Atorvastatin: side effects, contraindications

pharmachologic effect

Atorvastatin tablets have hypocholesterolemic properties. The drug reduces the rate of production (completely inhibits the process) of the enzyme responsible for converting HMG-CoA into mevalonate, which is later converted into fats. The decrease in the level of lipoproteins and cholesterol in the blood plasma after the use of Atorvastatin is due to a decrease in the volume of cholesterol produced by liver cells and a decrease in the activity of HMG-CoA reductase.

Atorvastatin reduces the risk of ischemia and reduces mortality rates in patients of all age groups who have had myocardial infarction. During a course of treatment, the likelihood of developing fatal/non-fatal stroke, cardiovascular pathologies, and fatal lesions of the cardiovascular system decreases.

conclusions

Atorvastatin is a synthetic drug from the Statin group used to treat dyslipidemia, hypercholesterolemia and prevent complications in patients with atherosclerosis and cardiovascular pathology. Before prescribing the Atorvastatin regimen, a general examination and blood sampling to assess cholesterol levels, LDL and HDL fractions, and triglycerides are indicated. Taking into account the risk of adverse reactions, the calculation of the dosage and duration of taking the medication is carried out by a general practitioner or cardiologist.

Application

Indications for use: what is the drug prescribed for? What does Atorvastatin help with?

Hypercholesterolemia

The use of Atorvastatin is justified as a dietary supplement when an increase in cholesterol is detected, as well as:

• increased LDL (low-density lipoprotein), apolipoprotein B and triglycerides;
• to increase the level of HDL cholesterol (high-density lipoprotein) in patients with primary hypercholesterolemia (hereditary heterozygous and non-hereditary hypercholesterolemia), combined (mixed) hyperlipidemia (Fredrickson type IIb and III), elevated plasma triglyceride levels (Fredrickson type III);
• when diet does not have sufficient effect.

Atorvastatin is recommended for use in order to lower total cholesterol and LDL cholesterol in people with homozygous hereditary hypercholesterolemia, if there is no sufficient response to diet or other non-drug measures.

Prevention of complications from the heart and blood vessels

Atorvastatin is prescribed to patients who do not have clinical signs of heart and vascular disease, with identified/absent dyslipidemia, but who have multiple risk factors for the formation of coronary artery disease (coronary heart disease) - smoking, high blood pressure, diabetes mellitus, low HDL.

The drug is used for the following purposes:

• reducing the risk of fatal coronary artery disease and non-fatal myocardial infarction;
• minimizing the likelihood of stroke, angina pectoris, hospitalization for the development of CHF (chronic heart failure).

Use in childhood (patients 10–17 years old)

The administration of Atorvastatin in childhood is recommended as an addition to the diet used to reduce cholesterol and apolipoprotein B levels if there is a history of heterozygous hereditary hypercholesterolemia.

The medicine is approved for use in girls only after the onset of the first menstruation

The drug is used if, despite dietary nutrition, the child maintains the following indicators:

• LDL exceeds 190 mg/dl;
• LDL exceeds 160 mg/dL, but if the patient has a predisposition to developing heart and vascular diseases at the genetic level or there are two or more factors that increase this risk.

