ROLE OF STATINS IN CORONARY ATHEROSCLROSIS

Introduction Cardiovascular disease (CVD) is one of the leading causes of death worldwide. The prevalence of CVD has increased dramatically over the past 100 years, and this disease will remain a major health concern, even under the most optimistic scenarios.13 The emergence of CVD as a major public health problem during the 1940s initiated research to understand the factors associated with this disease.

Projects such as the Framingham Heart Study were launched to find common biochemical, environmental, and behavioral factors or characteristics that contribute to CVD.4 As a result, several conditions, such as hypertension, obesity and diabetes, were identified and are commonly used today to detect and treat individuals at risk. CHD now leads to more death and disability in lowand middle-income countries, such as India, with rates that are increasing disproportionately (16% out of a total of 10.3 million deaths WHO 2009) compared to high-income countries and it affects people at younger ages and their Lifestyle changes in low-income and middle-income countries have

resulted in an increased prevalence of obesity and diabetes and, therefore, higher rates of CVD.5

Current recommendations for the treatment of CVD aim to reduce modifiable risk factors, such as high levels of LDL cholesterol.6 However, environmental and genetic effects can only explain a small part of the variability in CVD risk, even for well-established risk factors.7 New knowledge is needed, therefore, to find more efficacious and cost-effective preventive and therapeutic approaches.8

SYMPTOMS: Angina[9] is often the first symptom of coronary heart disease If your coronary arteries become partially blocked, the compromised blood flow to the heart muscle can cause angina. If they become completely blocked, a heart attack (myocardial infarction) occurs. Angina is a term used for a number of symptoms caused by compromised coronary blood flow. Not all heart attacks are preceded by chest pain Most people experience angina as chest pain, and chest pain should always be considered a warning sign as it commonly precedes heart attacks. Some heart attacks however occur without chest pain, especially in the elderly and those with diabetes. These are referred to as silent heart attacks. Angina comes in many forms Although angina, in the form of chest pain, is the most common symptom of a heart attack, some people experience angina differently. Angina can also be a mild, uncomfortable feeling that is similar to indigestion. A severe angina attack can cause a feeling of heaviness or tightness, usually in the centre of the chest, which may spread to the arms, neck, jaw, back or stomach. Angina is often triggered by physical activity or emotionally stressful situations. Symptoms of heart attack in women can be different than in men Symptoms of heart attack in women are often different than in men. Although women also experience chest pain, they are somewhat more likely than men to have some of the other common symptoms of angina, particularly shortness of breath, nausea and vomiting, and back or jaw pain.

RISK FACTORS

Coronary heart disease[10] may start as early as in childhood, the build-up of plaque within coronary arteries that is characteristic of coronary heart disease, may start as early as in childhood. This means that people may have this slowly progressive disease for a long time without knowing it. Atherosclerosis is the disease process that narrows the coronary arteries, Coronary artery disease starts when certain factors damage the inner layers of the coronary arteries. When damage occurs, the body starts a healing process. Excess fatty tissues release compounds that promote this process. This healing causes fatty substances to accumulate where the arteries are damaged. Over time, this fatty build-up (plaque) can narrow or completely block some the coronary arteries, a disease process known as atherosclerosis. Studies of large populations over several decades have revealed a number of risk factors for coronary heart disease and heart attacks. Some of these cannot be modified (such as age, gender, and family history or genetics), whereas others can. The more risk factors you have, the greater chance you have of developing coronary heart disease and having a heart attack. Many risk factors for coronary heart disease[11] can be changed Knowing your risk is the first step towards preventing coronary heart disease and heart attack. While some risk factors cannot be changed, the good news is that there are many you can change. Assessing your overall risk, is most important when planning your preventive actions. Risk factors that cant be changed Age. The risk of heart attack increases with age. The average age of a first heart attack is about 66 years for men and 70 years for women in the United States. Gender. Men are at a higher risk than women. Ethnicity. Certain ethnic groups have increased risk of known contributors to coronary heart disease. For example, African Americans have a higher risk of developing high blood pressure, a recognized risk factor for coronary heart disease and heart attack.

