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Theme: Antiatherosclerotic drugs. ANTIATHEROSCLEROTIC DRUGS Antihyperlipidemic drugs (hypolipidemic drugs; lipidlowering drugs) are used in patients with hyperlipoproteinemia. They are the essential components of the complex therapy used to prevent and treat atherosclerosis and its complications (ischemic disease of the heart, stroke, etc.). Their main effect includes the reduction of elevated levels of atherogenic lipoproteins in the plasma. Some of them also increase the levels of antiatherogenic lipoproteins. These principles of action are based on the fact that atherogenic dislipoproteinemia is known to be one of the main risk factors of atherosclerosis. LDLs (low density lipoproteins), IDLs (intermediate density lipoproteins), VLDLs (very low density lipoproteins) and LPs(a) (lipoprotein (a)) possess atherogenic properties. LDLs bind to lipoprotein tissue receptors and, when metabolized, they release free cholesterol and other compounds. Cholesterol in the form of esters is deposited in the tissues. Chylomicrons (CM) are not atherogenic. Nevertheless, remnants of chylomicrons can penetrate through thevascular endothelium and promote the development of an atheromatous plaque. HDLs are not atherogenic. Moreover, elevated HDL concentration in the plasma decreases the risk of atheromatous damage to the vessels (antiatherogenic action). Thus, in clinical practice the prevention and management of atherosclerosis and its complications consists of lowering the excessive concentrations of atherogenic lipoproteins and increasing the level of antiatherogenic HDLs in the blood plasma. Antihyperlipidemic drugs (hypolipidemic drugs) may be classified in the following way: A). Drugs primarily decreasing the content of cholesterol (LDL) in the blood - Inhibitors of cholesterol synthesis (inhibitors of 3-hydroxi-3-methylglutaryl coenzyme Areductase; statins) Lovastatin Mevastatin Pravastatin Fluvastatin Simvastatin Inhibitors of cholesterol absorption from the gut Ezetimib Drugs increasing elimination of bile acids and cholesterol from the body (sequestrants of bile acids) Cholestyramine Cholestipol Other drugs Probucol Treatment of lipid disorders begin with the appointment of diet and, if the first fails and used lipid-lowering drug or combination of drugs against the continuation of diet. Choose a diet and lipid-lowering agent depends on the identified type of hyperlipoproteinemia. Distinguish 5 types of hyperlipoproteinemia: Type I - giperhilomikronemii, i.e. an increase in the blood content of XM. Type II - hyper-β-lipoproteinemiya, Pa. subtype characterized by an increase in blood levels of cholesterol (LDL), a subtype of St Petersburg - additional increase in triglycerides (VLDL). Type III-dis-β-lipoproteinemiya, characterized by the appearance of blood "pathological ¬ cal" lipoprotein (LPPP, βVLDL), an increase in the content of ¬ cholesterol and triglycerides. Type IV - hypersimple-β-lipoproteinemiya, i.e. an increase in the blood content of trig ¬ litseridov (VLDL). Type V - giperhilomikronemii and hypersimple-βlipoproteinemiya, characterized by an increase in the blood content of the XM triglycerides (VLDL). These types of hyperlipoproteinemia may be primary (hereditary nature or effect of dietary disorders), and secondary, the associated number of diseases (diabetes, hypothyroidism, liver, kidney, etc.), as well as arising from prolonged ingestion of certain drugs. It should be borne in mind that the successful treatment of the underlying disease can lead to a significant reduction of atherogenic hyperlipoproteinemia. Lipid-lowering drugs can have the following courses: • inhibition of the biosynthesis of lipids and lipoproteins in the liver; • activation of the capture (endocytosis) lipoprotein liver by stimulating the synthesis of LDL receptors of the liver; • inhibition of cholesterol absorption and bile acids from the intestine; • activation of cholesterol catabolism, including its conversion to bile acids; • stimulation of lipoprotein lipase activity of vascular endothelium; • inhibition of fatty acid synthesis in the liver and their release from adipose tissue (lipolysis inhibition); • elevated levels of circulating antiatherogenic HDL. High lipid-lowering efficacy