1. ATORVASTATIN HISTORY

How was Atorvastatin discovered?
Atorvastatin is the number one prescribed cholesterol-lowering drug in the United States and the world.

Atorvastatin is proven to reduce your risk of having a heart attack by 36%.

Note: World-drugs.net sells generic version of Atorvastatin.

The U.S. Food and Drug Administration (FDA) approved the cholesterol-lowering therapy Atorvastatin for the prevention of cardiovascular disease by reducing heart attack risk in people with normal to mildly elevated levels of cholesterol but with other risk factors for heart disease.

The FDA's decision was based on the findings of a landmark clinical trial, known as the Anglo-Scandinavian Cardiac Outcomes Trial: Lipid-Lowering Arm (ASCOT-LLA), which found that Atorvastatin , at its lowest dose of 10 mg, reduced the relative risk of heart attack by 36 percent compared to placebo. Because of the significant benefits seen with Atorvastatin early in the trial, ASCOT-LLA was halted approximately two years ahead of schedule. The safety profile of the group treated with Atorvastatin was comparable to that of the group treated with placebo. The trial involved more than 10,300 people with normal or borderline cholesterol and no prior history of heart disease, but with high blood pressure and at least three other known risk factors for heart disease, such as family history, age over 55, smoking, diabetes and obesity.

The FDA also approved Atorvastatin to reduce the risk of angina (chest pain) and to reduce revascularization procedures, such as balloon angioplasty, that help open blocked arteries.

3. ABOUT ATORVASTATIN MEDICATION

What is cholesterol and what does it have to do with heart disease?
Cholesterol is a waxy, fat-like material that is found in all parts of the body. It comes from two sources: the liver produces it, and we consume it in meat and dairy products.

Cholesterol is a chemical that can do both good and harm in the body. On the good side, cholesterol plays important roles in the structure of cells and in the production of hormones. But too much cholesterol in the blood can lead to heart and blood vessel disease. To complicate matters, not all cholesterol contributes to heart and blood vessel problems.

One type, called high-density lipoprotein (HDL) cholesterol, or "good cholesterol," actually lowers the risk of these problems. High-density lipoproteins (HDL) remove cholesterol from the bloodstream. The other type, low-density lipoprotein (LDL) cholesterol, or "bad cholesterol," is the type that threatens people's health. Low-density lipoproteins (LDL) deliver cholesterol to the body. To travel through the bloodstream, cholesterol must attach itself to a protein. The combination of a protein and a fatty substance like cholesterol is called a lipoprotein.

Many factors may contribute to the fact that some people have higher cholesterol levels than others. A diet high in certain types of fats is one factor. Medical problems such as poorly controlled diabetes, an under active thyroid gland, an overactive pituitary gland, liver disease or kidney failure also may cause high cholesterol levels. And some people have inherited disorders that prevent their bodies from properly using and eliminating fats. This allows cholesterol to build up in the blood.

Treatment for high cholesterol levels usually begins with changes in habits. By losing weight, stopping smoking, exercising more and reducing the amount of fat and cholesterol in the diet, many people can bring their cholesterol levels down to acceptable levels. However, some may need to use cholesterol-reducing drugs to reduce their risk of health problems.

While some cholesterol is needed for good health, too much cholesterol in your blood can raise your risk of having a heart attack or stroke.

The extra cholesterol in your blood may be stored in your arteries (blood vessels) and cause them to narrow. (This is called atherosclerosis.) Large deposits of cholesterol can completely block an artery, so the blood cannot flow through.

If an artery that supplies blood to your heart becomes blocked, a heart attack can occur. If an artery that supplies blood to your brain becomes blocked, a stroke can occur.

Cholesterol Levels:

Total cholesterol level

• Less than 200 is best.
• Between 200 to 239 is borderline high.
• 240 or more means you're at increased risk for heart disease.

HDL cholesterol levels

• Less than 40 means you're at higher risk for heart disease.
• 60 or higher reduces your risk of heart disease.

What are Cholesterol Lowering agents?
Cholesterol-reducing drugs are medicines that lower the amount of cholesterol in the blood.

1. Bile acid sequestrants
   They are drugs that act by binding with the bile produced by the liver. Bile helps the digestion and absorption of fats in the intestine. By blocking the digestion of fats, bile acid sequesterants prevent the formation of cholesterol. Drugs in this class include:
   • Cholestyramine,
   • Colestipol, and
   • Colesevelam.
     
