Atorvastatin

Pharmacological properties

atorvastatin is a selective competitive inhibitor of HMG-coa reductase, an enzyme that converts HMG-coa to mevalonic acid, which is a precursor of sterols, including chs. atorvastatin reduces the level of cholesterol and lipoproteins in blood plasma due to the inhibition of HMG-coa reductase-mediated synthesis of cholesterol in the liver, as well as an increase in the number of LDL receptors on the surface of hepatocytes, which leads to increased uptake and catabolism. the drug reduces the level of LDL in serum in patients with homozygous familial hypercholesterolemia, reduces the level of total cholesterol, cholesterol, LDL, apolipoprotein B and tg, increases the level of cholesterol and HDL apolipoprotein in patients with heterozygous familial hypercholesterolemia and mixed hyperlipidemia, insulin-dependent diabetes mellitus.

Pharmacokinetics Atorvastatin is rapidly absorbed after oral administration: C_max in plasma is reached after 1-2 hours. The degree of absorption increases in proportion to the dose of atorvastatin and is about 95–99%. The absolute bioavailability is about 12%, and the systemic availability of the inhibitory activity against HMG-CoA reductase is about 30%. Low systemic bioavailability is due to presystemic metabolism in the gastrointestinal mucosa and biotransformation during the initial passage through the liver. The average distribution of atorvastatin is about 565 liters. About 98% of atorvastatin binds to plasma proteins. It is biotransformed under the influence of cytochrome P450 3A4 with the formation of ortho- and para-hydroxylated derivatives and various oxidation products. The effect of atorvastatin in relation to HMG-CoA reductase is approximately 70% determined by the activity of circulating metabolites. It is excreted in the bile, is not subjected to severe enterohepatic recirculation. Medium T_½ atorvastatin is 14 hours. The inhibitory activity against HMG-CoA reductase persists for about 20-30 hours due to the presence of active metabolites. There are no data on pharmacokinetics in children.

Indications

In atherosclerosis, in order to reduce the elevated levels of total cholesterol, cholesterol, LDL, apolipoprotein B and Tg in patients with primary hypercholesterolemia, mixed hyperlipidemia, heterozygous and homozygous familial hypercholesterolemia with insufficient diet and other non-drug correction methods.

Application

Before the appointment of the atocor, the patient is prescribed a standard hypocholesterolemic diet, which he must adhere to further during treatment. the dose is set individually, taking into account the initial level of LDL and the purpose of therapy. The recommended starting dose is 10 mg once daily. change the dose with an interval of 4 weeks or more. the maximum dose is 80 mg 1 time per day. the drug can be taken at any time of the day, regardless of food intake.

In primary hypercholesterolemia and mixed hyperlipidemia, 10 mg is prescribed once a day. The therapeutic effect develops over 2 weeks, and the maximum - 4 weeks. With prolonged therapy, the effect persists. In most adult patients with homozygous familial hypercholesterolemia, the use of Atocor at a dose of 80 mg / day leads to a decrease in LDL cholesterol by more than 15% (18–45%).

In case of heterozygous familial hypercholesterolemia, patients aged 10-17 years are recommended to prescribe Atocor in an initial dose of 10 mg once a day daily. The maximum recommended dose is 20 mg per day daily (doses above 20 mg have not been studied in patients of this age group). Dose adjustment can be carried out with an interval of 4 weeks or more.

In the case of the use of Atocor simultaneously with cyclosporine, the dose of Atocor should not exceed 10 mg.

In patients with impaired renal function, the concentration of atorvastatin in the blood plasma and its lipid-lowering effect do not change, therefore, dose adjustment is not required.

Contraindications

Hypersensitivity to the drug, active liver disease, or an increase in the activity of serum transaminases (more than 3 times higher than the norm) of unspecified genesis, the period of pregnancy and lactation, age up to 10 years. the drug is not prescribed for women of childbearing age who do not use effective methods of contraception.

Side effects

From the side of the central nervous system: headache, insomnia, peripheral neuropathy, paresthesia.

