New Frontiers on Hyperlipidemia in Pharmaceutical
Education
L.K.
Kanthal*, P. Mondal, D. Saha, D. Mridha
and S. Mandal
Bharat Technology,
Banitabla, Uluberia, Howrah, W.B. India.
ABSTRACT:
The condition of hyperlipidemia can be described as
high cholesterol in the blood (hypercholesterolemia), high triglycerides in the
blood (hypertriglyceridemia) or it could be both. Hyperlipidemia is a major risk
factor in the initiation and progression of atherosclerotic lesions, conditions
such as coronary heart disease, ischemic cerebrovascular disease and peripheral
vascular disease which leads high morbidity rate in developed countries. The
present article gives different classes of anti-hyperlipidemics highlighting
the pathophysiology of artherosclerosis, classification, side effects and
therapeutic uses of antihyperlipidemics.
KEYWORDS: Hyperlipidemia, cholesterol, atherosclerotic blood
vessel
INTRODUCTION
The medical term for this condition is hyperlipidemia,
which is made of three parts; hyper- is a prefix a meaning more or extra, lipid
is fat and emia is a suffix indicating that the condition is in the blood.
Hyperlipidemia is a general term, it could be either high cholesterol in the
blood (hypercholesterolemia), high triglycerides in the blood
(hypertriglyceridemia) or it could be both. Atherosclerosis is a disorder of
the arterial wall characterized by accumulation of cholesterol ester in cells
derived from the monocyte-macrophage line, smooth muscle cell proliferation and
fibrosis, and results in narrowing the blood vessel.1
The majority of the cases are not caused by hereditary
factors, but rather secondary to other conditions. Obesity is considered a risk
factor because it usually indicates a certain life style with high food
consumption and low physical exercises, both are incriminated in high blood
lipids. High consumption of food rich in saturated fat such as found
in meats, non-skim dairy products, butter and some artificially hydrogenated
vegetable oils is particularly risky. High intake of cholesterol prevents the
uptake of cholesterol circulating in the blood by the liver and these kinds of
food are not short of it.
Risk factors include both gender and age. If a woman 55
years or older, or if past menopause, then it is higher risk for heart disease.
The same is true in man, 45 years and older. Another fixed risk factor is a
family history of heart disease2. This disease mainly affects the
large and medium sized arteries, mainly the cerebral, coronary and renal
arteries. It also involves the aorta and the arteries of the legs. The
important clinical complications are coronary heart disease, cardio vascular
disease which is a major cause of death.3
Role of lipids in the body:
The major lipids in the bloodstream are cholesterol
and triglycerides. Lipid- lowering
medicines are used to lower cholesterol
and triglycerides Cholesterol
and triglycerides occur naturally in body and certain levels are vital as an
energy source, for regeneration of cells and for normal hormone production and
growth.
Cholesterol is a fatty substance in blood.
Only a small amount comes directly from cholesterol in
food. Cholesterol is transported around body in the bloodstream attached to a
protein (lipoprotein).There are three types of lipoprotein, depending on how
much protein there is in relation to fat: low density lipoproteins (LDL) -
accounting for 60-70% of total cholesterol,
high density lipoproteins (HDL) accounting for 20-30% of total cholesterol,
Very low density lipoproteins(VLDL)that are rich in triglycerides account for
10-15% of total cholesterol.
If there is too much LDL cholesterol
in blood
it can accumulate in the walls of blood vessels,
causing a buildup of plaques (fatty deposits of cholesterol,
cell waste and other substances, which form raised patches on the artery
wall) leading to narrowing (atherosclerosis), and possible blocking of the artery.
Blocked arteries can lead to strokes and death. A high level of LDL cholesterol
increases the risk of CAD and stroke. LDL is sometimes referred to as bad cholesterol.
High levels of HDL cholesterol
appear to help to protect against the development of narrowing of arteries. Low
levels of HDL may indicate that a greater risk of atherosclerosis. HDL is
sometimes referred to as good cholesterol.
In some people an increase in LDL cholesterol
is accompanied by raised triglyceride levels. Triglycerides are made in the
body from the food. People with high triglycerides often have high LDL cholesterol
and low HDL cholesterol
levels. Modifications in diet and lifestyle can realistically lower cholesterol
levels by 10%, but greater reductions require the concurrent use of drug
therapy.4
Cholesterol:
Cholesterol is a lipid (fat). It is manufactured by the
liver from the fatty foods that plays a vital part in allowing the body to
function normally. Cholesterol is present in the membrane (outer layer) of
every cell in the body. It insulates nerve fibers, and is an essential building
block for hormones, such as the sex hormones, and the hormones of the adrenal cortex.
It also enables the body to produce bile
salts. The amount of cholesterol
present in the blood
can range from 3.6 to 7.8 mmol/liter. A level above 6 mmol/liter is considered
as high, and a risk factor for arterial disease.
The target cholesterol
level is less than 5.
