Change in the activity of regulatory molecules. Statins (HMG-CoA reductase inhibitors) HMG coreductase inhibitors statins

28. Describe the mechanism of action of HMGCoA reductase inhibitors (eg, simvastatin, atorvastatin).

These substances dose-dependently inhibit HMG-CoA reductase, which is necessary for the conversion of 3-HMG-CoA to the cholesterol precursor mevalonate.

Fig 37). This reduces the production of LDL and the formation of atherosclerotic plaques.

29. Discuss the effect of statins (eg, pravastatin, lovaspmtin) on the thickness of the internal and middle shell coronary arteries

It is shown that the substances of this group at long-term use significantly reduce the thickness of the inner and middle lining of the arteries. Correspondingly, the frequency of strokes and heart attacks and mortality from them decrease.

30. Discuss side effects of HMG-CoA reductase inhibitors.

Side effects are reduced to dyspepsia, constipation and flatulence. More serious complications have also been described - obstruction of the renal tubules, rhabdomyolysis and myopia. Most often this is observed with the simultaneous use of means, a brake * "

Megabolism of HMG-CoA reductase inhibitors (for example, systemic anti-®0A - drugs or macroshid antibiotics), as well as when consumed

ev. There may also be an increase in the level of liver enzymes (for example,

measures, transaminases).

31. Discuss the interaction of calcium channel blockers with HMG-CoA reductase inhibitors.

Verapamil and diltiazem, acting on cytochrome CYP3A4, inhibit the metabolism of HMG-CoA reductase inhibitors during their first passage through the liver.

32. Why grapefruit is contraindicated when using statins

33. Describe the effect of pravastatin on HDL levels.

Pravastatin has been shown to increase HDL levels in patients with heterozygous familial and non-familial hypercholesterolemia and mixed dyslipidemia, as well as in dyslipoproteinemia types 2a and 26 (Frederickson classification)

More on the topic HMG-CoA REDUCTASE INHIBITORS:

1. C10. GIPOLIPIDEMICHNI REQUIREMENTS S10A. DRUGS THAT DECREASE THE CONCENTRATION OF CHOLESTEROL AND TRIGLYCERIDE IN THE BLOOD SIROVATSI. C10AA. Inhibitors HMG CoA reductase
2. Violations of mitochondrial β-oxidation of fatty acids Medium-chain acyl-CoA dehydrogenase deficiency

Treatment of hyperlipoproteinemia

Medical lipid-lowering therapy

There are four main groups of lipid-lowering drugs: inhibitors of GMC-CoA reductase (statins), bile acid sequestrants, nicotinic acid and fibrates. Probucol also has a certain effect, the place of which in the range of lipid-lowering drugs is not well defined.

Bile acid sequestrants and statins mainly have a cholesterol-lowering effect, fibrates predominantly reduce hypertriglyceridemia, and nicotinic acid reduces both cholesterol and triglycerides (Table 8).

Table 8. Effect of lipid-lowering drugs on lipid levels

"mind" - reduces; "uv" - increases

The main goal of treatment is to reduce the level of LDL-C in order to reduce the risk of coronary artery disease (primary prevention) or its complications (secondary prevention). At the same time, the normalization of TG levels is also desirable, since hypertriglyceridemia is one of the risk factors for coronary artery disease (although less significant than hypercholesterolemia). In this regard, one of the important factors in choosing lipid-lowering drugs is their effect on TG levels. He is regarded as normal<200 мг/дл, или 2,3 ммоль/л), умеренно повышенный (от 200 мг/дл до 400 мг/дл, или 4,5 ммоль/л), высокий (от 400 мг/дл до 1000 мг/дл, или 11,3 ммоль/л) и очень высокий (>1000 mg/dl). Indications for the appointment of various classes of lipid-lowering drugs, depending on the type of HLP, are presented in Table. nine.

Bile acid sequestrants, which not only do not reduce the level of TG, but can even significantly increase it, are not prescribed when the upper limit of the normal TG (200 mg / dL) is exceeded. Statins lower TG levels to a moderate degree (by 8-10%), and therefore they are not commonly prescribed to patients with severe hypertriglyceridemia (> 400 mg / dl). Nicotinic acid lowers both cholesterol and TG levels. Fibrates have the most pronounced ability to correct hypertriglyceridemia, but their cholesterol-lowering effect is inferior to that of other classes of lipid-lowering drugs.

Table 9. Indications for lipid-lowering drugs

Thus, bile acid sequestrants are characterized by the narrowest indications for prescribing, which are recommended exclusively for patients with type IIa HLP, occurring in no more than 10% of all patients with HLP. Statins are indicated for patients with both IIa and IIb HLP types, which account for at least half of all patients with HLP. Nicotinic acid can be administered to brl with any type of HLP. Fibrates are intended mainly for the correction of type IIa HLP and the extremely rare dysbetalipoproteinemia (type III HLP). The appointment of drug lipotropic therapy for frequently occurring isolated hypertriglyceridemia (type IV HLP) in accordance with modern settings is the exception, not the rule, and is recommended only for patients with very high level TG (>1000 mg / dl) to reduce the risk of developing acute pancreatitis and not IBS.

HMG-CoA reductase inhibitors (statins)

Statins are a new and most effective group of cholesterol-lowering drugs that have radically changed the approach to the prevention of coronary artery disease and its complications, pushing into the background traditional lipid-lowering drugs - nicotinic acid, fibrates and anion-exchange resins. The first inhibitor of HMG-CoA reductase, compactin, was isolated in 1976 by a group of Japanese researchers led by A. Endo from the waste products of the fungal mold Penicillium citrinum. Compactin has not been used in the clinic, but cell culture and in vivo studies have demonstrated its high efficiency and served as an incentive to search for other statins. In 1980, a powerful inhibitor of HMG-CoA reductase lovastatin was isolated from the soil fungal microorganism Aspergillus terreus, introduced into the clinic in 1987. A comprehensive evaluation of lovastatin in numerous scientific studies and rich clinical experience allow us to consider it as a reference drug of the group statins.

Lovastatin is a lipophilic tricyclic lactone compound that acquires biological activity as a result of partial hydrolysis in the liver. The lipophilic properties of lovastatin are important and provide a selective effect on cholesterol synthesis in this organ. The maximum concentration in the blood is created 2-4 hours after taking lovastatin, its elimination half-life is about 3 hours. The drug is excreted from the body mainly with bile.

The lipid-lowering effect of lovastatin is due to the inhibition of the activity of the key enzyme in the synthesis of cholesterol - HMG-CoA reductase. Of all the available lipid-lowering drugs, only statins have a similar mechanism of action, which explains their significantly higher efficacy compared to other drugs. As a result of depletion of the liver of cholesterol, the activity of B / E receptors of hepatocytes increases, which carry out the capture of circulating LDL from the blood, and also (to a lesser extent) - VLDL and LDL. This leads to a significant decrease in the concentration of LDL and cholesterol in the blood, as well as a moderate decrease in the content of VLDL and TG. During therapy with lovastatin 20 mg per day, the concentration of total cholesterol decreases by an average of 20%, LDL cholesterol - by 25%, and triglycerides - by 8-10%. The level of HDL cholesterol increases by 7% (Fig. 4).

The pharmacodynamic effect of lovastatin is not limited to its effect on lipid profile parameters. It causes activation of the fibrinolytic system of the blood, inhibiting the activity of one of the plasminogen inhibitors. In animal experiments and in experiments on human aortic cell culture, it has been shown that lovastatin suppresses the proliferation of intimal cells in response to endothelial damage by various agents.

Rice. 4. Effect of lovastatin 20 mg per day on the lipid profile

Lopastatin is prescribed once a day, during dinner, which ensures the inhibition of cholesterol synthesis at night, when this process is most active. Typically, lovastatin is given initially at a dose of 20 mg. Subsequently daily dose the drug can be reduced to 10 mg or increased in stages to 80 mg per day. The dependence of the cholesterol-lowering effect of lovastatin (as well as other statins) on the dose is described by a logarithmic curve, and therefore a sharp increase in dose is accompanied by a relatively small increase in effect. Therefore, the use of high doses is usually unjustified. The lipid-lowering effect of lovastatin develops during the first week of treatment, reaching a maximum after 3-4 weeks. and then remains unchanged.

The antiatherogenic properties of lovastatin have been convincingly demonstrated both in experimental models of atherosclerosis and in humans. The effect of long-term therapy with lovastatin on atherosclerotic changes in the coronary arteries in patients with coronary artery disease was specifically studied in the MARS, CCAIT, FATS and UCSF-SCOP studies. With the help of repeated coronary angiographic studies, it was shown that lovastatin, both in monotherapy and in combination with other lipid-lowering drugs, significantly slows down the progression of coronary atherosclerosis and leads to its regression in some patients. There is reason to believe that lovastatin also has the ability to strengthen the thin shell of "vulnerable" atherosclerotic plaques, thereby reducing the likelihood of their rupture and the risk of developing myocardial infarction and unstable angina.