Clinical pharmacology of atorvastatin

– HMG-CoA – 3-hydroxy-3 methylglutaryl-coenzyme A – IHD – coronary heart disease – cholesterol – cholesterol – LDL – low-density lipoproteins – VLDL – very low-density lipoproteins – DILP – intermediate-density lipoproteins – HDL – high-density lipoproteins – TG - triglycerides - OATP-C - organic anion transporter C - CYP - cytochrome P 450 - UGT - UDP-glucuronyltransferase - CPK - creatine phosphokinase - AST - asparagine transaminase - ALT - alanine transaminase - AH - arterial hypertension - ACS - acute coronary artery disease syndrome - MI - myocardial infarction Statins (HMG-CoA reductase inhibitors) are the most effective and well-studied group of lipid-lowering drugs. Drugs in this group have radically changed the approach to primary and secondary prevention of coronary heart disease and other atherosclerotic vascular lesions, pushing into the background traditional lipid-lowering drugs - nicotinic acid, fibrates, anion exchange resins. Lovastatin, the first representative of this group, was obtained in 1979 from a culture of the fungus Monascus ruber and has been used to treat atherosclerosis since 1987. Its synthetic analogue atorvastatin, due to its high effectiveness and safety, and a wide evidence base, has recently become the most widely prescribed statin. Pharmacodynamics Mechanism of hypolipidemic action. Atorvastatin inhibits 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) of hepatocytes, as a result, the conversion of HMG-CoA to mevalonic acid, which is an intermediate product in the synthesis of cholesterol, is inhibited. When cholesterol synthesis is inhibited and, as a consequence, cholesterol is depleted in the liver, the activity of LDL receptors in hepatocytes increases, which capture circulating atherogenic lipoproteins from the blood - LDL, and to a lesser extent VLDL and LDLP. As a result, the concentration of LDL and cholesterol in the blood noticeably decreases, and the content of VLDL and TG decreases moderately [1]. From a pharmacodynamic point of view, the distinctive feature of atorvastatin among all statins is its ability to reduce triglyceride levels along with cholesterol levels. In general, in its lipid-lowering activity, atorvastatin is superior to all known statins, except for rosuvastatin, which causes undesirable reactions (damage to striated muscles) much more often than others. Probable mechanism for the development of pleiotropic effects. It is known that, in addition to reducing the content of atherogenic lipoproteins in the blood plasma, statins are capable of causing a number of effects called pleiotropic (from the Greek pleios - “multiple” and tropos - “action”). These include, in particular: improving the function of the vascular endothelium, slowing down oxidative reactions, antithrombotic and anti-inflammatory effects. The mechanism of their occurrence is complex and not fully understood. However, it is known that inhibition of HMG-CoA reductase reduces the formation of a number of biologically active substances that are intermediate products in the synthesis of cholesterol. Thus, farnesyl pyrophosphate and geranylgeranyl pyrophosphate, called isoprenoids, are formed from mevalonic acid. Isoprenoids, in turn, activate the G proteins Ras and Rho, which are involved in the transmission of intracellular signals and processes that determine the shape, motility and proliferation of cells (Fig. 1). Thus, when using atorvastatin, the content of isoprenoids in the cell decreases, which means that the activation of the G proteins Ras and Rho also decreases. Currently, this mechanism is considered to be the main one in the development of pleiotropic effects [1,3]. Pharmacokinetics and pharmacogenetics A distinctive feature of statins is that to develop an effect it is not necessary to achieve a high concentration in the systemic circulation, because the main mechanism of action is realized directly in the liver after absorption. Unlike lovastatin and simvastatin, atorvastatin is an inherently active drug. Once absorbed and entering the portal vein, atorvastatin is taken up by hepatocytes with the participation of the organic anion transporter OATP-C. Atorvastatin is metabolized mainly by CYP3A4 to active metabolites (ortho- and parahydroxylated derivatives). Some of atorvastatin and its metabolites are subject to glucuronidation by two isoforms of glucuronyltransferase UGT1A1 and UGT1A2. Atorvastatin is actively secreted into bile via another transporter, glycoprotein-P. A characteristic feature of the pharmacokinetics of atorvastatin, which distinguishes it from other statins, is its relatively long half-life - it ranges from 15 to 32 hours, which allows it to be prescribed regardless of the time of day [2,4,7]. Unlike rosuvastatin, the pharmacokinetics of atorvastatin does not depend on the ethnicity of the patient [4]. The absence of differences in the pharmacokinetics of the drug among representatives of different races and ethnic groups is especially important for multinational states, which includes Russia. Currently, all over the world, along with the original statins, the so-called. reproduced drugs, or generics. For example, one of the first generics of atorvastatin is Tulip, produced by Lek. A study of the bioequivalence of Tulip showed that its pharmacokinetic parameters, such as maximum concentration, time to reach maximum concentration, etc., practically coincided with the pharmacokinetic parameters of Liprimar (Fig. 2). It is especially important that the