2. HMG-CoA inhibitors, often called "statins,"
   They are drugs that block an enzyme called "3-hydroxy-3-methyl-glutaryl-coenzyme A reductase." This blocks one of the steps in converting fat to cholesterol. These are the most effective cholesterol lowering agents available and in recent years have received increased attention for their benefits beyond helping patients with high cholesterol. In 2003, researchers reported that people with heart failure but no coronary artery disease received benefits after only 14 weeks of statin therapy. In addition, some research has connected the drugs to reduced risk for depression and dementia.
   Drugs in this group include:
   • Atorvastatin,
   • Cerivastatin,
   • Fluvastatin,
   • Lovastatin,
   • Pravastatin,
   • Simvastatin, and
   • Rosuvastatin
     
3. Fibric acid derivatives
   They include
   • Clofibrate,
   • Gemfibrozil, and
   • Fenofibrate.
   
   Although these drugs are less effective than the statins at lowering total cholesterol, they may be able to lower the low-density lipoprotein (LDL) cholesterol while raising the high-density lipoprotein (HDL) cholesterol. They probably act by inhibiting lipoprotein lipase activity.
   
4. Niacin, or vitamin B-3, also is effective in lowering cholesterol levels. Although the normal vitamin dose of niacin is only 20 mg, the dose required to reduce cholesterol levels is at least 500 mg each day. Niacin probably helps reduce cholesterol by inhibiting very low-density lipoprotein (VLDL) secretion in the bloodstream.

How does Atorvastatin work?
Atorvastatin decreases the production of LDL cholesterol by blocking the action of the enzyme in the liver (called HMG-CoA reductase) that is responsible for its production. This decreases the amount of cholesterol in the liver cells, which causes them to take up LDL cholesterol from the blood. The decreased cholesterol production and increased removal of LDL cholesterol from the blood ultimately results in lowered blood cholesterol levels.

As the body produces most cholesterol at night, Atorvastatin is generally more effective if taken at night.

Atorvastatin also causes a small decrease in the production of other 'bad fats' in the blood called triglycerides, and a small increase in the level of HDL cholesterol. This results in lowered levels of 'bad fats' and raised levels of 'good fats' in the blood.

Atorvastatin has an important role in the prevention of coronary heart disease. They reduce the risk of excess cholesterol being deposited in the major blood vessels of the heart. Any blockage in the blood vessels limits the amount of blood and therefore oxygen being carried to the heart muscle. In severe cases this can result in a heart attack (myocardial infarction).

Atorvastatin may also reduce the risk of stroke by decreasing the risk of excess cholesterol being deposited in the blood vessels leading to the brain. These fat deposits can cause blockage and therefore limit blood and oxygen supply to certain parts of the brain.

Atorvastatin is used to reduce high blood levels of cholesterol and other fats when these cannot be lowered by diet and exercise alone. This helps to reduce the risk of hardening of the arteries (atherosclerosis) and the problems described above that this could cause. It is important to continue to follow a cholesterol-lowering diet and exercise regime while taking Atorvastatin .

4. ATORVASTATIN EFFECTIVENESS

(When is Atorvastatin best taken?
Absorption : Atorvastatin is rapidly absorbed after oral administration; maximum plasma concentrations occur within 1 to 2 hours. Extent of absorption increases in proportion to Atorvastatin dose. The absolute bioavailability of Atorvastatin is approximately 14% and the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic availability is attributed to presystemic clearance in gastrointestinal mucosa and/or hepatic first-pass metabolism. Although food decreases the rate and extent of drug absorption by approximately 25% and 9%, respectively, as assessed by Cmax and AUC, LDL-C reduction is similar whether Atorvastatin is given with or without food. Plasma Atorvastatin concentrations are lower (approximately 30% for Cmax and AUC) following evening drug administration compared with morning. However, LDL-C reduction is the same regardless of the time of day of drug administration.

Distribution : Mean volume of distribution of Atorvastatin is approximately 381 liters. Atorvastatin is >/=98% bound to plasma proteins. A blood/plasma ratio of approximately 0.25 indicates poor drug penetration into red blood cells. Based on observations in rats, Atorvastatin is likely to be secreted in human milk.

Metabolism : Atorvastatin is extensively metabolized to ortho- and parahydroxylated derivatives and various beta-oxidation products. In vitro inhibition of HMG-CoA reductase by ortho- and parahydroxylated metabolites is equivalent to that of Atorvastatin . Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites. In vitro studies suggest the importance of Atorvastatin metabolism by cytochrome P450 3A4, consistent with increased plasma concentrations of Atorvastatin in humans following co-administration with erythromycin, a known inhibitor of this isozyme. In animals, the ortho-hydroxy metabolite undergoes further glucuronidation.

