Statin

The statins (or HMG-CoA reductase inhibitors) form a class of hypolipidemic agents, used as pharmaceuticals to lower cholesterol levels in people at risk for cardiovascular disease because of hypercholesterolemia. They work by inhibiting the enzyme HMG-CoA reductase, the enzyme that determines the speed of cholesterol synthesis. Inhibition of this enzyme in the liver stimulates the LDL-receptors, which results in an increased clearance of LDL from the bloodstream and a decrease in blood cholesterol levels. The first results can be seen after one week of use and the effect is maximal after four to six weeks.

Members
The statins include, in alphabetical order (brand names vary in different countries):
 * Atorvastatin (Lipitor, Torvast)
 * Blorivastatin (Lipex)
 * Cerivastatin (Lipobay, Baycol) – withdrawn from the market in 2001 due to risk of serious adverse effects.
 * Fluvastatin (Lescol)
 * Lovastatin (Mevacor, Altocor)
 * Mevastatin – naturally-occurring compound, found in red yeast rice.
 * Pitavastatin (Livalo, Pitava)
 * Pravastatin (Pravachol, Selektine, Lipostat)
 * Rosuvastatin (Crestor)
 * Simvastatin (Zocor, Lipex)

LDL-lowering potency varies between agents. Cerivastatin is the most potent, followed by (in order of decreasing potency) rosuvastatin, atorvastatin, simvastatin, lovastatin, pravastatin, and fluvastatin. The relative potency of pitavastatin has not yet been fully established.

The statins are divided into two groups:
 * Fermentation-derived: lovastatin, simvastatin and pravastatin
 * Synthetic: fluvastatin, atorvastatin, cerivastatin and rosuvastatin

Fermentation-derived statins appear more effective in reducing LDL, but no clear explanation has accounted for this phenomenon.

Cholesterol lowering
Most circulating cholesterol is manufactured internally, typically about 1000 mg/24 hours, out of the carbohydrate metabolism, by the HMG-CoA reductase pathway. Cholesterol, both from dietary intake and secreted into the duodenum as bile from the liver, is typically absorbed at a rate of 50% by the small intestines. The typical diet in the United States and many other Western countries, is estimated as adding about 200-300 mg/day to intestinal intake; much smaller than that secreted into the intestine in the bile. Thus internal production is an important factor.

Cholesterol is not water-soluble, and is therefore carried in the blood in the form of lipoproteins, the type being determined by the apoprotein, a protein coating that acts as an emulsifier. The relative balance between these lipoproteins is determined by various factors, including genetics, diet, insulin resistance. Low density lipoprotein (LDL) and very low density lipoprotein (VLDL) carry cholesterol towards tissues, and elevated levels of these lipoproteins are associated with atheroma formation (fat-containing deposits in the arterial wall) and cardiovascular disease. High density lipoprotein, in contrast, carries cholesterol back to the liver and is associated with protection against cardiovascular disease.

Statins act by competitively inhibiting HMG-CoA reductase, the first committed enzyme of the HMG-CoA reductase pathway. By reducing intracellular cholesterol levels, they cause liver cells to upregulate expression of the LDL receptor, leading to increased clearance of low-density lipoprotein from the bloodstream.

Direct evidence of the action of statin-based cholesterol lowering on atherosclerosis was presented in the ASTEROID trial, which demonstrated regression of atheroma employing intravascular ultrasound.

Non-cholesterol related actions
Statins exhibit action beyond lipid-lowering activity in the prevention of atherosclerosis. Researchers believe that statins prevent cardiovascular disease via four proposed mechanisms (all subjects of a large body of biomedical research): uiiyuiyuioyuiyuiyikyiuuliol7890789978978978okj,lj,.
 * 1) Improving endothelial function
 * 2) Modulate inflammatory responses
 * 3) Maintain plaque stability
 * 4) Prevent thrombus formation

Pharmacogenomics
A 2004 study showed that patients with one of two common single nucleotide polymorphisms (small genetic variations) in the HMG-CoA reductase gene were less responsive to statins.