Evidence strongly indicates that high cholesterol
levels can cause narrowing of the arteries
(atherosclerosis), heart attacks,
and strokes. The risk of coronary heart
disease
also rises as blood
cholesterol
levels increase. If other risk factors, such as high blood pressure
and smoking, are present, the risk increases even more.
Risk
Factors:
A number of different factors can contribute
to high blood cholesterol.
Lifestyle
risk factors:
They include: Unhealthy diet - some foods
contain cholesterol (known as dietary cholesterol) for example, liver, kidneys
and eggs. However, dietary cholesterol has little effect on blood cholesterol.
More important is the amount of saturated fat in diet. Foods that are high in
saturated fat include red meat, meat pies and sausages, hard cheese, butter and
lard, pastry, cakes and cookies, and cream, such as soured cream. Lack of
exercise or physical activity - can increase level of bad cholesterol (LDL),
and decrease level of good cholesterol (HDL).
Obesity - if overweight likely increased
level of LDL and a decreased level of HDL, increasing overall blood cholesterol
level, smoking, and drinking excessive amounts of alcohol - the recommended
amount is 3-4 units a day for men, and 2-3 units a day for women. Treatable
risk factors there are a number of treatable conditions that can cause high
blood cholesterol. They include:
Hypertension (high blood pressure), Diabetes, A high triglyceride blood level,
and Medical conditions, such as kidney and liver diseases, and an under-active
thyroid gland.5
Fixed
risk factors:
There are a number of fixed risk factors
that can cause high blood cholesterol. They include: a family history of heart
disease or stroke - are more likely to have high cholesterol if a close male
relative (father or brother) aged under 55, or a female relative (mother or
sister) aged under 65, who has been affected by coronary heart disease or
stroke, A family history of a cholesterol related conditions for example, if a
close relative, such as a parent, brother, or sister has familial
hyperchloresterolemia, or combined hyperlipidemia, Being male men are more at
risk of having high blood cholesterol than women, Early menopause in women, and
Ethnic group people who are of Indian, Pakistani, Bangladeshi, or Sri Lankan
descent have an increased risk of high blood cholesterol. High blood
cholesterol also depresses the immune system and thereby increases the
incidence of cancer6.
Complications:
High cholesterol levels can be made worse by any other
medical conditions. Medical problems such as an under-active thyroid gland, an
overactive pituitary gland, liver disease, or kidney failure, can all
contribute to high cholesterol levels. Some people have inherited disorders,
such as familial hyperchloresterolemia, or combined hyperlipidemia, that
prevent fats from being used properly and eliminated from the body. This allows
the level of cholesterol to build up in the blood. The major complications of
raised blood cholesterol are heart attacks, strokes and arterial disease. The
risks of all of these are increased if: Overweight, Smoke, High blood pressure,
a strong family history of these conditions are diabetic.
Pathophysiology:
Atherosclerosis begins when a fatty streak develops on
an arterial wall. This fatty streak is formed when monocytes congregate on the
arterial wall in response to lipoprotein oxidation or other influences7.
When monocytes leave the bloodstream and migrate to the intima, they become
macrophages. Macrophages then phagocytize oxidized LDL cholesterol and die, thereby
contributing to the lipid component of the fatty streak8. Before
they die, macrophages also secrete multiple growth factors that serve as the
principle mitogens for connective tissue cells, such as fibroblasts and smooth
muscle cells. Collagen is another principle contributor to atherosclerotic
plaque, and its production leads to the formation of hard fibrous plaques,
usually in the third decade of life. In response to increased plaque volume,
arterial remodeling occurs, which results in an outward expansion of the
coronary arteries. The arteries expand in an effort to overcome the effects of
the blockage allowing blood to flow through the stenosed vessel segment. This
expansion continues until the artery reaches its maximum point of flexibility
and can no longer accommodate the continued growth of the plaque. This
threshold generally occurs when the arterial stenosis reaches 40%. As the
plaque ages, an increasing amount of fibrous tissue accumulates, leading to the
formation of a fibrous cap, which is vulnerable to rupture. Progressive
arterial stenoses eventually lead to ischemic vascular disease, and the rupture
of a plaque can cause a myocardial infarction.
Classification of
Hyperlipidemias:
Hyperlipoproteinaemia type I:
This very rare form (also known as Buerger-Gruetz syndrome, primary hyperlipoproteinaemia, or familial hyperchylomicronemia) is due
to a deficiency of lipoprotein lipase (LPL) or altered apolipoproteinC2,
resulting in elevated chylomicrons, the particles that transfer fatty
acids from the digestive tract to the liver. Lipoprotein lipase
is also responsible for the initial breakdown of endogenously made
triacylglycerides in the form of very low density lipoprotein (VLDL). As such,
one would expect a defect in LPL to also result in elevated VLDL. Its
prevalence is 0.1% of the population.
