Atorvastatin

Article Author:
Lindsey McIver
Article Editor:
Momin Siddique
Updated:
9/12/2018 5:51:52 PM
PubMed Link:
Atorvastatin

Indications

Atorvastatin is FDA approved, in combination with dietary modifications, to prevent cardiovascular events in patients with cardiac risk factors and for patients with abnormal lipid profiles.

Primary prevention: 

For patients without coronary heart disease, but with multiple risk factors, atorvastatin is approved to reduce the risk of myocardial infarction, stroke, revascularization procedures and angina.

For patients diagnosed with type 2 diabetes mellitus without coronary heart disease, but with multiple risk factors, atorvastatin is approved to reduce the risk of myocardial infarction and stroke.  

Secondary prevention: 

For patients with coronary heart disease, atorvastatin is approved to reduce the risk of non-fatal myocardial infarction, fatal and non-fatal stroke, revascularization procedures, hospitalizations for congestive heart failure and angina. 

Atorvastatin is approved for the treatment of the following dyslipidemias: 

  • Adults with primary hyperlipidemia (heterozygous familial and nonfamilial) and mixed dyslipidemia
  • Hypertriglyceridemia
  • Primary dysbetalipoproteinemia
  • Homozygous familial hypercholesterolemia
  • Pediatric patients with heterozygous familial hypercholesterolemia (after failing dietary modifications)

Atorvastatin has not been studied in Fredrickson Type I and V dyslipidemias.

Mechanism of Action

Atorvastatin competitively inhibits 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. By preventing the conversion of HMG-CoA to mevalonate, statin medications decrease cholesterol production in the liver. Atorvastatin also increases the amount of LDL receptors on the surface of hepatic cells. 

In patients with homozygous or heterozygous familial hypercholesterolemia, mixed dyslipidemia, isolated hypertriglyceridemia or nonfamilial hypercholesterolemia, atorvastatin as been shown to reduce total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (apo B), very-low-density lipoprotein (VLDL-C) and triglycerides (TGs) while increasing high-density lipoprotein cholesterol (HDL-C). 

In patients with dysbetalipoproteinemia, atorvastatin has been shown to decrease intermediate-density lipoprotein (IDL-C).   

Pharmacokinetics: 

Absorption: 

Atorvastatin is rapidly absorbed after oral administration with a peak plasma concentration at 1-2 hours. The bioavailability is low at 14% due to extensive first-pass metabolism.

Distribution:

Atorvastatin is highly plasma protein bound (> 98%) and has a volume of distribution of about 380 liters. 

Metabolism:

Atorvastatin is metabolized by cytochrome P450 3A4 (CYP 3A4) to active ortho- and para-hydroxylated metabolites. 

Excretion:

Atorvastatin and its metabolites are eliminated in bile. Atorvastatin is not know to go through enterohepatic recirculation. The half-life of atorvastatin is about 14 hours, while its active metabolites have a half-life of about 20 - 30 hours. 

Administration

Atorvastatin is available as atorvastatin calcium tablets in strengths of 10, 20, 40, and 80 mg.  

This medication can be administered with or without food and should be taken at the same time every day. 

Adult dosing: 

Dosing of atorvastatin can be based on LDL-C lowering ability (intensity), or doses can be titrated to specific lipid goals. 

The American College of Cardiology/American Heart Association Guidelines recommends either moderate intensity (atorvastatin 10-20 mg) or high intensity (atorvastatin 40-80 mg) therapy depending on which statin benefit group a patient belongs. Moderate intensity statins should lower LDL-C by about 30-50% while high-intensity statins should lower LDL-C by > 50 %.[1]

Both the National Lipid Association and the American Association of Clinical Endocrinologists recommend utilizing statin therapy to reach specific lipid goals based on atherosclerotic cardiovascular disease risk.[2][3]

Pediatrics: 

Doses above 20 mg have not been studied in pediatric patients with heterozygous familial hypercholesterolemia. Doses up to 80 mg have been used in a limited number of pediatric patients familial hypercholesterolemia. Atorvastatin use has not been evaluated in pre-pubescent patients or those <10 years old. 