From the gastrointestinal tract: nausea, diarrhea, abdominal pain, dyspepsia, constipation, flatulence, pancreatitis, vomiting.

From the musculoskeletal system: myalgia, myopathy, myositis, cramps.

From the side of metabolism: hypoglycemia, hyperglycemia, anorexia.

From the liver: hepatitis, cholestatic jaundice.

Dermatological reactions: alopecia, itching, rash.

From the reproductive system: impotence.

From the body as a whole: asthenia.

Adverse reactions in children with heterozygous familial hypercholesterolemia (10-17 years).

From the hemopoietic system: thrombocytopenia.

Hypersensitivity reactions: allergic reactions (including anaphylaxis).

From the side of metabolism: weight gain.

From the side of the central nervous system: hypesthesia, amnesia, dizziness, dysgeusia.

From the side of the hearing organ: tinnitus.

Dermatological reactions: Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, bullous rash, urticaria.

From the musculoskeletal system: rhabdomyolysis, arthralgia, back pain, tendon rupture.

From the body as a whole: infections, chest pain, peripheral edema, malaise, fatigue.

special instructions

Women of reproductive age should use adequate methods of contraception when treating with atocor. kidney diseases do not affect the concentration of atorvastatin in blood plasma and the severity of its lipid-lowering effect, therefore dose adjustment is not required. the drug is prescribed with caution in patients who abuse alcohol and / or with liver diseases. Before starting atocor therapy, it is necessary to conduct a study of the functional parameters of the kidneys and liver. Before and during the entire treatment period, the patient should adhere to a standard hypocholesterolemic diet. in case of an increase in transaminase activity, indicators should be monitored until they are fully normalized. if the increase in activity of asat or alat exceeds the norm by more than 3 times, it is recommended to reduce the dose or cancel the drug.

No dose adjustment is required in the elderly. In clinical studies, the safety and efficacy of the drug in patients of this group were established with a maximum daily dose of 80 mg.

Atocor therapy should be discontinued in case of a marked increase in CPK activity or the development of myopathy. When symptoms of myopathy appear, KFK activity should be determined. If a significant increase in the level of CPK persists, the dose should be reduced or the drug should be discontinued.

The drug contains lactose, this should be considered when using the drug in patients with lactose intolerance.

Interactions

The simultaneous use of atocor and digoxin is accompanied by an increase in the equilibrium concentration of digoxin in blood plasma by almost 20%.

Atorvastatin and its metabolites are substances of the OATP1B1 carrier. OATP1B1 inhibitors (e.g., cyclosporine) may increase the bioavailability of atorvastatin. The simultaneous use of atorvastatin at a dose of 10 mg and cyclosporine 5.2 mg / kg / day causes an increase of 7.7 times the exposure of atorvastatin.

In healthy volunteers, the simultaneous use of erythromycin (at a dose of 500 mg 4 times a day), which has the ability to inhibit cytochrome P450 ZA4, led to an increase in the concentration of atorvastatin in blood plasma.

With the use of Atocor and hormonal contraceptives, the concentration of norethidrone and ethinyl estradiol in the blood plasma increases. When determining the dose of a contraceptive, it is necessary to take into account the possibility of increasing the concentration of these drugs.

Colestyramine reduces the level of atorvastatin in the blood by almost 25%, however, the lipid-lowering effect of the combination of Atocor and colestyramine is higher than when using each drug individually.

The simultaneous use of antacids containing magnesium and aluminum hydroxide can reduce the concentration of atorvastatin in blood plasma by almost 35%, without changing the effect of Atokor on the level of LDL cholesterol.

The risk of developing myopathy increases with the simultaneous use of cyclosporine, fibrates, erythromycin, antifungal drugs of the azole group, nicotinic acid.

Overdose

Perhaps the development of rhabdomyolysis, impaired liver function. there is no specific antidote. in case of an overdose, symptomatic and supportive treatment is performed. due to the significant binding of the drug to plasma proteins, hemodialysis is ineffective.

Storage conditions

At a temperature of 15–25 ° C.