May 2003 Lipid Management H01 HAVE YOU RECENTLY MOVED? PLEASE NOTIFY US.

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1 W-F Professional Associates, Inc. 400 Lake Cook Rd., Suite 207 Deerfield, IL May 2003 Lipid Management H01 MISSING A LESSON? IT S EASY TO GO TO OUR WEBSITE & DOWNLOAD WHAT YOU NEED. ( LESSONS ARE USUALLY ON THE WEBSITE BY THE FIRST DAY OF EACH MONTH. THIS MONTH Lipid Management ALWAYS KEEP A COPY OF YOUR QUIZZES. YOU MAY MAIL QUIZZES TO US, FAX THEM ( ), OR SEND US A CONVENTIONAL WITH YOUR ANSWERS. (info@wfprofessional.com) HAVE YOU RECENTLY MOVED? PLEASE NOTIFY US. Each year, among the most highly prescribed drugs are those for elevated cholesterol. Besides accurately dispensing these medications, it is our responsibility as pharmacists to provide current and accurate information to patients. Therefore, the rationale for discussing Lipid Management is obvious. Our goal is to present the most common treatment options. This lesson provides 1.25 hours (0.125 CEUs) of credit, and is intended for pharmacists in all practice settings. The program ID # for this lesson is H01. Pharmacists completing this lesson by May 31, 2006 may receive full credit. To obtain continuing education credit for this lesson, you must answer the questions on the quiz (70% correct required), and return the quiz. Should you score less than 70%, you will be asked to repeat the quiz. Computerized records are maintained for each participant. Complete List of 2003 Topics: See Page 10. If you have any comments, suggestions or questions, contact us at the above address, or call toll free (In Alaska and Hawaii phone ). Please write your ID Number (the number that is on the top of the mailing label) in the indicated space on the quiz page (for continuous participants only). The objectives of this lesson are such that upon completion the participant will be able to: 1. List the major classes of lipoproteins. 2. Describe lipoprotein metabolism. 3. Differentiate between sources of endogenous & exogenous cholesterol. 4. Recognize the significance of therapeutic lifestyle changes (TLC). 5. Describe the mechanisms of action, adverse effects & dosages of the drugs used for lipid management. All opinions expressed by the author/authors are strictly their own and are not necessarily approved or endorsed by W-F Professional Associates, Inc. Consult full prescribing information on any drugs or devices discussed.

2 Dyslipidemia is the manifestation of concurrent abnormalities differing in clinical features, prognosis, and therapeutic response. It is characterized by elevated low-density lipoprotein cholesterol LDL-C, elevated triglycerides, and decreased high-density lipoprotein cholesterol HDL-C. High serum cholesterol and elevated LDL-C are considered risk factors for causing coronary heart disease (CHD). The major plasma lipids are cholesterol, cholesteryl esters, and triglycerides. Cholesterol is a sterol that is widely distributed in animal tissue such as nerve tissue of the brain, spinal cord, liver and kidneys, and occurs in egg yolks and various steroids such as sex hormones and adrenocorticoids. It plays an important role in cell membranes. Cholesterol is obtained either from the diet or is synthesized in the liver. Each day, synthesized cholesterol contributes about mg of the total cholesterol pool, while the amount of cholesterol contributed by the diet is about mg daily. Triglycerides are composed of glycerol with three of five fatty acids. Plasma lipids are not present in the free form. They are bound to lipoproteins that are macromolecular complexes. These act as vehicles to carry the lipids in the circulating blood. Being nutrients, the lipids must be transported by the blood in order to be distributed throughout the body. Lipids, cholesterol and triglycerides are hydrophobic in nature, and, consequently, they are insoluble in the aqueous plasma. By binding to lipoprotein, the lipids become soluble, thereby making their transport by the plasma possible. Lipoproteins are spherical in structure and smaller than the red blood cells. Each sphere consists of an inner core of hydrophobic lipid (cholesterol, cholesteryl esters and triglycerides) surrounded by an outer core (membrane) made of protein that acts as the interface between the plasma and lipid core. Because the protein of the membrane is hydrophilic in nature, the entire sphere becomes compatible with plasma. CLASSIFICATION OF