Atorvastatin; Uses, Dosage, Side Effects, Drug Interactions

Atorvastatin








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Atorvastatin is a synthetic lipid-lowering agent. Atorvastatin competitively inhibits hepatic hydroxymethyl-glutaryl-coenzyme A (HMG-CoA) reductase, the enzyme which catalyzes the conversion of HMG-CoA to mevalonate, a key step in cholesterol synthesis. Atorvastatin also increases the number of LDL receptors on hepatic cell surfaces to enhance uptake and catabolism of LDL and reduces LDL production and the number of LDL particles. This agent lowers plasma cholesterol and lipoprotein levels and modulates immune responses by suppressing MHC II (major histocompatibility complex II) on interferon gamma-stimulated, antigen-presenting cells such as human vascular endothelial cells.

Atorvastatin is a member of the drug class known as statins. It is used for lowering cholesterol. Atorvastatin is a competitive inhibitor of hydroxymethyl-glutaryl-coenzyme A (HMG-CoA) reductase, the rate-determining enzyme in cholesterol biosynthesis via the mevalonate pathway. HMG-CoA reductase catalyzes the conversion of HMG-CoA to mevalonate. Atorvastatin acts primarily in the liver. It works by inhibiting HMG-CoA reductase, an enzyme found in liver tissue that plays a key role in the production of cholesterol in the body.

Mechanism of Action of Atorvastatin

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 stimulate upregulation of hepatic LDL-C receptors which increases hepatic uptake of LDL-C and reduces serum LDL-C concentrations. 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.

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Statins are largely used in clinics in the treatment of patients with cardiovascular diseases for their effect on lowering circulating cholesterol. Lectin-like oxidized low-density lipoprotein (LOX-1), the primary receptor for ox-LDL, plays a central role in the pathogenesis of atherosclerosis and cardiovascular disorders. We have recently shown that chronic exposure of cells to lovastatin disrupts LOX-1 receptor cluster distribution in plasma membranes, leading to a marked loss of LOX-1 function. Here we investigated the molecular mechanism of statin-mediated LOX-1 inhibition and we demonstrate that all tested statins /including atorvastatin/ are able to displace the binding of fluorescent ox-LDL to LOX-1 by a direct interaction with LOX-1 receptors in a cell-based binding assay. Molecular docking simulations confirm the interaction and indicate that statins completely fill the hydrophobic tunnel that crosses the C-type lectin-like (CTLD) recognition domain of LOX-1. Classical molecular dynamics simulation technique applied to the LOX-1 CTLD, considered in the entire receptor structure with or without a statin ligand inside the tunnel, indicates that the presence of a ligand largely increases the dimer stability. Electrophoretic separation and western blot confirm that different statins binding stabilize the dimer assembly of LOX-1 receptors in vivo. The simulative and experimental results allow us to propose a CTLD clamp motion, which enables the receptor-substrate coupling

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Indications of Atorvastatin

  • High cholesterol
  • Hyperlipoproteinemia
  • Indicated as an adjunct to diet for the reduction of elevated total cholesterol, to reduce total-C and LDL-C in patients adults with homozygous familial hypercholesterolemia. Prevention of cardiovascular events in adult patients
  • Coronary heart disease (CHD) and as secondary prevention in individuals with CHD
  • Reduce the risk of myocardial infarction (MI),
  • Stroke,
  • Angina, and revascularization 
  • Prevention of cardiovascular disease
  • High cholesterol, familial heterozygous
  • High cholesterol, familial homozygous
  • Hyperlipoproteinemia Type III, Elevated beta-VLDL IDL
  • Hyperlipoproteinemia Type IIa, Elevated LDL
  • Hyperlipoproteinemia Type IIb, Elevated LDL VLDL
  • Hyperlipoproteinemia Type IV, Elevated VLDL
  • Rheumatoid arthritis
  • Primary prevention of heart attack, stroke, and need for revascularization procedures in patients who have risk factors such as age, smoking, high blood pressure, low HDL-C, and a family history of early heart disease, but have not yet developed clinically evident coronary heart disease.
  • Secondary prevention of myocardial infarction, stroke, unstable angina, and revascularization in people with established coronary heart disease.
  • Myocardial infarction and stroke prophylaxis in patients with type II diabetes
  • Dysbetalipoproteinemia
  • Fredrickson type IIb hyperlipidemia
  • Heterozygous familial hypercholesterolemia
  • High blood cholesterol level
  • Homozygous familial hypercholesterolemia
  • Hypertriglyceridemias
  • Mixed hypercholesterolemia
  • Indicated as an adjunct to diet for the reduction of elevated total cholesterol, to reduce total-C and LDL-C in patients adults with homozygous familial hypercholesterolemia. Prevention of cardiovascular events in adult patients

Contraindications of Atorvastatin

  • Active liver disease- cholestasis, hepatic encephalopathy, hepatitis, and jaundice
  • Unexplained elevations in AST or ALT levels
  • Pregnancy -Atorvastatin may cause fetal harm by affecting serum cholesterol and triglyceride levels, which are essential for fetal development.
  • Breastfeeding – Small amounts of other statin medications have been found to pass into breast milk, although atorvastatin has not been studied, specifically.
  • Markedly elevated CPK levels or if a myopathy is suspected or diagnosed after dosing of atorvastatin has begun. Very rarely, atorvastatin may cause rhabdomyolysis, and it may be very serious leading to acute renal failure due to myoglobinuria.
  • If rhabdomyolysis is suspected or diagnosed, atorvastatin therapy should be discontinued immediately. The likelihood of developing a myopathy is increased by the co-administration of cyclosporine, fibric acid derivatives, erythromycin, niacin, and azole antifungals.
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Dosage of Atorvastatin

 Strengths: 10 mg; 20 mg; 40 mg; 80 mg

Cardiovascular Disease

  • Initial dose: 10 mg or 20 mg orally once a day; an initial dose of 40 mg may be used in patients who require a reduction in low-density lipoprotein (LDL-C) of more than 45%
  • Maintenance dose: 10 mg to 80 mg orally once a day

Hypercholesterolemia

  • 10 mg to 80 mg orally once a day

Hyperlipidemia

  • Initial dose: 10 mg or 20 mg orally once a day; an initial dose of 40 mg may be used in patients who require a reduction in low-density lipoprotein (LDL-C) of more than 45%
  • Maintenance dose: 10 mg to 80 mg orally once a day

Hypertriglyceridemia

  • Initial dose: 10 mg or 20 mg orally once a day; an initial dose of 40 mg may be used in patients who require a reduction in low-density lipoprotein (LDL-C) of more than 45%
  • Maintenance dose: 10 mg to 80 mg orally once a day

Side Effects of Atorvastatin

The most common

 Common

Rare

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Drug Interactions of Atorvastatin

Atovastatin may interact with following drugs, supplements & may change the efficasy of drugs

Pregnancy & Lactation of Atorvastatin

FDA Pregnancy Category X

Pregnancy

Cholesterol is necessary for the development of an unborn baby. Taking atorvastatin during pregnancy reduces the amount of cholesterol reaching the developing baby and may cause harm to the baby. Atorvastatin should not be taken by pregnant women. If you become pregnant while taking this medication, stop taking it immediately and contact your doctor.

Lactation

It is not known if atorvastatin passes into breast milk. If you are a breastfeeding mother and are taking this medication, it may affect your baby. Talk to your doctor about whether you should continue breastfeeding.

References

 

Atorvastatin

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