have means selectively ¬ relatively inhibits the synthesis of cholesterol in the liver, collectively referred to "statins." K. These include nutrients - lovastatin (Mevacor), in ¬ obtained was from cultures Monascus ruber and Aspergillus terreus, and mevastatin (compactin), which is a metabolite of Penicillium and Penicillium citricum brevicompactum.So semi ¬ Buildings (simvastatin, pravastatin) and synthetic (fluvastatin ) Substances with such type of action. These drugs inhibit the syn ¬ mes cholesterol in the liver by inhibiting the enzyme N-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Compensatory increases the number ¬ lo LDL receptors in the liver, which is accompanied by a decrease in the content LPPP and LDL cholesterol in the blood plasma, because of their increased endocytosis and catabolism ¬ ism. Drugs in this group also reduce the absorption of dietary cholesterol ¬ Rina. Furthermore, inhibited synthesis of VLDL in the liver, a small degree ¬ ceeding content in plasma HDL. Lipid-lowering effect of substances shows quickly and expressed all the ma ¬ substantially. An even greater effect was observed with a combination of these agents ¬ Ratov with cholestyramine. In recent years suggests that the effect of statins antiatherosclerotic connected not only with their hypolipidemic action, but also to a direct effect on the blood vessels. This leads to improvement in endothelial function ¬ NIJ, the suppression of the inflammatory process, increased a hundred ¬ bility of atherosclerotic plaques, and perhaps some of its regression, to reduce the likelihood of blood clots. The basis of these changes on the experimental data, many of the processes involved: inhibition of proliferation and migration of arterial myocytes, inhibition of the growth of monocyte / macrophage accumulation and a decrease in their cholesterol lowering metalloproteinase production by macrophages, enhancing formation in endothelial NO synthase, inhibition of endothelin-1 production , decreased platelet adhesion and aggregation, etc. The most significant clinical experience with lovastatin. It is a prodrug. Its active metabolite is formed in the liver. Assign lovastatin orally 1 time a day at bedtime. Bioavailability is low. Much of the drug and its metabolites bind to plasma proteins. Biotransformation of lovastatin in the liver. Allocated lovastatin and its metabolites in the intestine and primarily to a lesser extent by the kidneys. The drug is well tolerated. Side effects are relatively rare (dyspepsia, headache, skin rash, myopathy). In 2% of patients experienced higher levels of hepatic transaminases, which swarm, however, is not accompanied by any pathological phenomena. According ¬ ceeding the level of muscle creatine kinase (in 10-11% of patients), which may be accompanied by muscle aches, rarely - myopathy and possible damage to the muscle tissue (if you do not stop taking the drug). Indications for use of the same for the whole group of fibrates. Nicotinic acid (niacin) reduces the content of VLDL in blood plasma, to a lesser extent and LDL LPPP. Triglycerides begins to decline before (1-4 days) than cholesterol (5-7th day). Nicotinic acid inhibits lipolysis in adipose tissue (due to the activation of cAMP phosphodiesterase content decreases, which reduces the activity of intracellular ¬ accurate lipase). The content of fatty acids in the blood and their delivery to the liver are reduced. Naturally, this affects the biosynthesis of triglycerides and VLDL. The content of VLDL and LDL in plasma decreases. With prolonged use of nom ¬ nicotinic acid increases the level of HDL. She is well and rapidly absorbed from the gastrointestinal tract. ¬ is to stand out in the urine, mainly as unchanged substance and in part - its meta ¬ hurts. As hypolipidemic agents effective at II-V hyperlipoproteinemia type (especially III and V). Taken in high doses (at approximately ¬ 100 times above designated as vitamin). The use of nicotinic acid to limit its side effects: hy ¬ of change of the skin, itching, vomiting, diarrhea, and possible formation of peptic ulcers as ¬ gastric, hepatic dysfunction, hyperglycemia, hyperuricemia, etc. To reduce the severity of the side effects of nicotinic acid synthesized ¬ Wana its poorly soluble salts, esters, amides, slowly