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Project Title Guidelines for drugs used in Hyperlipidaemia A research presented by Student name: Student No: Asia Ibrahim Abdalla 9760093 Project supervisor Dr.Rafiq R. A. Abou-Shaaban Jan.2001 Ajman University for Sciences and Technology Abu Dhabi Branch UAE Research for this project was carried out by me during the period of Hospital Pharmacy Training-1 no.700315(academic year 2000-2001) Date Jan 10th 2000 Signed 1 ACKNOWLEDGMENTS Sincere gratitude were extended pharmaceutical department, to to Dr. Rafiq Abu Shaaban from the support, encouragement and the fruitful accompaniment through out the training and presentation of this project. The author is indebt to project supervisor Dr. Asim Ahmed, for the continuous follow up, constructive criticism, and valuable comments. The author wishes to express special gratitude and thanks to those contributing in this revolutionary, distinctive and advanced Hospital Pharmacy training 1; namely Dr.Danna Sallam and the staff of the New Medical Center Hospital. Finally the author wishes to express heartfelt thanks to Dr. Abduelmula R. Abduelkarem in charge of the central training committee for furnishing the entire clinical pharmacy services. 2 INDEX Description Section l Page no Introduction 1.0 Definition of Hyperlipidaemia. 1.1Different types of lipoproteins 1.2 Lipid’s pathway (endogenous &exogenous) 1.3 Diagnostic and laboratory test 1.4Types of Hyperlipidaemia 1.5Inborn born errors of lipid metabolism. 1.6 Complications accompanied with hyperlipidemia 5 6 7 7-10 11 11,12 13 Section 11 2.0 Behavioral Oriented therapy. 2.0.1Dietry guidelines for patients with high cholesterol. 14-15 2.0.2Using exercise in the management of hyperlipedemia. 16,17 2.0.3 Stopping smoking. 18 2.1Natural products used in lowering the lipid levels 19,20 Section 111 Drugs used in the treatment of hyperlipidemia This section will deal with: 21 3.0 The pharmacological mechanisms. 3.1 Anti hyperlipidaemic effect 23 3.2 Pharmacoeconomics 23 3 21,22 Section 1V Closer look on hypolipidemics 4.0 Bile salt sequestering agents. 4.1 Fibrates. 4.1.1 Clofibrate 4.1.2 Gemfibrozil 4.1.3 Fenofibrate 4.2 Nicotinic acid (Niacin) 4.3 HMG CoA reductase. 24-26 27,28 29,30 30,31 32 33-36 Section V Summary 37-39 Section V1 Conclusion 40 References 41 4 Section l: Introduction 1.0 Definition of hyperlipidaemia It’s a disorder characterized by the increase in circulating fatty acids, triglycerides and cholesterol. It can be diagnosed performing a complete lipid profile. It can be solely genetic in origin or secondary to a number of disease states such as diabetes, hypothyroidism, liver or renal disease or some types of drug treatment but most cases are attributable to diet. This increase in the circulating lipids is responsible for other cardiovascular complications. These complications can be fetal with high morbidity and mortality rate. The risk profile for specific lipid concentration Risk degree Total lipid LDL HDL Triglyceride (mg/dl) High Above 245 Above 190 Below 35 1000 Moderate 221-244 160-189 36-44 500-999 Mild 201-220 130-159 45-54 250-499 Average 182-200 100-129 55-65 152-249 Low Below 182 Below 100 Above 60 150 5 1.1 Types of lipoproteins: It’s very important to understand what are lipoproteins, their different types and their specific functions as the disease is nothing but a disturbance in their function or an abnormal count. Also hyperlipidemia was classified according to the type of lipoprotein found in excess. Lipoproteins are macromolecules found in the blood, their main function is to transport lipids and overcome the hydrophilicity of blood. While the Apolipoproteins are recognition sites found in the surface of lipoproteins facilitating their entry to the cell. Accordingly Hyperlipoproteinemia can be considered as a result of abnormal increase in lipoproteins or decrease in apolipoproteins. They are five main types of lipoproteins: 1-chylomicrons: large triglyceride rich lipoproteins formed in the intestinal mucosa following the digestion of dietary fat. They are released into the lymphatic system and then circulated via the blood to body tissue where cells remove triglyceride for their energy needs. 2-VLDL: [very low-density lipoprotein] triglyceride rich structures formed in the liver from chylomicron remnants and re-released into the circulation. 3-ILDL: [intermediate low-density lipoprotein] rare type of lipoprotein. 4-LDL: [low-density lipoprotein] derived from VLDL, these supply the tissue with cholesterol for functions such as membrane and hormones synthesis. Most of the cholesterol in the blood is carried on LDL and this fraction is associated with atherogensis. When the LDL is found in large amounts the liver will stop its synthesis of cholesterol. 5-HDL: [high-density lipoprotein] it gathers up surplus cholesterol and transport it to the liver for disposal. That is why a high level of it is protective. Their action can be summarized as lowers the LDL bind to free cholesterol and so prevent their disposition in muscles transport cholesterol from the liver and GIT to peripheral tissue. Activates lipoprotein lipase, which breaks down VLDL & Chylomicrons. 6 1.2 Lipids’ pathway: 1st) Exogenous pathway: 1. Chylomicrons formed from dietary cholesterol and triglycerides is metabolized in the adipose tissue and muscle by the enzyme lipoprotein lipase which removes the triglycerides leaving chylomicron remnants containing intact cholesterol esters. 2.When the chylomicron remnants reach the liver they are taken up by hepatocytes and then cleaved releasing free cholesterol. 3.Cholesterol can be: a) Stored in hepatocytes as cholesterol esters. b) Released in bile as cholesterol or bile acids. c) Used to form membranes or endogenous lipoprotein. B) Endogenous Pathway: 1.VLDL is formed in the liver from triglycerides and cholesterol generally as a result of high caloric intake. 2.VLDL is released in the plasma where lipoprotein lipase cleaves the triglycerides off. 3.The hydrolysis of VLDL produces IDL which: One. Can be taken up by the live via endocytosis and then cleave it to produce free cholesterol via LDL receptors. b. It can remain in circulation where triglycerides are removed so that IDL is metabolized to LDL. 4.LDL is involved in the transport of endogenous cholesterol ester to the liver or to the extrahepatic tissue. LDL is 60-70% of plasma cholesterol. Metabolic demand for cholesterol (bile acids, steroids, and membranes) is met by increasing the synthesis of LDL receptors, which promote endocytosis, and release of free cholesterol. 5. HDL: transports cholesterol from peripheral cells back to the liver. HDL absorbs free cholesterol released during cell turnover. This cholesterol is esterified by the enzyme lecithin: cholesterol acyltransferase and the cholesterol esters are transferred to VLDL or LDL particles. C) Non-Specific: 1.When lipoproteins increases macrophages take part in lipoprotein degradation. 2. This leads to cholesterol deposits in macrophages or arterial walls (atheromas) and tendons and skin xanthomas. Mainly this pathway will be responsible for the following complications 7 1.3 Diagnostic and laboratory test The protein component of lipoproteins, which plays an important role in lipid transport, is composed of several specific polypeptides called apolipoproteins. These are also involved in the binding of lipoproteins to their receptors at the cell surface and so the lipid uptake. There are two types: 1. Apolipoprotein A (apoA): it is the major polypeptide component of HDL lipoprotein. There are two types A-I that constitute 755 of the apoA and A-II, which constitute 20% of the total HDL protein. When the apo A-I level increases it indicates an increase in the HDL in the serum. That is why apo A is found in a higher concentration in women before menopause. It was found that apoA gives a better index of atherogenic risk more than the HDL assay. 2. Apolipoprotein B (apo B) : it is the major polypeptide component of LDL lipoprotein. At the same time it is 40% of protein portion of VLDL. It is found in two forms apo B-100 & apoB-48. The latter transports ingested lipids through the intestine and into the blood stream. While the former is mainly responsible for the disposition of cholesterol and is the principal transport mechanism for endogenous cholesterol. That is why it is a better indicator of atherosclerosis heart disease than LDL serum concentration. 