High cholesterol or Hypercholesterolemia is a popular condition in todays society where it is one of the major contributors to atherosclerosis and coronary heart disease. Varies people from different countries, cultures, age and gender can suffers from hypercholesterolemia. Having Hypercholesterolemia is not easy to detect visually and one must therefore undergo physical examination and laboratory testing to be diagnosed with hypercholesterolemia. There are varies treatments of hypercholesterolemia and they all have the same goal: to lower the risk for atherosclerotic heart disease.
Dyslipidaemia is a disorder of lipoprotein metabolism leading to abnormal concentrations of lipoproteins, overproduction or deficiency. High concentrations of low density lipoproteins (LDLs) often called the "bad" cholesterol or low concentrations of high- density lipoproteins (HDLs) often called the "good" cholesterol can cause deposition of lipids in blood vessels on the intimal layer.  The result is atherosclerosis which is hardening of blood vessels from a build-up of plague. The formation of plague occurs when damage to endothelium causes macrophages to ingest oxidised LDL in the blood and turn them into foam cells. These cells aggregate inducing the formation of athermanous plague consisting of fibrous tissue and smooth muscle cells covering the core of lipids and necrotised debris. This cause the lumens of blood vessels to narrow blocking or slowing the blood supply to the tissues.  Atherosclerosis can then cause several diseases, such as coronary heart disease, ischemic cerebrovascular disease or peripheral vascular disease. 
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4Figure 1.Comparison of a normal artery with an artery narrowed by atherosclerosis.
Hypercholesterolemia is elevated levels of cholesterol in the blood. There are two groups of hypercholesterolemia, nonfamilies (Non-inherited) hypercholesterolemia which can develop depending on the individual's life style and diet, the excessive intake of saturated fat and the lack of exercise. Familial hypercholesterolemia which is an inherited genetic disorder, where there is a defect of low- density (LDL) receptors that are responsible for removing cholesterol from the blood.
Lipids and cholesterol are the essential building blocks of every cell. To aid the transportation of the lipids in the bloodstream, complexes of lipids and protein are formed known as lipoproteins. These consist of a lipophilic lipid central core (including triglycerides and cholesteryl esters) encased in hydrophilic coat of polar phospholipids, free cholesterol and apoproteins. The structural stability is provided by apoproteins which act as ligands for lipoprotein receptors. The binding of the apoprotein to the receptors mediate uptake of lipoprotein particles into the liver, blood or other tissues. 
6Figure 2. Lipoprotein structure: The core consisting of triglycerides and cholesteryl esters, the coat consisting of polar phospholipids, free cholesterol and apoproteins.
Lipoproteins are important because they can transport different components throughout the body, such as cholesterol. There are different types of lipoproteins, the one related to hypercholesterolemia is known as very low- density lipoprotein (VLDL). The liver releases VLDL into the system and it circulate throughout the body to interact with an enzyme called lipoprotein lipase (LPL) presents in the capillaries. This enzyme will remove triglycerides from VLDL and the composition of the VLDL molecule will now change to intermediate- density lipoprotein (IDL). When the cholesterol content eventually become greater than the content of triglyceride because of the constant removal of triglycerides, IDL will then be converted to low- density lipoprotein (LDL). This low density lipoprotein is known as the "bad" cholesterol.  The LDL will be taken up via the LDL receptors present on the membrane of hepatocyte cells in the liver. 
Pharmacotherapy of hypercholesterolemia
Before starting a drug therapy for patient with hypercholesterolemia, lifestyle changes must be the first line of treatment. Lifestyle modification such as reduction of saturated fat intake and increased aerobic exercise has shown decreased level in LDL- cholesterol ( bad- cholesterol) and increased level in HDL- cholesterol (good - cholesterol). 
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If lifestyle changes are not effective then second line of treatment must be considered. The use of drug therapy such as statins in combination with diet and exercise is the second line of treatment. Atorvastatin is used at lower doses than Simvastatin for treating severe hypercholestermia. 
Atorvastatin (Endogenous pathway)
Atorvastatin is a selective, competitive and reversible long-lasting inhibitor for the rate- limiting enzyme in cholesterol synthesis. This enzyme is called 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, and is responsible for catalysing the conversion of HMG-CoA to mevalonate. The inhibition of the enzyme HMG- CoA reductase will decrease the biosynthesis of cholesterol. The low-density lipoprotein receptor synthesis is up-regulated by decreased hepatic cholesterol synthesis. The increased number of LDL receptors on the surface of liver cells (hepatocyte cells) causes the uptake of LDL into the cell from plasma. Hypercholesterolemia is elevated levels of cholesterol in the blood and it is reduced due to the uptake of LDL into the liver cell where it will be broken down and excreted via urine. 
12Figure 3. Endogenous pathway: Statins decreases the synthesis of Cholesterol by inhibiting the HMG CoA reductase enzyme. That also increases the uptake of LDL from plasma into the cells by the up-regulation of LDL receptor synthesis due to decreased hepatic cholesterol synthesis.
Atorvastatin is used in patients with high level of cholesterol due to homozygous familial hypercholesterolemia.  Patients with heterozygous familial hypercholesterolemia may have severe drug-resistant dyslipidaemia and have therefore to be treated with Ezetimibe in combination with statins and life style modifications. 
Ezetimibe (Exogenous pathway)
The lumen of the small intestine contains dietary and biliary cholesterol that is packed into micelles known as "chylomicrons". These chylomicrons will diffuse across a thin mucus layer to the surface of the intestinal enterocytes cells. As soon as the chylomicron reaches the enterocytes cells, the cholesterol will be released to pass through the mucosal membrane of the enterocyte. The transporter that is responsible for passing cholesterol through the mucosal membrane is located in the brush border of the membrane and it is known as Niemann- Pick C1-Like 1 (NPC1L1).
Administration of Ezetimibe which is used as lipid lowering compound by selectively inhibiting the intestinal absorption of cholesterol is thought to reduce the hepatic cholesterol. It targets the sterol transporter, Niemann-Pick C1-Like 1 (NPC1L1) which is responsible for the uptake of cholesterol to the intestine preventing biliary and dietary cholesterol from entering the bloodstream. When less cholesterol enters the bloodstream less cholesterol is delivered to the liver. That causes the reduction of hepatic cholesterol stores and increased clearance of cholesterol from the blood. The choice of combination of statins which reduces cholesterol synthesis in the liver with Ezetimibe will therefore provide a complementary cholesterol reduction.
Benefits of Atorvastatin and Ezetimibe
The use of Atorvastatin prevents atherosclerosis which develops due to high levels of LDLs. Oxidised Low density- lipoproteins are ingested by macrophages and form foam cells. The aggregation of foam cells in blood vessels on the intimal layer form plague, hardening of blood vessels resulting in atherosclerosis. The use of statins will inhibit the enzyme HMG- CoA reductase that will decrease the biosynthesis of cholesterol and also up regulate the low-density lipoprotein receptor synthesis by decreased hepatic cholesterol. Prevention of atherosclerosis lowers the risk of developing coronary heart disease, ischemic cerebrovascular disease or peripheral vascular disease.
A Study has been showing that the use of statins such as atorvastatin in patients without recognised cardiovascular disease but with cardiovascular risk factors was associated with significantly improved survival and large reductions in the risk of major vascular diseases. 
A clinical trial was about men and women who already had angina or a previous myocardial infraction and was receiving statins for 5 years. It was proven that the drug was effective in producing beneficial changes in blood lipid and therefore reducing the risk of non-fatal myocardial infarction or death from coronary heart disease. 
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