder or kidney disease this drug should be avoided
Clinical studies:
Fibrates mechanism of action is a question which is still attracting the attension of scientists.
A study was carried out by Dr. Bart Staels of the institute pasteur de Lille in France, this
study aimed to explain fibrates mechanism of action in lowering lipid level and treatment of
arteries inflammation accompanied with lipid accumulation in the vessels. Researchers
studied two groups of 19 patients who had slightly elevated cholesterol concentrations. In one
group, the participants had blocked arteries, and the concentration in their blood of
interleukin-6 (IL-6), an indicator of inflammation in blood vessels, was twice that of the other
participants. The fibrates lowered lipid levels and reduced IL-6 to a greater extent in the
group with clogged arteries. The fibrates also lowered the concentration of two proteins that
contribute to clogged arteries and to inflammation: CRP and fibrinogen. CRP is an
established risk marker for coronary heart disease but its mechanism is unknown. Fibrinogen
is important in the formation of the thrombus (blood clot) at the site of blood vessel injury
which can lead to acute blockage of the artery. Furthermore, elevated levels of fibrinogen are
an independent risk factor for the development of coronary artery disease. Also Fibrates bind
to and stimulate a receptor in the liver called PPARa, which is involved in the breakdown of
fatty acids researchers had known. The receptor "regulates the expression of genes involved
in fat metabolism. However, PPARa receptors are also present in the cells of vascular muscle
walls, where they inhibit the production of inflammatory cytokines such as IL-6 and
31
prostaglandin, the scientists found through examining the participants' blood. PPARa
receptors also inhibit the activity of an enzyme called Cox-2 (cyclooxygenase), another
contributor to vascular cell inflammation, they report. The chemical on Cox-2 helps inhibit
these inflammation processes by interfering with a signaling pathway called NFkB, (Nuclear
factor kappa B.) that is identified as a transcription factor regulating kB gene. Now it is
known to be a major signal transducer of inflammatory stimuli."
4.2
Nicotinic acid:
Indications:
Hyperlipidaemia which is not responding adequately to diet and weight loss.
Pharmacokinatices:
It’s effect in lowering lipid level starts within several days or even its possible after a single
dose. Also the return to pretreatment lipid level occur after 2-6 weeks from the drug
discontinuation. The drug should be completely absorbed from the standard formulation. The
peak serum levels are obtained 30-60 min after 1gm dose is 15-30g/L. It is metabolized in
the liver to active niacinamide that contributes in its lipid lowering ability. The t.5 is 20-48
min so its considered as short acting drugs but on the other hand it has active metabolites.
Administration & dosage:
Doses 1 to 2g three times/days. Maximum dose is 8g/ day
Contraindications and warning:
1.hepatotoxicity is common after high doses more than 2mg/day and is diagnosed by liver
function tests. In sever cases it might cause fulminant hepatic faliure, hepatic encephalopathy
and liver transplantation might be essential.
2.Most common is flushing which can be reversed with 300 mg aspirin given 30 minutes
before each dose.
Patient advice:
1. The sensation of flushing and facial warming is normal and it can be aggrevated with hot
drinks that’s why it has to be avoided.
2. Itching, tangling and headache is common so the patient has to be ready and used for
these side effects.
3. If dizziness occur avoid sudden change in posture and avoid driving or complex tasks.
4. When the drug causes GIT upset take it with meals.
32
5. Consult the doctor if an new symptoms appear like: jaundice, nausea or vomiting inorder
to carry out other tests like bilurubin concentration or prothrombin time.
4.3
HMG CoA Reductase inhibitors (statins)
Namely they are: Atorvastatin, Cerivastatin, Fluvastatin, Lovastatin, Pravastatin,
Simvastatin
Indication:
Treatment with statins (HMG Co-A reductase inhibitors) lowers serum cholesterol
substantially and has been shown to reduce myocardial infarction, coronary deaths and
overall mortality in recent controlled trials. That is why it is strongly advised to patients who
have had a myocardial infarction and is complaining of high lipid level. These patients have a
very high CHD risk, and treatment is indicated when the total cholesterol level is 4.8 mmol/l
(or Low Density Lipoprotein (LDL) 3.2 mmol/l
Other indications are:
1.Primary hypercholesterolemia , mixed dyslipidemia, hypertriglyceridemia, primary
dysbetalipoproteinemia, homozygous familial hyperlipidemia.
2.Primapy & secondary prevention from coronary artery events when there is:

Patients with angina or other clinically overt atherosclerotic disease who have total
cholesterol of 5.5 mmol/l or more (or LDL 3.7 mmol/l or more. This includes patients
with peripheral vascular or symptomatic carotid disease or who have had a bypass graft or
angioplasty. These patients have a risk of major coronary events which averages
approximately 3% a year.

