Hypolipidemic Drugs PDF

Hypolipidemic Drugs Yam Mun Fei School of Pharmaceutical Sciences, Universiti Sains Malaysia Atherosclerosis and arterial disease Plaque Formation The drugs in this chapter are referred to as the hypolipidemic or antilipemic drugs (lower the fats). The primary drug actio...

Hypolipidemic Drugs Yam Mun Fei School of Pharmaceutical Sciences, Universiti Sains Malaysia Atherosclerosis and arterial disease Plaque Formation The drugs in this chapter are referred to as the hypolipidemic or antilipemic drugs (lower the fats). The primary drug action is to reduce elevated circulating lipids (fats), but the therapeutic focus is to prevent coronary heart disease and associated heart attack and stroke. Atherosclerosis is a progressive condition that leads to coronary artery disease (CAD) and peripheral artery disease (PAD). Atherosclerosis is a disease that begins in early adulthood, even childhood, in which fat builds up inside the smooth lining of the arteries. This accumulated fat, called plaque, is mostly cholesterol with calcium, cell debris, and other substances found in the blood. The plaque begins as streaks of fat in the arterial wall.  When a vessel is damaged through infection, smoking, diabetes, or high blood pressure, a specific type of cholesterol , LDL - cholesterol, migrates to the injured area. In the wall of damaged arteries the LDL becomes oxidized and sends chemical signals directly to macrophages to “come and get me.” As the macrophages consume the LDL, they transform into cholesterol-rich foam cells. The oxidized LDL triggers more macrophage influx and inhibits their mobility so macrophages accumulate and form more foam cells. This is the beginning of fat streaks in the artery. Foam cell production is part of a local inflammatory response that continues over time, causing plaque to build up. Types of Plaque There are two kinds of plaque. Stable plaque has a cholesterol core with a fibrous cap and may contain calcium that hardens as it builds up within the cell. Eventually this plaque pushes into the space where the blood flows through the artery. This may reduce the local blood flow and oxygen supply to the tissues. Because plaque builds slowly over years, there are usually no symptoms until the artery becomes drastically narrowed or blocked, reducing oxygen to the tissues (ischemia). Unstable plaque also has a cholesterol core, but it is more dangerous because it has a thin cap that can erode, rupture, and break away. The ruptured material released into the bloodstream can form a clot (thrombus) that blocks blood flow and oxygenation of the tissues. Conditions Resulting from Vessel Blockage When blockage occurs in the heart, it can cause arrhythmias or an acute, life- threatening heart attack. Blockage in the arteries supplying the heart causes coronary artery disease (CAD); the characteristic symptom of an attack is crushing chest pain called angina. Blockage also can occur in other parts of the body like the carotid artery, which supplies the brain, resulting in a TIA (transient ischemic attack) or a debilitating stroke. When the wall of an artery weakens, it may bulge out, forming an aneurysm, which can leak or hemorrhage, thereby removing blood and oxygen from the tissues. When blood flow to the legs, pelvis, or arms is compromised in peripheral artery disease (PAD), it causes numbness and pain in the limbs, called intermittent claudication. Lipids, lipoproteins, and cholesterol Cholesterol Cholesterol is a critical substrate for the body because it is the fundamental building block of steroid hormones (sex hormones, glucocorticoids, aldosterone). It is essential for building cell membranes, the myelin sheath that provides the insulation for nerves, and the brain, and it is a core component of bile salts secreted by the gallbladder to digest dietary fats. A precise amount of cholesterol is required in cells so the body is finely tuned to balance cholesterol circulation and storage (homeostasis). With a balanced nutritional diet, the body absorbs 20 to 25% of its daily cholesterol from the diet and produces 75 to 80% through cellular synthesis (endogenous) in the liver and the small intestine. Endogenous cholesterol is synthesized through a complicated biochemical pathway starting with a 2-carbon molecule acetyl CoA and ending with 27 carbon atoms in cholesterol. Lipoproteins : LDL, HDL, VDL From the liver, cholesterol is stored in the gallbladder or it is transported to cells that need it. Because it is a fat (not water soluble), it can’t float in the bloodstream by itself. It has to be transported by specialized proteins called apoproteins. When apoproteins join cholesterol, they are called lipoproteins. The lipoprotein surrounds the fatty cholesterol core (like a hard-boiled egg, where cholesterol is the yolk). These lipoproteins come in different densities according to the amount of protein in the combined molecules. Although there are five lipoproteins, three will be mentioned in here: low-density