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Hypercholesterolaemia which is also known as high cholesterol is a disorder characterized by high levels of cholesterol in the bloodstream. Cholesterol can be classified as a fat-like or waxy substance that is naturally found in the walls of cells. Cholesterol is important for the formation of cell membranes and also manufacturing of some hormones such as estrogen and testosterone. Cholesterol is manufactured mainly in the liver and gets carried to cells throughout the body where it's needed for cell repair and other activities by low-density lipoprotein (LDL) which is often referred to as the "bad cholesterol". Cholesterol and other fats do not dissolve in water and as a result, cannot travel through the body unassisted. Lipoproteins are particles that are made in the liver to aid in the transportation of cholesterol and other fats through the bloodstream. Lipoproteins mainly consist of a central hydrophobic lipid core and surrounded by a hydrophilic coat. There are four main types of lipoproteins which are mainly dependent on their density and size. These are; the high density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), the very low-density lipoprotein (VLDL) and the chylomicrons1.
Triglycerides and cholesterol which are referred to as exogenous lipids are absorbed from our daily diets and transported as chylomicrons in the bloodstream to the adipose tissues and lymph to the muscles. The triglycerides are broken down to free fatty acids, glycerol and chylomicron remnants by the lipoprotein lipase (LPL) enzyme. The chylomicron remnants which still contain cholesterol esters are further transferred to the liver, and bind to receptors which are found on the hepatocytes. At this point, endocytosis takes place and the free cholesterol in the hepatocyte is oxidized to bile acids and then secreted in the bile2.
The hepatic cholesterol inhibits the synthesis and the expression of the lipoprotein lipase (LPL) receptor and this tends to reduce the removal low-density lipoprotein cholesterol and this further leads to hypercholesterolaemia. At this stage, the liver transports the newly synthesized triglycerides and cholesterol in the form as very low-density lipoprotein to the muscles and adipose tissues. The same mechanism as described above is used to break down the triglycerides.
After the breaking down of triglycerides, the very low density lipoprotein (VLDL) reduces in its size but the full complement of cholesterol esters are retained. There is an increase in size of the very low-density lipoprotein (VLDL) to intermediate density lipoprotein (IDL) cholesterol; this is then increased further to become low-density lipoprotein cholesterol (LDL-C). Low-density lipoproteins cholesterol (LDL-C) acts as the main source of cholesterol that is needed in the cell membrane but also it's vital in the synthesis of steroids. The relatively long half-life of low-density lipoproteins (LDL) in the plasma (1.5-2days) keeps the exposed longer to oxidative stimuli and become atherogenic2.
High-Density Lipoproteins (LDL) which is often referred to as the "good cholesterol" consist of a small amount of fat but mostly protein. The main aim of the high-density lipoprotein cholesterol (HDL-C) is to assist in the clearance of cholesterol from the body, and does this by returning excess cholesterol from cells and carrying them back to the liver for disposal. Having a low level of high-density lipoprotein cholesterol (HDL-C) often tends increase the risk of having a coronary artery disease and other forms of atherosclerotic disease. High levels of high-density lipoprotein cholesterol (HDL-C) help protect against heart disease.
The rate limiting enzyme in cholesterol synthesis is the 3-Hydroxy-3-methylglutaryly-coenzyme A (HMG-CoA) reductase. This enzyme (HMG-CoA) catalyzes the conversion of HMG-CoA to mevalonic acid. Mevalonic acid is the precursor for cholesterol and many other vital non-steroidal compounds which are involved in the mevalonate pathway. The synthesis of cholesterol by HMG-CoA reductase is reduced as cholesterol in the liver inhibits the synthesis of low-density lipoprotein (LDL) receptor 6.
Figure 1. Mevalonate Pathways.
In hypercholesterolaemia, low concentration of high-density lipoproteins (HDL) or high concentration of low-density lipoproteins (LDL) causes deposits or plaques of lipids, mostly cholesterol in blood vessels. These deposits or plaques represent the first stage of atherosclerosis. Build-up of these plaques often tends to block blood supply to the organs and congests blood vessels. The narrowing and hardening of blood vessels often leads to ischemic cerebrovascular disease, coronary heart disease and peripheral vascular disease. Therapies that seem to lower the levels of low-density lipoproteins (LDL) and raise the levels of high-density lipoprotein (HDL) have been shown to reduce the progression of coronary atherosclerosis 5.