People without clinically apparent vascular disease but who nevertheless have a high risk
of developing overt CHD People may have this risk because of a combination of other CHD
risk factors, particularly diabetes or hypertension. People with familial hyperlipidaemia are
at high risk of CHD.)

People over the age of 70.There is little trial evidence of benefit or harm fromstarting
statin treatment in people over the age of 70 for the primary prevention of CHD.
33

For patient with serum cholesterol above 6.3mmol/l and they are usually started at low
doses and they are expected to lower the cholesterol level by 20-25%
pharmacokinatices:
The onset is within two weeks while the peak effect was reported after 4-6 weeks. After
discontinuation of the drug the serum cholesterol returns back to the pretreatment levels.:
Absorption is rapid. Systemic bioavailability of the drug is low because of the extensive
first-pass metabolism (above 60%). Peak serum concentrations are achieved in 1-4hr.
They are bound to plasma proteins with different percents. The lipophilic drugs crosses
the blood brain barriers like Atorvastatin, Lovastatin &Simvastatin. The liver metabolizes
all the drugs and some gives active metabolites and then they are all excreted in the feces.
Renal insufficiency effects the plasma concentration as it decreases the clearance.The
different drugs have different duration of action indicated by their variable t.5.
Atorvastatin has the longest duration of action as its t.5 is 14hrs while Cerivastatin has a
t.5 of 2-3hrs on the other side Fluvastatin, Lovastatin, Pravastatin & Simvastatin have a
t.5 less than 2hrs.
Statins facts and comparisons:
Drug
Dosage
Doses initial (I)
form
Maintenance
Bioavailability
comment
(M)
Pravastatin
Tab 10, 20, 40
(I)10-20 mg q hs
34% , 17% subjected
Take without regard
mg
(M) 10-40 mg q hs
to first pass
to meals
metabolism,50% bind
to plasma proteins
Simvastatin
Tab 5, 10, 20,
(I)5-10 mg q hs
60-80%, 95 % bind to
Take without regard
40,80 mg
(M) 5-80 mg/day
plasma proteins and so
to meals
5%
reach
the
circulation.
Lovastatin
Atorvastatin
Tab 10, 20,40
(I)20 mg/day
35% , 95% bind to
Take with evening
mg
(M) 20-80 mg/day
plasma proteins and
meal
in
are subjected to first
1-2 divided doses
pass metabolism
Tab 10,20,40
(I)10 mg/day
14%,98%
mg
(M)10-80 mg/day
plasma proteins with
bind
to
first pass metabolism
34
Take at any time
Cerivastatin
Tab 0.2,0.3 mg
0.2-0.3 mg/day
60% , 99% bind to
Take at the evening
plasma proteins
Fluvastatin
Cap 20,40 mg
(I) 20 mg q hs
98% but
24% is
(M)20-40 mg q hs
subjected to first pass
Take at any time
metabolism
Precautions:
1. In women who are expected to be pregnant because the drug is contraindicated for both
pregnant and lactating women.
2. In alcoholic patients or those with history of liver disease.
3. In patients with fear of renal failure.
Drug interactions:
1)
Myositis and rhabdomyolysis when statins are given in combination with CYP3A4
inhibitors like: erythromycin, gemfibrozil, itraconazole, ketoconazole.
2)
Warfarin an anticoagulant its effect is increased when it is given with statins.
3)
Pravastatin bioavailability is decreased when taken with bile acid sequestrants.
4)
With peptic ulcer drugs : Its efficacy is decreased with antacids while omeprazole,
ranatidine & cemitidine lead to the increase of its plasma concentration.
5)
Propranalol is commonly used in patients with hyperlipidemia and associated
hypertension and in this case the a dose increasment has to be done.
6)
In patients with CHD and hyperlipidaemia it has to be taken into considration that
digoxin cause a increase in statins plasma concentration so dose has to be readjusted.
Side effects
This group of drugs are known to be well tolerated with minimum side effects.
Simvastatin has the least side effects and it is limited to headache and URTI. The most
common side effect for all the drugs is headache mainly noticed with cerivastatin which also
known for causing GIT disturbances. Pravastatin and maybe because of its high lipophilicity
has the main CNS side effects. Fluvastatin is known for its skeletal muscle side effects like
35
back pain and inflammation. The drug mostly given to the elderly is pravastatin in a dose of
10mg/day and simvastatin in a dose of 5mg/day.
Patient advice:
1) Before considering the use of statins, other methods to reduce the risk of coronary heart
disease (CHD) should be instigated
2) Monitoring of liver function, serum lipid & muscle enzymes is essential.
