Drugs For Hyperlipidemia PDF

DRUGS FOR HYPERLIPIDEMIA Dr Nneamaka Alo Dept. of Pharmacology and Therapeutics Ebonyi State University  OUTLINE Introduction Dyslipidemia Lipoproteins/structure Hyperlipoproteinaemias Very-low-density lipoproteins Low-density...

DRUGS FOR HYPERLIPIDEMIA Dr Nneamaka Alo Dept. of Pharmacology and Therapeutics Ebonyi State University  OUTLINE Introduction Dyslipidemia Lipoproteins/structure Hyperlipoproteinaemias Very-low-density lipoproteins Low-density lipoproteins High-density lipoproteins Cholesterol Prevention and treatment of dyslipidemia Management strategies for dyslipidemia Conclusion 2  Introduction Hyperlipidemia is also called hyperlipoproteinemia It is a condition in which there are elevated levels of lipids in the blood, which include cholesterol and triglycerides. Although it can be inherited, it often results from lifestyle factors, including an unbalanced diet and too little physical activity. 3  Hyperlipidemia is very common, especially in modern developed countries. It is also increasing around the world. In the United States, 94 million people over age 20 have elevated total cholesterol levels. This amounts to about 50 percent of all U.S. adults. About 60% of apparently healthy Nigerian adults are involved. 4  DYSLIPIDAEMIA: Is a metabolic disorder characterized by increased concentrations of lipids and lipoproteins. Lipid-lowering drugs are used along with dietary modifications to treat dyslipidaemia. There is an important relationship between high levels of circulating triglycerides, cholesterol and atherosclerosis. 5  Apolipoproteins Apolipoproteins are proteins that bind lipids (oil-soluble substances such as fats, cholesterol and fat soluble vitamins) to form lipoproteins. They also:  serve as ligands for cell receptors.  Activate enzymes involved in lipoprotein metabolism.  Provide structure for the lipoprotein. If apolipoprotein metabolism is impaired, an increased risk of atherosclerosis exists. Thus plasma concentrations of apolipoproteins are important in evaluating lipid disorders. They are cleared from the bloodstream by lipoprotein lipase (LPL) after 12–14 hours. 6  Apolipoproteins The apolipoproteins include apoA-I, apoA-II, apoA-IV, apoA-V, apoB-100, apoB-48, apoC-I, apoC-II, apoC-III, apoE and apo(a). Apolipoprotein A-I is thought to confer the beneficial effect of high-density lipoproteins (HDL). HDL particles that have both A-I and A-II appear not to be as atheroprotective. In contrast, a deficiency of the C-II apolipoprotein in very-low-density lipoprotein (VLDL) particles results in impaired triglyceride metabolism and hypertriglyceridaemia. 7  Lipoproteins A lipoprotein is a biochemical assembly whose primary function is to transport hydrophobic lipid (also known as fat) molecules in water, as in blood plasma or extracellular fluids. Generally spherical in shape. Comprise an interior core, consisting of cholesteryl esters and triglycerides, which are covered by a layer of phospholipids, free cholesterol and apolipoproteins, which are located near the surface. 8 Lipoprotein structure 9  LIPOPROTEINS Examples of plasma lipoprotein particles are: HDL: high density lipoprotein LDL: low density lipoprotein IDL: intermediate-density lipoprotein VLDL: very low density lipoprotein ULDL: chylomicrons/ultra-low-density- lipoprotein. 10  Hyperlipoproteinaemias Hyperlipoproteinaemias are always associated with an increased concentration of one or more lipoproteins. Dyslipidaemias can be classed as primary or secondary. The primary, or genetically determined hyperlipoproteinaemia forms are classified into six phenotypes, depending on the lipoprotein particle elevated. 11  Hyperlipoproteinaemias Cont. Factors such as diabetes mellitus, obesity, hypothyroidism, nephrotic syndrome, excess alcohol consumption and drug treatment (e.g. corticosteroids, thiazide diuretics) constitute the secondary causes of dyslipidaemia. In these cases, investigation of underlying disease pathology or current drug treatment is necessary before instituting lipid-lowering drug therapy 12  Very-low-density lipoproteins VLDLs, carry lipids from the liver to the peripheral cells. They contain a large amount of triglycerides (50–65%) and 20–30% cholesterol. Are formed in the liver from endogenously synthesized triglycerides, cholesterol and phospholipid. The apolipoproteins apoB-100, apoE and apoC-I-III are synthesized in the liver and, once incorporated, result in the final assembly of VLDL 13  VLDL VLDL particles are secreted from the liver into the circulation. Their triglyceride content is released by the action of the enzyme LPL, located in the endothelium of adipose, muscle and cardiac tissue capillaries. As the triglycerides are hydrolyzed by LPL the resulting free fatty acids are taken up by adjacent tissues. Drugs that enhance the action of LPL (e.g. the fibrates) will lower plasma triglyceride concentrations. 