pharmacokinetic bioequivalence of Tulip was confirmed by a therapeutic equivalence study conducted by R. Ceska et al. involving 73 patients with type IIB hyperlipidemia in 4 centers in the Czech Republic and Croatia. It turned out that the use of Tulip at a dose of 20 mg/day. and Liprimar at a similar dose for 8 weeks reduced the levels of total cholesterol, LDL cholesterol, and triglycerides to the same extent. Thus, the percentage of patients who achieved target levels of total cholesterol, LDL cholesterol and triglycerides did not differ in the groups using Tulip and Liprimar. The results of these studies allow us to speak of Tulip as a high-quality generic of atorvastatin. The effect of genetic polymorphism on the pharmacokinetics and pharmacodynamics of atorvastatin has not been sufficiently studied. It is known that pronounced polymorphism is characteristic of genes encoding glycoprotein-P and OATP-C. Thus, homozygous carriers of the TT genotype for the polymorphic marker C3435T of the MDR1 gene encoding glycoprotein-P are often found among Europeans - 24%, and the OATP-C gene has only up to 17 allelic variants, some of which are widespread: the allelic variant OATC-P *5 occurs in 14% of white Americans, the allelic variant OATP-C*15 was found only among Japanese (15%). There is evidence that in carriers of the TT genotype for the C3435T polymorphic marker of the MDR1 gene, when taking atorvastatin, there is a more pronounced decrease in LDL cholesterol and an increase in HDL cholesterol [5]. In carriers of the allelic variant OATP-C*15, there is a decrease in the activity of the organic anion transporter OATP-C, and, consequently, inhibition of the “uptake” of atorvastatin by hepatocytes from the blood. In this case, there is a decrease in the concentration of atorvastatin in hepatocytes, but an increase in it in the blood plasma. Consequently, in this category of patients one can expect a decrease in the lipid-lowering effect and an increase in the risk of ADRs of statins, and primarily from the striated muscles [6]. We are currently conducting a pharmacogenetic study, the purpose of which is to study the effect of carriage of genotypes for allelic variants of the genes encoding OATP-C (OATS-P*5 and OATS-P*15) and glycoprotein-P (C3435T) on the pharmacokinetics and pharmacodynamics of atorvastatin ( Tulip), a distinctive feature of which is that it does not involve healthy volunteers, as in most of the studies mentioned, but patients with hyperlipidemia types IIA and IIB. As a result, patients with a genetic predisposition to the high effectiveness of atorvastatin will be identified. The results of the study will be published in early 2007. It has also been shown that carriage of the A290G allelic variant of the CYP3A4 gene leads to a decrease in the expression of this enzyme, resulting in an increase in the concentration of atorvastatin in the blood plasma and a more pronounced decrease in LDL cholesterol levels [21]. However, there are currently no studies that have examined the relationship between polymorphisms in the genes of biotransformation enzymes and transporters and the incidence of cardiovascular events during statin therapy. Scope of application and dosage regimen The basis for the treatment of hyperlipidemia in any case should be dietary measures, recommended lifestyle and correction of risk factors (such as arterial hypertension, smoking, diabetes mellitus). The main indication for starting statin pharmacotherapy should be considered a “high” LDL cholesterol level despite a diet or a “too high” LDL cholesterol level before starting a diet, when dietary measures alone would presumably not be enough: specific figures differ for patients with and without coronary artery disease. For patients with pre-existing coronary artery disease, it is recommended to prescribe pharmacotherapy at LDL-C concentrations greater than 2.6 mmol/L (100 mg/dL), while prescribing statins at lower baseline LDL-C levels may also be considered justified to improve prognosis. For patients with hyperlipidemia, but without coronary artery disease, the critical level of LDL cholesterol at which lipid-lowering drugs should be prescribed is determined depending on cardiovascular risk calculated using the Framingham model (see calculator at www.nhlbi.nih.gov/guidelines/cholesterol ). Thus, in the presence of 2 or more risk factors, pharmacotherapy begins when the LDL cholesterol value is more than 3.36–4.14 mmol/l, and in the absence of risk factors - more than 4.9 mmol/l [8]. The first choice drugs for most patients with hyperlipidemia are statins, which are inferior to fibrates only in their effect on TG levels. It is known that statins reduce the total risk of deaths from all cardiovascular causes and should be prescribed to all patients with a high risk of cardiovascular diseases, incl. elderly. Moreover, statins are indicated as secondary prevention for pre-existing coronary artery disease (including angina pectoris and previous myocardial infarction), occlusive peripheral vascular diseases and stroke. The benefit of statin therapy has been proven even with initially normal lipoprotein levels, although a more pronounced effect is observed in patients with a cholesterol concentration before treatment of more than 5 mmol/l. Atorvastatin is taken once a day, usually in the evening, at an initial dose of 10 mg. The initial dose is adjusted once every 4 weeks under the control of plasma lipid levels, as well as CPK, AST and ALT (see below). As a result, the dose can be gradually