LIPOPROTEINS Plasma lipoproteins consist of 3 major classes that possess specific differences based on size, density, protein contents, transport function, and predominant core lipids (cholesterol or triglycerides.) Classification is usually based on the ultra centrifugal density. The three major classes of lipoproteins are: 1) very lowdensity lipoprotein (VLDL), which has an inner core consisting mainly of triglycerides, 2) low-density lipoprotein (LDL), consisting of a predominantly cholesterol inner core, and 3) high-density lipoprotein (HDL), which has a total lipid content slightly less than the weight of protein in the outer membrane, and, consequently, its density is high. The inner core of HDL is made of cholesterol. Very-Low Density Lipoproteins (VLDL): This lipoprotein is produced in the liver and has a triglyceride core. Its main function is to deliver triglycerides to adipose and muscular tissue. The triglycerides found in plasma originate mostly from the VLDL. Elevated levels of VLDL may contribute to the development of atherosclerosis. Low-Density Lipoproteins (LDL): Production of LDL occurs as a result of the breakdown of metabolism of VLDL. The primary core lipid of LDL is cholesterol. This lipoprotein accounts for 60% to 75% of all plasma cholesterol. The main function of LDL is to deliver cholesterol to the liver and other body tissues. Absorption of LDL by tissue cells is accomplished by means of endocytosis (engulfment), and requires the presence of CE PRN (ISSN ) is owned and published by W-F Professional Associates, Inc. 400 Lake Cook Road, Suite 207, Deerfield, Illinois William J. Feinberg, President CE PRN is published eleven times per year, monthly, January through November. Subscription rate is $90.00 per year. Second-Class Postage paid at Deerfield, Illinois and at additional mailing offices by W-F Professional Associates, Inc. All rights reserved. None of the contents of this publication may be reproduced in any form without the written permission of the publisher. POSTMASTER: Send all address changes to W-F Professional Associates, Inc., 400 Lake Cook Road, Suite 207, Deerfield, IL May

3 LDL receptors on the cell surface. As the cell demands for cholesterol increase, the cell begins to synthesize more LDL receptors, thereby absorbing more LDL. However, if the cell fails to increase the formation of LDL receptors, then LDL absorption will be impaired. LDL has been associated with the development of atherosclerosis and coronary heart disease (CHD). Reduction of LDL can result in a decrease in the development of CHD and regression of coronary atherosclerosis. The risk of CHD in men over 45 years of age increases when total plasma cholesterol is over 200 mg/dl. Conversely, a 25% reduction in plasma LDL level may reduce the risk of CHD by 50%. High-Density Lipoprotein (HDL): As with LDL, cholesterol is the lipid that exists within the core of HDL. Normally, approximately 20% to 30% of the total cholesterol in plasma is contributed by HDL. While LDL is responsible for delivery of cholesterol to tissues including the liver, the function of HDL is to enhance the removal of cholesterol from tissues. In contrast to LDL and VLDL, high levels of HDL reduce the incidence of CHD and provide protection from such diseases. METABOLISM OF LIPOPROTEIN The enzyme, lipoprotein lipase (LPL), is synthesized in fatty and muscular tissues. Its main function is to mediate the triglycerides of both chylomicrons (a chylomicron is a lipoprotein molecule formed in the small intestine from digested fats for transport of fats to other tissues) and VLDL to release fatty acids that are deposited into the adjacent tissue where they are utilized for energy or stored as fat. Insulin is responsible for the synthesis and secretion of LDL. Thus, impaired synthesis of LDL caused by low levels of insulin, as in diabetes, can cause impaired triglyceride clearance. Cholesterol is either produced endogenously or obtained exogenously. The endogenous lipid transport system is responsible for transferring lipids from the liver to the peripheral tissues, and from peripheral tissues back to the liver. Only 10% of the total cholesterol produced in the body originates from the liver. The remainder is synthesized by the peripheral tissues. Endogenous cholesterol production occurs as a result of enzymatically-mediated reactions such as the conversion of 3-hydroxy-3- methylglutaryl coenzyme A (HMG-CoA) to