3. A new independent risk factor for atherosclerosis is lipoprotein (a) referred to as “lipoprotein little a” which is made up of apoA and an LDL –like protein containing apoB . It was found that apoA is a deformed relative of plasminogen, the precursor of the proteolytic enzyme plasmin, which is responsible for dissolving fiber clots. This strong resemblance between an apolipoprotein and plasminogen may provide a link between lipids the clotting mechanism and atherosclerosis. Microthrombi containing fibrin on the vessel wall becomes incorporated into the atherosclerotic plaque. That is why it is suggested that, the following endothelial damage, Lp (a) may institute itself into the arterial wall inhibiting the cleavage of fibrin in microthrombi by computing with plasminogen for access fibrin. And the so the atherogenic damage occur causing an occlusive disease or damage. 8 A group of factors was found to interfere with the apoA & apoB values and so these factors can be classified as indications or risk factors for a patient with congestive heart disease or atherosclerosis. A] Factors interfering with the ApoA concentration: 1. Physical exercise will increase apoA and especially the apo A-I which constitute 75% of the apoA found in HDL. 2. Smoking decreases the level that is why it is a risk factor for CHF. 3. Some drugs increases apoA levels like carbamazepine, estrogen, ethanol (in low doses because in high doses or chronic use it increases the apoB), lovastatin, niacin, oral contraceptives, phenobarbital, pravastatin, and simvastatin. 4. Some drugs decrease the apoA which include androgens (that is why men usually have a lower HDL concentration and being a male is considered as one of the risk factors for CHD), beta blockers, diuretics, and progestines. B] Factors interfering with the ApoB concentration: 1. Diets high in saturated fat and cholesterol may increase apoB. 2. Drugs that increase apoB levels include androgens, beta blockers, diuretics and progestins 3. The drugs that decrease apoB are the statins, cholestyramine, estrogen, neomycin, niacin and thyroxin. C] Drugs that decrease lipoproteine (a) include estrogen, niacin, neomycin and stanzolol Patients care: 1. Before doing the test the procedure has to be explained to the patient and instruct him to fast for 12 to 14 hours and smoking is prohibited. 2. The test is done by collecting venous blood in a red-top tube. Any drugs taken which may affect the test results has to be indicated. 3. After the test apply pressure or pressure dressing on the venipuncture site and observe it. 9 Explanations of abnormal findings: Apolipoprotein Increase ApoA Decrease Pregnancy Heart disease Weight reduction Familial hypoalphalipo- Familial hyperalphalipo – proteinamia proteinaemia Fish eye disease Renal disease Hemodialysis ApoB Hyperlipoprotenimia Hyperthyroidism Coronary artery disease Malnutrition Nephrotic syndrome Weight reduction Hypothyroidism Chronic anemia Anorexia nervosa Reye’s syndrom COPD Inflammatory joint disease Lp(a) Chronic renal failure Alcoholism Estrogen depletion Malnutrition Sever hypothyroidism Chronic liver hepatocellular Premature coronary artery disease disease Stenosis of cerebral arteries or coronary arteries Familial hypercholesterolaemia 10 1.4Classification of hyperlipidaemia: Hyperlipidaema 1 11a 11b 111 1v V Lipid Cholesterol N+ + + N+ N- N+ Triglyceride + N + N+ + + Chylomicron + N N N N + VLDL N- N+ + N- + + Lipoprotein ILDL + LDL - + + + N- - HDL - N N N N- - N= normal level (+) = Increase (-) =Decrease N+ =slight increase N- = slight decrease 1.5 Inborn errors of lipid metabolism: Disorder of Sphingolipids This disorder has a particular importance in nervous tissue, probably as vital components of membranes. Disorders of their metabolism has sever consequences. Gaucher’s disease There are different forms with different ages of appearance of symptoms. In all glucocerebroside accumulate because of deficiency of glucocerebrosiclase in the spleen, liver, bone marrow, leukocytes, and sometimes in brain or lung. There is hepatospleenomegaly, anemia, bone disorder & often cerebral degeneration. 11 Niemann-Pick disease Sphingomyelin accumulation in spleen, bone marrow, liver & usually in brain and retina with cerebral degeneration & early death. Tay –Sachs disease Famulal amaurotic idiocy. It is characterized by the accumulation of ganglioside in brain resulting in progressive cerebral degeneration (with idiocy) and loss of vision (amaurosis). The specific enzyme defect is not known, but the disease is due to inheritance or a recessive gene. In the infantile form symptoms appear 4-6 months of age, and the disease is lethal in early childhood. Disorders of triglycerides metabolism: 1. Hyperlipidaemia : It is due to high levels of triglycerides . Chylomicrons sometimes occur in the plasma because of congenital absence of a specific lipase. The condition is relatively benign. There may be xanthomata consisting of small lumps of fat under the skin and enlargement of the liver and spleen. 2. Acanthocytosis : It is the hereditary absence or deficiency of lipoprotein results in a low level of plasma triglycerides. Cholesterol levels are also low. The red cells are spherical & thorny but are restored to the normal shape by addition of a surfactant. 3. Hypercholesterolaemia A : It is the hereditary tendency for high plasma level of cholesterol to occur engenders an early occurrence of atherosclerotic disorder, xanthomata are present in skin & tendon sheets Familial hyperlipidaemias: Type Hyper- Elevated Cholesterol Triglyceride lipoprotein Level Level LDL Very high Normal Cholesterolaemia Cause Impair removal Of LDL Combined LDL & Hyperlipidaemia VLDL Chylomicronaemia Chylomicron High High Increased in VLDL and LDL Normal High Enzyme deficiency High Increase VLDL or slight rise Hyper_ VLDL & Triglyceridaemia Chylomicron Slight rise &Triglycerides 12 1.6 Complications Accompanied with hyperlipedaemia: Atheriosclerosis: It’s a vascular disease characterized by patchy subintimal thickening of medium and large arteries which can reduce or obstruct blood flow. The pathogenesis of atheriosclerosis is, as yet, far from completely elucidated and, indeed, within the LDL particles themselves, there is a structural heterogeneity. Approximately fifteen sub-fractions have been isolated so far, presenting differing profiles in normal and hyperlipidaemic subjects. Some of these subgroups seem to be linked with an atherogenic potential, this is the case for the smaller and the denser of the particles. The particles must however undergo several in vivo and in vitro transformations which modify their metabolism and are all the more important when their half life is prolonged. These transformations, and in particular oxidation, lead, via the macrophage pathway, to the accumulation of cholesterol, the production of foam cells, and ultimately to the formation of the lipid streak. Antioxidants therefore open the way to new therapeutic approaches. They can act synergistically with drugs that have a profound effect on the quantity of circulating particle (mainly statins) or on the qualitative aspects (mainly fibrates). Atherosclerosis is considered of one of the risk factors causing ischemic heart diseases. This occurs when an atheroma (fatty tissue) is deposited in the wall of blood vessels, and the coronary arteries seem particularly susceptible. Atherosclerosis develops and is a complex mixture of fatty deposits, fibrous tissue, smooth muscle proliferation and some blood constituents. Ischemic heart disease has to will managed by drugs because it may lead to death. This is expected when a thrombus is formed in the coronary arteries and so leading to a myocardial infarction or it might lead to heart failure. This occurs when the heart fails to do its work of pumping the blood due to the lack of oxygen supply and so in the heart ability to contract. The bright side is that the development of atheroma occurs only when the lipids are found in excess amounts. This stimulates a new pathway for the metabolism of lipids and will lead to the development of complications. Also hyperlipidaemia along with smoking, hypertension and diabetes are one of the main causes of peripheral vascular diseases. Pancreatitis: This as an acute inflammation of the pancreas with a high mortality. The inflammation and necrosis are caused by activation of destructive pancreatic enzymes. It is associated with raised triglycerides 13 _______ ____________________ _Section11 2.0 Behavioral Oriented therapy This method of therapy couples low fat vegetarian diet, exercise , and stopping smoking along with stress reduction together to face cardiovascular complications such as Hyperlipidaemia . It also emphasis involvement of the patient in the treatment program so as to improve his well power and help him comply with medicine .The patient should know the effectiveness of the early management, which can be summarized in three points: 1 Every 1% reduction will decrease the risk of further complications by 2%. 