Pharma Jogot
Atorvastatin 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. It is taken by mouth.
Atorvastatin was patented in 1986 and approved for medical use in the United States in 1996. It is on the World Health Organization’s List of Essential Medicines. It is available as a generic medication. In 2020, it was the most commonly prescribed medication in the United States, with more than 114 million prescriptions.
Indications
Atorvastatin is indicated as an adjunct to diet to reduce elevated total cholesterol, LDL cholesterol, apolipoprotein B (Apo-B), and triglycerides levels in following diseases when the response to diet and other non-pharmacological measures is inadequate.
- To reduce total cholesterol and LDL cholesterol in patients with heterozygous and homozygous familial hypercholesterolemia.
- To reduce elevated cholesterol and triglycerides in patients with mixed dyslipidemia (Fredrickson Type Ia and Ib).
- For the treatment of patients with elevated serum triglyceride levels in hypertriglyceridemia (Fredrickson Type IV).
- For the treatment of patients with dysbetalipoproteinemia (Fredrickson Type III).
- To reduce cardiac ischaemic events in patients with asymptomatic or mild to moderate symptomatic coronary artery disease with elevated LDL-cholesterol levels.
- To reduce total and LDL-cholesterol concentrations in patients with hypercholesterolemia associated with or exacerbated by diabetes mellitus or renal transplantation.
Pharmacology
Atorvastatin is a selective inhibitor of HMG-CoA reductase. This enzyme is the rate-limiting enzyme responsible for the conversion of HMG-CoA to mevalonate, a precursor of sterols, including cholesterol. Atorvastatin lowers plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver and increases the number of hepatic LDL receptors on the cell surface for enhanced uptake and catabolism of LDL.
Absorption: Atorvastatin is rapidly absorbed after oral administration; maximum plasma concentrations occur within 1 to 2 hours. The extent of absorption increases in proportion to the Atorvastatin dose. The absolute bioavailability of Atorvastatin (parent drug) is approximately 14% and the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%.
Distribution: The mean volume of distribution of Atorvastatin is approximately 381 liters. Atorvastatin is 98% bound to plasma proteins. A blood/plasma ratio of approximately 0.25 indicates poor drug 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, inhibition of HMG-CoA reductase by ortho- and para-hydroxylated metabolites is equivalent to that of Atorvastatin. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites. In vitro, studies suggest the importance of Atorvastatin metabolism by cytochrome P450 3A4, consistent with increased plasma concentrations of Atorvastatin in humans following coadministration with erythromycin, a known inhibitor of this isozymes. In animals, the ortho-hydroxy metabolite undergoes further glucuronidation.
Excretion: Atorvastatin and its metabolites are eliminated primarily in bile following hepatic and/or extra-hepatic metabolism; however, the drug does not appear to undergo enterohepatic recirculation. The mean plasma elimination half-life of Atorvastatin in humans is approximately 14 hours, but the half-life of inhibitory activity for HMG-CoA reductase is 20 to 30 hours due to the contribution of active metabolites. Less than 2% of a dose of Atorvastatin is recovered in urine following oral administration.
Dosage & Administration
Primary hypercholesterolemia and combined hyperlipidemia-
- Adults: Usually 10 mg once daily; if necessary, may be increased at intervals of at least 4 weeks to max. 80 mg once daily.
- Child (10-18 years): Initially 10 mg once daily, increased if necessary at intervals of at least 4 weeks to usual max. 20 mg once daily.
Familial hypercholesterolemia-
- Adults: Initially 10 mg daily, increased at intervals of at least 4 weeks to 40 mg once daily; if necessary, further increased to max. 80 mg once daily (or 40 mg once daily combined with anion-exchange resin in heterozygous familial hypercholesterolemia).
- Child (10-18 years): Initially 10 mg once daily, increased if necessary at intervals of at least 4 weeks to usual max. 80 mg once daily.
Prevention of cardiovascular events-
- Adults: Initially 10 mg once daily adjusted according to response.
Another guideline:
The patient should be placed on a standard cholesterol-lowering diet before receiving Atorvastatin and should continue on this diet during treatment with Atorvastatin. The recommended starting dose of Atorvastatin is 10 or 20 mg once daily. Patients who require a large reduction in LDL-C (more than 45%) may be started at 40 mg once daily. The dosage range of Atorvastatin is 10 to 80 mg once daily. Atorvastatin can be administered as a single dose at any time of the day, with or without food. After initiation of Atorvastatin lipid levels should be analyzed within 2 to 4 weeks and dosage adjusted accordingly.