hydrolyzed to the acid, but the long-term to maintain a certain level in her blood. The most effective ¬ GOVERNMENTAL of them were pyridylcarbinol (ronikol) holeksamin. In addition, the use of such derivatives have found nicotinic acid as ksantinola nicotinate and inozitolnikotinat. Among the substances that promote catabolism and excretion of cholesterol, polyunsaturated relation ¬ syatsya (polyene) fatty acids (linoleic, linolenic and arachidonic). They increase cholesterol bile eksk ¬ rementah and the intensity of its catabolism in the liver. In clinical practice using drugs linetol and arachidonic (containing a mixture of ethyl ¬ ethers of unsaturated fatty acids). Linetol derived from flax w ¬ la and arachidonic - from lipids of the pancreas and adrenal glands of cattle. Both drugs are used as one component of the complex ¬ therapy hyperlipoproteinemia type II-V. Enter them enterally. Lipid-lowering effect has also dextrothyroxine (Dthyroxine). It is a synthetic dextrorotatory isomer of thyroid hormone thyroxine ¬ zy. Dextrothyroxine activate the catabolism of cholesterol in the liver. ¬ tion under the influence of microsomal liver enzymes cholesterol more rapidly transformed into bile acids. In plasma, the blood is reduced LDL content. In adipose tissue pre ¬ Parat can stimulate lipolysis, which increases the synthesis of VLDL. At the same time, the level of triglycerides, as well as the basal metabolic rate changed little. It is recommended for the treatment of hyperlipoproteinemia of type II and III. The effect of ¬ veins with enteral administration. Dextrothyroxine similar endogenous L-thyroxine sensitize the myocardium to the action of catecholamines, which contributes to the development or enhancement of angina and ser ¬ dechnyh arrhythmias. This can lead to increased mortality from coronary heart bo ¬'s disease. Therefore, in some countries, the use dextrothyroxine terminated or knowledge ¬ considerably limited, although the negative effect of the drug on the heart and may be offset by β-blockers. Dextrothyroxine mainly administered young people, especially thyroid hypofunction. Once again it should be emphasized that in many cases the treatment of hyperlipoproteinemia most pronounced effect is the combined use of drugs with different mechanisms of action (statins + cholestyramine; gemfibrozil + cholestyramine, colestipol + nicotinic acid, nicotinic acid statins + + sequestering bile acids). The complex antiatherosclerotic means used and the so-called mye ¬ endoteliotropnye drugs (angioprotektory), reducing the permeability of the endothelium to atherogenic lipoproteins. These drugs include Parmidin (piridinolkarbamat, anginin, prodektin). Possessing antibradikininovym effect, it inhibits the swelling and reduces the permeability of the vascular walls ¬ ki. Furthermore, Parmidin improves microcirculation vascular wall reduces platelet aggregation. Promotes regeneration of elastic and of muscle fibers in the ground cholesterol deposits. Reduces blood clotting ¬ ve. Enter it inside for a few months. Tolerated drug ho ¬ Rosho. Sometimes causes nausea, allergic reactions. A certain importance in the prevention of atherosclerosis and its complications ¬ tions is also given to antioxidants (tocopherol acetate, ascorbyl acid ¬ bins, etc.) affecting the peroxide mechanisms of atherosclerosis. The basic principle of action is the inhibition of free radical oxidation of lipids by molecular oxygen. Please be aware that the efficacy and safety of anti ¬ atherosclerotic drugs, or combinations thereof can only be judged on the basis of longterm clinical studies on a large cohort of patients. Triglycerides and cholesterol are essential constituents of the organism. Among other things, triglycerides represent a form of energy store and cholesterol is a basic building block of biological membranes. Both lipids are water insoluble and require appropriate "packaging” for transport in the aqueous media of lymph and blood. To this end, small amounts of lipid are coated with a layer of phospholipids, embedded in which are additional proteins—the apolipoproteins (A). According to the amount and the composition of stored lipids, as well as the type of apoli- poprotein, one distinguishes four transport forms (see table). other