The tolerability of lovastatin was carefully assessed in a study specifically dedicated to this issue: the Comprehensive Clinical Evaluation of Lovastatin (EXCEL), the results of which were published in 1991. It included more than 8000 patients with moderately severe hypercholesterolemia who received lovastatin at various dosages for 2 years. The EXCEL study found that lovastatin was similar in frequency and side effect profile to placebo. A small proportion of patients experienced gastrointestinal discomfort. An increase in transaminase activity three or more times higher than the upper limit of the norm, indicating a potential hepatotoxic effect of the drug, was registered in approximately 2% of patients with lovastatin therapy at maximum doses, and less than 1% of patients at usual doses. The toxic effect of the drug on muscle tissue, manifested by pain in various muscle groups and an increase in the level of creatine phosphokinase, was detected in less than 0.2% of patients.

Along with lovastatin (Rovacor, Mevacor, Medostatin), the group of TMG-CoA reductase inhibitors is also represented by other drugs (Table 10).

Table 10. Names and dosages of statins

international Name	Patented Name	Contents of the current ingredients in a tablet	Featured dosage (mg per day)
Lovastatin	Mevacor, Rovacor, Medostatin	10, 20, 40 mg	10-40 mg
Simvastatin	Zokor, Simvor	5, 10, 20, 40 mg	5-40 mg
Pravastatin	Lipostat	10 and 20 mg	10-20 mg
Fluvastatin	Lescol	20 and 40 mg	20-40 mg
Cerivastatin	Lipobai	100, 200, 300 mcg	100-300 mcg
Atorvastatin	Liprimar	10, 20, 40 mg	10-40 mg

Simvastatin is a semi-synthetic analogue of lovastatin, which is obtained by modifying one of the active chemical groups of its molecule. Like lovastatin, simvastatin is a lipophilic lactone prodrug that transforms into active drug as a result of metabolism in the liver. The efficacy of simvastatin in secondary prevention IHD was studied in the famous Scandinavian Study (4S), which included 4444 patients. Half of them received simvastatin for 5.5 years, and the other half received a placebo. The main outcome of the study was a 42% reduction in coronary mortality and a 30% reduction in overall mortality.

Pravastatin is very similar in chemical structure to lovastatin and simvastatin, however, it is not a prodrug, but an active pharmacological drug. In addition, pravastatin is a hydrophilic compound and therefore should be taken on an empty stomach. The effectiveness of pravastatin in the primary prevention of coronary artery disease was proven by the results of the Western Scottish Study (WOSCOPS), which included 6595 people aged 45-64 years with hypercholesterolemia. Treatment with pravastatin 40 mg daily for 5 years resulted in a 20% reduction in cholesterol levels, a 26% reduction in LDL-C, and a 31% reduction in the relative risk of developing coronary artery disease compared with the placebo group.

Fluvastatin, unlike the above drugs, is not a derivative of fungal metabolites. It is obtained synthetically. The basis of the fluvastatin molecule is the indole ring. The bioavailability of fluvastatin is independent of food intake. Fluvastatin has a pronounced cholesterol-lowering effect, which, however, is somewhat inferior to the effect of other statins.

The synthetic drug cerivastatin has been little studied and has not been widely used clinically.

The new HMG-CoA reductase inhibitor atorvastatin is obtained, like the more well-known drugs of this series lovastatin, simvastatin and pravastatin, from fungal metabolites. It has a slightly more pronounced effect on plasma lipid levels than other statins.

Thus, the group of statins is represented by a number of drugs that are obtained both from the waste products of fungal flora and synthetically. Some drugs in this group are prodrugs, while others are active pharmacological compounds. Despite some differences, the lipid-lowering effect of all statins at recommended dosages is approximately the same. The antiatherogenic effect of statins has been proven in coronary angiographically controlled studies. The ability of statins to prevent the development of coronary artery disease, reduce the risk of its complications and increase the survival of patients has been convincingly demonstrated in studies conducted at a high scientific level. The most valuable are drugs, the effectiveness and safety of which have been confirmed by many years of clinical practice.

Bile acid sequestrants

Bile acid sequestrants (or sorbents) cholestyramine and colestipol have been used to treat HLP for more than 30 years and are anion-exchange resins (polymers) that are insoluble in water and not absorbed in the intestine. The main mechanism of action of FFAs is the binding of cholesterol and bile acids, which are synthesized from cholesterol in the liver. About 97% of bile acids are reabsorbed from the intestinal lumen and enter the liver through the portal vein system, and then are again excreted in the bile. This process is called enterohepatic circulation. FFA "break" the enterohepatic circulation, which leads to additional formation of bile acids and to the depletion of the liver of cholesterol. The consequence of this is a compensatory increase in the activity of V / E receptors that capture LDL, and a decrease in the level of cholesterol in the blood. With FFA therapy, the level of total cholesterol decreases by 10-15%, and LDL cholesterol - by 15-20%. At the same time, there is a slight (3-5%) increase in the level of HDL cholesterol. The TG content either does not change or increases, which is explained by a compensatory increase in the synthesis of VLDL. This calls for great caution when prescribing cholestyramine and colestipol to patients with concomitant hypertriglyceridemia. Ideal candidates for the treatment of FFA are patients with "pure" hypercholesterolemia, that is, type IIa HLP, which occurs infrequently (in about 10% of patients with HLP). Moderate hypertriglyceridemia (TG>200 mg/dL) is relative, and severe (TG>400 mg/dL) is an absolute contraindication to their use.

FFAs are not absorbed in the intestine and therefore do not cause systemic toxic effects. This allows them to be prescribed to young patients, children and pregnant women. Due to the absorption of bile acids and digestive enzymes, FFAs can cause side effects such as constipation, flatulence, heaviness in the epigastric region. Gastrointestinal discomfort is the main factor limiting the intake of FFAs at high doses.

Cholestyramine and colestipol are available as granules packaged in sachets of 4 and 5 g, respectively. The efficacy and tolerability of drugs in these (and multiples of them) doses is the same. The contents of the sachet are dissolved in a glass of water or fruit juice and taken with food. The initial dose of cholestyramine is 4 g and colestipol is 5 g taken twice daily. With insufficient effectiveness, the dosage of drugs is increased, increasing the frequency of administration up to three times a day. As a rule, the dose of cholestyramine does not exceed 24 g (colestipol - 30 g) per day due to the occurrence of gastrointestinal side effects.

FFAs reduce the absorption of digoxin, indirect anticoagulants, thiazide diuretics, beta-blockers and many other drugs, in particular inhibitors of GMC-CoA reductase (lovastatin, simvastatin and others). Therefore, these drugs are prescribed 1 hour before taking or 4 hours after taking FFA. When treating FFA, the absorption of fat-soluble vitamins decreases: A, D, E, K, but the need for their additional intake usually does not arise.

The problems associated with poor tolerability of FFAs have been demonstrated not only in clinical practice, but also in the results of large-scale, multicenter, long-term, placebo-controlled studies. The most significant of these was the Lipid Clinics Primary Prevention of IHD (LRC) Study, which began in the mid-70s and ended in the mid-80s. It included 3806 men aged 35-59 years with hypercholesterolemia (CS>265 mg/dL). Against the background of a relatively mild lipid-lowering diet (cholesterol intake of no more than 400 mg per day, the ratio of polyunsaturated fats to saturated fats of 0.8), patients received cholestyramine (main group) or placebo (control group) for 7.5 years. It was planned to prescribe cholestyramine at 24 g per day, which was supposed to reduce the level of total cholesterol by about 28%. However, due to the high frequency of side effects, the actual dose of cholestyramine averaged only 14 g per day.

In the control group, the level of total cholesterol decreased by an average of 5%, LDL cholesterol - by 8%, and in the main group - by 13% and 20%, respectively. Thus, cholestyramine therapy while following a lipid-lowering diet led to an additional decrease in total cholesterol by only 8%, and LDL cholesterol by 12%. Nevertheless, in the main group of patients, a statistically significant decrease in the incidence of myocardial infarction and mortality from coronary artery disease by 19% was stated. However, in the subgroup of patients (32%), in whom the lipid-lowering effect of cholestyramine was maximum and was expressed in a decrease in LDL-C by more than 25%, mortality from coronary artery disease and the incidence of non-fatal myocardial infarction decreased very significantly - by 64%.

LRC - CPPT was the classic study that first supported the lipid hypothesis of atherogenesis. It allowed us to come to a number of important conclusions, in particular, that a decrease in cholesterol levels by 1% means a decrease in the risk of coronary catastrophes by 2-3%. It also showed that a real reduction in coronary risk can only be achieved with a very significant decrease in the level of total cholesterol and LDL cholesterol. One of the results of the study was the conclusion that FFA can solve the problem of prevention of coronary artery disease only in a small part of patients. Due to poor tolerance, drugs of this series are currently rarely prescribed, and usually not in monotherapy, but in combination with other lipid-lowering drugs, in particular, with statins and nicotinic acid.