In hypercholesterolemia in Pediatric Patients (10-17 years of age) the recommended starting dose of Atorvastatin is 10 mg/day; the maximum recommended dose is 20 mg/day (doses greater than 20 mg have not been studied in this patient population). Doses should be individualized according to the recommended goal of therapy. Adjustments should be made at intervals of 4 weeks or more.
Interaction
The risk of myopathy during treatment with drugs of this class is increased with concurrent administration of cyclosporine, fibric acid derivatives, niacin (nicotinic acid), erythromycin, and azole antifungals.
Antacid: When atorvastatin and antacid suspension were coadministered, plasma concentrations of atorvastatin decreased by approximately 35%. However, LDL-C reduction was not altered.
Colestipol: Plasma concentrations of atorvastatin decreased by approximately 25% when colestipol and atorvastatin were coadministered. However, LDL-C reduction was greater when atorvastatin and colestipol were coadministered than when either drug was given alone.
Digoxin: When multiple doses of atorvastatin and digoxin were coadministered, steady-state plasma digoxin concentrations increased by approximately 20%. Patients taking digoxin should be monitored appropriately.
Erythromycin: In healthy individuals, plasma concentrations of atorvastatin increased by approximately 40% with coadministration of atorvastatin and erythromycin, a known inhibitor of cytochrome P450 3A4.
Oral Contraceptives: Coadministration of atorvastatin and an oral contraceptive increased AUC values for norethindrone and ethinyl estradiol by approximately 30% and 20%. These increases should be considered when selecting an oral contraceptive for a woman taking atorvastatin.
Warfarin: Atorvastatin had no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin treatment.
Contraindications
Atorvastatin should not be used in patients with hypersensitivity to any component of this medication. Atorvastatin is contraindicated in active liver disease or unexplained persistent elevations of serum transaminases. It is also contraindicated in patients with a history of serious adverse reactions to prior administration of HMG-CoA reductase inhibitors.
Side Effects
Atorvastatin is generally well-tolerated. The most frequent side effects related to Atorvastatin are constipation, flatulence, dyspepsia, and abdominal pain. Other side effects include infection, headache, back pain, rash, asthenia, arthralgia, and myalgia.
Pregnancy & Lactation
Pregnancy: Atorvastatin is contraindicated during pregnancy. Safety in pregnant women has not been established. No controlled clinical trials with atorvastatin have been conducted in pregnant women. Rare reports of congenital anomalies following intrauterine exposure to HMG-CoA reductase inhibitors have been received. Animal studies have shown toxicity to reproduction. Maternal treatment with atorvastatin may reduce the fetal levels of mevalonate which is a precursor of cholesterol biosynthesis. Atorvastatin should not be used in women who are pregnant, trying to become pregnant, or suspect they are pregnant. Treatment with atorvastatin should be suspended for the duration of pregnancy or until it has been determined that the woman is not pregnant.
Lactation: It is not known whether atorvastatin or its metabolites are excreted in 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 atorvastatin should not breastfeed their infants. Atorvastatin is contraindicated during breastfeeding.
Precautions & Warnings
Liver effects: Liver function tests should be performed before the initiation of treatment and periodically thereafter. Atorvastatin should be used with caution in patients who consume substantial quantities of alcohol or have a history of liver disease. Atorvastatin therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected.
Use in Special Populations
Geriatric: Plasma concentrations of Atorvastatin are higher (approximately 40% for Cmax and 30% for AUC) in healthy elderly subjects (age 65 years) than in young adults. Clinical data suggest a greater degree of LDL-lowering at any dose of the drug in the elderly patient population compared to younger adults.
Pediatric: Pharmacokinetic data in the pediatric population are not available.
Gender: There is no clinically significant difference in LDL-C reduction with Atorvastatin between men and women.
Renal Insufficiency: Renal disease has no influence on the plasma concentrations or LDL-C reduction of Atorvastatin; thus, dose adjustment in patients with renal dysfunction is not necessary.
Hemodialysis: Hemodialysis is not expected to significantly enhance the clearance of Atorvastatin since the drug is extensively bound to plasma proteins.
Hepatic Insufficiency: In patients with chronic alcoholic liver disease, plasma concentrations of Atorvastatin are markedly increased.
Overdose Effects
Specific treatment is not available for atorvastatin overdose. The patient should be treated symptomatically and supportive measures instituted, as required. Liver function tests should be performed and serum CK levels should be monitored. Due to extensive atorvastatin binding to plasma proteins, hemodialysis is not expected to significantly enhance atorvastatin clearance.
Storage Conditions:
- Store in a cool & dry place below 30°C.
- Protect from light & moisture.
- Keep out of reach of children.
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