14  Low-density lipoproteins When triglyceride hydrolysis is almost complete the remnant of VLDL (termed IDL) is released from the capillary endothelium and re-enters the circulation. Approximately 40–50% of the IDL is cleared from plasma by the liver via LDL receptors, which recognize the apoB-100 and apoE v components of the remnants. The remainder of the IDL is converted to the cholesterol-rich lipoprotein LDL. This contains 60–70% of total blood cholesterol. Its relationship with the development of atherosclerosis has resulted in its label as ‘bad’ cholesterol. 15  LDL LDL particles have a half-life of 1–2 days. This accounts for their high concentration in plasma in comparison to VLDL and IDL. The quantity and density of systemic LDL particles correlate with the risk of atherosclerosis. Elevated LDL levels indicate that an individual has a greater risk of developing atherosclerosis. LDL (~75%) is cleared from plasma mainly via hepatic LDL receptors. Defects in the LDL receptor gene are associated with high plasma concentrations of LDL and familial hypercholesterolaemia 16  LDL When the liver and tissues outside the liver need cholesterol they increase the synthesis of LDL receptors on their respective cell surfaces. These receptors are necessary for the binding of LDL, thus enabling the release of free fatty acids The LDL particles are then cleared from plasma by LDL receptors principally in the liver. The level of hepatic LDL receptors generally controls the level of circulating LDL in humans. 17  LDL When the cellular need for cholesterol is met, synthesis of LDL receptors decreases. This controls the plasma level of LDL. Modulation of the number of hepatic LDL receptors is an integral part of the therapeutic approach to the management of hypercholesterolaemia. 18  High-density lipoproteins: The function of HDL is to carry about 25% of plasma cholesterol from the periphery back to the liver, where it is processed into bile acids. The cholesterol HDL carried is ultimately for excretion. It is known as ‘good’ cholesterol. HDLs are the smallest and most dense lipoproteins. 19  HDL Their function is to transfer cholesterol from peripheral cells to the liver. High levels of HDL are considered beneficial and decrease the risk of coronary heart disease. 20  HDL This transport mechanism prevents the accumulation of cholesterol in the arterial walls. Thereby providing protection against the development of atherosclerosis. Plasma lipoproteins are usually in a state of dynamic equilibrium. 21  Cholesterol Cholesterol is a fatty substance necessary for the proper functioning of the body. It participates in the synthesis of some hormones and vitamin D. It is a constituent of cell membranes. Is produced by the liver but can also be introduced with the diet (foods rich in animal fats such as meat, butter, salami, cheese, egg yolk, and liver). It is transported through the blood to a particular class of particles called lipoproteins. 22  Cholesterol The most important for cardiovascular prevention are: LDL, carrying liver cholesterol to the cells. HDL, that removes excess cholesterol from different tissues and carry it back to the liver, which then eliminates it. LDLs are known in common language as “bad cholesterol” because when present in excessive amounts, tend to settle on the walls of arteries, causing thickening and progressive hardening. This process, called atherosclerosis, can lead to the formation of true plaques (or atheromas) thus impeding blood flow, or even block it completely. 23  Cholesterol When the heart does not get enough oxygen-rich blood, angina pectoris may develop. A condition characterized by chest pain, which can radiate to the left arm or jaw, usually at the same time as effort or stress. The plaques may detach and form a thrombus, which can cause a sudden stopping of the bloodstream. Depending on where it is located, obstruction of a vessel may cause myocardial infarction, stroke, or intermittent claudication (at the lower limb level). 24  Cholesterol High cholesterol levels do not produce direct symptoms; many people ignore the fact that they suffer from hypercholesterolemia. Cholesterol can be easily measured with a simple blood test and must be kept under constant control. We talk about hypercholesterolemia when total cholesterol (LDL plus VLDL and HDL) is too high. Generally, desirable cholesterol levels are up to 200 mg/dl for total cholesterol, up to 100 mg/dl for LDL cholesterol (LDL-C), and not less than 50 mg/dl for HDL cholesterol (HDL-C). When plasma cholesterol concentrations exceed these levels, it is referred to as hypercholesterolemia. 