mevalonic acid, which is catalyzed by HMG CoA reductase enzyme. Once cholesterol is produced by the liver and peripheral tissues, it is released into the bloodstream in the form of VLDL, and rapidly becomes an intermediate density lipoprotein (IDL). Within 2 to 6 hours, IDL is either taken by liver receptors, or remains in circulation where it breaks down and loses more glycerides, and becomes LDL. Thus, the main source of LDL is VLDL. Diet is the source of exogenous cholesterol. In industrialized societies, a normal individual consumes approximately 70 to 150 g of fat and 0.5 g of cholesterol during 3 meals. Normally, the body disposes of the circulating fat within 8 hours of the last meal. However, some individuals with dyslipidemia may have fat in their bloodstream for up to 24 hours after the last meal. Triglycerides are absorbed from the entrocytes of the intestinal lumen where they are engulfed by chylomicron particles. The chylomicrons carry the triglycerides from the intestines to the venous system. Once they reach the adipose and muscular tissues, the vast majority of chylomicron glyceride is hydrolyzed by LPL. The fatty acids and glyceride derived from the hydrolysis enter the cells as energy sources or for storage. Remnants of chylomicrons, which are mostly cholesterol-rich particles, are removed from the bloodstream by receptors located in the liver. This exogenously obtained cholesterol joins the endogenously synthesized cholesterol in the liver to be utilized in forming bile acids or incorporated into VLDL and then released into the circulation where it is converted to LDL. About 60% of plasma LDL is removed by the liver, and the remainder by active receptor sites located on fibroblasts and other cells that bind to the protein of LDL. A small quantity of LDL is believed to be removed by ingestion of scavenger macrophages that may reach arterial walls and form part of the atherosclerotic plaque. 3

4 MANAGEMENT It is estimated that more than 500,000 Americans die annually of CHD. Economically, CHD is responsible for yearly expenditures of about $115 billion. Studies have shown that dyslipidemia plays an important role in the development and progression of CHD. Lowering of total cholesterol levels in the blood, especially that of LDL, is essential in reduction of CHD morbidity and mortality. In May 2001, the National Cholesterol Education Program (NCEP) published new Adult Treatment Panel III (ATP III) guidelines concerning detection, evaluation and management of dyslipidemia as well as quantification of risk for CHD. These updated guidelines differ from those of ATP I (1988) and ATP II (1983). The ATP III focuses on reducing LDL as the treatment goal that should be based on the degree of risk. Additionally, the guidelines reemphasize the importance of therapeutic lifestyle changes (TLC), such as eating a healthy diet, regular participation in physical activities, weight loss, and smoking cessation, in reducing CHD risk. A new feature in ATP III is evaluating, every 10 years, the risk of experiencing CHD, and classification of patients into 3 categories in accordance with overall risk for developing a CHD event in 10 years. Patients at the highest risk are those with CHD and CHD risk equivalent, whereas those with 0 1 risk factors are at a low 10-year risk. ATP III also identifies diabetes and peripheral vascular disease as CHD risk equivalents. Furthermore, it acknowledges the importance of HDL and triglycerides in altering CHD risk. It identifies LDL < 100 mg/dl as optimal, raises the target for HDL from < 35 mg/dl to < 40 mg/dl and lowered the target goal for triglycerides to 200 mg/dl. ATP III recommends two methods of therapy: therapeutic lifestyle changes and drug therapy. THERAPEUTIC LIFESTYLE CHANGES (TLC) Individuals without CHD or CHD risk equivalent and < 2 risk factors, should utilize TLC as first-time treatment. Diet modification, regular physical activity, smoking cessation, and weight reduction play an important role in reducing LDL and CHD risk. Eating a healthy diet is the cornerstone of TLC. Depending on the level of LDL elevation, diet modification may lead to an acceptable level without a need for drug therapy. The main goals of dietary therapy are to: reduce plasma LDL and reduce body weight of overweight and obese individuals. To achieve these goals the following nutrient composition of the TLC diet has been recommended by ATP III: saturated