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Lipid-lowering drug

Mechanism of action

Lipid-lowering agent from the group of statins, HMG-CoA reductase inhibitor. According to the principle of competitive antagonism, the statin molecule binds to the part of the coenzyme A receptor where this enzyme is attached. Another part of the statin molecule inhibits the conversion of hydroxymethylglutarate to mevalonate, an intermediate product in the synthesis of the cholesterol molecule. Inhibition of the activity of HMG-CoA reductase leads to a series of consecutive reactions, which result in a decrease in the intracellular cholesterol content and a compensatory increase in the activity of LDL receptors and, accordingly, an acceleration of cholesterol catabolism (Xc) of LDL.

The lipid-lowering effect of statins is associated with a decrease in total Xc due to Xc-LDL. A decrease in the level of LDL is dose-dependent and is not linear, but exponential.

Statins do not affect the activity of lipoprotein and hepatic lipases, do not have a significant effect on the synthesis and catabolism of free fatty acids, therefore their effect on the TG level is secondary and indirectly through their main effects on reducing the level of Xc-LDL.A moderate decrease in the level of TG in the treatment with statins seems to be associated with the expression of the remnant (apo E) receptors on the surface of hepatocytes involved in the catabolism of LPPP, which are approximately 30% TG.

In addition to the lipid-lowering action, statins have a positive effect on endothelial dysfunction (preclinical sign of early atherosclerosis), on the vascular wall, atheroma, improve the rheological properties of blood, have antioxidant, anti-proliferative properties.

The therapeutic effect is manifested within 1 week. after the start of therapy and after 2 weeks of treatment, it is 90% of the maximum possible effect, which is usually achieved by week 4 and then remains constant.

Pharmacokinetics

After ingestion C_maxRosuvastatin in plasma is reached after approximately 5 hours. Bioavailability is approximately 20%.

Rosuvastatin accumulates in the liver. V_d - about 134 liters. Binding to plasma proteins (mainly albumin) is approximately 90%.

It is biotransformed to a small extent (about 10%), being a non-core substrate for cytochrome P isoenzymes₄₅₀. CYP2C9 is the main isoenzyme involved in rosuvastatin metabolism. CYP2C19, CYP3A4, and CYP2D6 isoenzymes are less involved in metabolism.

The main identified metabolites of rosuvastatin are N-dismethyl and lactone metabolites. N-dismethyl is about 50% less active than rosuvastatin, lactone metabolites are pharmacologically inactive.

About 90% of the dose of rosuvastatin is excreted unchanged with feces. The rest is excreted in the urine. Plasma t_1/2 - approximately 19 h. T_1/2 does not change with increasing dose. The average plasma clearance is approximately 50 l / h (coefficient of variation 21.7%).

As in the case of other inhibitors of HMG-CoA redaction, the membrane transporter Xc, which plays an important role in the hepatic elimination of rosuvastatin, is involved in the process of hepatic uptake of rosuvastatin.

Systemic exposure of rosuvastatin increases in proportion to the dose.

In patients with severe renal insufficiency (CC <30 ml / min), plasma concentration of rosuvastatin is 3 times higher, and N-dismethyl concentration is 9 times higher than in healthy volunteers. The plasma concentration of rosuvastatin in hemodialysis patients was about 50% higher than in healthy volunteers.

In patients with liver failure, the degree of which was 8 and 9 on the Childe-Pugh scale, an increase in T was noted._1/2 at least 2 times.

Indications

Hypercholesterolemia (type IIa, including familial heterozygous hypercholesterolemia) or mixed hypercholesterolemia (type IIb) as a supplement to the diet, when diet and other non-drug therapies (eg exercise, weight loss) are insufficient.

Familial homozygous hypercholesterolemia as an adjunct to diet and other cholesterol-lowering therapy or in cases where such therapy is not suitable for the patient.

Dosage and administration

Is ingested. The recommended initial dose is 10 mg 1 time / day.If necessary, the dose can be increased to 20 mg after 4 weeks. Increasing the dose to 40 mg is possible only in patients with severe hypercholesterolemia and a high risk of cardiovascular complications (especially in patients with familial hypercholesterolemia) with insufficient effectiveness at a dose of 20 mg and subject to the supervision of a physician.

Side effect

From the side of the central nervous system: often - headache, dizziness, asthenic syndrome; possible - anxiety, depression, insomnia, neuralgia, paresthesia.

Gastrointestinal:: often - constipation, nausea, abdominal pain; possible - reversible transient increase in the activity of hepatic transaminases, dyspepsia (including diarrhea, flatulence, vomiting), gastritis, gastroenteritis.

On the part of the respiratory system: often - pharyngitis; possibly rhinitis, sinusitis, bronchial asthma, bronchitis, cough, dyspnea, pneumonia.

Cardiovascular: possible - angina, increased blood pressure, palpitations, vasodilation.

Musculoskeletal system: often myalgia; arthralgia, arthritis, muscle hypertonus, back pain, pathological pearl of a limb (without injuries) are possible; rarely - myopathy, rhabdomyolysis (simultaneously with impaired renal function, while receiving the drug in a dose of 40 mg).

Urogenital: tubular proteinuria (in less than 1% of cases - for doses of 10 and 20 mg, 3% of cases - for a dose of 40 mg); possible - peripheral edema (arms, legs, ankles, legs), lower abdominal pain, urinary tract infections.