Nicotinic acid (NA)

Like bile acid sequestrants, NK is a traditional lipid-lowering drug and has been used for about 35 years. They are united by a high frequency of side effects. NK belongs to the vitamins of group B. The lipid-lowering effect of NK is manifested in doses that significantly exceed the need for it as a vitamin. Close to NC, nicotinamide does not have a hypolipidemic effect. The mechanism of action of NK is to inhibit the synthesis of VLDL in the liver, as well as to reduce the release of free fatty acids from adipocytes, from which VLDL are synthesized. As a result, there is a secondary decrease in the formation of LDL. The most pronounced effect of NC has on the content of TG, which decreases by 20-50%. The decrease in cholesterol levels is not so significant (10-25%).

An essential feature of NC is its ability to increase the level of HDL cholesterol by 15-30%, which is associated with a decrease in HDL catabolism and the main apoprotein that is part of them - apo A-I. The favorable effect of NK on the main indicators of the lipid spectrum allows its use in HLP IIa, IIc and IV types.

The usual therapeutic dose range for NC is 1.5 to 3 g. Higher doses (up to 6 g per day) are sometimes used. However, the appointment of NK in therapeutic doses prevents its vasodilating effect, manifested by flushing of the face, headache, skin itching, tachycardia. Over time, with systematic use, the vasodilating effect of NK is reduced (although not completely) - tolerance develops to it. Therefore, NC therapy has to be started with taking small, obviously ineffective doses, waiting for the development of tolerance and then gradually increasing the dosage. The recommended initial dose of NK is 0.25 g 3 times a day. It usually takes 3-4 weeks. to reach the therapeutic level. In the event that the patient interrupts the intake of NK for 1-2 days, the sensitivity of arteriolar receptors to the drug is restored and the process of gradually increasing doses has to be started anew. The vasodilatory effect of NK is reduced when taken with food, and also in combination with small doses of aspirin, which is recommended in practice.

It should be borne in mind that taking NC can potentiate the effect of antihypertensive drugs and lead in patients with arterial hypertension to a sudden drop in blood pressure. NC often causes gastrointestinal disturbances such as nausea, flatulence, and diarrhea. Unfortunately, NK is not free from a number of serious toxic effects. Its use can lead to exacerbation of peptic ulcer, increased uric acid levels and exacerbation of gout, hyperglycemia and toxic liver damage. Therefore, NC is contraindicated in patients with peptic ulcer stomach and duodenum, patients with gout or asymptomatic severe hyperuricemia, liver disease.

An important contraindication to the appointment of NC is diabetes mellitus, since NC has a hyperglycemic effect. Hepatitis in NK therapy is rare, usually characterized by a benign course and, as a rule, completely reversible after discontinuation of the drug. However, the possibility of their development makes it necessary to carefully monitor the level of transaminases. This control is necessary before starting therapy, every 12 weeks. during the first year of treatment and somewhat less frequently thereafter.

In addition to the usual crystalline NK, its long-acting preparations are also known, for example, enduracin. Their advantages are ease of dosing and lesser severity of side effects associated with the vasodilating properties of NK. However, the safety of prolonged forms of NC with long-term use has not been studied enough. They are thought to be more likely to cause liver damage than crystalline NK. Therefore, retard forms of NDT are not approved for use in the USA.

The effectiveness of NC in the secondary prevention of coronary artery disease was studied in one of the most famous early long-term randomized controlled trials - the Coronary Drug Project, which ended in 1975. More than 1000 patients received NC at 3 g per day for 5 years. NC therapy was accompanied by a decrease in cholesterol levels by 10%, TG - by 26% and led to a statistically significant decrease in the incidence of non-fatal myocardial infarction by 27% compared with the placebo group. However, there was no significant reduction in total and coronary mortality. Only with a re-examination of patients conducted 15 years after the end of this study, it was shown that in the group of persons taking NK, a lower mortality rate was registered.

Thus, NK is an effective lipid-lowering drug, the widespread use of which is hampered by a high incidence of symptomatic side effects, the risk of organotoxic effects (especially hepatotoxicity), and the need for careful laboratory monitoring of transaminase levels.

Fibric acid derivatives

The ancestor of this group of drugs is clofibrate, which was widely used for the prevention and treatment of atherosclerosis in the 60-70s. Subsequently, after its shortcomings became apparent, it was practically replaced by other fibrates - gemfibrozil, bezafibrate, ciprofibrate and fenofibrate (Table 11). The mechanism of action of fibrates is quite complex and not fully understood. They increase the catabolism of VLDL by increasing the activity of lipoprotein lipase. There are also inhibition of LDL synthesis and increased excretion of cholesterol in the bile. In addition, fibrates lower the level of free fatty acids in the blood plasma. Due to the predominant effect of fibrates on the metabolism of VLDL, their main effect is to lower the level of triglycerides (by 20-50%). The level of cholesterol and LDL cholesterol is reduced by 10-15%, and the content of HDL cholesterol is slightly increased.

Table 11. Names and dosages of fibrates

international Name	Patented Name	release form, dosage	Featured dosage
Clofibrate	Atromid, Miscleron	Tablets, capsules 500 mg	0.5-1 g 2 times a day
Gemfibrozil	Innoghem, Hipipides	Capsules 300 mg	600 mg 2 times a day
Bezafibrate	Bezalip	200 mg tablets	200 mg 3 times a day
Ciprofibrate	Lipanor	100 mg tablets	100 mg once a day
Fenofibrate	Lipantil	Capsules 200 mg	200 mg once a day
Etofibrate	Lipo Merz	Capsules-retard 500 mg	500 mg once a day

In addition to affecting the level of LP, fibrates change their qualitative composition. It has been shown that gemfibrozil and bezafibrate reduce the concentration of "small dense" LDL, thereby reducing the atherogenicity of this class of drugs. However, the clinical significance of this effect has not been elucidated. In addition, during fibrate therapy, there is an increase in anticoagulant and fibrinolytic activity, in particular, a decrease in the level of circulating fibrinogen, as well as platelet aggregation. The significance of these potentially beneficial effects has also not been established.

Fibrates are the drugs of choice in patients with rare type III HLP, as well as type IV HLP with a high level of TT. In HLP IIa and IIc types, they are considered as a reserve group of drugs. Fibrates are generally well tolerated. The most significant side effect of clofibrate is an increase in the lithogenicity of bile and an increase in the incidence of gallstone disease, in connection with which it has practically ceased to be used. Increased risk cholelithiasis treatment with gemfibrozil, bezafibrate, ciprofibrate and fenofibrate has not been proven, but this possibility cannot be ruled out. In rare cases, fibrates cause myopathy, especially when combined with statins. There may also be a potentiation of the effect of indirect anticoagulants, and therefore it is recommended to halve their dosages. Of the symptomatic side effects, nausea, anorexia, a feeling of heaviness in the epigastric region that occur in 5-10% of patients deserve mention.

One of the factors hindering the widespread use of fibrates for primary and secondary prevention of coronary artery disease is the inconsistency of data on their effect on long-term prognosis. The first information about the use of fibrates for the primary prevention of coronary artery disease was received in 1978 after the completion of the WHO Collaborative Study. It included 10,000 men with hypercholesterolemia aged 30 to 59 years. Half of them received clofibrate 1600 mg per day for 5.3 g and half received placebo. Therapy with clofibrate was accompanied by a decrease in the level of total cholesterol by 9% and the incidence of coronary artery disease - by 20%. However, as a result of a significant increase in non-coronary deaths, overall mortality in the main group increased by 47%, which became widely known and led to the ban of the drug in many countries. However, it is currently believed that this result was the result of methodological miscalculations in the planning of the study and the analysis of the data obtained.

Evaluation of the impact of long-term therapy with clofibrate in the framework of the program for the secondary prevention of coronary artery disease was carried out in a well-known study - the Coronary Drug Project, the results of which were published in 1975. Clofibrate at 1800 mg per day for 5 years was received by 1103 patients who had myocardial infarction. The level of total cholesterol decreased by 6%, and TG - by 22%. A 9% reduction in the incidence of recurrent myocardial infarction and CHD mortality was noted, however, these changes were not statistically significant. The overall mortality rate did not change significantly.

The next attempt to study the effectiveness of fibrates in long-term therapy was made in the Helsinki study, the results of which were published in 1987. It included about 4000 men with hypercholesterolemia aged 40 to 55 years. Therapy for 5 years with gemfibrozil at 1200 mg per day led to a decrease in total cholesterol by 10%, LDL cholesterol by 11%, an increase in HDL cholesterol by 11% and a decrease in TG by 35%. The main outcome of the study was a 26% reduction in CHD mortality, but overall mortality did not decrease as a result of an increase in non-cardiac mortality. Subsequent analysis made it possible to identify a subgroup of subjects who were characterized by the highest risk of coronary artery disease in whom gemfibrozil therapy proved to be the most effective. These were individuals with a TG level of more than 200 mg / dl and with a ratio of LDL-C to HDL-C of more than 5. In such patients, the incidence of IHD complications during treatment decreased by 71%.

