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REVIEW PAPER INTERNATIONAL JOURNAL OF PHARMACY AND PHARMACEUTICAL ANALYSIS (2017, VOl. 01(02) WWW.IJPPA.COM ISSN: 2394-1618 Page numbers:96-105 ISSN:XXXXX “A REVIEW ON ROSUVASTATIN”

AISWARYA S*, GOWRISANKAR N L, FARSENA A AND SREE LAKSHMI P S

*Department of Pharmaceutics, Prime College of Pharmacy, Erattayal, Palakkad-678551, Kerala, India

ABSTRACT Rosuvastatin is a new generation HMG-CoA reductase inhibitor which exhibits some unique pharmacologic and pharmacokinetic properties. It has low extra hepatic tissue penetration, low potential for CYP3A4 interactions and substantial LDL-C lowering capacity and therefore has distinct advantages. Present review provides an account of pharmacology of rosuvastatin, highlighting its efficacy and safety and a brief comparison with other . Keywords: Rosuvastatin, Cardiovascular risk, Statins, Low density lipoprotein .

*Address of the corresponding author: Aiswarya S, M.Pharm, Department of Pharmaceutics, Prime college of Pharmacy, Erattayal, Mobile: 8547053123, E-mail address: [email protected]

INTRODUCTION and the incidence of cardiovascular Cholesterol is a waxy, fat like substance disease. The associated morbidity and that is found in all cells of the body. Our mortality is positively correlated to low body needs some cholesterol to make density lipoprotein cholesterol (LDL) and hormones, vitamin D, and substances that inversely related to high density help you process nourishment. Our body lipoprotein cholesterol (HDL). [1, 2] makes all the it needs. Ischemic heart diseases are the leading Cholesterols go through our circulatory cause of mortality worldwide and system in little bundles called lipoprotein. constitute a major health burden. These bundles are made of fat within and According to world health organization proteins on the outside. Two sorts of statistics it accounts for 12.8% of death, lipoproteins convey cholesterol all with strokes and other cerebrovascular through your body. Low thickness disease accounting for 10.8 %. In United lipoproteins (LDL) and high thickness Kingdom, data from the Health survey for lipoproteins (HDL). Having sound levels England suggest that while mortality may of both sorts of lipoproteins is important. decline, morbidity Epidemiological studies have established continues to rise. Epidemiology studies a strong correlation between cholesterol have established a strong correlation

REVIEW PAPER INTERNATIONAL JOURNAL OF PHARMACY AND PHARMACEUTICAL ANALYSIS (2017, VOl. 01(02) WWW.IJPPA.COM ISSN: 2394-1618 Page numbers:96-105 ISSN:XXXXX between cholesterol and the incidence of ischemic heart disease patients, cardiovascular disease. The associated irrespective of the cholesterol morbidity and mortality is positively concentration. In addition to the correlated to low density lipoprotein beneficial cholesterol lowering effects, cholesterol and inversely related to high statins improve endothelial function, density lipoprotein cholesterol.[3, 4] enhance stability of atherosclerotic Statins are 3-hydroxy-3-methylglutaryl plaques, and inhibit inflammatory as well coenzyme A (HMG Co A) reductase as thrombogenic responses in arterial inhibitors that are effective in the walls. Furthermore extensive post reduction of total and LDL cholesterol. [5] marketing surveillance has shown that A number of large randomized control long term therapy is generally well trials have demonstrated unequivocally tolerated. [11] that lowering LDL-C particularly with The reduction in cardiovascular events statins reduces the risk of cardiovascular from statins therapy is proportional to deaths and events. [6] HMG CoA inhibitors the LDL-C reduction; larger reductions in have been shown to prevent initial LDL-C are associated with greater cardiovascular events and subsequent reduction in cardiovascular events, so cardiovascular events in ischemic heart more potent statins results in greater disease patients, irrespective of the cardiovascular risk reduction. [12] cholesterol concentration. [7,8] In addition In this review, we outline the to the beneficial cholesterol lowering pharmacology of rosuvastatin, highlights effects, statins improve endothelial its effects on cholesterol level, sides function, enhance stability of effects and contraindications. atherosclerotic plaques, and inhibit inflammatory as well as thrombogenic DRUG CLASS AND MECHANISM responses in arterial walls. [9] Rosuvastatin is an oral drug for lowering Furthermore extensive post marketing blood cholesterol levels. surveillance has shown that long term It belongs to a class of drug called HMG- statin therapy is generally well tolerated. CoA reductase inhibitors, more commonly [10] referred to as statins. Other drugs in this The reduction in cardiovascular events class include; from unequivocally that lowering LDL-C * (Zocor) particularly with statins reduces the risk * (Mevacor) of cardiovascular deaths and events. * (Pravachol) HMG CoA inhibitors have been shown to *Atrovastatin (Lipitor) prevent initial cardiovascular events and * (Lescol) subsequent cardiovascular events in