2 Each 1mg/dl increase of HDL will decrease the risk of cardiovascular complications by 2-3% 3 A diet regimen that contains 30% of fat and 7% of the total diet is saturated fat will lower LDL by 15%. These results were very encouraging despite that several problems were encountered 1.It’s very hard for a patient to know the suitable diet and calculate the calorie intake daily. 2. The drug therapy shows fast and convincing results with least of effort. 3.Doctors prefer giving drugs because patient training to adapt a healthy life style will require long counseling secessions. 4.The results obtained were variable. 2.0.1 Dietary guidelines for patient with high cholesterol: Fruit and vegetable along with oats and pulses can lower the LDL and total cholesterol when they are taken in large amounts in order to have significant results. Dietary cholesterol has much less influence on blood cholesterol level than dietary fat. This is because a large proportion of the body’s cholesterol is synthesized by the liver rather than being obtained from diet. That is why within normal intake increased dietary cholesterol will be counterbalanced by decreased cholesterol production by the liver. Also he has to be aware of the type of fats found in his diet which can be classified to: 1 Saturated fatty acid, these can rise the serum LDL and total cholesterol, they are found in dairy & meat. 2 Monounsaturated fatty acids, they can lower LDL and total cholesterol and they are found in olive oil. 14 3 Polyunsaturated fatty acids, they lower LDL and total cholesterol but in large quantities they have the disadvantage of lowering HDL. This type is found in plant oils. 4 Trans fatty acids, they are isomers of unsaturated fatty acids and they can rise LDL and total cholesterol. They are artificially created when vegetable oils are hydrogenated . Dietary recommendations as listed in Mayo clinic diet manual 7th edition, chapter 7,P.141 Item Avoid Decrease Use instead Milk Whole or 2% milk ,ice cream cottage Skim milk or 1% fat, non fat yogurt from whole milk Ice- cheese 4% ,low fat yogurt 1- yogurt, fat free cheese, low fat cream 2% skim milk cheese cottage cheese, pot cheese. Egg yolks, peanut butter Lean meat, fish, water packed marbled, cold cuts, bacon Nuts, fish canned in oil tuna or salmon, low fat cold frankfurters, sausage fried oysters, shrimp cuts & frankfurters, egg white milk, cheese or nondietary Substituents Meat Grain Organ meats ,heavily meat, canned meat & meat Poultry without skin, Dried mixes beans Rich baked pies, cakes Baking products made with Whole Cookies,donuts,sweet unsaturated fat and less than cereal, English muffins Rolls, pastries & muffins 3g fat/serving Bagels & bread sticks, rice, ,crackers & chips grain breads and pasta, macaroni, potatoes,plain popcorn Fig bar cookies Fat Saturated fat, butter, lard, Mayonnaise, creamy salad Oils: corn, sunflower, bacon fat, gravy and cream, dressing, reduced calorie sour soybean, and sesame, cotton sauce cream, cream cheese, cream or cream cheese seed, canola, peanut. hydrogenated margarine & Fat free:spreads, dressing shortening coca butter & Cream cheese & sour non dietary creamers cream.Margarine & salad dressing from un-saturated oil. Fruit & Coconut or servings with Avocado & olives cream, creamy sauce, butter vegetable Fresh, frozen, canned or dried fruit and vegetable & dips Note: 15 In the previous table the term Low fat means less than 3g of fat/serving while fat free means 0-0.5 of fat/serving Patient advice: There are certain hints, which can help the patient get restricted to his diet regimen they are: Fat proof the house by throwing all the drugs which he has to avoid by this he can save him self from getting back from his decision. Set a rule that the only place for eating is the dinning table not the car or during work because this will help him diet and to stick to his diet. Find other interests and try to fill his time and revive old hobbies or start a new one and get in touch with old friends and try to do all the things which will help you enjoy your time then you can eat to live not live to eat. Check the food labels to know the amount of fat found in them because it is a common mistake to deprive ourselves from many things we like to eat and substitute them with others which has a higher fat content. Take it easy as the change in diet has to be done in steps and gradual until the person change all his eating habits and change his overall lifestyle. 2.0.2 Using exercise in the management of hyperlipidemia The National cholesterol education program (NCEP) Recommendations for the management of high lipids level Daily exercise is a healthy practice for all individuals of all age groups. Yet, in some cases exercise becomes an essential daily practice and can also be considered as part of medication and in case of dylipidaemia it is as important as diet . Individuals of high BMI more than 25 is of risk to cardiovascular complications especially when the BMI exceeds 35 then doing exercises and especially walking (moderate speed for 20 min) will be of great benefit. Also the regular exercise is of great use for the hyperlipidemic patient and this is because it was found to be of use in elevation of HDL which protects from the cardiovascular complications. On the other hand the weight reduction accompanied with the exercise will decrease the risk of hyperlipidemia complications. 16 To obtain this benefit there is a specific program, which must be followed for one year to obtain the wanted results. This program has to be supervised by professional trainers to help the patient getting the most out of it. Mainly the program is divided to three phases were the patient has to go through them in sequence. The following table shows the different training phases. Phase Aerobics Strength Sets/Reps Comments Walking General motion 2 set of 15 reps with 1-on 1 conditioning 10-15 min of major light weights 1 muscles OR Stationary Light dumb 2 sets of 15 reps or 1- Work on improving range of cycling Bells 2 sets of 5-10 reps motion and techniques. Light dumb 2-3 sets increase 8-10 5 lb. on upper body Bells reps/wk 10 lb. on lower body and 10-20 min 11 Work out 20 min 3-4 days/wk 111 Low classes improving self dependence impact Use strength machines 2-4 sets of Must work in perfection of 10-8-6 reps exercise strength and range of motion. Patient advice: Every day researchers discover new health benefits that come from regular exercise. And to do it regularly it has to part of the daily lifestyle and the patient has to enjoy it by: Find an activity which you like then you will have a motive to go out for it every day. Find a partner to exercise with this will keep you company and keep you motivated . when choosing the partner from the family or friends make sure that he is fit and of your level because it can be discouraging when training with someone who is much better shape. Join a local health club because the experts can answer your questions and set a program for you which are challenging but yet manageable. Start slowly until you can build your endurance then it will be easier for you to continue. Don’t give up easily you may feel sore muscles. But remember, it took you your body many years to become unhealthy so it will not magically change overnight. Just stick to it 17 and before you know it your muscles will stop aching , you’ll be able to work for longer periods of time, and your weight will start to decrease . 