Excretion : Atorvastatin and its metabolites are eliminated primarily in bile following hepatic and/or extra-hepatic metabolism; however, the drug does not appear to undergo enterohepatic recirculation. Mean plasma elimination half-life of Atorvastatin in humans is approximately 14 hours, but the half-life of inhibitory activity for HMG-CoA reductase is 20 to 30 hours due to the contribution of active metabolites. Less than 2% of a dose of Atorvastatin is recovered in urine following oral administration.

5. ATORVASTATIN EFFECTS ON SPECIAL POPULATION

How do different people react to Atorvastatin?
Geriatric: Plasma concentrations of Atorvastatin are higher in healthy elderly subjects (age >/=65 years) than in young adults. Clinical data suggest a greater degree of LDL-lowering at any dose of drug in the elderly patient population compared to younger adults.

Pediatric: Pharmacokinetic data in the pediatric population are not available.

Gender: Plasma concentrations of Atorvastatin in women differ from those in men; however, there is no clinically significant difference in LDL-C reduction with Lipitor between men and women.

6. ATORVASTATIN EFFECTS ON MEDICAL CONDITIONS

How does Atorvastatin affect your existing condition/ailment?
Renal Insufficiency : Renal disease has no influence on the plasma concentrations or LDL-C reduction of Atorvastatin; thus, dose adjustment in patients with renal dysfunction is not necessary.

Hemodialysis : While studies have not been conducted in patients with end-stage renal disease, hemodialysis is not expected to significantly enhance clearance of Atorvastatin since the drug is extensively bound to plasma proteins.

Hepatic Insufficiency : In patients with chronic alcoholic liver disease, plasma concentrations of Atorvastatin are markedly increased.

7. OTHER/ALTERNATE USES OF ATORVASTATIN

What else does Atorvastatin treat?
Atorvastatin is used to reduce the amounts of LDL (bad) cholesterol, total cholesterol, triglycerides (another type of fat), and apolipoprotein B (a protein needed to make cholesterol) in your blood. Atorvastatin is also used to increase the level of HDL (good) cholesterol in your blood. These actions are important in reducing the risk of hardening of the arteries, which can lead to heart attacks, stroke, and peripheral vascular disease.

8. ADVERSE/SIDE EFFECTS of ATORVASTATIN

What are the side effects of Atorvastatin?
Adverse experiences reported in >/=2% of patients in placebo-controlled clinical studies of Atorvastatin , regardless of causality assessment, are shown in the table below.

The following adverse events were reported, regardless of causality assessment in patients treated with Atorvastatin in clinical trials. The events in italics occurred in >/=2% of patients and the events in plain type occurred in <2% of patients.

Body as a Whole : Chest pain, face edema, fever, neck rigidity, malaise, photosensitivity reaction, generalized edema.

Digestive System: Nausea, gastroenteritis, liver function tests abnormal, colitis, vomiting, gastritis, dry mouth, rectal hemorrhage, esophagitis, eructation, glossitis, mouth ulceration, anorexia, increased appetite, stomatitis, biliary pain, cheilitis, duodenal ulcer, dysphagia, enteritis, melena, gum hemorrhage, stomach ulcer, tenesmus, ulcerative stomatitis, hepatitis, pancreatitis, cholestatic jaundice.

Respiratory System : Bronchitis, rhinitis, pneumonia, dyspnea, asthma, epistaxis.

Nervous System : Insomnia, dizziness, paresthesia, somnolence, amnesia, abnormal dreams, libido decreased, emotional lability, incoordination, peripheral neuropathy, torticollis, facial paralysis, hyperkinesia, depression, hypesthesia, hypertonia.

Musculoskeletal System : Arthritis, leg cramps, bursitis, tenosynovitis, myasthenia, tendinous contracture, myositis.

Skin and Appendages : Pruritus, contact dermatitis, alopecia, dry skin, sweating, acne, urticaria, eczema, seborrhea, skin ulcer.

Urogenital System : Urinary tract infection, urinary frequency, cystitis, hematuria, impotence, dysuria, kidney calculus, nocturia, epididymitis, fibrocystic breast, vaginal hemorrhage, albuminuria, breast enlargement, metrorrhagia, nephritis, urinary incontinence, urinary retention, urinary urgency, abnormal ejaculation, uterine hemorrhage.

Special Senses: Amblyopia, tinnitus, dry eyes, refraction disorder, eye hemorrhage, deafness, glaucoma, parosmia, taste loss, taste perversion.

Cardiovascular System : Palpitation, vasodilatation, syncope, migraine, postural hypotension, phlebitis, arrhythmia, angina pectoris, hypertension.

Metabolic and Nutritional Disorders : Peripheral edema, hyperglycemia, creatine phosphokinase increased, gout, weight gain, hypoglycemia.

Hemic and Lymphatic System : Ecchymosis, anemia, lymphadenopathy, thrombocytopenia, petechia.