Clinical studies:

A team from the St Elizabeth's Medical Center (Boston, MA, USA) have investigated
the molecular signaling mechanisms of statins in the ischaemic hind limbs of rabbits.
Simvastatin, they found, works by activating protein kinase Akt. This leads to nitric oxid
production and promotes endothelial cell survival in an Akt-dependent manner--cellular
responses that control angiogenesis and stabilisation of the vascular network. Akt
activity by statins enhances revascularisation of ischaemic tissue explaining the reduction
in cardiovascular events that are seen in patients who receive these drugs. A better
understanding of the Akt role could lead to new targets for angiogenic. Another
researcher stated that they cant be angiogenic, because if that was the cause then they
would have stimulated the growth of occult malignancies . The absence of reports of
such side-effects calls into question their potency as general stimulators of angiogenesis
in humans. Statins may instead promote angiogenesis by inhibiting cell apoptosis rather
than by stimulating vessel growth. This question is not yet solved but it calls to further
study.
 The pravastatin primary prevention study (west of scotland coronary prevention study)
the effect of pravastatin (LIPOSTAT) was assessed in 6595 men 45-64 age, without a
previous MI and with LDL-C levels between 156-254 mg/dl. In this randomized, double
–blind, placebo-controlled study, patients were treated with standard care, including
dietary control for 4.8 years. The result was reduction of the rate of the first coronary
events either CHD or nonfatal MI by 31%. The risk reduction with pravastatin was
similar and significant through out the entire range of baseline LDL cholesterol levels.
Also the reduction was similar and significant across the age range studied with 40% risk
36
reduction for patients younger than 55 years and 27% risk reduction for those 55 and
older. This shows the importance of early treatment.
Section V Summary
GUIDELINES FOR THE MANAGENMENT OF HYPERLIPIDAEMIA:
In the management of hyperlipidaemia and its associated disorders there are certain protocols
which has to be followed for proper advice in giving both diet and drugs.
1)
Identify the case wiether it is mild, moderate or sever, this is determined by the
elevation of lipid level.
2)
Make sure that this elevation is not caused by another secondary cause.
3)
Identify the type of lipoprotein or lipid which is elevated and this will help us diagnose
the type (type1,11….) or wiether it is familial hyperlipidaemia or familial triglyceridemia
or combined.
4)
In case of mild to moderate increase the patient is advised to reduce his weight (by
reducing the total calories intake & performing exercise), avoid alcohol consumption and
in case of elevated cholesterol level he has to reduce the total fat
Saturated fat & sometimes the dietary cholesterol. While in the case of elevated
triglyceride level he has to decrease dietary fat and carbohydrates.
5)
In sever cases a dietitian advice has to be taken because he is capable to draw the
boarder line for the amount of lipid permissible without causing any nutrient deficiency to
the patient.
6)
The drug therapy is not advised for patient with mild to moderate elevations, instead, a
more restricted diet is advisable. An exception is the patient with moderate cholesterol
level and with CHD in this case statins are advisable.
7)
Before starting drug therapy the diet therapy has to be tried for 6 monuth to one year
also rigorous attempts has to be done to control risk factors.
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8)
The drug of choice is chosen according to the type of the drug and according to the
patient state (the drug of choice might be contraindicated for a particular patient)
9)
The patient have to stick to his diet regimen after the initiation of therapy .
10) Lipid level monitoring after the start of therapy putting in mind that different agents
has different time for onset of action.
HOW TO CHOOSE THE MEDICATION
1.Predominant hypercholesterolaemia: Choose from resins (cholestyramine or colestipol);
HMG-CoA Reductase Inhibitors (simvastatin or pravastatin);
gemfibrozil; nicotinic acid; probucol.
2.Combined hyperlipidaemia: Choose from gemfibrozil, simvastatin or pravastatin; nicotinic
acid. (These drugs are also useful when HDL cholesterol is low).
3.Predominant hypertriglyceridaemia: Choose from gemfibrozil; nicotinic acid; high dose
fish oil (2 g/day n-3 fatty acid).
4.For elderly the statins are drugs of choice due to their safety and possible associated heart
problems with age.
5.For pregnancy and lactation avoid the statins and change to bile acid sequestrants . Because
malabsorption is possible it is important and so fat soluble vitamins should be prescribed to
the patient especially due to the increase in the daily requirements of vitamins during
pregnancy.
6.For pediatrics diet restrictions is the applicable coarse of action but in sever cases bile acid
sequestrate or niacin is advisable but close supervision and accurate dose calculation is
needed.
7.In patients with gall bladder obstruction avoid BAS or fibrates and usually statins are more
advisable.