25  Prevention and treatment of dyslipidemia Should be considered as an integral part of individual cardiovascular prevention interventions. 26  MANAGEMENT STRATEGIES FOR DYSLIPIDAEMIA A) Non-pharmacologic approach: Dietary modification and identification and management of modifiable risk factors: - smoking cessation -significant reduction in alcohol intake - physical activity (exercise) - appropriate weight (BMI) are important in the treatment of high LDL- cholesterol (LDL-C) levels. 27  MANAGEMENT STRATEGIES B) Pharmacologic approach: In the absence of a satisfactory reduction of high plasma lipid levels through non pharmacologic approach, lipid-lowering drugs are recommended. The main classes of lipid-lowering drugs used are:  inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (commonly referred to as ‘statins’).  fibrates.  bile acid-binding resins.  additional agents, including nicotinic acid, ezetimibe and fish oil 28  Pharmacologic Approach Cont. Statins Work by competitively blocking the active site of the first and key rate-limiting enzyme in the mevalonate pathway, HMG-CoA reductase. Inhibition of this site prevents substrate access, thereby blocking the conversion of HMG-CoA to mevalonic acid. 29  Within the liver, this reduces hepatic cholesterol synthesis, leading to increased production of microsomal HMG-CoA reductase and increased cell surface LDL receptor expression. This increases clearance of LDL-c from the bloodstream and a consequent reduction of circulating LDL-c 30  Statins Cont. All statins possess very low systemic bioavailability due to an extensive first-pass effect. Lovastatin and simvastatin, unlike most statins, are administered as inactive lactone prodrugs. Statins differ mainly in the degree of metabolism and the number of active and inactive metabolites. Pravastatin has the lowest protein-binding (around 50%) when compared to other statins (>90%). Furthermore, statins have a low half-life (1–4 h), while atorvastatin and rosuvastatin possess the longest terminal half-life (11–20 h). 31  Statins Cont. All statins are indicated in cases of primary hypercholesterolemia and mixed dyslipidemia in patients who do not respond to diet, exercise, and other non-pharmacological methods. Atorvastatin, rosuvastatin, and simvastatin, are effective in the treatment of homozygous familial hypercholesterolemic patients. Probably due to their ability to produce a significant decrease in liver production of LDL cholesterol. 32  Statins Cont. All statins can be used in cardiovascular prevention as adjuvants to reduce other risk factors with other cardioprotective therapies. In the case of hypercholesterolemia, the recommended dose is 10–20 mg/day administered in a single dose in the evening. Patients requiring a large reduction in LDL-C (greater than 45%) may start with 20–40 mg/day administered in a single dose in the evening. Only rosuvastatin should be initiated with a dosage of 5–10 mg/day, reaching maximum doses of up to 40 mg/day only in patients who have not reached the therapeutic goals established with the lowest doses. 33  Statins Cont. In the case of homozygous familial hypercholesterolemia, the recommended dose is 40 mg/day in the evening. In the case of cardiovascular prevention, the usual dose ranges from 20 to 40 mg/day administered as single dose at night. For atorvastatin, a dose of 10 mg/day is used, although it may be increased as needed. These can affect the activity/toxicity of statins. 34  Statin Interactions The interaction between spironolactones and statins can lead to additive effects of decreasing concentration and activity of endogenous steroid hormones. Cimetidine, ranitidine, and omeprazole may increase blood levels of fluvastatin, while rifampicin causes more rapid elimination. Coadministration of antacids results in a reduction in atorvastatin and rosuvastatin levels. Rosuvastatin should be given at least 2 h after an antacid. The anticoagulant activity of warfarin may increase if administered with fluvastatin, lovastatin, rosuvastatin, or simvastatin. 35  Pharmacological Approach Cont. 2) Fibrates. Fibrates (fenofibrate, bezafibrate, ciprofibrate, and gemfibrozil) are a class of lipid-lowering drugs and exert their effects mainly by activating the peroxisome proliferator-activated receptor-alpha (PPAR-alpha). Fibrates decrease triglyceride levels and increase HDL-C levels. Fibrates have nearly 100% oral bioavailability 36  Dosage/Formulations of Fibrates. The recommended dose for adults, of Bezafibrate is 200 mg three times a day, or 400 mg of modified release tablet a day at the main meals. Fenofibrate can be administered once a day (200 mg) or with four 67 mg capsules, if required. Some fenofibrate formulations using a NanoCrystal technology (48 and 145 mg) eliminate the requirement of taking the drug with a meal. Micronized capsules (67, 134, and 200 mg) result in greater solubility and improved bioavailability. The Gemfribozil dose range is 900–1200 mg daily. 