lipoprotein (LDL) formed from apoprotein B-100 and cholesterol, very-low-density lipoprotein (VLDL), and a high-density lipoprotein (HDL) comprised of apoproteins A-1 and E and cholesterol. Apoproteins B (LDL) and E (HDL) not only transport fat, they are recognized by LDL receptors on cell surfaces that allow the lipoproteins to enter the cells (receptor-mediated endocytosis). Cholesterol is then extracted from the lipoprotein for cell-specific biosynthesis. LDL cholesterol is bad cholesterol (remember it as lousy LDL), will damaged areas in the arteries and forms plaque. LDL is atherogenic. Good cholesterol is the HDL cholesterol because it goes looking for cholesterol to return to the liver for disposal (remember it as healthy HDL). HDL actually retrieves cholesterol from the artery walls, inhibits the oxidation of LDL, and inhibits platelet aggregation at plaque sites. HDL is a protective lipoprotein. It is anti-atherogenic. Triglycerides Triglycerides are another type of fat found in the blood. Triglycerides are the main form of fat from diet regardless of the source— carbohydrate, fat, or protein. The body converts any calories it doesn’t need to use right away into triglycerides and stores them in fat cells (adipose tissue). Triglycerides provide your body with energy. Chylomicrons are very large lipoproteins produced by the intestines to transport dietary (exogenous) cholesterol and triglycerides. They are mostly a triglyceride core (85%). In the circulation, chylomicrons deliver triglycerides to muscle and fat tissue but return to the liver with a full complement of cholesterol that was absorbed by the intestine. When circulating chylomicrons become anchored to blood capillaries of muscle and adipose tissue, the triglycerides are hydrolyzed by the enzyme lipoprotein lipase. The triglycerides are made into free fatty acids to be used by the muscle as energy or stored as fat. During times when dietary lipids are not available, the liver produces cholesterol and triglycerides itself (endogenous). The liver packages triglycerides into VLDL. Triglycerides transported by VLDL are hydrolyzed by lipoprotein lipase to provide energy to the target tissues. Moderately elevated plasma triglyceride levels contribute to increased risk for cardiovascular disease, and severe hypertriglyceridemia is associated with an increased risk of pancreatitis. Risk Factors for Atherosclerosis There is a dynamic communication among the liver, intestines, and lipoproteins that balances the cholesterol synthesis needed day-to-day. Although lipids are essential for cell structure and function, unusually high lipid levels in the plasma have been correlated with several diseases such as diabetes mellitus, lupus erythematosus, lipodystrophies, hypothyroidism, and premature atherosclerosis. There are hereditary conditions that predispose some individuals toe levated serum cholesterol (hypercholesterolemia) or triglyceridelevels (hypertriglyceridemia), but mostly it’s the dietary lifestyle that contributes to elevated lipid levels. Risk factors associated with the development of atherosclerosis are as follows: Age (men over age 45; women over age 55) History of smoking, hypertension, premature menopause, obesity, antihypertension medications Hormone imbalance (diabetes mellitus, hypothyroidism) Weight (30 percent overweight) Lipoprotein status (low HDL, high LDL) Lifestyle intervention, especially diet adjustment, can dramatically improve many of the risk factors (obesity, diabetes mellitus, and lipoprotein levels). The treatment of hyperlipidemia involves dietary restriction of saturated fats, cholesterol, and carbohydrates. Diet control is always the first line of defense. Monitoring Lipoprotein Levels Overall health status is evaluated by reviewing the levels of lipids and lipoproteins in the circulation. Routine lipid analysis includes fasting values of total cholesterol, triglycerides, and HDL-cholesterol. Quantitative analysis of serum cholesterol is not a routine assay and must be specifically ordered. This analysis identifies the circulating levels of free cholesterol and cholesterol esters. Triglycerides and cholesterol are measured from fasting (12 to 14 hours) blood samples where the patient has not consumed alcohol for the previous 24 hours. Although the literature speaks of plasma lipid levels, or plasma lipoproteins, blood samples used for analysis are serum samples. Serum, fluid that remains after the blood has been allowed to clot, is the preferred fluid because it provides the greatest amount of (previously circulating) cholesterol and triglyceride for measurement. The Lipoprotein Profile Lipoprotein electrophoresis is the separation of lipoproteins in a blood sample. It is performed to characterize the lipoprotein profile in a test called the lipid panel or lipid profile. Actually, the lipid panel measures total cholesterol, HDL-cholesterol, and triglycerides. LDL- cholesterol is calculated from the values for total cholesterol (TC), HDL-cholesterol (HDL), and triglycerides (TG) as follows: LDL=TC – HDL - TG/5. The recommended serum values to prevent heart disease for these lipoproteins are presented in next slide. Cholesterol values in the population range from 120 to 330 mg/dL. When cholesterol levels rise, the liver makes more LDL for transport. Circulating triglyceride values vary with age, ranging from 10 to 190 mg/dL. The clinical strategy is to keep the bad cholesterol (LDL) as low as possible by reducing total serum cholesterol and triglycerides and raising the good cholesterol (HDL) as high as possible. HDL levels can be elevated through vigorous exercise, a diet that includes fish and/or diet supplementation with omega-3-polyunsaturated fatty acids (fish oils), and moderate alcohol consumption. Factors that decrease HDL include smoking, obesity, liver damage, uremia, and starvation. Relationship of LDL-Cholesterol Values Calculated from Levels of Total Cholesterol, Triglycerides, and HDL- Cholesterol Measured in the Blood Primary and Secondary Hyperlipidemia Significant elevations in lipid levels that occur as a result of genetic disorders are primary hyperlipidemias. One or more lipids may be affected (hypercholesterolemia, hypertriglyceridemia, or mixed lipidemias). Secondary hyperlipidemias also involve one or more lipids, but they are caused by any of the three D’s: diet, drugs, or disease. Diet—cholesterol and triglycerides increase as a function of age, diets rich in saturated fats, and a nonactive lifestyle. Drugs—acute alcohol intoxication, thiazide and loop diuretics, beta-blockers, retinoic acid, progesterone, and steroids can elevate cholesterol and/or triglycerides and LDL. Disease—acute pancreatitis, chronic renal failure, diabetes mellitus, hypothyroidism, gout, and liver disease can elevate cholesterol and/or triglycerides. Secondary hyperlipidemias arising from diet or disease are risk factors that contribute to the development of atherosclerosis and heart disease. Whether treating primary or secondary hyperlipidemia, diet control is always initiated first. Saturated fat raises the LDL-cholesterol level more than anything else in a diet. Trans -fatty acids ( trans fats), made when vegetable oil is hydrogenated, also raise cholesterol levels. Genetics can’t be changed, but diet can be restructured to take in more unsaturated fats and eliminate trans fats. If diet adjustment does not adequately lower the target lipid, drugs may be added to reduce the bad lipid and raise the good cholesterol levels. Reduction in cholesterol has been demonstrated in large clinical trials to be associated with a 20 to 30 percent reduction in CAD. Combined diet and drug therapy reduces morbidity and CAD- related mortality. Classes of hypolipidemic drugs Hypolipidemic and Antilipemic Drugs There are five groups of drugs that are used alone or as adjunctive treatment to diet: in the management of hyperlipidemias for the prevention of coronary events in patients at risk for the treatment of clinically evident coronary heart disease to slow the progression of atherosclerosis These groups are the HMG-CoA reductase inhibitors (known as the statins), cholesterol absorption inhibitors, bile acid sequestrants, fibric acid derivatives, and nicotinic acid. Each group works at a specific location within the liver or intestine and has a different mechanism of action to affect cholesterol, triglycerides, and lipoproteins. Clinical Indications All of the hypolipidemic drugs are indicated as adjunctive therapy for the reduction of elevated cholesterol in patients with primary hypercholesterolemia and elevated LDL who do not adequately respond to diet. This class of drugs is used to decrease mixed lipidemias of primary or secondary origin, especially where high risk patients (diabetic and nephrotic lipidemia) have not responded to other treatments. HMG-CoA reductase inhibitors: statins Clinical Indications The statins are used for the treatment of primary hyperlipidemias and to slow the progression of atherosclerosis to reduce the risk of acute coronary episodes and sudden death. Mechanism of Action Lovastatin (Mevacor) was the first in the class of novel drugs that altered cholesterol synthesis in the liver by inhibiting the enzyme HMG-CoA reductase. Lovastatin was discovered in the fermentation product (red yeast rice) of the fungus Monascus ruber. Four of the widely used statins drugs are derived from a variety of different fungi and synthetically (*) made. All drugs in this class— atorvastatin (Lipitor*), fluvastatin (Lescol*), lovastatin (Mevacor), pravastatin (Pravachol), pitavastatin (Livalo*), rosuvastatin (Crestor*), and simvastatin (Zocor)— have the same site of action and effectively reduce total cholesterol and LDL plasma levels.  