Genetics. Family history is one of the major risk factors for coronary heart disease and heart attacks, and common genetic variants have been found that are associated with increased risk. For men, the likelihood of developing atherosclerosis is increased if they have a close family member (father or brother) who has had a heart attack or angina before the age of 55. For women, the risk is increased if they have a close family member (mother or sister) who has had a heart attack or angina before the age of 65. Risk factors that you can change Smoking is a major risk factor for coronary heart disease[12]. Chemicals in cigarette smoke damage the inner lining of the coronary arteries, which can trigger faster buildup of fatty material within the artery walls. Around 20% of coronary heart disease-related deaths are attributable to smoking. High Cholesterol. Cholesterol is made by the liver from the saturated fat that we eat. Cholesterol is necessary for healthy cells, but if there is too much cholesterol in the blood it can lead to coronary heart disease. There are different types of cholesterol. The most important types are called LDL and HDL. LDL is often referred to as bad cholesterol and HDL as the good cholesterol. LDL cholesterol tends to accumulate on the inside of the coronary artery walls, increasing risk of coronary heart disease, whereas HDL reduces the risk of fatty buildup within arteries because it carries cholesterol away from the cells and back to the liver. If the total cholesterol in the blood reaches a level above 6 mmol/L (millimoles cholesterol per liter of blood) equivalent to 240 mg/dL (milligrams cholesterol per deciliter of blood), the blood cholesterol level is considered to be high, and a risk factor for coronary heart disease. The American Heart Association recommends a target total blood cholesterol level of less than 5 mmol/L or below 200 mg/dL. High blood pressure or hypertension puts a strain on the heart and can lead to coronary heart disease. High blood pressure is defined as a systolic pressure of 140mmHg or more, or a diastolic pressure of 90mmHg or more. Obesity. People who have excess body fat, especially around the waist, are more likely to develop coronary heart disease, even if they have no other risk factors. Excess weight raises blood pressure and LDL cholesterol and lowers HDL choloesterol levels. It can also increase the risk of developing Type 2 diabetes. Studies have shown that losing even as few as 10 pounds (5 kg) reduces the risk of coronary heart disease.

Diabetes seriously increases the risk of developing coronary heart disease, even when blood sugar levels are under control. The risk becomes even greater if blood sugar is not well controlled. People who are obese or overweight can often control blood sugar by losing weight, but should always discuss management of blood sugar with their doctor. Lack of exercise is a risk factor for coronary heart disease. Regular, moderateto-vigorous physical activity can help control blood cholesterol, diabetes and obesity, as well as help lower blood pressure in some people. Treatments : Statins (HMG-CoA reductase inhibitors[13] are a class of medicines that are frequently used to treat coronary heart disease.Statins inhibit an enzyme called HMG-CoA reductase, which controls cholesterol production in the liver. These drugs are able to block the action of an enzyme (HMG COA Reductase) in the liver that is necessary for making cholesterol. Although cholesterol is necessary for normal cell and body function, very high levels of it can lead to atherosclerosis, a condition where cholesterol-containing plaques build up in arteries and block blood flow. The medicines actually act to replace the HMG-CoA that exists in the liver, thereby slowing down the cholesterol production process. Additional enzymes in the liver cell sense that cholesterol production has decreased and respond by creating a protein that leads to an increase in the production of LDL (low density lipoprotein, or "bad" cholesterol) receptors. These receptors relocate to the liver cell membranes and bind to passing LDL and VLDL (very low density lipoprotein). The LDL and VLDL then enter the liver and digested. Many people who begin statin treatment do so in order to lower their cholesterol level to less than 5 mmol/l, or by 25-30%. The dosage may be increased if this target is not reached. Treatment with the statin usually continues even after the target cholesterol level is reached in order to sustain atherosclerosis prevention, By reducing blood cholesterol levels, statins lower the risk of chest pain (angina), heart attack, and stroke.

Mechanism Statins are a competitive antagonists of HMG CoA, as they directly compete with the endogenous substrate for the active site cavity of HMGR. Statins are also noncompetitive with the cosubstrate NADPH (nicotinamide adenine dinucleotide phosphate).[18] By blocking the HMGR enzyme they inhibit the synthesis of cholesterol via the mevalonate pathway. The end result is lower LDL (Low Density Lipoprotein), TG (Triglycerides) and total cholesterol levels as well as increased HDL (High Density Lipoprotein) levels in serum).[15][16][17]
Interactive pathway map

Statin Pathway

Statin drug design The ideal statin should have the following properties:[20]

High affinity for the enzyme active site Marked selectivity of uptake into hepatic cells compared with nonhepatic cells Low systemic availability of active inhibitory equivalents Relatively prolonged duration of effect.