2.0.3 Stopping smoking: smoking is a bad habit and unfortunately many people are engaged to it despite of the warning found in it which indicates that it is a direct cause for cancer, heart problems, dyslipidaemia and atherosclerosis. That is why the patient has to be advised of the importance of quitting smoking immediately and completely. It is not enough to decrease the number of cigarettes or to switch to a filtered brand of cigarettes. Further smoking of any kind increase the risk of having a heart attack. The good news is that it is easier to quit smoking than ever before, thanks to nicotine replacement therapies and innovative support programs. But yet it is the role of the patient to seek help after deciding to quit now and forever. For some people it is hard to quit and for these they need to consult a professional person to help him out. It is also important not to get discouraged if you failed or you didn’t succeed right away, or you have a history of quitting and coming back. That is because the benefit you are getting is worth trying on and on again. Start now… It is important for the patient to know that there is a lot to do which can save your heart and your whole body. That’s why don’t waste another minute and know that the right time to start is now. Toss out the bad habits and start living and make sure you know why are you doing all this, because this will be your real motive to continue. Ask for a professional help and consult him regularly to check that you progress toward a healthier heart and a better future. Even if you failed, never mind as it’s the time to start again , learn from your mistakes and then you may be a professional who can help others getting into the right tract you are now in. A healthier life is worth going for and 18 2.1 Natural lipid lowering agents Chromium: It’s an element, which was first indicated for diabetic patients, as the chromium is a cofactor for the insulin action. A similar action was found for the lipid metabolism. Yet it’s not so effective as enough of it is already present in our diet and any excess will be excreted. That’s why chromium supplement is only given to patients with deficiency. Cod liver oil (anti- thrombogenic) It’s common name is “oleum morrhuea” and it’s the partially destearinated fixed oil obtained by aid of steam from fresh liver of the cod fish Gadus morrhua family Gadidae. The oil is pale yellow liquid with slight fishy odour and taste. The oil consists of glycerides of unsaturated acids 85% & glycerides of saturated acids in addition to VitA and the VitD. It was found to increase the HDL and so it can protect from vascular complication like atherosclerosis and ischemic heart disease. In commerce it is found in the form of capsules and syrup known as Maxipam rich in omega-3-marine triglycerides. It is useful in the treatment of hypertriglyceridemia however it can aggravate hypercholesterolemia. Indications: to reduce plasma triglycerides especially after IHD or pancreatitis. S/E: nausea and belching. Capsules description: 1ml concentrated fish oil, Eicosapentaaenoic acid 18%, Docosahexaenoic acid 12% Vit. A <100 unit/g, Vit. D < 10 units/g Liquid description Golden colored liquid with the same constituent. Olive liver oil: Its common name is “sweat oil” and its obtained from the expressed fixed oil from ripe fruits of olea europaea family oleaceae. The olive oil is pale yellow or light greenish yellow oil with characteristic odour and a bland faintly acrid taste. There are two varieties of olive Turkish & Italian. Research has provided proof that a Mediterranean style diet, including olive oil, is a healthy diet and that olive oil may reduce cholesterol levels. 19 The American Heart Association found that in researching the modern day diet that Greece an especially the island of Crete had the lowest mortality rate due to cardio-vascular illness. Finland and the United States had the highest mortality rate. The only notable difference between the countries was the type of fat ingested. In countries with high incidents of cardio-vascular disease, saturated fats were most often consumed. Saturated fats are high in cholesterol. Monounsaturated, on the other hand, contain no cholesterol. Olive oil contains unsaturated fatty acids and they are Oleic and linoleic acid. Olive oil is 80% oleic acid, placing it at the top of the list of monounsaturated fats. Research has proved that using olive oil significantly increases HDL levels and that olive oil is the main source of monounsaturated fatty acids. Garlic was worshipped by the ancient Egyptians, chewed by Greek Olympian atheletes and thought to be essential for keeping vampires at bay! But it is also good for zapping bacteria, keeping your heart healthy, warding off coughs and colds .There are now over 12 well designed studies published around the world that confirm that garlic in several forms can reduce cholesterol. Most recently researchers in Oxford and America have published some summaries of all the good data on garlic. Garlic as lipid lowering agent a meta analysis The Journal of the Royal College of Physicians. The authors state that garlic supplements have an important part to play in the treatment of high cholesterol and that this paper reviews all the published and unpublished data from around the world. Overall a 12% reduction in total cholesterol was shown over a placebo and that this reduction was normally evident after only 4 weeks treatment and that this was likely to persist for as long as the study was in progress. The largest study so far was conducted in Germany where 261 patients from 30 general practices were given either garlic powder tablets or a placebo. After a 12 week treatment period mean serum cholesterol levels dropped by 12% in the garlic treated group and triglycerides dropped by 17% compared to the placebo group Diet rich in fiber is also useful in people suffer from high lipid levels because it will decrease the appetite and so help the patient decrease the weight to the normal BMI which is 20-25.It also decreases the lipid absorption from the GIT. 20 Section 111 3.0 Drugs used in the management of hyperlipidemia: The use of drug for the management of hyperlipidaemia is not the first line of treatment. As before prescribing any medication the physician first has to: 1. Define the type of hyperlipoproteinemia and establish the baseline serum cholesterol and triglyceride levels. 2. Institute a trial of diet, weight reduction and physical activity and make sure that the patient adhere to the diet regimen, 3. If the dietary program failed to reduce the lipids level then therapy has to initiate. 4. Monitor serum cholesterol and triglyceride during therapy. 5. If the prescribed medicine failed to reduce the cholesterol and triglycerides within three to four month then this medication has to be discontinued and start a new drug or use combination therapy. Hypolipidemics is a classification for a group of drugs, which has the ability to lower the serum cholesterol or triglycerides. Their correction of blood lipid abnormalities offers scope for a major impact on cardiovascular disease. They are classified into four main groups according to their mechanism of action 1) Anion exchange resins [bile salt sequestrates] 2) Fibric acid derivatives 3) Nicotinic acid and derivatives 4) Stations [HMG COA reductase inhibitor] 3.1 pharmacology of lipid lowering agents: Anion exchange resins They act by binding to bile acids in the intestine and so they are lost in the feces and so the depletion of the bile acid pool stimulates conversion of cholesterol to bile acid in the liver. This will lower LDL by 20-25%. That’s why they are first line treatment in hypercholesteraemia but it can aggravate hypertriglyceridaemia It’s suitable for type 11a, 11b hyperlipidaemia. 21 Fibric acid derivatives These drugs inhibit hepatic lipid synthesis. This will cause a drop in plasma cholesterol by 10-15% and triglycerides by 20-30%. This effect is associated rise in the protective HDL that’s why it was found that the use of this group of drugs will decrease the danger of myocardial infarction in patients with history of ischemic heart disease. Suitable for type 11b,111,1V & V of hyperlipdaemia Nicotinic acid and it’s derivatives They exert their action by reducing the supply of non-esterified free fatty acids and hence the availability of substrate for hepatic triglyceride synthesis. Another mechanism of action is that it increases lipoprotein lipase activity. That’s why its beneficial in lowering both cholesterol (VLDL & LDL) and triglycerides . It also increases HDL cholesterol. It is suitable for 11a, 11b, 111, 1V And type V of hyperlipidaemia. Statins They inhibit the rate-limiting enzyme in endogenous cholesterol synthesis, hydroxyl-methylglutaryl coenzyme A reductase. This result in increased synthesis of LDL receptors (up regulation) in the liver and clearing of LDL from the circulation; plasma total Cholesterol and LDL cholesterol undergo a dose-related reduction. LDL cholesterol falls by about 30% at a dose of 20 mg/dl. Statins are the drugs of choice for type 11a with severs intractable hypercholesterolaemia especially those with established vascular disease. Others 1. Probucol: this drug increases the excretion of bile acids and reduces cholesterol biosynthesis; the resulting fall in plasma lipid concentration affects both LDL and the protective HDL. It’s useful For type 11a & type 11b hyperlipidemia. It is useful in atherosclerosis and its also thought to be carditoxic. 