Adverse effects
While some patients on statin therapy report myalgias, muscle cramps, or far less-frequent gastrointestinal or other symptoms, similar symptoms are also reported with placebo use in all the large statin safety/efficacy trials and usually resolve, either on their own or on temporarily lowering/stopping the dose. Liver enzyme derangements may also occur, typically in about 0.5%, are also seen at similar rates with placebo use and repeated enzyme testing, and generally return to normal either without discontinuance over time or after briefly discontinuing the drug. Multiple other side-effects occur rarely; typically also at similar rates with only placebo in the large statin safety/efficacy trials.

A clearer major safety concern, myositis, myopathy, rarely with rhabdomyolysis (the pathological breakdown of skeletal muscle) may lead to acute renal failure when muscle breakdown products damage the kidney. One 2004 study found that of 10,000 patients treated for one year, 0.44 will develop this side-effect. Cerivastatin, which was withdrawn by its manufacturer for this reason in 2001, had a much higher incidence (more than 10x). All commonly used statins show somewhat similar results, however the newer statins, characterized by longer pharmacological half-lifes and more cellular specificity, have had a better ratio of efficacy to lower adverse effect rates.The risk of myopathy is lowest with pravastatin and fluvastatin probably because they are more hydrophillic and as a result have less muscle penetration.

Despite initial concerns that statins might increase the risk of cancer, various studies concluded later that statins have no influence on cancer risk (including the heart protection study and a 2006 meta-analysis ). Indeed, a 2005 trial showed that patients taking statins for over 5 years reduced their risk of colorectal cancer by 50%; this effect was not exhibited by fibrates. The trialists warn that the number needed to treat would approximate 5000, making statins unlikely tools for primary prevention.

Drug interactions
Combining any statin with a fibrate, another category of lipid-lowering drugs, increases the risks for rhabdomyolysis to almost 6.0 per 10,000 person-years. Most physicians have now abandoned routine monitoring of liver enzymes and creatine kinase, although they still consider this prudent in those on high-dose statins or in those on statin/fibrate combinations, and mandatory in the case of muscle cramps or of deterioration in renal function.

Consumption of grapefruit or grapefruit juice inhibits the metabolism of statins&mdash;furanocoumarins in grapefruit juice inhibit the cytochrome P450 enzyme CYP3A4, which is involved in the metabolism of most statins and some other medications (it had been thought that flavonoids were responsible). This increases the levels of the statin, increasing the risk of dose-related adverse effects (including myopathy/rhabdomyolysis). Consequently, consumption of grapefruit juice is not recommended in patients undergoing therapy with most statins. An alternative, somewhat risky, approach is that some users take grapefruit juice to enhance the effect of lower (hence cheaper) doses of statins.

History
Akira Endo and Masao Kuroda of Tokyo, Japan commenced research into inhibitors of HMG-CoA reductase in 1971 (Endo 1992). This team reasoned that certain microorganisms may produce inhibitors of the enzyme to defend themselves against other organisms, as mevalonate is a precursor of many substances required by organisms for the maintenance of their cell wall (ergosterol) or cytoskeleton (isoprenoids).

The first agent isolated was mevastatin (ML-236B), a molecule produced by Penicillium citrinum. The pharmaceutical company Merck & Co. showed an interest in the Japanese research in 1976, and isolated lovastatin (mevinolin, MK803), the first commercially marketed statin, from the mold Aspergillus terreus. Dr Endo was awarded the 2006 Japan Prize for his work on the development of statins.

Dosage forms
Oral


 * Atorvastatin
 * Tablets (U.S. and Canada)
 * Cerivastatin
 * Tablets #
 * Fluvastatin
 * Capsules (U.S. and Canada)
 * Lovastatin
 * Extended-Release Tablets (U.S.)
 * Tablets (U.S. and Canada)
 * Pravastatin
 * Tablets (U.S. and Canada)
 * Simvastatin
 * Tablets (U.S. and Canada)

Before Using This Medicine In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For HMG-CoA reductase inhibitors, the following should be considered:

Allergies—Tell your doctor if you have ever had any unusual or allergic reaction to HMG-CoA reductase inhibitors. Also tell your health care professional if you are allergic to any other substances, such as foods, preservatives, or dyes.