fat and transfatty acids (< 7% of total calories); polysaturated fat, up to 10% of total calories; nonsaturated fat, up to 20% of total calories; total fat, 25% to 35% of total calories; carbohydrate, 50% - 60% of total calories; fiber, g daily; protein, approximately 15% of total calories; cholesterol, < 200 mg daily; and, total calories should be balanced between energy intake and expenditure to maintain desirable body weight and prevent weight gain. Consultation with a dietitian is recommended. The following dietary modification is recommended to lower serum cholesterol. Fish; poultry without skin; lean cuts of beef, lamb, or veal; skim and 1% fat milk; nonfat or low fat sorbet; egg white; cholesterol-free egg substitute; fruits; vegetables that have not been prepared in butter or other fatty source; bread prepared with little or no unsaturated oils; angel food cake; low-fat crackers and cookies; rice; pasta; whole grain bread and cereal such as oatmeal, whole wheat, bran, etc; unsaturated vegetable oils such as olive, corn, sesame, soybean, and sunflower; regular or diet margarine; shortening made from one of the aforementioned oils; mayonnaise and salad dressing made from unsaturated vegetable oils; seeds and nuts, but not coconut. Additionally, daily intake of 2 g of plant sterol/stenol and approximately g of viscous (soluble) fiber in the diet is recommended. A decreased intake of the following foods is recommended: fatty cuts of beef, lamb and pork; spareribs; organ meat; regular cold cuts; regular sausage and hot dogs; 4% fat milk; cream; half and half cream; whole-milk yogurt; all natural cheeses such as blue, cheddar, and Swiss; regular ice cream; egg yolks; commercially prepared pies, cakes, muffins, doughnuts, croissants, high fat crackers or cookies; butter; coconut oil; palm oil; palm kernel oil; bacon fat; coconut and chocolate. A sedentary lifestyle may lead to increased risk of CHD. Physical activity such as running, walking, swimming, bicycling, etc., tend to reduce LDL and elevate HDL. To achieve full benefit, an exercise program should be instituted and should be followed regularly. Weight reduction is important for success of TLC. Smoking cessation should be encouraged. Smoking, hypertension, diabetes, and obesity play a role in increasing the risk of CHD. 4

5 DRUG THERAPY Individuals with evidence of CHD are at the highest risk and will require cholesterol testing and LDL lowering drugs, in addition to TLC. Persons with CHD or CHD risk equivalents (10-year risk > 20%) should attain an LDL level of < 100 mg/dl. The LDL level at which to initiate TLC is ³ 100 mg, and the LDL level at which to consider drug therapy is ³ 130 mg/dl. For persons with more than 2 risk factors (10-year risk 20%), the LDL goal level is < 130 mg/dl; the LDL level at which to initiate TLC is ³ 130 mg/dl, and the LDL at which to consider drug therapy for 1-year risk of 10% - 20% is ³ 130, and for 10-year risk < 10% is ³ 160 mg/dl. For persons with 0 1 risk factors, the LDL goal is < 160 mg/dl, and the LDL level at which to initiate TLC is ³ 160 mg/dl, and the LDL level of mg/dl, drug therapy is optional. It is important to realize that when LDL lowering drugs are utilized, one should maintain TLC. There are several classes of lipid-lowering drugs that are currently employed: 1) the 3-hydroxy-3- methylglutaryl-coenzymea (HMG-CoA) reductase inhibitors, commonly referred to as statins, 2) Ezetimibe, 3) the bile acid sequestrants or bile binding resins, 4) niacin, 5) fibric acid derivatives, and 6) plant sterols. Statins The statins are considered the foundation for treating dyslipidemia, as they possess a predominant effect on lowering LDL cholesterol, reduce triglycerides, and may moderately increase HDL cholesterol level. They are most widely used, most effective and the best tolerated form of lipid-lowering drugs. In addition, they have the highest level of patient compliance. Combination therapy with a statin and one of the other lipid lowering drugs may be beneficial in patients who do not respond to monotherapy. The first generation, or fermentation, statins are: lovastatin, pravastatin, and simvastatin; the second generation consists of the synthetically prepared fluvastatin; and the third-generation statins are pure enantiomers, such as cerivastatin (no longer marketed), atorvastatin and rosuvastatin (not yet approved.) The mechanism of action by which the statins reduce LDL