Lipophilic or Hydrophilic Nature of Statins Is Important

Alexander Motylev, RPh, PhD
Published Online: Tuesday, March 1, 2005
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Humans cannot live without cholesterol. Cholesterol is a member of the sterol group of lipids, and it must be present in the membrane of every cell in the body. Cholesterol plays a role in the synthesis of steroid hormones (except retinoic acid) and the synthesis of bile acids. The latter help facilitate the absorption of fat-soluble vitamins in the intestine. In addition, cholesterol is necessary for the synthesis of vitamin D, which plays an essential role in the absorption of calcium. Cholesterol, which is a hydrophobic substance, gets transported in the bloodstream to and from cells with the help of lipoproteins.

Although cholesterol is important to the body, excessive levels of cholesterol in the blood can be dangerous. Much clinical information is available that shows that an excess of cholesterol in plasma potentially leads to cardiovascular complications and, if left untreated, can cause death.

Once the condition of hypercholesterolemia (high levels of cholesterol in the blood) is detected in the patient and a physician identifies high levels of low-density lipoprotein (LDL), low levels of high-density lipoprotein (HDL), elevated levels of total cholesterol, and high levels of triglycerides, the doctor should, first of all, analyze whether a change in lifestyle would help. Strict control of these parameters—keeping them within normal ranges—will decrease mortality and morbidity from cardiovascular complications.

Lifestyle changes should be adopted to reduce such risk factors as smoking, hypertension, obesity, and diabetes mellitus. In addition to suggesting lifestyle changes, a pharmacist can advise a patient to watch his or her weight by exercising and by honoring a low-cholesterol and low-saturated-fat-content diet and increasing intake of soluble fiber. If, however, such modifications do not show desired results in terms of laboratory values for total cholesterol, LDL, HDL, and triglycerides, a patient should start medication therapy while simultaneously keeping up with the new lifestyle and diet.

Many therapeutic groups are used for the treatment of hypercholesterolemia, once lifestyle modifications alone fail to work. One of the most important groups is the 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase inhibitors, called statins. The older statins—such as lovastatin, pravastatin, and simvastatin—were derived from naturally occurring compounds, whereas newer agents—such as atorvastatin and rosuvastatin—were chemically designed and synthesized. Because hypercholesterolemia is a chronic condition, patients must take statins for a long period of time. Therefore, patients' compliance and safe administration of the medication play an important role in treatment, especially among the elderly population.

Statins inhibit the HMG-CoA reductase enzyme, which acts as the catalyst for the formation of mevalonate from HMG CoA (the rate-limiting step in cholesterol synthesis). By blocking HMG-CoA reductase, statins can control the production of mevalonate and eventually control the amounts of cholesterol produced in the body, while at the same time up-regulating the LDL receptors on the surface of liver cells. The processes described above lead to a decline in the level of cholesterol and the removal of LDL cholesterol from the circulating blood. In addition, statins increase HDL cholesterol and lower triglycerides in the blood. Besides the lipid-lowering capabilities, this therapeutic group of drugs offers protection against the growth of atherosclerotic plaque.

Like any other medications, HMGCoA reductase inhibitors have side effects. Some possible side effects are an increase in hepatic aminotransferases, myalgia/rhabdomyolysis, and gastrointestinal intolerance. In addition, all statins have a category X pregnancy usage, so patients with chronic and active liver disease and pregnant women should avoid using them.

The goal of this article is to discuss other possible side effects, such as insomnia and cognitive changes. These particular 2 side effects are especially important for the elderly population. Once elderly patients are put on a statin, they take it for a long period of time, and, in addition, they may tend to have sleep disturbances and cognitive problems.

The majority of other side effects are related to the chemical nature of the statin group. Scientists like to describe medical compounds based on their hydrophilic or lipophilic nature. These parameters play a very significant role in the pharmacodynamic and pharmacokinetic behavior of every medication. In terms of lipophilic nature, lovastatin and simvastatin are the most lipophilic, followed by atorvastatin, fluvastatin, and pravastatin. Rosuvastatin is a relatively new statin, having a polar methane sulfonamide group, and it can be placed between fluvastatin and pravastatin.

The mechanism by which statins cause rhabdomyolysis is not known yet. The lipophilic nature of medical compounds and the lowering of the cholesterol level in the blood, however, seem to play an important role in the occurrence of this side effect. As stated above, it has been determined that HMG-CoA inhibitors block the production of mevalonate, which leads to deficient production of coenzyme Q10, isopentenyl, and dolichols. Deficiency of these 3 chemical compounds can lead to the muscle cell injury and toxicity. Predominantly lipophilic statins penetrate muscle cell at a higher degree than predominantly hydrophilic statins. In addition, it has been shown in mice that highly lipophilic statins have a pronounced effect in disturbing the normal activity of myoblasts, the proper performance of which is especially necessary during muscle injury.

This month's FDA MedWatch 2005 Safety Summary states that physicians should use extra caution when prescribing statins, especially rosuvastatin, to patients with hypothyroidism and/or renal insufficiency. These patients have a greater risk for experiencing myopathy, especially when given a statin at higher-than-normal doses, because the higher serum concentrations of the drug increase the risk of myopathy.

Studies that have been conducted regarding cognitive effects of statins have had controversial outcomes. Scientists believe that, by decreasing the levels of cholesterol, statins may slow down the formation of amyloid peptide (A-beta). On the other hand, there have been reports that, in rare cases, patients on statin therapy experience cognitive impairments, especially if they are taking highly lipophilic medical compounds. In fact, some studies indicate that high-lipophilic statins can decrease cognitive function. The cognitive function can be influenced directly by statins—the ones that pass the blood-brain barrier, particularly highly lipophilic medical compounds—or by a very low cholesterol level in neuronal membranes.

Another atypical side effect of the statins is insomnia. Although they have been observed, such side effects as insomnia and decrease in cognitive function are still questionable. It is very important for a pharmacist to suggest a less lipophilic member of the statin group when dealing with patients who have an existing or potential condition of insomnia or decreased cognitive function.

Dr. Motylev is a pharmacy manager in the hospital setting.



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