Atorvastatin is a hypolipidemic drug of the third generation from the group of statins. It is recommended to use only after other measures, such as diet, exercise and weight loss have not improved cholesterol levels sufficiently.
Selective competitive inhibitor of HMG-CoA reductase - an enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonic acid, which is a precursor of sterols, including cholesterol. Triglycerides and cholesterol in the liver are included in very low density lipoproteins (VLDL), enter the plasma and are transported to peripheral tissues. Low density lipoproteins (LDL) are formed from VLDLP during interaction with LDL receptors.
Reduces plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase, cholesterol synthesis in the liver and increasing the number of “liver” LDL receptors on the cell surface, which leads to increased uptake and catabolism of LDL. Reduces the formation of LDL, causes a pronounced and persistent increase in the activity of LDL receptors. Reduces the level of LDL in patients with homozygous familial hypercholesterolemia, which usually does not respond to therapy with lipid-lowering drugs. Reduces the level of total cholesterol by 30-46%, LDL - by 41-61%, apolipoprotein B - by 34-50% and triglycerides - by 14-33%; causes an increase in cholesterol-HDL and apolipoprotein A.
Dose-dependently reduces the level of LDL in patients with homozygous hereditary hypercholesterolemia resistant to therapy with other lipid-lowering drugs. Significantly reduces the risk of ischemic complications (including the development of death from myocardial infarction) by 16%, the risk of re-hospitalization for angina, accompanied by signs of myocardial ischemia, by 26%. It has no carcinogenic and mutagenic effects. The therapeutic effect is achieved 2 weeks after the start of therapy, reaches a maximum after 4 weeks and lasts for the entire period of treatment.
Absorption is high. TCmax - 1-2 hours, Cmax in women is 20% higher, AUC - 10% lower; Cmax in patients with alcoholic cirrhosis of the liver is 16 times, AUC - 11 times higher than normal. Food somewhat reduces the rate and duration of absorption of the drug (by 25 and 9%, respectively), but lowering LDL cholesterol is similar to that with atorvastatin without food. Atorvastatin concentration when applied in the evening is lower than in the morning (approximately 30%).
A linear relationship was found between the degree of absorption and the dose of the drug. Bioavailability - 14%, systemic bioavailability of inhibitory activity against HMG-CoA reductase - 30%. Low systemic bioavailability is caused by presystemic metabolism in the mucous membrane of the gastrointestinal tract and during the "first pass" through the liver. The average volume of distribution is 381 liters, the association with plasma proteins is more than 98%. Metabolized mainly in the liver under the action of cytochrome CYP3A4, CYP3A5 and CYP3A7 with the formation of pharmacologically active metabolites (ortho and parahydroxylated derivatives, beta-oxidation products).
In vitro ortho- and para-hydroxylated metabolites have an inhibitory effect on HMG-CoA reductase, comparable to that of atorvastatin. The inhibitory effect of the drug against HMG-CoA reductase is approximately 70% determined by the activity of circulating metabolites and persists for about 20-30 hours due to their presence. T1 / 2 - 14 hours. It is removed with bile after hepatic and / or extrahepatic metabolism (it does not undergo a pronounced enterohepatic recirculation). Less than 2% of the ingested dose of the drug is determined in the urine.
Not excreted during hemodialysis due to intense binding to plasma proteins. When liver failure in patients with alcoholic cirrhosis of the liver, Cmax and AUC increase significantly (16 and 11 times, respectively). Cmax and AUC of the drug in the elderly (65 years older) by 40 and 30%, respectively, higher than those in adult patients of young age (has no clinical significance). Cmax in women is 20% higher, and AUC is 10% lower than those in men (it has no clinical significance). Renal failure does not affect the plasma concentration of the drug.