tissues with fatty acids. Left behind are LDL particles that either return into the liver or supply extrahepatic tissues with cholesterol. LDL particles carry the apolipoprotein B- 100, by which they are bound to receptors that mediate uptake of LDL into the cells, including the hepatocytes (receptor-mediated endocytosis, p. 26). HDL particles are able to transfer cholesterol from tissue cells to LDL particles. In this way, cholesterol is transported from tissues to the liver. Drugs. As nonabsorbable anion-exchange resins, colestyramine and colestipol can bind bile acids in the gut lumen, which are thus removed from cholesterol metabolism. The required dosage is rather high (15-30 g/day) and liable to produce gastrointestinal disturbances. Consequently, patient compliance is low. Moreover, the resins trap needed drugs and vitamins. A more promising approach to lowering absorption of cholesterol derives from a novel mechanism of action probably based on the specific inhibition of intestinal cholesterol transporters that are required for absorption of cholesterol. An inhibitor of this type is ezetimibe. p-Sitosterin is a plant steroid that is not absorbed after oral administration; in suf ciently high dosage it impedes enteral absorption of cholesterol. Treatment with sitosterin has become obsolete. The drug is no longer on the market. The statins lovastatin and fluvastatin inhibit HMG-CoA reductase. They contain a molecular moiety that chemically resembles the physiological substrate of the enzyme (A). Lovastatin is a lactone that is rapidly absorbed by the enteral route, subjected to extensive first-pass extraction in the liver, and there hydrolyzed to active metabolites. Fluvastatin represents the active form and, as an acid, is actively transported by a specific anion carrier that moves bile acids from blood into liver and also mediates the selective uptake of the mycotoxin amanitin (A). Normally viewed as presystemic elimination, ef cient hepatic extraction serves to confine the action of statins to the liver. Despite the inhibition of HMG-CoA reductase, hepatic cholesterol content does not fall because hepatocytes compensate any drop in cholesterol levels by increasing the synthesis of LDL receptor protein (along with the reductase). Since, in the presence of statins, the newly-formed reductase is inhibited as well, the hepatocyte must meet its cholesterol demand entirely by uptake of LDL from the blood (B). Accordingly, the concentration of circulating LDL falls. As LDL remains in blood for a shorter time, the likelihood of LDL being oxidized to its proatherogenic degradation product decreases pari passu. Other statins include simvastatin (also a lactone prodrug), pravastatin, atorvastatin, and cerivastatin (active form with open ring). The statins are the most important therapeutics for lowering cholesterol levels. Their notable cardiovascular protective effect, however, appears to involve additional actions. The combination of a statin with an inhibitor of cholesterol absorption (e.g., ezetimibe) can lower LDL levels even further. A rare but dangerous adverse effect of statins is damage to skeletal muscle (rhab- domyolysis). This risk is increased by combined use of fibric acid agents (see below). Cerivastatin has proved particularly toxic. Besides muscle damage associated with myoglobinuria and renal failure, severe hepatotoxicity has also been noted, prompting withdrawal of the drug. Nicotinic acid and its derivatives (pyridyl- carbinol, xanthinol nicotinate, and acipimox) activate endothelial lipoprotein lipase and thereby mainly lower triglyceride levels. At the start of therapy, a prostaglandin-mediated vasodilation occurs (flushing, hypotension) that can be prevented by low doses of acetylsalicylic acid. Clofibrate and derivatives (bezafibrate, fe- nofibrate, and gemfibrozil) lower concentrations of VLDL (triglycerides) along with LDL (cholesterol). They may cause damage to liver and skeletal muscle (myalgia, myopathy, rhabdomyolysis with myoglobinemia and renal failure). The mechanism of action of fibrates is not completely understood. They bind to a peroxisome proliferator-activated receptor (PPARa) and thereby influence genes regulating lipid metabolism. 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