One of the main design objectives of statin design is the selective inhibition of HMGR in the liver, as cholesterol synthesis in non-hepatic cells is needed for normal cell function and inhibition in non-hepatic cells could possibly be harmful.[21]
[edit] The statin pharmacophore

Fig 1. The statin pharmacophore

The essential structural components of all statins are a dihydroxyheptanoic acid unit and a ring system with different substituents. The statin pharmacophore is modified hydroxyglutaric acid component, which is structurally similar to the endogenous substrate HMG CoA and the mevaldyl CoA transition state intermediate (Figure 1). The statin pharmacophore binds to the same active site as the substrate HMG-CoA and inhibits the HMGR enzyme. It has also been shown that the HMGR is stereoselective and as a result all statins need to have the required 3R,5R stereochemistry.[22]

Differences in statin structure The statins differ with respect to their ring structure and substituents. These differences in structure affect the pharmacological properties of the statins, such as:[20]

Affinity for the active site of the HMGR Rates of entry into hepatic and non-hepatic tissues Availability in the systemic circulation for uptake into non-hepatic tissues Routes and modes of metabolic transformation and elminination

Fig.2 Lovastatin, a type 1 statin

Fig.3 Fluvastatin, a type 2 statin

Types of Statins Statins have sometimes been grouped into two groups of statins according to their structure.[23] Type 1 statins Statins that have substituted decalin-ring structure that resemble the first statin ever discovered, mevastatin have often been classified as type 1 statins due to their structural relationship. Statins that belong to this group are:[10]

Lovastatin (Figure 2) Pravastatin Simvastatin

Type 2 statins Statins that are fully synthetic and have larger groups linked to the HMG-like moiety are often referred to as type 2 statins. One of the main differences between the type 1 and type 2 statins is the replacement of the butyryl group of type 1 statins by the fluorophenyl group of type 2 statins. This group is responsible for additional polar interactions that causes tighter binding to the HMGR enzyme. Statins that belong to this group are:[23]

Fluvastatin (Figure 3) Cerivastatin Atorvastatin Rosuvastatin

Lovastatin is derived from a fungus source and simvastatin and pravastatin are chemical modifications of lovastatin and as a result do not differ much in structure from lovastatin.[21] All three are partially reduced napthylene ring structures. Simvastatin and lovastatin are inactive lactones which must be metabolized to their active hydroxy-acid forms in order to inhibit HMGR.[21] Type 2 statins all exist in their active hydroxy-acid forms. Fluvastatin has indole ring structure, while atorvastatin and rosuvastatin have pyrrole and pyrimidine based ring structure respectively. The lipophilic cerivastatin has a pyridine-based ring structure. Structure-activity relationship (SAR) All statins have the same pharmacophore so the difference in their pharmacodynamic effect is mostly based on the substituents. The activity of each statin is dependent on the binding affinity of the compound for the substrate site and the length of time it binds to the site.[18] Type 2 statins have unique fluorophenyl group that causes additional polar interaction between the

enzyme and the statins, which results in a tighter binding to the enzyme. The newest statin, rosuvastatin has a unique polar methane sulfonamide group, which is quite hydrophilic and confers low lipophilicity. The sulfonamide group forms a unique polar interaction with the enzyme. As a result rosuvastatin has superior binding affinity to the HMGR enzyme compared to the other statins, which is directly related to its efficiency to lower LDL cholesterol.[20] Lipophilicity Lipophilicity of the statins is considered to be quite important since the hepatoselectivity of the statins is related to their lipophilicity. The more lipophilic statins tend to achieve higher levels of exposure in non-hepatic tissues, while the hydrophilic statins tend to be more hepatoselective. The difference in selectivity is because lipophilic statins passively and nonselectively diffuse into both hepatocyte and non-heptatocyte, while the hydrophilic statins rely largely on active transport into hepatocyte to exert their effects.[18][26] High hepatoselectivity is thought to translate into reduced risk of adverse effects.[21] It has been reported that the organic anion transporting polypeptide (OATP) is important for the hepatic uptake of hydrophilic statins such as rosuvastatin and pravastatin.[18][26] OATP-C is expressed in liver tissue on the basolateral membrane of hepatocytes and is considered to be a potential contributor for the low IC50 for rosuvastatin in hepatocytes. Of the marketed statins, cerivastatin was the most lipophilic and also had the largest percentage of serious adverse effects due to its ability to inhibit vascular smooth muscle proliferation and as a result was voluntarily removed from the market by the manufacturer.[18] Metabolism All statins are (metabolized) by the liver, which causes their low systemic bioavailability.[27] Lovastatin and simvastatin are administered in their lactone forms, which is more lipophilic than their free acid forms, and therefore they have to be activated by hydrolysis to the active anionic carboxylate form.[22][27] Cytochrome P450(CYP) isoenzymes are involved in the oxidative metabolism of the statins, with CYP3A4 and CYP2C9 isoenzymes being the most dominant. CYP3A4 isoenzyme is the most predominant isoform involved in metabolism of lovastatin, simvastatin, atorvastatin and cerivastatin.[22][27] CYP2C9 isoenzyme is the most predominant isoform involved in metabolism of Fluvastatin, but CYP3A4 and CYP2C8 isoenzymes also contribute to the metabolism of Fluvastatin.[27]