cholesterol concentration is to competitively inhibit HMG CoA reductase, the enzyme that catalyzes the rate-limiting step in hepatic cholesterol biosynthesis (conversion of HMG CoA to mevalonate), causing an increase in hepatic LDL cholesterol receptors and enhanced receptor-mediated LDL cholesterol removal from circulation. It also tends to cause an alteration in the formation of LDL cholesterol. It has been shown that the statins are capable of reducing LDL cholesterol levels by 24% to 60% in patients with dyslipidemia, and lowering triglyceride levels by 10% to 29%. Furthermore, statins may cause an increase in HDL cholesterol levels by up to 12%. Active treatment with statins has resulted in reduced risk of CHD death, nonfatal myocardial infarction or stroke. The most significant adverse effects of statins are those that affect the liver and skeletal muscle. Mild, transient elevations in serum transaminase occur in about 1% - 2% of individuals taking statins. When serum aminotranferase becomes more than three times of the upper limit of normal, therapy should be discontinued. Myopathy, a rare side effect that occurs in about 1 in 1000 patients, is dose related. Serum creatine phosphokinase (CPK) may reach 10 times the upper limit of normal. Myopathy may lead to rhabdomyolysis and acute renal failure. These side effects rarely occur in statin monotherapy, but may be enhanced when statins are used in combination with niacin, or gemfibrozil, or given to patients with hepatic or renal impairment, acute infection, and hypothyroidism. Liver function should be assessed prior to initiation of therapy and at regular intervals thereafter. Patients should be advised to report any unexplained muscle pain. Lovastatin: is partially absorbed from the GI tract and undergoes first pass extraction. Food appears to enhance the rate of absorption after oral administration. Lovastatin is excreted in urine and feces. The main side effects involve the GI tract. They are usually transient and mild and include abdominal pain, inflammation, cramps, diarrhea, nausea, and dyspepsia. An increase in serum concentration of hepatic transaminase, as well as elevated creatine phosphokinase, may occur in some patients. Headache, rash and pruritus may be experienced. Dosage of lovastatin varies from one individual to another and should be determined in accordance with the requirements and response of the patient. The usual initial dose in adults is 20 mg daily given in the 5

6 evening with dinner. The dose may be increased at an interval of 4 weeks or more until the desired lipoprotein concentration is achieved or a maximum daily dose is reached. The usual maintenance dose is mg daily given in a single or divided dose. Care must be exercised when giving lovastatin to patients with renal impairment due to its slow excretion in the urine. Pravastatin: Pravastatin sodium is used in the reduction of total serum and LDL cholesterol blood levels, as well as triglyceride concentrations. At the usual dose, the drug is usually well tolerated, and minimal side effects are mild and transient. They include nausea and/or vomiting, diarrhea, abdominal cramps, heartburn, flatulence, constipation, increased serum aminotransferase, muscular pain, headache, skin rash and increased serum creatine kinase. Pravastatin can be taken with meals, as food does not appear to affect its resultant antilipidemic activity. As with all statins, patients on pravastatin should remain on TLC during treatment, and the drug should be given according to the need and response of the patient. The usual initial adult dosage is 20 mg at bedtime, while that for individuals with renal or hepatic impairment, and geriatric patients, is 10 mg daily. The dose should be increased at intervals of no less than 4 weeks, until the targeted lipoprotein concentration is reached, or a maximum dose of 40 mg is attained. The usual maintenance dose is mg daily. Simvastatin: Simvastatin possesses mild and transient adverse effects that are well tolerated when given at the recommended dosage. The most frequently encountered side effects include: abdominal discomfort, constipation, flatulence, nausea, dyspepsia, anorexia, heartburn, increased serum creatine kinase, rash and headache. Myalgia and/or muscle weakness were rarely reported. Simvastatin is given orally, and its absorption does not appear to be adversely affected by a low fat meal. The usual initial dose in