Thus, at present there are no data that would allow us to state that long-term fibrate therapy leads to an increase in the survival of patients with coronary artery disease (with the exception of a selective group of patients) or patients at an increased risk of its development.

Probucol

Probucol is a drug similar in structure to hydroxytoluene, a compound with powerful antioxidant properties. Actually the hypolipidemic effect of probucol is very moderate and is characterized by a decrease in the level of total cholesterol by 10% and a decrease in HDL cholesterol by 5-15%. It is interesting to note that, unlike other lipid-lowering drugs, probucol does not increase, but reduces the level of HDL-C. The lipid-lowering effect of probucol is due to the activation of non-receptor pathways for the extraction of LDL from the blood. It is believed that probucol has strong antioxidant properties and prevents the oxidation of LDL.

The effectiveness of probucol has mainly been studied in experimental models of atherosclerosis. In particular, it has been shown that in Watanabe rabbits, which are a model of familial hypercholesterolemia due to the absence of B/E receptors, probucol causes the regression of atherosclerotic plaques. The effectiveness of probucol in humans has not been proven, in particular, its antioxidant properties have not been demonstrated. The effect of long-term therapy with this drug on the incidence of coronary artery disease and the frequency of its complications has not been studied.

The drug is usually well tolerated. Sometimes there are side effects from the gastrointestinal tract. Probucol causes an increase in the duration of the QT interval, which can lead to severe ventricular arrhythmias.

Therefore, patients taking this drug require careful ECG monitoring. The drug should be taken on an empty stomach, as it is lipophilic and fatty foods increase its absorption. Probucol is prescribed 500 mg 2 times a day.

Combined drug therapy GLP

A combination of lipid-lowering drugs is used to enhance the cholesterol-lowering effect in patients with severe hypercholesterolemia, as well as to normalize concomitant lipid disorders - elevated TG levels and low HDL cholesterol levels. Typically, a combination of relatively low doses of two drugs with different mechanisms of action is not only more effective, but also better tolerated than taking high doses of a single drug. Combination therapy can neutralize the potentially adverse effects of monotherapy with certain drugs on lipid profile parameters. For example, in patients with type II HLP, fibrates, by normalizing the level of TG and HDL cholesterol, can increase the content of LDL. When combined in this situation, fibrates with nicotinic acid or with statins, this unwanted effect does not occur. Classic combination nicotinic acid with anion exchange resins is very effective, but is characterized, like monotherapy with these drugs, by a fairly high frequency side effects. Currently, in patients with type IIa HLP, the combination of statins with anion exchange resins or with nicotinic acid is most often used, and in patients with type IIb HLP, statins with nicotinic acid or fibrates are used (Table 12).

Table 12. Combinations of lipid-lowering drugs

The ability of combined lipid-lowering therapy to prevent the progression of coronary artery atherosclerosis has been specifically studied in a number of studies with serial coronary angiographic control. The Familial Atherosclerosis Treatment Study (FATS) included 120 men with hypercholesterolemia, increased level apoprotein B, aggravated family history and documented coronary angiography stenosis of 1-3 coronary arteries. For 2.5 years, patients received the bile acid sequestrant colestipol 30 g per day in combination with lovastatin (40-80 mg per day) or nicotinic acid (4-6 g per day). Therapy with lovastatin and colestipol led to a decrease in total cholesterol by 34%, and LDL cholesterol by 46%, and to the prevention of progression and regression of stenotic changes in the coronary arteries in most patients. A somewhat less pronounced hypolipidemic and angioprotective effect was observed when taking colestipol in combination with nicotinic acid. In the group of patients taking placebo, the progression of atherosclerotic changes occurred in 90% of patients.

With insufficient effectiveness of the combination of two lipid-lowering drugs in the most severe, refractory cases, one has to resort to a combination of three drugs, for example, statins with bile acid sequestrants and nicotinic acid. Such tactics can ensure success, for example, in patients with heterozygous familial hypercholesterolemia.

It should be borne in mind that when using combinations of lipid-lowering drugs, the risk of toxic adverse reactions which requires appropriate precautions to be taken. Therapy with statins in combination with fibrates is associated with the risk of developing myopathy, and the combined use of statins and nicotinic acid is associated with an increased risk of myopathy and liver damage. Therefore, such combinations of lipid-lowering drugs require fairly frequent monitoring of both the level of transaminases and creatine phosphokinase.

Non-drug therapy of HLP

In special cases, in the treatment of HLP can be used surgical methods, plasmapheresis, in the future, genetic engineering methods are being developed.

In 1965, partial ileo-bypass surgery was proposed for the treatment of hypercholesterolemia. It consists in turning off most of the ileum with the imposition of an anastomosis between its proximal end and the initial section of the colon. At the same time, the content small intestine bypasses the sites where reabsorption of bile salts occurs, and their excretion increases several times. As a result, there is a significant decrease in the level of cholesterol and LDL cholesterol (up to 40%), which is comparable in severity to that which occurs when taking cholestyramine 32 g per day. After surgery, severe diarrhea sometimes occurs, which is successfully treated with cholestyramine. Patients require lifelong injections of vitamin B12 at 1000 micrograms once every three months.

In the past, partial ileo-bypass surgery was considered as a serious alternative. pharmacological therapy in patients with severe, refractory variants of HLP. In 1980, a special study was launched and completed in 1990 - the Program for Surgical Control of HLP (POSCH), which included 838 patients with hypercholesterolemia who had myocardial infarction. According to the 10-year follow-up and periodically repeated coronary angiographic studies, in the group of patients who underwent surgical intervention, a decrease in cholesterol levels by 23%, a decrease in the incidence of repeated heart attack myocardial infarction and the frequency of coronary death - by 35% and a slowdown in the progression of coronary atherosclerosis compared with patients in the control group who received conventional therapy. At present, with the replenishment of the therapeutic arsenal of lipid-lowering drugs with a group of statins, partial ileo-shunting has practically lost its significance.

A radical treatment for patients with extremely rare homozygous familial hypercholesterolemia is liver transplantation. Due to the fact that the donor liver contains normal amount V / E receptors that capture cholesterol from the blood, its level decreases to normal a few days after the operation. The first successful liver transplantation for familial hypercholesterolemia was performed in 1984 on a 7-year-old girl. After that, several more successful cases of this intervention are described.

For the treatment of patients with homozygous and heterozygous familial hypercholesterolemia, resistant to dietary therapy and lipid-lowering drugs, LDL apheresis is used. The essence of the method lies in the extraction of apo-B-containing drugs from the blood using extracorporeal binding with immunosorbents or dextrancellulose. Immediately after this procedure, the level of LDL cholesterol is reduced by 70-80%. The effect of the intervention is temporary, and therefore regular lifelong repeated sessions are required at intervals of 2 weeks - 1 month. Due to the complexity and high cost this method treatment, it can be used in a very limited circle of patients.

Results of controlled clinical research with the use of statins indicate that these drugs have a lipid-lowering effect, reduce cardiovascular and total mortality, improve the quality of life and prognosis in patients with coronary heart disease (CHD) and atherosclerosis.

IN modern conditions using atorvastatin and rosuvastatin, the possibility of stabilization and reverse development of atroscalerotic plaques in the coronary arteries was demonstrated. Results of clinical trials of statins recent years demonstrated their efficacy and safety in patients with arterial hypertension, type 2 diabetes mellitus, and acute coronary syndrome.

The classification of HMG-CoA reductase inhibitors is based both on differences in the chemical structure of statins (drugs obtained by fermentation of fungi and synthetic statins) and on the time of their use in clinical practice (statins I-IV generation).

All statins are produced and used in tablet form. As a rule, statins are prescribed once, usually at bedtime, due to the fact that cholesterol synthesis occurs most intensively at night.

Atorvastatin and rosuvastatin can be used at any time of the day.