REVIEW PAPER INTERNATIONAL JOURNAL OF PHARMACY AND PHARMACEUTICAL ANALYSIS (2017, VOl. 01(02) WWW.IJPPA.COM ISSN: 2394-1618 Page numbers:96-105 ISSN:XXXXX These drugs reduce cholesterol levels by inhibiting HMG-CoA reductase, an The oral of rosuvastatin is that produces cholesterol in the lever. 20 %, which is comparable to Rosuvastatin and other statins lower , pravastatin and fluvastatin, blood total cholesterol as well as blood and qualitatively higher than simvastatin LDL cholesterol levels. LDL cholesterol is and lovastatin. After a single oral dose the the bad type of cholesterol that increases peak plasma concentration is reached at 5 the risk of coronary artery disease and hours. This is longer than other HMG-CoA heart attacks. Lowering LDL cholesterol inhibitors which achieve maximum levels shows the progression of coronary plasma concentrations in less than 3 artery disease and may even reverse it. hours. In compiled data from Statins also increase HDL cholesterol, the pharmacokinetic trials, the peak plasma good type of cholesterols, and reduce concentration and area under the . concentration time curve show a largely linear relationship as the dose of PHARMACOLOGY rosuvastatin increases from 5 to 80 mg. Rosuvastatin is a fully synthetic HMG-CoA Food intake decreases the rate of reductase inhibitor. Other HMG-CoA absorption of rosuvastatin by 20 % but reductase inhibitors are either natural, not the extent of absorption. This does mevinic acid derived (lovastatin, not reduce the cholesterol lowering simvastatin, pravastatin ) or synthetic, potency; therefore rosuvastatin can be heptenoic acid derived (atorvastatin, taken with or without food, and in the fluvastatin). Rosuvastatin belongs to a morning or evening. [13-18] new generation of methane • Approximately 90 % of rosuvastatin is sulphonamide •pyrimidine and N- protein bound mainly to albumin; other methane sulfonyl pyrrole-substituted 3, statins have approximately 95 % protein 5-dihydroxy-heptenoates. Although the binding except pravastatin which has a characteristic statin pharmacophore lower protein binding of 50 %. The mean remains similar to other statins, the volume of distribution is 134 litres in addition of a stable polar methane- steady state. Rosuvastatin is less sulphonamide group provides low lipophilic than other statins such as lipophilicity and enhanced ionic atorvastatin and simvastatin but more interaction with HMG-CoA reductase lipophilic than pravastatin. Penetration of enzyme thus improving its binding statins into extra-hepatic tissues occurs affinity to this enzyme. by passive diffusion and is dependent on their lipophilicity. This has implications on their muscle safety as increased

REVIEW PAPER INTERNATIONAL JOURNAL OF PHARMACY AND PHARMACEUTICAL ANALYSIS (2017, VOl. 01(02) WWW.IJPPA.COM ISSN: 2394-1618 Page numbers:96-105 ISSN:XXXXX was reported in patients rosuvastatin is responsible for on lipophilic agents like and approximately 90 % of plasma HMG-CoA lovastatin. [19, 20] inhibitor activity. Rosuvastatin is less Human hepatocyte studies indicate that likely to cause metabolic drug to drug rosuvastatin is a poor substrate for interactions since it has limited metabolism by cytochrome P450 and metabolism by CYP isoenzymes. Other hence 90 % of the drug is excreted HMG-CoA reductase inhibitors such as unchanged. CYP2C9 is the main atorvastatin and simvastatin are isoenzyme involved in metabolism with metabolised via CYP3A4. Their plasma minimal effect from CYP2C19. concentrations are increased by Rosuvastatin is metabolised to an N- inhibitors of CYP3A4 such as itraconazole, desmethyl metabolite which is less potent protease inhibitors and macrolide than the parent drug in inhibiting HMG- antibiotics. CoA reductase activity. The parent drug