adults is 20 mg daily at bedtime. A dosage of 10 mg daily is initiated, and this dose may be increased at intervals of no less than 4 weeks, until the recommended lipoprotein concentration is obtained, or a maximum dosage of 80 mg daily is reached. Fluvastatin: At the recommended dosage, fluvastatin possesses a low incidence of side effects, and usually is well tolerated. The most encountered adverse effects include GI disturbances, back pain, headache, upper respiratory infections, a potentially serious increase in hepatic aminotransferase, myopathy, elevated creatine kinase concentration, rash and headache. Tooth disorder, gynecomastia, loss of libido, erectile dysfunction, and thyroid abnormalities have been reported. Atorvastatin: Like fluvastatin, this drug is synthetically prepared, and differs structurally from lovastatin, pravastatin, and simvastatin. Atorvastatin calcium is used along with TLC to reduce elevated serum total and LDL cholesterol, and triglyceride concentrations. The drug is used orally without restriction to meal type or time of the day. Atorvastatin is contraindicated in patients with liver diseases. Patients should undergo liver function tests prior to and at 12 weeks following the initial therapy, and periodically thereafter. Adult dosage of atorvastatin should be personalized and should be adjusted within 2 4 weeks after the initial dose of 10 mg daily. The maintenance daily adult dose is mg. Ezetimibe Ezetimibe is the first drug of a new class to be used in the management of dyslipidemia. This drug, which was approved by the FDA in October 2002, appears to be effective as monotherapy for patients with a low risk of CHD, and who cannot tolerate the statins. For patients with moderate to high risk for CHD, ezetimibe has been shown to be capable of reducing LDL cholesterol comparable to that achieved following the administration of high doses of stains, with short term safety levels identical to placebo. Because of its safety, tolerability, and effectiveness, ezetimibe appears to lead to enhanced patient compliance. The mechanism of action of ezetimibe differs from that of the currently available lipid lowering medications. The drug is a selective cholesterol absorption inhibitor. Following a meal, approximately 50% 6

7 of the total cholesterol contributed by food is absorbed by the intestines, and the remainder is excreted in the feces. In the intestines, the cholesterol is stored as triglyceride rich chylomicrons. TLC can reduce the amounts of cholesterol available for intestinal absorption. Dietary restrictions may favorably influence LDL cholesterol levels in many patients, while little or no response may occur with others. Ezetimibe acts by blocking the absorption of dietary and biliary cholesterol. The precise mechanism of action by which ezetimibe blocks the uptake of cholesterol into the intestines is not known, but it is believed that it interacts with a cholesterol transport protein. Bile Acid Sequestrants The bile acid binding resins, cholestyramine and colestipol, have been in use for over 30 years, and tend to lower LDL cholesterol by an indirect mechanism. They bind with bile acids present in the intestine to form an insoluble complex that prevents reabsorption of bile acids, thereby accelerating their excretion. Since bile acids are made from cholesterol, bile acid sequestrants result in a compensatory increase in bile acid synthesis that takes place in the liver. This leads to a reduction in hepatic cholesterol. The needed cholesterol is provided by LDL cholesterol. To avail themselves for more LDL cholesterol, the hepatocytes increase their number of LDL receptors, causing an increase in the LDL uptake. The increase in absorption of LDL cholesterol from plasma results in lipid lowering effects of bile acid sequestrants. Additionally, the reduction in hepatic cholesterol causes a secondary activation of HMG-CoA reductase, and may increase cholesterol production. In order to block their secondary effect, the inclusion of a statin to bile acid sequestrants is advisable. The bile acid binding resins can be used alone or in combination with statins. When used concurrently with TLC, they can produce a 15% to 30% reduction in LDL cholesterol levels. Because the bile acid binding resins are not absorbed from the GI tract, they do not have systemic adverse effects. However, these drugs are associated with side effects that are limited to the GI