2. Dextrothyroxine sodium: this drug stimulates the liver to increase catabolism and excretion of cholesterol and it’s degradation products via the biliary route into the feces. In this mechanism cholesterol synthesis is not inhibited and it is normally metabolized so no accumulation occur in the blood. This drug was also used for obese patients as it has a significant effect in weight reduction but on the other hand it was found that large doses could produce toxic life threatening side effect. 22 This effect was more encouraged by along term study that stated that the subjects taking dextrothyroxine had a higher mortality than placebo subjects. That is why dextrothyroxine is considerably no more used. 3.2 Antihyperlipidaemic effects Drugs Lipid Lipoprotein Cholesterol Triglyceride VLDL LDL HDL Cholestyramine D -I -I D -I Clofibrate D D D +D -I Gemfibrozil D D D +D I Fenofibrate D D D I I Nicotinic acid D D D D I Statins D D D D I Dextrothyroxine D +- +- D +- NOTE: D = Decrease, I = Increase , -I = Increase or unchanged, +D= Decrease or unchanged, +- = unchanged 3.3 Pharmacoeconomics The price of the drug is one of the considerations, which has to be taken into consideration when prescribing a drug. Generally all lipid-lowering agents are expensive so the physician has to consider the economical status of the patient so that to obtain the optimum compliance. Trade name Drug Produced by Price Dhs Lopid 600 mg Gemfibrozil Parke- Davis 151.5 Dhs Lipitor 20/10mg Atrovastatin Parke-Davis 256.5 Dhs Lipostat 20/10 mg Provastatin B.M.S 146.5 Dhs Zocor 20 mg Semvastatin MSD 225.5 Dhs Lescol 40 mg Fluvastatin Novartis 116.5 Dhs Lipobay 0.3/0.2 mg Cerivastatin Roche 145 Dhs Xenical 120 mg Fournier 361 Dhs Lipase inhibitor 23 Lipanthyl Fenofibrate Bayer 20.5 Dhs Section 1V Closer look on Hypolipidemics 4.0 Bile salt sequestrants (BAS) Namely Cholestyramine & Colestipol Indications: 1. Hyperlipoproteinemia which doesn’t respond to diet 2. Cholestyramine is used for biliary obstruction. 3. It can be used for pesticide poisoning by binding to chlordecone (kepone) 4. Antidote for digitalis toxicity as it decreases its absorption from the GIT. 5. Cholestyramine is given for thyroid hormone overdose. Pharmacokinatices Reduction in cholesterol begins in the first month. Its not absorbed from the GIT tract. Resin and its complexes are excreted in the feces. Dosage form: Cholestyramine: It is found in the form of powder 4g resin/9g drug packet or scoop. Or in the form of powder 4g resin/5g packet or scoop. Colestipol : Granules 5g resin/7.5g packet or scoop Or in the form of 1g tablet not to be broken. Doses : Cholestyramine: Initial dose 4g daily bid Maintenance dose 8-16 g/day in 1-6 doses, to maximum of 24g/day. Colestipol : Initial dose 5g daily bid Maintenance dose 15-30g/day in 1-4 doses. Note : 24 The increase in the dose was not always accompanied with decrease in the lipid levels that’s why the drug is best given at its low doses. Also because at low doses the side effects are less and are well tolerated Warning: 1. Not to be given in powder form and accidental inhalation has to be avoided 2. Calcified material was observed during the treatment with BAS but it is not certain that this material is due to the treatment as it can be due to a pre-existing liver disease 3. Carcinogensis: Alimentary system cancer was noticed during the treatment with cholestyramine but in a study done on mice it was found that fatal and non-fatal neoplasm was similar in both treated and controlled. Precautions: 1. The serum cholesterol has to closely monitored for the first few month. Then periodical check for serum cholesterol and triglycerides has to be carried out. 2. Malabsorption: It interferes with normal fat absorption and digestion and so causes deficiency in vit A,D,E,K & folic acid .That is why supplements of these vitamins should be given with the treatment. 3. Hyperchloremic acidosis : this is common in young patients and those using high doses 4. Constipation :this is due to the accumulation of feces and its impaction which might aggravate hemorrhoids. This side effect is dangerous in patients with symptomatic coronary artery disease. When constipation is so sever decreasing the dose or even discontinuation of the treatment is advisable. Also laxatives or stool softeners can be given. Drug interactions: Cholestyramine interactions: 1. Decrease anticoagulants effect so increase their dose, this interaction is most possible in pateint with high lipid levels using BAS and is taking aspirin prophylactically after a history of MI. 2. Decrease the AUC of Mycophenolate by 40%. This indicates a change in drug clearance which is possibly an increase, that is why a recalculation of the dose will be important. 3. Increase piroxicam elimination. That makes other NSAIDs more suitable. 25 4. Causes loss thyroid hormone efficiency and so aggravates hypothyrodism. Colestipol decreases the bioavailability of gemfibrozil BAS (colestipol & cholestyramine) causes: 1. Decrease the AUC and Cmax of Diclofenac. It can be subistituted with another NSAID. 2. Decrease the absorption of Ursodiol. 3. Decreases the GIT absorption of many drugs like: Aspirin, Clindamycin, Clofibrate, Digitalis, Furosemide, Glipizide, Hydrocortisone, Imipramin, Methyl dopa, Nicotinic acid, Penicillin Phenytoin, Phosphate supplement, Propranalol, Tetracyclines, Thiazide diuretics & Tolbutamide Adverse reactions: 1. The most common adverse reaction is constipation. 2. In the CNS it has a vasoconstriction effect that’s why headache, syncope, dizziness, drowsiness are common. Also the use of the drug might be accompanied with insomnia, fatigue & vertigo. 3. Hemolytic problems will lead to anemia & echymosis. 4. Hypersensitivity in the skin or respiratory system. 5. In the renal it might induce dysuria, hematouria or diuresis. 6. Others: edema, weakness and loss of weight can a result of hemolytic problems or malabsorption which will also lead to Vit A, K, D deficiency and if supplement were not given then other complications might arise like rash, osteoporosis & bleeding abnormalities. Patient advice: 1. The drug is taken before meals. 2. The drug is not taken in a dry form but it has to taken with fluids. 3. Other medications should not be taken 1hr before or 4 to 6hrs after. 4. GIT disturbances can disappear upon repeated administration of the drug. And constipation can be decreased by laxatives. 26 5. Regular counseling with the doctor to perform the laboratory investigations for the LDL level, liver function tests & hemoglobin. 6. If the patient cannot tolerate the side effects he has to be aware of measuring the risk to benefit ratio and these facts has to clearly explained to him. 4.1Fibric Acid derivatives: Namely they are: Clofibrate, Gemfibrozil & Fenofibrate . They all share the major pharmacological action of all fibric acid derivatives but they are different in other aspects like the indications, contraindications, doses and patient advice when being on any of them. 4.1.1 Clofibrate: Indications: 1.Dysbetalipoproteinemia: this is type 111 hyperlipidaemia which is not responding to diet therapy. 2.hyperlipidaemia for type 1v & v hyperlipidaemia. Pharmacokinatices: It is a prodrug as it is hydrolysed in the body to the active form of the drug which is CPIB. The plasma peak levels occur within 3 to 6hrs. The drug has a 97% plasma protein binding which decreases with the increase of plasma concentration. 40-70% of the drug was found in the urine in the form of glucuronide ester derivative of CPIB. The plasma elimination half life is about 15%hrs which increases in case of renal impairment. Administration & Dosage: The adult dose is 2g daily in divided doses. Contraindications & warning : 1.The use of clofibrate was found to be related with a high incidence of liver tumorigenicity as well as malignancy and choletethiasis. 