Diet—Before prescribing medicines to lower your cholesterol, your doctor will probably try to control your condition by prescribing a personal diet for you. Such a diet will be lower in total fat, particularly saturated fat, and dietary cholesterol. Many people are able to control their condition by carefully following their doctor's orders for proper diet and exercise. Medicine is prescribed only when additional help is needed and is effective only when a schedule of diet and exercise is properly followed.

Also, this medicine is less effective if you are greatly overweight. It may be very important for you to go on a reducing diet. However, check with your doctor before going on any diet. Pregnancy—HMG-CoA reductase inhibitors should not be used during pregnancy or by women who plan to become pregnant in the near future. These medicines block formation of cholesterol, which is necessary for the fetus to develop properly. HMG-CoA reductase inhibitors may cause birth defects or other problems in the baby if taken during pregnancy. An effective form of birth control should be used during treatment with these medicines. Check with your doctor immediately if you think you have become pregnant while taking this medicine. Be sure you have discussed this with your doctor.

Breast-feeding—These medicines are not recommended for use during breast-feeding because they may cause unwanted effects in nursing babies.

Children—Studies on this medicine have been done only in adult patients, and there is no specific information comparing use of HMG-CoA reductase inhibitors in children with use in other age groups. However, atorvastatin, lovastatin, and simvastatin have been used in a limited number of children under 18 years of age. Early information seems to show that these medicines may be effective in children, but their long-term safety has not been studied. Older adults—This medicine has been tested in a limited number of patients 65 years of age or older and has not been shown to cause different side effects or problems in older people than it does in younger adults.

Other medicines—Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking HMG-CoA reductase inhibitors, it is especially important that your health care professional know if you are taking any of the following:
 * Cyclosporine (e.g., Sandimmune) or
 * Gemfibrozil (e.g., Lopid) or
 * Clofibrate (e.g., Atromid-S) or
 * Fenofibrate (e.g., Tricor) or
 * Niacin—Use of these medicines with an HMG-CoA reductase inhibitor may increase the risk of developing muscle problems and kidney failure
 * Digoxin (e.g., Lanoxin)—Use with atorvastatin, fluvastatin, or simvastatin may increase blood levels of digoxin, increasing the risk of side effects
 * Oral contraceptives, (birth control tablets)—Atorvastatin may increase the blood levels of the birth control hormones, increasing the risk of side effects
 * HIV protease inhibitors (Amprenavir [e.g., Agenerase], Indinavir [e.g., Crixivan], Nelfinavir [e.g., Viracept], Ritonavir [e.g., Norvir], Saquinavir [e.g., Fortovase, Invirase]) or
 * Nefazodone (e.g. Serzone)—Use with simvastatin may increase the risk of developing muscle problems and kidney failure
 * Verapamil (e.g. Calan, Isoptin)—Use with simvastatin may increase the risk of muscle problems

Other medical problems—The presence of other medical problems may affect the use of HMG-CoA reductase inhibitors. Make sure you tell your doctor if you have any other medical problems, especially:
 * Alcohol abuse (or history of) or
 * Liver disease—Use of this medicine may make liver problems worse
 * Convulsions (seizures), not well-controlled, or
 * Organ transplant with therapy to prevent transplant rejection or
 * If you have recently had major surgery—Patients with these conditions may be at risk of developing problems that may lead to kidney failure

