Cholesterol is a waxy, fat-like substance found in cells including blood cells of human body. It is needed by human body to make hormones, vitamin D, and digestive juices. People with high blood cholesterol have a greater chance of getting heart disease. There are several kinds, but the ones to focus on are low-density lipoprotein (LDL), and high-density lipoprotein (HDL). Each has a different job in human body
Low-density lipoprotein is sometimes called bad cholesterol. High LDL leads to a buildup of cholesterol in arteries. The higher the LDL level in your blood, the greater chance you have of getting heart disease. HDL is sometimes called good cholesterol. The higher your HDL cholesterol level, the lower your chance of getting heart disease.
High blood cholesterol
Cholesterol levels are determined through chemical analysis of a blood sample. The value of total cholesterol, amounts of LDL, HDL, and another type of blood fat called triglycerides give doctors a better idea of heart disease risk and helps guide any treatment.
Cholesterol levels are measured in milligrams per deciliter (mg/dL). Table -1 shows the value of LDL and HDL for people over the age of twenty.
Table-1: Level of LDL & HDL
How to reduce high blood cholesterol?
The main goal of cholesterol treatment is to lower LDL in people without heart disease. If the LDL level is in the "high" category and fewer than two other risk factors for heart disease are present, the goal is an LDL level lower than 160 mg/dL. If two or more risk factors are present, the goal is less than 130 mg/dL. If a patient already has heart disease, LDL levels should be 100 mg/dL or less. By reducing LDL, heart disease patients may prevent future heart attacks, prolong their lives, and slow down or even reverse cholesterol buildup in the arteries, according to the National Heart, Lung, and Blood Institute.
Generally, diet control and regular exercise may reduce cholesterol, but sometimes diet and exercise alone are not enough to reduce cholesterol to goal levels. Perhaps a patient is genetically predisposed to high blood cholesterol. In these cases, doctors often prescribe drugs. In USA more than 10 million persons take some form of cholesterol-lowering drug therapy. The most prominent cholesterol drugs are in the statin family, an array of powerful treatments that includes:
" Lovastatin
" Fluvastatin
" Pravastatin
" Simvastatin
" Cervastatin
" Atorvastatin
Statin drugs are very effective for lowering LDL cholesterol levels and have few immediate short-term side effects.
" They are easy to administer, have high patient acceptance and have few drug-drug interactions.
" Patients, who are pregnant, have active or chronic liver disease, or who are allergic to statins shouldn't use statin drugs.
" The most common side effects are gastrointestinal, including constipation and abdominal pain and cramps. These symptoms are usually mild to severe and generally subside as therapy continues.
" Many doctors say statin drugs have revolutionized patient care. "These drugs have had a fantastic impact on cholesterol treatment," says Redonda Miller, MD, assistant professor of medicine at Johns Hopkins University School of Medicine. "They all lower cholesterol levels, but the side effects are minimal."
Heart patient Norbert Hoffmann, 65, of Northfield, Minn., saw what he calls "a dramatic drop" in cholesterol levels after taking Zocor for three months. For example, his total cholesterol went from 270 to 145 mg/dL and LDL from 182 to 82 mg/dL.
Now we will discuss about some recently developed drugs for lowering cholesterol.
Atorvastatin calcium
Atorvastatin calcium (Trade name: Lipitor) is a synthetic lipid-lowering agent. Atorvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in cholesterol biosynthesis. Atorvastatin calcium is [R-(R*, R*)]-2-(4-fluorophenyl)-ß,-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino) carbonyl]-1H-pyrrole-1-heptanoic acid, calcium salt (2:1) tri hydrate. The empirical formula of atorvastatin calcium is (C33H34 FN2O5) 2Cao3H2O and its molecular weight is 1209.42.
Structural formula of atorvastatin calcium:
Mechanism of action
Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the ratelimiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme. With ultracentrifugation, these complexes separate into HDL (high-density lipoprotein), IDL (intermediate-density lipoprotein), LDL (low-density lipoprotein), and VLDL (very-low-density lipoprotein) fractions.
