indication

May be used as primary prevention in individuals with multiple risk factors for coronary heart disease (CHD) and as secondary prevention in individuals with CHD to reduce the risk of myocardial infarction (MI), stroke, angina, and revascularization procedures. May be used to reduce the risk of cardiovascular events in patients with acute coronary syndrome (ACS). May be used in the treatment of primary hypercholesterolemia and mixed dyslipidemia, homozygous familial hypercholesterolemia, primary dysbetalipoproteinemia, and/or hypertriglyeridemia as an adjunct to dietary therapy to decrease serum total and low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (apoB), and triglyceride concentrations, while increasing high-density lipoprotein cholesterol (HDL-C) levels.

pharmacology

Atorvastatin, a selective, competitive HMG-CoA reductase inhibitor, is used to lower serum total and LDL cholesterol, apoB, and triglyceride levels while increasing HDL cholesterol. High LDL-C, low HDL-C and high TG concentrations in the plasma are associated with increased risk of atherosclerosis and cardiovascular disease. The total cholesterol to HDL-C ratio is a strong predictor of coronary artery disease and high ratios are associated with higher risk of disease. Increased levels of HDL-C are associated with lower cardiovascular risk. By decreasing LDL-C and TG and increasing HDL-C, atorvastatin reduces the risk of cardiovascular morbidity and mortality. Atorvastatin has a unique structure, long half-life, and hepatic selectivity, explaining its greater LDL-lowering potency compared to other HMG-CoA reductase inhibitors.

mechanism of action

Atorvastatin selectively and competitively inhibits the hepatic enzyme HMG-CoA reductase. As HMG-CoA reductase is responsible for converting HMG-CoA to mevalonate in the cholesterol biosynthesis pathway, this results in a subsequent decrease in hepatic cholesterol levels. Decreased hepatic cholesterol levels stimulates upregulation of hepatic LDL-C receptors which increases hepatic uptake of LDL-C and reduces serum LDL-C concentrations.

toxicity

Generally well-tolerated. Side effects may include myalgia, constipation, asthenia, abdominal pain, and nausea. Other possible side effects include myotoxicity (myopathy, myositis, rhabdomyolysis) and hepatotoxicity. To avoid toxicity in Asian patients, lower doses should be considered.

biotransformation

Atorvastatin is extensively metabolized to ortho- and parahydroxylated derivatives and various beta-oxidation products. In vitro inhibition of HMG-CoA reductase by ortho- and parahydroxylated metabolites is equivalent to that of atorvastatin. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites.

absorption

Atorvastatin is rapidly absorbed after oral administration with maximum plasma concentrations achieved in 1 to 2 hours. The absolute bioavailability of atorvastatin (parent drug) is approximately 12% and the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic bioavailability is due to presystemic clearance by gastrointestinal mucosa and first-pass metabolism in the liver.

half life

14 hours, but half-life of HMG-CoA inhibitor activity is 20-30 hours due to longer-lived active metabolites

route of elimination

Eliminated primarily in bile after hepatic and/or extrahepatic metabolism. Does not appear to undergo significant enterohepatic recirculation. Less than 2% of the orally administered dose is recovered in urine.

drug interactions

Amprenavir: Amprenavir may increase the serum concentration of atorvastatin by decreasing its metabolism. Concomitant therapy is contraindicated.

Atazanavir: Atazanavir may increase the serum concentration of atorvastatin by decreasing its metabolism. Concomitant therapy is contraindicated.

Bezafibrate: Increased risk of myopathy/rhabdomyolysis

Bosentan: Bosentan may decrease the serum concentration of atorvastatin by increasing its metabolism. Monitor for changes in the therapeutic and adverse effects of atorvastatin if bosentan is initiated, discontinued or dose changed.

Carbamazepine: Carbamazepine, a p-glycoprotein inducer and strong CYP3A4 inducer, may decrease the effect of atorvastatin by increasing its efflux and metabolism. Monitor for changes in the therapeutic and adverse effects of atorvastatin if carbamazepine is initiated, discontinued or dose changed.

Clarithromycin: The macrolide, clarithromycin, may increase the toxicity of the statin, atorvastatin.

Colchicine: Increased risk of rhadbomyolysis with this combination.