Alcohol, diet, smoking, exercise and certain illnesses such as kidney diseases and liver diseases can also affect the levels of both types of cholesterol. Also hereditary is another factor that tends to affect cholesterol levels, if the inherited cholesterol levels are very high, this is known as familial hypercholesterolaemia (FH).
Since hypercholesterolaemia causes no symptoms, precautionary measures and regular measurement of cholesterol levels are important for people in high-risk categories. A high fat diet will increase the levels of low-density lipoprotein cholesterol within the body and on the other hand lots of exercise and weight reduction tends to increase the levels of high-density lipoprotein cholesterol whilst lowering the levels of low-density lipoprotein cholesterol 5.
Atorvastatin belongs to the group of drugs known as statins and are HMG-CoA reductase inhibitors. It mainly aids in the reduction of myocardial infarction, angina and stroke in patients who are at risk of coronary artery disease such as familial hypercholesterolaemia and dyslipidaemia6. Atorvastatin is an orally administered drug that comes in the form of 10mg, 20mg, 40mg and 80mg film coated tablet7. Atorvastatins are effective in reducing the total levels of cholesterol and low-density lipoproteins within the body.
Figure 2. Chemical Structure of Atorvastatin
Mechanism of action:
Atorvastatin is a selective competitive inhibitor which blocks the synthesis of cholesterol in the liver by inhibiting the 3-Hydroxy-3-methylglutaryly-coenzyme A (HMG-CoA) reductase in the hepatocytes. After competing with rate limiting enzyme (HMG-CoA), atorvastatin changes the shape of the active site of the HMG-CoA and thus prevent it from achieving its functional structure. This mechanism of action makes atorvastatin a specific and effective drug for the reduction of dyslipidaemia and hypercholesterolaemia in the prevention of any form of atherosclerosis and the management of any associated rick factors. The inhibition of HMG-CoA reductase also causes reduction of intracellular cholesterol and this induces the activation of protease, this then increases the gene expression of low-density lipoprotein (LDL) receptors which are found on the hepatocyte and hence causes a decrease in the concentration of low-density lipoprotein (LDL) cholesterol in the plasma6.
Recommended dose of Atorvastatin
The daily recommended dose of atorvastatin in the treatment of hypercholesterolaemia and combined dyslipidaemia is 10mg once daily which may be increased at intervals of at least four weeks to a maximum of 80mg once daily3.
After administration, the commonest possible side effects of atorvastatin include; headaches, pain, muscle aches, and constipation6.
Ezetimibe is an orally administered drug that comes in the form of 10mg tablet. Ezetimibe is known as a cholesterol absorption inhibitor. Ezetimibe is mainly taken to help in lowering the levels of cholesterol.
Figure 3. Chemical Structure of Ezetimibe.
Mechanism of Action
The mode of action of Ezetimibe is by blocking Neimann-Pick C1 like 1 (NPC1L1) protein, this protein is plays a vital role in the absorption of cholesterol from the small intestines into the bloodstream. It also helps prevent cholesterol and any form of plant sterols which are consumed in diet from also being absorbed back into the bloodstream. Ezetimibe inhibits the reabsorption of cholesterol that is released from the bile duct into the intestine from being reabsorbed back into the bloodstream7.
Ezetimibe could be used on its own to aid in the reduction of cholesterol in patient with hypercholesterolaemia who can't take statins. It could also be used in conjunction with statins to reduce cholesterol levels in patient with familial hypercholesterolaemia7.
Recommended Dose of Ezetimibe
The recommended daily dose for Ezetimibe in the treatment of hypercholesterolaemia is 10mg once daily both in an adult and a child over the age of 10 years8.
Possible side effects after administration of Ezetimibe include; pain in muscles or joints, headache, fatigue, nausea and diarrhoea8.
Hypercholesterolaemia is a condition of abnormal high levels of cholesterol in the bloodstream. Hypercholesterolaemia could lead to atherosclerosis; which is where plaques or deposits of cholesterol blocks and narrows the blood vessels. Atorvastatin helps reduce the levels of low-density lipoprotein (LDL) in the bloodstream and hence reduces atherosclerosis. Atorvastatin also increase the levels of high-density lipoprotein (HDL) in the bloodstream. It is effective for the treatment and/or prevention of cardiovascular diseases such as heart attack, angina, stroke and hypertension. Ezetimibe is also a lipid lowering drug that mainly inhibits the absorption of dietary cholesterol and not fat soluble vitamins from the small intestines.