Simvastatin

Simvastatin (INN) ( /ˈsɪmvəstætɨn/) (Zocor and generics) is a hypolipidemic drug used to control elevated cholesterol, or hypercholesterolemia. Simvastatin is a member of the statin class of pharmaceuticals, is a synthetic derivate of a fermentation product of Aspergillus terreus.

There is also evidence of raising high density lipoprotein (HDL) and lowering triglyceride (TG) levels.

Simvastatin and other statins may inhibit the progression of atherosclerosis beyond their effects on LDL. Many explanations have been proposed, for example its inhibitory effect on macrophages in the atherosclerotic plaque lesions.

In one non-randomized study, simvastatin halved the risk of developing dementia or Parkinson's disease.

Common side effects (>1% incidence) may include abdominal pain, diarrhea, indigestion, and a general feeling of weakness. Rare side effects include joint pain, memory loss, and muscle cramps. Cholestatic hepatitis, hepatic cirrhosis, rhabdomyolysis and myositis have been reported in patients receiving the drug chronically.

A type of DNA variant known as a single nucleotide polymorphism (SNP) may help predict individuals prone to developing myopathy when taking simvastatin; a study ultimately including 32,000 patients concluded that carriers of one or two risk alleles of particular SNPs rs4149056 were at 5x or 16x increased risk, respectively.

On June 8, 2011, the FDA announced new safety recommendations for high-dose simvastatin (80 mg) due to muscle injury risk.

Since its introduction, there has been a large debate surrounding the price for lipid-lowering treatment and its benefits with regard to atherosclerosis. Although this has affected the other statins, simvastatin was the first statin drug to be used extensively in clinical practice.

A number of large epidemiological studies were conducted to discover which patients would benefit most from statin drugs; most studies involve simvastatin as the study drug. The most influential studies were the Scandinavian Simvastatin Survival Study (4S) and the Heart protection study (HPS).

It has been suggested that patients with one or more risk factors for cardiovascular disease (such as diabetes mellitus, hypertension or a positive family history) can benefit from statins even if they do not have substantially elevated cholesterol levels.

Simvastatin was introduced in the late 1980s, and in many countries it is now available as a generic preparation. This has led to a decrease of the price of most statin drugs, and a reappraisal of the health economics of preventive statin treatment. In the UK in 2008 the typical per patient cost to the NHS of simvastatin was approx £1.50 per month.

Simvastatin is a powerful lipid-lowering drug that can decrease low density lipoprotein (LDL) levels by up to 50%. It is used in doses of 5 mg up to 80 mg. Higher doses (160 mg) have been found to be too toxic, while giving only minimal benefit in terms of lipid lowering.

In secondary prevention, 80 mg per day reduced major cardiovascular events by an absolute rate of 1.2% compared to 20 mg per day in a randomized controlled trial.

All statins act by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A HMG-CoA reductase, the rate-limiting enzyme of the HMG-CoA reductase pathway, the metabolic pathway responsible for the endogenous production of cholesterol. Statins are more effective than other lipid-regulating drugs at lowering LDL-cholesterol concentration but they are less effective than the fibrates in reducing triglyceride concentration. However, statins reduce cardiovascular disease events and total mortality irrespective of the initial cholesterol concentration.

The drug is in the form of an inactive lactone that is hydrolyzed after ingestion to produce the active agent. It is a white, nonhygroscopic, crystalline powder that is practically insoluble in water, and freely soluble in chloroform, methanol and ethanol.

Grapefruit contains furanocoumarins, notably bergamottin and 6',7'-dihydroxybergamottin, which inhibit the intestinal cytochrome P450 3A4 isoform. This in turn slows metabolization of simvastatin and a large number of other drugs resulting in higher plasma levels of the drug. Due to the risk of toxicity patients taking simvastatin should avoid intake of grapefruit and grapefruit-containing products.

On August 8, 2008, the U.S. Food and Drug Administration (FDA) issued a warning of the risk of rhabdomyolysis, which can lead to kidney failure or death, when simvastatin is used with amiodarone. This interaction is dose-dependent with simvastatin doses exceeding 20 mg. This drug combination especially with higher doses of simvastatin should be avoided.