Cyclosporine: Possible myopathy and rhabdomyolysis

Delavirdine: Delavirdine, a strong CYP3A4 inhibitor, may increase the serum concentration of atorvastatin by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of atorvastatin if delavirdine is initiated, discontinued or dose changed.

Diltiazem: Diltiazem may increase the serum concentration of atorvastatin. Atorvastatin may increase the serum concentration of diltiazem. Monitor for changes in the therapeutic and adverse effects of both agents if concomitant therapy is initiated, discontinued or if doses are changed.

Efavirenz: Efavirenz may decrease the serum concentration of atorvastatin by increasing its metabolism. Monitor for changes in the therapeutic and adverse effects of atorvastatin if efavirenz is initiated, discontinued or dose changed.

Erythromycin: The macrolide, erythromycin, may increase the toxicity of the statin, atorvastatin.

Fenofibrate: Increased risk of myopathy/rhabdomyolysis

Fluconazole: Increased risk of myopathy/rhabdomyolysis

Fosamprenavir: Fosamprenavir, a strong CYP3A4 inhibitor, may increase the serum concentration of atorvastatin by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of atorvastatin if fosamprenavir is initiated, discontinued or dose changed.

Fusidic Acid: Increased risk of myopathy/rhabdomyolysis

Gemfibrozil: Increased risk of myopathy/rhabdomyolysis

Imatinib: Imatinib, a strong CYP3A4 inhibitor, may increase the effect and toxicity of atorvastatin by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of atorvastatin if imatinib is initiated, discontinued or dose changed.

Indinavir: Indinavir, a strong CYP3A4 inhibitor, may increase the serum concentration of atorvastatin by decreasing its metabolism. Concomitant therapy is contraindicated.

Itraconazole: Increased risk of myopathy/rhabdomyolysis

Josamycin: The macrolide, josamycin, may increase the toxicity of the statin, atorvastatin.

Ketoconazole: Increased risk of myopathy/rhabdomyolysis

Nefazodone: Nefazodone, a strong CYP3A4 inhibitor, may increase the serum concentration of atorvastatin by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of atorvastatin if nefazodone is initiated, discontinued or dose changed.

Nelfinavir: Nelfinavir, a strong CYP3A4 inhibitor, may increase the serum concentration of atorvastatin by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of atorvastatin if nelfinavir is initiated, discontinued or dose changed.

Nevirapine: Nevirapine, a strong CYP3A4 inducer, may decrease the serum concentration of atorvastatin by increasing its metabolism. Monitor for changes in the therapeutic and adverse effects of atorvastatin if nevirapine is initiated, discontinued or dose changed.

Quinupristin: This combination presents an increased risk of toxicity

Rifabutin: Rifabutin may decrease the effect of atorvastatin by increasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of atorvastatin if rifabutin is initiated, discontinued or dose changed.

Rifampin: Rifampin may decrease the effect of atorvastatin by increasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of atorvastatin if rifampin is initiated, discontinued or dose changed.

Ritonavir: Ritonavir may increase the serum concentration of atorvastatin by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of atorvastatin if ritonavir is initiated, discontinued or dose changed.

Saquinavir: Saquinavir may increase the serum concentration of atorvastatin by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of atorvastatin if saquinavir is initiated, discontinued or dose changed.

Telithromycin: The macrolide antibiotic, telithromycin, may increase the serum concentration of atorvastatin by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of atorvastatin if telithromycin is initiated, discontinued or dose changed.

Tipranavir: Tipranavir, co-administered with Ritonavir, increases the adverse/toxic effects of Atorvastatin. Concomitant therapy should be avoided.

Topotecan: The p-glycoprotein inhibitor, Atorvastatin, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided.

Verapamil: Verapamil, a moderate CYP3A4 inhibitor, may increase the serum concentration of Atorvastatin by decreasing its metabolism. Avoid concurrent use if possible or reduce lovastatin dose during concomitant therapy. Monitor for changes in the therapeutic/adverse effects of Atorvastatin if Verapamil is initiated, discontinued or dose changed.

Voriconazole: Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of atorvastatin by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of atorvastatin if voriconazole is initiated, discontinued or dose changed.