Cholesterol.

Cholesterol

Outline What is cholesterol? Drugs to reduce cholesterol Synthesis
Functions Lipoproteins Drugs to reduce cholesterol Statins Bile-Acid Sequestrants Niacin (Nicotinic Acid) Fibric Acid Derivatives Ezetimibe and the Inhibition of Dietary Cholesterol

What is cholesterol? Waxy, fat-like substance Steroid alcohol (sterol)
Found in all cells of the body 75% of cholesterol is synthesized 25% comes from diet

Cholesterol synthesis
Synthesized primarily in the liver Occurs in the cytoplasm and ER The HMG-CoA Reductase reaction is rate-limiting Highly regulated Target of pharmaceutical intervention Very complex process involving over 30 enzymes Small amounts are synthesized by the lining of the small intestine and the individual cells of the body

Triparanol, which inhibits a late step in the pathway, was introduced into clinical use in the mid-1960s, but was withdrawn from the market shortly after because of the development of cataracts and various cutaneous adverse effects. [6] These side effects were attributable to tissue accumulation of desmosterol, the substrate for the inhibited enzyme. It’s actually what is turned into cholesterol.

Functions of Cholesterol
Cell membranes Sex hormones Hormones released by the adrenal glands Production of bile acids Vitamin D Builds and maintains cell membranes Plays a role in cell membrane permeability The –OH interacts with the polar head groups of membrane phospholipids and sphingolipids while the bulky steroid and the hydrocarbon chain are embedded in the membrane. This increases membrance packing and reduces membrane fluidity to things such as neutral solutes, protons and sodium ions. Involved in the production of sex hormones progesterone, estrogen and testosterone Essential for the production of hormones released by the adrenal glands such as cortisol (increases blood sugar through gluconeogenesis and aids in fat, protein and carbohydrate metabolism) and aldosterone (helps control blood pressure by regulating sodim and potassium levels) Aids in the production of bile acids that work to digest food in the intestines Insulates nerve fibers Cholesterol is involved in the process of synthesizing vitamin D from sunlight

Dangers of High Cholesterol Levels
Atherosclerosis Increased coronary heart disease risk Heart attack Angina Stroke High cholesterol levels can cause: Atherosclerosis - narrowing of the arteries. Higher coronary heart disease risk - an abnormality of the arteries that supply blood and oxygen to the heart. Heart attack - occurs when the supply of blood and oxygen to an area of heart muscle is blocked, usually by a clot in a coronary artery. This causes your heart muscle to die. Angina - chest pain or discomfort that occurs when your heart muscle does not get enough blood. Other cardiovascular conditions - diseases of the heart and blood vessels. Stroke and mini-stroke - occurs when a blood clot blocks an artery or vein, interrupting the flow to an area of the brain. Can also occur when a blood vessel breaks. Brain cells begin to die. For stroke and heart attack: the plaques that build up in the arteries can rupture and travel through the bloodstream. If they get stuck in the coronary artery this can result in a heart attack. If they get stuck in the carotid artery, this can cause a stroke.