Starts as two acetyl-CoA molecules. An early, very important step in this process is the conversion of acetyl- CoA molecules into HMG-CoA, which is then converted to mevalonic acid by HMG-CoA reductase. Mevalonic acid is a rate-limiting pivotal step in steroid and cholesterol synthesis. Drug action in the synthetic pathway has a significant impact on circulating cholesterol levels because the liver makes two-thirds of the daily cholesterol requirement. This reduces the need to make apolipoproteins B and E to form LDL for cholesterol transport, so circulating LDL drops. The plasma levels of LDL and cholesterol are reduced. Similarly, VLDL also is reduced by the statins, so plasma levels of triglycerides decrease. At the same time, levels of HDL-cholesterol are increased in the circulation. These are very effective hypolipidemic drugs. The effect on circulating lipids is observable within 2 weeks of treatment; the maximum effect requires up to 6 weeks of drug therapy. When the medication is stopped, the reduction in lipoprotein plasma levels disappears within 6 weeks. Maintenance of therapeutic benefit requires diet adjustment and continued drug treatment for years. Of course, the most appropriate drug and dose may be adjusted during this time.  Comparative effect The HMG-CoA reductase inhibitor rosuvastatin (Crestor) is the second-most prescribed drug in the United States in adults aged 18 to 64. Atorvastatin (Lipitor) and the combination ezetimibe and simvastinin (Vytorin) are among the top 100 prescriptions written. While each drug in this class can lower cholesterol levels, they differ by how greatly they can reduce total cholesterol, LDL, and triglyceride levels. All of the statins reduce LDL up to 30 %. When a greater reduction of LDL is required, simvastatin (Zocor), atorvastatin (Lipitor), and rosuvastatin (Crestor) which reduce LDL by more than 45 % are used; in fact, rosuvastatin and atorvastatin have been demonstrated to reduce up to 60 %. All of these reductions are patient and dose dependent and most individuals would not require reductions above 40 %. All of the statins raise the HDL level up to 20 %. Again, simvastatin (Zocor), atorvastatin (Lipitor), and rosuvastatin (Crestor) increase HDL by more than 30 %. Anti-inflammatory Effect Remember that LDL initiates an inflammatory response when it begins the plaque-building process. The recruitment of macrophages and development of foam cells are part of the local inflammation in the atherosclerotic artery. C-reactive protein (CRP) is a protein released during injury and inflammation, and in some chronic conditions such as arthritis. High levels of CRP in the blood may raise the risk for atherosclerosis. Statins lower CRP while performing lipid-lowering tasks, which may have an additional clinical benefit. Extensive research is being done on this anti-inflammatory action. Meanwhile, simvastatin and atorvastatin are being used in patients with multiple sclerosis and adult and juvenile arthritis. Administration All of these drugs are well absorbed following oral administration. All of the other drugs in this class may be taken with or without meals without affecting the therapeutic effect. Except for pravastatin, all are highly bound (95 to 98 %) to plasma protein. However, lovastatin is better absorbed when administered with meals. Lovastatin is metabolized in the liver to active metabolites. Generally, it is recommended to take the statins in the evening because the majority of cholesterol is produced by the body at night. Atorvastatin (Lipitor) can be taken at any time of the day. Lovastatin and simvastatin have been used successfully in combination with other lipid-lowering drugs. Two products are now available that combine a statin with another lipid-lowering drug. Advicor combines niacin (500, 750, or 1000 mg) with 20 mg of lovastatin. Vytorin combines 10, 20, 40 or 80 mg simvastatin (Zocor) with 10 mg of ezetimibe (Zetia). Lovastatin and simvastatin can be used with cholestyramine to lower cholesterol. Any of these combination treatments dramatically reduces cholesterol and LDL to levels that cannot be attained by the individual drugs alone. When using combination therapy with cholestyramine, the statin should be taken 4 to 6 hours after the bile acid sequestrant to avoid the possibility of the sequestrant binding the statin while in the intestinal tract. Adverse Effects and Contraindications Contraindications Clinical manifestations of hypersensitivity, active liver disease, or unexplained persistent elevation in liver function enzymes are contraindications to the use or continued use of these drugs. Statins are absolutely contraindicated during pregnancy because of their ability to inhibit essential lipid metabolism in the developing fetus. While no human data are available, skeletal malformations have occurred in animals. Adverse Effects The range of adverse effects includes headache, dizziness, alteration of taste, insomnia, diarrhea, flatulence, abdominal cramping, and photosensitivity. Some people experience memory loss or an inability to concentrate as well. Because the HMG-CoA reductase inhibitors are absorbed and are able to affect lipid metabolism in a variety of tissues, the spectrum of adverse effects is greater than other