Atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (a statin), is a lipid regulating drug with actions on plasma lipids. HMG-CoA reductase inhibitors reduce total cholesterol, low-density lipoprotein (LDL)-cholesterol and very-low-density lipoprotein (VLDL)-cholesterol concentrations in plasma. They also tend to reduce triglycerides and to increase high-density lipoprotein (HDL)-cholesterol concentrations. They are also considered to exert their hypocholesterolaemic action by stimulating an increase in LDL-receptors on hepatocyte membranes thereby increasing the clearance of LDL from the circulation.
Pharmacokinetics:
Atorvastatin is rapidly absorbed from the gastro-intestinal tract. It has low absolute bioavailability of about 12% due to presystemic clearance in the gastro-intestinal mucosa and/or first-pass metabolism in the liver, its primary site of action. Atorvastatin is metabolised by the cytochrome P450 isoenzyme CYP3A4 to a number of compounds which are also active inhibitors of HMG-CoA reductase. The mean plasma elimination half-life of Atorvastatin is about 14 hours although the half-life of inhibitory activity for HMG-CoA reductase is approximately 20 to 30 hours due to the contribution of the active metabolites. It is 98% bound to plasma proteins. Atorvastatin is excreted as metabolites, primarily in the bile.
USES:
Atorvastatin is used to reduce LDL-cholesterol, apolipoprotein B, and triglycerides, and to increase HDL-cholesterol in the treatment of hyperlipidaemias including hypercholesterolaemias and combined (mixed) hyperlipidaemia (type IIa or IIb hyperlipoproteinaemias), hypertriglyceridaemia (type IV), and dysbetalipoproteinaemia (type III). Atorvastatin can also be effective as adjunctive therapy in patients with homozygous familial hypercholesterolaemia who have some LDL-receptor function.
DOSAGE AND ADMINISTRATION:
The initial dose is 10mg to 20mg daily which may be adjusted at intervals of 4 weeks up to a maximum of 80mg daily.
CONTRA-INDICATIONS AND WARNINGS:
Precautions:
Atorvastatin should not be given to patients with acute liver disease or unexplained persistently raised serum-aminotransferase concentrations. It should be avoided during pregnancy since there is a possibility that it could interfere with foetal sterol synthesis; there have been a few reports of congenital abnormalities associated with statins. Discontinue if marked or persistent increases in serum-aminotransferase or creatine phosphokinase concentrations occur. Use with caution in patients with severe renal impairment.
Adverse Effects:
The commonest adverse effects of therapy with Atorvastatin and other statins are gastro-intestinal disturbances. Other adverse effects reported include headache, skin rashes, dizziness, blurred vision, insomnia and dysgeusia. Reversible increases in serum- aminotransferase concentrations may occur and liver function should be assessed before treatment is initiated and then monitored periodically until one year after the last elevation in dose. Hepatitis and pancreatitis have been reported. Hypersensitivity reactions including anaphylaxis and angioedema have also occurred. Myopathy, characterised by myalgia and muscle weakness and associated with increased creatine phosphokinase concentrations, has been reported, especially in patients taking Atorvastatin concurrently with ciclosporin, fibric acid derivatives, or nicotinic acid. Rarely, rhabdomyolysis with acute renal failure may develop.
Interactions:
There is an increased risk of myopathy if certain drugs are given concurrently with statins. Concomitant administration of drugs that inhibit the cytochrome P450 isoenzyme CYP3A4, such as ciclosporin, itraconazole, ketoconazole, erythromycin, clarithromycin, HIV-protease inhibitors, and nefazodone, might produce high plasma levels of Atorvastatin, thus increasing the risk of myopathy. Drugs that alone can cause myopathy, such as fibric acid derivatives or nicotinic acid, can increase the risk of this reaction when given with Atorvastatin. Bleeding and increases in prothrombin time have been reported in patients taking Atorvastatin with coumarin anticoagulants. Raised concentrations of Atorvastatin have occurred in patients also given mibefradil.
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