Geriatrics: 

Patients > 65 years old may have higher plasma concentrations of atorvastatin when compared to young adults. Older patients may be at increased risk of statin-induced myopathies. 

Renal impairment: 

Atorvastatin and its metabolites are not renally eliminated, so no dose adjustments are required with reduced renal function. Hemodialysis will not likely remove atorvastatin due to plasma protein binding. 

Hepatic impairment: 

Increased plasma concentrations of atorvastatin have been noted in patients with chronic alcoholic liver disease. Drug exposure is 4x higher in patients with Child-Pugh Class A and 11x higher in patients with Child-Pugh Class B. Atorvastatin is contraindicated in patients with active liver disease. 

Drug Interactions: 

Use of atorvastatin with strong CYP3A4 inhibitors can lead to increased plasma concentrations which may result in increase adverse events including myopathies. OATP1B1 inhibitors can increase bioavailability of atorvastatin.

CYP3A4 inducers may cause decreased plasma concentrations of atorvastatin. 

Patients taking digoxin should be monitored when starting atorvastatin as plasma concentrations of digoxin may increase.

Atorvastatin may also increase drug exposure of norethindrone and ethinyl estradiol.

Adverse Effects

Common adverse effects for patients taking atorvastatin include arthralgia, dyspepsia, diarrhea, nausea, nasopharyngitis, insomnia, urinary tract infection and pain in extremities.

Myopathies have been noted in patients taking atorvastatin including muscle aches, muscle tenderness or muscle weakness with elevated creatine phosphokinase > 10x the upper limit of normal. Rhabdomyolysis has been reported in patients using atorvastatin. Patients with the impaired renal function may be at increased risk of developing rhabdomyolysis. Using atorvastatin in combination with other medications which increase atorvastatin levels increases the risk for myopathies and rhabdomyolysis. Management of statin-induced myopathies includes temporarily holding therapy, switching to an alternative statin or reducing the dose. 

Atorvastatin can cause liver function test abnormalities. If patients develop serum transaminases >3x the upper limit of normal, levels should be monitored more frequently until normalized or atorvastatin should be dose reduced or discontinued. 

Contraindications

Atorvastatin is contraindicated in patients with hypersensitivity to any of its components.

While atorvastatin is contraindicated in patients with the active liver disease, the benefits of lipid-lowering therapy in chronic liver diseases, such as non-alcoholic fatty liver disease and hepatitis, likely outweigh the possible risks.[4]

Atorvastatin is contraindicated during pregnancy or in female patients who may become pregnant. All female patients of childbearing age should be counseled of the potential risks to a fetus should they become pregnant while on atorvastatin. This medication should be immediately discontinued if a patient becomes pregnant. 

Atorvastatin should be avoided in patients who are nursing. If a patient requires atorvastatin therapy, they should be counseled to discontinue breastfeeding. 

Monitoring

Patients starting atorvastatin should have liver function tests and a lipid panel performed at baseline. The lipid panel should be repeated after six weeks on therapy. Liver function tests should be repeated as clinically indicated. Once the patient is stable, lipids can be checked every 6 to 12 months.

Toxicity

There are no antidotes available for atorvastatin overdose. Patients should be monitored for adverse events and provided with supportive care. 

Enhancing Healthcare Team Outcomes

The success of statins in lowering lipids or preventing cardiovascular events depends on the patient's medication adherence. Experiencing adverse effects, lack of understanding of the importance of statin therapy and cost are a few of the many barriers that may prevent patients from taking these medications as prescribed. All members of the health care team can help identify barriers to adherence. Additional education and counseling around patient concerns and medication benefits may help improve adherence. [5](Level III)