Table 1. Compares the pharmacokinetics of different statins

Parameter Rosuva Atorva Simva Prava Fluva Pitava Lova statin statin statin statin statin statin statin Tmax (h) 3 2–3 1.3–2.4 0.9–1.6 0.4–2.1 0.6–0.8 2–4 Bioavailability 20 12 5 18 24 80 5 Lipophilicity No Yes Yes No Yes Yes Yes Protein 88 80–90 94–98 43–55 .98 96 95 binding Minimal Sulfation CYP2C9 Minimal Biliary Metabolism CYP2C19 CYP3A4 CYP3A4 CYP2C9 CYP2C8 CYP3A4 & Biliary CYP2C9 excretion Active Active Metabolites Active Active Inactive Inactive Active (minor) (minor) T1/2 (h) 19 15 2–3 1.3–2.8 1.2 10–11 2.9 Urinary 10 2 13 20 6 NA 10 excretion Fecal 90 70 58 71 90 90 83 excretion

REVIEW PAPER INTERNATIONAL JOURNAL OF PHARMACY AND PHARMACEUTICAL ANALYSIS (2017, VOl. 01(02) WWW.IJPPA.COM ISSN: 2394-1618 Page numbers:96-105 ISSN:XXXXX PHARMACODYNAMICS BIOAVAILIBILITY Rosuvastatin competitively inhibits HMG- CoA reductive enzyme selectively and 1. It is observed that the absolute reversibly. This enzyme converts HMG- bioavailability of rosuvastatin is ready 20 CoA to mevalonic acid in the cholesterol % and Cmax is reached in 3 to 5 hours. biosynthetic pathway which is the rate 2. Rosuvastatin is metabolized primarily limiting step in cholesterol synthesis. by CYP2C9 and not extensively Rosuvastatin there-fore decreases hepatic metabolized; close to 10 is recovered as sterol synthesis, which, in turn, leads to a matter. It is excreted in excreta (90 %) decreased concentration of hepatocellular primarily and therefore the elimination cholesterol. Hepatocytes respond to this half-life is close to 19 hours. [24, 25] decreased intracellular cholesterol concentration by increased synthesis of DRUG INTERACTIONS LDL receptors to enhance hepatic LDL The following drugs can have negative reuptake from the circulation. The net interactions with rosuvastatin and should result of this process is an increased be discussed with the prescribing doctor: fractional catabolism of LDL which [26] reduces serum LDL-C concentration and • Coumarin ('blood total cholesterol. [21, 22] thinners', e.g. ) can affect the As observed with other statins, removal of rosuvastatin rosuvastatin has pleiotropic effects • Drugs that may decrease the levels or independent of HMG-CoA reductase activity of endogenous inhibition. These include improvements hormones, e.g. , in endothelial function, anti- , and . inflammatory, antithrombotic and anti- • Additional medications for high oxidant effects. Rosuvastatin and other cholesterol such as , statins improve endothelial function by , , and increasing the production of endothelial (when taken in lipid-modifying doses nitric oxide and reducing the production of 1 g/day and above) of oxygen derived free radicals. This in • Specific protease inhibitors including turn reduces endothelial dysfunction that (when taken with has been implicated in atherosclerosis. ), lopinavir/ritonavir and Rosuvastatin reduces high sensitivity C . reactive protein (hsCRP) which is a • Alcohol intake should be reduced marker of inflammation and an while on rosuvastatin in order to independent cardiovascular risk decrease risk of developing predictor and other inflammatory damage Aluminum and magnesium markers. Rosuvastatin inhibits platelet hydroxide antacids should not be aggregation to leukocytes which inhibit taken within two hours of taking formation of clots in injured endothelium. rosuvastatin [23] • Co-administration of rosuvastatin with may increase the risk of rhabdomyolysis and myopathy. [27]