hypolipidemic drugs. The statins do cause myalgias, leg ache, and muscle weakness in some patients, which are not serious conditions and may not require a change in treatment. Rhabdomyolysis There is a rare adverse effect that affects muscle metabolism. Cerivastatin (Baycol) was removed from the market due to safety concerns about muscle impairment. In long-term treatment, patients on cerivastatin showed evidence of muscle breakdown (rhabdomyolysis). The incidence of this life-threatening side effect was significantly higher with cerivastatin alone than with other statin drugs. Rabdomyolysis is a condition in which the contents of the skeletal muscle cells (enzymes, creatinine, myoglobin) leak into the circulation. The patient experiences muscle pain and weakness, and renal failure develops when the large molecules of myoglobin obstruct normal renal flow. Transient elevations in creatine phosphokinase (CPK) may occur before and during the myalgia. Depending on the medical profile of the patient, periodic monitoring of serum enzymes, including liver function (AST, ALT) and CPK, will indicate the need for dose adjustment or discontinuation. Rhabdomyolysis is a very rare adverse event with the use of the other statins. The chance of it occurring is less than one per million statin prescriptions. It is worth understanding the difference between rhabdomyolysis and the less-serious myalgias statins do cause. Patients should be instructed to report muscle tenderness or weakness to their physician. Sometimes the leg pain is only a leg pain, but it’s important to the patient. There are significant drug interactions that increase the statin level in the blood and the risk of developing myalgias. Liver Function Status There is no special boxed warning with the use of the HMG-CoA reductase inhibitor class of drugs. The FDA has determined that liver injury due to statins can occur, but it is a rare event. The current recommendation is to perform liver function tests prior to initiating drug treatment. Liver function tests may be performed to confirm the status of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the patient. Liver function tests are no longer required to be repeated every 6 to 12 weeks but only as appropriate to the clinical situation. Overdose Accidental overdose (up to 6 g) has occurred in adults and children (being treated for primary hyperlipidemias) with these drugs. There is no specific antidote. Using general supportive measures for overdose of any medication, these patients recovered without complication.  Cholesterol absorption inhibitors: Ezetimibe Mechanism of Action Ezetimibe (Zetia) is the first of a novel class of selective cholesterol-absorption inhibitors. It has a mechanism of action unlike all the other hypolipidemic drugs. Ezetimibe acts at the surface of the small intestine called the brush border to block absorption of dietary cholesterol. This decreases the content of cholesterol in chylomicrons, so the amount of cholesterol delivered to the liver is reduced. This results in a decrease in VLDL particles that are precursors to LDL, thereby decreasing circulating LDL cholesterol. This drug is very selective in its action and does not prevent absorption of other dietary fats or fat soluble vitamins. Ezetimibe is metabolized in the intestinal wall to an active metabolite that is even more potent than ezetimibe. The metabolite is taken directly to the liver and then passed back to the small intestine to continue reducing cholesterol absorption. This cycle of recirculation between the intestine and liver continues to give ezetimibe its long half-life (22 hours) and allows it to be used once a day. Remember cholesterol balance (homeostasis) is very tightly controlled. Well, when cholesterol from the intestine decreases and the liver isn’t seeing dietary cholesterol, it starts making cholesterol. This does partially offset the total cholesterol decrease from ezetimibe. This may be the reason ezetimibe produces a less dramatic reduction in the lipid profile compared to the statins. Administration Ezetimibe (10 mg) taken once daily will modestly reduce total cholesterol, LDL, and triglyceride blood levels. Its mechanism, site of action, and safety profile make it an ideal drug to combine with other hypolipidemic drugs. This drug primarily stays within the blood between the liver and intestine (the entero-hepatic circulation). It does not interact with other organs and produces very few side effects. In clinical practice, the role of ezetimibe (Zetia) as monotherapy is for patients who require modest reductions in their LDL level or who cannot tolerate other lipid-lowering agents. When combined with other lipid-lowering drugs, it has a complementary mechanism of action without increasing potential adverse effects. In fact, it has been demonstrated that when added to the statin drugs, circulating LDL has been reduced by an additional 20 percent or more. This is beneficial in patients who cannot tolerate high statin dosage alone