tract such as constipation, nausea, flatulence and indigestion. These adverse effects may become unpalatable enough to limit patient compliance. Cholestyramine is taken orally as a suspension prepared from the powder. Caution should be exercised not to take the powder in the dry form as it may cause esophageal irritation or blockage. The usual initial adult dose is 3 g, 3 times daily before meals. The usual maintenance adult dose is 4 g, 3 to 4 times daily before meals and at bedtime. Similar results may be achieved by administering the drug twice daily. The patient should be instructed to mix the powder with liquid such as water, fruit juices and soups, or with pulpy fruits such as applesauce or crushed pineapple. Because cholestyramine is an anion exchange resin, it may bind certain drugs in the GI tract, and retard or interfere with their absorption. Thyroid hormones, warfarin sodium, thiazide diuretics and phosphate supplements are examples of drugs that may be affected when administered along with cholestyramine. Colestipol hydrochloride is a high molecular weight, basic anion exchange resin. The mechanisms of action, adverse effects and mode of administration are similar to those of cholestyramine. It is dispensed in the tablet and granular forms. The tablets must be taken whole with plenty of water or other liquids. The granules must be added to a glass of water, fruit juice, or milk, and stirred until uniformly mixed. The usual adult dosage is 1 to 16 g daily. Niacin (Nicotinic Acid) Niacin is capable of reducing LDL cholesterol (15% - 25%), VLDL cholesterol (25% - 35%) and triglyceride concentration, and at the same time results in elevation of HDL cholesterol (15% -25%). The mechanism of action is not fully understood, but in has been postulated that niacin can partially inhibit free fatty acid release from adipose tissue and reduce the rate of synthesis of VLDL cholesterol. Because LDL cholesterol occurs mostly as a result of metabolism of VLDL cholesterol, any reduction in the synthesis of VLDL cholesterol will lead to a decrease in the formation of LDL cholesterol. Niacin is considered safe and effective in reducing practically all forms of dyslipidemia. However, it has side effects that are not only unpleasant, but can be 7

8 hazardous. The most frequent adverse reactions include uncomfortable and potentially dose limiting flushing of the skin. Flushing may be accompanied by itching. Intensity of flushing tends to diminish after several weeks of use, and the effect can be minimized by a low initial dose. Other adverse effects include nausea, vomiting, diarrhea and elevation of liver enzymes and serum uric acid. Niacin is available in tablets, timedrelease capsules, and an elixir. The usual adult maintenance dose is 1 to 2 g, three times daily after meals. Fibric Acid Derivatives Gemfibrozil has a minimal effect on lowering LDL cholesterol serum concentration, but is effective in reducing plasma triglyceride content by increasing fatty acid oxidation in the liver, thereby reducing secretion of VLDL cholesterol. Gemfibrozil can increase HDL cholesterol levels. The drug may be used in combination with niacin or bile acid sequestrants in order to assist in lowering of HDL cholesterol levels. When used with bile acid sequestrants, gemfibrozil should be given at least two hours after the ingestion of the sequestrants. The usual adult dose is 600 mg, twice daily. Gemfibrozil is well-tolerated. The most frequently encountered adverse effects are rashes and GI disturbances. Plant Sterols Plant sterols are capable of lowering LDL cholesterol by approximately 10%. They act by reducing cholesterol absorption from the intestines. Plant sterols are available as nonprescription drugs and should not be recommended as primary therapy, especially in high-risk patients. CONCLUSION Coronary heart disease is a leading cause of morbidity and mortality in both men and women in industrialized societies. It has been shown that lipid lowering drugs have contributed to cardiovascular risk reduction. There are a number of classes of lipid lowering drugs, the most effective of which are the statins. It is essential that drug therapy should be coupled with therapeutic lifestyle changes such as diet modification, regular physical activity, smoking cessation and weight reduction. REFERENCES 1. Cleeman, J.I., et al, Execution Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III), JAMA, 285, 2486 (2001). 