Triglycerides (TG) and cholesterol in the liver are incorporated into VLDL and released into the plasma for delivery to peripheral tissues. LDL is formed from VLDL and is catabolized primarily through the high-affinity LDL receptor. Clinical and pathologic studies show that elevated plasma levels of total cholesterol (total-C), LDL-cholesterol (LDL-C), and apolipoprotein B (apo B) promote human atherosclerosis and are risk factors for developing cardiovascular disease, while increased levels of HDL-C are associated with a decreased cardiovascular risk.
Pregnancy and lactation: Atherosclerosis is a chronic process and discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. Cholesterol and other products of cholesterol biosynthesis are essential components for fetal development (including synthesis of steroids and cell membranes).
Side effects
Liver dysfunction: HMG-CoA reductase inhibitors, like some other lipid-lowering therapies, have been associated with biochemical abnormalities of liver function. Persistent elevations (>3 times the upper limit of normal [ULN] occurring on 2 or more occasions) in serum transaminases occurred in 0.7 per cent of patients who received atorvastatin in clinical trials. The incidence of these abnormalities was 0.2 per cent, 0.2 per cent, 0.6 per cent, and 2.3 per cent for 10, 20, 40, and 80 mg, respectively.
It is recommended that liver function tests be performed prior to and at 12 weeks following both the initiation of therapy and any elevation of dose, and periodically. Liver enzyme changes generally occur in the first three months of treatment with atorvastatin. Patients who develop increased transaminase levels should be monitored until the abnormalities resolve. Should an increase in ALT or AST of greater than 3 times ULN persist, reduction of dose or withdrawal of atorvastatin is recommended.
Atorvastatin should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of liver disease. Active liver disease or unexplained persistent transaminase elevations are contraindications to the use of atorvastatin.
Skeletal muscle: Uncomplicated myalgia has been reported in atorvastatin-treated patients. Myopathy, defined as muscle aches or muscle weakness in conjunction with increases in creatine phosphokinase (CPK) values >10 times ULN, should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of CPK. Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. Atorvastatin therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected.
Precautions
Before instituting therapy with atorvastatin, an attempt should be made to control hypercholesterolemia with appropriate diet, exercise, and weight reduction in obese patients, and to treat other underlying medical problems.
Information for patients: Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever.
Antipyrine: Because atorvastatin does not affect the pharmacokinetics of antipyrine, interactions with other drugs metabolized via the same cytochrome isozymes are not expected.
Colestipol: Plasma concentrations of atorvastatin decreased approximately 25 per cent when colestipol and atorvastatin were coadministered. However, LDL-C reduction was greater when atorvastatin and colestipol were coadministered than when either drug was given alone.
Erythromycin: In healthy individuals, plasma concentrations of atorvastatin increased approximately 40 per cent with coadministration of atorvastatin and erythromycin, a known inhibitor of cytochrome P450 3A4 (see WARNINGS, Skeletal Muscle).
Endocrine function: HMG-CoA reductase inhibitors interfere with cholesterol synthesis and theoretically might blunt adrenal and/or gonadal steroid production. Clinical studies have shown that atorvastatin does not reduce basal plasma cortisol concentration or impair adrenal reserve. The effects of HMG-CoA reductase inhibitors on male fertility have not been studied in adequate numbers of patients. The effects, if any, on the pituitary-gonadal axis in premenopausal women are unknown. Caution should be exercised if an HMG-CoA reductase inhibitor is administered concomitantly with drugs that may decrease the levels or activity of endogenous steroid hormones, such as ketoconazole, spironolactone, and cimetidine.