2.It is not used in the management of fatal myocardial infarctions as it was found to be accompanied with increase in cardiac arrythmias, definite or suspected thromboemoblic events and angina. Pregnancy & lactation: 27 The drug is not indicated for pregnant or lactating women as it was found that it can cross the placenta and is excreted in the milk. Drug interactions: 1.It decreases the effectiveness of anticoagulants so the dose has to be increased when given with clofibrate. 2.reduction of the plasma protein binding of dantrolene so its dose has to be decreased in order to avoid the toxicity which can occur when the two drugs are given together. 3.an exaggerated diuretic effect was experienced with furosemide when taken with clofibrate so dose reduction has to be done and take care of the dehydration or hypotension which can be one of the complications of this therapy. 4.When given with ursodiol its effectiveness especially when gallstones are produced. 5.Oral contraceptives increase the elimination of clofibrate and so its dose has to be increased. 6.Probenecid increase the effectiveness and toxicity of the drug by decreasing its renal clearence so lowering the dose is necessary. Major side effects: 1.Was found to induce ischemic heart diseases and arrythmia, this side effect is significant if we put in mind that most hyperlipidaemic patients is suffering from cardiovascular complications. 2.Induces allergy in the skin and kidney causing hematuria, dysuria and in some cases proteinuria. Another side effect is loss of lipido and impotence. 3.commenly is flu-like side effects 4.GIT disorders nausea is most common & inflammation or gall stone Patient advice: 1.Monitor the lipid level as in some cases it was found that clofibrate was not effective in lowering the lipid levels. 2.Perform complete blood count regularly as the use of the drug was found to be associated with anemia and leuckopneia. 28 3.Perform frequent liver function tests to indicate any liver dysfunction at its early stages. 4.Any contributing factor should be pointed out and treated like alcohol, obesity, hypothyroidism and diabetes mellitus. 5.Adhere to the prescribed diet after the start of therapy. 6.If any GIT upset was noticed then the patient should be advised to take the drug after food. 4.1.2 Gemfibrozil Indications: 1.Hyperlipidemias of type 1V and V with very high serum triglycerides 2.Patients at risk of pancreatitis and not responding to diet. 3.Patients with low HDL levels and are not responding to weight loss, diet or exercise and other drugs like BAS or niacin. 3.For type 11b patients but they do not have a CHD history. Pharmacokinatices: It is well absorbed from the GIT. The maximum action is obtained after 4-12 weeks and the lipid return to the pretreatment level after drug discontinuation. They are rapidly and completely absorbed after oral administration Mean peak serum concentration of 15-25 mg/L occur within 1-2 hr. Metabolism is done by oxidation. Serum concentrations are directly proportional to dose. The drug is 97-98.6% bound to plasma albumin. Clearance appear to be independent of renal function, but in this case further study and dose adjustment has to done.70% of the dose is excreted in the urine primarily as glucuronide conjugates. 2% is excreted unchanged. The t.5 is 1.5 –2 hr. but it may be longer allowing complete distribution. Dosage form: A 600 mg tablets are present. Doses: Adult dose is 1200mg/daily in divided doses. Contraindications and warnings: 1. Cholelithiasis and liver carcinoma was noticed that’s why the drug has to be discontinued when gall stones appear. 2. Rhabdomyolysis, myositis and elevation in creatinine level noticed 3. Not given to patient with renal insufficiency as it may cause myoglobinuria leading to acute renal faliure. 29 4. When giving high doses fertility impairment were noticed which was reversed upon discontinuation of therapy. 5. It was found to be safe during pregnancy but not given during lactation. Drug interactions: 1. HMG CoA reductase inhibitors when used in combination with gemfibrozil this therapy was found to increase the incidence of rhabdomyolysis. 2. Gemfibrozil enhances the effect of oral anticoagulants. Common side effects: GIT disturbances are most common like dyspepsia, abdominal pain &Diarrhea others are: inflammation of muscles, gall stones and elevated liver function tests. Patient Advice: 1.the drug is taken 30 minutes before morning and evening doses 2.Dizziness or blurred vision was noticed after the treatment with gemfibrozil so caution has to be done when doing physical or driving. 3.If GIT disturbances were pronounced consult the physician 4.Periodic liver function test has to be performed. 6.Moderate hyperglycemia effect was noticed so contraindicated in diabetic patient and glucose monitoring is essential. 4.1.3 Fenofibrate Indication: 1.For type 1V & V hyperlipidemia. 2.Reduces platelets aggregation and decrease serum uric acid . Pharmacokinatices: It is a prodrug as after it’s absorption they are hydrolyzed to the active drug. They are highly bound to plasma proteins. They are predominantly excreted unchanged in the urine with half-life of 20hrs; this duration is prolonged in case of kidney dysfunction. 30 Dosage Form: Capsules of 67 mg. Adult dose: Initial dose is 67mg/ day which can be increased within 4-8 weeks to a maximum dose of 201 mg/day. Side effects: 1.GIT disturbances as well as allergic reaction and pain. 2.Cholelithiasis was reported but not frequent. Patient advice: 1.Drug should be taken with a meal 2.In case of a history of liver, gall bladder or kidney disease this drug should be avoided Clinical studies: Fibrates mechanism of action is a question which is still attracting the attension of scientists. A study was carried out by Dr. Bart Staels of the institute pasteur de Lille in France, this study aimed to explain fibrates mechanism of action in lowering lipid level and treatment of arteries inflammation accompanied with lipid accumulation in the vessels. Researchers studied two groups of 19 patients who had slightly elevated cholesterol concentrations. In one group, the participants had blocked arteries, and the concentration in their blood of interleukin-6 (IL-6), an indicator of inflammation in blood vessels, was twice that of the other participants. The fibrates lowered lipid levels and reduced IL-6 to a greater extent in the group with clogged arteries. The fibrates also lowered the concentration of two proteins that contribute to clogged arteries and to inflammation: CRP and fibrinogen. CRP is an established risk marker for coronary heart disease but its mechanism is unknown. Fibrinogen is important in the formation of the thrombus (blood clot) at the site of blood vessel injury which can lead to acute blockage of the artery. Furthermore, elevated levels of fibrinogen are an independent risk factor for the development of coronary artery disease. Also Fibrates bind to and stimulate a receptor in the liver called PPARa, which is involved in the breakdown of fatty acids researchers had known. The receptor "regulates the expression of genes involved in fat metabolism. However, PPARa receptors are also present in the cells of vascular muscle walls, where they inhibit the production of inflammatory cytokines such as IL-6 and 31 prostaglandin, the scientists found through examining the participants' blood. PPARa receptors also inhibit the activity of an enzyme called Cox-2 (cyclooxygenase), another contributor to vascular cell inflammation, they report. The chemical on Cox-2 helps inhibit these inflammation processes by interfering with a signaling pathway called NFkB, (Nuclear factor kappa B.) that is identified as a transcription factor regulating kB gene. Now it is known to be a major signal transducer of inflammatory stimuli." 4.2 Nicotinic acid: Indications: Hyperlipidaemia which is not responding adequately to diet and weight loss. Pharmacokinatices: It’s effect in lowering lipid level starts within several days or even its possible after a single dose. Also the return to pretreatment lipid level occur after 2-6 weeks from the drug discontinuation. The drug should be completely absorbed from the standard formulation. The peak serum levels are obtained 30-60 min after 1gm dose is 15-30g/L. It is metabolized in the liver to active niacinamide that contributes in its lipid lowering ability. The t.5 is 20-48 min so its considered as short acting drugs but on the other hand it has active metabolites. Administration & dosage: Doses 1 to 2g three times/days. Maximum dose is 8g/ day Contraindications and warning: 1.hepatotoxicity is common after high doses more than 2mg/day and is diagnosed by liver function tests. In sever cases it might cause fulminant hepatic faliure, hepatic encephalopathy and liver transplantation might be essential. 