Rosuvastatin
When ATH:
C10AA07
Pharmacological action
Lipid-lowering agents of the statin, HMG-CoA reductase. According to the principle of competitive antagonism statin molecule binds with the part of coenzyme A receptor, where the enzyme is attached. Another part of the statin molecule inhibits the process of converting to mevalonate gidroksimetilglutarata, intermediate in the synthesis of cholesterol molecules. Inhibition of HMG-CoA reductase leads to a series of successive reactions, resulting in reduced intracellular cholesterol and takes a compensatory increase in the activity of LDL receptors and consequently accelerate the catabolism of cholesterol (Xc) LDL.
Lipid-lowering effect of statins is associated with a reduction in total cholesterol by LDL-C. Lowering LDL cholesterol is dose-dependent and is not linear, and the exponential nature.
Statins do not affect the activity of lipoprotein lipase and hepatic, no significant effect on the synthesis and catabolism of free fatty acids, so their impact on the level of a second Tg and indirectly through their major effects on the reduction of LDL-C. A moderate reduction in triglycerides in the treatment of statins, apparently, associated with expression remnantnyh (apo E) receptors on the surface of hepatocytes, involved in the catabolism of LPPP, a composition which approximately 30% TG.
In addition to lipid-lowering action, Statins have a positive impact in the endothelial dysfunction (preclinical signs of early atherosclerosis), on the vascular wall, state of atheroma, improve the rheological properties of blood, have antioxidant, antiproliferative properties.
The therapeutic effect for 1 Sun. after initiation of therapy and 2 weeks of treatment 90% of maximum possible effect, that is typically achieved by 4 week and then remains constant.
Pharmacokinetics
After oral administration, Cmax rosuvastatin plasma levels achieved approximately 5 no. Bioavailability – about 20%.
Rosuvastatin accumulates in the liver. Vd – about 134 l. Plasma protein binding (mostly to albumin) approximately 90%.
Biotransformiroetsa to a small extent (about 10%), It is a non-core substrate for isozymes of cytochrome P450. The basic isoenzyme, involved in the metabolism of rosuvastatin, is CYP2C9. Isoenzyme CYP2C19, CYP3A4 and CYP2D6 are involved in metabolism less.
The main metabolites identified are the N-rosuvastatin dismetil and lactone metabolites. N-dismetil approximately 50% less active, than rosuvastatin, lactone metabolites are pharmacologically inactive.
About 90% rosuvastatin dose is excreted unchanged in the feces. The remaining part is excreted in urine. Plasma T1/2 – about 19 no. T1/2 It does not change with increasing doses. The average value of the plasma clearance is approximately 50 l / (coefficient of variation 21.7%).
As in the case of other HMG-CoA redukazy, in the process of hepatic capture rosuvastatin membrane transporter involved XC, plays an important role in hepatic elimination of rosuvastatin.
Systemic exposure of rosuvastatin increases in proportion to dose.
In patients with severe renal insufficiency (CC<30 ml / min) rosuvastatin concentrations in blood plasma 3 times higher, and the concentration of N-dismetila in 9 times higher, than in healthy volunteers. The concentration in the blood plasma of rosuvastatin in patients on dialysis was approximately 50% higher, than in healthy volunteers.
In patients with hepatic insufficiency, the degree of which was 8 and 9 on a scale of Childe-Pugh was an increase in T1/2 at least 2 times.
Testimony
Hypercholesterolemia (type IIa, including heterozygous familial hypercholesterolemia) hypercholesterolemia or mixed (TYPE IIb) as an adjunct to diet, when diet and other non-pharmacological treatments (eg, physical exercise, weight loss) are insufficient.
Familial homozygous hypercholesterolemia as an adjunct to diet and other holesterinsnizhayuschey therapy or in cases, when such therapy is not appropriate to the patient.
Dosage regimen
Is the inside. The recommended starting dose is 10 mg 1 time / day. If necessary, the dose may be increased to 20 mg after 4 of the week. Increasing the dose to 40 mg is possible only in patients with severe hypercholesterolaemia and high risk for cardiovascular complications (especially in patients with familial hypercholesterolemia) the lack of effectiveness in dose 20 mg and provided medical supervision.
Side effect
CNS: often – headache, dizziness, asthenic syndrome; perhaps - anxiety, depression, insomnia, neuralgia, paresthesia.
From the digestive system:: often – constipation, nausea, abdominal pain; possible - reversible transient dose-dependent increases in liver transaminases, dyspepsia (incl. diarrhea, flatulence, vomiting), gastritis, gastroenteritis.
The respiratory system: often - pharyngitis; possible - rhinitis, sinusitis, bronchial asthma, bronchitis, cough, dyspnoea, pneumonia.
Cardio-vascular system: possible - angina, increased blood pressure, heartbeat, vasodilation.
On the part of the musculoskeletal system: Private - myalgia; vozmozhnы - arthralgia, arthritis, Muscle hypertonicity, backache, abnormal limb pearl (no damage); a rare - myopathy, raʙdomioliz (simultaneously with impaired renal function, while taking the drug at a dose of 40 mg).
