Lipophilic or Hydrophilic Nature of Statins Is Important

Alexander Motylev, RPh, PhD

Pharmacy Times, Volume 0,0

Humans cannot live withoutcholesterol. Cholesterol is amember of the sterol groupof lipids, and it must bepresent in the membrane of every cellin the body. Cholesterol plays a role inthe synthesis of steroid hormones(except retinoic acid) and the synthesisof bile acids. The latter help facilitatethe absorption of fat-soluble vitaminsin the intestine. In addition,cholesterol is necessary for the synthesisof vitamin D, which plays an essentialrole in the absorption of calcium.Cholesterol, which is a hydrophobicsubstance, gets transported in thebloodstream to and from cells withthe help of lipoproteins.

Although cholesterol is importantto the body, excessive levels of cholesterolin the blood can be dangerous.Much clinical information is availablethat shows that an excess of cholesterolin plasma potentially leads tocardiovascular complications and, ifleft untreated, can cause death.

Once the condition of hypercholesterolemia(high levels of cholesterol inthe blood) is detected in the patientand a physician identifies high levelsof low-density lipoprotein (LDL), lowlevels of high-density lipoprotein(HDL), elevated levels of total cholesterol,and high levels of triglycerides,the doctor should, first of all, analyzewhether a change in lifestyle wouldhelp. Strict control of these parameters—keeping them within normalranges—will decrease mortality andmorbidity from cardiovascular complications.

Lifestyle changes should be adoptedto reduce such risk factors as smoking,hypertension, obesity, and diabetesmellitus. In addition to suggestinglifestyle changes, a pharmacist canadvise a patient to watch his or herweight by exercising and by honoring alow-cholesterol and low-saturated-fat-contentdiet and increasing intake ofsoluble fiber. If, however, such modificationsdo not show desired results interms of laboratory values for total cholesterol,LDL, HDL, and triglycerides, apatient should start medication therapywhile simultaneously keeping upwith the new lifestyle and diet.

Many therapeutic groups are usedfor the treatment of hypercholesterolemia,once lifestyle modificationsalone fail to work. One of the mostimportant groups is the 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA)reductase inhibitors, calledstatins. The older statins—such aslovastatin, pravastatin, and simvastatin—were derived from naturallyoccurring compounds, whereas neweragents—such as atorvastatin and rosuvastatin—were chemically designedand synthesized. Because hypercholesterolemiais a chronic condition,patients must take statins for a longperiod of time. Therefore, patients'compliance and safe administration ofthe medication play an important rolein treatment, especially among the elderlypopulation.

Statins inhibit the HMG-CoA reductaseenzyme, which acts as the catalystfor the formation of mevalonate fromHMG CoA (the rate-limiting step incholesterol synthesis). By blockingHMG-CoA reductase, statins can controlthe production of mevalonate andeventually control the amounts of cholesterolproduced in the body, while atthe same time up-regulating the LDLreceptors on the surface of liver cells.The processes described above lead to adecline in the level of cholesterol andthe removal of LDL cholesterol fromthe circulating blood. In addition,statins increase HDL cholesterol andlower triglycerides in the blood.Besides the lipid-lowering capabilities,this therapeutic group of drugs offersprotection against the growth of atheroscleroticplaque.

Like any other medications, HMGCoAreductase inhibitors have sideeffects. Some possible side effects are anincrease in hepatic aminotransferases,myalgia/rhabdomyolysis, and gastrointestinalintolerance. In addition,all statins have a category X pregnancyusage, so patients with chronic andactive liver disease and pregnantwomen should avoid using them.

The goal of this article is to discussother possible side effects, such as insomniaand cognitive changes. These particular2 side effects are especially importantfor the elderly population. Onceelderly patients are put on a statin, theytake it for a long period of time, and, inaddition, they may tend to have sleepdisturbances and cognitive problems.

The majority of other side effects arerelated to the chemical nature of thestatin group. Scientists like to describemedical compounds based on theirhydrophilic or lipophilic nature. Theseparameters play a very significant role inthe pharmacodynamic and pharmacokineticbehavior of every medication. Interms of lipophilic nature, lovastatin andsimvastatin are the most lipophilic, followedby atorvastatin, fluvastatin, andpravastatin. Rosuvastatin is a relativelynew statin, having a polar methane sulfonamidegroup, and it can be placedbetween fluvastatin and pravastatin.

The mechanism by which statinscause rhabdomyolysis is not knownyet. The lipophilic nature of medicalcompounds and the lowering of thecholesterol level in the blood, however,seem to play an important role in theoccurrence of this side effect. As statedabove, it has been determined thatHMG-CoA inhibitors block the productionof mevalonate, which leads to deficientproduction of coenzyme Q10,isopentenyl, and dolichols. Deficiencyof these 3 chemical compounds canlead to the muscle cell injury and toxicity.Predominantly lipophilic statinspenetrate muscle cell at a higher degreethan predominantly hydrophilic statins.In addition, it has been shown inmice that highly lipophilic statins havea pronounced effect in disturbing thenormal activity of myoblasts, the properperformance of which is especiallynecessary during muscle injury.

This month's FDA MedWatch 2005Safety Summary states that physiciansshould use extra caution when prescribingstatins, especially rosuvastatin,to patients with hypothyroidismand/or renal insufficiency.These patients have a greater risk forexperiencing myopathy, especiallywhen given a statin at higher-than-normaldoses, because the higherserum concentrations of the drugincrease the risk of myopathy.

Studies that have been conductedregarding cognitive effects of statinshave had controversial outcomes.Scientists believe that, by decreasingthe levels of cholesterol, statins mayslow down the formation of amyloidpeptide (A-beta). On the other hand,there have been reports that, in rarecases, patients on statin therapy experiencecognitive impairments, especiallyif they are taking highly lipophilicmedical compounds. In fact, somestudies indicate that high-lipophilicstatins can decrease cognitive function.The cognitive function can beinfluenced directly by statins—theones that pass the blood-brain barrier,particularly highly lipophilic medicalcompounds—or by a very low cholesterollevel in neuronal membranes.

Another atypical side effect of thestatins is insomnia. Although theyhave been observed, such side effectsas insomnia and decrease in cognitivefunction are still questionable. It isvery important for a pharmacist to suggesta less lipophilic member of thestatin group when dealing withpatients who have an existing orpotential condition of insomnia ordecreased cognitive function.

Dr. Motylev is a pharmacy manager in thehospital setting.