Simvastatin
Simvastatin (INN) is a hypolipidemic drug belonging to the class of pharmaceuticals called
"statins". It is used to control hypercholesterolemia (elevated
cholesterol levels) and to prevent cardiovascular disease. Simvastatin is a
synthetic derivate of a fermentation product of Aspergillus terreus.
History
The development of simvastatin was closely linked with the
research and development of lovastatin. Biochemist Jesse Huff and his
colleagues at Merck began researching the biosynthesis of cholesterol in the
early 1950s. In 1956, mevalonic acid was isolated from a yeast extract by Karl
Folkers, Carl Hoffman, and others at Merck; while Huff and his associates
confirmed that mevalonic acid was an intermediate in cholesterol biosynthesis.
In 1959, the HMG-CoA reductase enzyme (a major contributor of internal
cholesterol production) was discovered by researchers at the Max Planck
Institute. This discovery encouraged scientists worldwide to find an effective
inhibitor of this enzyme.
By 1976, Akira Endo had isolated the first inhibitor
(compactin ML-236B) from the fungus, Penicillium citrinium in Sankyo, Japan.
In 1979, Hoffman and colleagues isolated lovastatin from a strain of the fungus
Aspergillus terreus. While developing and researching lovastatin, Merck
scientists synthetically derived a more potent HMG-CoA reductase inhibitor from
a fermentation product of Aspergillus terreus, which was designated MK-733
(later to be named simvastatin).
Uses
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. There is no real
effect on HDL and triglyceride levels.
From recent research it has become apparent that simvastatin
and other statins inhibit the progression of atherosclerosis beyond their
effects on LDL. A large number of explanations has been proposed, for example
its inhibitory effect on macrophages in the atherosclerotic plaque lesions.
Rationing
Since its introduction, there has been a large debate
surrounding the price for lipid-lowering treatment and its benefits on
atherosclerosis. Although this has affected the other statins as well,
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 now become apparent 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,
simvastatin (in a dose of 10mg) has recently become available to purchase from
pharmacies without prescription.
Pharmacology
All statins act by inhibiting HMG-CoA reductase, the
rate-limiting enzyme of the HMG-CoA reductase pathway, the metabolic pathway
responsible for the endogenous production of cholesterol.
The drug is the form of an inactive lactone that is
hydrolized 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.
Interactions
Grapefruit contains the flavanones naringenin and
bergamottin, which inhibit the liver cytochrome P450 3A4. This in turn slows
metabolization of simvastatin and a large number of other drugs. Therefore,
patients taking simvastatin should restrict their intake of grapefruit and
grapefruit-containing products.
Marketing
Brand names: ZocorŽ, Zocor Heart ProŽ, marketed by the
pharmaceutical company Merck & Co. and Denan (Germany), Liponorm, Sinvacor,
Sivastin (Italy), Lipovas (Japan), Lodales (France), Zocord (Austria and
Sweden), Zimstat, Simvahexal and Lipex (Australia) and other.
The primary US patent for Zocor expired on June 23, 2006;
Ranbaxy Laboratories (at the 80-mg strength) and Teva Pharmaceutical Industries
thru its Ivax Pharmaceuticals unit (at all other strengths) were given approval
by the FDA to manufacture and sell simvastatin as a generic drug with 180-day
exclusivity. Dr. Reddy's Laboratories also has a license from Merck & Co.
to sell simvastatin as an authorized generic drug.
Ezetimibe/simvastatin is a combination product to lower
lipids and marketed as Vytorin.
Source: wikipedia GFDL