Lipoproteins Chylomicrons Very low density lipoproteins (VLDL)
Intermediate-density lipoproteins (IDL) Low density lipoproteins (LDL) High density lipoproteins (HDL) Cholesterol is insoluble in blood so it is transports in the circulatory system within lipoproteins Because lipids are oil-based and blood is water-based, they don't mix. If cholesterol were simply dumped into your bloodstream, it would congeal into unusable globs. To get around this problem, the body packages cholesterol and other fats into minuscule protein-covered particles called lipoproteins (lipid + protein) that do mix easily with blood. The proteins used are known as apolipoproteins. Lipoproteins: contain a lipid and a protein Lower the density: more fat:protein ratio is increased LDL (low density lipoprotein) - people often refer to it as bad cholesterol. LDL carries cholesterol from the liver to cells. If too much is carried, too much for the cells to use, there can be a harmful buildup of LDL. This lipoprotein can increase the risk of arterial disease if levels rise too high. Most human blood contains approximately 70% LDL - this may vary, depending on the person. HDL (high density lipoprotein) - people often refer to it as good cholesterol. Experts say HDL prevents arterial disease. HDL does the opposite of LDL - HDL takes the cholesterol away from the cells and back to the liver. In the liver it is either broken down or expelled from the body as waste. Chylomicrons carry triglycerides (fat) from the intestines to the liver, to skeletal muscle, and to adipose tissue. Very-low-density lipoproteins (VLDL) carry (newly synthesised) triglycerides from the liver to adipose tissue. Intermediate-density lipoproteins (IDL) are intermediate between VLDL and LDL. They are not usually detectable in the blood. Low-density lipoproteins (LDL) carry cholesterol from the liver to cells of the body. LDLs are sometimes referred to as the "bad cholesterol" lipoprotein % of cholesterol is carried in LDL particles. They play an important role in your body, however, they become a problem if there is more LDL thean required for normal functions. High-density lipoproteins (HDL) collect cholesterol from the body's tissues, and take it back to the liver. HDLs are sometimes referred to as the "good cholesterol" lipoprotein. Lipoproteins. The insolubility of cholesterol and TG in plasma requires that they are transported in sphe - roidal macromolecules called lipoproteins, which have a hydrophobic core containing phospholipid, fat- soluble antioxidants and vitamins, and cholesteryl ester, and a hydrophilic coat that contains free cholesterol, phospholipid and apolipoprotein molecules. The main TG carrying lipoproteins are chylomicron (CM) and very low-density lipoprotein (VLDL). The main cholesterol- carrying lipoproteins are low-density lipoprotein (LDL) and high-density lipoprotein (HDL) Class % Protein % Cholesterol % Phospholipid % Triglyceride Chylomicrons <2 8 7 84 VLDL 10 22 18 50 IDL 29 31 LDL 25 21 HDL 33 30 4

Apolipoproteins Six major classes A, B, C, D, E and H Apolipoprotein
Site of Synthesis Function(s) ApoA-I Liver, intestine Structural in HDL; reverse cholesterol transport ApoA-V Liver Modulates triglyceride incorporation into hepatic VLDL ApoB-100 Structural protein of VLDL, IDL, LDL ApoB-48 Intestine Structural protein of chylomicrons ApoE Liver, brain, skin, gonads, spleen

Chylomicron C: cholesterol T: triglyceride Green: phospholipids
ApoA,B,C,E: apolipoproteins