Indications for use
- Primary hypercholesterolemia (heterozygous familial and non-familial hypercholesterolemia (Frederickson type IIa);
- Combined (mixed) hyperlipidemia (Frederickson type IIa and IIb types);
- Disbetalipoproteinemia (type III according to Frederickson) (as a supplement to the diet);
- Familial endogenous hypertriglyceridemia (type IV by Frederickson), resistant to diet;
- Homozygous familial hypercholesterolemia with insufficient effectiveness of diet therapy and other nonpharmacological treatment methods;
- Primary prevention of cardiovascular complications in patients without clinical signs of coronary artery disease, but with several risk factors for its development - age over 55 years, nicotine dependence, arterial hypertension, diabetes mellitus, low concentrations of HD-C-HDL, genetic predisposition, in t. h against dyslipidemia;
- Secondary prevention of cardiovascular complications in patients with coronary artery disease with the aim of reducing the total mortality rate, myocardial infarction, stroke, re-hospitalization for angina and the need for revascularization.
Hypersensitivity, active liver disease, increased activity of “liver” transaminases (more than 3 times) of unclear genesis, pregnancy, lactation period, children under 18 years of age (efficacy and safety have not been established).
Alcoholism, liver disease in history.
Inside, take at any time of the day, regardless of the meal. The initial dose for the prevention of coronary heart disease for adults - 10 mg 1 time per day. The dose should be changed at intervals of at least 2-4 weeks under the control of the plasma lipid profile. The maximum daily dose is 80 mg in 1 reception. In case of primary hypercholesterolemia and combined (mixed) hyperlipidemia, 10 mg is administered once a day.
The effect appears within 2 weeks, the maximum effect is observed within 4 weeks. With homozygous familial hypercholesterolemia, 80 mg is prescribed 1 time per day (decrease in LDL content by 18–45%). Before starting therapy, the patient should be prescribed a standard cholesterol-lowering diet, which he must follow during treatment. In case of hepatic insufficiency, the dose must be reduced. Children from 10 to 17 years old (boys and only menstruating girls should be included in this population) with heterozygous familial hypercholesterolemia, the initial dose is 10 mg 1 time per day. Increase the dose should be no earlier than 4 weeks or more. The maximum daily dose is 20 mg (the use of doses over 20 mg has not been studied).
Most often (1% or more): insomnia, headache, asthenic syndrome; nausea, diarrhea, abdominal pain, dyspepsia, flatulence, constipation; myalgia. Less frequent (less than 1%):
- From the nervous system: malaise, dizziness, amnesia, paresthesia, peripheral neuropathy, hypoesthesia.
- On the part of the digestive system: vomiting, anorexia, hepatitis, pancreatitis, cholestatic jaundice.
- On the part of the musculoskeletal system: back pain, muscle cramps, myositis, myopathy, arthralgia, rhabdomyolysis.
- Allergic reactions: urticaria, pruritus, skin rash, anaphylaxis, bullous rash, polymorphic exudative erythema (including Stevens-Johnson syndrome), Lyell's syndrome.
- From the side of blood-forming organs: thrombocytopenia.
- On the part of the metabolism: hypo-or hyperglycemia, increased activity of serum CPK.
- Other: impotence, peripheral edema, weight gain, chest pain, secondary renal failure, alopecia, tinnitus, fatigue.
Atorvastatin can tire the heart muscle.
In March 2012, the FDA updated its statin guide to include reports of memory loss, liver damage, high blood sugar, type 2 diabetes, and muscle damage. The new manual states:
- The FDA found that liver damage associated with the use of statins is rare, but can occur.
- Reports of memory loss, forgetfulness, and confusion intervals are noted in all statins and in all age groups. These experiences are rare, but victims often report a “lack of clarity” in their thinking.
- A slight increase in the risk of elevated blood sugar and the development of type 2 diabetes have been reported with the use of statins.
- Some drugs interact with statins in a way that increases the risk of muscle damage (myopathy), manifested by unexplained muscle weakness and pain.
Treatment: no specific antidote, symptomatic therapy. Hemodialysis is ineffective.
