Atorvastatin

The primary uses of atorvastatin are for the treatment of dyslipidemia and for the prevention of cardiovascular disease. The effect is dose-dependent and is amplified at higher doses. Close monitoring of liver function tests is required when high doses are used • Alongside other lifestyle changes in primary and secondary prevention of angina • Myocardial infarction and stroke prevention in people with type 2 diabetes The SATURN trial, which compared the effects of high-dose atorvastatin and rosuvastatin, also confirmed these findings. Kidney disease Atorvastatin may have modest renal protective effects at higher daily oral doses, as shown by a slowed progression or maintenance of the estimated glomerular filtration rate (eGFR) and a reduction in urinary protein excretion. Prior to contrast medium (CM) administration, pre-treatment with atorvastatin therapy can reduce the risk of contrast-induced acute kidney injury (CI-AKI) in people with pre-existing chronic kidney disease (CKD) (eGFR 3.75 mmol/L), findings are inconsistent and potentially misleading. Evidence suggests that LDL-C levels are not a reliable predictor of mortality in the hemodialysis population given the complex interplay of patient factors in ESRD. Therefore, LDL-C levels cannot be considered a true predictor of composite risk. Additionally, the impact and relevance of hemodialysis on statin levels and efficacy were not addressed in these trials. • Liver impairment: Increased drug levels can be seen in people with advanced cirrhosis. ==Contraindications==

• Active liver disease: cholestasis, hepatic encephalopathy, hepatitis, and jaundice • Pregnancy: Atorvastatin is classified as a pregnancy category X medication by the U.S. Food and Drug Administration (FDA), indicating that it is contraindicated during pregnancy due to evidence of potential harm to the fetus and a lack of demonstrated benefit in this population. While limited human data suggest that atorvastatin is unlikely to cause major congenital anomalies, some studies have reported an association with adverse pregnancy outcomes such as low birth weight and preterm labor. Statins, including atorvastatin, act by inhibiting HMG-CoA reductase, a key enzyme in the biosynthesis of cholesterol. Cholesterol is essential for fetal development, particularly during early embryogenesis, as it plays a critical role in cell membrane formation and steroid hormone production. Due to these concerns, atorvastatin should be discontinued prior to conception or as soon as pregnancy is confirmed. • Breastfeeding: Small amounts of other statin medications have been found to pass into breast milk, although atorvastatin has not been studied specifically. • Markedly elevated CPK levels or if a myopathy is suspected or diagnosed after dosing of atorvastatin has begun. Very rarely, atorvastatin may cause rhabdomyolysis, and it may be very serious leading to acute kidney injury due to myoglobinuria. When rhabdomyolysis is suspected or diagnosed, atorvastatin therapy is discontinued immediately. The likelihood of developing a myopathy is increased by the co-administration of cyclosporine, fibric acid derivatives, erythromycin, niacin, and azole antifungals. ==Side effects==

Major • Type 2 diabetes is observed in a small number of people, and is an uncommon class effect of all statins. It appears it may be more likely in people who were already at a higher risk of developing diabetes before starting a statin due to multiple risk factors, for example raised fasting glucose levels. However, the benefits of statin therapy in preventing fatal and non-fatal stroke, fatal coronary heart disease, and non-fatal myocardial infarction are significant. A 2010 meta-analysis demonstrated that every 255 people treated with a statin for four years produced a reduction of 5.4 major coronary events and induced only one new case of diabetes. However, this increase was not related to statin therapy in 90% of cases in a large meta-analysis of randomized controlled trials. Statin induced rhabdomyolysis, as with other statin associated muscle symptoms, occurs most commonly in the first year of treatment but can occur at any time during treatment. Elevations threefold greater than normal were recorded in 0.5% of people treated with atorvastatin 10 mg-80 mg rather than placebo. Usage instructions in package inserts for this statin define the requirement that hepatic function be assessed with laboratory tests before beginning atorvastatin treatment and repeated periodically as clinically indicated—usually a clinicians' judgement. Package inserts for this statin recommend actions should liver abnormalities be detected. Ultimately, this is the judgment of the prescribing physician. Increased fasting blood glucose Atorvastatin has been associated with a small increase in fasting blood glucose levels over a 2-year period, particularly in patients with type 2 Diabetes, however evidence is conflicting and clinical significance of this increase has not been determined. Regular blood glucose monitoring may be advised in patients with type 2 Diabetes. Cognitive While rare cases of reversible memory loss and confusion have been reported with statin use, including atorvastatin, multiple systematic review and meta-analyses have found no consistent evidence of a causal relationship. Current evidence, including large-scale observational studies and randomised trials, supports the continued use of atorvastatin, as its cardiovascular and cerebrovascular benefits outweigh the unproven risks related to cognition. Pancreatitis A 2012 meta-analysis found that statin therapy might reduce the risk of pancreatitis in people with normal or mildly elevated blood triglyceride levels. Erectile dysfunction Statins seem to have a positive effect on erectile dysfunction. Interactions Co-administration of atorvastatin with one of CYP3A4 inhibitors such as itraconazole, Niacin also is proved to increase the risk of myopathy or rhabdomyolysis. In contrast to some other statins, atorvastatin does not interact with warfarin concentrations in a clinically meaningful way (similar to pitavastatin). Small studies (using mostly young participants) examining the effects of grapefruit juice consumption on mainly lower doses of atorvastatin have shown that grapefruit juice increases blood levels of atorvastatin, which could increase the risk of adverse effects. No studies assessing the impact of grapefruit juice consumption have included participants taking the highest dose of atorvastatin (80 mg daily), A few cases of myopathy have been reported when atorvastatin is given with colchicine. ==Mechanism of action==