CNS toxicity: Brain hemorrhage was seen in a female dog treated for three months at 120 mg/kg/day. Brain hemorrhage and optic nerve vacuolation were seen in another female dog that was sacrificed in moribund condition after eleven weeks of escalating doses up to 280 mg/kg/day. CNS vascular lesions, characterized by perivascular hemorrhages, edema, and mononuclear cell infiltration of perivascular spaces, have been observed in dogs treated with other members of this class. A chemically similar drug in this class produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibres) in clinically normal dogs in a dose-dependent fashion at a dose that produced plasma drug levels about thirty times higher than the mean drug level in humans taking the highest recommended dose.
Other drug treatments
"Folic acid therapy may provide a safe and inexpensive tool to reduce cardiovascular risk," reports a team led by Dr. Ton Rabelink, of University Hospital Utrecht in the Netherlands. Their findings are published in the July 27th issue of Circulation: Journal of the American Heart Association.
Experts believe that folic acid -- a B vitamin found in green, leafy vegetables, orange juice, beans and fortified grains -- reduces risk for heart disease by lowering blood levels of the amino acid homocysteine.
The Dutch researchers sought to determine the effects of folate supplementation on a group of patients known to be at increased risk for heart disease due to a family history of high cholesterol. Twenty patients were asked to take either (an inactive) placebo or 5 milligrams of folic acid daily for 4 weeks, then switch over to the other regimen for a second 4-week period.
When blood vessels are flexible - contracting or expanding in volume as needed - risks for high blood pressure and clots may be reduced. This restoration of vessel responsiveness is especially important in patients with high cholesterol, who are at increased risk for narrowed arteries and dangerous clots.
The authors believe their findings may have "important clinical implications." Folic acid supplementation may turn out to be a cheap and effective therapy for patients with high cholesterol "who do not respond sufficiently to (cholesterol)-lowering medications," they conclude.
In addition to the above there are some drugs to reduce heart risk. These include:
" Nicotinic acid (niacin) - this lowers total and LDL cholesterol and raises HDL cholesterol. It also can lower triglycerides. Because the dose needed for treatment is about 100 times more than the Recommended Daily Allowance for niacin and thus can potentially be toxic, the drug must be taken under a doctor's care.
" Resins - doctors have been prescribing Questran (cholestyramine) and Colestid (colestipol) for about 20 years. These "resins" bind bile acids in the intestine and prevent their recycling through the liver.
" Fibric acid derivatives - used mainly to lower triglycerides, Lopid (gemfibrozil) and Tricor (fenofibrate) can also increase HDL levels.
" Aspirin--Because studies have shown that aspirin can have a protective effect against heart attacks in patients with clogged blood vessels, doctors often prescribe the drug to patients with heart disease.
" The decision of which drug to prescribe is one the doctor makes based on factors such as degree of cholesterol lowering desired, side effects, and cost. "If a patient has only a modest cholesterol elevation, I might prescribe Mevacor," says Johns Hopkins' Miller. "But if a more drastic reduction is needed, especially of LDL, I'll prescribe Lipitor."
Colesevelam, cholestyramine and colestipol, and nicotinic acid (niacin) are good for lowering LDL. These drugs appear to be free of serious side effects. But they can have troublesome side effects and require considerable patient education to achieve adherence. Nicotinic acid is preferred in patients with triglyceride levels that exceed 250 mg/dL because bile acid has tendency to raise triglyceride levels.
Niacin (nicotinic acid) comes in prescription form and as "dietary supplements." Dietary supplement niacin is not regulated by the US Food and Drug Administration (FDA) the same way that prescription niacin is. It may contain widely variable amounts of niacin - from none to much more than the label states. The amount of niacin may even vary from lot to lot of the same brand.
Other drugs to treat high cholesterol
Other available drugs are gemfibrozil, probucol and clofibrate. Gemfibrozil and clofibrate are most effective for lowering high triglyceride levels. They moderately reduce LDL cholesterol levels in hypercholesterolemic patients, but the FDA hasn't approved them for this purpose. Probucol also moderately lowers LDL levels. It has FDA approval for this purpose.
(The author is an expert in chemical and pharmaceuticals:E-mail: pm_mandal@yahoo.co.in )