REVIEW PAPER INTERNATIONAL JOURNAL OF PHARMACY AND PHARMACEUTICAL ANALYSIS (2017, VOl. 01(02) WWW.IJPPA.COM ISSN: 2394-1618 Page numbers:96-105 ISSN:XXXXX • SIDE EFFECTS AND • Itching CONTRAINDICATIONS • Difficulty breathing or swallowing Side effects are uncommon. The • Swelling of the face, throat, tongue, following side effects should be reported lips, eyes, hands, feet, ankles, or to the prescribing doctor if they persist or lower legs get worse; • Hoarseness • • Numbness or tingling in fingers or • toes • Sleeplessness Rosuvastatin has multiple • Depression contraindications, conditions that • Joint pain warrant withholding treatment with • rosuvastatin, including hypersensitivity • Memory loss or forgetfulness to rosuvastatin or any component of the • formulation, active liver disease, elevation The following rare side effects are more of serum transaminases, , or serious. Like all statins, rosuvastatin can breastfeeding. Rosuvastatin must not be possibly cause myopathy, taken while pregnant as it can cause rhabdomyolysis. Stop taking rosuvastatin serious harm to the unborn baby. In the and contact the prescribing doctor if any case of breastfeeding, it is unknown of these occur: whether rosuvastatin is passed through • Muscle pain, tenderness, or breast milk, but due to the potential of weakness disrupting the infant's lipid metabolism, • Lack of energy patients should not breast feed while on • rosuvastatin. • • : yellowing of the skin or MORE SERIOUS SIDE EFFECTS eyes The more serious side effects include; • Dark colored, or foamy urine *Liver failure * Muscles breakdown • Pain in the upper right part of the (rhabdomyolysis) *Kidney failure abdomen Severe liver diseases of liver • failure caused by statins are very rare. • Extreme tiredness More often, statins cause mild • Weakness abnormalities in liver tests due to injury • Unusual bleeding or bruising to the liver. The abnormalities usually • Loss of appetite disappear with continued therapy, but if • Flu-like symptoms the level is over three times the upper • , , or other signs of limit of normal or baselines, practitioners usually stop the statins. Liver function If any signs of an allergic reaction tests should be performed at the develop, contact an emergency medical beginning of treatment then as needed service immediately thereafter. •

REVIEW PAPER INTERNATIONAL JOURNAL OF PHARMACY AND PHARMACEUTICAL ANALYSIS (2017, VOl. 01(02) WWW.IJPPA.COM ISSN: 2394-1618 Page numbers:96-105 ISSN:XXXXX Rhabdomyolysis is a very rare but serious EFFECTS ON CHOLESTROL LEVEL side effect of statins therapy. When used The effects of rosuvastatin on LDL alone the frequency of rhabdomyolysis cholesterol are dose-related. Higher doses due to statins is less than one percent. were more efficacious in improving the Rhabdomyolysis is a process in which lipid profile of patients with there is severe injury to muscles leading than milligram- severe pain and the release of muscles equivalent doses of atorvastatin and protein into the blood. Myoglobin may milligram-equivalent or higher doses of cause kidney failure. To prevent the simvastatin and pravastatin. [30, 31] occurrence of rhabdomyolysis, patients Meta-analysis showed that rosuvastatin is taking statins who develop unexplained able to modestly increase levels of HDL muscle pain, weakness, or tenderness cholesterol as well, as with other statins. should report the symptoms to their A 2014 Cochrane review determined health care professionals. there was good evidence for rosuvastatin Rosuvastatins may cause reversible lowering non-HDL levels linearly with increase in the amount of protein dose HDL increases by 7 % with no dose excreted by the kidney, and in some effect noted. patients kidney failure has occurred as a result. The effects depend on the dose and WHY THIS MEDICATION IS occur more often at 40 mg dose. Statins PRESCRIBED? have been associated with increase in Rosuvastatin is used together with diet, HbA1c and fasting serum glucose levels, weight loss, and exercise to reduce to risk as occurs with . [28] of heart attack and stroke and to decrease the chance that heart surgery will be MEDICAL USE needed in people who are at risk of Rosuvastatin is employed in conjunction developing heart disease. Rosuvastatin is with a correct diet to assist lower ‘bad’ also used to decrease the amount of cholesterol and fats and lift good cholesterol such as low –density cholesterol within the blood; it belongs to lipoprotein and cholesterol and a gaggle of medicine referred to as statins. in the blood and to increase It works by reducing the quantity of the amount of high-density lipoprotein cholesterol created by the liver. Lowering and cholesterol in the blood. Rosuvastatin bad cholesterol and triglyceride and may also be used to decrease the amount raising good cholesterol decreases the of cholesterol and other fatty substance in danger of cardiovascular diseases and the blood in children and teenagers 10 to helps to stops strokes and heart attacks 17 years of age who have familial ingestion a correct diet , alternative style heterozygous hypercholesterolemia. change which will facilities this Rosuvastatin is in a class of medication medication works higher embrace elbow called HMG-CoA reductase inhibitors. It grease, losing weight if overweight , and works by slowing the production of stopping smoking. [29] cholesterol in the body to decrease the amount of cholesterol that may build up on the walls of the arteries and block