8. cerivastatin either as monotherapy or in combination with a fibrate should be considered
an important treatment option for diabetic dyslipidaemia.
38
9. Patients with renal impairment or liver disease should be closely monitored. A test for liver
and kidney function should be done periodically when the patient is on any therapy. If the
patient has a gall bladder obstruction then BAS will be an absolute contraindication and
maybe niacin (in low doses) or statin will be more preferred .
COMBINATION THERAPY:
Lipid lowering drugs may be used in combination in severe cases and when the monotherapy
is
of
limited
use.
Also
when
VLDL
is
elevated
during
the
treatment
of
hypercholesterolaemia.
Guidelines have pointed out that strict adherence to policies would result in "over treatment"
of hyperlipidaemia.
1. When Cerivastatin 0.3mg was used in combination with fenofibrate and bezafibrate. The
effect was reduction of LDL by over 42%, TGs were reduced by 44% and HDL increased
by more than 32%. Clearly further cost benefit analysis and further analysis is required to
determine the sub-groups most likely to benefit.
2. BAS is given with statins in case of refractory sever forms of hypercholesterolemia, also
given in combination with nicotinic acid
3. Statins can be given in combination with resins but its not advisable to give it with fibrates
because might induce myopathy.
4. Gemfibrizol & bile acid resin is given in combination and this is useful in treating familial
combined hyperlipidaemia. This combination might induce choleithiasis.
5. Bile acid binding resin & niacin this combination is used in familial combined
hyperlipidaemia where there is an elevation in both LDL, VLDL. The effectivness is due to
increase of LDL catabolism by resin and decrease in VLDL synthesis by niacin. Perhaps
there is also reduction of cholesterol synthesis in the live and increase in HDL. This method
is widely used so there is a good experience when dealing with it and it doesn’t aggravate the
side effects. On the other hand it was found that resin has acid neutralizing property which
39
can reduce the gastric irritation produced by niacin. The combination is used for
heterozygous familial hypercholesterolemia in a dose of 6.5g of niacin and 24-30g of resin.
6. Niacin
& statins for familial combined hypercholesterolemia. But the experience is
limited.
7. Resins, niacin & statins in sever disorder involving elevated LDL . this combination has
limited toxicity. The combination has the advantage of lowering the dose of each and so the
side effects and in the same times potentates the action.
Section VI
Hyperlipideamia
along
with
hypertensive
Conclusion
disease,
diabetes
mellitus, smoking, obesity, heavy alcohol consumption and physical
activity is recognized as contributory factors in the development of
coronary heart disease.
A recent study with lipid lowering agent has clearly shown that
reduction of raised serum cholesterol in individual with coronary heart
disease will reduce mortality. The present study was therefor
undertaken to determine if there was a relationship between the
various indicators of coronary health and the supply of lipid lowering
agents. Prescribing analysis and coast data was collected for each
target region on a quarterly basis over a two years period of time. The
quantity of each lipid lowering agent supplied to patients was
expressed in term of its defined daily dose (DDD) and presented as
DDD per 1000 inhabitants per day. All other risk factors were
obtained from different statistical indicators data service. The
prevalence of risk factors across each target country was high and
associated with coronary heart disease mortality. (rs=0.88;p 0.01).
However, there was no relationship between the supply of Lipid
lowering Agents and mortality. The results reinforce the need to
40
change the lifestyle of the population and to promote guidelines on the
appropriate use of lipid lowering agents.
This is the role of clinical pharmacy and pharmaceutical care in the
management of hyperlipidemia. It is a responsibility to point out the
importance of diet and exercise & to illustrate the appropriate use of
medicine to patients and to be always ready with updated, correct and
accurate information for patient advice and counseling.
References
1. Drug facts and comparisons 2000
2. Internet: www.Ixquick.com
3. Clinical drug data
4. Dean Ornish D,brown Se, Lancet 1990
5. Dr. Bart staels, Pasteur institute, France, Lancet 2000
6. Mayo clinic diet manual 7th edition
7. BNF edition 2000
8. Clinical pharmacology 7th edition DR. Laurence, P.N. Bennett
9. Pharmacology 3rd edition Leonard S.Jacob
10. Essential Medicine 2nd edition edited by John Vann Jones & Charles R.V
Tomson.
11. Article about dietary fats & hyperlipidaemia by Briony Thomas BSc, PhD
, SRD.
12. Pharmacology Text book
13. Lipostat (Pravastatin sodium tablets) leaflet by Bristol-Myers Squibb
14. An educational service from PARKE-DAVIS the markers of Lopid.
15. Diagnostic and laboratory test reference ,third edition, Mosby’s
‫الحمد هلل رب العالمين‬
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