Allergic reactions: possible - skin rash, pruritus; rarely - angioedema.

From the laboratory indicators: a transient dose-dependent increase in the activity of CPK (with an increase in the activity of CPK by more than 5 times compared to VGN, therapy should be temporarily suspended).

Other: often - asthenic syndrome; possibly - accidental trauma, anemia, chest pain, diabetes, ecchymosis, flu-like syndrome, periodontal abscess.

Contraindications

Liver diseases in the active phase (including a persistent increase in liver transaminase activity or any increase in transaminase activity by more than 3 times as compared with VGN), pronounced renal dysfunction (CC <30 ml / min), myopathy, cyclosporine co-administration, pregnancy, lactation (breastfeeding), women of reproductive age who do not use adequate methods of contraception, children and adolescents under 18 years old (since efficacy and safety have not been established), increased sensitivity to rosuvastatin.

Use during pregnancy and lactation

Contraindicated in pregnancy and lactation.

Do not use in women of reproductive age who do not use reliable methods of contraception.

Application for violations of the liver

Contraindicated in liver diseases in the active phase (including a persistent increase in the activity of hepatic transaminases or any increase in the activity of transaminases by more than 3 times compared to VGN).

Application for violations of kidney function

Contraindicated in marked impaired renal function (CC <30 ml / min).

Use in children

Contraindicated in children and adolescents under 18 years old (since efficacy and safety have not been established).

Special notes

Use with caution in the presence of risk factors for the development of rhabdomyolysis (including renal failure, hypothyroidism, personal or family history of hereditary muscular diseases and previous history of muscle toxicity when using other HMG-CoA reductase inhibitors or fibrates) in patients with chronic alcoholism, in patients over the age 65 years old, with a history of liver diseases, sepsis, hypotension, with extensive surgical interventions, injuries, severe metabolic endocrine silt electrolyte disturbances, with uncontrolled epilepsy in people of Asian descent (Chinese, Japanese).

Therapy should be discontinued if the level of CPK is significantly increased (more than 5 times compared to VGN) or if the muscle symptoms are pronounced and cause daily discomfort (even if the level of CPK is 5 times less than VGN).

When using rosuvastatin at a dose of 40 mg, it is recommended to monitor indicators of renal function.

In most cases, proteinuria diminishes or disappears during therapy and does not mean the onset or the progression of an existing kidney disease.

An increase in the incidence of myositis and myopathy has been reported in patientswho took other HMG-CoA reductase inhibitors in combination with fibrin acid derivatives (including gemfibrozil), cyclosporin, nicotinic acid, azole antifungal drugs, protease inhibitors and macrolide antibiotics. Gemfibrozil increases the risk of myopathy in combination with some inhibitors of HMG-CoA reductase. Thus, the simultaneous administration of rosuvastatin and gemfibrozil is not recommended. Care should be taken to weigh the balance between risk and potential benefits when rosuvastatin and fibrates or niacin are used together.

It is recommended to carry out the determination of indicators of liver function before the start of therapy and 3 months after the start of therapy. The use of rosuvastatin should be discontinued or reduced in dose if the level of transaminase activity in serum is 3 times higher than VGN.

In patients with hypercholesterolemia due to hypothyroidism or nephrotic syndrome, the treatment of major diseases should be carried out before starting treatment with rosuvastatin.

Influence on ability to drive motor transport and control mechanisms

When engaging in potentially hazardous activities, patients should be aware that dizziness may occur during therapy.

Drug interaction

With the simultaneous use of rosuvastatin and cyclosporine, the AUC of rosuvastatin was on average 7 times higher than that observed in healthy volunteers, while the plasma concentration of cyclosporin did not change.

Initiation of rosuvastatin therapy or an increase in the dose in patients receiving vitamin K antagonists (eg, warfarin) at the same time can lead to an increase in prothrombin time and INR, and the withdrawal of rosuvastatin or a decrease in dose can lead to a decrease in INR (monitoring of INR is recommended in such cases).

The combined use of rosuvastatin and gemfibrozil leads to an increase of 2 times C_max in blood plasma and rosuvastatin AUC.

The simultaneous use of rosuvastatin and antacids containing aluminum and Magnesium hydroxide, reduces the plasma concentration of rosuvastatin by about 50%. This effect is less pronounced if antacids are applied 2 hours after taking rosuvastatin (the clinical significance is unknown).

The simultaneous use of rosuvastatin and Erythromycin reduces the AUC of rosuvastatin by 20% and C_max rosuvastatin by 30% (probably as a result of increased intestinal motility caused by taking erythromycin).

The simultaneous use of rosuvastatin and oral contraceptives increases the AUC of ethinyl estradiol and AUC of norgestrel by 26% and 34%, respectively. Such interaction cannot be ruled out with simultaneous use of rosuvastatin and hormone replacement therapy.

Gemfibrozil, other fibrates and hypolipidemic doses of nicotinic acid (≥1 g / day) increased the risk of myopathy, while being used with other HMG-CoA reductase inhibitors, possibly because they can cause myopathy and when used as monotherapy.

The combined use of rosuvastatin and itraconazole (CYP3A4 inhibitor) increases the AUC of rosuvastatin by 28% (clinically insignificant).