Triglyceride, LDL and HDL Metabolism
The main lipids in lipoproteins are free and esterified cholesterol (C) and triglyceride (TG). The metabolism of TG, low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol is shown. In TG metabolism, hydrolysed dietary fats enter intestinal cells (enterocytes) via fatty acid (FA) transporters. Reconstituted TG is packaged with C ester and the apolipoprotein B (APOB) isoform B48 into chylomicrons (CMs) by microsomal TG-transfer protein (MTTP) through a vesicular pathway. CMs, secreted via the lymphatic system, enter the vena cava and circulate until they interact with lipoprotein lipase (LPL), the secretion of which depends on lipase-maturation factor 1 (not shown), and which is secured to endothelium by proteoglycans and glycosylphosphatidylinositol-anchored HDL-binding protein 1 (not shown). CMs contain apoliproteins, including APOA5 (A5), APOC2 (C2) and APOC3 (C3). Released free FAs incompletely enter peripheral cells. In adipocytes, enzymes including acyl CoA:diacylglycerol acyltransferase (DGAT) resynthesize TG, which is hydrolysed by adipose TG lipase (ATGL) and hormone sensitive lipase (HSL). CM remnants (CMRs) are taken up by hepatic LDL receptor (LDLR), in the absence of LDLR they are taken up by LDLR-related protein-1 (LRP1). In liver cells (hepatocytes), TG is packaged with cholesterol and the APOB isoform B100 into very low-density lipoprotein (VLDL); the TG contained in VLDL is hydrolysed by LPL, releasing FAs and VLDL remnants (IDL) that are hydrolysed by hepatic lipase (HL), thereby yielding LDL. In LDL cholesterol metabolism, sterols in the intestinal lumen enter enterocytes via the Niemann-Pick C1-like 1 (NPC1L1) transporter and some are resecreted by heterodimeric ATP-binding cassette transporter G5/G8 (ABCG5/G8). In enterocytes, cholesterol is packaged with TG into CM. In hepatocytes, cholesterol is recycled or synthesized de novo, with 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) being rate-limiting. LDL transports cholesterol from the liver to the periphery. LDL is endocytosed by peripheral cells and hepatocytes by LDLR, assisted by an adaptor protein (AP). Proprotein convertase subtilisin/kexin type 9 (PCSK9), when complexed to LDLR, short-circuits recycling of LDLR from the endosome, leading to its degradation (X). In HDL cholesterol metabolism, HDL, via APOA-I (A1), mediates reverse cholesterol transport by interacting with ATP-binding cassette A1 (ABCA1) and ABCG1 transporters on non-hepatic cells. Lecithin-cholesterol acyltransferase (LCAT) esterifies cholesterol so it can be used in HDL cholesterol, which, after remodelling by cholesterol ester transfer protein (CETP) and by endothelial lipase (LIPG), enters hepatocytes via scavenger receptor class B type I (SRB1). HDL: picks up extra cholesterol from the cells and tissues and takes it back to the liver, which takes the cholesterol out of the particle and either uses it to make bile or recycles it. This action is thought to explain why high levels of HDL are associated with low risk for heart disease.

Atherosclerosis Plaque: fat, cholesterol, calcium and other substances in the blood. Overtime it hardens and narrows arteries limiting the flow of oxygen-rich blood to your organs and other parts of your body. Atherosclerosis develops over years. It happens through a complicated process of cholesterol plaque formation that involves: Damaged endothelium. The smooth, delicate lining of blood vessels is called the endothelium. High cholesterol, smoking, high blood pressure, or diabetes can damage the endothelium, creating a place for cholesterol to enter the artery's wall. Cholesterol invasion. "Bad" cholesterol (LDL cholesterol) circulating in the blood crosses the damaged endothelium. LDL cholesterol starts to accumulate in the wall of the artery. Plaque formation. White blood cells (macrophages) stream in to digest the LDL cholesterol. Over years, the toxic mess of cholesterol and cells becomes a cholesterol plaque in the wall of the artery. Some LDL cholesterol circulating through the bloodstream tends to deposit in the walls of arteries. This process starts as early as childhood or adolescence. White blood cells swallow and try to digest the LDL, possibly in an attempt to protect the blood vessels. In the process, the white blood cells convert the LDL to a toxic (oxidized) form. More white blood cells and other cells migrate to the area, creating steady low-grade inflammation in the artery wall. Over time, more LDL cholesterol and cells collect in the area. The ongoing process creates a bump in the artery wall called a plaque. The plaque is made of cholesterol, cells, and debris. The process tends to continue, growing the plaque and slowly blocking the artery. Can cause: CHD if it occurs in the coronary arteries: #1 killer of men and women in the US Angina or heart attack Chronic kidney disease if it occures in the renal arteries Slow loss of kidney function Figure B shows a normal coronary artery with normal blood flow. The inset image shows a cross-section of a normal coronary artery. Figure C shows a coronary artery narrowed by plaque. The buildup of plaque limits the flow of oxygen-rich blood through the artery. The inset image shows a cross-section of the plaque-narrowed artery.

