Which statins are lipophilic

Drugs can be classified as hydrophilic or lipophilic depending on their ability to dissolve in water or in lipid-containing media. The predominantly lipophilic statins simvastatin, fluvastatin, pitavastatin, lovastatin and atorvastatin can easily enter cells, whereas hydrophilic statins rosuvastatin and pravastatin present greater hepatoselectivity. 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. The authors found that pravastatin 40 mg and simvastatin 20 mg were similarly well tolerated, with 2. The former hypothesis of a systematically reduced muscular risk in association with hydrophilic statins was based on in vitro data demonstrating a lower cytotoxicity on C2C12 myotubes for hydrophilic statins than lipophilic statins, 10 and in particular on the consideration that hydrophilic statins penetrate skeletal muscles less easily due to lower passive diffusion.

For instance, statins are substrates of the organic anion transporting polypeptide OATP transport proteins, which are involved in the hepatic and muscular uptake of statins. In addition, genetic polymorphism in the SLCO1B1 gene, which encodes the OATP1B1 hepatic uptake transporter, has been linked to reduced transport activity and increased plasma statin levels.

Differences in the metabolism of statins, i. In this study, we observed an absolute risk of muscular events of 1. Other observational studies reported higher risks for patients in the routine care setting; the PRIMO study, a countrywide survey including 7, patients with hyperlipidemia and high-dosage statin therapy in France, reported an absolute risk of muscular events of We defined muscular events based on Read codes recorded in electronic primary care records, whereas the PRIMO study conducted standardized interviews, and the Swedish cohort study used patient questionnaires to specifically enquire about muscular symptoms.

However, any such outcome misclassification was most likely non-differential and thus, if at all, biased HRs towards unity. In the comparison of low-intensity statin therapy with pravastatin vs simvastatin, more pravastatin users The imbalance of censoring reasons may be related to the intensified target levels for low-density lipoprotein cholesterol published in the European guidelines in 39 or the British guidelines in When we restricted the comparison of pravastatin vs simvastatin to statin users with a CED between and , i.

Some additional limitations need to be considered. First, small sample size in the secondary prevention cohorts prevented calculation of reliable risk estimates. We therefore focused on the study results from the primary prevention cohorts, though we did present all findings for completeness. Second, the dose ratios at which statin doses are comparable in efficacy may vary depending on the literature source.

Third, rosuvastatin was the only study drug that was newly licensed in the UK after , i. However, when we restricted the analysis of rosuvastatin vs atorvastatin to users with a CED 2 years after licensing of the former, the HR of muscular events did not change.

Finally, after PS matching, baseline characteristics were balanced between treatment groups compared, but not necessarily between cohorts. Thus, indirect comparison of the muscular risk of rosuvastatin vs simvastatin, both used for the moderate- to high-intensity statin therapy, was not possible. In conclusion, this study of UK-based primary health care data does not suggest a systematically reduced risk of muscular events for hydrophilic statins when compared with lipophilic statins at comparable lipid-lowering doses.

Low-intensity statin therapy with hydrophilic pravastatin vs lipophilic simvastatin and moderate- to high-intensity statin therapy with lipophilic atorvastatin vs hydrophilic rosuvastatin and lipophilic simvastatin may be associated with a decreased muscular risk. However, further studies that will replicate our findings are warranted before implications for clinical practice are discussed.

National Institute for Health and Care Excellence. Clinical guideline CG - Cardiovascular disease: risk assessment and reduction, including lipid modification. Published Accessed November 25, Eur Heart J. Article PubMed Google Scholar. Narrative review: statin-related myopathy. Ann Intern Med. Statin myopathy: A review of recent progress. Curr Opin Rheumatol. Muscle- and skeletal-related side-effects of statins: tip of the iceberg?. Eur J Prev Cardiol.

Risk factors and drug interactions predisposing to statin-induced myopathy: implications for risk assessment, prevention and treatment. Drug Saf. Intolerance to statins: Mechanisms and management. Diabetes Care. Turner RM, Pirmohamed M. Biochim Biophys Acta. Google Scholar. Discovery Netherlands Investigators. Int J Clin Pract. How Clinical Practice Research Datalink data are used to support pharmacovigilance. Ther Adv Drug Saf.

