Atorvastatin

Atorvastatin, sold under the brand name Lipitor among others, is a statin medication used to prevent cardiovascular disease in those at high risk and to treat abnormal lipid levels. For the prevention of cardiovascular disease, statins are a first-line treatment in reducing cholesterol. It is taken by mouth.

Common side effects may include diarrhea, heartburn, nausea, muscle pain (typically mild and dose-dependent) and, less frequently, joint pain. Muscle symptoms often occur during the first year and are commonly influenced by pre-existing health issues and the nocebo effect.[4] Most patients can continue therapy with dose adjustment or statin switching. Rare (<0.1%) but serious side effects may include rhabdomyolysis (severe muscle disorder), liver problems and diabetes.[5] Use during pregnancy may harm the fetus. Like all statins, atorvastatin works by inhibiting HMG-CoA reductase, an enzyme found in the liver that plays a role in producing cholesterol.

Atorvastatin was patented in 1986, and approved for medical use in the United States in 1996.[6][7] It is on the World Health Organization's List of Essential Medicines.[8] It is available as a generic medication.[6] In 2023, it was the most commonly prescribed medication in the United States, with more than 115million prescriptions filled for over 29 million people.[9][10] In Australia, in 2023, it was the second most prescribed medication after Rosuvastatin.[11]

Medical uses

The primary uses of atorvastatin are for the treatment of dyslipidemia and for the prevention of cardiovascular disease.[6]

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. Due to risk of disrupting a breastfeeding infant's metabolism of lipids, atorvastatin is not regarded as compatible with breastfeeding.[38]
• 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

Side effects

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.[68][69] 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.[69]

Pharmacokinetics

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[74] than people without the polymorphism.

There are several studies showing genetic variants and variable response to atorvastatin.[75] The polymorphisms that showed genome wide significance in Caucasian population were the SNPs in the apoE region; rs445925, rs7412,[75] rs429358[75] and rs4420638 which showed variable LDL-c response depending on the genotype when treated with atorvastatin.[75] 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

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.[76]

Once the compound entered pre-clinical development, process chemistry developed a cost-effective and scalable synthesis. In atorvastatin's case, a key element of the overall synthesis was ensuring stereochemical purity in the final drug substance, and hence establishing the first stereocenter became a key aspect of the overall design.

The final commercial production of atorvastatin relied on:

The atorvastatin calcium complex involves two atorvastatin ions, one calcium ion and three water molecules.[80]

• a chiral pool

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.[81] It was first made in August 1985.[82][83][84][85][86] 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.

Society and culture

Further reading