Simvastatin detailed information

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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.

Simvastatin was demonstrated to reduce older adults' chances of developing dementia by more than half. It was also found to reduce the risk of Parkinson's disease by 49%.

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&mdash;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 10 mg) 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 in 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
Simvastatin interacts with many drugs that could raise its levels in the body. This in turn, increases the risk of myopathy and other associated complications. The new FDA guidelines contraindicate its use with some antifungals(Itraconazole, Ketoconazole, Posaconazole), HIV protease inhibitors and others like Erythromycin, Clarithromycin, Telithromycin, Nefazodone, Gemfibrozil, Cyclosporin, Danazol. Also, with drugs like Amiodarone, Verapamil and Diltiazem the dose of Simvastatin should not exceed 10 mg. These drugs are containdicated with Simcor (a combination of simvastatin with niacin as simcor comes only with 20 or 40 mg simvastatin). Furthermore, with amlodipine and ranolazine the simvastatin dose should not exceed 20mg FDA US Food and Drug Administration.The alternatives available for simvastatin 80 mg are Crestor 10mg and Lipitor 40mg. They have LDL lowering effects comparable to simvastatin 80 mg (crestor 10 mg lowers LDL by 52% and Lipitor 40mg by 50% compared to 47% seen with simvastatin 80mg). However, presently they are 50-60 times costlier than simvastatin (average cost/month for them is as follow- simvastatin $ 3-4, crestor 10mg $157 and Lipitor 40mg $173). Patients not reaching their LDL goals with simvastatin 40mg or Vytorin 10/40 mg shouldn’t be titrated to simvastatin 80 mg rather crestor 5mg/10mg or Lipitor 20/40 mg should be tried. 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 (avoid >1 quart of grape juice daily).

Side effects
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. Recent FDA recommendations suggest limiting the use of highest approved simvastatin doses to 80mg FDA U.S. Food and Drug Administration. The 80 mg simvastatin dose lowers LDL cholesterol by an additional 6% compared to 40 mg dose. Nevertheless, these recommendations are based on the results of the SEARCH trial (Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine) that has shown an increased incidence of myopathy in patients on higher simvastatin doses (80mg) when compared to lower doses (20 mg) of this drug or other drugs in the same class. FDA is also reviewing data from other clinical trials, observational studies, and adverse event reports. Some of the changes recommended by FDA regarding the 80 mg simvastatin doses are- Patients with myopathy generally presents with muscle pain, tenderness, weakness and an elevation of muscle enzyme in blood (creatine kinase or CK >10 times the upper limits of normal (ULN) as taken in the SEARCH trial). Rhabdomyolysis (Unexplained muscle weakness or pain with serum CK>40 times ULN, dark or red urine) is the rare but most serious form of myopathy that could occur with high doses of statins. The myoglobin released due to muscle injury by statins in rhabdomyolysis can cause renal failure that could be fatal. Higher doses of simvastatin, older age, female sex and patients with Chinese descent have increased risks of myopathies (The Heart protection Study 2).
 * 1) It should not be started in new patients (the risks are higher in first year of treatment).
 * 2) It should not be given to patients already taking lower doses.
 * 3) It should be used only in patients who have been taking this dose for 12 months without evidence of myopathy.
 * 4) Changes in simvastatin labels, contraindicating its use with certain drugs and dose limitations with some other medications (see interaction section).
 * 5) Patients who do not meet their LDL cholesterol goal with simvastatin 40 mg should be placed on alternative LDL cholesterol lowering treatments rather than 80 mg simvastatin.

Contraindications
Statins are contraindicated in liver diseases, pregnancy and nursing females and should be used with cautions with medicines like Gemfibrozil, Fenofibrates, Amiodarone, Verapamil, anticoagulants, some HIV medicines, Oral contraceptives, nefazodone, and niacin among others.