Risk Factors Diet Medical conditions Genetics Sex Age Smoking
Diabetes Hypertension Genetics Sex Age Smoking Inactivity & obesity Diet: Eating foods high in saturated fats and cholesterol will raise your levels of total cholesterol and your levels of LDLs. Diabetes: High blood sugar contributes to higher LDL cholesterol and lower HDL cholesterol. High blood sugar also damages the lining of your arteries. Hypertension: Increased pressure on your artery walls damages your arteries, which can speed the accumulation of fatty deposits. Your sex - men have a greater chance of having high blood cholesterol levels than women. Your age – Age 55+ Smoking. Cigarette smoking damages the walls of your blood vessels, making them likely to accumulate fatty deposits. Smoking may also lower your level of HDL, or "good," cholesterol.The American Heart Association states that when you stop smoking, your risk for heart disease and stroke is cut in half after quitting for only one year. Your risk continues to decline until it's as low as a nonsmoker's risk. Inactivity and Obesity: Being physically inactive can play a role in raising your level of LDL cholesterol. When you participate in cardiovascular exercise, you stimulate your body to respond by providing more blood and oxygen to meet the body's needs. This helps make your heart strong and keeps your arteries clear. Being inactive can lead to obesity. which also raises your risk. Being overweight may raise triglycerides, lower HDL and raise LDL levels.

Drugs Therapy of Hyperlipidemia
Statins Bile-Acid Sequestrants Niacin (Nicotinic Acid) Fibric Acid Derivatives Ezetimibe and the Inhibition of Dietary Cholesterol Hyperlipidemias may basically be classified as either familial (also called primary[2]) caused by specific genetic abnormalities, or acquired (also called secondary)[2] when resulting from another underlying disorder that leads to alterations in plasma lipid and lipoprotein metabolism.[2] Also, hyperlipidemia may be idiopathic, that is, without known cause.

Statins Competitive inhibitors of HMG-CoA reductase Reduce LDL levels
Decreased cholesterol synthesis Increased expression of the LDL receptor gene Reduce LDL levels Documented in reducing fatal and nonfatal CHD events, strokes, and total mortality Adverse effects were similar in placebo and drug groups Statins were isolated from a mold and identified as inhibitors of cholesterol biosynthesis, specifically HMG-CoA reduatase, in 1976 by Akira Endo and colleagues. The first statin studied was compactin, renamed mevastatin, which demonstrated the therapeutic potential of this class of drugs however caused toxic effects at higher doses and believed to be too toxic to be given to humans. In 1978, Alfred Alberts and colleagues at Merck developed the first statin approved for use in humans, lovastatin (formerly known as mevinolin). As a result of their structural similarity to HMG-CoA, statins are reversible competitive inhibitors of the enzyme's natural substrate, HMG-CoA. The inhibition constant (Ki) of the statins is 1nM; the dissociation constant of HMG-CoA is three orders of magnitude higher. Inhibit an early and rate limiting step in cholesterol biosynthesis Heptocytes respond to the decreased production of cholesterol by synthesizing LDL receptors to draw cholesterol out of circulation. To do this, membrane-bound SREBPs is cleaved and translocates to the nucleus to increase production of LDL receptors. The LDL receptors take up LDL and VLDL into the liver from the circulation and can reprocess it into bile salts The greater number of LDL receptors on the surface of hepatocytes results in increased removal of LDL from the blood, thereby lowering LDL-C levels. Some studies suggest that statins also can reduce LDL levels by enhancing the removal of LDL precursors (VLDL and IDL) and by decreasing hepatic VLDL production. Because VLDL remnants and IDL are enriched in apoE, a statin-induced increase in the number of LDL receptors, which recognize both apoB-100 and apoE, enhances the clearance of these LDL precursors. The reduction in hepatic VLDL production induced by statins is thought to be mediated by reduced synthesis of cholesterol, a required component of VLDL. This mechanism also likely accounts for the triglyceride-lowering effect of statins and may account for the reduction (25%) of LDL-C levels in patients with homozygous familial hypercholesterolemia treated with 80 mg of atorvastatin or simvastatin.

Statins Zocor Lipitor Crestor
Type 1 statins: Top row: due to their structural relationship to the first statin, mevastatin Type 2 statins: Fully synthetic; one main difference is the replacement of the butyryl group with a fluorophenyl group. This is responsible for additional polar interactions that cause tighter binding to the HMGR enzyme Pravastatin and simvastatin are chemically modified derivatives of lovastatin (Figure 31–2). Atorvastatin, fluvastatin, rosuvastatin, and pitavastatin are structurally distinct synthetic compounds.