2.Most common is flushing which can be reversed with 300 mg aspirin given 30 minutes before each dose. Patient advice: 1. The sensation of flushing and facial warming is normal and it can be aggrevated with hot drinks that’s why it has to be avoided. 2. Itching, tangling and headache is common so the patient has to be ready and used for these side effects. 3. If dizziness occur avoid sudden change in posture and avoid driving or complex tasks. 4. When the drug causes GIT upset take it with meals. 32 5. Consult the doctor if an new symptoms appear like: jaundice, nausea or vomiting inorder to carry out other tests like bilurubin concentration or prothrombin time. 4.3 HMG CoA Reductase inhibitors (statins) Namely they are: Atorvastatin, Cerivastatin, Fluvastatin, Lovastatin, Pravastatin, Simvastatin Indication: Treatment with statins (HMG Co-A reductase inhibitors) lowers serum cholesterol substantially and has been shown to reduce myocardial infarction, coronary deaths and overall mortality in recent controlled trials. That is why it is strongly advised to patients who have had a myocardial infarction and is complaining of high lipid level. These patients have a very high CHD risk, and treatment is indicated when the total cholesterol level is 4.8 mmol/l (or Low Density Lipoprotein (LDL) 3.2 mmol/l Other indications are: 1.Primary hypercholesterolemia , mixed dyslipidemia, hypertriglyceridemia, primary dysbetalipoproteinemia, homozygous familial hyperlipidemia. 2.Primapy & secondary prevention from coronary artery events when there is: Patients with angina or other clinically overt atherosclerotic disease who have total cholesterol of 5.5 mmol/l or more (or LDL 3.7 mmol/l or more. This includes patients with peripheral vascular or symptomatic carotid disease or who have had a bypass graft or angioplasty. These patients have a risk of major coronary events which averages approximately 3% a year. People without clinically apparent vascular disease but who nevertheless have a high risk of developing overt CHD People may have this risk because of a combination of other CHD risk factors, particularly diabetes or hypertension. People with familial hyperlipidaemia are at high risk of CHD.) People over the age of 70.There is little trial evidence of benefit or harm fromstarting statin treatment in people over the age of 70 for the primary prevention of CHD. 33 For patient with serum cholesterol above 6.3mmol/l and they are usually started at low doses and they are expected to lower the cholesterol level by 20-25% pharmacokinatices: The onset is within two weeks while the peak effect was reported after 4-6 weeks. After discontinuation of the drug the serum cholesterol returns back to the pretreatment levels.: Absorption is rapid. Systemic bioavailability of the drug is low because of the extensive first-pass metabolism (above 60%). Peak serum concentrations are achieved in 1-4hr. They are bound to plasma proteins with different percents. The lipophilic drugs crosses the blood brain barriers like Atorvastatin, Lovastatin &Simvastatin. The liver metabolizes all the drugs and some gives active metabolites and then they are all excreted in the feces. Renal insufficiency effects the plasma concentration as it decreases the clearance.The different drugs have different duration of action indicated by their variable t.5. Atorvastatin has the longest duration of action as its t.5 is 14hrs while Cerivastatin has a t.5 of 2-3hrs on the other side Fluvastatin, Lovastatin, Pravastatin & Simvastatin have a t.5 less than 2hrs. Statins facts and comparisons: Drug Dosage Doses initial (I) form Maintenance Bioavailability comment (M) Pravastatin Tab 10, 20, 40 (I)10-20 mg q hs 34% , 17% subjected Take without regard mg (M) 10-40 mg q hs to first pass to meals metabolism,50% bind to plasma proteins Simvastatin Tab 5, 10, 20, (I)5-10 mg q hs 60-80%, 95 % bind to Take without regard 40,80 mg (M) 5-80 mg/day plasma proteins and so to meals 5% reach the circulation. Lovastatin Atorvastatin Tab 10, 20,40 (I)20 mg/day 35% , 95% bind to Take with evening mg (M) 20-80 mg/day plasma proteins and meal in are subjected to first 1-2 divided doses pass metabolism Tab 10,20,40 (I)10 mg/day 14%,98% mg (M)10-80 mg/day plasma proteins with bind to first pass metabolism 34 Take at any time Cerivastatin Tab 0.2,0.3 mg 0.2-0.3 mg/day 60% , 99% bind to Take at the evening plasma proteins Fluvastatin Cap 20,40 mg (I) 20 mg q hs 98% but 24% is (M)20-40 mg q hs subjected to first pass Take at any time metabolism Precautions: 1. In women who are expected to be pregnant because the drug is contraindicated for both pregnant and lactating women. 2. In alcoholic patients or those with history of liver disease. 3. In patients with fear of renal failure. Drug interactions: 1) Myositis and rhabdomyolysis when statins are given in combination with CYP3A4 inhibitors like: erythromycin, gemfibrozil, itraconazole, ketoconazole. 2) Warfarin an anticoagulant its effect is increased when it is given with statins. 3) Pravastatin bioavailability is decreased when taken with bile acid sequestrants. 4) With peptic ulcer drugs : Its efficacy is decreased with antacids while omeprazole, ranatidine & cemitidine lead to the increase of its plasma concentration. 5) Propranalol is commonly used in patients with hyperlipidemia and associated hypertension and in this case the a dose increasment has to be done. 6) In patients with CHD and hyperlipidaemia it has to be taken into considration that digoxin cause a increase in statins plasma concentration so dose has to be readjusted. Side effects This group of drugs are known to be well tolerated with minimum side effects. Simvastatin has the least side effects and it is limited to headache and URTI. The most common side effect for all the drugs is headache mainly noticed with cerivastatin which also known for causing GIT disturbances. Pravastatin and maybe because of its high lipophilicity has the main CNS side effects. Fluvastatin is known for its skeletal muscle side effects like 35 back pain and inflammation. The drug mostly given to the elderly is pravastatin in a dose of 10mg/day and simvastatin in a dose of 5mg/day. Patient advice: 1) Before considering the use of statins, other methods to reduce the risk of coronary heart disease (CHD) should be instigated 2) Monitoring of liver function, serum lipid & muscle enzymes is essential. Clinical studies: A team from the St Elizabeth's Medical Center (Boston, MA, USA) have investigated the molecular signaling mechanisms of statins in the ischaemic hind limbs of rabbits. Simvastatin, they found, works by activating protein kinase Akt. This leads to nitric oxid production and promotes endothelial cell survival in an Akt-dependent manner--cellular responses that control angiogenesis and stabilisation of the vascular network. Akt activity by statins enhances revascularisation of ischaemic tissue explaining the reduction in cardiovascular events that are seen in patients who receive these drugs. A better understanding of the Akt role could lead to new targets for angiogenic. Another researcher stated that they cant be angiogenic, because if that was the cause then they would have stimulated the growth of occult malignancies . The absence of reports of such side-effects calls into question their potency as general stimulators of angiogenesis in humans. Statins may instead promote angiogenesis by inhibiting cell apoptosis rather than by stimulating vessel growth. This question is not yet solved but it calls to further study. The pravastatin primary prevention study (west of scotland coronary prevention study) the effect of pravastatin (LIPOSTAT) was assessed in 6595 men 45-64 age, without a previous MI and with LDL-C levels between 156-254 mg/dl. In this randomized, double –blind, placebo-controlled study, patients were treated with standard care, including dietary control for 4.8 years. The result was reduction of the rate of the first coronary events either CHD or nonfatal MI by 31%. The risk reduction with pravastatin was similar and significant through out the entire range of baseline LDL cholesterol levels. Also the reduction was similar and significant across the age range studied with 40% risk 36 reduction for patients younger than 55 years and 27% risk reduction for those 55 and older. This shows the importance of early treatment. Section V Summary GUIDELINES FOR THE MANAGENMENT OF HYPERLIPIDAEMIA: In the management of hyperlipidaemia and its associated disorders there are certain protocols which has to be followed for proper advice in giving both diet and drugs. 