Atorvastatin can cause an increase in serum CPK, which should be taken into account in the differential diagnosis of chest pain. It should be borne in mind that an increase in CPK 10 times compared with the norm, accompanied by myalgia and muscle weakness, may be associated with myopathy, treatment should be stopped. It is necessary to regularly monitor indicators of liver function before starting treatment, after 6 and 12 weeks after starting the drug or after increasing the dose, and periodically (every 6 months) during the entire period of use (until full normalization of the condition of patients whose transaminase levels exceed normal).
An increase in liver transaminases is observed mainly in the first 3 months of the drug. It is recommended to cancel the drug or reduce the dose with an increase in AST and ALT more than 3 times. Atorvastatin should be temporarily discontinued in the development of clinical symptoms suggesting the presence of acute myopathy or in the presence of factors predisposing to the development of acute renal failure against the background of rhabdomyolysis (severe infections, reduction in blood pressure, extensive surgical interventions, trauma, metabolic, endocrine or pronounced electrolyte disorders ).
Patients should be warned that they should immediately consult a doctor if they develop unexplained pain or weakness in the muscles, especially if they are accompanied by indisposition or fever. There are reports of the development of atonic fasciitis against the background of the use of atorvastatin, however, the connection with the administration of the drug is possible, but so far not proven, the etiology is not known. Women of reproductive age should use reliable methods of contraception. Since cholesterol and substances synthesized from cholesterol are important for fetal development, the potential risk of inhibition of HMG-CoA reductase exceeds the benefits of using the drug during pregnancy.
When mothers use Lovastatin (an HMG-CoA reductase inhibitor) with dextroamphetamine in the first trimester of pregnancy, there have been cases of births of children with deformities of the bones, tracheoesophageal fistula, and anus atresia. In the event of pregnancy in the course of therapy, the drug should be immediately discontinued, and patients warned of the potential risk to the fetus. Data on the penetration of the drug into human breast milk is not, however, in experiments on rats found that atorvastatin penetrates into breast milk of lactating animals (the concentration in breast milk reaches 50% of the concentration of the drug in plasma).
In controlled clinical trials for 6 months in children from 10 to 17 years old (boys and menstruating adolescent girls) with heterozygous familial hypercholesterolemia, there was no effect on growth rates and puberty in boys and the duration of the menstrual cycle in girls. In uncontrolled studies on the use of the drug in 8 children older than 9 years with familial homozygous hypercholesterolemia at a dose of up to 80 mg / day for 1 year, no adverse reactions were detected. Well-controlled studies in children (including those younger than 10 years old) have not been carried out, the safety and efficacy of doses higher than 20 mg have not been established.
Influence on ability to steer the car and difficult technics
There is no data on the effect of atorvastatin on the ability to drive a car and engage in potentially hazardous activities that require increased concentration and psychomotor speed.
With the simultaneous appointment of cyclosporine, fibrates, erythromycin, clarithromycin, immunosuppressive, antifungal drugs (related to azoles) and nicotinamide, plasma atorvastatin concentration (and the risk of myopathy) increases. Antacids reduce the concentration by 35% (the effect on LDL cholesterol does not change). The simultaneous use of atorvastatin with protease inhibitors, known as cytochrome CYP3A4 inhibitors, is accompanied by an increase in plasma atorvastatin concentration (with simultaneous use of atorvastatin with erythromycin Cmax 40%).
When using digoxin in combination with atorvastatin at a dose of 80 mg / day, the concentration of digoxin increases by about 20%. Increases the concentration (when prescribed with atorvastatin at a dose of 80 mg / day) oral contraceptives containing norethisterone by 30% and ethinyl estradiol by 20%. The hypolipidemic effect of the combination with colestipol exceeds that for each drug separately, despite the decrease in the concentration of atorvastatin by 25% when used simultaneously with colestipol. Simultaneous use with drugs that reduce the concentration of endogenous steroid hormones (including cimetidine, ketoconazole, spironolactone) increases the risk of reducing endogenous steroid hormones (caution should be exercised).