Pharmacological action
Gipolipidemicescoe means of a group of statins, an inhibitor of hmg-Coa reductase. On the principle of competitive antagonism molecule statin associated with that part of the receptor of coenzyme A, which is attached the enzyme. The other part of the molecule statin inhibits the process of transformation of gidroksimetilglutarata in mevalonate, intermediate product in the synthesis of cholesterol molecules. The inhibition of the activity of hmg-Coa reductase leads to a series of consecutive reactions that result in decreases intracellular cholesterol and is a compensatory increase in the activity of LDL receptors and, accordingly, the acceleration of the catabolism of cholesterol (Xc) LDL.
Lipid-lowering effect of statins is associated with a reduction in the general level of Activity at the expense of Cholesterol-LDL. Reduction of the level of LDL cholesterol is dose-dependent and is not a linear and exponential character.
Statins do not affect the activity of lipoprotein lipase and hepatic, do not have a significant impact on the synthesis and catabolism of free fatty acids, therefore, their impact on the level of TG a second time, and indirectly through their main effects to reduce the level of Cholesterol-LDL. A moderate reduction in TG levels in the treatment of statins, apparently, is connected with the expression of remnantnyh (apo E) receptors on the surface of hepatocytes, participating in the catabolism of LPPP, in structure of which approximately 30% of the TG.
In addition hypolipidemic action, statins have a positive influence on endothelial dysfunction medicine (sign of early atherosclerosis), the vascular wall, state of atheroma, improve the rheological properties of the blood, have antioxidant, antiproliferative properties.
Therapeutic effect manifests itself in a period of one week after the start of therapy and after 2 weeks of treatment is 90% of the maximum possible effect, which is usually achieved by week 4 and then remains constant.


The Pharmacokinetics Of
After the reception inside Cmax rosuvastatin in blood plasma is reached after approximately 5 hours. Bioavailability is about 20%.
Rosuvastatin stored in the liver. Vd - about 134 l. Linking plasma proteins (mostly with albuminom) is approximately 90%.
Biotransformiroetsa in a small extent (about 10%), a non-core substrate for the izofermentov zitohroma P450. The major isoform involved in the metabolism of rosuvastatin, is CYP2C9. Isoenzymes CYP2C19, and CYP3A4 and CYP2D6 are involved in the metabolism to a lesser extent.
The key findings identified metabolites are N-rosuvastatin dismetil and lactone metabolites. N-dismetil approximately 50% less active than rosuvastatin, lactone metabolites pharmacologically inactive.
About 90% of the doses rosuvastatin output unchanged to the faeces. The remainder is excreted in the urine. Plasma T1 / 2 - about 19 hours. T1 / 2 does not change with increasing doses. The average plasma clearance is approximately 50 l / h (coefficient of variation 21.7%).
As in the case of other inhibitors of hmg-Coa redukazy, in the process of hepatic capture rosuvastatin involved membrane carrier Ks that performs an important role in hepatic elimination rosuvastatin.
Systemic exposure rosuvastatin is increased proportionally to the dose.
In patients with severe renal insufficiency (CLCR <30 ml / min), the concentration of rosuvastatin in the plasma of blood in three times above, and the concentration of N-9 in dismetila times higher, than in healthy volunteers. The concentration of rosuvastatin in blood plasma in patients on hemodialysis was about 50% higher than in healthy volunteers.
In patients with hepatic insufficiency, the degree of which was 8 and 9 on a scale of Child-Pugh been an increase in T1 / 2 at least two times.


Indications
Hypercholesterolemia (type IIa, including family heterozygous hypercholesterolemia or mixed hypercholesterolemia (type IIb) as an adjunct to diet when diet and other non-pharmacological treatments (eg exercise, weight reduction body) are not sufficient.
Family homozygous hypercholesterolemia as an adjunct to diet and other holesterinsnizhayuschey therapy or in cases when such therapy is not suitable to the patient.


The dosage
Taken inside. The recommended initial dose is 10 mg once / If necessary, the dose may be increased to 20 mg after 4 weeks. Increasing doses up to 40 mg is possible only in patients with severe hypercholesterinemia and a high risk of cardiovascular complications (especially in patients with familial hypercholesterinemia) the lack of efficiency in the dose of 20 mg and subject to the control of the doctor.