As with other statins, atorvastatin is a competitive inhibitor of HMG-CoA reductase. Unlike most others, however, it is a completely synthetic compound. HMG-CoA reductase catalyzes the reduction of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) to mevalonate, which is the rate-limiting step in hepatic cholesterol biosynthesis. Inhibition of the enzyme decreases de novo cholesterol synthesis, increasing expression of low-density lipoprotein receptors (LDL receptors) on hepatocytes. This increases LDL uptake by the hepatocytes, decreasing the amount of LDL-cholesterol in the blood. Like other statins, atorvastatin also reduces blood levels of triglycerides and slightly increases levels of HDL-cholesterol. In people with acute coronary syndrome, high-dose atorvastatin treatment may play a plaque-stabilizing role. At high doses, statins have anti-inflammatory effects, incite reduction of the necrotic plaque core, and improve endothelial function, leading to plaque stabilization and, sometimes, plaque regression. Pharmacodynamics The liver is the primary site of action of atorvastatin, as this is the principal site of both cholesterol synthesis and LDL clearance. It is the dosage of atorvastatin, rather than systemic medication concentration, which correlates with extent of LDL-C reduction. ==Pharmacokinetics==

Absorption Atorvastatin undergoes rapid absorption when taken orally, with an approximate time to maximum plasma concentration (Tmax) of 1–2 h. The absolute bioavailability of the medication is about 14%, but the systemic availability for HMG-CoA reductase activity is approximately 30%. Atorvastatin undergoes high intestinal clearance and first-pass metabolism, which is the main cause for the low systemic availability. Administration of atorvastatin with food produces a 25% reduction in Cmax (rate of absorption) and a 9% reduction in AUC (extent of absorption), although food does not affect the plasma LDL-C-lowering efficacy of atorvastatin. Evening dose administration is known to reduce the Cmax and AUC by 30% each. However, time of administration does not affect the plasma LDL-C-lowering efficacy of atorvastatin. Distribution The mean volume of distribution of atorvastatin is approximately 381 L. It is highly protein bound (≥98%), and studies have shown it is likely secreted in human breastmilk. Metabolism Atorvastatin metabolism is primarily through cytochrome P450 3A4 hydroxylation to form active ortho- and parahydroxylated metabolites, as well as various beta-oxidation metabolites. The ortho- and parahydroxylated metabolites are responsible for 70% of systemic HMG-CoA reductase activity. The ortho-hydroxy metabolite undergoes further metabolism via glucuronidation. As a substrate for the CYP3A4 isozyme, it has shown susceptibility to inhibitors and inducers of CYP3A4 to produce increased or decreased plasma concentrations, respectively. This interaction was tested in vitro with concurrent administration of erythromycin, a known CYP3A4 isozyme inhibitor, which resulted in increased plasma concentrations of atorvastatin. It is also an inhibitor of cytochrome 3A4. Excretion Atorvastatin is primarily eliminated via hepatic biliary excretion, with less than 2% recovered in the urine. Bile elimination follows hepatic and/or extrahepatic metabolism. There does not appear to be any entero-hepatic recirculation. Atorvastatin has an approximate elimination half-life of 14 hours. Noteworthy, the HMG-CoA reductase inhibitory activity appears to have a half-life of 20–30 hours, which is thought to be due to the active metabolites. Atorvastatin is also a substrate of the intestinal P-glycoprotein efflux transporter, which pumps the medication back into the intestinal lumen during medication absorption. In hepatic insufficiency, plasma concentrations of atorvastatin are significantly affected by concurrent liver disease. People with Child-Pugh Stage A liver disease show a four-fold increase in both Cmax and AUC. People with Child Pugh stage B liver disease show a 16-fold increase in Cmax and an 11-fold increase in AUC. Geriatric people (>65years old) exhibit altered pharmacokinetics of atorvastatin compared to young adults, with mean AUC and Cmax values that are 40% and 30% higher, respectively. Additionally, healthy elderly people show a greater pharmacodynamic response to atorvastatin at any dose; therefore, this population may have lower effective doses. ==Pharmacogenetics==