Effects on Triglycerides & Lipoprotein Levels
Decrease triglycerides in hypertriglyceridemic 35-45% Increase HDL-C Normal patients: 5-10% Low patients: 15-20% Decrease LDL-C 20-55% Non-lipid lowering effects Endothelial function (Enhances production of nitric oxide) Anti-inflammatory Reduce venous thromboembolic events 43% Adverse Effects Hepatotoxicity Elevated hepatic transaminase values One case of liver failure per million person-years of use Myopathy One death per million prescriptions caused by rhabdomyolysis LDL-C depends on dose and drug used Dose-response relationships for all statins demonstrates that the efficacy of LDL-C lowering is log-linear; LDL-C is reduced by 6% (from baseline) with each doubling of the dose Maximal effects on plasma cholesterol levels are achieved within 7-10 days. The statins are effective in almost all patients with high LDL-C levels. The exception is patients with homozygous familial hypercholesterolemia, who have very attenuated responses to the usual doses of statins because both alleles of the LDL receptor gene code for dysfunctional LDL receptors; the partial response in these patients is due to a reduction in hepatic VLDL synthesis associated with the inhibition of HMG-CoA reductase–mediated cholesterol synthesis. Statins reduce platelet aggregation and reduce the deposition of platelet thrombi. In addition, the different statins have variable effects on fibrinogen levels. Elevated plasma fibrinogen levels are associated with an increase in the incidence of CHD. thromboembolic :the blocking of a blood vessel by a blood clot dislodged from its site of origin. Transaminase values: indicator of liver damage; synthesize and break down amino acids to convert energy storage molecules; in the case of liver damage heptocyte membranes become more permeable and some of the enzymes leak out into blood circulation myopathy is a muscular disease[1] in which the muscle fibers do not function Rhabdomyolysis: Rhabdomyolysis is the breakdown of muscle fibers that leads to the release of muscle fiber contents (myoglobin) into the bloodstream. Myoglobin is harmful to the kidney and often causes kidney damage. Usually caused by drug interactions with fibrates or other drugs that affect statin catabolism or uptake into heptocytes

Bile-Acid Sequestrants
Highly positively charged Bind negatively charged bile acids Large size keeps them from being absorbed Secreted in stool Hepatic bile-acid synthesis increases Hepatic cholesterol declines stimulating the production of LDL receptors and lowers LDL levels Partially offset by the enhanced cholesterol synthesis caused by upregulation of HMG-CoA reductase Combining these with a statin substantially increases their effect One of the oldest hypolipidemic drugs Safest Not absorbed from the intestine Used as a second agent if statins are not sufficient Maximal dose can reduce LDL-C by up to 25% Cause bloating and constipation so compliance is low Since the bile acids cannot be reabsorbed hepatic bile-acid synthesis increases

Cholestryamine and colestipol are established. These are the ones known to cause GI distress at maximal dose. Colesevelam is newer. Shown to decrease LDL-C by 18% at maximal dose. Less side effects.

Effects on Lipoprotein Levels & Adverse Effects
Dose dependent decrease in LDL-C Normal dose: 12-18% reduction Maximal dose (2x normal): Up to 25% reduction GI side effects HDL-C: Increase 4-5% Combined with statins or niacin: 40-60% reduction Adverse Effects Generally safe Hyperchloremic acidosis Are not used in patients with hypertriglyceridemia May increase triglycerides They are chloride forms of anion exchange resins and may produce hyperchloremic acidosis with chronic use.