or who need further LDL reductions despite treatment with the maximum statin dosage. This therapeutic combination success led to the preparation of a fixed-dose combination of ezetimibe with simvastatin (Vytorin). Ezetimibe can be used with any of the hypolipidemic drugs. The only significant dosing sequence issue is when it is given with a bile acid sequestrant; it must be taken 2 to 4 hours after the bile acid sequestrant to avoid an absorption interaction. The mechanism of the bile acid sequestrants could bind ezetimibe and keep it from acting in the small intestine. Bile acid sequestrants: cholestyramine, colestipol, and colesevelam Mechanism of Action Bile salts are synthesized from cholesterol and released into the duodenum as a part of bile. The main function of bile salts is to break down fats ingested in the diet into absorbable forms. The bile salts are recycled by intestinal absorption and stored within the gallbladder through the enterohepatic circulation. Cholestyramine (Questran) is an ion-exchange resin that combines with the bile salts and cholesterol in the intestinal tract. This insoluble binding prevents the absorption of the bile salts and cholesterol. The result is an increased elimination of bile salts, cholesterol, and other fats in the feces. Low-density lipoprotein and cholesterol levels decrease during treatment. Liver synthesis of cholesterol may increase, however—the circulating cholesterol concentration decreases because cholesterol is cleared from the plasma. Changes in LDL levels may be observed within 1 week of treatment, while changes in circulating cholesterol may require 1 month. Cholestyramine is also recommended in the management of partial biliary obstruction. The action of colestipol (Colestid) is similar to that of cholestyramine. Colestipol interferes with the absorption of bile acids and cholesterol from the intestinal tract. Administration Cholestyramine, 4 to 6 g per dose, is mixed with liquid and taken twice a day before meals. Cholestyramine is a powder that must be mixed with water, fruit juice, noncarbonated beverages, or fluid soups (broth, not cream). Applesauce or crushed pineapple also may be used to suspend the powder. The daily oral dose of colestipol tablets is 2 to 16 g/day given once or in divided doses. Patients are often started at 2 g once or twice daily and raised 2 g once or twice daily at 1 to 2 month intervals until the lipid profile is acceptable. Colestipol comes as tablets or granules. Colesevelam (Welchol) is recommended to start with three tablets twice daily or six tablets once daily with a meal. Each tablet contains 625 mg of active drug, so the maximum dose is more than 3 g daily. Adverse Effects Cholestyramine is not absorbed from the gastrointestinal tract, so systemic effects do not usually occur. Because it remains within the intestinal lumen, GI disturbances are the most common adverse effect, notably constipation. Some patients may experience severe constipation accompanied by fecal impaction. The most serious adverse effect with the bile acid sequestrants is intestinal obstruction. Because of the large doses required, nausea and vomiting may occur. With continued use of the drug, constipation, flatulence, and nausea may disappear. Headache, dizziness, drowsiness, and anxiety have been reported to occur in some patients. Colestipol has produced transient elevations in aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase.  Nicotinic Acid, Niacin ( Niacor, Niaspan ) Niacin, vitamin B3, is a general term that refers to nicotinic acid and its derivatives nicotinamide and inositol nicotinate. It is an important vitamin in the metabolism of carbohydrates. A deficiency of niacin that causes severe dermatitis, peripheral neuritis, and photosensitivity is known as pellagra. However, in very large doses (2000 mg, compared to the daily vitamin requirement of 15 mg), niacin, in the form of nicotinic acid, lowers plasma lipid levels. Mechanism of Action Nicotinic acid reduces the level of the VLDL and LDL, lipoproteins responsible for carrying triglycerides and cholesterol in a dose-dependent manner. The mechanism of action is unclear, but it appears to affect cholesterol synthesis in the liver through a recently discovered G protein–coupled receptor for nicotinic acid. HDL is significantly increased as well. At the same time, fat metabolism in adipose tissue is affected. In adipose tissue, nicotinic acid inhibits triglyceride lipase and stimulates lipoprotein lipase, which decreases free fatty acid release and removes triglycerides. Consequently, the plasma lipid level is significantly reduced. The effects of nicotinic acid on lipoproteins are evident within 4 days of treatment and maximum effects occur within 3 to 5 weeks.  