Side effect
Central nervous system: often - headache, dizziness, asthenia; may - anxiety, depression, insomnia, neuralgia, paresthesia.
From the digestive system:: often - constipation, nausea, abdominal pain; there may be reversible transient dose-dependent increase in liver transaminaz, dyspepsia (including diarrhoea, flatulence, vomiting, gastritis, gastroenteritis.
From the respiratory system: often - pharyngitis; may - rhinitis, sinusitis, asthma, bronchitis, cough, dyspnoea, pneumonia.
From the cardiovascular system: possible - angina, increase in blood pressure, palpitation, vasodilatation.
From the musculoskeletal system: often - mialgia; may - arthralgia, arthritis, muscle gipertonus, back pain, pathological pearl of the limbs (without damage); rare: myopathy, rhabdomyolysis (simultaneously with impaired kidney function, on the face of the reception of the drug in the dose of 40 mg).
On the part of the urinary system: tubular proteinuria (in less than 1% of cases - for doses of 20 10 and mg, 3% of the cases - for a dose of 40 mg); may - peripheral edema (hands, feet, ankles, shins), lower abdominal pain, infections of the urinary system.
Allergic reactions: possible skin rashes, itchy skin; rarely angioneuroticeski swelling.
From the laboratory parameters: transient dose-dependent increase in the activity of CK (at enhancing the activity of CK in more than five times in comparison with the ULN therapy should be temporarily suspended).
Other: often - asthenic syndrome; may - accidental injury, anemia, chest pain, diabetes, ekhimozy, grippopodobnyy syndrome, periodontal abscess.


Contraindications
Liver disease in the active phase (including the persistent increase in liver transaminaz, or any increase in transaminaz more than in 3 times in comparison with the ULN), expressed by the human kidney function (CLCR <30 ml / min), myopathy, the simultaneous reception of cyclosporine, pregnancy, lactation (breastfeeding), women of reproductive age, not using adequate methods of contraception, childhood and adolescence to 18 years of age (because the safety and efficacy not established), increased sensitivity to rosuvastatin.


Application of pregnancy and breastfeeding
Contraindicated in pregnancy and during lactation.
Do not use in women of reproductive age who do not use reliable methods of contraception.


Special instructions
To apply caution in the presence of risk factors for development of rhabdomyolysis (including renal function, hypothyroidism, personal or family history of hereditary muscular diseases and previous history of muscular toxicity with the use of other inhibitors of hmg-Coa reductase or fibrates), chronic alcoholism, in patients over 65 years of age, with liver diseases in history, sepsis, arterial hypotension, when conducting extensive surgical interventions, trauma, severe metabolic endocrine, or electrolyte disorders, with uncontrolled epilepsy, the people of asian origin (chinese, japanese .)
Therapy should be discontinued if the level of CPK increased significantly (more than 5 times in comparison with the ULN), or if muscular symptoms are clearly expressed and cause daily discomfort, even if the level of CPK in five times less in comparison with the ULN .)
In the application of rosuvastatin in the dose of 40 mg is recommended to monitor the performance of the functions of the kidneys.
In most cases, proteinuria decreases or disappears in the process of therapy and does not mean the occurrence of acute or progression of existing kidney disease.
Reported an increase in the number of cases of myositis and myopathy in patients taking other inhibitors of hmg-Coa reductase in conjunction with fibrin acid derivatives (including gemfibrosil), cyclosporine, nicotinic acid, azole antifungal drugs, protease inhibitors and macrolide antibiotics. Gemfibrosil increases the risk of myopathy when combined appointment with some of the inhibitors of hmg-Coa reductase. Thus, it is not recommended simultaneous appointment of rosuvastatin and gemfibrozil. You should carefully weigh the risks and potential benefits in a joint application rosuvastatin and fibrates or niacin.
It is recommended to conduct the definition of the functions of the liver prior to the commencement of treatment, and within three months after the start of therapy. The use of rosuvastatin should stop or reduce the dose, if the level of transaminaz activity in the blood serum in three times exceeds the ULN.
In patients with giperholesterinemiei due to hypothyroidism or face nefroticski syndrome therapy of the main disease should be conducted prior to the start of treatment with rosuvastatin.
Effects on ability to drive and use machines
During the occupation potentially hazardous activities patients should take into account that in the time of therapy can cause dizziness.


Drug interaction
While the use of rosuvastatin and cyclosporine AUC rosuvastatin was, on average, seven times higher than the value, which was observed in healthy volunteers, the plasma concentration of cyclosporine in this hasn't changed.
The beginning of therapy with rosuvastatin or increasing the dose of the drug in patients receiving both antagonists vitamin K (eg, warfarin), can lead to an increase in prothrombin time and INR, and the abolition of rosuvastatin or dose reduction may lead to reduction of the INR (in such cases, it is recommended that monitoring of the INR).
The joint application of rosuvastatin and gemfibrozil