Proper Use of This Medicine Use this medicine only as directed by your doctor. Do not use more or less of it, and do not use it more often or for a longer time than your doctor ordered. Remember that this medicine will not cure your condition but it does help control it. Therefore, you must continue to take it as directed if you expect to keep your cholesterol levels down. Follow carefully the special diet your doctor gave you. This is the most important part of controlling your condition, and is necessary if the medicine is to work properly. For patients taking atorvastatin and simvastatin: For patients taking lovastatin: Dosing— The dose of these medicines will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of these medicines. If your dose is different, do not change it unless your doctor tells you to do so. The number of capsules or tablets that you take depends on the strength of the medicine. For atorvastatin For cerivastatin
 * Do not take these medicines with large amounts of grapefruit juice
 * For extended-release tablets: This medicine works better when it is taken at bedtime. The extended-release tablets should be swallowed whole. They should not be chewed, crushed, or cut.
 * For tablets: This medicine works better when it is taken with food. If you are taking this medicine once a day, take it with the evening meal. If you are taking more than one dose a day, take each dose with a meal or snack.
 * For oral dosage form (tablets):
 * For high cholesterol:
 * Adults—10 to 80 milligrams (mg) once a day.
 * Children 10 to 17 years of age—10 to 20 milligrams (mg) once a day.
 * Childrenyounger than 10 years of age—Use and dose must be determined by your doctor.

Note: Removed from the market by Bayer in August 2001 For fluvastatin For lovastatin For pravastatin For simvastatin Missed dose— If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses. Storage— To store this medicine:
 * For oral dosage form :
 * For oral dosage form (capsules):
 * For high cholesterol:
 * Adults—20 to 40 milligrams (mg) once a day in the evening.
 * Children—Use and dose must be determined by your doctor.
 * For oral dosage form (extended-release tablets):
 * For high cholesterol:
 * Adults—10 to 60 milligrams (mg) once a day at bedtime.
 * Children—Use and dose must be determined by your doctor.
 * For oral dosage form (tablets):
 * For high cholesterol:
 * Adults— 20 to 80 milligrams (mg) a day taken as a single dose or divided into smaller doses. Take with evening meals.
 * Children—Use and dose must be determined by your doctor.
 * For oral dosage form (tablets):
 * For high cholesterol:
 * Adults—10 to 40 mg once a day at bedtime.
 * Children—Use and dose must be determined by your doctor.
 * For oral dosage form (tablets):
 * For high cholesterol:
 * Adults—5 to 80 mg a day.
 * Children—Use and dose must be determined by your doctor.
 * Keep out of the reach of children.
 * Store away from heat and direct light.
 * Do not store in the bathroom, near the kitchen sink, or in other damp places. Heat or moisture may cause the medicine to break down.
 * Keep the medicine from freezing. Do not refrigerate.
 * Do not keep outdated medicine or medicine no longer needed. Be sure that any discarded medicine is out of the reach of children.

Precautions While Using This Medicine  It is very important that your doctor check your progress at regular visits. This will allow your doctor to see if the medicine is working properly to lower your cholesterol levels and that it does not cause unwanted effects. Check with your doctor immediately if you think that you may be pregnant. HMG-CoA reductase inhibitors may cause birth defects or other problems in the baby if taken during pregnancy. Your doctor may recommend an appropriate method of birth control to prevent adolescent girls and women of child bearing potential from getting pregnant. Do not stop taking this medicine without first checking with your doctor. When you stop taking this medicine, your blood cholesterol levels may increase again. Your doctor may want you to follow a special diet to help prevent this from happening. Before having any kind of surgery (including dental surgery) or emergency treatment, tell the medical doctor or dentist in charge that you are taking this medicine. Check with your doctor immediately if you have unexplained muscle pain, tenderness, or weakness.

Side Effects of This Medicine

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention. Check with your doctor as soon as possible if any of the following side effects occur:
 * Side Effects of This Medicine
 * Less common or rare
 * Fever; muscle aches or cramps;  severe stomach pain;  unusual tiredness or weakness

Other side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. However, check with your doctor if any of the following side effects continue or are bothersome:
 * More common
 * Constipation; diarrhea;  dizziness;  gas;  headache;  heartburn;  nausea ;  skin rash;  stomach pain


 * Rare
 * Decreased sexual ability; trouble in sleeping

Other side effects not listed above may also occur in some patients. If you notice any other effects, check with your doctor.

Brand Names Some commonly used brand names are: In the U.S.—
 * Altoprev
 * Lescol
 * Lipitor
 * Mevacor
 * Pravachol
 * Zocor

In Canada—
 * Lescol
 * Mevacor
 * Pravachol
 * Zocor