The other forms of niacin, nicotinamide and inositol nicotinate, do not lower cholesterol. Niacin is available over the counter in strengths up to 500 mg per tablet. Niacor (500 mg) and Niaspan (500, 750, and 1000 mg) are available by prescription. Although these are all taken orally, these formulations. are not interchangeable. Niaspan is a once-daily extended-release tablet. Interestingly, the formulations of the vitamin affect circulating lipids differently. The immediate-release preparation increases HDL, while the sustained-release product reduces total cholesterol and LDL preferentially. Nicotinic acid (Niacor), an immediate-release tablet, is administered orally several times per day. Initial doses (100 mg TID) are gradually increased to 1 to 2 g three times a day. The maximum dose is usually 8 g per day. Because niacin has a good effect on raising HDL, it complements other hypolipidemic drug action. It has been successfully used in combination with colestipol and lovastatin, leading to the preparation of a fixed-dose combination product with lovastatin (Advicor). For patients that require an aggressive lipid- lowering strategy, the triple combination is more effective in reducing LDL than the dual combination of nicotinic acid with one of the others. Adverse Effects Common adverse effects include nausea, vomiting, diarrhea, and vasodilation. Nicotinic acid produces vasodilation that manifests as flushing of the skin. The flushing is accompanied by a sensation of warmth on the face and upper body, sometimes with tingling, itching, or headache. This effect is not harmful but may not be well tolerated by patients who experience persistent flushing. Patients should be advised to avoid drinking hot liquids just before and after dosing to avoid the potential for producing more vasodilation from the liquids. Aspirin taken 30 minutes before dosing also mitigates the vasodilation in many patients. Nicotinic acid also may increase uric acid levels in the blood (hyperuricemia). Individuals with high uric acid levels may develop symptoms of gout. The sustained-release product in doses greater than 2 g per day may promote jaundice, increased bilirubin, nausea, and prolonged prothrombin time. These effects appear to be mediated by an alteration of liver function. Periodic monitoring of liver enzymes every 6 to 12 weeks for the first year, especially if combined with a statin drug, will provide adequate indication of liver status. There had been concern that nicotinic acid might compromise blood sugar control if used in patients with elevated blood glucose or diabetic patients. As diabetes is a significant risk factor for atherosclerosis, diabetic patients are likely to be recipients of nicotinic acid therapy. Results from recent studies with immediate-release nicotinic acid and a new once-daily extended-release form show that effects on glucose control are minimal at doses commonly used for the treatment of lipidemia (i.e., up to 2 g daily).  For patients treated with the new once-daily formulation, the adverse event and tolerability profile, including flushing, liver function test elevations, and occurrence of myopathy, are the same among those with and without diabetes, monitoring is required. Moreover, nicotinic acid reduces the risk of cardiovascular events and long-term mortality similarly among patients at all levels of baseline glucose, including those patients with elevated fasting glucose, metabolic syndrome, or glucose values in the overtly diabetic range, Nicotinic acid may be considered as a therapeutic option in these patients, alone or in combination with a statin, as part of a comprehensive program of cardiovascular risk factor reduction. There are significant drug interactions that occur with nicotinic acid. Fibric Acid Derivatives Gemfibrozil ( Lopid ) and fenofibrate ( Tricor ) are derivatives of fibric acid that decrease triglyceride and VLDL, and increase HDL. The mechanism of action is directed at triglyceride production. It inhibits triglyceride lipolysis in adipose tissue, decreases free fatty acid uptake by the liver, and decreases hepatic VLDL-triglyceride synthesis. Overall there is a modest cholesterol-lowering effect. Both drugs are well absorbed from the intestinal tract. The oral dose of gemfibrozil is usually 600 mg BID, while the dose of fenofibrate is 54–160 mg daily. Fenofibrate is a micronized formulation of fibric acid, meaning the particles are reduced to a very small size to facilitate absorption. These drugs are approved for use in hypertriglyceridemia patients who do not respond to diet where triglyceride levels can exceed 1000 mg/dl (compared to the normal range of 10 to 190 mg/dl) to prevent pancreatitis, an inflammation of the pancreas. They also can be used in combination with other cholesterol lowering drugs to facilitate a further reduction in triglycerides. Gemfibrozil is usually taken twice a day, 30 minutes before the morning and evening meals. Adverse Effects Common adverse effects involve the GI tract and include nausea, vomiting, diarrhea, and flatulence. They also may produce dizziness and blurred vision that may interfere with the ability to perform intricate hand work or operate equipment. Since this class of drugs—fibrates—can produce muscle pain and weakness, combination with HMG-CoA reductase inhibitors potentiates the development of myopathy and elevated creatine phosphokinase levels. Gemfibrozil may increase cholesterol excretion into the bile, leading to gallstone formation. The drug must be discontinued in the presence of cholelithiasis or elevated creatine phosphokinase.  