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 Simvastatin
DESCRIPTION
Pharmaniaga Simvastatin tablet 5 mg.
Beige, oval shaped biconvex film-coated tablets with
characteristic markings.
Pharmaniaga Simvastatin tablet 10 mg.
Peach, oval shaped biconvex film-coated tablets with
characteristic markings.
Pharmaniaga Simvastatin tablet 20 mg.
Brown, oval shaped biconvex film-coated tablets with
characteristic markings.
Pharmaniaga Simvastatin tablet 40 mg.
Red, oblong shaped biconvex film-coated tablets with
characteristic markings.
COMPOSITION
Each film-coated tablet contains Simvastatin 5 mg, 10 mg, 20 mg and 40 mg
ACTION
Simvastatin is a cholesterol-lowering agent derived synthetically from a fermentation product of Aspergillus terreus.
After oral ingestion, simvastatin, which is an inactive lactone, is hydrolysed to the corresponding β-hydroxyacid form. This is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyses the conversion of HMG-CoA to mevalonate, which is an early and rate-limiting step in the biosynthesis of cholesterol.
As a result, in clinical studies simvastatin reduced total plasma
cholesterol, low-density lipoprotein (LDL) and very low density liproprotein (VLDL)-cholesterol concentrations. In addition, simvastatin moderately increased high density lipoprotein (HDL)-cholesterol and reduced plasma triglycerides.
The active form of simvastatin is a specific inhibitor of HMG-CoA reductase, the enzyme which catalyses the conversion of HMG-CoA to mevalonate. Because the conversion of HMG-CoA to mevalonate is an early step in the biosynthetic pathway of cholesterol, therapy with simvastatin would not be expected to cause an accumulation of potentially toxic sterols. In addition, HMG-CoA is also metabolised readily back to acetyl-CoA, which participates in many biosynthetic processes in the body.
Simvastatin is a lactone that is readily hydrolysed in vivo to the corresponding β-hydroxyacid, a potent inhibitor of HMG-CoA reductase. Inhibition of HMG-CoA reductase is the basis for an assay in pharmacokinetics studies of the β-hydroxyacid metabolites (active inhibitors) and, following base hydrolysis, active plus latent inhibitors (total inhibitors) in plasma following administration of simvastatin. Following an oral dose of simvastatin in man 13% of the dose was excreted in urine and 60% in faeces. The latter represents absorbed drug equivalents excreted in bile, as well as any unabsorbed drug. Plasma concentrations of total radioactivity (simvastatin plus metabolites) peaked at 4 hours and declined rapidly to about 10% of peak by 12 hours post-dose.
In animal studies, after oral dosing, simvastatin achieved substantially higher concentrations in the liver than in nontarget tissues. Simvastatin undergoes extensive first-pass extraction in the liver, its primary site of action, with subsequent excretion of drug equivalents in the bile. As a consequence of extensive hepatic extraction of simvastatin, the availability of drug to the general circulation is low.
Both simvastatin and its β-hydroxyacid metabolite are highly bound (approximately 95%) to human plasma proteins. Animal studies have not been performed to determine whether simvastatin crosses the blood-brain and placental barriers. However, when radio-labelled simvastatin was administered to rats, simvastatin derived radioactivity crossed the blood-brain barrier.
The major active metabolites of simvastatin present in human plasma are the β-hydroxyacid of simvastatin and its 6'-hydroxy, 6'-hydroxymethyl and 6'-exomethylene derivatives. Peak plasma concentrations of both active and total inhibitors were attained within 1.3 - 2.4 hours post-dose. Relative to the fasting state, the plasma profile of inhibitors was not affected when simvastatin was administered immediately before an AHA recommended low-fat meal.
Simvastatin has been shown to reduce both normal and elevated LDL cholesterol concentrations. The effect of simvastatin-induced changes in lipoprotein levels, including reduction of serum cholesterol, on cardiovascular morbidity or mortality has not been established. LDL is formed from very-low-density lipoprotein (VLDL) and is catabolised predominantly by the high affinity LDL receptor. The mechanism of the LDL-lowering effect of simvastatin may involve both reduction of VLDL cholesterol concentration and induction of the LDL receptor, leading to reduced production and/or increased catabolism of LDL cholesterol.
Apolipoprotein B also falls substantially during treatment with simvastatin. Since each LDL particle contains 1 molecule of apolipoprotein B and since little apolipoprotein B is found in other lipoproteins, this strongly suggests that simvastatin does not merely cause cholesterol to be lost from LDL, but also reduces the concentration of circulating LDL particles. In addition, simvastatin modestly reduces VLDL cholesterol and plasma triglycerides and can produce increases of variable magnitude in HDL cholesterol.
Simvastatin is a specific inhibitor of HMG-CoA reductase, the enzyme that catalyses the conversion of HMG-CoA to mevalonate. The conversation of HMG-CoA to mevalonate is an early step in the biosynthetic pathway for cholesterol.
INDICATIONS
Coronary heart disease :
Simvastatin is indicated to reduce the risk of coronary death and non-fatal myocardial infarction; reduce the risk for undergoing myocardial revascularisation procedures (coronary artery bypass grafting and percutaneous transluminal coronary angioplasty); and slow the progression of coronary atherosclerosis, including reducing the development of new lesions and new total occlusions.
Hyperlipidemia :
Simvastatin is indicated as an adjunct to diet to reduce elevated total-C, LDL-C, Apo B and TG, and to increase HDL-C in patients with primary hypercholesterolemia, heterozygous familial hypercholesterolemia or combined (mixed) hyperlipidemia when response to diet and other nonpharmacological measures is inadequate. Simvastatin, therefore, lowers the LDL-C/HDL-C and the total-C/HDL-C ratios.
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