2. Stein, E.A., Management of Dyslipidemia in the High-risk Patient, 3. Amer.Heart J. 144, 543 (2002). 4. Nguyen, V.D., and McLaughlin, M.A., Coronary Artery Disease in Women: A Review of Emerging Cardiovascular Risk Factors, The Mount Sinai J. Med., 69, 338 (2002). 5. Xydakis, A.M. and Ballantyne, C.M., Combination Therapy for Combined Dyslipidemia, Amer.J.Card., 90 (10B), 21K (2002). 6. Fauci, A.S., et al, Eds. Harrison s Principles of Internal Medicine, 14 th Ed., McGraw Hill, 2138 (1998). Jan: Pharmacy Law Update 2003 Mar: COPD May: Lipid Management Jul: Hepatitis Sep: Psoriasis TOPICS FOR 2003 Feb: Osteoporosis Apr: Cystic Fibrosis Jun: Acne Aug: Ulcer Management Oct: Essential Hypertension Nov/Dec: Anxiety MISSING ANY LESSONS? GO TO OUR WEBSITE ( & DOWNLOAD THEM. 8

9 Fill in the information below, answer questions and return Quiz Only for certification of participation to: CE PRN, 400 Lake Cook Road, Suite 207, Deerfield, IL NAME (1st line on label) ADDRESS CITY STATE ZIP CHECK IF NEW ADDRESS COMPANY WHERE EMPLOYED LESSON EVALUATION Please fill-out this section as a means of evaluating this lesson. The information will aid us in improving future efforts. Please rate each of the following from 1 to 7. Circle your choices. (1 is the lowest rating; 7 is the highest). Poor Average Excellent 1. Relevance of topic to practice Author s ability to communicate Author s knowledge of topic Appropriateness of topic Do you have any further comments about this lesson? Please Select the Most Correct Answer 1. The inner core of VLDL is made of: 6. Which drug acts as a selective cholesterol A. Cholesterol absorption inhibitor? B. Triglycerides A. Colestipol C. Protein B. Nicotinic acid D. Carbohydrate C. Atorvastatin 2. High levels of HDL cholesterol: D. Ezetimibe A. May reduce incidence of CHD 7. Niacin: B. May increase development of CHD A. Is capable of reducing C. Has no effect on development of CHD VLDL by 5% - 10% D. May increase formation of B. Is given by injection atherosclerosis C. Causes cutaneous flushing 3. The statins lower blood lipids by: D. Must be administered before meals A. Binding bile acids 8. Gemfibrozil: B. Inhibiting intestinal absorption A. Is very effective in lowering LDL-C of cholesterol B. Is not effective in reducing C. Inhibiting HMG-CoA reductase triglycerides D. Preventing breakdown of fatty acids C. Is not absorbed from the GI tract 4. Which of the following adverse reactions D. May be used in combination with may be caused by the statins? niacin or bile acid sequestrants A. Anemia 9. Plasma lipids: B. Myopathy A. Are present in the free form C. Hypertension B. Are bound to lipoprotein in order D. Dyspnea to be carried in circulation 5. Which statement is correct regarding C. The outer core of lipoprotein bile acid sequestrants? sphere is hydrophobic A. Are not absorbed from GI tract D. Are not required by body tissues B. Cause moderate to severe 10. Which of these has the highest systemic adverse effects cholesterol content? C. Liver function tests must be A. Whole wheat assessed prior to initiating therapy B. Angel food cake D. Cause an increase in serum C. Organ Meat creatine phosphokinase D. Olive oil 9

10 Contributing Author Farid Sadik, PhD, Dean Univ. of South Carolina College of Pharmacy Columbia, SCL Executive Editor William J. Feinberg, BS Pharm, MBA CE PRN is a publication of W-F Professional Associates, Inc. This program is in printed format. W-F Professional Associates, Inc. is approved by the American Council on Pharmaceutical Education (ACPE) as a provider of continuing pharmaceutical education. Providers who are approved by ACPE are recognized by the following states: Alaska, Arizona, Arkansas, California, Connecticut, Delaware, District of Columbia, Florida, Georgia, Hawaii, Idaho, Illinois, Indiana, Iowa, Kansas, Kentucky, Louisiana, Maine, Maryland, Massachusetts, Michigan, Minnesota, Mississippi, Missouri, Montana, Nebraska, Nevada, New Hampshire, New Jersey, New Mexico, New York, North Carolina, North Dakota, Ohio, Oregon, Pennsylvania, Puerto Rico, Rhode Island, South Carolina, South Dakota, Tennessee, Texas, Utah, Vermont, Virginia, Washington, West Virginia, Wisconsin and Wyoming. Pharmacists completing this course by March 31, 2006 may receive full credit. This program has been approved by the State Boards of Pharmacy in Alabama and Oklahoma. This lesson furnishes 1.25 hours (0.125 CEUs) of credit. Program ID # H01.