• Lovastatin (Mevacor, Medostatin, Choletar) - an initial dose of 20 mg once a day immediately after dinner; the target LDL cholesterol content in most cases can be achieved with the appointment of 40 mg / day. Currently, lovastatin is practically not used due to the emergence of more modern statins.
• Simvastatin (Zokor, Actolipid, Atherostat, Vasilip, Vero-simvastatin, Zovatin, Zorstat, Levomir, Simvahexal, Simvacard, Simvakol, Simvastatin-Verte, Simvalimit, Simvastol, Simvor, Simgal, Simlo) - by equivalence twice as strong as lovastatin, that is, reception 10 mg/day Simvastatin produces the same reduction in LDL cholesterol as lovastatin 20 mg/day. Initial dose 10-20 mg 1 time per day; the target content is usually reached at 40 mg; the maximum dose is 80 mg (rarely used in practice due to the high risk of complications - increased liver enzymes, myopathy and rhabdomyolysis).
• Pravastatin (Lipostat) - is prescribed at a dose of 20-40 mg / day. At any time of the day. The 80 mg dose has not been studied and is not commonly used.
• Fluvastatin (Leskol, Leskol XL - is prescribed at a dose of 20-40 mg / day, but more often in the form of a sustained release of 80 mg once a day. Taking into account the peculiarities of pharmacokinetics (high selectivity of action in the liver and metabolism through the 2C9 isoform of cytochrome P-450), fluvastatin is prescribed to patients after organ transplantation receiving cytostatics.
• Atorvastatin (Liprimar, Atoris, Liptonorm, Torvacard, Tulip) is a third-generation synthetic statin. It is twice as effective as simvastatin and fluvastatin. Therapy begins with a dose of 10-20 mg / day; if there is no effect to achieve the target level, the dose can be increased to 40 mg. In patients with acute coronary syndrome or in the very high risk category, based on the results of studies on "aggressive" lipid-lowering therapy (IDEAL, REVERSAL, MIRACLE, PROVE-IT TIM122), atorvastatin is recommended to be prescribed at a dose of 80 mg / day.
• Rosuvastatin (Crestor) is superior to atorvastatin in terms of equivalent efficacy. This is the newest of the drugs presented, and many large-scale studies on its use have not yet been completed (GALAXY, JUPITER, CORONA, AURORA). However, already completed studies (STELLAR, MERCURY I, II, ASTEROID, METEOR, EXPLORER) have demonstrated the maximum effectiveness of the drug. It is prescribed at a dose of 5-10 mg / day; The maximum dose used primarily in patients with severe familial hypercholesterolemia is 40 mg/day.

Currently, generic statins are widely used. More than 30 generic statins (reproduced copies of original drugs) are registered in Russia. All generics have been tested for bioequivalence original drugs However, post-registration, fact-finding, clinical studies have not been carried out for all generics, which, according to experts of the All-Russian Scientific Society of Cardiologists, is wrong, since practice shows that in some cases there is no complete equivalence of generics to original drugs in terms of the degree of change in lipid spectrum parameters.

Generic statins are used in the same doses as brand-name statins. As a rule, in terms of lipid-lowering activity, they are not inferior to the original drugs, but are less expensive, which to some extent helps to solve the problem of their availability to a wider range of patients.

Statins are well tolerated and are among the safest drug classes according to clinical studies.

Occasionally, taking statins can be accompanied by abdominal pain, flatulence, and constipation.

An increase in the activity of hepatic enzymes ALT, AST is observed in 1-5% of patients taking statins. In the usual practice of using each of the statins in monotherapy, the first monitoring of enzyme activity is prescribed after 1 month from the start of treatment, and then every 3-6 months.

If the activity of at least one of the listed enzymes in two consecutive measurements exceeds 3 times the upper limits of normal values, the statin should be discontinued. In cases of a more moderate increase in the content of enzymes, it is enough to limit the dose of the drug.

Enzyme levels usually return to normal within a short time, and treatment can be restarted either with the same drug at a lower dose or with a different statin.

According to modern ideas, statin therapy may be recommended for patients with chronic liver disease, non-alcoholic steatohepatitis, fatty liver - subject to careful monitoring of liver enzyme activity.

Very rarely, when taking statins, fatigue, sleep disturbances, taste disorders, skin itching, headaches, dizziness can be noted; possible teratogenic effect.

Rarely (0.1-3%) when taking statins, myopathy and myalgia are observed, which are manifested by pain and weakness in the muscles, accompanied by an increase in CPK activity by more than 5 times and require discontinuation of the drug.

The most dangerous complication of statin therapy, rhabdomyolysis, or breakdown of muscle tissue with possible damage to the renal tubules, occurs when the presence of myopathy is not diagnosed in time and treatment with a statin continues if it is present.

Rhabdomyolysis is a severe, life-threatening complication that is accompanied by myalgia, myopathy, muscle weakness, more than 10-fold increase in CPK, elevated creatinine, and dark urine due to myoglobinuria.

In the event of rhabdomyolysis, statins should be stopped immediately. The patient needs urgent hospitalization. In severe cases of rhabdomyolysis ( kidney failure) for its treatment, extracorporeal methods of blood purification are used - plasmapheresis and hemodialysis.

Rhabdomyolysis is more often observed with the simultaneous appointment of statins with fibrates, cytostatics, macrolide antibiotics; in these cases, patients should be under careful, intensive medical supervision with the control of all of these enzymes at least once a month.

Cause more frequent occurrence complications with this combination is due to the fact that the metabolism of lovastatin, simvastatin, atorvastatin occurs through the cytochrome-450 system and its 3A4 isoform. Competitive binding of the enzyme leads to an increase in the concentration of statins in the blood plasma and, consequently, to an increase in their myotoxic properties.

The table shows through which enzyme isoforms of cytochrome P-450 the metabolism of various statins occurs, as well as a list of the main drugs of other classes, the metabolism of which is carried out through the same isoforms.

Cytochrome P 3A4	Cytochrome P 2C9
Cyclosporine	Atenolol
Erythromycin	Diclofenac
Felodipine	Hexobarbital
Lidocaine	N-desmethyldiazepam
Mibephradil	tolbutamide
Midazolam	warfarin
Nifedipine
Quinidine
Terbinafine
Triazolam
Verapamil
warfarin

If it is necessary to combine these drugs with statins, especially potent ones, a minimum dose of statins should be prescribed and the levels of liver enzymes and creatine phosphokinase (CPK) should be carefully monitored at least once a month.

Particular care must be taken if a patient has a severe injury during treatment with statins, a large abdominal operation, there are endocrine or electrolyte disorders.

• Statins interact with the following drugs: antacids, antipyrine, colestipol, digoxin, erythromycin, clarithromycin, azithromycin, hormonal contraceptives, amlodipine, proteinase inhibitors.

  statin drug interactions.

  interacting medicines	Statins	Result of interaction
  Antifungal drugs- azole derivatives (ketoconazole, itraconazole)	Lovastatin, simvastatin, atorvastatin, rosuvastatin
  Immunosuppressants (cyclosporine)	Simvastatin, fluvastatin, pravastatin, rosuvastatin	Increased risk of myopathy and rhabdomyolysis
  Fibrates	Lovastatin, fluvastatin, atorvastatin, rosuvastatin	Increased risk of developing myopathy
  A nicotinic acid

HMG-CoA reductase:

1) increase a) insulin

2) decrease b) glucagon

c) glucocorticoids

d) mevalonate

e) cholesterol

CHOOSE THE CORRECT ANSWER.

The mechanism of regulation of HMG CoA - cholesterol reductase:

a) allosteric activation

b) covalent modification

c) induction of synthesis

d) synthesis repression

e) protector activation

Test 18.

CHOOSE THE CORRECT ANSWER.

Coenzyme HMG CoA reductase(synthesis of cholesterol) is an:

b) NADPH + H +

c) NADH + H +

e) biotin

Test 19.

CHOOSE THE CORRECT ANSWER.

The mechanism of regulation of the synthesis of B 100, E-receptors for LDL cholesterol:

a) allosteric activation of the regulatory enzyme

b) covalent modification

c) induction of synthesis

d) synthesis repression

e) inhibition of the regulatory enzyme by the allosteric mechanism

Test 20.

CHOOSE THE CORRECT ANSWER.

Synthesis intermediate cholesterol is used by the body to synthesize:

a) purines

b) pyrimidines

c) coenzyme Q

d) ornithine

e) thiamine

Test 21.

ADD ANSWER.

Regulatory enzyme for cholesterol conversion in bile acids is ________________.

Test 22.

Cholesterol synthesis in the liver increases with a diet rich in:

a) proteins

b) carbohydrates

c) animal fats

G) vegetable oils

d) vitamins

SET STRICT COMPLIANCE.

Enzyme: Process:

1) 7a cholesterol hydroxylase a) synthesis of cholesterol esters in the cell

2) AChAT b) synthesis of cholesterol esters in the blood

on the surface of HDL

3) 1acholesterol hydroxylase c) synthesis of bile acids in the liver

4) LCAT d) synthesis of steroid hormones

e) formation of the active form

vitamin D 3 in the kidneys

CHOOSE THE CORRECT ANSWER.

Chylomicron triglycerides and VLDL are hydrolyzed:

a) pancreatic lipase

b) triacylglyceride lipase

c) lipoprotein lipase

ADD ANSWER.

ADD ANSWER.

Statins reduce the activity of HMG-CoA reductase by the mechanism of ______________ ___________ inhibition.

MATCH

(for each question - several correct answers, each answer can be used once)

SET THE CORRECT SEQUENCE.

The flow of cholesterol from the liver to peripheral tissues:

a) formation of LDL

b) attachment in the blood of Apo C to VLDL

c) the formation of VLDL

d) the action of LP-lipase

e) uptake of lipoproteins by specific tissue receptors

CHOOSE ALL CORRECT ANSWERS.