37  Benefits Bezafibrate prevents cardiovascular events in coronary artery disease patients with high triglycerides. Bezafibrate significantly reduces new-onset diabetes and myocardial infarction in the patients with metabolic syndrome. Fenofibrate as monotherapy decreases serum TG levels by 20–50% and increases HDL-C levels by 10– 50%. 38  SEs/Interractions Very early in the use of clofibrate, a high incidence of myopathy was described. The statement that the combination of gemfibrozil and lovastatin can lead to myopathy was made within a few months of lovastatin becoming available for prescription use. This interaction between gemfibrozil and statins became tragically clear after cerivastatin became commercially available. Higher plasma concentrations of cerivastatin were commonly toxic to muscle. However, this effect seems to be much less of a problem with other fibrates. 39  Pharmacologic Approach Cont. 3) Bile Acid Sequestrants Bile acid-binding resins, including cholestyramine, colesevelam, and colestipol. Are orally administered. Neither absorbed systemically nor metabolised by digestive enzymes. At the intestinal level, they bind to the two main biliary acids (glycocholic acid and taurocholic acid) making an insoluble complex that is excreted with the faeces. This leads to a continuous, though partial, removal of bile acids from the enterohepatic circulation. Consequently, they increase the hepatic conversion of cholesterol to bile acids. 40  Bile Acid Sequestrants Cont. They are effective in lowering total and LDL-C. Reduce mortality and cardiovascular events (7% and 24%, respectively). However, they are usually not well tolerated since they show significant gastrointestinal side effects (abdominal pain, heartburn, bloating, and constipation). Indicated in patients who do not respond adequately to dietary adjustments for the treatment of primary hypercholesterolemia. Not indicated if the primary alteration is only hypertriglyceridemia. 41  Bile Acid Sequestrants Cont. Recommended starting doses for adults range from 4 to 10 g a day before meals. A more pronounced effect can be achieved at maximal recommended doses of 24 and 30 g/day, for cholestyramine and colestipol respectively. The recommended dosage for patients aged 10–16 years is 4 g up to 10 g 42  Bile Acid Sequestrants Cont. Colesevelam has six-fold higher bile acid- binding capacity and fewer side effects than cholestyramine. Probably due to its greater binding affinity for glycocholic acid. 43  SEs/Interactions The chronic use of resins can interfere with digestion, fat absorption, and liposoluble vitamins (Vitamin A, D, K, ). The latter, causing an increase in bleeding tendency due to hypoprothrombinemia from Vitamin K deficiency. Bile acid sequestrants may delay or reduce the absorption of certain drugs: phenylbutazone, warfarin, chlorothiazide, tetracycline, penicillin G, phenobarbital, preparations of thyroid hormone and thyroxine, and digitalis. It is advisable to administer any other medication at least one hour before or 4–6 h after taking resins. 44  Pharmacologic Approach Cont. Ezetimibe Belongs to the Zetia class of drugs which is a cholesterol absorption inhibitor Ezetimibe is the first representative of a group of drugs capable of selectively inhibiting the intestinal absorption of phytosterols and dietary cholesterol. Once orally taken, it is located on the small intestine brush lining and inhibits cholesterol absorption, resulting in a decrease in intestinal cholesterol passage to the liver. Is excreted mostly in the feces, with a minor part appearing in the urine. 45  Ezetimibe Cont. The administration of ezetimibe 10 mg + simvastatin 10 mg reduces LDL-C serum levels (−44%) to the same extent as simvastatin 80 mg monotherapy. It is also indicated for homozygous familial hypercholesterolemia in combination with atorvastatin or simvastatin, and homozygous familial sitosterolemia. In all cases, patient should not have responded to diet, physical activity, and other non-pharmacological measures. The recommended dose for adults is one tablet of ezetimibe 10 mg once daily, while for children the start of treatment should be under the supervision of a specialist. 46  Pharmacologic Approach Cont. 5) Niacin Niacin, also called vitamin B3 or nicotinic acid, significantly raises HDL levels while decreasing those of VLDL and LDL. Mechanisms do not involve cholesterol biosynthesis or catabolism. This molecule, in fact, prevents lipolysis in adipose tissue as it is a powerful inhibitor of the intracellular lipase system. Generates multiple effects that eventually lead to the reduction of plasma cholesterol and triglycerides. 