From the urinary system: kanalytsevaya proteinuria (less 1% cases - for doses 10 and 20 mg, 3% cases - for dose 40 mg); possible - peripheral edema (hands, Foot, ankles, goleneй), lower abdominal pain, infections of the urinary system.
Allergic reactions: possible - skin rash, itching; rarely - angioedema.
From the laboratory parameters: prehodyaschee dozozavysymoe Increase CPK activity (by increasing the activity of CK in more than 5 times compared to the ULN therapy should be temporarily suspended).
Other: often - asthenic syndrome; perhaps – accidental injury, anemia, chest pain, diabetes, ecchymosis, flu-like symptoms, periodontal abscess.
Contraindications
Liver disease in active phase (including persistent increase in liver transaminases, or any increase in transaminases more than 3 fold compared with CAH), expressed by the human kidney (CC<30 ml / min), myopathy, concomitant use of cyclosporine, pregnancy, lactation (breast-feeding), women of reproductive age, not using adequate contraceptive methods, childhood and adolescence up 18 years (tk. efficacy and safety have not been established), hypersensitivity to rosuvastatin.
Pregnancy and lactation
Is contraindicated in pregnancy and lactation.
Do not use in women of reproductive age, not using reliable methods of contraception.
Cautions
Be wary of the presence of risk factors for rhabdomyolysis (including kidney failure, gipotireoz, personal or family history of hereditary muscular diseases and previous history of muscular toxicity with other HMG-CoA reductase inhibitor or fibrate), chronic alcoholism, patients aged over 65 years, with a history of liver disease, sepsis, hypotension, during major surgery, injuries, severe metabolic endocrine and electrolyte disorders, from uncontrolled epilepsy, in people of Asian descent (Chinese, Japanese).
Therapy should be discontinued, If CK levels increased significantly (more than 5 times compared with FHG) or if muscular symptoms are pronounced and cause daily discomfort (even if the level of CK 5 times less than the ULN).
When applied in a dose of rosuvastatin 40 mg is recommended to monitor renal function.
In most cases, proteinuria is reduced or disappears during therapy and means of acute or progression of existing kidney disease.
It has been reported to increase the incidence of myositis and myopathy patients, taking other inhibitors of HMG-CoA reductase inhibitor in combination with a fibric acid (including gemfibrozil), cyclosporine, nicotinic acid, azole antifungals, protease inhibitors and macrolide antibiotics. Gemfibrozil increases the risk of myopathy when combined with the appointment of some HMG-CoA reductase. Thus, not recommended for co-administration of rosuvastatin and gemfibrozil. You should carefully consider the balance of risk and potential benefits in the combined use of rosuvastatin and fibrates or niacin.
It is recommended that the definition of liver function tests before and after treatment 3 months after initiation of therapy. The use of rosuvastatin should be discontinued or the dose reduced, if the level of transaminase activity in serum 3 times the ULN.
For patients with hypercholesterolemia due to hypothyroidism or nephrotic syndrome therapy of major diseases should be carried out prior to treatment with rosuvastatin.
Effects on ability to drive vehicles and management mechanisms
When the lesson potentially dangerous activities should take into account patients, that during the treatment may occur dizziness.
Drug Interactions
With simultaneous use of rosuvastatin and cyclosporine AUC of rosuvastatin it was average 7 times higher than the, which was observed in healthy volunteers, plasma concentration of cyclosporine is not changed.
Initiation of therapy with rosuvastatin or increasing the dose of the drug in patients, receiving concomitant vitamin K antagonists (eg, warfarin), may lead to an increase in prothrombin time and INR, and cancellation or reduction of the dose of rosuvastatin may lead to a decrease in INR (In such cases, monitoring of INR).
The combined use of gemfibrozil and rosuvastatin increases in 2 times Cmax plasma rosuvastatin and AUC.
Concomitant use of rosuvastatin and antacids, containing aluminum and magnesium hydroxide, It leads to a decrease in plasma concentrations of rosuvastatin approximately 50%. This effect is less pronounced, If antacids are used by 2 hours after receiving rosuvastatin (the clinical significance is unknown).
The simultaneous use of rosuvastatin and erythromycin decreases the AUC rosuvastatin on 20% and Cmax of rosuvastatin 30% (probably, by enhancing gut motility, caused by taking erythromycin).
Concomitant use of rosuvastatin and oral contraceptives increases the AUC of ethinyl estradiol and norgestrel AUC for 26% and 34% respectively. We can not exclude such interaction, while the use of rosuvastatin and hormone replacement therapy.
Gemfiʙrozil, other fibrates and lipid lowering doses of niacin (≥1 g / day) increased risk of myopathy when applied simultaneously with other inhibitors of HMG-CoA reductase inhibitors is possible due to the fact, they can cause myopathy and when used as monotherapy.
The combined use of rosuvastatin and itraconazole (CYP3A4 inhibitor) AUC increases rosuvastatin on 28% (clinically insignificant).