increased to a maximum of 80 mg per day. No change in the dose of the drug is required in patients with impaired renal function, as well as in the elderly. Side effects (adverse drug reactions) and monitoring of therapy The most important side effects of atorvastatin include increased liver enzymes, less commonly hepatitis, myopathy and myositis, and extremely rarely rhabdomyolysis. In addition to the above, atorvastatin may in some cases cause headache, abdominal pain, flatulence, constipation, diarrhea, nausea and vomiting. The appearance of rash and allergic reactions (including angioedema and anaphylaxis) is uncommon. The mechanism of the toxic effect on muscles is still not entirely clear. There is evidence of significant changes in cholesterol metabolism and the activity of respiratory chain enzymes in the myocytes of patients taking high doses of atorvastatin [10]. Another study describing a familial case of statin-induced myopathy in a Norwegian family suggests a possible hereditary predisposition to this adverse drug reaction; Interestingly, in these patients, CPK levels were normal, and clinical signs of myopathy were confirmed by electromyography and muscle biopsy [11]. There is also evidence that the toxic effect on muscles is not caused by atorvastatin itself, because does not depend on its concentration, but by its metabolites: atorvastatin lactone and p-atorvastatin, the concentrations of which are increased several times in patients with atorvastatin-induced myopathy [22]. To date, 4 mechanisms can be considered candidates for the role of the main one in the development of statin-induced myopathy: depletion of intracellular cholesterol reserves, leading to calcium overload; inhibition of protein synthesis, intracellular signal transmission and metabolism due to a lack of mevalonic acid and its metabolites; decreased concentration of ubiquinone (coenzyme Q); triggering apoptosis. At the same time, it is known for sure that a number of factors can increase the risk of developing myopathy when taking statins - these include hypothyroidism, liver dysfunction, diabetes mellitus, infections, alcohol and heavy physical activity, as well as a family history of myopathy (however, not only statin –induced) [12]. In addition, the likelihood of muscle damage increases with the combined use of statins and other drugs that interact with them at the level of cytochrome 450 isoenzymes (and primarily CYP3A4) and transporters (OATP-C and glycoprotein-P) - this list may include more than 90 drugs [13]. The most important among the latter are fibrates, nicotinic acid, cyclosporine, erythromycin, clarithromycin, and azole antimycotics. The laboratory method for assessing muscle damage is the level of CPK. Liver function tests as well as CPK should be assessed prior to treatment, repeated after 2–3 weeks, after 2–3 months, and then every 6–12 months or more frequently. Atorvastatin is discontinued: with a persistent increase in ALT and/or AST by more than 3 times, with CPK activity more than 5 times higher than normal, or with severe symptoms of muscle damage. Evidence base A distinctive feature of atorvastatin among all statins is its extensive evidence base, which allows us to speak of its high effectiveness and safety in various doses, incl. for certain conditions, thanks to which atorvastatin took the place of the leader in its group in terms of frequency of prescriptions. More than 25 thousand patients in total took part in the ASCOT, CARDS, PROVE-IT, TNT studies. The ASCOT-LL study included 10,305 patients (81% men, 19% women) 40–79 years old (mean age 63 years) with moderate arterial hypertension, no history of coronary artery disease, but at least 3 risk factors for its development, in addition to arterial hypertension, with moderate hyperlipidemia. In the active treatment group (5168 subjects), in addition to antihypertensive therapy, atorvastatin was prescribed at a dose of 10 mg/day; the control group (5131 patients) was prescribed placebo. The initial design of the study involved studying the effectiveness of lipid-lowering therapy for 5 years, but a significant positive effect of atorvastatin occurred earlier and, for ethical reasons, the ASCOT-LL study was stopped early - after 3.5 years. In middle-aged patients with arterial hypertension, for whom the use of statins is not necessary according to current recommendations, atorvastatin for 3.5 years convincingly reduced the combined risk of non-fatal heart attack and death from coronary artery disease (by 36%), the total risk of cardiovascular complications and the need for revascularization ( by 21%), the risk of coronary complications (by 29%), strokes (by 27%) and the occurrence of stable coronary artery disease (by 41%). At the same time, in the studied sample, atorvastatin did not change indicators such as overall and cardiovascular mortality, the risk of heart failure, unstable angina, asymptomatic myocardial infarction, symptoms of peripheral atherosclerosis, diabetes mellitus and chronic renal failure. Thus, the ASCOT-LL study proved the need for prophylactic administration of atorvastatin to middle-aged patients with arterial hypertension and additional cardiovascular risk factors, even with normal or slightly elevated levels of atherogenic plasma lipoproteins. However, in such patients, the positive effect of statins on prognosis is not as impressive as in individuals with proven coronary artery disease and severe hyperlipidemia [9]. The MIRACLE study, conducted back in 2001, showed the ability