Niacin (Nicotinic Acid)
Inhibits the lipolysis by hormone-sensitive lipase Reduces transport of free fatty acids to the liver Decreases hepatic triglyceride synthesis May inhibit diacylglycerol acyltransferase-2 Rate-limiting in triglyceride synthesis Reducing triglyceride synthesis reduces hepatic VLDL production Raises HDL levels by decreasing the fractional clearance of apoA-I in HDL One of the oldest drugs used to treat dyslipidemia Favorably affects virtually all lipid parameters Acts on its receptor (GPCR) to stimulate Gi thus inhibiting cAMP production and decreasing hormone-sensitive lipase activity, triglyceride lipolysis and release of fatty acids Reduced VLDL accounts for reduced LDL B-complex vitamin that functions as a vitamin after being converted to nicotinamide. Only niacin affects lipid levels; requires higher doses that are required for the vitamin effect Most effective HDL-C increasing drugs: increased apaA-I means more HDL since it is one of the main apolipoproteins in HDL

Increases HDL: 30-40% Lowers triglycerides by 35-45% Reduces LDL: 20-30% Half-life: 60 minutes Requires 2-3 doses/day Therapeutic Use Hypertriglyceridemia and low HDL levels Adverse Effects Flushing Dyspepsia Hepatotoxicity Hyperglycemia Adverse effects limit patient compliance Flushing ceases after 1-2 weeks of a stable dose. Daily aspirin alleviates flushing in many patients. Dyspepsia: indigestion Limited if it is taken after a meal. Not good for patients with peptic ulcer disease because it can reactive ulcer disease. Hepatotoxicity: elevated serum transaminases AST, ALT are elevated, serum albumin declines and total cholesterol and LDL-C decline substantialy >50% in LDL-C should be viewed as a sign of niacin toxicity Hyperglycemia: cautiously used in patients with diabetes Niacin induced insulin resistance causes hyperglycemia A history of gout (elevated uric acid levels) is a relative contraindication for niacin use. (increase uric acid levels) Tredaptive: announced in 2007 by Merck. It combines Niacin and another drug to reduce the vitamin’s main side effect: flushing. Did a clinical study with almost 26,000 patients where have received a statin + placebo and half received a statin + tredaptive. Was halted prematurely after 4 years because patients on Treadaptive had higher rates of bleeding, infections and new onset diabetes. Also, they did not have lower rates of heart attack or stroke. Because niacin alone has not caused these side affects, it is believed the anti-flushing drug is the cause. Because of this, niacin has a bad rap even thought it inexpensive, effective and has been used very safely for decades.

Fibric Acid Derivatives: PPAR Activators
Mechanism of action still remains unclear Thought to interact with peroxisome proliferator-activated receptors (PPARs) Bind to PPARα Increase LPL synthesis Reduce expression of apoC-III Stimulate apoA-I and apoA-II Increasing LPL: LPL hydrolyzes TG into free fatty acids. However, increasing this also causes the breakdown of VLDL into LDL which is why LDL may increase. ApoC-III is a component of VLDL and decreasing this (the triglyceride-carrying particle that circulates in the blood) TG are reduced. ApoA-I and II are components of HDL so increasing these increases HDL 1962: ethyl cholophenoxyisobutyarte lowered lipid levels in rats 1967: ester form, Clofibrate, was approved for use in the U.S. In 1962, Thorp and Waring reported that ethyl chlorophenoxyisobutyrate lowered lipid levels in rats. In 1967, the ester form (clofibrate) was approved for use in the U.S. and became the most widely prescribed hypolipidemic drug. Its use declined dramatically, however, after the World Health Organization (WHO) reported that, despite a 9% reduction in cholesterol levels, clofibrate treatment did not reduce fatal cardiovascular events, although nonfatal infarcts were reduced. Total mortality was significantly greater in the clofibrate group. The increased mortality was due to multiple causes, including cholelithiasis. Interpretation of these negative results was clouded by failure to analyze the data according to the intention-to-treat principle. A later analysis demonstrated that the apparent increase in noncardiac mortality did not persist in the clofibrate-treated patients after discontinuation of the drug (Heady et al., 1992). Clofibrate use was virtually abandoned after publication of the results of the 1978 WHO trial. Clofibrate as well as two other fibrates, gemfibrozil and fenofibrate, remain available in the U.S.