Electronic Health Record Databases. In: Pharmacoepidemiology. Sixth edit. Hoboken, NJ: Wiley-Blackwell; Int J Epidemiol. Electronic medicines compendium. Crestor 10 mg film-coated tablets - Summary of Product Characteristics. Accessed February 11, Discontinuation and restarting in patients on statin treatment: Prospective open cohort study using a primary care database.

Can J Cardiol. Dalakas MC. Toxic and drug-induced myopathies. Hydrophilic statins include pravastatin and fluvastatin. Protein binding also plays a role in the potential for adverse effects of statins. Statins other than pravastatin are highly protein bound. Decreases in serum protein levels, often seen in frail older adults may result in higher concentrations—and higher toxicity.

Pravastatin, fluvastatin and rosuvastatin, the hydrophilic statins , are also the three statins not metabolized by the Cytochrome p 3A4 enzyme CYP3A4 , though fluvastatin and, to a lesser extent, rosuvastatin, which is largely excreted unchanged, 3 are metabolized by CYP2C9.

Pravastatin is not metabolized by the cytochrome P system at all and has the lowest risk of drug-drug interactions of all the statins. The medications most likely to affect statin metabolism and thereby increase the risk of adverse effects such as myopathy include, but are not limited to: amiodarone; fluconazole, ketoconazole and other azole anti-fungals; the non-dihydropyridine calcium channel blockers- diltiazem and verapamil; cyclosporine; danazol; the anti-arrhythmic dronedarone; erythromycin and other macrolide antibiotics; nefazodone; phenytoin; and the protease inhibitors.

Grapefruit juice also inhibits CYP 3A4 and can potentiate statin myotoxicity. The potential for toxicity works both ways. Statins co-administered with warfarin can result in elevated INRs. They can also contribute to phenytoin and digoxin toxicity when given with these medications.

While statins as a class of drugs are generally safe, they are associated with two primary types of adverse effects: asymptomatic elevation of liver enzymes, and myopathies.

There is no evidence that the incidence of these two side effects are associated with each other; that is, patients with elevations of liver enzymes are not more likely to experience myopathies, or vice versa.

All statins are associated with elevations of alanine aminotransferase ALT and aspartate aminotransferase AST up to three times the upper limit of normal. For patients with persistent elevations of liver enzymes, discontinuation or lowering the statin dose almost always effects a return of liver enzyme levels to normal. Myopathy is the most common side effect associated with the use of statins and, since the withdrawal of cerivastatin Baycol from the market in after its use resulted in a large number of cases of rhabdomyolisis, myopathy is also the side effect of most concern to clinicians.

Definitions of the term myopathy vary. Myopathy —a general term referring to any disease of muscles; myopathies can be acquired or inherited and can occur at birth or later in life. Myalgia —muscle ache or weakness without creatine kinase CK elevation. Myositis —muscle symptoms with increased CK levels. Rhabdomyolysis — muscle symptoms with marked CK elevation typically substantially greater than 10 times the upper limit of normal [ULN] and with creatinine elevation usually with brown urine and urinary myoglobin.

For the purposes of this review, myopathy is used in this more general sense of any muscle-related disorder. Older age, along with small size, female gender, preexisting liver, renal or endocrine disease are all patient-dependent risks for statin induced myopathy. Any statin can cause any muscle symptom-- from mild myalgias to rhabdomyolisis. Fluvastatin and pravastatin, two relatively low potency statins that are not metabolized by CYP3A4, carry the lowest risk of rhabdomyolisis; high dose simvastatin 80 mg carries the highest risk.

Along with high dosing, drug-drug interactivity highly impacts the myopathic potential of statins. When statins which are metabolized by CYP3A4 atorvastatin, lovastatin, and simvastatin , are given with CYP3A4 inhibitors, their metabolism is decreased, and the potential for toxicity increases.

Atorvastatin is less affected by CYP3A4 inhibitors than lovastatin or simvastatin. In addition to CYP3A4 effects, the risk for myopathy is also compounded when statins are given with other medications which cause myopathy. Cyclosporin and danazol fit into this category as well as being CYP3A4 inhibitors. In efforts to synergize lipid lowering effects, non-statin lipid lowering agents are often co-administered with statins.

Unfortunately some of these medications such as niacin and fibric acid derivatives also cause myopathy—fenofibrate less so than gemfibrozil. Alcohol overuse is also associated with an increased incidence of myopathy—both independently and in combination with statins. It was especially toxic when prescribed with a second lipid lowering drug, gemfibrozil.