Contraindications and drug interaction Contraindications For the systemically absorbed drugs (all but the bile acid sequestrants), clinical manifestations of hypersensitivity, active liver disease, or persistent elevation in liver function, enzymes are contraindications to the use or continued use of the hypolipidemic drug. The bile acid sequestrants should not be used in patients who are hypersensitive to the drug or have biliary or intestinal obstruction. Nicotinic acid is contraindicated in patients with gallbladder disease, glaucoma, impaired liver function, or peptic ulcer. HMG-CoA reductase inhibitors are absolutely contraindicated during pregnancy because of their ability to inhibit essential lipid metabolism in the developing fetus. Hypolipidemic drugs have been designated as FDA Pregnancy Category B or C, except for HMG-CoA reductase inhibitors, which are designated Category X. The safety for use of hypolipidemic drugs during pregnancy has not been clearly established through well controlled clinical trials. Even niacin at the doses used to lower cholesterol has not been studied. The usual recommendation is to discontinue treatment once pregnancy is confirmed and restart after breast-feeding has been discontinued. The risk of temporarily interrupting hypolipidemic treatment is usually far less than the potential for harm to the fetus. Drug Interactions The bile acid sequestrants stay in the lumen of the intestine and trap other substances during transit through the intestine. Cholestyramine binds with fat-soluble vitamins (A, D, and K), folic acid, and many drugs, thus reducing their GI absorption. Supplementation at time intervals when the bile acids are no longer in the absorption area may be necessary to avoid vitamin deficiencies. It is recommended that any other medications be taken 1 hour before or at least 4 hours after cholestyramine to avoid interaction within the intestinal tract that would delay or inhibit absorption of the concomitant medication. Inhibition of Drug Metabolism—Statins Often drug metabolism occurs in the liver by forms of P-450 enzymes. There is a cytochrome P-450 enzyme CYP3A4 in the wall of the small intestine that metabolizes many drugs. This enzyme has become well known in recent years because it can be inhibited by grapefruit pulp and grapefruit juice. Eating one whole grapefruit causes the same effect as a juice serving because both contain the compound bergamottin that is the enzyme inhibitor. That means taking some medication in the presence of grapefruit juice can significantly decrease drug metabolism at the intestinal wall and increase its bioavailability. For example, the bioavailability of simvastatinis about 5 percent, meaning that a dose of simvastatin is about 95 percent metabolized before it reaches the blood. Imagine how powerful this drug is if only 5 percent can reduce lipoproteins.  This large amount of normally metabolized drug can be systemically available if an inhibitor of CYP3A4, such as grapefruit juice, is present. Increasing a drug’s bioavailability will increase risk of developing adverse effects. Grapefruit juice interacts only with drugs that are administered orally. The degree of inhibition varies among patients, but it may last up to 24 hours after a single glass of juice and up to 72 hours after multiple glasses of juice. Atorvastatin, lovastatin, and simvastatin are definitely affected by grapefruit. Although the studies concerning grapefruit interactions with pravastatin, fluvastatin, or rosuvastatin were not as significant, it probably would be prudent not to consume grapefruit a few hours before or after taking these medications. Orange juice does not have any effect on absorption of these drugs. Drugs that are potent inhibitors of CYP3A4 and also cause an increase in statin blood levels include cyclosporine, itraconazole, ketoconazole, erythromycin, clarithromycin, and HIV protease inhibitors. For patients who require antifungal therapy, the statins should be stopped until the fungal treatment is discontinued. Only lovastatin labeling has been revised to indicate that this drug is contraindicated for use with the azole antifungal drugs, HIV protease inhibitors, erythromycin, clarithromycin, telithromycin, nefazodone, boceprevir, and telaprevir. Lovastatin use with cyclosporine and gemfibrozil should also be avoided. Myopathy Gemfibrozil should not be administered with the statins because this combination was used in patients who developed rhabdomyolysis. The combination may predispose patients to develop severe myopathy. Similarly severe myopathy has occurred in patients taking nicotinic acid in doses over 1 g with statin drugs.