Fibric Acid Derivatives: PPAR Activators

Decreases triglycerides Increases HDL-C LDL-C can decrease, increase or be unchanged Should not be used in patients with renal failure or hepatic dysfunction Therapeutic Use Type III hyperlipoproteinemia Hypertriglyceridemia Chylomicronemia syndrome Adverse Effects Rash Hair loss Fatigue The effects of the fibric acid agents on lipoprotein levels differ widely, depending on the starting lipoprotein profile, the presence or absence of a genetic hyperlipoproteinemia, the associated environmental Influences, and the specific fibrate used. Mild hypertriglyceridemia: increase or unchange LDL-C Hyperlipiemia: Decrease Excretion of these drugs is impaired in renal failure type III hyperlipoproteinemia: increased LDL, cholesterol, triglycerides and decreased HDL Mutation in ApoE that serves as a ligand for the liver receptors for chylomicrons, IDL and VLDL. When defective, it prevents the normal metabolism of chylomicrons, IDL and VLDL and leads to accumulation of their content: triglycerides and cholesterol, especially in the form of LDL. Chylomicronemia syndrome is a disorder passed down through families in which the body does not break down fats (lipids) correctly. This causes fat particles called chylomicrons to build up in the blood. Chylomicronemia syndrome can occur due to a rare genetic disorder in which a protein (enzyme) called lipoprotein lipase (LpL) is broken or missing. LpL is normally found in fat and muscle and helps break down certain lipids. When LpL is missing or broken, fat particles called chylomicrons build up in the blood. This build up is called chylomicronemia. Primary therapy is to remove alcohol and have a fat free diet Fibrates help by increasing triglyceride clearance and decreasing hepatic triglyceride synthesis

Ezetimibe and the Inhibition of Dietary Cholesterol Uptake
Inhibits cholesterol absorption by enterocytes in the small intestine 54% in humans Inhibits the transport protein NPC1L1 Inhibiting the transport proteins inhibits the uptake of cholesterol Doing this reduces the incorporation of cholesterol into chylomicrons which diminished the delivery of cholesterol to the liver by chylomicron remnants. This may decrease a therogenesis directly. It also increase expression of hepatic LDL receptors and enhances LDL- clearance from the plasma. Inhibits absorption by about 70% in wt mice. Cholesterol absorption is lowered by 86% in NPC1L1 ko mice compared to wt and ezetimibe has no further effect Even though there is a decrease in humans, there is a compensatory increase in cholesterol synthesis This is why they administer statins with it to inhibit cholesterol synthesis

Combination Therapy & Adverse Effects
Reduces LDL by 15-20% alone Reduces LDL by 60% in combination with simvastatin Should not be given with bile-acid sequestrants Adverse Effects Rare allergic reactions Only good as a monotherapy in patients that are statin-intolerant Used frequently as an adjunct therapy with statins The actions of ezetimibe are complementary to those of statins. Statins, which inhibit cholesterol biosynthesis, increase intestinal cholesterol absorption (Miettinen and Gylling, 2003). Ezetimibe, which inhibits intestinal cholesterol absorption, enhances cholesterol biosynthesis by as much as 3.5 times in experimental animals Dual therapy with these two classes of drugs prevents both the enhanced cholesterol synthesis induced by ezetimibe and the increase in cholesterol absorption induced by statins. This combination provides additive reductions in LDL-C levels irrespective of the statin employed Dual therapy is greater than statin monotherapy Bile-acid sequestrants: inhibit its absorption