Functions of HDL in the blood:

a) transport of cholesterol from extrahepatic tissues to the liver

b) supply of apoproteins to other drugs in the blood

c) antioxidant functions in relation to modified LDL

d) take away free cholesterol and transfer cholesterol esters

LP in the blood

e) transport of cholesterol from the liver to peripheral tissues

CHOOSE ALL CORRECT ANSWERS.

Risk factors for atherosclerosis are:

a) hypercholesterolemia

b) smoking

in) high pressure

d) weight loss

e) hypodynamia

Answers on the topic: "CHOLESTEROL METABOLISM. Lipoproteins"

1. d 2 . b 3 . but 4. but

5. b 6. in 7. G 8 . d

9. b 10 .G 11 . b, c, d 12 . a, b, d, e

13. a, b, d, e 14 . 1c, 2a, 3d, 4b

15. mevalonate, HMGCoA reductase

16. 1a 2bcd

21. 7α-cholesterol hydroxylase

22. b,c

23. 1c, 2a, 3d, 4b

25. increases

26 . competitive reversible

27. 1ad 2bwg

28. vbgad

29. a B C D

30. a, b, c, d

1. Topic 20. Lipid metabolism disorders

Independent work of students in the classroom

Venue – Department of Biochemistry

The duration of the lesson is 180 min.

2. The purpose of the lesson: to teach students to work independently with special and reference literature on the proposed topic by solving situational problems, speak with reason on specific issues, discuss among their colleagues and answer their questions; consolidate knowledge on the topic "Chemistry and lipid metabolism".

3. Specific tasks:

3.1. The student must know:

3.1.1. The structure and properties of lipids.

3.1.2. Digestion of lipids in the gastrointestinal tract.

3.1.3. Tissue metabolism of fatty acids (oxidation and synthesis).

3.1.4. Exchange of ketone bodies.

3.1.5. Synthesis of triglycerides and phospholipids.

3.1.6. Interconversion of nitrogenous alcohols.

3.1.7. Cholesterol exchange. Exchange of cholesterol esters.

3.1.8. CTC as a single pathway for the metabolism of lipids, carbohydrates and proteins.

3.2. The student must be able to:

3.2.1. Analyze, summarize and present literature materials.

4. Motivation: the ability to correctly adapt the materials of reference books and journal articles is necessary for the work of a future specialist; knowledge of lipid metabolism, metabolism of ketone bodies, cholesterol in normal and pathological conditions is mandatory for the practical work of a doctor.

5. Task for self-training: students should study the recommended literature using questions for self-study.

Main:

5.1.1. Lecture material and materials of practical work on the topic "Lipids".

5.1.2. Berezov T.T., Korovkin B.F. "Biological Chemistry". - M., Medicine. - 1998. - S.194-203, 283-287, 363-406.

5.1.3. Biochemistry: Textbook / Ed. E.S. Severina. - M.: GEOTAR-Med., 2003. - S.405-409, 417-431, 437-439, 491.

Additional:

5.1.4. Klimov A.N., Nikulcheva N.G. Metabolism of lipids and lipoproteins and its disorders. Guide for doctors, St. Petersburg. - 1999. - Peter. - 505 p.

5.2. Prepare for test control.

6. Questions for self-study:

6.1. Synthesis of ketone bodies, their use by the body is normal.

6.2. The concept of ketoacidosis. Reasons for the formation of ketosis, protective

mechanisms that prevent fatal consequences for the body.

6.3. What is b-oxidation of fatty acids. Prerequisites for

process.

6.4. Synthesis of phospholipids. Possibilities of synthesis in the body.

6.5. Interconversion of nitrogenous alcohols.

6.6. Sphingolipidoses, gangliosidoses. The reasons leading to them

occurrence.

6.7. Digestion of lipids in the gastrointestinal tract.

6.8. Bile acids. Structure and functions in the body.

6.9. Cholesterol. Causes of high blood cholesterol levels. Synthesis, breakdown and transport of cholesterol.

6.10. The concept of lipoproteins.

6.11. Reasons for the development of atherosclerosis

6.12. Lipid peroxidation and bioantioxidants.

6.13. The transformation of arachidonic acid in the body.

For citation: Langsyon P.H., Langsyon A.M. medical application HMG-CoA reductase inhibitors and concomitant deficiency of coenzyme Q10. Review of experimental work performed on mammals and humans // RMJ. 2007. No. 9. S. 747

Introduction All major trials of statins have shown that long-term use of statins may not be safe in patients with type 3 and 4 heart failure. HMG-CoA reductase inhibitors, or statins, are a class of drugs that effectively lower LDL-cholesterol levels. In addition, these drugs have positive effect on the cardiovascular system and a decrease in mortality. These are currently one of the most commonly prescribed drugs in the US, with millions of patients taking them regularly. According to the latest NCEP (National Cholesterol Research Program) recommendations, even patients with normally low LDL-cholesterol levels take proactive statins to prevent strokes and heart attacks. Statins are often prescribed for older people and have gained widespread acceptance in the medical community. More recently, statins have been shown to have anti-inflammatory and platelet-stabilizing effects, leading to their increased use. It has been reliably shown that the mevalonate pathway is involved not only in the biosynthesis of cholesterol, but also in the biosynthesis of the vital coenzyme Q10 (CoQ10 or ubiquinone). Thus, HMG-CoA reductase inhibitors block the synthesis of both cholesterol and CoQ10. The interaction between statins and CoQ10 has been discussed previously.