of atorvastatin to positively influence the course of coronary artery disease during an exacerbation, regardless of the initial lipid level [14]. The PROVE-IT study, which included 4162 patients with ACS, demonstrated a 16% reduction in the risk of death from all causes, myocardial infarction, unstable angina, myocardial revascularization and stroke when LDL cholesterol levels were reduced to 1.6 mmol/L [15]. This study, in turn, stimulated the study of TNT (Treating to New Targets - treatment for new purposes), the purpose of which was to confirm the hypothesis that the reduction in the level of LDL cholesterol is significantly lower than the generally accepted 2.6 mmol/l with high doses of atorvastatin (80 mg) will improve the prognosis of patients with stable coronary heart disease. The control group were patients who received atorvastatin at a dose of 10 mg per day. A relative reduction in risk in a group of more intense lipidswalling therapy amounted to 22% [16]. The Cards test was devoted to the study of the effectiveness of atorvastatin in the primary prevention of atherosclerotic diseases in type 2 diabetes. The test was discontinued 2 years before the intended period due to obvious advantages of atorvastatin over placebo: a relative reduction in the risk of death from all causes was 27%, and the risk of any of the specified cardiovascular events (non -pharmaceutical, non -taby angina pectoris, coronary reward, coronary requa. Stroke) - 32% [17]. These studies also provided important material regarding the safety of prolonged therapy of atorvastatin. In a study of the Prove --it, the proportion of patients with an increase in ALT was 3 times or more than 3.3%, atorvastatin was canceled due to muscle pain or increasing the level of KFK in 3.3% of patients, there were no rabdomysis cases. In TNT, among those who received 80 mg of atorvastatin, 1.2% had a persistent increase in liver transaminases, 99% of patients did not require a dose of the drug. In Cards, the frequency of unwanted phenomena associated with taking the drug was the same in groups of atorvastatin and placebo - 1.1%; Also, not a single case of rabdomiolysis was registered, and there were one in each group of myopathy [15,16,17]. Contraindications and drug interaction, given the possible severe consequences of improper tactics of hyalipidemic therapy, it is necessary to remember contraindications for the purpose of atorvastatin, as well as cases requiring special caution. Absolute contraindications include active liver diseases (with a persistent increase in liver enzymes), pregnancy and breastfeeding. Special caution is required in patients with a history of liver disease or often taking alcohol. In patients with hypothyroidism, an adequate appropriate treatment should be performed before the prescription of atorvastatin. Atorvastatin should not be used for orfiria. In patients 10-17 years old, the clinical experience of prescribing atorvastatin is insufficient, especially in doses exceeding 20 mg per day. Separately, mentioning drug interaction should be mentioned. The importance of this problem is proved by the history of cerivastatin, which was banned in 2002 in connection with the development of more than 100 cases of deaths from rabdomyolysis, most of which were associated with a combination of cerivastatin with hemfibrozil (simultaneously inhibits CYP3A4 and OAR -S). Preparations that increase the risk of undesirable reactions of atorvastatin include the same fibrates (including hemfibrosil), nicotinic acid (in doses used for hypolipidemic therapy), cyclosporine and other cytostatics, such powerful CYP3A4 inhibitors, like erythromycin, clarithromycin,, such powerful inhibitors,, Ritonavir, Azosol antimicotics (ketoconazole, itraconazole, etc.). Combinations of these drugs with statins should be avoided if possible, when using it, careful monitoring of the activity of the KFK is required. Another widely discussed issue is the possibility of the interaction of atorvastatin and clopidogrel at the level of CYP3A4. The anti -cargant of Klopidogrell is a prodiganism, which under the action of CYP3A4 is metabolized to an active 2 -oxaclapidogrel, blocking adf -receptors of platelets. As indicated above, atorvastatin is also metabolized by CYP3A4. There are studies indicating that atorvastatin significantly reduces the anti -aggregate effect of clopidogrel [18,19]. However, the subgroup analysis of the multicenter controlled study of Credo, which studied the influence of clopidogrel on the “final points” (fatal outcomes, myocardial infarction and strokes), did not reveal differences in the effect of clopidogrel on “finite points” in the group that receive statins metabolized CYP3A4 (atorvastatin, Simvastatin, Simvastatin, Simvastatin, Simvastatin, Simvastatin, Simvastatin, Simvastatin, Simvastatin, Simvastatin, Simvastatin Lovastatin, Cerivastatin), and in the group receiving statins that are not metabolized CYP3A4 (Pravustatin, Fluvastatin) [20]. Thus, to determine the clinical value of the interaction of atorvastatin and clopidogrel, more data is needed. The conclusion of atorvastatin is the first choice for the treatment of hyperlipidemia, coronary heart disease, including patients with diabetes and acute coronary syndrome (in the recovery period). The advantages of atorvastatin include: • the optimal ratio of efficiency and safety; • flexible dosing mode with a large dose range (from 10 to 80 mg), taken once a day; • Rich experience in practical application and a wide evidence base.