Rosuvastatin is metabolized to a small degree by CYP2C9 and to a lesser extent by CYP2C19 isoenzymes. Pravastatin is not metabolized by CYP isoenzymes to any appreciable extent.[20][22][27] The statins that have the ability to be metabolized by multiple CYP isoenzymes may therefore avoid drug accumulation when one of the pathways is inhibited by co-administered drugs.[27] Properties of Statins

Several types of statins exist such as atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin. Atorvastatin and rosuvastatin are the most potent, while fluvastatin is the least potent. These medicines are sold under several different brand names including Lipitor (an atorvastatin), Pravachol (a pravastatin), Crestor (a rosuvastatin), Zocor (a simvastatin), Lescol (a fluvastatin) and Vytorin (a combination of simvastatin and ezetimibe). Mevastatin is a naturally occurring statin that is found in red yeast rice. Statins differ in several ways. The most obvious difference is in their ability to reduce cholesterol. Currently, atorvastatin (Lipitor) and rosuvastatin (Crestor) are the most potent, and fluvastatin (Lescol) is the least potent. The statins also differ in how strongly they interact with other drugs. Specifically, pravastatin (Pravachol) and rosuvastatin (Crestor) levels in the body are less likely to be elevated by other drugs that may be taken at the same time as the statins. This is so because the enzymes in the liver that eliminate pravastatin and rosuvastatin are not blocked by many of the drugs that block the enzymes that eliminate other statins. Statins differ in the frequency with which they cause a severe type of myopathy called rhabdomyolysis, in which muscles are severely damaged. Cerivastatin (Baycol) was withdrawn from pharmacies worldwide because it caused rhabdomyolysis 10 to 100 times more often than other statins. Rhabdomyolysis may occur more often in patients taking statins with drugs that also cause rhabdomyolysis or drugs that increase the blood concentration of the statin. The most serious (but fortunately rare) side effects are liver failure and rhabdomyolysis. Rhabdomyolysis is a serious side effect in which there is damage to muscles. Rhabdomyolysis often begins as muscle pain and can progress to loss of muscle cells, kidney failure, and death.

ACTION OF STATINS: Statins have some important drug interactions. The first type of interaction involves the enzymes responsible for the elimination of statins[13] by the liver. Liver enzymes (specifically, the cytochrome P-450 liver enzymes) are responsible for eliminating all statins from the body with the exception of pravastatin and rosuvastatin. Therefore, drugs that block the action of these liver enzymes increase the levels of simvastatin, lovastatin, fluvastatin, and atorvastatin (but not pravastatin or rosuvastatin) in the blood and can lead to the development of rhabdomyolysis. Drugs or agents that block these enzymes include:

protease inhibitors (used in treating AIDS), erythromycin, itraconazole, (Sporanox) clarithromycin, (Biaxin) diltiazem, (Cardizem, Dilacor, Tiazac) verapamli (Calan, Verelan, Verelan PM, Isoptin, Isoptin SR, Covera-HS).

Conclusion: Preclinical and clinical studies have demonstrated that statins reduces the CVD risk,. An increased understanding of Statin mechanisms and their pleiotropic effects may lead to the development of novel and targeted CVD therapies that act at the risk-factor level, as well as directly on the vascular system.

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