1) Identify the case wiether it is mild, moderate or sever, this is determined by the elevation of lipid level. 2) Make sure that this elevation is not caused by another secondary cause. 3) Identify the type of lipoprotein or lipid which is elevated and this will help us diagnose the type (type1,11….) or wiether it is familial hyperlipidaemia or familial triglyceridemia or combined. 4) In case of mild to moderate increase the patient is advised to reduce his weight (by reducing the total calories intake & performing exercise), avoid alcohol consumption and in case of elevated cholesterol level he has to reduce the total fat Saturated fat & sometimes the dietary cholesterol. While in the case of elevated triglyceride level he has to decrease dietary fat and carbohydrates. 5) In sever cases a dietitian advice has to be taken because he is capable to draw the boarder line for the amount of lipid permissible without causing any nutrient deficiency to the patient. 6) The drug therapy is not advised for patient with mild to moderate elevations, instead, a more restricted diet is advisable. An exception is the patient with moderate cholesterol level and with CHD in this case statins are advisable. 7) Before starting drug therapy the diet therapy has to be tried for 6 monuth to one year also rigorous attempts has to be done to control risk factors. 37 8) The drug of choice is chosen according to the type of the drug and according to the patient state (the drug of choice might be contraindicated for a particular patient) 9) The patient have to stick to his diet regimen after the initiation of therapy . 10) Lipid level monitoring after the start of therapy putting in mind that different agents has different time for onset of action. HOW TO CHOOSE THE MEDICATION 1.Predominant hypercholesterolaemia: Choose from resins (cholestyramine or colestipol); HMG-CoA Reductase Inhibitors (simvastatin or pravastatin); gemfibrozil; nicotinic acid; probucol. 2.Combined hyperlipidaemia: Choose from gemfibrozil, simvastatin or pravastatin; nicotinic acid. (These drugs are also useful when HDL cholesterol is low). 3.Predominant hypertriglyceridaemia: Choose from gemfibrozil; nicotinic acid; high dose fish oil (2 g/day n-3 fatty acid). 4.For elderly the statins are drugs of choice due to their safety and possible associated heart problems with age. 5.For pregnancy and lactation avoid the statins and change to bile acid sequestrants . Because malabsorption is possible it is important and so fat soluble vitamins should be prescribed to the patient especially due to the increase in the daily requirements of vitamins during pregnancy. 6.For pediatrics diet restrictions is the applicable coarse of action but in sever cases bile acid sequestrate or niacin is advisable but close supervision and accurate dose calculation is needed. 7.In patients with gall bladder obstruction avoid BAS or fibrates and usually statins are more advisable. 8. cerivastatin either as monotherapy or in combination with a fibrate should be considered an important treatment option for diabetic dyslipidaemia. 38 9. Patients with renal impairment or liver disease should be closely monitored. A test for liver and kidney function should be done periodically when the patient is on any therapy. If the patient has a gall bladder obstruction then BAS will be an absolute contraindication and maybe niacin (in low doses) or statin will be more preferred . COMBINATION THERAPY: Lipid lowering drugs may be used in combination in severe cases and when the monotherapy is of limited use. Also when VLDL is elevated during the treatment of hypercholesterolaemia. Guidelines have pointed out that strict adherence to policies would result in "over treatment" of hyperlipidaemia. 1. When Cerivastatin 0.3mg was used in combination with fenofibrate and bezafibrate. The effect was reduction of LDL by over 42%, TGs were reduced by 44% and HDL increased by more than 32%. Clearly further cost benefit analysis and further analysis is required to determine the sub-groups most likely to benefit. 2. BAS is given with statins in case of refractory sever forms of hypercholesterolemia, also given in combination with nicotinic acid 3. Statins can be given in combination with resins but its not advisable to give it with fibrates because might induce myopathy. 4. Gemfibrizol & bile acid resin is given in combination and this is useful in treating familial combined hyperlipidaemia. This combination might induce choleithiasis. 5. Bile acid binding resin & niacin this combination is used in familial combined hyperlipidaemia where there is an elevation in both LDL, VLDL. The effectivness is due to increase of LDL catabolism by resin and decrease in VLDL synthesis by niacin. Perhaps there is also reduction of cholesterol synthesis in the live and increase in HDL. This method is widely used so there is a good experience when dealing with it and it doesn’t aggravate the side effects. On the other hand it was found that resin has acid neutralizing property which 39 can reduce the gastric irritation produced by niacin. The combination is used for heterozygous familial hypercholesterolemia in a dose of 6.5g of niacin and 24-30g of resin. 6. Niacin & statins for familial combined hypercholesterolemia. But the experience is limited. 7. Resins, niacin & statins in sever disorder involving elevated LDL . this combination has limited toxicity. The combination has the advantage of lowering the dose of each and so the side effects and in the same times potentates the action. Section VI Hyperlipideamia along with hypertensive Conclusion disease, diabetes mellitus, smoking, obesity, heavy alcohol consumption and physical activity is recognized as contributory factors in the development of coronary heart disease. A recent study with lipid lowering agent has clearly shown that reduction of raised serum cholesterol in individual with coronary heart disease will reduce mortality. The present study was therefor undertaken to determine if there was a relationship between the various indicators of coronary health and the supply of lipid lowering agents. Prescribing analysis and coast data was collected for each target region on a quarterly basis over a two years period of time. The quantity of each lipid lowering agent supplied to patients was expressed in term of its defined daily dose (DDD) and presented as DDD per 1000 inhabitants per day. All other risk factors were obtained from different statistical indicators data service. The prevalence of risk factors across each target country was high and associated with coronary heart disease mortality. (rs=0.88;p 0.01). However, there was no relationship between the supply of Lipid lowering Agents and mortality. The results reinforce the need to 40 change the lifestyle of the population and to promote guidelines on the appropriate use of lipid lowering agents. This is the role of clinical pharmacy and pharmaceutical care in the management of hyperlipidemia. It is a responsibility to point out the importance of diet and exercise & to illustrate the appropriate use of medicine to patients and to be always ready with updated, correct and accurate information for patient advice and counseling. References 1. Drug facts and comparisons 2000 2. Internet: www.Ixquick.com 3. Clinical drug data 4. Dean Ornish D,brown Se, Lancet 1990 5. Dr. Bart staels, Pasteur institute, France, Lancet 2000 6. Mayo clinic diet manual 7th edition 7. BNF edition 2000 8. Clinical pharmacology 7th edition DR. Laurence, P.N. Bennett 9. Pharmacology 3rd edition Leonard S.Jacob 10. Essential Medicine 2nd edition edited by John Vann Jones & Charles R.V Tomson. 11. Article about dietary fats & hyperlipidaemia by Briony Thomas BSc, PhD , SRD. 12. Pharmacology Text book 13. Lipostat (Pravastatin sodium tablets) leaflet by Bristol-Myers Squibb 14. An educational service from PARKE-DAVIS the markers of Lopid. 15. Diagnostic and laboratory test reference ,third edition, Mosby’s الحمد هلل رب العالمين 41 42