Hyperlipoproteinaemia type II:
Hyperlipoproteinaemia type II, by far the most
common form, is further classified into type IIa and type IIb, depending mainly
on whether there is elevation in the triglyceride level in addition to LDL
cholesterol.
Type IIa: This may be sporadic (due
to dietary factors), polygenic, or truly familial as a result of a mutation
either in the LDL receptor gene on chromosome 19
(0.2% of the population) or the ApoB
gene (0.2%). The familial form is characterized by tendon
xanthoma, xanthelasma and premature cardiovascular
disease. The incidence of this disease is about 1 in 500 for heterozygote, and
1 in 1,000,000 for homozygote.
Type IIb: The high VLDL levels are
due to overproduction of substrates, including triglycerides, acetyl CoA. They
may also be caused by the decreased clearance of LDL. Prevalence in the
population is 10%.Familial combined hyperlipoproteinemia (FCH) Secondary
combined hyperlipoproteinemia (usually in the context of metabolic syndrome, for which it is a
diagnostic criterion).
Hyperlipoproteinemia type III:
This form is due to high chylomicrons
and IDL (intermediate density lipoprotein). Also known as broad beta disease or dysbetalipoproteinemia, the most
common cause for this form is the presence of ApoE
E2/E2 genotype. It is due to cholesterol-rich VLDL (β-VLDL). Prevalence is
0.02% of the population.9
Fig:
1Diagram showing atherosclerotic blood vessel
1.
Narrowing of blood vessel
2.
Atherosclerotic plaque
3.
Endothelium of blood vessel
Fig: 2 Diagram showing high
blood cholesterol
CONCLUSION:
As per WHO reports concerned 29.2% of total global
deaths occurred due to the Coronary Heart Disease (CHD). Around 80% of CHD
deaths took place in low and middle income countries. At least 20 million
people survive heart attacks and strokes every year; many require continuing
costly clinical care. Heart disease has no geographic, gender, socio-economic
boundaries.
1. Devlin, T. (1995):
Textbook of biochemistry with clinical correlations, New York, Wiley - Liss
Inc, 3rd edition, pp.376-381.
2. Yan Feng, Xiumei
Hong, Elissa Wilker, Zhiping Li, Wenbin Zhang, Delai Jin, Xue Liu, Tonghua
Zang, Xiping Xu, and Xin Xu; Effects of
age at menarche, reproductive years, and menopause on metabolic risk factors
for cardiovascular diseases; Atherosclerosis. Feb 2008; 196(2) pp 590–597.
3. Claudio Rigatto, Patrick Parfrey; Factors
Governing Cardiovascular Risk In The Patient With A Failing Renal Transplant; Peritoneal Dialysis
International, June 2001;Vol. 21 (3), pp 275.
4. Olin B.R, Hebel S.K, Dombek C.E, Drug Facts and Comparisons. 2007
edition. pp- 57.
5. Simon C, Everitt H,
Kendrick T. Oxford Handbook of General Practice. 2nd edn. Oxford: Oxford
University Press, 2007: pp-324-325.
6. Axel K. Duwe; Depressed Natural Killer and Lecithin-Induced
Cell-Mediated Cytotoxicity in Cholesterol-Fed Guinea Pigs; journal of the
national cancer institute; 1984; 72(2): pp- 333-338.
7. Peter Libby; Review article Inflammation in atherosclerosis; Nature, December 2002; 420, pp-868-874.
8. Kumar A
& Sharma A Kumar; Ayurvedic Management Of High Cholesterol; Ayurveda;
December, 2009; 1(15); pp- 23-26.
9. Allain,
C.C., Poon, L.S. and Chen, C.S. Enzymatic determination of total serum
cholesterol, Clin Chem, 1974: 20, pp.470-475.
10. Murty,
M.K.M.Surulivel. and Manavalan, R. (2006): “The effect of hippophae rhamnoidis L fruit juice and rhododendron
arboreum flower juice mixture in rabbit
model of hyperlipidaemia”, pp. 1.
11. Tripathi, K.D.
(2003): Essentials of medical pharmacology, Jaypee brothers medical publishers
(P) LTD, New Delhi, 5th edn., pp. 575.
12. Inoue, M., Wu, C.Z.
and Ogihara, Y. (1999): “Antihyperlipidemic action of Ogi- Keishi-Gomotsu- To-
Ka- Kojin against
cyclophosphamide-induced hyperlipidemia in rabbits”, Biol Pharm Bull,
pp. 486.
13. Inoue, M. (2000):
Shosaikoto “as a potential antiatherosclerotic agent”, Drug News Perspect. pp.
407.
14.
Johnston,
T.P. (2004): “The P-407-induced murine model of dose-controlled
hyperlipidemia and atherosclerosis”, J Cardiovasc Pharmacol, pp. 595.
Received on 23.05.2010
Accepted on 12.06.2010
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Research J. Pharmacology and
Pharmacodynamics. 2(4): July-August 2010, 257-260