All major trials of statins have shown that long-term use of statins may not be safe for patients with type 3 and 4 heart failure. HMG-CoA reductase inhibitors, or statins, are a class of drugs that effectively lower LDL-cholesterol levels. In addition, these drugs have a positive effect on the cardiovascular system and reduce mortality. These are currently one of the most commonly prescribed drugs in the US, with millions of patients taking them regularly. According to the latest NCEP (National Cholesterol Research Program) recommendations, even patients with normally low LDL-cholesterol levels take proactive statins to prevent strokes and heart attacks. Statins are often prescribed for older people and have gained widespread acceptance in the medical community. More recently, statins have been shown to have anti-inflammatory and platelet-stabilizing effects, leading to their increased use. It has been reliably shown that the mevalonate pathway is involved not only in the biosynthesis of cholesterol, but also in the biosynthesis of the vital coenzyme Q10 (CoQ10 or ubiquinone). Thus, HMG-CoA reductase inhibitors block the synthesis of both cholesterol and CoQ10. The interaction between statins and CoQ10 has been discussed previously.
Facts currently known
Coenzyme Q10 is the coenzyme for mitochondrial enzyme complexes involved in oxidative phosphorylation in ATP production. The bioenergetic effect of CoQ10 is thought to be critical in its clinical application, especially for cells with an increased level of metabolism, such as cardiomyocytes. The second fundamental property of CoQ10 is its antioxidant activity (the ability to scavenge free radicals). CoQ10 is the only fat-soluble antioxidant known to have an enzyme system to regenerate its oxidized form, ubiquinol. CoQ10 circulates in the blood with low-density lipids and serves to reduce LDL-cholesterol oxidation during oxidative stress. It is known that CoQ10 is closely related to vitamin E and serves to regenerate its active (reduced) form - a-tocopherol, as well as to restore ascorbic acid. From more recent studies, it is known that CoQ10 is involved in electron transfer outside the mitochondria, for example, during the work of cytoplasmic membrane oxidoreductase, takes part in cytosolic glycolysis, and is probably active in the Golgi apparatus and in lysosomes. CoQ10 also plays a role in increasing membrane fluidity. The numerous biochemical functions of CoQ10 have been reviewed previously in a review by Crane.
CoQ10 is essential for the synthesis of ATP in the cell and is especially important for the functioning of the heart muscle due to its high metabolic activity. Deficiency of CoQ10 in blood and heart muscle has been frequently reported in heart failure. An Australian group of cardiac surgeons showed a deterioration in heart muscle function associated with age-related CoQ10 deficiency in patients undergoing coronary artery bypass surgery, which was fully compensated by an artificial increase in CoQ10. Later, these investigators tested preoperative CoQ10 therapy and showed improvement in coronary bypass surgery outcomes. Clinical trials of additional CoQ10 therapy for heart disease (including heart failure, ischemic disease, hypertension) and in cardiac surgery have been discussed previously.
The US is currently experiencing an epidemic of congestive heart failure with a significant increase in mortality. The number of deaths due to congestive heart failure increased from 10,000 cases per year in 1968 to 42,000 in 1993. The frequency of hospitalizations with this diagnosis more than tripled from 1970 to 1994. The statistics of the largest centers for the study of this problem - the Henry Ford Research Center "Heart" and the Detroit Institute for the Study of Vascular Diseases - says that from 1989 to 1997. this diagnosis began to be made twice as often. During this nine-year period, 26,442 cases were reported at the Henry Ford Center, corresponding to an increase of 9 to 20 cases per 100 patients per year. The results were processed and provided by the research organization REACH (Resource Utilization Among Congestive Heart Failure) .
Statins were first introduced in 1987 and are considered the most effective drugs for the regulation of elevated cholesterol levels. Although statins are well tolerated by most patients, they can cause a variety of myopathies, of which rhabdomyolysis is the most serious. This problem discussed in a recent article by Thompson, and briefly summarizing the negative effects of statin on muscle tissue, the following conclusions can be drawn:
- taking statins leads to a decrease in the amount of cholesterol in the membranes of skeletal muscles,
- to reduce the level of ubiquinone,
- to a decrease in the level of farnesyl pyrophosphate, an intermediate in the synthesis of ubiquinone, necessary for the activation of a group of small G-proteins.
In this article, we review the existing literature on animal and human trials evaluating the effects of statins, blood and tissue levels of CoQ10. Statin-induced CoQ10 deficiency should also be considered in the context of the aforementioned epidemic of heart failure. The negative effect of statins, leading to a decrease in CoQ10 levels, should be taken into account by doctors when prescribing them.
Animal experiments
From 1990 to 2001 published the results of 15 animal trials of six various kinds: six on rats, three on hamsters, three on dogs, one on rabbits, one on guinea pigs and one on monkeys. In experiments on pigs and hamsters, the effect of statins on the level of CoQ10 in the blood and tissues was evaluated. Nine of these 15 studies showed a particularly adverse effect of statin-induced CoQ10 deficiency: decreased ATP production, increased adverse effects of ischemia, increased mortality from cardiomyopathy, and skeletal muscle damage and dysfunction. Some of the animals use coenzyme Q9 as ubiquinone. It is a shorter chain homologue than coenzyme Q10 and in these cases the coenzyme is referred to simply as CoQ.
The first animal data were published in 1990 by Willis and showed a significant decrease in the concentration of CoQ in the blood, heart and liver of adult male rats after taking lovastatin. Lovastatin-induced deficiency of CoQ in the blood and tissues was fully compensated by the additional intake of CoQ. In 1992, Low showed a similar decrease in CoQ concentration in the liver and heart of rats after taking lovastatin (mevilonin), confirming Willis' data.
In 1993 Fukami et al. studied simvastatin in rabbits and showed an increase in creatinine kinase and lactate dehydrogenase activities and skeletal muscle necrosis. In rabbits treated with simvastatin, there was a significant decrease in the concentration of CoQ in the liver and myocardium compared with the control group. Interestingly, skeletal muscle CoQ levels did not change. Also in 1993, Belihard studied the effects of lovastatin in hamsters with cardiomyopathy and showed a 33% reduction in myocardial CoQ levels compared to controls. Artificial reduction of cholesterol levels in hamsters with fenofibrate did not lead to a decrease in the level of coenzyme Q10. Statins are the only class of lipid-blocking drugs that also block the synthesis of mevalonic acid.
In 1994, Diebold showed a decrease in CoQ concentration in the myocardium of adult guinea pigs (from 2 years old), while lovastatin had no effect on the level of CoQ in young animals (2-4 months). Adult animals have been shown to be more sensitive to the side effects of statin therapy. Also in 1994, Loop showed a decrease in the concentration of CoQ in the liver of rats, which was fully compensated by the additional intake of coenzyme Q.
In 1995, Seito showed that simvastatin significantly reduced the level of CoQ10 in the myocardium of a dog with ischemia. The water-soluble pravastatin has also been studied in this model and does not appear to impair mitochondrial oxidation in the canine myocardium, nor does it reduce myocardial CoQ10.
It is assumed that the fat-soluble simvastatin is more harmful due to the fact that it better penetrates the mitochondrial membrane.
In 1997, Morand studied hamsters, monkeys, and guinea pigs and showed a decrease in CoQ10 levels in the heart and liver when taking simvastatin. Researchers have not seen any reduction in heart and liver CoQ10 levels with the experimental cholesterol-lowering drug 2,3-oxidosqualenelanosterol cyclase, which blocks cholesterol synthesis downstream of mevalonate and therefore does not reduce coenzyme Q10 biosynthesis.
In 1998, Nakahara compared the effects of simvastatin (a fat-soluble inhibitor of HMG-CoA reductase) and pravastatin (a water-soluble inhibitor). In group 1, rabbits received simvastatin at 50 mg/kg per day for four weeks. CoQ10 reduction in skeletal muscles of 22-36% and their necrosis have been reported. Group 2 received pravastatin 100 mg/kg per day for four weeks. Pravastatin did not cause skeletal muscle damage, but lowered their CoQ10 levels by 18-52%. In group 3, the animals received a high dose of pravastatin - 200 mg/kg per day for three weeks and 300 mg/kg per day for the next three weeks. At the same time, there was a greater decrease in the level of CoQ10 in skeletal muscles by 49-72% and their necrosis. In 1998, Sugiyama showed that pravastatin causes a significant decrease in the activity of mitochondrial complex I in the muscle tissue of the diaphragm of rats aged 35-55 weeks. The authors concluded that rigorous clinical trials of pravastatin and its effect on the respiratory muscles are needed, especially for elderly patients.
In 1999, Ishihara investigated the effects of statins in ischemic dogs. At the same time, fat-soluble simvastatin, atorvastatin, fluvastatin and serivastatin led to a deterioration in myocardial contraction after reperfusion, while water-soluble pravastatin had no adverse effect on heart contraction. In 2000, Seito confirmed his data on the negative effect of atorvastatin, fluvastatin and serivastatin. In 2000, Caliscan showed in experiments on rats that simvastatin leads to a significant decrease in cholesterol levels and plasma ATP concentration in direct proportion to the decrease in CoQ10 levels. In 2000, Marz, in experiments on hamsters with hereditary cardiomyopathy, showed that lovastatin, but not pravastatin, at a dose of 10 mg/kg, significantly increased mortality in hamsters as a result of a decrease in myocardial CoQ10 levels. Finally, in 2001, Pisarenko's experiments on rats treated with simvastatin at a dose of 24 mg/kg for 30 days showed a significant decrease in ATP and creatinine phosphate in the myocardium, showing that statin-induced CoQ10 deficiency has a negative effect on myocardial energy.
Results of animal experiments
Data from animal studies show that statin therapy leads to a deficiency of coenzyme Q10 in the blood and tissues, and a deficiency of coenzyme Q leads to adverse effects in cardiomyopathy and ischemic disease, as well as to skeletal muscle necrosis. It has been shown in guinea pigs that statin administration leads to a decrease in the CoQ level in the myocardium only in adult animals. A significant decrease in the level of CoQ was found in the tissue of the heart and liver in hamsters, monkeys, and pigs. Separately, it should be noted that fat-soluble statins have a high degree of toxicity, which was especially evident in dogs with ischemia.
Thus, we can conclude that statins are able to reduce the level of coenzyme Q in animals, and the degree of Q-deficiency depends on the dose of the statin taken. In all experiments where animals received an additional dose of coenzyme Q before taking statins, the deficiency of coenzyme Q was fully compensated.
Human studies
