Orvatin

Atorvastatin is a selective inhibitor of HMG-CoA reductase. This enzyme controls the rate at which HMG-CoA is converted to mevalonate, a precursor of sterols, including cholesterol. By blocking HMG-CoA reductase and cholesterol synthesis in the liver, atorvastatin lowers plasma cholesterol and lipoprotein levels. It also increases the number of hepatic LDL receptors on the cell surface, so more LDL is taken up and broken down. Absorption: atorvastatin is absorbed rapidly after oral use, and maximum plasma concentrations occur within 1 to 2 hours. Absorption increases in proportion to the dose. Absolute bioavailability of the parent drug is approximately 14%, and systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. Distribution: mean volume of distribution of atorvastatin is approximately 381 liters, and 98% of the drug is bound to plasma proteins. A blood/plasma ratio of approximately 0.25 points to poor penetration into red blood cells. Based on observations in rats, atorvastatin is likely to be secreted in human milk. Metabolism: atorvastatin is extensively metabolized to ortho- and parahydroxylated derivatives and various beta-oxidation products. In vitro, these ortho- and parahydroxylated metabolites inhibit HMG-CoA reductase just as atorvastatin does. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase comes from active metabolites. In vitro studies suggest that metabolism by cytochrome P450 3A4 matters here, and this fits with the higher plasma concentrations of atorvastatin seen in humans when it is given together with erythromycin, a known inhibitor of this isozyme. In animals, the ortho-hydroxy metabolite goes on to undergo glucuronidation. Excretion: atorvastatin and its metabolites leave the body mainly in bile, after hepatic and/or extra-hepatic metabolism, but the drug does not appear to undergo enterohepatic recirculation. Mean plasma elimination half-life of atorvastatin in humans is approximately 14 hours. Half-life of inhibitory activity for HMG-CoA reductase is 20 to 30 hours, because active metabolites contribute to it. Less than 2% of a dose is recovered in urine after oral use.

Atorvastatin is contraindicated during pregnancy, and its safety in pregnant women has not been established. No controlled clinical trials have been done with it in pregnant women. There have been rare reports of congenital anomalies after exposure in the womb to HMG-CoA reductase inhibitors, and animal studies have shown toxicity to reproduction. Treating the mother with atorvastatin may also lower the fetal levels of mevalonate, which is a precursor of cholesterol biosynthesis. So women who are pregnant, trying to become pregnant or suspect they are pregnant should not use it. Treatment should be suspended for the length of the pregnancy, or until it has been determined that the woman is not pregnant.

It is not known whether atorvastatin or its metabolites pass into human milk. In rats, plasma concentrations of atorvastatin and its active metabolites are similar to those in milk. Because of the potential for serious adverse reactions, women taking it should not breastfeed their infants. Atorvastatin is contraindicated during breastfeeding.

Geriatric

Atorvastatin Calcium levels in the blood are higher in healthy elderly people (age 65 years) than in young adults, by approximately 40% for Cmax and 30% for AUC. Clinical data also suggest that LDL is lowered more at any dose in elderly patients than in younger adults.

Pediatric

No pharmacokinetic data are available for the pediatric population.

Gender

Atorvastatin Calcium lowers LDL-C about the same in men and women, with no clinically significant difference between them.

Renal Insufficiency

Renal disease has no influence on the plasma concentrations of Atorvastatin Calcium or on its LDL-C reduction. So patients with renal dysfunction don't need a dose adjustment.

Hemodialysis

Hemodialysis is not expected to significantly enhance clearance of Atorvastatin Calcium, since the drug is extensively bound to plasma proteins.

Hepatic Insufficiency

In patients with chronic alcoholic liver disease, plasma concentrations of Atorvastatin Calcium are markedly increased.

There is no specific treatment for an atorvastatin overdose. The patient is treated for the symptoms and given supportive care as needed. Liver function tests should be done, and serum CK levels should be monitored. Atorvastatin binds heavily to plasma proteins, so hemodialysis is not expected to increase its clearance to any significant extent.

Store Atorvastatin Calcium in a dry place, away from light and heat. Keep it out of the reach of children.