Literature 1. Kukes V.G. Clinical pharmacology. M.: GEOTARMED, 2004. 2. Kukes V.G. Metabolism of drugs: clinical and pharmacological aspects. M.: Reafarm, 2004. 3. Martin G, Duez H, Blanquart C, Berezowski V, Poulain P, Fruchart JC, Najib–Fruchart J, Glineur C, Staels B. Statin-induced inhibition of the Rho-signaling pathway activates PPARalpha and induces HDL apoA–I. J Clin Invest. 2001 Jun;107(11):1423–32. 4. Garcia MJ, Reinoso RF, Sanchez Navarro A, Prous JR. Clinical pharmacokinetics of statins. Methods Find Exp Clin Pharmacol. 2003 Jul-Aug;25(6):457–81. 5. Kajinami K, Brousseau ME, Ordovas JM, Schaefer EJ. Polymorphisms in the multidrug resistance–1 (MDR1) gene influence the response to atorvastatin treatment in a gender–specific manner. Am J Cardiol. 2004 Apr 15;93(8):1046–50. 6. Kajinami K, Takekoshi N, Brousseau ME, Schaefer EJ. Pharmacogenetics of HMG–CoA reductase inhibitors: exploring the potential for genotype–based individualization of coronary heart disease management. Atherosclerosis. 2004 Dec;177(2):219–34. 7. Lennernas H. Clinical pharmacokinetics of atorvastatin. Clin Pharmacokinet. 2003; 42(13): 1141–60. 8. Grundy SM, Cleeman JI, Merz CN, Brewer HB Jr, Clark LT, Hunninghake DB, Pasternak RC, Smith SC Jr, Stone NJ; Coordinating Committee of the National Cholesterol Education Program. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. J Am Coll Cardiol. 2004 Aug 4;44(3):720–32. 9. Sever PS, Dahlof B, Poulter NR, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower–than–average cholesterol concentrations, in the Anglo–Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm (ASCOT–LLA): a multicentre randomized controlled trial. The Lancet, 2003 10. Paiva H, Thelen KM, van Coster R, Smet J, de Paepe B, Mattila KM, et al. High-dose statins and skeletal muscle metabolism in humans: a randomized controlled trial Clin Pharmacol Ther 2005; 78:60–8. 11. Troseid M, Henriksen OA, Lindal S. Statin-associated myopathy with normal creatine kinase levels. Case report from a Norwegian family. APMIS 2005; 113:635–7. 12. Laaksonen R. On the mechanisms of statin-induced myopathy. Clin Pharmacol Ther 2006; E-pub. 13. Mukhtar RY, Reckless JP. Statin–induced myositis: a commonly encountered or rare side effect? Curr Opin Lipidol 2005; 16:640–7. 14. Schwartz GG, Olsson AG, Ezekowitz MD, Ganz P, Oliver MF, Waters D, Zeiher A, Chaitman BR, Leslie S, Stern T; Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study Investigators. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA. 2001 Apr 4;285(13):1711–8. 15. Cannon CP, McCabe CH, Belder R, Breen J, Braunwald E. Design of the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE IT)–TIMI 22 trial. Am J Cardiol. 2002 Apr 1;89(7):860–1. 16. La Rosa J. et al. for the Treating to New Targets (TNT) Investigators. NEJM 2005; 352. 17. Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ, Thomason MJ, Mackness MI, Charlton–Menys V, Fuller JH; CARDS investigators. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomized placebo–controlled trial. Lancet. 2004 Aug 21–27;364(9435):685–96. 18. Clarke, Waskell. The Metabolism of Clopidogrel Is Catalyzed by Human Cytochrome P450 3A and Is Inhibited by Atorvastatin. Drug Metab Dispos. 2003. Vol. 31, Issue 1, 53–59 19. Lau WC, Waskell LA, Watkins PB, Neer CJ, Horowitz K, Hopp AS, Tait AR, Carville DG, Guyer KE, Bates ER. Atorvastatin reduces the ability of clopidogrel to inhibit platelet aggregation: a new drug–drug interaction. Circulation. 2003 Jan 7;107(1):32–7. 20. Saw J, Steinhubl SR, Berger PB, Kereiakes DJ, Serebruany VL, Brennan D, Topol EJ; Clopidogrel for the Reduction of Events During Observation Investigators. Lack of adverse clopidogrel–atorvastatin clinical interaction from secondary analysis of a randomized, placebo–controlled clopidogrel trial. Circulation. 2003 Aug 26;108(8):921–4 21. Kajinami K, Brousseau ME, Ordovas JM, Schaefer EJ. CYP3A4 genotypes and plasma lipoprotein levels before and after treatment with atorvastatin in primary hypercholesterolemia. Am J Cardiol. 2004 Jan 1;93(1):104–7. 22. Hermann M, Bogsrud MP, Molden E, Aasberg A, Mohebi BU, Ose L, et al. Exposure of atorvastatin is unchanged while lactone and acid metabolites are several–fold increased in patients with atorvastatin myopathy. Clin Pharmacol Ther 2006; E-pub.