Since 1990, 15 human studies have been published investigating the interaction of statins on CoQ10. Nine of these were approved by medical trials, and eight of those nine trials showed artificial CoQ10 deficiency as a result of statin use.
Folkers in 1990 observed five patients with cardiomyopathy who had a significant decrease in the level of CoQ10 in the blood and deterioration after taking lovastatin. The marked decrease in blood levels of CoQ10 and clinical deterioration was compensated for by additional intake of CoQ10.
In 1993, Watts studied 20 hyperlipidemic patients on a low-cholesterol diet and simvastatin and compared them with 20 hyperlipidemic patients on a diet and 20 controls. Patients taking simvastatin had significantly lower plasma coenzyme Q10 levels and the lowest ratio of coenzyme Q10 to cholesterol than dieted or healthy subjects. It was concluded that simvastatin lowers plasma CoQ10 levels and is more effective than cholesterol levels. The authors emphasize that this side effect of simvastatin on CoQ10 biosynthesis is important and requires further research. Also in 1993, Ghirlanda double-blinded 30 patients with elevated cholesterol and 10 healthy volunteers comparing placebo, pravastatin, and simvastatin for three months. Pravastatin and simvastatin have shown significant reductions in cholesterol and plasma CoQ10 levels, not only in sick patients but also in healthy volunteers.
In 1994, Bargossi et al. conducted a study on 34 patients with elevated cholesterol levels, prescribing 20 mg of simvastatin for six months, or 20 mg of simvastatin plus 100 mg of CoQ10. The study showed that simvastatin lowered both LDL-cholesterol levels and plasma and platelet CoQ10 levels. The noted decrease in the level of CoQ10 was compensated by its additional intake in the corresponding group of patients. CoQ10 supplementation had no effect on simvastatin's cholesterol-lowering effect.
In 1995, Laaksonen showed a significant reduction in serum CoQ10 in patients with elevated cholesterol who took simvastatin for four weeks, without a decrease in skeletal muscle CoQ10. In 1996, Laaksonen also examined muscle biopsies from 19 patients with elevated cholesterol treated with simvastatin 20 mg daily and found no reduction in skeletal muscle CoQ10 levels compared to controls.
In 1996, De Pignet studied 80 patients with elevated cholesterol levels; 40 patients were on statins, 20 on fibrates, and 20 were controls. The results were compared with data from 20 healthy people. Serum CoQ10 levels were lowest in the statin group and did not change in the rest. The lactate/pyruvate ratio in the statin group was elevated and indicated mitochondrial dysfunction, which was not observed in the other groups.
In 1997, Palomaki studied 27 men with elevated cholesterol levels in a double-blind manner for six weeks (lovastatin 60 mg daily or placebo). In patients treated with lovastatin, there was a significant decrease in serum ubiquinol levels and increased oxidation of LDL-cholesterol.
In 1997, Mortensen studied 45 patients with elevated cholesterol in a mixed double-blind trial with lovastatin or pravastatin for 18 weeks. Depending on the dose, a significant decrease in the level of CoQ10 in the blood serum was noted in the group of patients taking pravastatin: 1.27±0.34-1.02±0.31 mmol/L, p<0,01. В группе пациентов, принимавших ловастатин, было более выраженное снижение CoQ10 в сыворотке крови: 1,18±0,36-0,84±0,17 mmol/L p<0,001. Авторы заключили: несмотря на то, что данные препараты довольно эффективны и безопасны для кратковременных курсов, при более длительной терапии необходимо учитывать негативные последствия снижения уровня CoQ10.
In 1998, Palomaki studied 19 men with high cholesterol and coronary artery disease taking lovastatin with or without CoQ10 supplementation. In the group of patients taking lovastatin with CoQ10, isolation time for copper-mediated LDL oxidation increased by 5% (p = 0.02). In AMVN (2,2-azobis(2,4-dimethylvaleronitrile)) oxidation, the faster depletion of LDL-ubiquinol and isolation time in coupled diene formation with lovastatin was significantly improved with CoQ10 supplementation.
In 1999, Miyake studied 97 patients with non-insulin-dependent diabetes while taking lovastatin and showed a significant decrease in serum CoQ10 along with a decrease in cholesterol levels. Oral intake of CoQ10 significantly increased serum levels of CoQ10 without any effect on cholesterol reduction. In addition, additional intake of CoQ10 significantly reduced cardiothoracic ratios from 51.4±5.1-49.2±4.7% (p<0,03). Авторы заключили, что уровень CoQ10 в сыворотке крови значительно снизился при статиновой терапии и, возможно, связан с субклинической диабетической кардиомиопатией, обратимой дополнительным приемом CoQ10.
In 1999, De Lorgheri double-blinded 32 patients treated with simvastatin 20 mg versus 32 patients treated with fenofibrate 200 mg. In the serum of patients treated with simvastatin, there was a significant decrease in the level of CoQ10, which was not observed in the group treated with fenofibrate. After 12 weeks of therapy, there were no noticeable changes in the ejected fraction of blood from the left ventricle of the heart. There was a decrease in myocardial reserve with an equalization of the ejection peak in response to exercise, which can be explained by statin-induced diastolic dysfunction in patients. Unfortunately, only systolic values ​​were measured in this study.
In 2001, Bleske failed to show an overall reduction in blood levels of CoQ10 in 12 young healthy volunteers with normal cholesterol levels when taking pravastatin or atorvastatin for four weeks. Also in 2001, Wong noted that the beneficial anti-inflammatory effect of simvastatin on human monocytes is fully reversible with the addition of mevalonate, but not with CoQ10. He showed that CoQ10 supplementation did not correlate in any way with a statin-mediated anti-inflammatory effect. The most recent research on statins and coenzyme Q was by Jula and published in JAMA. Simvastatin at a dose of 20 mg per day caused a decrease in serum CoQ10 levels by 22% (p<0,001). Клинические последствия дефицита CoQ10 не были выявлены ввиду краткосрочности данного исследования.
Results of human studies
Human studies have clearly shown a decrease in blood levels of CoQ10, especially with higher doses of statins and in older patients. In one study of patients with prior heart failure, it was shown that a lack of CoQ10 in their blood correlated with a drop in blood ejection fraction and with overall clinical deterioration. Supplementing with CoQ10 helps prevent deficiency in the blood and, in one study, in platelets. A decrease in serum CoQ10 levels was associated with an increase in the lactate/pyruvate ratio, which seems to be due to deterioration in mitochondrial function due to statin-induced CoQ10 deficiency. Moreover, two studies have shown an increase in LDL-cholesterol oxidizability associated with a statin-induced decrease in blood levels of CoQ10. It has been shown that the additional intake of CoQ10 leads to an increase in its content in low-density lipids, and also significantly reduces the oxidizability of LDL-cholesterol. One study, conducted on 12 young healthy volunteers with normal lipid balance, showed no decrease in CoQ10 levels when taking statins. And another study showed no reduction in skeletal muscle CoQ10 levels with statins in patients with elevated cholesterol levels. In diabetic patients, CoQ10 deficiency clearly correlates with subclinical cardiomyopathy, with a marked improvement in performance with supplementation. From these studies, it can be concluded that taking CoQ10 helps to prevent its deficiency in statin therapy without any side effects.
Side effects and interactions
with other drugs
CoQ10 is a widely sold drug in the US and other countries, well known, safe, non-toxic, and extensively tested in humans and animals. One of the latest results of research on its safety was published by Williams. The possible toxicity of CoQ10 was studied in rats for a year, injecting them with doses of 100, 300, 600 and 1200 mg per kg of body weight per day; however, no pathologies were found. Human clinical trials were conducted in 23 patients with Parkinson's disease who received a dose of 1200 mg per day, and in patients suffering from hereditary cerebellar ataxia with acute deficiency of CoQ10 in the muscles, who were prescribed up to 3000 mg of CoQ10 per day. No side effects were noted when taking. So far, about 34 placebo-controlled trials of CoQ10 have been conducted in a total of 2152 patients, and no side effects have been reported. Most of the trials have been reviewed previously. In addition to those listed, a number of voluntary long-term (up to 8 years) trials of CoQ10 (at doses up to 600 mg per day) in cardiovascular diseases were conducted, which did not reveal any side effects or toxicity of the drug. In the case of a diagnosis of heart failure, 39 trials were conducted with 4498 participants, which showed complete safety of the drug and only in one case - mild nausea. The long - term safety and neutrality of CoQ10 was shown by Langsjohn in 1990 in a six - year trial on 126 patients . More recently, in 1993, Morisco published the results of a double-blind trial of CoQ10 on 126 patients diagnosed with heart failure. The researchers showed a significant reduction in hospitalizations and ill health in the CoQ10 treated groups and no side effects. In 1994, Baggio published the results of large-scale trials on 2664 patients with heart failure who received 150 mg CoQ10 per day, which showed the neutrality of the drug.
Also in 1994, Langsjohn published the results of a long-term follow-up of 424 patients with cardiovascular disease receiving 75 to 600 mg CoQ10 per day for 8 years. The study did not reveal side effects of interaction with other drugs. Only one of the patients experienced mild nausea. There have been two brief reports that CoQ10 may interact with coumadin (warfarin) and possibly have an effect similar to vitamin K. But at the moment this has not been proven and is the subject of research in the near future. Physicians should carefully and closely monitor patients taking Coumadin, especially when changing diets or combining CoQ10 with other drugs. Despite 18 years of experience with CoQ10, only one case of the combination of CoQ10 and Coumadin in the same patient at a dose of 6000 mg per day has been known so far (unpublished data).
conclusions
Commonly recognized HMG-CoA inhibitor drugs
reductases block the biosynthesis of both cholesterol and CoQ10. The decrease in the level of both of these substances is directly dependent on the dose of the drug. Deficiency of CoQ10 does not appear to affect young healthy patients, especially with short-term use, however, animal studies have shown a number of negative effects on the myocardium, especially in adult animals. This is confirmed by data obtained in people with heart failure, which demonstrated the manifestation of statin-induced CoQ10 deficiency. CoQ10 deficiency is known to be pronounced in the blood and tissues in heart failure. The normal level of CoQ10 in the blood is 1.0±0.2 µg/ml, and the level of 0.6±0.2 µg/ml is considered deficient. CoQ10 levels are also known to drop steadily with age, after age 40. Statins lead to a deficiency in CoQ10, which, combined with the already existing decrease in CoQ10 in cardiovascular disease and with age, can worsen myocardial function. However, the unpleasant feature of statin drugs to lower the level of CoQ10 along with the level of cholesterol can be fully compensated by the additional intake of CoQ10 during statin therapy.

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