Videos http://www.youtube.com/watch?v=9Tbo-0GfDcg Cholesterol
Atherosclerosis

Mechanism of Action Statins
Inhibit an early and rate limiting step in cholesterol biosynthesis Inhibiting hepatic cholesterol synthesis results in increased expression of the LDL receptor gene Decreased free cholesterol causes membrane-bound SREBPs to be cleaved and translocated to the nucleus to bind the sterol responsive element of the LDL receptor gene. This enhancnes transcription and increases the synthesis of LDL receptors It also reduces the degradation of LDL receptors The greater number of LDL receptors on the surface of hepatocytes results in increased removal of LDL from the blood, thereby lowering LDL-C levels. Some studies suggest that statins also can reduce LDL levels by enhancing the removal of LDL precursors (VLDL and IDL) and by decreasing hepatic VLDL production. Because VLDL remnants and IDL are enriched in apoE, a statin-induced increase in the number of LDL receptors, which recognize both apoB-100 and apoE, enhances the clearance of these LDL precursors. The reduction in hepatic VLDL production induced by statins is thought to be mediated by reduced synthesis of cholesterol, a required component of VLDL. This mechanism also likely accounts for the triglyceride-lowering effect of statins and may account for the reduction (25%) of LDL-C levels in patients with homozygous familial hypercholesterolemia treated with 80 mg of atorvastatin or simvastatin.

Adverse Effects Hepatotoxicity Myopathy
Elevated hepatic transaminase values One case of liver failure per million person-years of use Myopathy One death per million prescriptions caused by rhabdomyolysis Transaminase values: indicator of liver damage; synthesize and break down amino acids to convert energy storage molecules; in the case of liver damage heptocyte membranes become more permeable and some of the enzymes leak out into blood circulation myopathy is a muscular disease[1] in which the muscle fibers do not function Rhabdomyolysis: Rhabdomyolysis is the breakdown of muscle fibers that leads to the release of muscle fiber contents (myoglobin) into the bloodstream. Myoglobin is harmful to the kidney and often causes kidney damage. Usually caused by drug interactions with fibrates or other drugs that affect statin catabolism or uptake into heptocytes

One of the oldest hypolipidemic drugs Safest Not absorbed from the intestine Used as a second agent if statins are not sufficient Maximal dose can reduce LDL-C by up to 25% Cause bloating and constipation so compliance is low One of the oldest hypolipidemic drugs Safest Not absorbed from the intestine Used as a second agent if statins are not sufficient Maximal dose can reduce LDL-C by up to 25% Cause bloating and constipation so compliance is low

Mechanism of Action Inhibits the lipolysis by hormone-sensitive lipase
Reduces transport of free fatty acids to the liver Decreases hepatic triglyceride synthesis May inhibit diacylglycerol acyltransferase-2 Rate-limiting in triglyceride synthesis Reducing triglyceride synthesis reduces hepatic VLDL production Raises HDL-C levels by decreasing the fractional clearance of apoA-I in HDL Acts on its receptor (GPCR) to stimulate Gi thus inhibiting cAMP production and decreasing hormone-sensitive lipase activity, triglyceride lipolysis and release of fatty acids Reduced VLDL accounts for reduced LDL

Mechanism of Action Still remain unclear
Thought to interact with peroxisome proliferator-activated receptors (PPARs) Bind to PPARα and stimulate fatty acid oxidation, increase LPL synthesis and reduce expression of apoC-III to reduce triglycerides Bind to PPARα to stimulate apoA-I and apoA-II expression to increase HDL-C levels An increase in LPL would enhance the clearance of triglyceride-rich lipoproteins. A reduction in hepatic production of apoC-III, which serves as an inhibitor of lipolytic processing and receptor-mediated clearance, would enhance the clearance of VLDL.

Mechanism of Action Inhibits the transport protein NPC1L1
Inhibits absorption by 54% in humans Inhibiting the transport proteins inhibits the uptake of cholesterol Doing this reduces the incorporation of cholesterol into chylomicrons which diminished the delivery of cholesterol to the liver by chylomicron remnants. This may decrease a therogenesis directly. It also increase expression of hepatic LDL receptors and enhances LDL- clearance from the plasma. Inhibits absorption by about 70% in wt mice. Cholesterol absorption is lowered by 86% in NPC1L1 ko mice compared to wt and ezetimibe has no further effect Even though there is a decrease in humans, there is a compensatory increase in cholesterol synthesis This is why they administer statins with it to inhibit cholesterol synthesis

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