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What is Lipitor?

By , MD, PhD

Lipitor is a brand name for drug atorvastatin, which is a newer selective and competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme (HMG-CoA) reductase that belongs to a group of drugs known as statins. Atorvastatin was synthesized in 1985 and its development was mostly based on molecular comparisons of fungal metabolites and other synthetic inhibitors.

Atorvastatin is approved for the reduction of elevated total cholesterol, LDL cholesterol, apo B and triglyceride levels, but it also increases HDL cholesterol in individuals with primary hypercholesterolemia and mixed dyslipidemia. Furthermore, the drug is approved for use in patients with dysbetalipoproteinemia and elevated triglyceride levels, as well as for the prevention of cardiovascular diseases.

Lipitor tablets for oral administration are film-coated and available in different dosages, containing 10, 20, 40 and 80 milligrams of the active ingredient. Recommended dosage for the initial therapy is 10 mg per day, whereas the upper limit is 80 mg per day. The drug can be administered as a single dose at any time of the day, with or without food.

Chemistry and mechanism of action

Akin to other statins, atorvastatin binds to and subsequently blocks the action of HMG-CoA reductase, a key and rate-limiting enzyme in the synthesis of mevalonate. This decreases de novo hepatic cholesterol synthesis, leading in turn to an up-regulation of hepatic LDL-C receptors with increased LDL-C uptake and decreased plasma LDL-C levels.

The binding of the drug and the enzyme is taking place in preference to the myriad of other potential enzyme targets because atorvastatin has a shape complementary to the active site of HMG-CoA reductase, but also because it can form nine or more specific hydrogen bonds with functional groups at the active site.

Such complementarity and patterned hydrogen bonding ensure that atorvastatin binds strongly with their target molecules, avoiding at the same time the interaction with other molecules and proteins that could lead to undesired side effects. Still, its adverse-effect profile is similar to other statins in doses up to 80 mg a day.

There is also ample evidence of pleiotropic effects of atorvastatin, such as improvements in endothelial functions and increased production of nitrous oxide. In addition, its use is linked to the reduction of atherosclerotic lesions and decrescence of vascular smooth muscle cell proliferation. Such effects give hope that atorvastatin may be used to promote vasodilatation and deaggregation of platelets in dyslipidemic patients.

Pharmacology of atorvastatin

Atorvastatin is well absorbed with maximum plasma concentrations occurring within 1-2 hours following oral administration. Still, its absolute bioavailability is low (approximately 12%), which is due to high hepatic first-pass metabolism, but also presystemic metabolism (primarily in the gut wall). Atorvastatin concentrations in plasma are lower after evening drug administration in comparison to morning administration.

Two active metabolites can be found in plasma – 2-hydroxy-atorvastatin and 4-hydroxy-atorvastatin – both of which are in equilibrium with their respective inactive lactone forms. It must be emphasized that 70% of circulating inhibitory activity for the enzyme HMG-CoA reductase can be attributed to this pair of active metabolites.

The half-life of atorvastatin is approximately 20 hours, which is often increased in individuals with hepatic disease. The biliary tract represents the major route of elimination, and less than 2% of the drug is excreted as unchanged in urine; therefore changes in renal function have no significant effect on the pharmacokinetics of atorvastatin.

Sources

  1. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3411536/
  2. http://pharmrev.aspetjournals.org/content/64/1/102.full
  3. www.cochrane.org/CD008226/VASC_effect-of-atorvastatin-on-cholesterol
  4. www.fda.gov/.../..._16_02_KP%20Atorvastatin%20Label%20FDA%208-7-06.pdf
  5. www.jpgmonline.com/article.asp
  6. Frishman WH, Aronow WS. Lipid-Lowering Drugs. In: Frishman WH, Sica DA, editors. Cardiovascular Pharmacotherapeutics, Third Edition. Cardiotext Publishing LLC, Minneapolis, Minnesota, 2011; pp. 323-376.

Further Reading

Last Updated: Dec 7, 2015

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