Several genetic polymorphisms may be linked to an increase in statin-related side effects with single nucleotide polymorphisms (SNPs) in the SLCO1B1 gene showing a 45 fold higher incidence of statin related myopathy than people without the polymorphism. There are several studies showing genetic variants and variable response to atorvastatin. The polymorphisms that showed genome wide significance in Caucasian population were the SNPs in the apoE region; rs445925, rs7412, rs429358 and rs4420638 which showed variable LDL-c response depending on the genotype when treated with atorvastatin. Another genetic variant that showed genome wide significance in Caucasians was the SNP rs10455872 in the LPA gene that lead to higher Lp(a) levels which cause an apparent lower LDL-c response to atorvastatin. These studies were in Caucasian population, more research with a large cohort need to be conducted in different ethnicities to identify more polymorphisms that can affect atorvastatin pharmacokinetics and treatment response. ==Chemical synthesis==

approach). The first synthesis of atorvastatin at Parke-Davis that occurred during drug discovery was racemic followed by chiral chromatographic separation of the enantiomers. An early enantioselective route to atorvastatin made use of an ester chiral auxiliary to set the stereochemistry of the first of the two alcohol functional groups via a diastereoselective aldol reaction. Once the compound entered pre-clinical development, process chemistry developed a cost-effective and scalable synthesis. • a convergent synthesis, where the formation of the pyrrole ring with Paal-Knorr cyclocondensation replaced the dipolar [3 + 2] cycloaddition from the earlier routes. The atorvastatin calcium complex involves two atorvastatin ions, one calcium ion and three water molecules. ==History==

Bruce Roth, who was hired by Warner-Lambert as a chemist in 1982, had synthesized an "experimental compound" codenamed CI 981—later called atorvastatin. It was first made in August 1985. Warner-Lambert management was concerned that atorvastatin was a me-too version of rival Merck & Co.'s orphan drug lovastatin (brand name Mevacor). Mevacor, which was first marketed in 1987, was the industry's first statin and Merck's synthetic version—simvastatin—was in the advanced stages of development. In 1996, Warner-Lambert entered into a co-marketing agreement with Pfizer to sell Lipitor, and in 2000, Pfizer acquired Warner-Lambert for $90.2billion. By 2003, Lipitor had become the best selling pharmaceutical in the United States. and $13 billion a year at its peak, Lipitor alone "provided up to a quarter of Pfizer Inc.'s annual revenue for years." == Society and culture ==

Economics Atorvastatin is relatively inexpensive. Under provisions of the Patient Protection and Affordable Care Act (PPACA) in the United States, health plans may cover the costs of atorvastatin 10 mg and 20 mg for adults aged 40–75 years based on United States Preventive Services Task Force (USPSTF) recommendations. Some plans only cover other statins. Brand names Atorvastatin calcium tablets are sold under the brand name Lipitor. Pfizer also packages the medication in combination with other medications, such as atorvastatin/amlodipine. Pfizer's U.S. patent on Lipitor expired on 30 November 2011. Initially, generic atorvastatin was manufactured only by Watson Pharmaceuticals and India's Ranbaxy Laboratories. Prices for the generic version did not drop to the level of other generics—$10 or less for a month's supply—until other manufacturers began to supply the medication in May 2012. In other countries, atorvastatin calcium is made in tablet form by generic medication makers under various brand names including Atoris, Atorlip, Atorva, Atorvastatin Teva, Atorvastatina Parke-Davis, Avas, Cardyl, Liprimar, Litorva, Mactor, Orbeos, Prevencor, Sortis, Stator, Tahor, Torid, Torvacard, Torvast, Totalip, Tulip, Xarator, Zarator (Pfizer). In the US, Lipitor is marketed by Viatris after Upjohn was spun off from Pfizer. Medication recalls On 9 November 2012, Indian drugmaker Ranbaxy Laboratories Ltd. voluntarily recalled 10-, 20- and 40-mg doses of its generic version of atorvastatin in the United States. The lots of atorvastatin, packaged in bottles of 90 and 500 tablets, were recalled due to possible contamination with very small glass particles similar to the size of a grain of sand (less than 1mm in size). The FDA received no reports of injury from the contamination. Ranbaxy also issued recalls of bottles of 10-milligram tablets in August 2012 and March 2014, due to concerns that the bottles might contain larger, 20-milligram tablets and thus cause potential dosing errors. On September 19, 2025, the FDA announced a nationwide recall of atorvastatin calcium tablets manufactured by Ascend Laboratories of New Jersey because the medication failed to dissolve appropriately during testing. On October 10, 2025, the recall was reassigned to Class II level, indicating a risk of temporary or medically reversible adverse health consequences. == References ==