Contraindications

The use of the medicine in adult patients will be contraindicated in the following cases:

Tablets that lower blood cholesterol

• hypersensitivity to the components of the drug;
• liver pathologies in the active stage;
• an increase in the activity of liver transaminases by three or more times of unknown origin;
• women of reproductive age who do not use contraceptives; lactation;
• children under 18 years of age - the exception is the treatment of heterozygous hereditary hypercholesterolemia;
• simultaneous use with HIV protease inhibitors.

A woman can take Atorvastatin only if it is known for certain that she is not pregnant. Relative contraindications are:

• chronic alcoholism;
• history of liver disease;
• complex disorders during metabolic reactions, electrolyte balance;
• disturbances in the functioning of the endocrine system;
• arterial hypotension;
• hemorrhagic form of stroke;
• sepsis;
• uncontrollable epilepsy;
• extensive surgical interventions;
• injuries.

Gestation period and breastfeeding

The use of the drug is prohibited during the entire period of pregnancy. There have been several reports of children being born with congenital anomalies from mothers taking Atorvastatin. Conducted studies (on animals) have shown the presence of a toxic effect of the HMG-CoA reductase inhibitor on the reproductive function of females.

When a pregnant woman takes the drug, there is a risk of a significant decrease in the volume of mevalonate produced, which is a precursor of cholesterol. It is worth understanding that atherosclerosis is a chronic disease that is not characterized by rapid development. For this reason, temporary discontinuation of Atorvastatin does not pose a significant risk in the presence of primary hypercholesterolemia.

Doctors do not know whether the active substance itself and its metabolites penetrate into a woman’s breast milk. But in the course of studies on female animals, it was found that the concentrations of atorvastatin and its metabolites are the same in both blood plasma and milk.

Important! The use of Atorvastatin should be discontinued during the entire period of breastfeeding. If there is a need to start treatment with this drug, you will need to stop breastfeeding.

The effect of alcohol on cholesterol

Drugs that lower blood cholesterol

Liver enzymes are responsible for the process of breakdown, neutralization and utilization of ethanol. At the primary stage, under the influence of alcohol dehydrogenase (ADH), alcohol is broken down into relatively safe components and poisonous acetaldehyde.

The second stage is the conversion of the poison into acetic acid using acetaldehyde dehydrogenase (ACDH). The acid then breaks down into carbon dioxide (carbon dioxide) and simple water.

As a chemical compound, ethyl alcohol is capable of changing the amount of cholesterol. Small doses of alcohol increase HDL levels, provided that blood cholesterol levels are consistently normal.

With alcohol abuse, the production of high-density lipoproteins is inhibited, while low-density compounds remain unchanged. Thus, the level of total cholesterol increases. In this case, ethanol acts directly on the lipophilic alcohol, and not on its production in the liver, like statin drugs.

An additional factor in increasing cholesterol levels is food consumed as a snack. When drinking alcoholic beverages, fatty foods are usually consumed. Considering that alcohol provokes polyphagia (increased appetite), control over the amount of food eaten is lost. This increases the acceptable level of exogenous cholesterol.

Directions for use and dosage

The instructions for use indicate that treatment with Atorvastatin should be preceded by a special diet that helps lower blood cholesterol levels. It will need to be adhered to throughout the entire period of use of the product.

The initial dosage (recommended by the manufacturer) is 10 mg. If necessary, it can be increased to a maximum of 80 mg. Atorvastatin should be taken strictly at the same time of day, regardless of meals.

How long to take the product? The duration of the course is selected individually and depends on the diagnosis.

The development of the therapeutic effect should be expected after 14 days from the start of treatment. Its maximum is observed after 4 weeks of regular use, and for this reason it is advisable to review and change the initial dosage after a month from the start of therapy. The drug must be taken without interruption throughout the entire course prescribed by the doctor.

Dosages depending on the diagnosis:

• Hereditary/non-hereditary hyperlipidemia, combined dyslipidemia. The initial dosage (according to the annotation) is 10 mg daily. It can be increased to 80 mg.
• Homozygous familial hypercholesterolemia. The active substance range is 10–80 mg. The drug is prescribed as an additional drug to complement the prescribed treatment, or if therapy with other drugs is not possible.
• Heterozygous hereditary hypercholesterolemia in childhood (children 10–17 years old). The starting dosage is 10 mg per day. The maximum recommended is 20 mg per day. The rate is calculated individually and depends on the final goal. The dosage needs to be changed at intervals of 4 weeks, sometimes more.
• Prevention of the development of cardiovascular complications. In order to prevent possible complications, a dosage of 10 mg is used. If necessary, it can be increased.

Special patient groups:

• With kidney failure. Kidney pathologies do not affect the concentration of atorvastatin or reduce the level of LDL in the blood plasma. In this regard, no adjustment of the initial dosage is required.
• With liver dysfunction. The dosage is calculated individually, due to the slow rate of elimination of the active substance from the body.
• Elderly patients. Patients over 70 years of age do not need dosage adjustment.

Concomitant use of lipid-lowering drugs

Atorvastatin can be used with bile acid sequestrants. Concomitant use of HMG-CoA reductase inhibitors with drugs from the fibrate group should be done with caution.

Other combinations

Dosage in patients taking Itraconazole, Cyclosporine, Clarithromycin and protease inhibitors is discussed here. The recommendations will be as follows:

• Concomitant use of Cyclosporine and HIV protease inhibitors or hepatitis C virus inhibitors with Atorvastatin is prohibited.
• In patients with HIV infection undergoing treatment with the combination of Lopinavir + Ritonavir, Atorvastatin is prescribed with caution. The dosage should be minimal.
• Patients taking Itraconazole, Clarithromycin, as well as HIV-infected patients (if they are receiving the following drug regimens: Saquinavir + Ritonavir, Darunavir + Ritonavir, Fosamprenavir, Fosamprenovir + Ritonavir) should receive a dose not exceeding 20 mg.
• When undergoing treatment with HIV protease inhibitors Nelfanavir or Boceprivir (hepatitis C virus protease inhibitor), the dosage of Atorvastatin is limited to 40 mg.