47  Niacin Cont. A further mechanism of action of niacin consists of the ability of nicotinic acid to stimulate the activity of lipoprotein lipase. This increases the clearance of VLDL. The lower quantity of VLDL leads to reduced levels of LDL, which is derived from LDL. After oral administration, niacin is absorbed rapidly so that plasma cmax are reached in 30–60 min. The plasma half-life after administration of 1 g nicotinic acid is around 1 h. 48  Niacin Cont. Niacin is approved for the treatment of hypercholesterolemia and hypertriglyceridemia. In both cases, daily oral doses of 1.5–3.5 g are generally sufficient. It is also indicated for familial combined hyperlipidaemia in patients who do not respond to non-pharmacological approaches such as diet and exercise. For the treatment of heterozygous familial hypercholesterolemia, 2–6 g is usually given per day. Niacin should be taken in multiple doses during the day, starting from 50–100 mg 2–3 times a day. The reduction of triglycerides can be already observed several hours after the intake of niacin, while the effects on cholesterol decrease take a few days. 49  SEs of Niacin The most common side effect of niacin is skin vasodilatation (flushing and itching). This sensation that can be prevented by taking aspirin, ibuprofen, or indomethacin before the drug. Gastrointestinal intolerance is an effect that can be minimized by administering the drug with meals. 50  Ses of Niacin Cont. Niacin is contraindicated in patients with liver disease. It often causes a reversible increase in plasma levels of AST, ALT, LDH, and alkaline phosphatase. Should be used with caution in patients with diabetes mellitus and gout as it can raise glucose and uric acid levels. The association of niacin with HMG-CoA reductase inhibitors may lead to an increased risk of myopathy and rhabdomyolysis. 51  Pharmacologic Approach Cont. 6) Omega-3 Fatty Acids Omega-3 fatty acids are polyunsaturated fatty acids with a double bond at the third carbon atom from the end of the carbon chain. They become part of the cell membrane, as with other fatty acids. By their chemical–physical characteristics, they determine the fluidity characteristics of membranes. Omega-3 has shown to decrease CVD events as monotherapy in secondary prevention. 52  Omega-3 fatty acids cont. From a metabolic point of view, omega-3 mainly reduces serum triglycerides through an increase in the oxidation of fatty acids, further decreasing their synthesis and modulating the composition of membrane phospholipids. 53  Omega-3 Highly-purified omega-3 is usually used together with other drugs for the treatment of certain forms of hypertriglyceridemia. The pharmaceutical form is represented by soft capsules of 1000 mg, containing 460–465 mg of eicosapentaenoic acid (EPA) and 375–380 mg of docosaexaenoic acid (DHA), taken twice a day. The common side effects are: stomach problems, indigestion (dyspepsia), and nausea. Uncommon side- effects are abdominal and stomach pain, allergic reactions, dizziness, problems with taste, diarrhea, and vomiting. 54  7) PCSK9 Inhibitors (PCSK9 means proprotein convertase subtilisin/kexin type 9) 7.a. Alirocumab Alirocumab is a fully human Ig G1 monoclonal antibody. PCSK9 binds to LDLRs on the surface of hepatocytes, promoting LDLR degradation. This in turn elevates LDL-C blood levels By inhibiting the binding of PCSK9 to LDLR, alirocumab reduces LDL-C levels 55  Alirocumab Cont. LDLR receptors also bind residues of VLDL rich in triglycerides and intermediate density lipoproteins (IDL). Therefore, treatment with alirocumab may result in a reduction in these lipoprotein residues. 56  Alirocumab Cont. Is indicated in adults with primary hypercholesterolemia (heterozygous or unhealthy family), in mixed dyslipidemia in addition to dietary changes. Alirocumab has near 90% bioavailability and a long half-life (around 17–20 days). Initial dose of 75 mg is administered subcutaneously once every two weeks. In patients requiring a major reduction in LDL-C (>60%), an initial dose of 150 mg, always subcutaneously, may be given once every two weeks. 57  Alirocumab Cont. The dose of alirocumab can be personalized according to the patient’s characteristics, such as baseline LDL-C, target therapy, and response. Lipid levels can be evaluated four weeks after the start of treatment. Compared to alirocumab monotherapy, alirocumab exposure is reduced by about 40% if the drug is used in combination with a statin, and about 15% if the drug is used in association with ezetimibe. 58  Conclusion Non pharmacologic and sometimes pharmacologic approaches should be considered extremely important when managing dyslipidaemia. Quality of life of our patients is improved if our patients obtain good lipid profile results 59