REVIEW PAPER INTERNATIONAL JOURNAL OF PHARMACY AND PHARMACEUTICAL ANALYSIS (2017, VOl. 01(02) WWW.IJPPA.COM ISSN: 2394-1618 Page numbers:96-105 ISSN:XXXXX blood flow to the heart, brain, and other REFERENCE parts of the body. [32] Accumulation of cholesterol and fats 1. Ohvo-Rekila H, Ramsetedt B, along the walls of your arteries a process Leppimaki P. Slotte JP. Cholesterol known as atherosclerosis which interactions with phospholipids in decreases blood flow and therefore, the membranes. Prog Lipid Res. 2002; oxygen supply to your heart , brain, and 41: 66-97. other parts of our body. Lowering your 2. Olson RE. Discovery of the blood level of cholesterol and fats with lipoproteins, their role in fat rosuvastatin has been shown to prevent transport and their significance as heart disease, angina (chest pain), strokes risk factors. J Nutr. 1998; 128:439S- and heart attack. [33] 443S. 3. Chenz, Peto r, Collins R , Macmahon HOW TO USE ROSUVASTATIN s. serum cholesterol concentration Take this medication orally with or while and coronary heart disease in not food as directed by your, typically population with low cholesterol once daily. The dose is predicated on your concentration . BMJ. 1991; 303; 276- medical condition, response to treatment, 82. age, and alternative medication you’ll be 4. Heart Protection Study Collaborative taking take care to inform your doctor Group. MRC/BHF Heart Protection and health professional regarding all the Study of cholesterol lowering with merchandise you utilize. It’s vital to still simvastatin in 20,536 high-risk follow your doctor’s recommendation individuals: a randomised placebo- regarding diet and exercise. It is going to controlled trial. Lancet. 2002; take up to four weeks before you get the 360:7–22. complete advantage of this drug. [34-37] 5. Colhoun HM, Betteridge DJ, Durrington PN. Primary prevention CONCLUSION of cardiovascular disease with In conclusion rosuvastatin is a effective atorvastatin type 2 diabetes in the and safe statin which is ideal second line Collaborative Atorvastatin Diabetes treatment for most patients requiring Study (CARDS): multicentre primary or secondary prevention. When randomized placebo-controlled trial. there is a history of previous statin in Lancet. 2004; 364:685–96. tolerance or multiple drug therapy, low 6. Koren MJ, Hunninghake DB. dose rosuvastatin may be considered. For ALLIANCE Investigators. Clinical patient group at high risk where stringent outcomes in managed-care patients – LDL cholesterol reduction is envisaged, with coronary heart disease treated rosuvastatin should be considered as aggressively in lipid-lowering potential first line treatment. Its benefits disease management clinics: the against cost in patients with lower ALLIANCE study. J Am Coll Cardiol. cardiovascular risk remain an issue of 2004; 44:72–9. debate. 7. Durrington PN. Hyperlipidemia: diagnosis and management. 3rd

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