Combining alcohol and statin drugs

Biotransformation of lipid-lowering drugs occurs in the liver, while the drugs undergo presystemic elimination (first-pass effect) - entering from the intestine directly into the liver and only then into the systemic bloodstream.

The liver is designed in such a way that when drinking alcoholic beverages, all functions are inhibited, except one - the processing and neutralization of ethanol. The body tries to neutralize the effects of alcohol as quickly as possible and rid the body of alcohol toxins.

When statins and alcohol simultaneously enter the body, hepatocytes (liver cells) completely switch to the rapid processing of ethanol and its breakdown products. Biotransformation of statins becomes an additional burden.

Unprocessed pharmacological substances are concentrated in the liver, and the therapeutic effect is lost, but their aggressive effect is affected. Because of this, when there is a correlation between alcoholic beverages and hypocholesterol medications, side effects from the medication occur. Alcohol intoxication, in turn, increases the symptoms of undesirable effects.

In chronic alcoholism, some hepatocytes are inoperative. Simultaneous processing of ethanol and statins by the liver becomes impossible. Considering that a contraindication to statin treatment is exacerbation of chronic liver diseases, there is a risk of developing liver failure.

Alcohol increases blood pressure and heart rate, which is especially dangerous when taking lipid-lowering drugs.

Ethanol increases the load on the kidney apparatus. When combining statins with alcohol, the active substance of the medication and the breakdown products of alcohol are retained in the body and poison the kidneys.

Alcoholic drinks irritate the mucous membrane of the gastrointestinal tract, statin drugs, like chemicals, enhance the ulcerogenic (corrosive) effect, which provokes the development of erosive and ulcerative defects.

Side effects

Various side effects may occur during use. These are:

• dizziness;
• headache;
• lack of coordination;
• neuropathy;
• asthenic conditions;
• hallucinations;
• spasms;
• loss of appetite in the direction of its decrease;
• nausea, vomiting;
• increased gas formation;
• sudden weight loss;
• constipation;
• attack of pancreatitis;
• gastritis;
• ulcerative pathology;
• cholestasis;
• colitis;
• convulsions;
• myositis;
• muscle spasms;
• joint pain;
• circulatory disorders;
• itching of the skin;
• hair loss;
• dermatitis;
• hives;
• bronchospasm.

Overdose

Patients taking Atorvastatin must strictly adhere to the dosage recommended by their doctor. Otherwise, an overdose of the active ingredient cannot be ruled out. Against this background, the following side effects may develop: myalgia, fungal pathologies, increased fatigue, memory impairment.

In case of overdose, the patient is treated symptomatically; there is no specific antidote

Reviews

Reviews from cardiologists are numerous and generally positive. Specialists often prescribe the drug to their patients as a prophylactic agent. Atorvastatin prevents the development of complications from the cardiovascular system in patients with impaired cholesterol levels. Patient reviews are varied. There are both positive and negative responses.

Valentina Semyonovna, 65 years old: The doctor recommended taking Atorvastatin. I took the product for about three weeks. During this time, the size of cholesterol plaques decreased, the condition of blood vessels improved, and blood cholesterol returned to normal. The doctor said that the progression of atherosclerosis had stopped. And in order to consolidate the therapeutic effect, she prescribed another course of medication for preventive purposes.

Olga, 35 years old: I was diagnosed with high cholesterol. The doctor prescribed a course of Atorvastatin. But the product didn’t work for me. While taking it, nausea and heartburn appeared. I had to replace it.

Elena Valerievna, 45 years old: Atorvastatin was recommended to me by my attending physician as a replacement for Warfarin. I read a lot of negative comments about him. I was afraid there would be problems too. But I had nothing. But my cholesterol levels returned to normal. I took three two-week courses with a break of a month.

Analogues of "Atorvastatin"

Currently, three generations of drugs are actively used to treat atherosclerosis, dyslipidemia and hypercholesterolemia. Modern analogues of Atorvastatin are the drugs Rosuvastatin, Simvastatin, Pravastatin, Fluvastatin and others. Depending on the manufacturer of the product, its trade name may also change.

The original drug with the active ingredient atorvastatin is called “Liprimar”. Its substitutes, or imported analogues, have the names: “Atoris”, “Tulip”, “Liptonorm”. Such drugs are generics - drugs under an international name, or under a patented name that differs from the original one, and is registered to another pharmaceutical developer (company). It should be borne in mind that such medications can be produced in different dosages and different numbers of tablets per package.