Simvastatain

Simvastatain (BAN, USAN, rINN)

L-644158-000U; MK-733; Simvastatain; synvinolin; velastatin.

(IS, 3R, 7S, 8S.8a-HEXAHYDRO-3, 7-dimethyl-8

{2-[(2R.4R)-tetrahydro-4hydroxy-8oxo-2H-pyaran-2-yl] ethyl}-l –naphtyl 2, 2-dimethylbutyrate.

C25H38O5 =418.6.

CAS—79902–63–9

ATC—C 1 0AA 0 1

Pharmacopoeias in Eur. (see p.vi) and US

Pharmacopoeia description

Ph. Eur.: A white or almost white crystalline powder.

Practically insoluble in water freely soluble in alcohol; every soluble in dichloromethane. Store under nitrogen in airtight containers Protect from light

U.S.P 25: A white to off-white powder.

Practically insoluble in water freely soluble freely in alcohol, in chloroform, and in methyl alcohol; sparingly soluble in petroleum spirit store under nitrogen

Usage and administration

Simvastatain is a lipid regulating drug.

It is a competitive inhibitor of 3-hydroxy-3-methylglutary. Coenzyme A reeducates (HMG-CoA reeducate)

The redeterming enzyme for cholesterol synthesis HMGoA reeducate inhibitors (also called satins) reduce total cholesterol; low density lipoprotein (VLDL) cholesterol concentration in plasma.

They also tend to reduce triglycerides and to increase high density lipoprotein (HDL) cholesterol concentration. They are considers to exert their hypercholesterolemic action by stimulating an increase in LDL receptors on hepatocyte membrane thereby increasing the clearance of LDL from the circulation.

Simvastatain is used to reduced LDL-cholesterol apoloporotein B, and triglycerides, and to increase HDL-cholesterol in the treatment of hyperlipidaemias (below), including hypercholesterolemia and combined (mixed) hyperlipideamia (type IIa of IIb hyperlippoproteinaemias) statins can be effective as adjunct therapy in patient with homozygous familial hypercholesterolemia who have some LDL-receptor function.Simvastatin is also given prophylactically to hypercholesterolemia patient with ischemic heart disease.

Simvastatain is given by mouth in an initial dose of 5 to 10 mg in the evening; an initial dose of 20 mg may be used in patient with ischemic heart disease. The dose may be adjusted at interval of not less than 4 weeks up to a maximum of 80 mg once daily in the evening. Patient with homozygous familial hypercholesterolemia may be treated with 40mg once daily in the evening, or 80mg daily in three divided dose of 20mg, 20mg, and an evening dose of 40mg.A maximum of 10 mg daily is recommended in those taking cyclosporine, fibrin acid

Derivatives, or nicotinic acid, and the risk of myopathy must be considered.

Pharmacokinetics

Simvastatain is absorbed from the gastrointestinal tract and is hydrolyzed to its active metabolites heave been detected and a number of inactive metabolites are also formed. Simvastatain undergoes extensive first-pass metabolism in the liver, its primary site of action. Less than 5% of the oral dose has been reported to reach the circulation as active metabolite. Both Simvastatain and its β-hydroxyacid metabolite are about 95%bound to plasma protein. It is metabolites. About 10 to 15% is recovered in the urine, mainly in inactive forms. The half-life the active metabolite is 1.9 hour.

Adverse Effects and Precautions

The comments adverse effects of therapy with Simvastatain and other statins are gastrointestinal disturbance. Other adverse effects reported include headache, skin rash, dizziness, blurred vision, insomnia, and dysgeusia. Reversible increases in serum-aminotransferase concentration may occur and liver function should be assessed before treatment is initiated and then monitored periodically unite one year after the last elevation in dose. Hepatitis and pancreatitis heave been reported. A hypersensitivity syndrome whose feature heave included angioedema has been reported. Myopathy, characterized by myalgia and muscle weakness and associated with increased creatinine phosphokinase concentrations, has been reported, especially in patients taking Simvastatain concurrently with cyclosporine, fabric acid derivatives, or nicotinic acid

may develop.

Simvastatain should be given to patients with acute liver diseases or unexplained persistently raised serum aminotransferase concentration. It should be avoided during pregnancy since there is a possibility that it could interfere with fetal sterol synthesis; there have been a raw reports of congenital abnormalities associated with statins (but see pregnancy, below). It should be discontinued if marked or persistent increase in serum- aminotransferase or creatinine phosphokinase concentration accrue it should be used with cautions in patients with sever renal impairment.

Interactions

There is an increase risk of mayopathy if certain drug is given concurrently with stains.

Concomitant administration of drug that inhibit that cytochrome P450 isoenzyme CYP3A4, such as ciclorin, itraconazole ketoconazole, erythromycin, clarithromycin, HIV-protease inhibitors and nefazodone might produce high plasma levels of Simvastatain thus increasing the risk of myothathy. Drugs that alone can cause myopathy, such as fabric acid derivative or nicotinic acid can increase the risk of this reaction when given with Simvastatain.

For further details see effects on skeletal muscles, under adverse thrombin time have effects, above.

Bleeding and increase in prothombin time have been reported in patients taking Simvastatain with coumarin anticoagulants. Raised concentrations of Simvastatain have occurred in patients also given mibefradil.